8/11/2019 Farmacos en Personalidad http://slidepdf.com/reader/full/farmacos-en-personalidad 1/24 Luis H. Ripoll Joseph Triebwasser Larry J. Siever Evidence-Based Pharmacotherapy for Personality Disorders Abstract: Patients with personality disorders are prescribed psychotropic medications with greater frequency than almost any other diagnostic group. Prescribing practices in these populations are often based on anecdotal evidence rather than rigorous data. Although evidence-based psychotherapy remains an integral part of treatment, Axis II psychopathology is increasingly conceptualized according to neurobiological substrates that correspond to speci c psychopharmacological strategies. We summarize the best available evidence regarding medication treatment of personality disordered patients and provide optimal strategies for evidence-based practice. Most available evidence is concentrated around borderline and schizotypal personality disorders, with some additional evidence concerning the treatment of avoidant and antisocial personality disorders. Although maladaptive personality symptoms respond to antidepressants, antipsychotics, mood stabilizers, and other medications, evidence-based pharmacotherapy is most useful in treating circumscribed symptom domains andinduces only partial improvement.Most availableevidence supports useof medication in reducing impulsivity and aggression, characteristic of borderline and antisocial psychopathology. Efforts have also begun to reduce psychotic-like symptoms and improve cognitive decits characteristic of schizotypy. Indirect evidence is also provided for psychopharmacologicalreductionof social anxiety central toavoidantpersonality disorder.Evidence-basedpracticerequires attention to domains of expected clinical improvement associated with a medication, relative to the potential risks. The developmentoffuturerationalpharmacotherapywillrequireincreasedunderstandingoftheneurobiologicalunderpinnings of personality disorders and their component dimensions. Increasing efforts to translate personality theory and social cognitive neuroscience into increasingly specic neurobiological substrates may provide more effective targets for pharmacotherapy. (Reprinted with permission from International Journal of Neuropsychopharmacology 2011; 14:1257 –1288) INTRODUCTION Personalitydisordersaredenedbyan ‘enduring pattern of inner experience and behavior that … is inexible and pervasive across a broad range of personal and social situations’, with symptomatic disturbances in cognition, affect, impulsivity, and interpersonal functioning leading to distress (APA, 1994). Until recently, guidelines recommended sparing use of pharmacotherapy, and expectations remained guarded regarding expected benets from medications. Since then, distinctions between Axis I disorders, considered ‘ genetic … biological … brain disorders’ treated with medications; and Axis II dis- orders, alternatively considered ‘psychological’ and therefore treated with psychotherapy,has undergone a paradigm shift (Siever & Davis, 1991). In this at- mosphere, clinicians must rely on the most up-to- date, evidence-based practices for pharmacotherapy to be effective. Component dimensions of personality, such as im- pulsivity or aggressiveness, have demonstrable neuro- biologicalcorrelates,asshownviaavarietyofendocrine, electrophysiological, and neuroimaging measures (Brambilla et al. 2004; Goodman et al. 2004; Houston et al. 2004; Juengling et al. 2003; Levitt et al. 2004; Minzenberg et al. 2006; New et al. 1997, 2004; Ogiso et al. 1993; Oquendo et al. 2005; Prossin et al. 2010; Rusch et al. 2003; Russ focus.psychiatryonline.org FOCUS Spring 2013, Vol. XI, No. 2 225 I N F L U E N T I A L P U B L I C A T I O N S
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Larry J Siever Evidence-Based Pharmacotherapy forPersonality Disorders
Abstract Patients with personality disorders are prescribed psychotropic medications with greater frequency than almost
any other diagnostic group Prescribing practices in these populations are often based on anecdotal evidence rather than
rigorous data Although evidence-based psychotherapy remains an integral part of treatment Axis II psychopathology is
increasingly conceptualized according to neurobiological substrates that correspond to speci1047297c psychopharmacological
strategies We summarize the best available evidence regarding medication treatment of personality disordered patients and
provide optimal strategies for evidence-based practice Most available evidence is concentrated around borderline and
schizotypal personality disorders with some additional evidence concerning the treatment of avoidant and antisocial
personality disorders Although maladaptive personality symptoms respond to antidepressants antipsychotics mood
stabilizers and other medications evidence-based pharmacotherapy is most useful in treating circumscribed symptom
domains and induces only partial improvement Most available evidence supports use of medication in reducing impulsivity
and aggression characteristic of borderline and antisocial psychopathology Efforts have also begun to reduce psychotic-like
symptoms and improve cognitive de1047297cits characteristic of schizotypy Indirect evidence is also provided for
psychopharmacological reduction of social anxiety central to avoidant personality disorder Evidence-based practice requires
attention to domains of expected clinical improvement associated with a medication relative to the potential risks The
development of future rational pharmacotherapy will require increased understanding of the neurobiological underpinnings
of personality disorders and their component dimensions Increasing efforts to translate personality theory and social
cognitive neuroscience into increasingly speci1047297c neurobiological substrates may provide more effective targets for
pharmacotherapy
(Reprinted with permission from International Journal of Neuropsychopharmacology 2011 141257 ndash1288)
INTRODUCTION
Personality disorders are de1047297nedbyan lsquoenduring
pattern of inner experience and behavior thathellip
isin1047298exible and pervasive across a broad range of personal and social situationsrsquo with symptomaticdisturbances in cognition affect impulsivity and interpersonal functioning leading to distress (APA1994) Until recently guidelines recommended sparing use of pharmacotherapy and expectationsremained guarded regarding expected bene1047297ts frommedications Since then distinctions between Axis Idisorders considered lsquo genetichellip biologicalhellip braindisordersrsquo treated with medications and Axis II dis-orders alternatively considered lsquopsychologicalrsquo and
therefore treated with psychotherapy has undergonea paradigm shift (Siever amp Davis 1991) In this at-
mosphere clinicians must rely on the most up-to-
date evidence-based practices for pharmacotherapy to be effective
Component dimensions of personality such as im-pulsivity or aggressiveness have demonstrable neuro-biologicalcorrelatesasshownviaavarietyofendocrineelectrophysiological and neuroimaging measures(Brambilla et al 2004 Goodman et al 2004Houston et al 2004 Juengling et al 2003 Levittet al 2004 Minzenberg et al 2006 New et al
1997 2004 Ogiso et al 1993 Oquendo et al
2005 Prossin et al 2010 Rusch et al 2003 Russ
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 225
et al 1991 Simeon et al 1992 Soderstrom ampForesman 2004) Identifying neurobiological sub-strates of personality has allowed for increasingly speci1047297c pharmacotherapy Nevertheless improvementfrom effective pharmacotherapeutic interventions isoften transient andor restricted to several symptom
domains In the USA there are no FDA-approved medications for treating personality disorders Thuspharmacotherapy for personality disorders remainsoff-label and psychopharmacological strategies for evidence-based practices remain lacking
Themajorityofpsychopharmacologicalresearchon personality disorders has focused on borderlinepersonality disorder (BPD) In the most recenttreatment guidelines for BPD the AmericanPsychiatric Association (APA 2001) acknowl-edges that lsquopharmacotherapy has an importantadjunctive rolersquo along with lsquoextended psycho-
therapy to attain and maintain lasting improvementinhellip personality interpersonal problems and overallfunctioning rsquo Similarly others have described psy-chopharmacological treatment of BPD as resulting only in lsquoa mild degree of symptom relief rsquo (Paris2005) Moreover there remainsa dearth of evidence-based medication treatments for other personality disorders
Often pharmacotherapy for severe personality disorders is used to stabilize patientsrsquo symptomssuf 1047297ciently in order to facilitate psychosocial inter-ventions and foster re1047298ective functioning Close
communication between psychotherapists and psychopharmacologists remains crucial Althoughfunctional gains can be expected from medicationsthe magnitude and time-course vary There is littleevidence regarding distinctions between acute and maintenance pharmacotherapy or how long to
continue patients on a medication Empirical data on recurrence or relapse is similarly scarce There-fore evidence-based practices must be judged case-by-case weighing clinical risks and bene1047297ts
Clinicians canreferto accompanyingtables forthebest available evidence regarding pharmacotherapy for personality disorders (see Tables 1ndash4) This data
was compiled by searching the Medline database with the main combinations pharmacotherapy and each of the various DSM-IV personality disorder diagnoses In addition we paid particularly closeattention to randomized placebo-controlled trials
(along with some lower-level evidence if this type of evidence was severely limited) We focused onstudies published in the past 3 years since thepublication of the last World Federation of Societiesof Biological Psychiatry Guidelines for the BiologicalTreatment of Personality Disorders (Herpertz et al
2007) Additional research regarding medicationsfor treating impulsive aggression was found via a similar Medline search on impulsivity aggressionand pharmacotherapy
Unfortunately only a few novel trials of pharmaco-therapy for personality disorders have been published
Table 1 Schizotypal Personality Disorder (SPD)
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
Koenigsberg
et al (2003)
SPD 25 males
and
females
Risperidone Started
at 025 mgd
titrated up to
2 mgd
Parallel
design
9 wk
Significantly lower scores on PANSS
negative and general symptom scales
by week 3 and positive symptoms by
week 7
McClureet al (2007b )
SPD 29 malesand
females
Guanfacine Titrated up to2 mgd within
first 2 wk
Paralleldesign
4 wk
After 4 wk greater improvements frombaseline in neuropsychological
measures of working memory (Modified
AX-Continuous Performance Task)
compared to placebo
McClure
et al (2010)
SPD 25 males
and
females
Pergolide 0025 mgd for
first 3 d then
005 mgd for 4 d
then 01 mgd for 1 wk
then 02 mgd for 1 wk
then 03 mgd
Parallel
design
4 wk
Greater improvement from baseline in
tasks measuring executive function
(Trail-Making Test Part B) verbal
memory (Word List Learning-
immediate and delayed recall) verbal
working memory (Letter Number Span)
long-term visuospatial memory
(Wechsler Memory Scale Visual
Reproduction Test) and visuospatial
working memory (Dot Test) comparedto placebo Dot findings were largely
driven by worsening in placebo group
PANSS Positive and Negative Symptom Scale
226 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
during this recent period Several recent meta-analyses have been published in this time which we utilized to establish areas of consensus for evidence-basedpracticeandidentifygapsthatneed to be addressed with future research Many prior reviews cover only BPD but we expanded our scope to include all personality disorders Thus
we include a comprehensive summary of the bestcurrent evidence with commentary on recentconsensus and recommendations for evidence-based practices and future directions regarding pharmacotherapeutic strategies that have been in-
suf 1047297
ciently tested but appear promising for further research This situates this review as a nexuscompiling evidence-based practices for treating personality disorders for interested clinicians as
well as providing avenues for future psychophar-macological research
SCHIZOTYPAL PERSONALITY DISORDER
(SPD)
SPD is characterized by interpersonal de1047297citsand psychotic-like symptoms Like schizophrenia
Table 2 Antisocial Personality Disorder
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
Sheard
(1971)
Inmates of
maximum security
prison with verbal
and physical
aggression whilein prison
12 males Lithium
carbonate
Lithium levels of
06ndash15 meql
mean dose
1200 mgd
Crossoversingle-
blind three
4-wk phases
Decrease in serious incidents of verbal
or physical aggression Improvements
in self-rated anger and tension
Single-blind Aggressive incidents
scored on basis of prison guardsrsquo
issuing of punitive tickets not by
psychiatristsrsquo ratings
Sheard
et al
(1976)
Prisoners
convicted of
lsquoserious
aggressive
crimesrsquo
80 males Lithium
carbonate
Lithium levels of
06ndash10 meql
mean lithium level
during last week
of medication
phase 089 meql
Parallel design
5 months with
first and
last months
medication
free and 3
months lithium
vs placebo
Decrease in violent infractions of prison
rules in lithium group
Lion
(1979)
lsquo All patients had
past histories of
temper outbursts
belligerenceassaultive
behaviour and
impulsiveness
had experienced
legal difficulties
and some
had committed
criminal actsrsquo
65 males
and females
Chlordiazepoxide
oxazepam
Chlordiazepoxide
100 mgd for 2 wk
then 200 mgd for
2 wk Oxazepam120 mgd for 2 wk
then 240 mgd
for 2wk
Parallel design
4 wk
Oxazepam superior to chlordiazepoxide
and placebo for indirect hostility
(Buss-Durkee Hostility Scale) anxiety
Barratt
et al
(1991)
Maximum security
prison inmates
with impulsive
aggression
while in prison
19 males Phenytoin 100 mgd or
300 mgd
Crossover design
three 4-wk
phases
Significant reduction in aggressive
acts at 300 mgd but not
100 mgd Improvements in
tension-anxiety and
depression-dejection at 300 mgd
but not anger-hostility
Barratt
et al
(1997)
Prison inmates
with aggression
while in prison
150 total but only
30 males with
primarily impulsive
aggression and
30 males with
primarily
pre-meditated
aggression included
in analysis (other
66 had mixture
of both types)
Phenytoin 300 mgd Crossover
design two
6-wk phases
Significant reduction in frequency
and intensity of aggressive acts
in impulsive aggressive group
but not pre-meditated aggressive
group
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 227
patients SPD patients often demonstrate cognitivede1047297cits in working memory particularly sustained attention and executive functioning (Bergida ampLenzenweger 2006 McClure et al 2007a Parc ampMcTigue 1997) as well as signi1047297cant abnormalitiesin empathic understanding (Langdon amp Coltheart2004 Pickup 2006 Ripoll et al unpublished data)Unlike schizophrenic patients there is greater preservation of frontal volume in SPD (Siever ampDavis 2004)
Overall clinical trials for SPD have been com-plicated by comorbidity particularly with other personality disorders Most early RCTs on BPDalso included SPD patients (Goldberg et al 1986Serban amp Siegel 1984 Soloff et al 1986c ) be-cause both SPD and BPD were considered rooted in lsquoborderlinersquo schizophrenia but psychoticsymptoms in SPD and BPD are clinically distin-guishable
The conceptualization of SPD within theschizophrenia spectrum supports treatment withantipsychotic medications Antipsychotics appear
tobeusefulinthetreatmentofSPDparticularlyinterms of psychotic-like symptoms (Goldberg et al
1986 Koenigsberg e t a l 2003) Open-labelstudies have suggested a role for antidepressantsin treating self-injury psychotic-like and de-pressive symptomatology (Jensen amp Andersen1989 Markovitz et al 1991) but the evidence is
weaker Recent RCTs targeting cognitive de1047297citsin SPD compared performance on neuro-psychological tasks before and after treatment
with medication or placebo Both pergolidea dopaminergic agonist active at both the D1 and
D2 receptor (McClure et al 2010) and the nor-adrenergic a2A agonist guanfacine (McClure et al
2007b ) improved SPD patientsrsquo cognitive per-formance on distinct neuropsychological mea-sures Whether this improvement extends tooverall clinical functioning in SPD remains sub-
ject to future investigationIn sumSPDpatients respondto low-dose atypical
antipsychotics targeting psychotic-like symptomsand general functioning First-generation antipsy-
chotic medication and antidepressants may alsoplay a role although the evidence is not as reliableEvidence-based practice requires weighing risk of extrapyramidal side-effects or tardive dyskinesia against potential bene1047297ts Cognitive enhancementvia noradrenergic a2A or dopaminergic agonismmay be future avenues of research given that by analogy with schizophrenia the cognitive impair-ment in SPD may be responsible for the overalldysfunction observed in the disorder Researchefforts to understand neurobiological substratesof social cognitive dysfunction have heretofore
mainly focused on BPD and schizophrenia Be-cause SPD involves social isolation relationalparanoia and empathic de1047297cits research on phar-macotherapeutic effects on social cognition may also be fruitful
A NTISOCIAL PERSONALITY DISORDER
(A SPD)
Peer-reviewed trials of AsPD include studieson groups of individuals likely to have been antiso-cial based on histories of repeated violence and
criminality and an absence of other stated causes for these behaviours Lithium has been associated withdecreases in serious rule infractions in incarcerated males (Sheard 1971 Sheard et al 1976) Prisonerstreated with phenytoin committed fewer aggressiveacts and evidenced decreased tension-anxiety and depression-dejection (although not anger-hostility)and improvements in aggression appeared to belimited to impulsive (not pre-meditated) aggres-sion (Barratt et al 1991 1997) At presentevidenced-based pharmacotherapy for AsPD isrestricted to treatment of impulsive aggressionFuture neurobiological research in AsPD and psychopathy will probably increase our un-derstanding of the dysfunctional emotional em-pathy often seen in this disorder (Blair 2005) and
whether this may be susceptible to psychophar-macological intervention
BPD
Most RCTs on personality disorders focused onBPD which consists of several domains of dys-function affective instability impulsivity and an-ger transient psychotic or dissociative symptomsand intense unstable relationships (Lieb et al
2004 Zanarini et al 1990) BPD patients oftendemonstrate high comorbidity (Zanarini et al
2004a c ) and make numerous suicide attempts and parasuicidal gestures conferring signi1047297cantly higher risk for completed suicide (Welch amp Linehan2000)
Early studies employed a distinct nosology incharacterizing subjects some of whom actually had
what might be called BPD today (Rifkin et al 1972)In studies on suicidal or parasuicidal subjects themajority often have BPD (Battaglia et al 1999Montgomery amp Montgomery 1982 Montgomery et al 1983 Verkes et al 1998) Early studies oftenincluded combinations of BPD and SPD subjects(Goldberg et al 1986 Serban amp Siegel 1984 Soloff et al 1986c ) and studies recruiting a range of allpersonality disorders ultimately include BPD as themost frequent diagnosis (Coccaro amp Kavoussi
1997 Hollander et al 2003)Cliniciansshouldexercisecautioninattemptingtoapplyresearch1047297ndingstoseverelyillBPDpatientsasmany RCTs recruited only outpatients who further
were excluded if they expressed acute suicidality (Frankenburg amp Zanarini 2002 Tritt et al 2005Zanarini amp Frankenburg 2003 Zanarini et al
2004b ) or had made a recent suicide attempt(Bogenschutz amp Nurnberg 2004) In additionsmall sample sizes predominated and most studieslasted 3 months The few trials lasting $6 monthssuffered from high drop-out rates (Frankenburg amp
Zanarini 2002 Zanarini amp Frankenburg 2001) or concomitant recruitment of subjects without BPD(Battaglia et al 1999 Montgomery et al 1983Verkes et al 1998) Moreover RCTs with BPDsubjects appear to be prone to highplacebo responserates (Lieb et al 2004 Salzman et al 1995)meaning that open-label trial data should be inter-preted with caution
APA practice guidelines (APA 2001) recom-mended a symptom-targeted approach in pharma-cotherapy of BPD This leaves open the possibility for patients to improve in some but not all symptomdimensions Some clinicians have based their de-cision to implement polypharmacy on this butthere is actually little evidence as to the effectivenessof this strategy The only study on combined pharmacotherapy in BPD (Zanarini et al 2004b )found no superior ef 1047297cacy for combination treat-ment compared to one medication alone Using asfew medications as possible to target central areas of
clinical dysfunction together with evidence-based psychotherapy is usually the optimal treatmentstrategy In light of this although the 2001 guide-lines suggest a prominent role for serotonergicpharmacotherapy recent reviews have questioned this and instead emphasized anticonvulsants and antipsychotics (Abraham amp Calabrese 2008 Mercer et al 2009)
TRICYCLIC ANTIDEPRESSANTS (TCA S)
Disturbances of serotonin have been associated
with BPD impulsive aggression self-harm and suicidality (Coccaro et al 1995 Evenden 1999Malone et al 1996 Pitchot et al 2005) Low CSFlevels of serotonin metabolites have been associated
with suicide attempts and completion (Samuelssonet al 2006 Traskman et al 1981) impulsivityaggression (Mehlman et al 1994 Virkkunen et al
1994) lifetime aggressiveness and suicidal lethality (Placidi et al 2001) Impulsive aggression withsuicidality has been linked to blunted prolactinresponses to the serotonergic probe fen1047298uramine(Coccaro et al 1989) PET scans of personality-
disordered subjects high in impulsive aggressionhave demonstrated reduced response to fen1047298ur-amine in orbitofrontal ventromedial and cingulateregions (Siever et al 1999)
Nevertheless early research on TCAs for BPDproved disappointing (Montgomery et al 1983Soloff et al 1989) Amitryptiline has been associ-ated with paradoxical increases in suicidality para-noia and behavioural dysregulation attributed tolsquogeneralized disinhibition of cognitive and affec-tive controlsrsquo (Soloff et al 1986a 1987) Indeedborderline patients have dif 1047297culty cognitively
236 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
resolving con1047298ict among stimulus dimensions(Posner et al 2002) and prefrontal hypofunctioncan be seen after a serotonergic stimulus in subjects
with prominent impulsive aggression (New et al
2002) Thus medications with adverse cognitivesequelae including anticholinergic side-effects may contribute to worsening impulsivity As mentioned in prior reviews the use of TCAs in treating BPD isdiscouraged (Abraham amp Calabrese 2008 Mercer et al 2009) Their use is also associated with po-tentially signi1047297cant risk of overdose
MONOAMINE OXIDASE INHIBITORS (MAOIS)
Despite hesitancyinprescribingMAOIstopatients with prominent impulsivity or self-injurious behav-iour some recommend these medications for BPDpatientswhocantakethemsafelyandreliablyInterestin MAOIs for BPD is rooted in their differential ef-1047297cacy for conditions such as hysteroid dysphoria or atypical depression viewed as being related to oneother and BPD (Kayser et al 1985 Liebowitz ampKlein 1981) In a crossover trial with multiplemedication phases only tranylcypromine was as-sociated with higher patient-rated improvementscores and completion rates (Cowdry amp Gardner1988)
Similarly relative prominence of BPD symptomspredicted superiority of phenelzine (Parsons et al
1989) Phenelzine is bene1047297cial in the treatment of hostility anxiety and borderline symptoms (Soloff et al 1993) In some patients it could cause un-
comfortable excitement and emotional reactivity (Cornelius et al 1993) Thus although there isevidence for their ef 1047297cacy many patients may nottolerate these medications Other associated risksof MAOIs include toxicity in overdose and po-tentially fatal hypertensive crises or serotoninsyndrome
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIS)
SSRIs are thought to potentiate serotonergicneuromodulation but demonstrate more favour-able side-effect pro1047297les Fluoxetine reduced anger in BPD independent of any antidepressant ef-fect (Salzman et al 1995) It also improved verbaland impulsive aggression irritability and overallfunctioning (Coccaro amp Kavoussi 1997) Simi-larly a RCT with paroxetine demonstrated ef 1047297cacy in preventing recurrent suicidal behaviour but nosigni1047297cant effect on depression hopelessness or anger (Verkes et al 1998) By contrast there waslittle added bene1047297t from 1047298uoxetine when added to
dialectical behavioural therapy (DBT) (Simpsonet al 2004)
On the other hand 1047298uvoxamine decreased af-fective lability but not scores of impulsivity or ag-gression (Rinne et al 2002) Although SSRIsdecrease impulsivity and aggression in BPD patients
with comorbid intermittent explosive disorder (IED Coccaro amp Kavoussi 1997 New et al 2004)data from BPD subjects without comorbid IED areinconsistent (Rinne et al 2002) Previous reviewshave emphasized that effect sizes for antidepressantpharmacotherapy vary widely between classes and trials (Ingenhoven et al 2010 Lieb et al 2010Mercer et al 2009) Nevertheless current evidence-based practice recommends use of SSRIs due topotential bene1047297ts on impulsive aggression that may outweigh associated risks There has been no evi-dence that antidepressants alleviate the chronicemptiness shameful self-concept and intrapsychicpain in BPD
FIRST-GENERATION ANTIPSYCHOTICS
An early interest in antipsychotic medications for treating BPD probably arose from a conception of BPD as a variant of schizophrenia (eg Deutsch1942) Antipsychotics have demonstrated partialef 1047297cacy re1047298ecting underlying abnormalities in do-paminergic signalling Borderline subjects demon-strate high levels of the dopamine metabolitehomovallinic acid in both plasma and cerebrospinal1047298uid (Siever et al unpublished data) Prior to more
widespread use of SSRIs antipsychotics demon-strated ef 1047297cacy in decreasing psychotic-like symptoms(Goldberg et al 1986 Soloff et al 1986b ) depression(Soloff et al 1986b ) irritability (Cornelius et al
1993) and general symptom severity (Cowdry ampGardner 1988 Soloff et al 1986b )
A recent Cochrane review suggests haloperidol isef 1047297cacious in reducing anger in BPD and treatment
with 1047298upenthixol decanoate reduced suicidal be-haviour (Lieb et al 2010) By contrast evidence for ef 1047297cacy of neuroleptics on affective symptomspsychosis and anxiety remains inconsistent The
dosage of antipsychotic medication for evidence-based treatment of BPD is usually lower thanschizophrenia High drop-out rates are noted and risk of extrapyramidal symptoms may further limitthe utility of neuroleptics
SECOND-GENERATION ANTIPSYCHOTICS
Classical neuroleptics have largely been superseded by atypical antipsychotics whose broader therapeuticbene1047297ts may be explained by activity beyond the D2
receptor As mentioned in prior reviews olanzapine
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 237
has proven bene1047297cial in treatment of BPD patientsrsquoanxiety anger interpersonal sensitivity and para-noia but not depression (Zanarini amp Frankenburg2001) as well as improving general clinical func-tioning and BPD symptomatology (Bogenschutz ampNurnberg 2004) A recent large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulzet al 2008) although the authors suggested thatpatients may have been underdosed A study comparing olanzapine to haloperidol showed nobetween-group differences except with respect toside-effects with more weight gain associated witholanzapine and more extra-pyramidal side-effects
with haloperidol (Shafti amp Shahveisi 2010) Adding 1047298uoxetine to olanzapine did not elicit
further bene1047297t except that subjects receiving bothmedications gained less weight than those receiving only olanzapine (Zanarini et al 2004b ) The addi-tion of olanzapine to DBT reduced depressionanxiety and impulsive aggression but the magni-
tude and timing of these bene1047297ts relative to DBT was dif 1047297cult to interpret (Soler et al 2005)
Aripiprazolehas a novelmechanismof action(partialagonist at the dopamine D2 receptor and serotonin 5-HT1A receptor antagonist at the 5-HT2A receptor) Itmay be more favourable than other atypicals withrespect to metabolic side-effects A longer half-lifemay be more effective for patients susceptible to non-adherence In non-suicidal BPD patients aripipra-zole was effective in reducing aggression anxietydepression psychosis interpersonal symptoms self-injurious behaviour and subjective distress There
were no signi1047297cant differences between groups in weight gain (Nickel et al 2006) An 18-month open-label follow-up showed sustained improvements and continued tolerability (Nickel et al 2007)
Previously open-label trials suggested possibleef 1047297cacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al 2004 2006) Theside-effect and psychopharmacological pro1047297les of ziprasidone indicated lesser metabolic risks and an-tidepressant and anxiolytic effects thought to beindependent of antidopaminergic activity (Keck et al 1998 Tandon 2000 Wilner et al 2002)
Despite such promise a recent RCT with ziprasi-done was negative (Pascual et al 2008) Thusevidence-based practice supports use of aripiprazolebut not ziprasidone in treating BPD
In meta-analyses the class of antipsychotics had moderate effect in treating aggression but no sig-ni1047297cant effect on depression although aripiprazoleand olanzapine may be exceptions (Lieb et al 2010Mercer et al 2009) For aypicals metabolic side-effects may limit clinical utility Because 29-53of borderline patients ful1047297l criteria for an eating disorder at some point in their lives (Lieb et al
2004) and a signi1047297cant number suffer from obesity (Frankenburg amp Zanarini 2006) iatrogenic meta-bolic risks must be regarded as serious Althoughevidence-based practices have advanced in treating aggression associated with BPD chronic emptinessaffective lability and interpersonal dysfunction lack effective evidence-based medication treatments
MOOD STABILIZERS AND ANTICONVULSANTS
Due to BPD patientsrsquo affective dysregulation and comorbidity with bipolar disorder some have clas-si1047297ed BPD within the bipolar spectrum (Akiskal2004 Smith et al 2004) although most continue todistinguish between the two particularly withregard to interpersonal dysfunction (Bolton ampGunderson 1996 Henry et al 2001 Paris 2004)Mood stabilizers are indeed becoming a more in-tegral component of evidence-based treatmentpractices for BPD
Lithium is bene1047297cial in treating BPD particularly in terms of quieting affective instability (Links et al
1990 Rifkin et al 1972) Lithium toxicity andor non-compliance may be problematic due to BPDpatientsrsquo characteristic impulsive self-destructivebehaviour
However anticonvulsants are more often rec-ommended for treatment of rapid-cycling bipolar disorder the variant most closely resembling BPDCarbamazepine demonstrated lsquodramaticrsquo reductionsin behavioural dyscontrol and improvements inglobal functioning anxiety anger euphoria im-
pulsivity and suicidality but it was associated with worsening melancholic depression (Gardner ampCowdry 1986a b ) and therapeutic bene1047297ts could not be replicated in in-patients (de la Fuente ampLotstra 1994)
Although high drop-out rates were reported withdivalproex (Hollander et al 2001) it subsequently demonstrated bene1047297ts on interpersonal sensitivityanger and aggression in euthymic borderline wo-men with bipolar II (Frankenburg amp Zanarini2002) Divalproex reduced aggression irritabilityand overall disease severity in patients with Cluster
B personality disorders and prominent impulsiveaggression (Hollander et al 2003) Differentialtreatment response in Cluster B subjects was en-hanced by baseline trait impulsivity and state ag-gression although not affective instability (Hollander et al 2005)
Lamotrigine extends periods of euthymia in bi-polar patients (eg Goodwin et al 2004) Potentialbene1047297ts also include pro-cognitive activity as pre-viously demonstrated in normal volunteers(Aldenkamp et al 2002) Lamotrigine effectively reduced BPD patientsrsquo anger (Tritt et al 2005) and
238 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
242 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 243
antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
et al 1991 Simeon et al 1992 Soderstrom ampForesman 2004) Identifying neurobiological sub-strates of personality has allowed for increasingly speci1047297c pharmacotherapy Nevertheless improvementfrom effective pharmacotherapeutic interventions isoften transient andor restricted to several symptom
domains In the USA there are no FDA-approved medications for treating personality disorders Thuspharmacotherapy for personality disorders remainsoff-label and psychopharmacological strategies for evidence-based practices remain lacking
Themajorityofpsychopharmacologicalresearchon personality disorders has focused on borderlinepersonality disorder (BPD) In the most recenttreatment guidelines for BPD the AmericanPsychiatric Association (APA 2001) acknowl-edges that lsquopharmacotherapy has an importantadjunctive rolersquo along with lsquoextended psycho-
therapy to attain and maintain lasting improvementinhellip personality interpersonal problems and overallfunctioning rsquo Similarly others have described psy-chopharmacological treatment of BPD as resulting only in lsquoa mild degree of symptom relief rsquo (Paris2005) Moreover there remainsa dearth of evidence-based medication treatments for other personality disorders
Often pharmacotherapy for severe personality disorders is used to stabilize patientsrsquo symptomssuf 1047297ciently in order to facilitate psychosocial inter-ventions and foster re1047298ective functioning Close
communication between psychotherapists and psychopharmacologists remains crucial Althoughfunctional gains can be expected from medicationsthe magnitude and time-course vary There is littleevidence regarding distinctions between acute and maintenance pharmacotherapy or how long to
continue patients on a medication Empirical data on recurrence or relapse is similarly scarce There-fore evidence-based practices must be judged case-by-case weighing clinical risks and bene1047297ts
Clinicians canreferto accompanyingtables forthebest available evidence regarding pharmacotherapy for personality disorders (see Tables 1ndash4) This data
was compiled by searching the Medline database with the main combinations pharmacotherapy and each of the various DSM-IV personality disorder diagnoses In addition we paid particularly closeattention to randomized placebo-controlled trials
(along with some lower-level evidence if this type of evidence was severely limited) We focused onstudies published in the past 3 years since thepublication of the last World Federation of Societiesof Biological Psychiatry Guidelines for the BiologicalTreatment of Personality Disorders (Herpertz et al
2007) Additional research regarding medicationsfor treating impulsive aggression was found via a similar Medline search on impulsivity aggressionand pharmacotherapy
Unfortunately only a few novel trials of pharmaco-therapy for personality disorders have been published
Table 1 Schizotypal Personality Disorder (SPD)
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
Koenigsberg
et al (2003)
SPD 25 males
and
females
Risperidone Started
at 025 mgd
titrated up to
2 mgd
Parallel
design
9 wk
Significantly lower scores on PANSS
negative and general symptom scales
by week 3 and positive symptoms by
week 7
McClureet al (2007b )
SPD 29 malesand
females
Guanfacine Titrated up to2 mgd within
first 2 wk
Paralleldesign
4 wk
After 4 wk greater improvements frombaseline in neuropsychological
measures of working memory (Modified
AX-Continuous Performance Task)
compared to placebo
McClure
et al (2010)
SPD 25 males
and
females
Pergolide 0025 mgd for
first 3 d then
005 mgd for 4 d
then 01 mgd for 1 wk
then 02 mgd for 1 wk
then 03 mgd
Parallel
design
4 wk
Greater improvement from baseline in
tasks measuring executive function
(Trail-Making Test Part B) verbal
memory (Word List Learning-
immediate and delayed recall) verbal
working memory (Letter Number Span)
long-term visuospatial memory
(Wechsler Memory Scale Visual
Reproduction Test) and visuospatial
working memory (Dot Test) comparedto placebo Dot findings were largely
driven by worsening in placebo group
PANSS Positive and Negative Symptom Scale
226 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
during this recent period Several recent meta-analyses have been published in this time which we utilized to establish areas of consensus for evidence-basedpracticeandidentifygapsthatneed to be addressed with future research Many prior reviews cover only BPD but we expanded our scope to include all personality disorders Thus
we include a comprehensive summary of the bestcurrent evidence with commentary on recentconsensus and recommendations for evidence-based practices and future directions regarding pharmacotherapeutic strategies that have been in-
suf 1047297
ciently tested but appear promising for further research This situates this review as a nexuscompiling evidence-based practices for treating personality disorders for interested clinicians as
well as providing avenues for future psychophar-macological research
SCHIZOTYPAL PERSONALITY DISORDER
(SPD)
SPD is characterized by interpersonal de1047297citsand psychotic-like symptoms Like schizophrenia
Table 2 Antisocial Personality Disorder
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
Sheard
(1971)
Inmates of
maximum security
prison with verbal
and physical
aggression whilein prison
12 males Lithium
carbonate
Lithium levels of
06ndash15 meql
mean dose
1200 mgd
Crossoversingle-
blind three
4-wk phases
Decrease in serious incidents of verbal
or physical aggression Improvements
in self-rated anger and tension
Single-blind Aggressive incidents
scored on basis of prison guardsrsquo
issuing of punitive tickets not by
psychiatristsrsquo ratings
Sheard
et al
(1976)
Prisoners
convicted of
lsquoserious
aggressive
crimesrsquo
80 males Lithium
carbonate
Lithium levels of
06ndash10 meql
mean lithium level
during last week
of medication
phase 089 meql
Parallel design
5 months with
first and
last months
medication
free and 3
months lithium
vs placebo
Decrease in violent infractions of prison
rules in lithium group
Lion
(1979)
lsquo All patients had
past histories of
temper outbursts
belligerenceassaultive
behaviour and
impulsiveness
had experienced
legal difficulties
and some
had committed
criminal actsrsquo
65 males
and females
Chlordiazepoxide
oxazepam
Chlordiazepoxide
100 mgd for 2 wk
then 200 mgd for
2 wk Oxazepam120 mgd for 2 wk
then 240 mgd
for 2wk
Parallel design
4 wk
Oxazepam superior to chlordiazepoxide
and placebo for indirect hostility
(Buss-Durkee Hostility Scale) anxiety
Barratt
et al
(1991)
Maximum security
prison inmates
with impulsive
aggression
while in prison
19 males Phenytoin 100 mgd or
300 mgd
Crossover design
three 4-wk
phases
Significant reduction in aggressive
acts at 300 mgd but not
100 mgd Improvements in
tension-anxiety and
depression-dejection at 300 mgd
but not anger-hostility
Barratt
et al
(1997)
Prison inmates
with aggression
while in prison
150 total but only
30 males with
primarily impulsive
aggression and
30 males with
primarily
pre-meditated
aggression included
in analysis (other
66 had mixture
of both types)
Phenytoin 300 mgd Crossover
design two
6-wk phases
Significant reduction in frequency
and intensity of aggressive acts
in impulsive aggressive group
but not pre-meditated aggressive
group
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 227
patients SPD patients often demonstrate cognitivede1047297cits in working memory particularly sustained attention and executive functioning (Bergida ampLenzenweger 2006 McClure et al 2007a Parc ampMcTigue 1997) as well as signi1047297cant abnormalitiesin empathic understanding (Langdon amp Coltheart2004 Pickup 2006 Ripoll et al unpublished data)Unlike schizophrenic patients there is greater preservation of frontal volume in SPD (Siever ampDavis 2004)
Overall clinical trials for SPD have been com-plicated by comorbidity particularly with other personality disorders Most early RCTs on BPDalso included SPD patients (Goldberg et al 1986Serban amp Siegel 1984 Soloff et al 1986c ) be-cause both SPD and BPD were considered rooted in lsquoborderlinersquo schizophrenia but psychoticsymptoms in SPD and BPD are clinically distin-guishable
The conceptualization of SPD within theschizophrenia spectrum supports treatment withantipsychotic medications Antipsychotics appear
tobeusefulinthetreatmentofSPDparticularlyinterms of psychotic-like symptoms (Goldberg et al
1986 Koenigsberg e t a l 2003) Open-labelstudies have suggested a role for antidepressantsin treating self-injury psychotic-like and de-pressive symptomatology (Jensen amp Andersen1989 Markovitz et al 1991) but the evidence is
weaker Recent RCTs targeting cognitive de1047297citsin SPD compared performance on neuro-psychological tasks before and after treatment
with medication or placebo Both pergolidea dopaminergic agonist active at both the D1 and
D2 receptor (McClure et al 2010) and the nor-adrenergic a2A agonist guanfacine (McClure et al
2007b ) improved SPD patientsrsquo cognitive per-formance on distinct neuropsychological mea-sures Whether this improvement extends tooverall clinical functioning in SPD remains sub-
ject to future investigationIn sumSPDpatients respondto low-dose atypical
antipsychotics targeting psychotic-like symptomsand general functioning First-generation antipsy-
chotic medication and antidepressants may alsoplay a role although the evidence is not as reliableEvidence-based practice requires weighing risk of extrapyramidal side-effects or tardive dyskinesia against potential bene1047297ts Cognitive enhancementvia noradrenergic a2A or dopaminergic agonismmay be future avenues of research given that by analogy with schizophrenia the cognitive impair-ment in SPD may be responsible for the overalldysfunction observed in the disorder Researchefforts to understand neurobiological substratesof social cognitive dysfunction have heretofore
mainly focused on BPD and schizophrenia Be-cause SPD involves social isolation relationalparanoia and empathic de1047297cits research on phar-macotherapeutic effects on social cognition may also be fruitful
A NTISOCIAL PERSONALITY DISORDER
(A SPD)
Peer-reviewed trials of AsPD include studieson groups of individuals likely to have been antiso-cial based on histories of repeated violence and
criminality and an absence of other stated causes for these behaviours Lithium has been associated withdecreases in serious rule infractions in incarcerated males (Sheard 1971 Sheard et al 1976) Prisonerstreated with phenytoin committed fewer aggressiveacts and evidenced decreased tension-anxiety and depression-dejection (although not anger-hostility)and improvements in aggression appeared to belimited to impulsive (not pre-meditated) aggres-sion (Barratt et al 1991 1997) At presentevidenced-based pharmacotherapy for AsPD isrestricted to treatment of impulsive aggressionFuture neurobiological research in AsPD and psychopathy will probably increase our un-derstanding of the dysfunctional emotional em-pathy often seen in this disorder (Blair 2005) and
whether this may be susceptible to psychophar-macological intervention
BPD
Most RCTs on personality disorders focused onBPD which consists of several domains of dys-function affective instability impulsivity and an-ger transient psychotic or dissociative symptomsand intense unstable relationships (Lieb et al
2004 Zanarini et al 1990) BPD patients oftendemonstrate high comorbidity (Zanarini et al
2004a c ) and make numerous suicide attempts and parasuicidal gestures conferring signi1047297cantly higher risk for completed suicide (Welch amp Linehan2000)
Early studies employed a distinct nosology incharacterizing subjects some of whom actually had
what might be called BPD today (Rifkin et al 1972)In studies on suicidal or parasuicidal subjects themajority often have BPD (Battaglia et al 1999Montgomery amp Montgomery 1982 Montgomery et al 1983 Verkes et al 1998) Early studies oftenincluded combinations of BPD and SPD subjects(Goldberg et al 1986 Serban amp Siegel 1984 Soloff et al 1986c ) and studies recruiting a range of allpersonality disorders ultimately include BPD as themost frequent diagnosis (Coccaro amp Kavoussi
1997 Hollander et al 2003)Cliniciansshouldexercisecautioninattemptingtoapplyresearch1047297ndingstoseverelyillBPDpatientsasmany RCTs recruited only outpatients who further
were excluded if they expressed acute suicidality (Frankenburg amp Zanarini 2002 Tritt et al 2005Zanarini amp Frankenburg 2003 Zanarini et al
2004b ) or had made a recent suicide attempt(Bogenschutz amp Nurnberg 2004) In additionsmall sample sizes predominated and most studieslasted 3 months The few trials lasting $6 monthssuffered from high drop-out rates (Frankenburg amp
Zanarini 2002 Zanarini amp Frankenburg 2001) or concomitant recruitment of subjects without BPD(Battaglia et al 1999 Montgomery et al 1983Verkes et al 1998) Moreover RCTs with BPDsubjects appear to be prone to highplacebo responserates (Lieb et al 2004 Salzman et al 1995)meaning that open-label trial data should be inter-preted with caution
APA practice guidelines (APA 2001) recom-mended a symptom-targeted approach in pharma-cotherapy of BPD This leaves open the possibility for patients to improve in some but not all symptomdimensions Some clinicians have based their de-cision to implement polypharmacy on this butthere is actually little evidence as to the effectivenessof this strategy The only study on combined pharmacotherapy in BPD (Zanarini et al 2004b )found no superior ef 1047297cacy for combination treat-ment compared to one medication alone Using asfew medications as possible to target central areas of
clinical dysfunction together with evidence-based psychotherapy is usually the optimal treatmentstrategy In light of this although the 2001 guide-lines suggest a prominent role for serotonergicpharmacotherapy recent reviews have questioned this and instead emphasized anticonvulsants and antipsychotics (Abraham amp Calabrese 2008 Mercer et al 2009)
TRICYCLIC ANTIDEPRESSANTS (TCA S)
Disturbances of serotonin have been associated
with BPD impulsive aggression self-harm and suicidality (Coccaro et al 1995 Evenden 1999Malone et al 1996 Pitchot et al 2005) Low CSFlevels of serotonin metabolites have been associated
with suicide attempts and completion (Samuelssonet al 2006 Traskman et al 1981) impulsivityaggression (Mehlman et al 1994 Virkkunen et al
1994) lifetime aggressiveness and suicidal lethality (Placidi et al 2001) Impulsive aggression withsuicidality has been linked to blunted prolactinresponses to the serotonergic probe fen1047298uramine(Coccaro et al 1989) PET scans of personality-
disordered subjects high in impulsive aggressionhave demonstrated reduced response to fen1047298ur-amine in orbitofrontal ventromedial and cingulateregions (Siever et al 1999)
Nevertheless early research on TCAs for BPDproved disappointing (Montgomery et al 1983Soloff et al 1989) Amitryptiline has been associ-ated with paradoxical increases in suicidality para-noia and behavioural dysregulation attributed tolsquogeneralized disinhibition of cognitive and affec-tive controlsrsquo (Soloff et al 1986a 1987) Indeedborderline patients have dif 1047297culty cognitively
236 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
resolving con1047298ict among stimulus dimensions(Posner et al 2002) and prefrontal hypofunctioncan be seen after a serotonergic stimulus in subjects
with prominent impulsive aggression (New et al
2002) Thus medications with adverse cognitivesequelae including anticholinergic side-effects may contribute to worsening impulsivity As mentioned in prior reviews the use of TCAs in treating BPD isdiscouraged (Abraham amp Calabrese 2008 Mercer et al 2009) Their use is also associated with po-tentially signi1047297cant risk of overdose
MONOAMINE OXIDASE INHIBITORS (MAOIS)
Despite hesitancyinprescribingMAOIstopatients with prominent impulsivity or self-injurious behav-iour some recommend these medications for BPDpatientswhocantakethemsafelyandreliablyInterestin MAOIs for BPD is rooted in their differential ef-1047297cacy for conditions such as hysteroid dysphoria or atypical depression viewed as being related to oneother and BPD (Kayser et al 1985 Liebowitz ampKlein 1981) In a crossover trial with multiplemedication phases only tranylcypromine was as-sociated with higher patient-rated improvementscores and completion rates (Cowdry amp Gardner1988)
Similarly relative prominence of BPD symptomspredicted superiority of phenelzine (Parsons et al
1989) Phenelzine is bene1047297cial in the treatment of hostility anxiety and borderline symptoms (Soloff et al 1993) In some patients it could cause un-
comfortable excitement and emotional reactivity (Cornelius et al 1993) Thus although there isevidence for their ef 1047297cacy many patients may nottolerate these medications Other associated risksof MAOIs include toxicity in overdose and po-tentially fatal hypertensive crises or serotoninsyndrome
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIS)
SSRIs are thought to potentiate serotonergicneuromodulation but demonstrate more favour-able side-effect pro1047297les Fluoxetine reduced anger in BPD independent of any antidepressant ef-fect (Salzman et al 1995) It also improved verbaland impulsive aggression irritability and overallfunctioning (Coccaro amp Kavoussi 1997) Simi-larly a RCT with paroxetine demonstrated ef 1047297cacy in preventing recurrent suicidal behaviour but nosigni1047297cant effect on depression hopelessness or anger (Verkes et al 1998) By contrast there waslittle added bene1047297t from 1047298uoxetine when added to
dialectical behavioural therapy (DBT) (Simpsonet al 2004)
On the other hand 1047298uvoxamine decreased af-fective lability but not scores of impulsivity or ag-gression (Rinne et al 2002) Although SSRIsdecrease impulsivity and aggression in BPD patients
with comorbid intermittent explosive disorder (IED Coccaro amp Kavoussi 1997 New et al 2004)data from BPD subjects without comorbid IED areinconsistent (Rinne et al 2002) Previous reviewshave emphasized that effect sizes for antidepressantpharmacotherapy vary widely between classes and trials (Ingenhoven et al 2010 Lieb et al 2010Mercer et al 2009) Nevertheless current evidence-based practice recommends use of SSRIs due topotential bene1047297ts on impulsive aggression that may outweigh associated risks There has been no evi-dence that antidepressants alleviate the chronicemptiness shameful self-concept and intrapsychicpain in BPD
FIRST-GENERATION ANTIPSYCHOTICS
An early interest in antipsychotic medications for treating BPD probably arose from a conception of BPD as a variant of schizophrenia (eg Deutsch1942) Antipsychotics have demonstrated partialef 1047297cacy re1047298ecting underlying abnormalities in do-paminergic signalling Borderline subjects demon-strate high levels of the dopamine metabolitehomovallinic acid in both plasma and cerebrospinal1047298uid (Siever et al unpublished data) Prior to more
widespread use of SSRIs antipsychotics demon-strated ef 1047297cacy in decreasing psychotic-like symptoms(Goldberg et al 1986 Soloff et al 1986b ) depression(Soloff et al 1986b ) irritability (Cornelius et al
1993) and general symptom severity (Cowdry ampGardner 1988 Soloff et al 1986b )
A recent Cochrane review suggests haloperidol isef 1047297cacious in reducing anger in BPD and treatment
with 1047298upenthixol decanoate reduced suicidal be-haviour (Lieb et al 2010) By contrast evidence for ef 1047297cacy of neuroleptics on affective symptomspsychosis and anxiety remains inconsistent The
dosage of antipsychotic medication for evidence-based treatment of BPD is usually lower thanschizophrenia High drop-out rates are noted and risk of extrapyramidal symptoms may further limitthe utility of neuroleptics
SECOND-GENERATION ANTIPSYCHOTICS
Classical neuroleptics have largely been superseded by atypical antipsychotics whose broader therapeuticbene1047297ts may be explained by activity beyond the D2
receptor As mentioned in prior reviews olanzapine
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 237
has proven bene1047297cial in treatment of BPD patientsrsquoanxiety anger interpersonal sensitivity and para-noia but not depression (Zanarini amp Frankenburg2001) as well as improving general clinical func-tioning and BPD symptomatology (Bogenschutz ampNurnberg 2004) A recent large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulzet al 2008) although the authors suggested thatpatients may have been underdosed A study comparing olanzapine to haloperidol showed nobetween-group differences except with respect toside-effects with more weight gain associated witholanzapine and more extra-pyramidal side-effects
with haloperidol (Shafti amp Shahveisi 2010) Adding 1047298uoxetine to olanzapine did not elicit
further bene1047297t except that subjects receiving bothmedications gained less weight than those receiving only olanzapine (Zanarini et al 2004b ) The addi-tion of olanzapine to DBT reduced depressionanxiety and impulsive aggression but the magni-
tude and timing of these bene1047297ts relative to DBT was dif 1047297cult to interpret (Soler et al 2005)
Aripiprazolehas a novelmechanismof action(partialagonist at the dopamine D2 receptor and serotonin 5-HT1A receptor antagonist at the 5-HT2A receptor) Itmay be more favourable than other atypicals withrespect to metabolic side-effects A longer half-lifemay be more effective for patients susceptible to non-adherence In non-suicidal BPD patients aripipra-zole was effective in reducing aggression anxietydepression psychosis interpersonal symptoms self-injurious behaviour and subjective distress There
were no signi1047297cant differences between groups in weight gain (Nickel et al 2006) An 18-month open-label follow-up showed sustained improvements and continued tolerability (Nickel et al 2007)
Previously open-label trials suggested possibleef 1047297cacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al 2004 2006) Theside-effect and psychopharmacological pro1047297les of ziprasidone indicated lesser metabolic risks and an-tidepressant and anxiolytic effects thought to beindependent of antidopaminergic activity (Keck et al 1998 Tandon 2000 Wilner et al 2002)
Despite such promise a recent RCT with ziprasi-done was negative (Pascual et al 2008) Thusevidence-based practice supports use of aripiprazolebut not ziprasidone in treating BPD
In meta-analyses the class of antipsychotics had moderate effect in treating aggression but no sig-ni1047297cant effect on depression although aripiprazoleand olanzapine may be exceptions (Lieb et al 2010Mercer et al 2009) For aypicals metabolic side-effects may limit clinical utility Because 29-53of borderline patients ful1047297l criteria for an eating disorder at some point in their lives (Lieb et al
2004) and a signi1047297cant number suffer from obesity (Frankenburg amp Zanarini 2006) iatrogenic meta-bolic risks must be regarded as serious Althoughevidence-based practices have advanced in treating aggression associated with BPD chronic emptinessaffective lability and interpersonal dysfunction lack effective evidence-based medication treatments
MOOD STABILIZERS AND ANTICONVULSANTS
Due to BPD patientsrsquo affective dysregulation and comorbidity with bipolar disorder some have clas-si1047297ed BPD within the bipolar spectrum (Akiskal2004 Smith et al 2004) although most continue todistinguish between the two particularly withregard to interpersonal dysfunction (Bolton ampGunderson 1996 Henry et al 2001 Paris 2004)Mood stabilizers are indeed becoming a more in-tegral component of evidence-based treatmentpractices for BPD
Lithium is bene1047297cial in treating BPD particularly in terms of quieting affective instability (Links et al
1990 Rifkin et al 1972) Lithium toxicity andor non-compliance may be problematic due to BPDpatientsrsquo characteristic impulsive self-destructivebehaviour
However anticonvulsants are more often rec-ommended for treatment of rapid-cycling bipolar disorder the variant most closely resembling BPDCarbamazepine demonstrated lsquodramaticrsquo reductionsin behavioural dyscontrol and improvements inglobal functioning anxiety anger euphoria im-
pulsivity and suicidality but it was associated with worsening melancholic depression (Gardner ampCowdry 1986a b ) and therapeutic bene1047297ts could not be replicated in in-patients (de la Fuente ampLotstra 1994)
Although high drop-out rates were reported withdivalproex (Hollander et al 2001) it subsequently demonstrated bene1047297ts on interpersonal sensitivityanger and aggression in euthymic borderline wo-men with bipolar II (Frankenburg amp Zanarini2002) Divalproex reduced aggression irritabilityand overall disease severity in patients with Cluster
B personality disorders and prominent impulsiveaggression (Hollander et al 2003) Differentialtreatment response in Cluster B subjects was en-hanced by baseline trait impulsivity and state ag-gression although not affective instability (Hollander et al 2005)
Lamotrigine extends periods of euthymia in bi-polar patients (eg Goodwin et al 2004) Potentialbene1047297ts also include pro-cognitive activity as pre-viously demonstrated in normal volunteers(Aldenkamp et al 2002) Lamotrigine effectively reduced BPD patientsrsquo anger (Tritt et al 2005) and
238 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
242 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 243
antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
during this recent period Several recent meta-analyses have been published in this time which we utilized to establish areas of consensus for evidence-basedpracticeandidentifygapsthatneed to be addressed with future research Many prior reviews cover only BPD but we expanded our scope to include all personality disorders Thus
we include a comprehensive summary of the bestcurrent evidence with commentary on recentconsensus and recommendations for evidence-based practices and future directions regarding pharmacotherapeutic strategies that have been in-
suf 1047297
ciently tested but appear promising for further research This situates this review as a nexuscompiling evidence-based practices for treating personality disorders for interested clinicians as
well as providing avenues for future psychophar-macological research
SCHIZOTYPAL PERSONALITY DISORDER
(SPD)
SPD is characterized by interpersonal de1047297citsand psychotic-like symptoms Like schizophrenia
Table 2 Antisocial Personality Disorder
Study Diagnosis N Medication(s) Dosage(s)
Design
duration Results in active drug group(s)
Sheard
(1971)
Inmates of
maximum security
prison with verbal
and physical
aggression whilein prison
12 males Lithium
carbonate
Lithium levels of
06ndash15 meql
mean dose
1200 mgd
Crossoversingle-
blind three
4-wk phases
Decrease in serious incidents of verbal
or physical aggression Improvements
in self-rated anger and tension
Single-blind Aggressive incidents
scored on basis of prison guardsrsquo
issuing of punitive tickets not by
psychiatristsrsquo ratings
Sheard
et al
(1976)
Prisoners
convicted of
lsquoserious
aggressive
crimesrsquo
80 males Lithium
carbonate
Lithium levels of
06ndash10 meql
mean lithium level
during last week
of medication
phase 089 meql
Parallel design
5 months with
first and
last months
medication
free and 3
months lithium
vs placebo
Decrease in violent infractions of prison
rules in lithium group
Lion
(1979)
lsquo All patients had
past histories of
temper outbursts
belligerenceassaultive
behaviour and
impulsiveness
had experienced
legal difficulties
and some
had committed
criminal actsrsquo
65 males
and females
Chlordiazepoxide
oxazepam
Chlordiazepoxide
100 mgd for 2 wk
then 200 mgd for
2 wk Oxazepam120 mgd for 2 wk
then 240 mgd
for 2wk
Parallel design
4 wk
Oxazepam superior to chlordiazepoxide
and placebo for indirect hostility
(Buss-Durkee Hostility Scale) anxiety
Barratt
et al
(1991)
Maximum security
prison inmates
with impulsive
aggression
while in prison
19 males Phenytoin 100 mgd or
300 mgd
Crossover design
three 4-wk
phases
Significant reduction in aggressive
acts at 300 mgd but not
100 mgd Improvements in
tension-anxiety and
depression-dejection at 300 mgd
but not anger-hostility
Barratt
et al
(1997)
Prison inmates
with aggression
while in prison
150 total but only
30 males with
primarily impulsive
aggression and
30 males with
primarily
pre-meditated
aggression included
in analysis (other
66 had mixture
of both types)
Phenytoin 300 mgd Crossover
design two
6-wk phases
Significant reduction in frequency
and intensity of aggressive acts
in impulsive aggressive group
but not pre-meditated aggressive
group
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 227
patients SPD patients often demonstrate cognitivede1047297cits in working memory particularly sustained attention and executive functioning (Bergida ampLenzenweger 2006 McClure et al 2007a Parc ampMcTigue 1997) as well as signi1047297cant abnormalitiesin empathic understanding (Langdon amp Coltheart2004 Pickup 2006 Ripoll et al unpublished data)Unlike schizophrenic patients there is greater preservation of frontal volume in SPD (Siever ampDavis 2004)
Overall clinical trials for SPD have been com-plicated by comorbidity particularly with other personality disorders Most early RCTs on BPDalso included SPD patients (Goldberg et al 1986Serban amp Siegel 1984 Soloff et al 1986c ) be-cause both SPD and BPD were considered rooted in lsquoborderlinersquo schizophrenia but psychoticsymptoms in SPD and BPD are clinically distin-guishable
The conceptualization of SPD within theschizophrenia spectrum supports treatment withantipsychotic medications Antipsychotics appear
tobeusefulinthetreatmentofSPDparticularlyinterms of psychotic-like symptoms (Goldberg et al
1986 Koenigsberg e t a l 2003) Open-labelstudies have suggested a role for antidepressantsin treating self-injury psychotic-like and de-pressive symptomatology (Jensen amp Andersen1989 Markovitz et al 1991) but the evidence is
weaker Recent RCTs targeting cognitive de1047297citsin SPD compared performance on neuro-psychological tasks before and after treatment
with medication or placebo Both pergolidea dopaminergic agonist active at both the D1 and
D2 receptor (McClure et al 2010) and the nor-adrenergic a2A agonist guanfacine (McClure et al
2007b ) improved SPD patientsrsquo cognitive per-formance on distinct neuropsychological mea-sures Whether this improvement extends tooverall clinical functioning in SPD remains sub-
ject to future investigationIn sumSPDpatients respondto low-dose atypical
antipsychotics targeting psychotic-like symptomsand general functioning First-generation antipsy-
chotic medication and antidepressants may alsoplay a role although the evidence is not as reliableEvidence-based practice requires weighing risk of extrapyramidal side-effects or tardive dyskinesia against potential bene1047297ts Cognitive enhancementvia noradrenergic a2A or dopaminergic agonismmay be future avenues of research given that by analogy with schizophrenia the cognitive impair-ment in SPD may be responsible for the overalldysfunction observed in the disorder Researchefforts to understand neurobiological substratesof social cognitive dysfunction have heretofore
mainly focused on BPD and schizophrenia Be-cause SPD involves social isolation relationalparanoia and empathic de1047297cits research on phar-macotherapeutic effects on social cognition may also be fruitful
A NTISOCIAL PERSONALITY DISORDER
(A SPD)
Peer-reviewed trials of AsPD include studieson groups of individuals likely to have been antiso-cial based on histories of repeated violence and
criminality and an absence of other stated causes for these behaviours Lithium has been associated withdecreases in serious rule infractions in incarcerated males (Sheard 1971 Sheard et al 1976) Prisonerstreated with phenytoin committed fewer aggressiveacts and evidenced decreased tension-anxiety and depression-dejection (although not anger-hostility)and improvements in aggression appeared to belimited to impulsive (not pre-meditated) aggres-sion (Barratt et al 1991 1997) At presentevidenced-based pharmacotherapy for AsPD isrestricted to treatment of impulsive aggressionFuture neurobiological research in AsPD and psychopathy will probably increase our un-derstanding of the dysfunctional emotional em-pathy often seen in this disorder (Blair 2005) and
whether this may be susceptible to psychophar-macological intervention
BPD
Most RCTs on personality disorders focused onBPD which consists of several domains of dys-function affective instability impulsivity and an-ger transient psychotic or dissociative symptomsand intense unstable relationships (Lieb et al
2004 Zanarini et al 1990) BPD patients oftendemonstrate high comorbidity (Zanarini et al
2004a c ) and make numerous suicide attempts and parasuicidal gestures conferring signi1047297cantly higher risk for completed suicide (Welch amp Linehan2000)
Early studies employed a distinct nosology incharacterizing subjects some of whom actually had
what might be called BPD today (Rifkin et al 1972)In studies on suicidal or parasuicidal subjects themajority often have BPD (Battaglia et al 1999Montgomery amp Montgomery 1982 Montgomery et al 1983 Verkes et al 1998) Early studies oftenincluded combinations of BPD and SPD subjects(Goldberg et al 1986 Serban amp Siegel 1984 Soloff et al 1986c ) and studies recruiting a range of allpersonality disorders ultimately include BPD as themost frequent diagnosis (Coccaro amp Kavoussi
1997 Hollander et al 2003)Cliniciansshouldexercisecautioninattemptingtoapplyresearch1047297ndingstoseverelyillBPDpatientsasmany RCTs recruited only outpatients who further
were excluded if they expressed acute suicidality (Frankenburg amp Zanarini 2002 Tritt et al 2005Zanarini amp Frankenburg 2003 Zanarini et al
2004b ) or had made a recent suicide attempt(Bogenschutz amp Nurnberg 2004) In additionsmall sample sizes predominated and most studieslasted 3 months The few trials lasting $6 monthssuffered from high drop-out rates (Frankenburg amp
Zanarini 2002 Zanarini amp Frankenburg 2001) or concomitant recruitment of subjects without BPD(Battaglia et al 1999 Montgomery et al 1983Verkes et al 1998) Moreover RCTs with BPDsubjects appear to be prone to highplacebo responserates (Lieb et al 2004 Salzman et al 1995)meaning that open-label trial data should be inter-preted with caution
APA practice guidelines (APA 2001) recom-mended a symptom-targeted approach in pharma-cotherapy of BPD This leaves open the possibility for patients to improve in some but not all symptomdimensions Some clinicians have based their de-cision to implement polypharmacy on this butthere is actually little evidence as to the effectivenessof this strategy The only study on combined pharmacotherapy in BPD (Zanarini et al 2004b )found no superior ef 1047297cacy for combination treat-ment compared to one medication alone Using asfew medications as possible to target central areas of
clinical dysfunction together with evidence-based psychotherapy is usually the optimal treatmentstrategy In light of this although the 2001 guide-lines suggest a prominent role for serotonergicpharmacotherapy recent reviews have questioned this and instead emphasized anticonvulsants and antipsychotics (Abraham amp Calabrese 2008 Mercer et al 2009)
TRICYCLIC ANTIDEPRESSANTS (TCA S)
Disturbances of serotonin have been associated
with BPD impulsive aggression self-harm and suicidality (Coccaro et al 1995 Evenden 1999Malone et al 1996 Pitchot et al 2005) Low CSFlevels of serotonin metabolites have been associated
with suicide attempts and completion (Samuelssonet al 2006 Traskman et al 1981) impulsivityaggression (Mehlman et al 1994 Virkkunen et al
1994) lifetime aggressiveness and suicidal lethality (Placidi et al 2001) Impulsive aggression withsuicidality has been linked to blunted prolactinresponses to the serotonergic probe fen1047298uramine(Coccaro et al 1989) PET scans of personality-
disordered subjects high in impulsive aggressionhave demonstrated reduced response to fen1047298ur-amine in orbitofrontal ventromedial and cingulateregions (Siever et al 1999)
Nevertheless early research on TCAs for BPDproved disappointing (Montgomery et al 1983Soloff et al 1989) Amitryptiline has been associ-ated with paradoxical increases in suicidality para-noia and behavioural dysregulation attributed tolsquogeneralized disinhibition of cognitive and affec-tive controlsrsquo (Soloff et al 1986a 1987) Indeedborderline patients have dif 1047297culty cognitively
236 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
resolving con1047298ict among stimulus dimensions(Posner et al 2002) and prefrontal hypofunctioncan be seen after a serotonergic stimulus in subjects
with prominent impulsive aggression (New et al
2002) Thus medications with adverse cognitivesequelae including anticholinergic side-effects may contribute to worsening impulsivity As mentioned in prior reviews the use of TCAs in treating BPD isdiscouraged (Abraham amp Calabrese 2008 Mercer et al 2009) Their use is also associated with po-tentially signi1047297cant risk of overdose
MONOAMINE OXIDASE INHIBITORS (MAOIS)
Despite hesitancyinprescribingMAOIstopatients with prominent impulsivity or self-injurious behav-iour some recommend these medications for BPDpatientswhocantakethemsafelyandreliablyInterestin MAOIs for BPD is rooted in their differential ef-1047297cacy for conditions such as hysteroid dysphoria or atypical depression viewed as being related to oneother and BPD (Kayser et al 1985 Liebowitz ampKlein 1981) In a crossover trial with multiplemedication phases only tranylcypromine was as-sociated with higher patient-rated improvementscores and completion rates (Cowdry amp Gardner1988)
Similarly relative prominence of BPD symptomspredicted superiority of phenelzine (Parsons et al
1989) Phenelzine is bene1047297cial in the treatment of hostility anxiety and borderline symptoms (Soloff et al 1993) In some patients it could cause un-
comfortable excitement and emotional reactivity (Cornelius et al 1993) Thus although there isevidence for their ef 1047297cacy many patients may nottolerate these medications Other associated risksof MAOIs include toxicity in overdose and po-tentially fatal hypertensive crises or serotoninsyndrome
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIS)
SSRIs are thought to potentiate serotonergicneuromodulation but demonstrate more favour-able side-effect pro1047297les Fluoxetine reduced anger in BPD independent of any antidepressant ef-fect (Salzman et al 1995) It also improved verbaland impulsive aggression irritability and overallfunctioning (Coccaro amp Kavoussi 1997) Simi-larly a RCT with paroxetine demonstrated ef 1047297cacy in preventing recurrent suicidal behaviour but nosigni1047297cant effect on depression hopelessness or anger (Verkes et al 1998) By contrast there waslittle added bene1047297t from 1047298uoxetine when added to
dialectical behavioural therapy (DBT) (Simpsonet al 2004)
On the other hand 1047298uvoxamine decreased af-fective lability but not scores of impulsivity or ag-gression (Rinne et al 2002) Although SSRIsdecrease impulsivity and aggression in BPD patients
with comorbid intermittent explosive disorder (IED Coccaro amp Kavoussi 1997 New et al 2004)data from BPD subjects without comorbid IED areinconsistent (Rinne et al 2002) Previous reviewshave emphasized that effect sizes for antidepressantpharmacotherapy vary widely between classes and trials (Ingenhoven et al 2010 Lieb et al 2010Mercer et al 2009) Nevertheless current evidence-based practice recommends use of SSRIs due topotential bene1047297ts on impulsive aggression that may outweigh associated risks There has been no evi-dence that antidepressants alleviate the chronicemptiness shameful self-concept and intrapsychicpain in BPD
FIRST-GENERATION ANTIPSYCHOTICS
An early interest in antipsychotic medications for treating BPD probably arose from a conception of BPD as a variant of schizophrenia (eg Deutsch1942) Antipsychotics have demonstrated partialef 1047297cacy re1047298ecting underlying abnormalities in do-paminergic signalling Borderline subjects demon-strate high levels of the dopamine metabolitehomovallinic acid in both plasma and cerebrospinal1047298uid (Siever et al unpublished data) Prior to more
widespread use of SSRIs antipsychotics demon-strated ef 1047297cacy in decreasing psychotic-like symptoms(Goldberg et al 1986 Soloff et al 1986b ) depression(Soloff et al 1986b ) irritability (Cornelius et al
1993) and general symptom severity (Cowdry ampGardner 1988 Soloff et al 1986b )
A recent Cochrane review suggests haloperidol isef 1047297cacious in reducing anger in BPD and treatment
with 1047298upenthixol decanoate reduced suicidal be-haviour (Lieb et al 2010) By contrast evidence for ef 1047297cacy of neuroleptics on affective symptomspsychosis and anxiety remains inconsistent The
dosage of antipsychotic medication for evidence-based treatment of BPD is usually lower thanschizophrenia High drop-out rates are noted and risk of extrapyramidal symptoms may further limitthe utility of neuroleptics
SECOND-GENERATION ANTIPSYCHOTICS
Classical neuroleptics have largely been superseded by atypical antipsychotics whose broader therapeuticbene1047297ts may be explained by activity beyond the D2
receptor As mentioned in prior reviews olanzapine
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 237
has proven bene1047297cial in treatment of BPD patientsrsquoanxiety anger interpersonal sensitivity and para-noia but not depression (Zanarini amp Frankenburg2001) as well as improving general clinical func-tioning and BPD symptomatology (Bogenschutz ampNurnberg 2004) A recent large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulzet al 2008) although the authors suggested thatpatients may have been underdosed A study comparing olanzapine to haloperidol showed nobetween-group differences except with respect toside-effects with more weight gain associated witholanzapine and more extra-pyramidal side-effects
with haloperidol (Shafti amp Shahveisi 2010) Adding 1047298uoxetine to olanzapine did not elicit
further bene1047297t except that subjects receiving bothmedications gained less weight than those receiving only olanzapine (Zanarini et al 2004b ) The addi-tion of olanzapine to DBT reduced depressionanxiety and impulsive aggression but the magni-
tude and timing of these bene1047297ts relative to DBT was dif 1047297cult to interpret (Soler et al 2005)
Aripiprazolehas a novelmechanismof action(partialagonist at the dopamine D2 receptor and serotonin 5-HT1A receptor antagonist at the 5-HT2A receptor) Itmay be more favourable than other atypicals withrespect to metabolic side-effects A longer half-lifemay be more effective for patients susceptible to non-adherence In non-suicidal BPD patients aripipra-zole was effective in reducing aggression anxietydepression psychosis interpersonal symptoms self-injurious behaviour and subjective distress There
were no signi1047297cant differences between groups in weight gain (Nickel et al 2006) An 18-month open-label follow-up showed sustained improvements and continued tolerability (Nickel et al 2007)
Previously open-label trials suggested possibleef 1047297cacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al 2004 2006) Theside-effect and psychopharmacological pro1047297les of ziprasidone indicated lesser metabolic risks and an-tidepressant and anxiolytic effects thought to beindependent of antidopaminergic activity (Keck et al 1998 Tandon 2000 Wilner et al 2002)
Despite such promise a recent RCT with ziprasi-done was negative (Pascual et al 2008) Thusevidence-based practice supports use of aripiprazolebut not ziprasidone in treating BPD
In meta-analyses the class of antipsychotics had moderate effect in treating aggression but no sig-ni1047297cant effect on depression although aripiprazoleand olanzapine may be exceptions (Lieb et al 2010Mercer et al 2009) For aypicals metabolic side-effects may limit clinical utility Because 29-53of borderline patients ful1047297l criteria for an eating disorder at some point in their lives (Lieb et al
2004) and a signi1047297cant number suffer from obesity (Frankenburg amp Zanarini 2006) iatrogenic meta-bolic risks must be regarded as serious Althoughevidence-based practices have advanced in treating aggression associated with BPD chronic emptinessaffective lability and interpersonal dysfunction lack effective evidence-based medication treatments
MOOD STABILIZERS AND ANTICONVULSANTS
Due to BPD patientsrsquo affective dysregulation and comorbidity with bipolar disorder some have clas-si1047297ed BPD within the bipolar spectrum (Akiskal2004 Smith et al 2004) although most continue todistinguish between the two particularly withregard to interpersonal dysfunction (Bolton ampGunderson 1996 Henry et al 2001 Paris 2004)Mood stabilizers are indeed becoming a more in-tegral component of evidence-based treatmentpractices for BPD
Lithium is bene1047297cial in treating BPD particularly in terms of quieting affective instability (Links et al
1990 Rifkin et al 1972) Lithium toxicity andor non-compliance may be problematic due to BPDpatientsrsquo characteristic impulsive self-destructivebehaviour
However anticonvulsants are more often rec-ommended for treatment of rapid-cycling bipolar disorder the variant most closely resembling BPDCarbamazepine demonstrated lsquodramaticrsquo reductionsin behavioural dyscontrol and improvements inglobal functioning anxiety anger euphoria im-
pulsivity and suicidality but it was associated with worsening melancholic depression (Gardner ampCowdry 1986a b ) and therapeutic bene1047297ts could not be replicated in in-patients (de la Fuente ampLotstra 1994)
Although high drop-out rates were reported withdivalproex (Hollander et al 2001) it subsequently demonstrated bene1047297ts on interpersonal sensitivityanger and aggression in euthymic borderline wo-men with bipolar II (Frankenburg amp Zanarini2002) Divalproex reduced aggression irritabilityand overall disease severity in patients with Cluster
B personality disorders and prominent impulsiveaggression (Hollander et al 2003) Differentialtreatment response in Cluster B subjects was en-hanced by baseline trait impulsivity and state ag-gression although not affective instability (Hollander et al 2005)
Lamotrigine extends periods of euthymia in bi-polar patients (eg Goodwin et al 2004) Potentialbene1047297ts also include pro-cognitive activity as pre-viously demonstrated in normal volunteers(Aldenkamp et al 2002) Lamotrigine effectively reduced BPD patientsrsquo anger (Tritt et al 2005) and
238 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
242 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 243
antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
patients SPD patients often demonstrate cognitivede1047297cits in working memory particularly sustained attention and executive functioning (Bergida ampLenzenweger 2006 McClure et al 2007a Parc ampMcTigue 1997) as well as signi1047297cant abnormalitiesin empathic understanding (Langdon amp Coltheart2004 Pickup 2006 Ripoll et al unpublished data)Unlike schizophrenic patients there is greater preservation of frontal volume in SPD (Siever ampDavis 2004)
Overall clinical trials for SPD have been com-plicated by comorbidity particularly with other personality disorders Most early RCTs on BPDalso included SPD patients (Goldberg et al 1986Serban amp Siegel 1984 Soloff et al 1986c ) be-cause both SPD and BPD were considered rooted in lsquoborderlinersquo schizophrenia but psychoticsymptoms in SPD and BPD are clinically distin-guishable
The conceptualization of SPD within theschizophrenia spectrum supports treatment withantipsychotic medications Antipsychotics appear
tobeusefulinthetreatmentofSPDparticularlyinterms of psychotic-like symptoms (Goldberg et al
1986 Koenigsberg e t a l 2003) Open-labelstudies have suggested a role for antidepressantsin treating self-injury psychotic-like and de-pressive symptomatology (Jensen amp Andersen1989 Markovitz et al 1991) but the evidence is
weaker Recent RCTs targeting cognitive de1047297citsin SPD compared performance on neuro-psychological tasks before and after treatment
with medication or placebo Both pergolidea dopaminergic agonist active at both the D1 and
D2 receptor (McClure et al 2010) and the nor-adrenergic a2A agonist guanfacine (McClure et al
2007b ) improved SPD patientsrsquo cognitive per-formance on distinct neuropsychological mea-sures Whether this improvement extends tooverall clinical functioning in SPD remains sub-
ject to future investigationIn sumSPDpatients respondto low-dose atypical
antipsychotics targeting psychotic-like symptomsand general functioning First-generation antipsy-
chotic medication and antidepressants may alsoplay a role although the evidence is not as reliableEvidence-based practice requires weighing risk of extrapyramidal side-effects or tardive dyskinesia against potential bene1047297ts Cognitive enhancementvia noradrenergic a2A or dopaminergic agonismmay be future avenues of research given that by analogy with schizophrenia the cognitive impair-ment in SPD may be responsible for the overalldysfunction observed in the disorder Researchefforts to understand neurobiological substratesof social cognitive dysfunction have heretofore
mainly focused on BPD and schizophrenia Be-cause SPD involves social isolation relationalparanoia and empathic de1047297cits research on phar-macotherapeutic effects on social cognition may also be fruitful
A NTISOCIAL PERSONALITY DISORDER
(A SPD)
Peer-reviewed trials of AsPD include studieson groups of individuals likely to have been antiso-cial based on histories of repeated violence and
criminality and an absence of other stated causes for these behaviours Lithium has been associated withdecreases in serious rule infractions in incarcerated males (Sheard 1971 Sheard et al 1976) Prisonerstreated with phenytoin committed fewer aggressiveacts and evidenced decreased tension-anxiety and depression-dejection (although not anger-hostility)and improvements in aggression appeared to belimited to impulsive (not pre-meditated) aggres-sion (Barratt et al 1991 1997) At presentevidenced-based pharmacotherapy for AsPD isrestricted to treatment of impulsive aggressionFuture neurobiological research in AsPD and psychopathy will probably increase our un-derstanding of the dysfunctional emotional em-pathy often seen in this disorder (Blair 2005) and
whether this may be susceptible to psychophar-macological intervention
BPD
Most RCTs on personality disorders focused onBPD which consists of several domains of dys-function affective instability impulsivity and an-ger transient psychotic or dissociative symptomsand intense unstable relationships (Lieb et al
2004 Zanarini et al 1990) BPD patients oftendemonstrate high comorbidity (Zanarini et al
2004a c ) and make numerous suicide attempts and parasuicidal gestures conferring signi1047297cantly higher risk for completed suicide (Welch amp Linehan2000)
Early studies employed a distinct nosology incharacterizing subjects some of whom actually had
what might be called BPD today (Rifkin et al 1972)In studies on suicidal or parasuicidal subjects themajority often have BPD (Battaglia et al 1999Montgomery amp Montgomery 1982 Montgomery et al 1983 Verkes et al 1998) Early studies oftenincluded combinations of BPD and SPD subjects(Goldberg et al 1986 Serban amp Siegel 1984 Soloff et al 1986c ) and studies recruiting a range of allpersonality disorders ultimately include BPD as themost frequent diagnosis (Coccaro amp Kavoussi
1997 Hollander et al 2003)Cliniciansshouldexercisecautioninattemptingtoapplyresearch1047297ndingstoseverelyillBPDpatientsasmany RCTs recruited only outpatients who further
were excluded if they expressed acute suicidality (Frankenburg amp Zanarini 2002 Tritt et al 2005Zanarini amp Frankenburg 2003 Zanarini et al
2004b ) or had made a recent suicide attempt(Bogenschutz amp Nurnberg 2004) In additionsmall sample sizes predominated and most studieslasted 3 months The few trials lasting $6 monthssuffered from high drop-out rates (Frankenburg amp
Zanarini 2002 Zanarini amp Frankenburg 2001) or concomitant recruitment of subjects without BPD(Battaglia et al 1999 Montgomery et al 1983Verkes et al 1998) Moreover RCTs with BPDsubjects appear to be prone to highplacebo responserates (Lieb et al 2004 Salzman et al 1995)meaning that open-label trial data should be inter-preted with caution
APA practice guidelines (APA 2001) recom-mended a symptom-targeted approach in pharma-cotherapy of BPD This leaves open the possibility for patients to improve in some but not all symptomdimensions Some clinicians have based their de-cision to implement polypharmacy on this butthere is actually little evidence as to the effectivenessof this strategy The only study on combined pharmacotherapy in BPD (Zanarini et al 2004b )found no superior ef 1047297cacy for combination treat-ment compared to one medication alone Using asfew medications as possible to target central areas of
clinical dysfunction together with evidence-based psychotherapy is usually the optimal treatmentstrategy In light of this although the 2001 guide-lines suggest a prominent role for serotonergicpharmacotherapy recent reviews have questioned this and instead emphasized anticonvulsants and antipsychotics (Abraham amp Calabrese 2008 Mercer et al 2009)
TRICYCLIC ANTIDEPRESSANTS (TCA S)
Disturbances of serotonin have been associated
with BPD impulsive aggression self-harm and suicidality (Coccaro et al 1995 Evenden 1999Malone et al 1996 Pitchot et al 2005) Low CSFlevels of serotonin metabolites have been associated
with suicide attempts and completion (Samuelssonet al 2006 Traskman et al 1981) impulsivityaggression (Mehlman et al 1994 Virkkunen et al
1994) lifetime aggressiveness and suicidal lethality (Placidi et al 2001) Impulsive aggression withsuicidality has been linked to blunted prolactinresponses to the serotonergic probe fen1047298uramine(Coccaro et al 1989) PET scans of personality-
disordered subjects high in impulsive aggressionhave demonstrated reduced response to fen1047298ur-amine in orbitofrontal ventromedial and cingulateregions (Siever et al 1999)
Nevertheless early research on TCAs for BPDproved disappointing (Montgomery et al 1983Soloff et al 1989) Amitryptiline has been associ-ated with paradoxical increases in suicidality para-noia and behavioural dysregulation attributed tolsquogeneralized disinhibition of cognitive and affec-tive controlsrsquo (Soloff et al 1986a 1987) Indeedborderline patients have dif 1047297culty cognitively
236 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
resolving con1047298ict among stimulus dimensions(Posner et al 2002) and prefrontal hypofunctioncan be seen after a serotonergic stimulus in subjects
with prominent impulsive aggression (New et al
2002) Thus medications with adverse cognitivesequelae including anticholinergic side-effects may contribute to worsening impulsivity As mentioned in prior reviews the use of TCAs in treating BPD isdiscouraged (Abraham amp Calabrese 2008 Mercer et al 2009) Their use is also associated with po-tentially signi1047297cant risk of overdose
MONOAMINE OXIDASE INHIBITORS (MAOIS)
Despite hesitancyinprescribingMAOIstopatients with prominent impulsivity or self-injurious behav-iour some recommend these medications for BPDpatientswhocantakethemsafelyandreliablyInterestin MAOIs for BPD is rooted in their differential ef-1047297cacy for conditions such as hysteroid dysphoria or atypical depression viewed as being related to oneother and BPD (Kayser et al 1985 Liebowitz ampKlein 1981) In a crossover trial with multiplemedication phases only tranylcypromine was as-sociated with higher patient-rated improvementscores and completion rates (Cowdry amp Gardner1988)
Similarly relative prominence of BPD symptomspredicted superiority of phenelzine (Parsons et al
1989) Phenelzine is bene1047297cial in the treatment of hostility anxiety and borderline symptoms (Soloff et al 1993) In some patients it could cause un-
comfortable excitement and emotional reactivity (Cornelius et al 1993) Thus although there isevidence for their ef 1047297cacy many patients may nottolerate these medications Other associated risksof MAOIs include toxicity in overdose and po-tentially fatal hypertensive crises or serotoninsyndrome
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIS)
SSRIs are thought to potentiate serotonergicneuromodulation but demonstrate more favour-able side-effect pro1047297les Fluoxetine reduced anger in BPD independent of any antidepressant ef-fect (Salzman et al 1995) It also improved verbaland impulsive aggression irritability and overallfunctioning (Coccaro amp Kavoussi 1997) Simi-larly a RCT with paroxetine demonstrated ef 1047297cacy in preventing recurrent suicidal behaviour but nosigni1047297cant effect on depression hopelessness or anger (Verkes et al 1998) By contrast there waslittle added bene1047297t from 1047298uoxetine when added to
dialectical behavioural therapy (DBT) (Simpsonet al 2004)
On the other hand 1047298uvoxamine decreased af-fective lability but not scores of impulsivity or ag-gression (Rinne et al 2002) Although SSRIsdecrease impulsivity and aggression in BPD patients
with comorbid intermittent explosive disorder (IED Coccaro amp Kavoussi 1997 New et al 2004)data from BPD subjects without comorbid IED areinconsistent (Rinne et al 2002) Previous reviewshave emphasized that effect sizes for antidepressantpharmacotherapy vary widely between classes and trials (Ingenhoven et al 2010 Lieb et al 2010Mercer et al 2009) Nevertheless current evidence-based practice recommends use of SSRIs due topotential bene1047297ts on impulsive aggression that may outweigh associated risks There has been no evi-dence that antidepressants alleviate the chronicemptiness shameful self-concept and intrapsychicpain in BPD
FIRST-GENERATION ANTIPSYCHOTICS
An early interest in antipsychotic medications for treating BPD probably arose from a conception of BPD as a variant of schizophrenia (eg Deutsch1942) Antipsychotics have demonstrated partialef 1047297cacy re1047298ecting underlying abnormalities in do-paminergic signalling Borderline subjects demon-strate high levels of the dopamine metabolitehomovallinic acid in both plasma and cerebrospinal1047298uid (Siever et al unpublished data) Prior to more
widespread use of SSRIs antipsychotics demon-strated ef 1047297cacy in decreasing psychotic-like symptoms(Goldberg et al 1986 Soloff et al 1986b ) depression(Soloff et al 1986b ) irritability (Cornelius et al
1993) and general symptom severity (Cowdry ampGardner 1988 Soloff et al 1986b )
A recent Cochrane review suggests haloperidol isef 1047297cacious in reducing anger in BPD and treatment
with 1047298upenthixol decanoate reduced suicidal be-haviour (Lieb et al 2010) By contrast evidence for ef 1047297cacy of neuroleptics on affective symptomspsychosis and anxiety remains inconsistent The
dosage of antipsychotic medication for evidence-based treatment of BPD is usually lower thanschizophrenia High drop-out rates are noted and risk of extrapyramidal symptoms may further limitthe utility of neuroleptics
SECOND-GENERATION ANTIPSYCHOTICS
Classical neuroleptics have largely been superseded by atypical antipsychotics whose broader therapeuticbene1047297ts may be explained by activity beyond the D2
receptor As mentioned in prior reviews olanzapine
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 237
has proven bene1047297cial in treatment of BPD patientsrsquoanxiety anger interpersonal sensitivity and para-noia but not depression (Zanarini amp Frankenburg2001) as well as improving general clinical func-tioning and BPD symptomatology (Bogenschutz ampNurnberg 2004) A recent large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulzet al 2008) although the authors suggested thatpatients may have been underdosed A study comparing olanzapine to haloperidol showed nobetween-group differences except with respect toside-effects with more weight gain associated witholanzapine and more extra-pyramidal side-effects
with haloperidol (Shafti amp Shahveisi 2010) Adding 1047298uoxetine to olanzapine did not elicit
further bene1047297t except that subjects receiving bothmedications gained less weight than those receiving only olanzapine (Zanarini et al 2004b ) The addi-tion of olanzapine to DBT reduced depressionanxiety and impulsive aggression but the magni-
tude and timing of these bene1047297ts relative to DBT was dif 1047297cult to interpret (Soler et al 2005)
Aripiprazolehas a novelmechanismof action(partialagonist at the dopamine D2 receptor and serotonin 5-HT1A receptor antagonist at the 5-HT2A receptor) Itmay be more favourable than other atypicals withrespect to metabolic side-effects A longer half-lifemay be more effective for patients susceptible to non-adherence In non-suicidal BPD patients aripipra-zole was effective in reducing aggression anxietydepression psychosis interpersonal symptoms self-injurious behaviour and subjective distress There
were no signi1047297cant differences between groups in weight gain (Nickel et al 2006) An 18-month open-label follow-up showed sustained improvements and continued tolerability (Nickel et al 2007)
Previously open-label trials suggested possibleef 1047297cacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al 2004 2006) Theside-effect and psychopharmacological pro1047297les of ziprasidone indicated lesser metabolic risks and an-tidepressant and anxiolytic effects thought to beindependent of antidopaminergic activity (Keck et al 1998 Tandon 2000 Wilner et al 2002)
Despite such promise a recent RCT with ziprasi-done was negative (Pascual et al 2008) Thusevidence-based practice supports use of aripiprazolebut not ziprasidone in treating BPD
In meta-analyses the class of antipsychotics had moderate effect in treating aggression but no sig-ni1047297cant effect on depression although aripiprazoleand olanzapine may be exceptions (Lieb et al 2010Mercer et al 2009) For aypicals metabolic side-effects may limit clinical utility Because 29-53of borderline patients ful1047297l criteria for an eating disorder at some point in their lives (Lieb et al
2004) and a signi1047297cant number suffer from obesity (Frankenburg amp Zanarini 2006) iatrogenic meta-bolic risks must be regarded as serious Althoughevidence-based practices have advanced in treating aggression associated with BPD chronic emptinessaffective lability and interpersonal dysfunction lack effective evidence-based medication treatments
MOOD STABILIZERS AND ANTICONVULSANTS
Due to BPD patientsrsquo affective dysregulation and comorbidity with bipolar disorder some have clas-si1047297ed BPD within the bipolar spectrum (Akiskal2004 Smith et al 2004) although most continue todistinguish between the two particularly withregard to interpersonal dysfunction (Bolton ampGunderson 1996 Henry et al 2001 Paris 2004)Mood stabilizers are indeed becoming a more in-tegral component of evidence-based treatmentpractices for BPD
Lithium is bene1047297cial in treating BPD particularly in terms of quieting affective instability (Links et al
1990 Rifkin et al 1972) Lithium toxicity andor non-compliance may be problematic due to BPDpatientsrsquo characteristic impulsive self-destructivebehaviour
However anticonvulsants are more often rec-ommended for treatment of rapid-cycling bipolar disorder the variant most closely resembling BPDCarbamazepine demonstrated lsquodramaticrsquo reductionsin behavioural dyscontrol and improvements inglobal functioning anxiety anger euphoria im-
pulsivity and suicidality but it was associated with worsening melancholic depression (Gardner ampCowdry 1986a b ) and therapeutic bene1047297ts could not be replicated in in-patients (de la Fuente ampLotstra 1994)
Although high drop-out rates were reported withdivalproex (Hollander et al 2001) it subsequently demonstrated bene1047297ts on interpersonal sensitivityanger and aggression in euthymic borderline wo-men with bipolar II (Frankenburg amp Zanarini2002) Divalproex reduced aggression irritabilityand overall disease severity in patients with Cluster
B personality disorders and prominent impulsiveaggression (Hollander et al 2003) Differentialtreatment response in Cluster B subjects was en-hanced by baseline trait impulsivity and state ag-gression although not affective instability (Hollander et al 2005)
Lamotrigine extends periods of euthymia in bi-polar patients (eg Goodwin et al 2004) Potentialbene1047297ts also include pro-cognitive activity as pre-viously demonstrated in normal volunteers(Aldenkamp et al 2002) Lamotrigine effectively reduced BPD patientsrsquo anger (Tritt et al 2005) and
238 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
242 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 243
antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
patients SPD patients often demonstrate cognitivede1047297cits in working memory particularly sustained attention and executive functioning (Bergida ampLenzenweger 2006 McClure et al 2007a Parc ampMcTigue 1997) as well as signi1047297cant abnormalitiesin empathic understanding (Langdon amp Coltheart2004 Pickup 2006 Ripoll et al unpublished data)Unlike schizophrenic patients there is greater preservation of frontal volume in SPD (Siever ampDavis 2004)
Overall clinical trials for SPD have been com-plicated by comorbidity particularly with other personality disorders Most early RCTs on BPDalso included SPD patients (Goldberg et al 1986Serban amp Siegel 1984 Soloff et al 1986c ) be-cause both SPD and BPD were considered rooted in lsquoborderlinersquo schizophrenia but psychoticsymptoms in SPD and BPD are clinically distin-guishable
The conceptualization of SPD within theschizophrenia spectrum supports treatment withantipsychotic medications Antipsychotics appear
tobeusefulinthetreatmentofSPDparticularlyinterms of psychotic-like symptoms (Goldberg et al
1986 Koenigsberg e t a l 2003) Open-labelstudies have suggested a role for antidepressantsin treating self-injury psychotic-like and de-pressive symptomatology (Jensen amp Andersen1989 Markovitz et al 1991) but the evidence is
weaker Recent RCTs targeting cognitive de1047297citsin SPD compared performance on neuro-psychological tasks before and after treatment
with medication or placebo Both pergolidea dopaminergic agonist active at both the D1 and
D2 receptor (McClure et al 2010) and the nor-adrenergic a2A agonist guanfacine (McClure et al
2007b ) improved SPD patientsrsquo cognitive per-formance on distinct neuropsychological mea-sures Whether this improvement extends tooverall clinical functioning in SPD remains sub-
ject to future investigationIn sumSPDpatients respondto low-dose atypical
antipsychotics targeting psychotic-like symptomsand general functioning First-generation antipsy-
chotic medication and antidepressants may alsoplay a role although the evidence is not as reliableEvidence-based practice requires weighing risk of extrapyramidal side-effects or tardive dyskinesia against potential bene1047297ts Cognitive enhancementvia noradrenergic a2A or dopaminergic agonismmay be future avenues of research given that by analogy with schizophrenia the cognitive impair-ment in SPD may be responsible for the overalldysfunction observed in the disorder Researchefforts to understand neurobiological substratesof social cognitive dysfunction have heretofore
mainly focused on BPD and schizophrenia Be-cause SPD involves social isolation relationalparanoia and empathic de1047297cits research on phar-macotherapeutic effects on social cognition may also be fruitful
A NTISOCIAL PERSONALITY DISORDER
(A SPD)
Peer-reviewed trials of AsPD include studieson groups of individuals likely to have been antiso-cial based on histories of repeated violence and
criminality and an absence of other stated causes for these behaviours Lithium has been associated withdecreases in serious rule infractions in incarcerated males (Sheard 1971 Sheard et al 1976) Prisonerstreated with phenytoin committed fewer aggressiveacts and evidenced decreased tension-anxiety and depression-dejection (although not anger-hostility)and improvements in aggression appeared to belimited to impulsive (not pre-meditated) aggres-sion (Barratt et al 1991 1997) At presentevidenced-based pharmacotherapy for AsPD isrestricted to treatment of impulsive aggressionFuture neurobiological research in AsPD and psychopathy will probably increase our un-derstanding of the dysfunctional emotional em-pathy often seen in this disorder (Blair 2005) and
whether this may be susceptible to psychophar-macological intervention
BPD
Most RCTs on personality disorders focused onBPD which consists of several domains of dys-function affective instability impulsivity and an-ger transient psychotic or dissociative symptomsand intense unstable relationships (Lieb et al
2004 Zanarini et al 1990) BPD patients oftendemonstrate high comorbidity (Zanarini et al
2004a c ) and make numerous suicide attempts and parasuicidal gestures conferring signi1047297cantly higher risk for completed suicide (Welch amp Linehan2000)
Early studies employed a distinct nosology incharacterizing subjects some of whom actually had
what might be called BPD today (Rifkin et al 1972)In studies on suicidal or parasuicidal subjects themajority often have BPD (Battaglia et al 1999Montgomery amp Montgomery 1982 Montgomery et al 1983 Verkes et al 1998) Early studies oftenincluded combinations of BPD and SPD subjects(Goldberg et al 1986 Serban amp Siegel 1984 Soloff et al 1986c ) and studies recruiting a range of allpersonality disorders ultimately include BPD as themost frequent diagnosis (Coccaro amp Kavoussi
1997 Hollander et al 2003)Cliniciansshouldexercisecautioninattemptingtoapplyresearch1047297ndingstoseverelyillBPDpatientsasmany RCTs recruited only outpatients who further
were excluded if they expressed acute suicidality (Frankenburg amp Zanarini 2002 Tritt et al 2005Zanarini amp Frankenburg 2003 Zanarini et al
2004b ) or had made a recent suicide attempt(Bogenschutz amp Nurnberg 2004) In additionsmall sample sizes predominated and most studieslasted 3 months The few trials lasting $6 monthssuffered from high drop-out rates (Frankenburg amp
Zanarini 2002 Zanarini amp Frankenburg 2001) or concomitant recruitment of subjects without BPD(Battaglia et al 1999 Montgomery et al 1983Verkes et al 1998) Moreover RCTs with BPDsubjects appear to be prone to highplacebo responserates (Lieb et al 2004 Salzman et al 1995)meaning that open-label trial data should be inter-preted with caution
APA practice guidelines (APA 2001) recom-mended a symptom-targeted approach in pharma-cotherapy of BPD This leaves open the possibility for patients to improve in some but not all symptomdimensions Some clinicians have based their de-cision to implement polypharmacy on this butthere is actually little evidence as to the effectivenessof this strategy The only study on combined pharmacotherapy in BPD (Zanarini et al 2004b )found no superior ef 1047297cacy for combination treat-ment compared to one medication alone Using asfew medications as possible to target central areas of
clinical dysfunction together with evidence-based psychotherapy is usually the optimal treatmentstrategy In light of this although the 2001 guide-lines suggest a prominent role for serotonergicpharmacotherapy recent reviews have questioned this and instead emphasized anticonvulsants and antipsychotics (Abraham amp Calabrese 2008 Mercer et al 2009)
TRICYCLIC ANTIDEPRESSANTS (TCA S)
Disturbances of serotonin have been associated
with BPD impulsive aggression self-harm and suicidality (Coccaro et al 1995 Evenden 1999Malone et al 1996 Pitchot et al 2005) Low CSFlevels of serotonin metabolites have been associated
with suicide attempts and completion (Samuelssonet al 2006 Traskman et al 1981) impulsivityaggression (Mehlman et al 1994 Virkkunen et al
1994) lifetime aggressiveness and suicidal lethality (Placidi et al 2001) Impulsive aggression withsuicidality has been linked to blunted prolactinresponses to the serotonergic probe fen1047298uramine(Coccaro et al 1989) PET scans of personality-
disordered subjects high in impulsive aggressionhave demonstrated reduced response to fen1047298ur-amine in orbitofrontal ventromedial and cingulateregions (Siever et al 1999)
Nevertheless early research on TCAs for BPDproved disappointing (Montgomery et al 1983Soloff et al 1989) Amitryptiline has been associ-ated with paradoxical increases in suicidality para-noia and behavioural dysregulation attributed tolsquogeneralized disinhibition of cognitive and affec-tive controlsrsquo (Soloff et al 1986a 1987) Indeedborderline patients have dif 1047297culty cognitively
236 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
resolving con1047298ict among stimulus dimensions(Posner et al 2002) and prefrontal hypofunctioncan be seen after a serotonergic stimulus in subjects
with prominent impulsive aggression (New et al
2002) Thus medications with adverse cognitivesequelae including anticholinergic side-effects may contribute to worsening impulsivity As mentioned in prior reviews the use of TCAs in treating BPD isdiscouraged (Abraham amp Calabrese 2008 Mercer et al 2009) Their use is also associated with po-tentially signi1047297cant risk of overdose
MONOAMINE OXIDASE INHIBITORS (MAOIS)
Despite hesitancyinprescribingMAOIstopatients with prominent impulsivity or self-injurious behav-iour some recommend these medications for BPDpatientswhocantakethemsafelyandreliablyInterestin MAOIs for BPD is rooted in their differential ef-1047297cacy for conditions such as hysteroid dysphoria or atypical depression viewed as being related to oneother and BPD (Kayser et al 1985 Liebowitz ampKlein 1981) In a crossover trial with multiplemedication phases only tranylcypromine was as-sociated with higher patient-rated improvementscores and completion rates (Cowdry amp Gardner1988)
Similarly relative prominence of BPD symptomspredicted superiority of phenelzine (Parsons et al
1989) Phenelzine is bene1047297cial in the treatment of hostility anxiety and borderline symptoms (Soloff et al 1993) In some patients it could cause un-
comfortable excitement and emotional reactivity (Cornelius et al 1993) Thus although there isevidence for their ef 1047297cacy many patients may nottolerate these medications Other associated risksof MAOIs include toxicity in overdose and po-tentially fatal hypertensive crises or serotoninsyndrome
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIS)
SSRIs are thought to potentiate serotonergicneuromodulation but demonstrate more favour-able side-effect pro1047297les Fluoxetine reduced anger in BPD independent of any antidepressant ef-fect (Salzman et al 1995) It also improved verbaland impulsive aggression irritability and overallfunctioning (Coccaro amp Kavoussi 1997) Simi-larly a RCT with paroxetine demonstrated ef 1047297cacy in preventing recurrent suicidal behaviour but nosigni1047297cant effect on depression hopelessness or anger (Verkes et al 1998) By contrast there waslittle added bene1047297t from 1047298uoxetine when added to
dialectical behavioural therapy (DBT) (Simpsonet al 2004)
On the other hand 1047298uvoxamine decreased af-fective lability but not scores of impulsivity or ag-gression (Rinne et al 2002) Although SSRIsdecrease impulsivity and aggression in BPD patients
with comorbid intermittent explosive disorder (IED Coccaro amp Kavoussi 1997 New et al 2004)data from BPD subjects without comorbid IED areinconsistent (Rinne et al 2002) Previous reviewshave emphasized that effect sizes for antidepressantpharmacotherapy vary widely between classes and trials (Ingenhoven et al 2010 Lieb et al 2010Mercer et al 2009) Nevertheless current evidence-based practice recommends use of SSRIs due topotential bene1047297ts on impulsive aggression that may outweigh associated risks There has been no evi-dence that antidepressants alleviate the chronicemptiness shameful self-concept and intrapsychicpain in BPD
FIRST-GENERATION ANTIPSYCHOTICS
An early interest in antipsychotic medications for treating BPD probably arose from a conception of BPD as a variant of schizophrenia (eg Deutsch1942) Antipsychotics have demonstrated partialef 1047297cacy re1047298ecting underlying abnormalities in do-paminergic signalling Borderline subjects demon-strate high levels of the dopamine metabolitehomovallinic acid in both plasma and cerebrospinal1047298uid (Siever et al unpublished data) Prior to more
widespread use of SSRIs antipsychotics demon-strated ef 1047297cacy in decreasing psychotic-like symptoms(Goldberg et al 1986 Soloff et al 1986b ) depression(Soloff et al 1986b ) irritability (Cornelius et al
1993) and general symptom severity (Cowdry ampGardner 1988 Soloff et al 1986b )
A recent Cochrane review suggests haloperidol isef 1047297cacious in reducing anger in BPD and treatment
with 1047298upenthixol decanoate reduced suicidal be-haviour (Lieb et al 2010) By contrast evidence for ef 1047297cacy of neuroleptics on affective symptomspsychosis and anxiety remains inconsistent The
dosage of antipsychotic medication for evidence-based treatment of BPD is usually lower thanschizophrenia High drop-out rates are noted and risk of extrapyramidal symptoms may further limitthe utility of neuroleptics
SECOND-GENERATION ANTIPSYCHOTICS
Classical neuroleptics have largely been superseded by atypical antipsychotics whose broader therapeuticbene1047297ts may be explained by activity beyond the D2
receptor As mentioned in prior reviews olanzapine
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 237
has proven bene1047297cial in treatment of BPD patientsrsquoanxiety anger interpersonal sensitivity and para-noia but not depression (Zanarini amp Frankenburg2001) as well as improving general clinical func-tioning and BPD symptomatology (Bogenschutz ampNurnberg 2004) A recent large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulzet al 2008) although the authors suggested thatpatients may have been underdosed A study comparing olanzapine to haloperidol showed nobetween-group differences except with respect toside-effects with more weight gain associated witholanzapine and more extra-pyramidal side-effects
with haloperidol (Shafti amp Shahveisi 2010) Adding 1047298uoxetine to olanzapine did not elicit
further bene1047297t except that subjects receiving bothmedications gained less weight than those receiving only olanzapine (Zanarini et al 2004b ) The addi-tion of olanzapine to DBT reduced depressionanxiety and impulsive aggression but the magni-
tude and timing of these bene1047297ts relative to DBT was dif 1047297cult to interpret (Soler et al 2005)
Aripiprazolehas a novelmechanismof action(partialagonist at the dopamine D2 receptor and serotonin 5-HT1A receptor antagonist at the 5-HT2A receptor) Itmay be more favourable than other atypicals withrespect to metabolic side-effects A longer half-lifemay be more effective for patients susceptible to non-adherence In non-suicidal BPD patients aripipra-zole was effective in reducing aggression anxietydepression psychosis interpersonal symptoms self-injurious behaviour and subjective distress There
were no signi1047297cant differences between groups in weight gain (Nickel et al 2006) An 18-month open-label follow-up showed sustained improvements and continued tolerability (Nickel et al 2007)
Previously open-label trials suggested possibleef 1047297cacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al 2004 2006) Theside-effect and psychopharmacological pro1047297les of ziprasidone indicated lesser metabolic risks and an-tidepressant and anxiolytic effects thought to beindependent of antidopaminergic activity (Keck et al 1998 Tandon 2000 Wilner et al 2002)
Despite such promise a recent RCT with ziprasi-done was negative (Pascual et al 2008) Thusevidence-based practice supports use of aripiprazolebut not ziprasidone in treating BPD
In meta-analyses the class of antipsychotics had moderate effect in treating aggression but no sig-ni1047297cant effect on depression although aripiprazoleand olanzapine may be exceptions (Lieb et al 2010Mercer et al 2009) For aypicals metabolic side-effects may limit clinical utility Because 29-53of borderline patients ful1047297l criteria for an eating disorder at some point in their lives (Lieb et al
2004) and a signi1047297cant number suffer from obesity (Frankenburg amp Zanarini 2006) iatrogenic meta-bolic risks must be regarded as serious Althoughevidence-based practices have advanced in treating aggression associated with BPD chronic emptinessaffective lability and interpersonal dysfunction lack effective evidence-based medication treatments
MOOD STABILIZERS AND ANTICONVULSANTS
Due to BPD patientsrsquo affective dysregulation and comorbidity with bipolar disorder some have clas-si1047297ed BPD within the bipolar spectrum (Akiskal2004 Smith et al 2004) although most continue todistinguish between the two particularly withregard to interpersonal dysfunction (Bolton ampGunderson 1996 Henry et al 2001 Paris 2004)Mood stabilizers are indeed becoming a more in-tegral component of evidence-based treatmentpractices for BPD
Lithium is bene1047297cial in treating BPD particularly in terms of quieting affective instability (Links et al
1990 Rifkin et al 1972) Lithium toxicity andor non-compliance may be problematic due to BPDpatientsrsquo characteristic impulsive self-destructivebehaviour
However anticonvulsants are more often rec-ommended for treatment of rapid-cycling bipolar disorder the variant most closely resembling BPDCarbamazepine demonstrated lsquodramaticrsquo reductionsin behavioural dyscontrol and improvements inglobal functioning anxiety anger euphoria im-
pulsivity and suicidality but it was associated with worsening melancholic depression (Gardner ampCowdry 1986a b ) and therapeutic bene1047297ts could not be replicated in in-patients (de la Fuente ampLotstra 1994)
Although high drop-out rates were reported withdivalproex (Hollander et al 2001) it subsequently demonstrated bene1047297ts on interpersonal sensitivityanger and aggression in euthymic borderline wo-men with bipolar II (Frankenburg amp Zanarini2002) Divalproex reduced aggression irritabilityand overall disease severity in patients with Cluster
B personality disorders and prominent impulsiveaggression (Hollander et al 2003) Differentialtreatment response in Cluster B subjects was en-hanced by baseline trait impulsivity and state ag-gression although not affective instability (Hollander et al 2005)
Lamotrigine extends periods of euthymia in bi-polar patients (eg Goodwin et al 2004) Potentialbene1047297ts also include pro-cognitive activity as pre-viously demonstrated in normal volunteers(Aldenkamp et al 2002) Lamotrigine effectively reduced BPD patientsrsquo anger (Tritt et al 2005) and
238 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
242 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 243
antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
patients SPD patients often demonstrate cognitivede1047297cits in working memory particularly sustained attention and executive functioning (Bergida ampLenzenweger 2006 McClure et al 2007a Parc ampMcTigue 1997) as well as signi1047297cant abnormalitiesin empathic understanding (Langdon amp Coltheart2004 Pickup 2006 Ripoll et al unpublished data)Unlike schizophrenic patients there is greater preservation of frontal volume in SPD (Siever ampDavis 2004)
Overall clinical trials for SPD have been com-plicated by comorbidity particularly with other personality disorders Most early RCTs on BPDalso included SPD patients (Goldberg et al 1986Serban amp Siegel 1984 Soloff et al 1986c ) be-cause both SPD and BPD were considered rooted in lsquoborderlinersquo schizophrenia but psychoticsymptoms in SPD and BPD are clinically distin-guishable
The conceptualization of SPD within theschizophrenia spectrum supports treatment withantipsychotic medications Antipsychotics appear
tobeusefulinthetreatmentofSPDparticularlyinterms of psychotic-like symptoms (Goldberg et al
1986 Koenigsberg e t a l 2003) Open-labelstudies have suggested a role for antidepressantsin treating self-injury psychotic-like and de-pressive symptomatology (Jensen amp Andersen1989 Markovitz et al 1991) but the evidence is
weaker Recent RCTs targeting cognitive de1047297citsin SPD compared performance on neuro-psychological tasks before and after treatment
with medication or placebo Both pergolidea dopaminergic agonist active at both the D1 and
D2 receptor (McClure et al 2010) and the nor-adrenergic a2A agonist guanfacine (McClure et al
2007b ) improved SPD patientsrsquo cognitive per-formance on distinct neuropsychological mea-sures Whether this improvement extends tooverall clinical functioning in SPD remains sub-
ject to future investigationIn sumSPDpatients respondto low-dose atypical
antipsychotics targeting psychotic-like symptomsand general functioning First-generation antipsy-
chotic medication and antidepressants may alsoplay a role although the evidence is not as reliableEvidence-based practice requires weighing risk of extrapyramidal side-effects or tardive dyskinesia against potential bene1047297ts Cognitive enhancementvia noradrenergic a2A or dopaminergic agonismmay be future avenues of research given that by analogy with schizophrenia the cognitive impair-ment in SPD may be responsible for the overalldysfunction observed in the disorder Researchefforts to understand neurobiological substratesof social cognitive dysfunction have heretofore
mainly focused on BPD and schizophrenia Be-cause SPD involves social isolation relationalparanoia and empathic de1047297cits research on phar-macotherapeutic effects on social cognition may also be fruitful
A NTISOCIAL PERSONALITY DISORDER
(A SPD)
Peer-reviewed trials of AsPD include studieson groups of individuals likely to have been antiso-cial based on histories of repeated violence and
criminality and an absence of other stated causes for these behaviours Lithium has been associated withdecreases in serious rule infractions in incarcerated males (Sheard 1971 Sheard et al 1976) Prisonerstreated with phenytoin committed fewer aggressiveacts and evidenced decreased tension-anxiety and depression-dejection (although not anger-hostility)and improvements in aggression appeared to belimited to impulsive (not pre-meditated) aggres-sion (Barratt et al 1991 1997) At presentevidenced-based pharmacotherapy for AsPD isrestricted to treatment of impulsive aggressionFuture neurobiological research in AsPD and psychopathy will probably increase our un-derstanding of the dysfunctional emotional em-pathy often seen in this disorder (Blair 2005) and
whether this may be susceptible to psychophar-macological intervention
BPD
Most RCTs on personality disorders focused onBPD which consists of several domains of dys-function affective instability impulsivity and an-ger transient psychotic or dissociative symptomsand intense unstable relationships (Lieb et al
2004 Zanarini et al 1990) BPD patients oftendemonstrate high comorbidity (Zanarini et al
2004a c ) and make numerous suicide attempts and parasuicidal gestures conferring signi1047297cantly higher risk for completed suicide (Welch amp Linehan2000)
Early studies employed a distinct nosology incharacterizing subjects some of whom actually had
what might be called BPD today (Rifkin et al 1972)In studies on suicidal or parasuicidal subjects themajority often have BPD (Battaglia et al 1999Montgomery amp Montgomery 1982 Montgomery et al 1983 Verkes et al 1998) Early studies oftenincluded combinations of BPD and SPD subjects(Goldberg et al 1986 Serban amp Siegel 1984 Soloff et al 1986c ) and studies recruiting a range of allpersonality disorders ultimately include BPD as themost frequent diagnosis (Coccaro amp Kavoussi
1997 Hollander et al 2003)Cliniciansshouldexercisecautioninattemptingtoapplyresearch1047297ndingstoseverelyillBPDpatientsasmany RCTs recruited only outpatients who further
were excluded if they expressed acute suicidality (Frankenburg amp Zanarini 2002 Tritt et al 2005Zanarini amp Frankenburg 2003 Zanarini et al
2004b ) or had made a recent suicide attempt(Bogenschutz amp Nurnberg 2004) In additionsmall sample sizes predominated and most studieslasted 3 months The few trials lasting $6 monthssuffered from high drop-out rates (Frankenburg amp
Zanarini 2002 Zanarini amp Frankenburg 2001) or concomitant recruitment of subjects without BPD(Battaglia et al 1999 Montgomery et al 1983Verkes et al 1998) Moreover RCTs with BPDsubjects appear to be prone to highplacebo responserates (Lieb et al 2004 Salzman et al 1995)meaning that open-label trial data should be inter-preted with caution
APA practice guidelines (APA 2001) recom-mended a symptom-targeted approach in pharma-cotherapy of BPD This leaves open the possibility for patients to improve in some but not all symptomdimensions Some clinicians have based their de-cision to implement polypharmacy on this butthere is actually little evidence as to the effectivenessof this strategy The only study on combined pharmacotherapy in BPD (Zanarini et al 2004b )found no superior ef 1047297cacy for combination treat-ment compared to one medication alone Using asfew medications as possible to target central areas of
clinical dysfunction together with evidence-based psychotherapy is usually the optimal treatmentstrategy In light of this although the 2001 guide-lines suggest a prominent role for serotonergicpharmacotherapy recent reviews have questioned this and instead emphasized anticonvulsants and antipsychotics (Abraham amp Calabrese 2008 Mercer et al 2009)
TRICYCLIC ANTIDEPRESSANTS (TCA S)
Disturbances of serotonin have been associated
with BPD impulsive aggression self-harm and suicidality (Coccaro et al 1995 Evenden 1999Malone et al 1996 Pitchot et al 2005) Low CSFlevels of serotonin metabolites have been associated
with suicide attempts and completion (Samuelssonet al 2006 Traskman et al 1981) impulsivityaggression (Mehlman et al 1994 Virkkunen et al
1994) lifetime aggressiveness and suicidal lethality (Placidi et al 2001) Impulsive aggression withsuicidality has been linked to blunted prolactinresponses to the serotonergic probe fen1047298uramine(Coccaro et al 1989) PET scans of personality-
disordered subjects high in impulsive aggressionhave demonstrated reduced response to fen1047298ur-amine in orbitofrontal ventromedial and cingulateregions (Siever et al 1999)
Nevertheless early research on TCAs for BPDproved disappointing (Montgomery et al 1983Soloff et al 1989) Amitryptiline has been associ-ated with paradoxical increases in suicidality para-noia and behavioural dysregulation attributed tolsquogeneralized disinhibition of cognitive and affec-tive controlsrsquo (Soloff et al 1986a 1987) Indeedborderline patients have dif 1047297culty cognitively
236 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
resolving con1047298ict among stimulus dimensions(Posner et al 2002) and prefrontal hypofunctioncan be seen after a serotonergic stimulus in subjects
with prominent impulsive aggression (New et al
2002) Thus medications with adverse cognitivesequelae including anticholinergic side-effects may contribute to worsening impulsivity As mentioned in prior reviews the use of TCAs in treating BPD isdiscouraged (Abraham amp Calabrese 2008 Mercer et al 2009) Their use is also associated with po-tentially signi1047297cant risk of overdose
MONOAMINE OXIDASE INHIBITORS (MAOIS)
Despite hesitancyinprescribingMAOIstopatients with prominent impulsivity or self-injurious behav-iour some recommend these medications for BPDpatientswhocantakethemsafelyandreliablyInterestin MAOIs for BPD is rooted in their differential ef-1047297cacy for conditions such as hysteroid dysphoria or atypical depression viewed as being related to oneother and BPD (Kayser et al 1985 Liebowitz ampKlein 1981) In a crossover trial with multiplemedication phases only tranylcypromine was as-sociated with higher patient-rated improvementscores and completion rates (Cowdry amp Gardner1988)
Similarly relative prominence of BPD symptomspredicted superiority of phenelzine (Parsons et al
1989) Phenelzine is bene1047297cial in the treatment of hostility anxiety and borderline symptoms (Soloff et al 1993) In some patients it could cause un-
comfortable excitement and emotional reactivity (Cornelius et al 1993) Thus although there isevidence for their ef 1047297cacy many patients may nottolerate these medications Other associated risksof MAOIs include toxicity in overdose and po-tentially fatal hypertensive crises or serotoninsyndrome
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIS)
SSRIs are thought to potentiate serotonergicneuromodulation but demonstrate more favour-able side-effect pro1047297les Fluoxetine reduced anger in BPD independent of any antidepressant ef-fect (Salzman et al 1995) It also improved verbaland impulsive aggression irritability and overallfunctioning (Coccaro amp Kavoussi 1997) Simi-larly a RCT with paroxetine demonstrated ef 1047297cacy in preventing recurrent suicidal behaviour but nosigni1047297cant effect on depression hopelessness or anger (Verkes et al 1998) By contrast there waslittle added bene1047297t from 1047298uoxetine when added to
dialectical behavioural therapy (DBT) (Simpsonet al 2004)
On the other hand 1047298uvoxamine decreased af-fective lability but not scores of impulsivity or ag-gression (Rinne et al 2002) Although SSRIsdecrease impulsivity and aggression in BPD patients
with comorbid intermittent explosive disorder (IED Coccaro amp Kavoussi 1997 New et al 2004)data from BPD subjects without comorbid IED areinconsistent (Rinne et al 2002) Previous reviewshave emphasized that effect sizes for antidepressantpharmacotherapy vary widely between classes and trials (Ingenhoven et al 2010 Lieb et al 2010Mercer et al 2009) Nevertheless current evidence-based practice recommends use of SSRIs due topotential bene1047297ts on impulsive aggression that may outweigh associated risks There has been no evi-dence that antidepressants alleviate the chronicemptiness shameful self-concept and intrapsychicpain in BPD
FIRST-GENERATION ANTIPSYCHOTICS
An early interest in antipsychotic medications for treating BPD probably arose from a conception of BPD as a variant of schizophrenia (eg Deutsch1942) Antipsychotics have demonstrated partialef 1047297cacy re1047298ecting underlying abnormalities in do-paminergic signalling Borderline subjects demon-strate high levels of the dopamine metabolitehomovallinic acid in both plasma and cerebrospinal1047298uid (Siever et al unpublished data) Prior to more
widespread use of SSRIs antipsychotics demon-strated ef 1047297cacy in decreasing psychotic-like symptoms(Goldberg et al 1986 Soloff et al 1986b ) depression(Soloff et al 1986b ) irritability (Cornelius et al
1993) and general symptom severity (Cowdry ampGardner 1988 Soloff et al 1986b )
A recent Cochrane review suggests haloperidol isef 1047297cacious in reducing anger in BPD and treatment
with 1047298upenthixol decanoate reduced suicidal be-haviour (Lieb et al 2010) By contrast evidence for ef 1047297cacy of neuroleptics on affective symptomspsychosis and anxiety remains inconsistent The
dosage of antipsychotic medication for evidence-based treatment of BPD is usually lower thanschizophrenia High drop-out rates are noted and risk of extrapyramidal symptoms may further limitthe utility of neuroleptics
SECOND-GENERATION ANTIPSYCHOTICS
Classical neuroleptics have largely been superseded by atypical antipsychotics whose broader therapeuticbene1047297ts may be explained by activity beyond the D2
receptor As mentioned in prior reviews olanzapine
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 237
has proven bene1047297cial in treatment of BPD patientsrsquoanxiety anger interpersonal sensitivity and para-noia but not depression (Zanarini amp Frankenburg2001) as well as improving general clinical func-tioning and BPD symptomatology (Bogenschutz ampNurnberg 2004) A recent large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulzet al 2008) although the authors suggested thatpatients may have been underdosed A study comparing olanzapine to haloperidol showed nobetween-group differences except with respect toside-effects with more weight gain associated witholanzapine and more extra-pyramidal side-effects
with haloperidol (Shafti amp Shahveisi 2010) Adding 1047298uoxetine to olanzapine did not elicit
further bene1047297t except that subjects receiving bothmedications gained less weight than those receiving only olanzapine (Zanarini et al 2004b ) The addi-tion of olanzapine to DBT reduced depressionanxiety and impulsive aggression but the magni-
tude and timing of these bene1047297ts relative to DBT was dif 1047297cult to interpret (Soler et al 2005)
Aripiprazolehas a novelmechanismof action(partialagonist at the dopamine D2 receptor and serotonin 5-HT1A receptor antagonist at the 5-HT2A receptor) Itmay be more favourable than other atypicals withrespect to metabolic side-effects A longer half-lifemay be more effective for patients susceptible to non-adherence In non-suicidal BPD patients aripipra-zole was effective in reducing aggression anxietydepression psychosis interpersonal symptoms self-injurious behaviour and subjective distress There
were no signi1047297cant differences between groups in weight gain (Nickel et al 2006) An 18-month open-label follow-up showed sustained improvements and continued tolerability (Nickel et al 2007)
Previously open-label trials suggested possibleef 1047297cacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al 2004 2006) Theside-effect and psychopharmacological pro1047297les of ziprasidone indicated lesser metabolic risks and an-tidepressant and anxiolytic effects thought to beindependent of antidopaminergic activity (Keck et al 1998 Tandon 2000 Wilner et al 2002)
Despite such promise a recent RCT with ziprasi-done was negative (Pascual et al 2008) Thusevidence-based practice supports use of aripiprazolebut not ziprasidone in treating BPD
In meta-analyses the class of antipsychotics had moderate effect in treating aggression but no sig-ni1047297cant effect on depression although aripiprazoleand olanzapine may be exceptions (Lieb et al 2010Mercer et al 2009) For aypicals metabolic side-effects may limit clinical utility Because 29-53of borderline patients ful1047297l criteria for an eating disorder at some point in their lives (Lieb et al
2004) and a signi1047297cant number suffer from obesity (Frankenburg amp Zanarini 2006) iatrogenic meta-bolic risks must be regarded as serious Althoughevidence-based practices have advanced in treating aggression associated with BPD chronic emptinessaffective lability and interpersonal dysfunction lack effective evidence-based medication treatments
MOOD STABILIZERS AND ANTICONVULSANTS
Due to BPD patientsrsquo affective dysregulation and comorbidity with bipolar disorder some have clas-si1047297ed BPD within the bipolar spectrum (Akiskal2004 Smith et al 2004) although most continue todistinguish between the two particularly withregard to interpersonal dysfunction (Bolton ampGunderson 1996 Henry et al 2001 Paris 2004)Mood stabilizers are indeed becoming a more in-tegral component of evidence-based treatmentpractices for BPD
Lithium is bene1047297cial in treating BPD particularly in terms of quieting affective instability (Links et al
1990 Rifkin et al 1972) Lithium toxicity andor non-compliance may be problematic due to BPDpatientsrsquo characteristic impulsive self-destructivebehaviour
However anticonvulsants are more often rec-ommended for treatment of rapid-cycling bipolar disorder the variant most closely resembling BPDCarbamazepine demonstrated lsquodramaticrsquo reductionsin behavioural dyscontrol and improvements inglobal functioning anxiety anger euphoria im-
pulsivity and suicidality but it was associated with worsening melancholic depression (Gardner ampCowdry 1986a b ) and therapeutic bene1047297ts could not be replicated in in-patients (de la Fuente ampLotstra 1994)
Although high drop-out rates were reported withdivalproex (Hollander et al 2001) it subsequently demonstrated bene1047297ts on interpersonal sensitivityanger and aggression in euthymic borderline wo-men with bipolar II (Frankenburg amp Zanarini2002) Divalproex reduced aggression irritabilityand overall disease severity in patients with Cluster
B personality disorders and prominent impulsiveaggression (Hollander et al 2003) Differentialtreatment response in Cluster B subjects was en-hanced by baseline trait impulsivity and state ag-gression although not affective instability (Hollander et al 2005)
Lamotrigine extends periods of euthymia in bi-polar patients (eg Goodwin et al 2004) Potentialbene1047297ts also include pro-cognitive activity as pre-viously demonstrated in normal volunteers(Aldenkamp et al 2002) Lamotrigine effectively reduced BPD patientsrsquo anger (Tritt et al 2005) and
238 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
242 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 243
antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
patients SPD patients often demonstrate cognitivede1047297cits in working memory particularly sustained attention and executive functioning (Bergida ampLenzenweger 2006 McClure et al 2007a Parc ampMcTigue 1997) as well as signi1047297cant abnormalitiesin empathic understanding (Langdon amp Coltheart2004 Pickup 2006 Ripoll et al unpublished data)Unlike schizophrenic patients there is greater preservation of frontal volume in SPD (Siever ampDavis 2004)
Overall clinical trials for SPD have been com-plicated by comorbidity particularly with other personality disorders Most early RCTs on BPDalso included SPD patients (Goldberg et al 1986Serban amp Siegel 1984 Soloff et al 1986c ) be-cause both SPD and BPD were considered rooted in lsquoborderlinersquo schizophrenia but psychoticsymptoms in SPD and BPD are clinically distin-guishable
The conceptualization of SPD within theschizophrenia spectrum supports treatment withantipsychotic medications Antipsychotics appear
tobeusefulinthetreatmentofSPDparticularlyinterms of psychotic-like symptoms (Goldberg et al
1986 Koenigsberg e t a l 2003) Open-labelstudies have suggested a role for antidepressantsin treating self-injury psychotic-like and de-pressive symptomatology (Jensen amp Andersen1989 Markovitz et al 1991) but the evidence is
weaker Recent RCTs targeting cognitive de1047297citsin SPD compared performance on neuro-psychological tasks before and after treatment
with medication or placebo Both pergolidea dopaminergic agonist active at both the D1 and
D2 receptor (McClure et al 2010) and the nor-adrenergic a2A agonist guanfacine (McClure et al
2007b ) improved SPD patientsrsquo cognitive per-formance on distinct neuropsychological mea-sures Whether this improvement extends tooverall clinical functioning in SPD remains sub-
ject to future investigationIn sumSPDpatients respondto low-dose atypical
antipsychotics targeting psychotic-like symptomsand general functioning First-generation antipsy-
chotic medication and antidepressants may alsoplay a role although the evidence is not as reliableEvidence-based practice requires weighing risk of extrapyramidal side-effects or tardive dyskinesia against potential bene1047297ts Cognitive enhancementvia noradrenergic a2A or dopaminergic agonismmay be future avenues of research given that by analogy with schizophrenia the cognitive impair-ment in SPD may be responsible for the overalldysfunction observed in the disorder Researchefforts to understand neurobiological substratesof social cognitive dysfunction have heretofore
mainly focused on BPD and schizophrenia Be-cause SPD involves social isolation relationalparanoia and empathic de1047297cits research on phar-macotherapeutic effects on social cognition may also be fruitful
A NTISOCIAL PERSONALITY DISORDER
(A SPD)
Peer-reviewed trials of AsPD include studieson groups of individuals likely to have been antiso-cial based on histories of repeated violence and
criminality and an absence of other stated causes for these behaviours Lithium has been associated withdecreases in serious rule infractions in incarcerated males (Sheard 1971 Sheard et al 1976) Prisonerstreated with phenytoin committed fewer aggressiveacts and evidenced decreased tension-anxiety and depression-dejection (although not anger-hostility)and improvements in aggression appeared to belimited to impulsive (not pre-meditated) aggres-sion (Barratt et al 1991 1997) At presentevidenced-based pharmacotherapy for AsPD isrestricted to treatment of impulsive aggressionFuture neurobiological research in AsPD and psychopathy will probably increase our un-derstanding of the dysfunctional emotional em-pathy often seen in this disorder (Blair 2005) and
whether this may be susceptible to psychophar-macological intervention
BPD
Most RCTs on personality disorders focused onBPD which consists of several domains of dys-function affective instability impulsivity and an-ger transient psychotic or dissociative symptomsand intense unstable relationships (Lieb et al
2004 Zanarini et al 1990) BPD patients oftendemonstrate high comorbidity (Zanarini et al
2004a c ) and make numerous suicide attempts and parasuicidal gestures conferring signi1047297cantly higher risk for completed suicide (Welch amp Linehan2000)
Early studies employed a distinct nosology incharacterizing subjects some of whom actually had
what might be called BPD today (Rifkin et al 1972)In studies on suicidal or parasuicidal subjects themajority often have BPD (Battaglia et al 1999Montgomery amp Montgomery 1982 Montgomery et al 1983 Verkes et al 1998) Early studies oftenincluded combinations of BPD and SPD subjects(Goldberg et al 1986 Serban amp Siegel 1984 Soloff et al 1986c ) and studies recruiting a range of allpersonality disorders ultimately include BPD as themost frequent diagnosis (Coccaro amp Kavoussi
1997 Hollander et al 2003)Cliniciansshouldexercisecautioninattemptingtoapplyresearch1047297ndingstoseverelyillBPDpatientsasmany RCTs recruited only outpatients who further
were excluded if they expressed acute suicidality (Frankenburg amp Zanarini 2002 Tritt et al 2005Zanarini amp Frankenburg 2003 Zanarini et al
2004b ) or had made a recent suicide attempt(Bogenschutz amp Nurnberg 2004) In additionsmall sample sizes predominated and most studieslasted 3 months The few trials lasting $6 monthssuffered from high drop-out rates (Frankenburg amp
Zanarini 2002 Zanarini amp Frankenburg 2001) or concomitant recruitment of subjects without BPD(Battaglia et al 1999 Montgomery et al 1983Verkes et al 1998) Moreover RCTs with BPDsubjects appear to be prone to highplacebo responserates (Lieb et al 2004 Salzman et al 1995)meaning that open-label trial data should be inter-preted with caution
APA practice guidelines (APA 2001) recom-mended a symptom-targeted approach in pharma-cotherapy of BPD This leaves open the possibility for patients to improve in some but not all symptomdimensions Some clinicians have based their de-cision to implement polypharmacy on this butthere is actually little evidence as to the effectivenessof this strategy The only study on combined pharmacotherapy in BPD (Zanarini et al 2004b )found no superior ef 1047297cacy for combination treat-ment compared to one medication alone Using asfew medications as possible to target central areas of
clinical dysfunction together with evidence-based psychotherapy is usually the optimal treatmentstrategy In light of this although the 2001 guide-lines suggest a prominent role for serotonergicpharmacotherapy recent reviews have questioned this and instead emphasized anticonvulsants and antipsychotics (Abraham amp Calabrese 2008 Mercer et al 2009)
TRICYCLIC ANTIDEPRESSANTS (TCA S)
Disturbances of serotonin have been associated
with BPD impulsive aggression self-harm and suicidality (Coccaro et al 1995 Evenden 1999Malone et al 1996 Pitchot et al 2005) Low CSFlevels of serotonin metabolites have been associated
with suicide attempts and completion (Samuelssonet al 2006 Traskman et al 1981) impulsivityaggression (Mehlman et al 1994 Virkkunen et al
1994) lifetime aggressiveness and suicidal lethality (Placidi et al 2001) Impulsive aggression withsuicidality has been linked to blunted prolactinresponses to the serotonergic probe fen1047298uramine(Coccaro et al 1989) PET scans of personality-
disordered subjects high in impulsive aggressionhave demonstrated reduced response to fen1047298ur-amine in orbitofrontal ventromedial and cingulateregions (Siever et al 1999)
Nevertheless early research on TCAs for BPDproved disappointing (Montgomery et al 1983Soloff et al 1989) Amitryptiline has been associ-ated with paradoxical increases in suicidality para-noia and behavioural dysregulation attributed tolsquogeneralized disinhibition of cognitive and affec-tive controlsrsquo (Soloff et al 1986a 1987) Indeedborderline patients have dif 1047297culty cognitively
236 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
resolving con1047298ict among stimulus dimensions(Posner et al 2002) and prefrontal hypofunctioncan be seen after a serotonergic stimulus in subjects
with prominent impulsive aggression (New et al
2002) Thus medications with adverse cognitivesequelae including anticholinergic side-effects may contribute to worsening impulsivity As mentioned in prior reviews the use of TCAs in treating BPD isdiscouraged (Abraham amp Calabrese 2008 Mercer et al 2009) Their use is also associated with po-tentially signi1047297cant risk of overdose
MONOAMINE OXIDASE INHIBITORS (MAOIS)
Despite hesitancyinprescribingMAOIstopatients with prominent impulsivity or self-injurious behav-iour some recommend these medications for BPDpatientswhocantakethemsafelyandreliablyInterestin MAOIs for BPD is rooted in their differential ef-1047297cacy for conditions such as hysteroid dysphoria or atypical depression viewed as being related to oneother and BPD (Kayser et al 1985 Liebowitz ampKlein 1981) In a crossover trial with multiplemedication phases only tranylcypromine was as-sociated with higher patient-rated improvementscores and completion rates (Cowdry amp Gardner1988)
Similarly relative prominence of BPD symptomspredicted superiority of phenelzine (Parsons et al
1989) Phenelzine is bene1047297cial in the treatment of hostility anxiety and borderline symptoms (Soloff et al 1993) In some patients it could cause un-
comfortable excitement and emotional reactivity (Cornelius et al 1993) Thus although there isevidence for their ef 1047297cacy many patients may nottolerate these medications Other associated risksof MAOIs include toxicity in overdose and po-tentially fatal hypertensive crises or serotoninsyndrome
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIS)
SSRIs are thought to potentiate serotonergicneuromodulation but demonstrate more favour-able side-effect pro1047297les Fluoxetine reduced anger in BPD independent of any antidepressant ef-fect (Salzman et al 1995) It also improved verbaland impulsive aggression irritability and overallfunctioning (Coccaro amp Kavoussi 1997) Simi-larly a RCT with paroxetine demonstrated ef 1047297cacy in preventing recurrent suicidal behaviour but nosigni1047297cant effect on depression hopelessness or anger (Verkes et al 1998) By contrast there waslittle added bene1047297t from 1047298uoxetine when added to
dialectical behavioural therapy (DBT) (Simpsonet al 2004)
On the other hand 1047298uvoxamine decreased af-fective lability but not scores of impulsivity or ag-gression (Rinne et al 2002) Although SSRIsdecrease impulsivity and aggression in BPD patients
with comorbid intermittent explosive disorder (IED Coccaro amp Kavoussi 1997 New et al 2004)data from BPD subjects without comorbid IED areinconsistent (Rinne et al 2002) Previous reviewshave emphasized that effect sizes for antidepressantpharmacotherapy vary widely between classes and trials (Ingenhoven et al 2010 Lieb et al 2010Mercer et al 2009) Nevertheless current evidence-based practice recommends use of SSRIs due topotential bene1047297ts on impulsive aggression that may outweigh associated risks There has been no evi-dence that antidepressants alleviate the chronicemptiness shameful self-concept and intrapsychicpain in BPD
FIRST-GENERATION ANTIPSYCHOTICS
An early interest in antipsychotic medications for treating BPD probably arose from a conception of BPD as a variant of schizophrenia (eg Deutsch1942) Antipsychotics have demonstrated partialef 1047297cacy re1047298ecting underlying abnormalities in do-paminergic signalling Borderline subjects demon-strate high levels of the dopamine metabolitehomovallinic acid in both plasma and cerebrospinal1047298uid (Siever et al unpublished data) Prior to more
widespread use of SSRIs antipsychotics demon-strated ef 1047297cacy in decreasing psychotic-like symptoms(Goldberg et al 1986 Soloff et al 1986b ) depression(Soloff et al 1986b ) irritability (Cornelius et al
1993) and general symptom severity (Cowdry ampGardner 1988 Soloff et al 1986b )
A recent Cochrane review suggests haloperidol isef 1047297cacious in reducing anger in BPD and treatment
with 1047298upenthixol decanoate reduced suicidal be-haviour (Lieb et al 2010) By contrast evidence for ef 1047297cacy of neuroleptics on affective symptomspsychosis and anxiety remains inconsistent The
dosage of antipsychotic medication for evidence-based treatment of BPD is usually lower thanschizophrenia High drop-out rates are noted and risk of extrapyramidal symptoms may further limitthe utility of neuroleptics
SECOND-GENERATION ANTIPSYCHOTICS
Classical neuroleptics have largely been superseded by atypical antipsychotics whose broader therapeuticbene1047297ts may be explained by activity beyond the D2
receptor As mentioned in prior reviews olanzapine
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 237
has proven bene1047297cial in treatment of BPD patientsrsquoanxiety anger interpersonal sensitivity and para-noia but not depression (Zanarini amp Frankenburg2001) as well as improving general clinical func-tioning and BPD symptomatology (Bogenschutz ampNurnberg 2004) A recent large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulzet al 2008) although the authors suggested thatpatients may have been underdosed A study comparing olanzapine to haloperidol showed nobetween-group differences except with respect toside-effects with more weight gain associated witholanzapine and more extra-pyramidal side-effects
with haloperidol (Shafti amp Shahveisi 2010) Adding 1047298uoxetine to olanzapine did not elicit
further bene1047297t except that subjects receiving bothmedications gained less weight than those receiving only olanzapine (Zanarini et al 2004b ) The addi-tion of olanzapine to DBT reduced depressionanxiety and impulsive aggression but the magni-
tude and timing of these bene1047297ts relative to DBT was dif 1047297cult to interpret (Soler et al 2005)
Aripiprazolehas a novelmechanismof action(partialagonist at the dopamine D2 receptor and serotonin 5-HT1A receptor antagonist at the 5-HT2A receptor) Itmay be more favourable than other atypicals withrespect to metabolic side-effects A longer half-lifemay be more effective for patients susceptible to non-adherence In non-suicidal BPD patients aripipra-zole was effective in reducing aggression anxietydepression psychosis interpersonal symptoms self-injurious behaviour and subjective distress There
were no signi1047297cant differences between groups in weight gain (Nickel et al 2006) An 18-month open-label follow-up showed sustained improvements and continued tolerability (Nickel et al 2007)
Previously open-label trials suggested possibleef 1047297cacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al 2004 2006) Theside-effect and psychopharmacological pro1047297les of ziprasidone indicated lesser metabolic risks and an-tidepressant and anxiolytic effects thought to beindependent of antidopaminergic activity (Keck et al 1998 Tandon 2000 Wilner et al 2002)
Despite such promise a recent RCT with ziprasi-done was negative (Pascual et al 2008) Thusevidence-based practice supports use of aripiprazolebut not ziprasidone in treating BPD
In meta-analyses the class of antipsychotics had moderate effect in treating aggression but no sig-ni1047297cant effect on depression although aripiprazoleand olanzapine may be exceptions (Lieb et al 2010Mercer et al 2009) For aypicals metabolic side-effects may limit clinical utility Because 29-53of borderline patients ful1047297l criteria for an eating disorder at some point in their lives (Lieb et al
2004) and a signi1047297cant number suffer from obesity (Frankenburg amp Zanarini 2006) iatrogenic meta-bolic risks must be regarded as serious Althoughevidence-based practices have advanced in treating aggression associated with BPD chronic emptinessaffective lability and interpersonal dysfunction lack effective evidence-based medication treatments
MOOD STABILIZERS AND ANTICONVULSANTS
Due to BPD patientsrsquo affective dysregulation and comorbidity with bipolar disorder some have clas-si1047297ed BPD within the bipolar spectrum (Akiskal2004 Smith et al 2004) although most continue todistinguish between the two particularly withregard to interpersonal dysfunction (Bolton ampGunderson 1996 Henry et al 2001 Paris 2004)Mood stabilizers are indeed becoming a more in-tegral component of evidence-based treatmentpractices for BPD
Lithium is bene1047297cial in treating BPD particularly in terms of quieting affective instability (Links et al
1990 Rifkin et al 1972) Lithium toxicity andor non-compliance may be problematic due to BPDpatientsrsquo characteristic impulsive self-destructivebehaviour
However anticonvulsants are more often rec-ommended for treatment of rapid-cycling bipolar disorder the variant most closely resembling BPDCarbamazepine demonstrated lsquodramaticrsquo reductionsin behavioural dyscontrol and improvements inglobal functioning anxiety anger euphoria im-
pulsivity and suicidality but it was associated with worsening melancholic depression (Gardner ampCowdry 1986a b ) and therapeutic bene1047297ts could not be replicated in in-patients (de la Fuente ampLotstra 1994)
Although high drop-out rates were reported withdivalproex (Hollander et al 2001) it subsequently demonstrated bene1047297ts on interpersonal sensitivityanger and aggression in euthymic borderline wo-men with bipolar II (Frankenburg amp Zanarini2002) Divalproex reduced aggression irritabilityand overall disease severity in patients with Cluster
B personality disorders and prominent impulsiveaggression (Hollander et al 2003) Differentialtreatment response in Cluster B subjects was en-hanced by baseline trait impulsivity and state ag-gression although not affective instability (Hollander et al 2005)
Lamotrigine extends periods of euthymia in bi-polar patients (eg Goodwin et al 2004) Potentialbene1047297ts also include pro-cognitive activity as pre-viously demonstrated in normal volunteers(Aldenkamp et al 2002) Lamotrigine effectively reduced BPD patientsrsquo anger (Tritt et al 2005) and
238 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
242 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 243
antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
patients SPD patients often demonstrate cognitivede1047297cits in working memory particularly sustained attention and executive functioning (Bergida ampLenzenweger 2006 McClure et al 2007a Parc ampMcTigue 1997) as well as signi1047297cant abnormalitiesin empathic understanding (Langdon amp Coltheart2004 Pickup 2006 Ripoll et al unpublished data)Unlike schizophrenic patients there is greater preservation of frontal volume in SPD (Siever ampDavis 2004)
Overall clinical trials for SPD have been com-plicated by comorbidity particularly with other personality disorders Most early RCTs on BPDalso included SPD patients (Goldberg et al 1986Serban amp Siegel 1984 Soloff et al 1986c ) be-cause both SPD and BPD were considered rooted in lsquoborderlinersquo schizophrenia but psychoticsymptoms in SPD and BPD are clinically distin-guishable
The conceptualization of SPD within theschizophrenia spectrum supports treatment withantipsychotic medications Antipsychotics appear
tobeusefulinthetreatmentofSPDparticularlyinterms of psychotic-like symptoms (Goldberg et al
1986 Koenigsberg e t a l 2003) Open-labelstudies have suggested a role for antidepressantsin treating self-injury psychotic-like and de-pressive symptomatology (Jensen amp Andersen1989 Markovitz et al 1991) but the evidence is
weaker Recent RCTs targeting cognitive de1047297citsin SPD compared performance on neuro-psychological tasks before and after treatment
with medication or placebo Both pergolidea dopaminergic agonist active at both the D1 and
D2 receptor (McClure et al 2010) and the nor-adrenergic a2A agonist guanfacine (McClure et al
2007b ) improved SPD patientsrsquo cognitive per-formance on distinct neuropsychological mea-sures Whether this improvement extends tooverall clinical functioning in SPD remains sub-
ject to future investigationIn sumSPDpatients respondto low-dose atypical
antipsychotics targeting psychotic-like symptomsand general functioning First-generation antipsy-
chotic medication and antidepressants may alsoplay a role although the evidence is not as reliableEvidence-based practice requires weighing risk of extrapyramidal side-effects or tardive dyskinesia against potential bene1047297ts Cognitive enhancementvia noradrenergic a2A or dopaminergic agonismmay be future avenues of research given that by analogy with schizophrenia the cognitive impair-ment in SPD may be responsible for the overalldysfunction observed in the disorder Researchefforts to understand neurobiological substratesof social cognitive dysfunction have heretofore
mainly focused on BPD and schizophrenia Be-cause SPD involves social isolation relationalparanoia and empathic de1047297cits research on phar-macotherapeutic effects on social cognition may also be fruitful
A NTISOCIAL PERSONALITY DISORDER
(A SPD)
Peer-reviewed trials of AsPD include studieson groups of individuals likely to have been antiso-cial based on histories of repeated violence and
criminality and an absence of other stated causes for these behaviours Lithium has been associated withdecreases in serious rule infractions in incarcerated males (Sheard 1971 Sheard et al 1976) Prisonerstreated with phenytoin committed fewer aggressiveacts and evidenced decreased tension-anxiety and depression-dejection (although not anger-hostility)and improvements in aggression appeared to belimited to impulsive (not pre-meditated) aggres-sion (Barratt et al 1991 1997) At presentevidenced-based pharmacotherapy for AsPD isrestricted to treatment of impulsive aggressionFuture neurobiological research in AsPD and psychopathy will probably increase our un-derstanding of the dysfunctional emotional em-pathy often seen in this disorder (Blair 2005) and
whether this may be susceptible to psychophar-macological intervention
BPD
Most RCTs on personality disorders focused onBPD which consists of several domains of dys-function affective instability impulsivity and an-ger transient psychotic or dissociative symptomsand intense unstable relationships (Lieb et al
2004 Zanarini et al 1990) BPD patients oftendemonstrate high comorbidity (Zanarini et al
2004a c ) and make numerous suicide attempts and parasuicidal gestures conferring signi1047297cantly higher risk for completed suicide (Welch amp Linehan2000)
Early studies employed a distinct nosology incharacterizing subjects some of whom actually had
what might be called BPD today (Rifkin et al 1972)In studies on suicidal or parasuicidal subjects themajority often have BPD (Battaglia et al 1999Montgomery amp Montgomery 1982 Montgomery et al 1983 Verkes et al 1998) Early studies oftenincluded combinations of BPD and SPD subjects(Goldberg et al 1986 Serban amp Siegel 1984 Soloff et al 1986c ) and studies recruiting a range of allpersonality disorders ultimately include BPD as themost frequent diagnosis (Coccaro amp Kavoussi
1997 Hollander et al 2003)Cliniciansshouldexercisecautioninattemptingtoapplyresearch1047297ndingstoseverelyillBPDpatientsasmany RCTs recruited only outpatients who further
were excluded if they expressed acute suicidality (Frankenburg amp Zanarini 2002 Tritt et al 2005Zanarini amp Frankenburg 2003 Zanarini et al
2004b ) or had made a recent suicide attempt(Bogenschutz amp Nurnberg 2004) In additionsmall sample sizes predominated and most studieslasted 3 months The few trials lasting $6 monthssuffered from high drop-out rates (Frankenburg amp
Zanarini 2002 Zanarini amp Frankenburg 2001) or concomitant recruitment of subjects without BPD(Battaglia et al 1999 Montgomery et al 1983Verkes et al 1998) Moreover RCTs with BPDsubjects appear to be prone to highplacebo responserates (Lieb et al 2004 Salzman et al 1995)meaning that open-label trial data should be inter-preted with caution
APA practice guidelines (APA 2001) recom-mended a symptom-targeted approach in pharma-cotherapy of BPD This leaves open the possibility for patients to improve in some but not all symptomdimensions Some clinicians have based their de-cision to implement polypharmacy on this butthere is actually little evidence as to the effectivenessof this strategy The only study on combined pharmacotherapy in BPD (Zanarini et al 2004b )found no superior ef 1047297cacy for combination treat-ment compared to one medication alone Using asfew medications as possible to target central areas of
clinical dysfunction together with evidence-based psychotherapy is usually the optimal treatmentstrategy In light of this although the 2001 guide-lines suggest a prominent role for serotonergicpharmacotherapy recent reviews have questioned this and instead emphasized anticonvulsants and antipsychotics (Abraham amp Calabrese 2008 Mercer et al 2009)
TRICYCLIC ANTIDEPRESSANTS (TCA S)
Disturbances of serotonin have been associated
with BPD impulsive aggression self-harm and suicidality (Coccaro et al 1995 Evenden 1999Malone et al 1996 Pitchot et al 2005) Low CSFlevels of serotonin metabolites have been associated
with suicide attempts and completion (Samuelssonet al 2006 Traskman et al 1981) impulsivityaggression (Mehlman et al 1994 Virkkunen et al
1994) lifetime aggressiveness and suicidal lethality (Placidi et al 2001) Impulsive aggression withsuicidality has been linked to blunted prolactinresponses to the serotonergic probe fen1047298uramine(Coccaro et al 1989) PET scans of personality-
disordered subjects high in impulsive aggressionhave demonstrated reduced response to fen1047298ur-amine in orbitofrontal ventromedial and cingulateregions (Siever et al 1999)
Nevertheless early research on TCAs for BPDproved disappointing (Montgomery et al 1983Soloff et al 1989) Amitryptiline has been associ-ated with paradoxical increases in suicidality para-noia and behavioural dysregulation attributed tolsquogeneralized disinhibition of cognitive and affec-tive controlsrsquo (Soloff et al 1986a 1987) Indeedborderline patients have dif 1047297culty cognitively
236 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
resolving con1047298ict among stimulus dimensions(Posner et al 2002) and prefrontal hypofunctioncan be seen after a serotonergic stimulus in subjects
with prominent impulsive aggression (New et al
2002) Thus medications with adverse cognitivesequelae including anticholinergic side-effects may contribute to worsening impulsivity As mentioned in prior reviews the use of TCAs in treating BPD isdiscouraged (Abraham amp Calabrese 2008 Mercer et al 2009) Their use is also associated with po-tentially signi1047297cant risk of overdose
MONOAMINE OXIDASE INHIBITORS (MAOIS)
Despite hesitancyinprescribingMAOIstopatients with prominent impulsivity or self-injurious behav-iour some recommend these medications for BPDpatientswhocantakethemsafelyandreliablyInterestin MAOIs for BPD is rooted in their differential ef-1047297cacy for conditions such as hysteroid dysphoria or atypical depression viewed as being related to oneother and BPD (Kayser et al 1985 Liebowitz ampKlein 1981) In a crossover trial with multiplemedication phases only tranylcypromine was as-sociated with higher patient-rated improvementscores and completion rates (Cowdry amp Gardner1988)
Similarly relative prominence of BPD symptomspredicted superiority of phenelzine (Parsons et al
1989) Phenelzine is bene1047297cial in the treatment of hostility anxiety and borderline symptoms (Soloff et al 1993) In some patients it could cause un-
comfortable excitement and emotional reactivity (Cornelius et al 1993) Thus although there isevidence for their ef 1047297cacy many patients may nottolerate these medications Other associated risksof MAOIs include toxicity in overdose and po-tentially fatal hypertensive crises or serotoninsyndrome
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIS)
SSRIs are thought to potentiate serotonergicneuromodulation but demonstrate more favour-able side-effect pro1047297les Fluoxetine reduced anger in BPD independent of any antidepressant ef-fect (Salzman et al 1995) It also improved verbaland impulsive aggression irritability and overallfunctioning (Coccaro amp Kavoussi 1997) Simi-larly a RCT with paroxetine demonstrated ef 1047297cacy in preventing recurrent suicidal behaviour but nosigni1047297cant effect on depression hopelessness or anger (Verkes et al 1998) By contrast there waslittle added bene1047297t from 1047298uoxetine when added to
dialectical behavioural therapy (DBT) (Simpsonet al 2004)
On the other hand 1047298uvoxamine decreased af-fective lability but not scores of impulsivity or ag-gression (Rinne et al 2002) Although SSRIsdecrease impulsivity and aggression in BPD patients
with comorbid intermittent explosive disorder (IED Coccaro amp Kavoussi 1997 New et al 2004)data from BPD subjects without comorbid IED areinconsistent (Rinne et al 2002) Previous reviewshave emphasized that effect sizes for antidepressantpharmacotherapy vary widely between classes and trials (Ingenhoven et al 2010 Lieb et al 2010Mercer et al 2009) Nevertheless current evidence-based practice recommends use of SSRIs due topotential bene1047297ts on impulsive aggression that may outweigh associated risks There has been no evi-dence that antidepressants alleviate the chronicemptiness shameful self-concept and intrapsychicpain in BPD
FIRST-GENERATION ANTIPSYCHOTICS
An early interest in antipsychotic medications for treating BPD probably arose from a conception of BPD as a variant of schizophrenia (eg Deutsch1942) Antipsychotics have demonstrated partialef 1047297cacy re1047298ecting underlying abnormalities in do-paminergic signalling Borderline subjects demon-strate high levels of the dopamine metabolitehomovallinic acid in both plasma and cerebrospinal1047298uid (Siever et al unpublished data) Prior to more
widespread use of SSRIs antipsychotics demon-strated ef 1047297cacy in decreasing psychotic-like symptoms(Goldberg et al 1986 Soloff et al 1986b ) depression(Soloff et al 1986b ) irritability (Cornelius et al
1993) and general symptom severity (Cowdry ampGardner 1988 Soloff et al 1986b )
A recent Cochrane review suggests haloperidol isef 1047297cacious in reducing anger in BPD and treatment
with 1047298upenthixol decanoate reduced suicidal be-haviour (Lieb et al 2010) By contrast evidence for ef 1047297cacy of neuroleptics on affective symptomspsychosis and anxiety remains inconsistent The
dosage of antipsychotic medication for evidence-based treatment of BPD is usually lower thanschizophrenia High drop-out rates are noted and risk of extrapyramidal symptoms may further limitthe utility of neuroleptics
SECOND-GENERATION ANTIPSYCHOTICS
Classical neuroleptics have largely been superseded by atypical antipsychotics whose broader therapeuticbene1047297ts may be explained by activity beyond the D2
receptor As mentioned in prior reviews olanzapine
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 237
has proven bene1047297cial in treatment of BPD patientsrsquoanxiety anger interpersonal sensitivity and para-noia but not depression (Zanarini amp Frankenburg2001) as well as improving general clinical func-tioning and BPD symptomatology (Bogenschutz ampNurnberg 2004) A recent large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulzet al 2008) although the authors suggested thatpatients may have been underdosed A study comparing olanzapine to haloperidol showed nobetween-group differences except with respect toside-effects with more weight gain associated witholanzapine and more extra-pyramidal side-effects
with haloperidol (Shafti amp Shahveisi 2010) Adding 1047298uoxetine to olanzapine did not elicit
further bene1047297t except that subjects receiving bothmedications gained less weight than those receiving only olanzapine (Zanarini et al 2004b ) The addi-tion of olanzapine to DBT reduced depressionanxiety and impulsive aggression but the magni-
tude and timing of these bene1047297ts relative to DBT was dif 1047297cult to interpret (Soler et al 2005)
Aripiprazolehas a novelmechanismof action(partialagonist at the dopamine D2 receptor and serotonin 5-HT1A receptor antagonist at the 5-HT2A receptor) Itmay be more favourable than other atypicals withrespect to metabolic side-effects A longer half-lifemay be more effective for patients susceptible to non-adherence In non-suicidal BPD patients aripipra-zole was effective in reducing aggression anxietydepression psychosis interpersonal symptoms self-injurious behaviour and subjective distress There
were no signi1047297cant differences between groups in weight gain (Nickel et al 2006) An 18-month open-label follow-up showed sustained improvements and continued tolerability (Nickel et al 2007)
Previously open-label trials suggested possibleef 1047297cacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al 2004 2006) Theside-effect and psychopharmacological pro1047297les of ziprasidone indicated lesser metabolic risks and an-tidepressant and anxiolytic effects thought to beindependent of antidopaminergic activity (Keck et al 1998 Tandon 2000 Wilner et al 2002)
Despite such promise a recent RCT with ziprasi-done was negative (Pascual et al 2008) Thusevidence-based practice supports use of aripiprazolebut not ziprasidone in treating BPD
In meta-analyses the class of antipsychotics had moderate effect in treating aggression but no sig-ni1047297cant effect on depression although aripiprazoleand olanzapine may be exceptions (Lieb et al 2010Mercer et al 2009) For aypicals metabolic side-effects may limit clinical utility Because 29-53of borderline patients ful1047297l criteria for an eating disorder at some point in their lives (Lieb et al
2004) and a signi1047297cant number suffer from obesity (Frankenburg amp Zanarini 2006) iatrogenic meta-bolic risks must be regarded as serious Althoughevidence-based practices have advanced in treating aggression associated with BPD chronic emptinessaffective lability and interpersonal dysfunction lack effective evidence-based medication treatments
MOOD STABILIZERS AND ANTICONVULSANTS
Due to BPD patientsrsquo affective dysregulation and comorbidity with bipolar disorder some have clas-si1047297ed BPD within the bipolar spectrum (Akiskal2004 Smith et al 2004) although most continue todistinguish between the two particularly withregard to interpersonal dysfunction (Bolton ampGunderson 1996 Henry et al 2001 Paris 2004)Mood stabilizers are indeed becoming a more in-tegral component of evidence-based treatmentpractices for BPD
Lithium is bene1047297cial in treating BPD particularly in terms of quieting affective instability (Links et al
1990 Rifkin et al 1972) Lithium toxicity andor non-compliance may be problematic due to BPDpatientsrsquo characteristic impulsive self-destructivebehaviour
However anticonvulsants are more often rec-ommended for treatment of rapid-cycling bipolar disorder the variant most closely resembling BPDCarbamazepine demonstrated lsquodramaticrsquo reductionsin behavioural dyscontrol and improvements inglobal functioning anxiety anger euphoria im-
pulsivity and suicidality but it was associated with worsening melancholic depression (Gardner ampCowdry 1986a b ) and therapeutic bene1047297ts could not be replicated in in-patients (de la Fuente ampLotstra 1994)
Although high drop-out rates were reported withdivalproex (Hollander et al 2001) it subsequently demonstrated bene1047297ts on interpersonal sensitivityanger and aggression in euthymic borderline wo-men with bipolar II (Frankenburg amp Zanarini2002) Divalproex reduced aggression irritabilityand overall disease severity in patients with Cluster
B personality disorders and prominent impulsiveaggression (Hollander et al 2003) Differentialtreatment response in Cluster B subjects was en-hanced by baseline trait impulsivity and state ag-gression although not affective instability (Hollander et al 2005)
Lamotrigine extends periods of euthymia in bi-polar patients (eg Goodwin et al 2004) Potentialbene1047297ts also include pro-cognitive activity as pre-viously demonstrated in normal volunteers(Aldenkamp et al 2002) Lamotrigine effectively reduced BPD patientsrsquo anger (Tritt et al 2005) and
238 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
242 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 243
antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
patients SPD patients often demonstrate cognitivede1047297cits in working memory particularly sustained attention and executive functioning (Bergida ampLenzenweger 2006 McClure et al 2007a Parc ampMcTigue 1997) as well as signi1047297cant abnormalitiesin empathic understanding (Langdon amp Coltheart2004 Pickup 2006 Ripoll et al unpublished data)Unlike schizophrenic patients there is greater preservation of frontal volume in SPD (Siever ampDavis 2004)
Overall clinical trials for SPD have been com-plicated by comorbidity particularly with other personality disorders Most early RCTs on BPDalso included SPD patients (Goldberg et al 1986Serban amp Siegel 1984 Soloff et al 1986c ) be-cause both SPD and BPD were considered rooted in lsquoborderlinersquo schizophrenia but psychoticsymptoms in SPD and BPD are clinically distin-guishable
The conceptualization of SPD within theschizophrenia spectrum supports treatment withantipsychotic medications Antipsychotics appear
tobeusefulinthetreatmentofSPDparticularlyinterms of psychotic-like symptoms (Goldberg et al
1986 Koenigsberg e t a l 2003) Open-labelstudies have suggested a role for antidepressantsin treating self-injury psychotic-like and de-pressive symptomatology (Jensen amp Andersen1989 Markovitz et al 1991) but the evidence is
weaker Recent RCTs targeting cognitive de1047297citsin SPD compared performance on neuro-psychological tasks before and after treatment
with medication or placebo Both pergolidea dopaminergic agonist active at both the D1 and
D2 receptor (McClure et al 2010) and the nor-adrenergic a2A agonist guanfacine (McClure et al
2007b ) improved SPD patientsrsquo cognitive per-formance on distinct neuropsychological mea-sures Whether this improvement extends tooverall clinical functioning in SPD remains sub-
ject to future investigationIn sumSPDpatients respondto low-dose atypical
antipsychotics targeting psychotic-like symptomsand general functioning First-generation antipsy-
chotic medication and antidepressants may alsoplay a role although the evidence is not as reliableEvidence-based practice requires weighing risk of extrapyramidal side-effects or tardive dyskinesia against potential bene1047297ts Cognitive enhancementvia noradrenergic a2A or dopaminergic agonismmay be future avenues of research given that by analogy with schizophrenia the cognitive impair-ment in SPD may be responsible for the overalldysfunction observed in the disorder Researchefforts to understand neurobiological substratesof social cognitive dysfunction have heretofore
mainly focused on BPD and schizophrenia Be-cause SPD involves social isolation relationalparanoia and empathic de1047297cits research on phar-macotherapeutic effects on social cognition may also be fruitful
A NTISOCIAL PERSONALITY DISORDER
(A SPD)
Peer-reviewed trials of AsPD include studieson groups of individuals likely to have been antiso-cial based on histories of repeated violence and
criminality and an absence of other stated causes for these behaviours Lithium has been associated withdecreases in serious rule infractions in incarcerated males (Sheard 1971 Sheard et al 1976) Prisonerstreated with phenytoin committed fewer aggressiveacts and evidenced decreased tension-anxiety and depression-dejection (although not anger-hostility)and improvements in aggression appeared to belimited to impulsive (not pre-meditated) aggres-sion (Barratt et al 1991 1997) At presentevidenced-based pharmacotherapy for AsPD isrestricted to treatment of impulsive aggressionFuture neurobiological research in AsPD and psychopathy will probably increase our un-derstanding of the dysfunctional emotional em-pathy often seen in this disorder (Blair 2005) and
whether this may be susceptible to psychophar-macological intervention
BPD
Most RCTs on personality disorders focused onBPD which consists of several domains of dys-function affective instability impulsivity and an-ger transient psychotic or dissociative symptomsand intense unstable relationships (Lieb et al
2004 Zanarini et al 1990) BPD patients oftendemonstrate high comorbidity (Zanarini et al
2004a c ) and make numerous suicide attempts and parasuicidal gestures conferring signi1047297cantly higher risk for completed suicide (Welch amp Linehan2000)
Early studies employed a distinct nosology incharacterizing subjects some of whom actually had
what might be called BPD today (Rifkin et al 1972)In studies on suicidal or parasuicidal subjects themajority often have BPD (Battaglia et al 1999Montgomery amp Montgomery 1982 Montgomery et al 1983 Verkes et al 1998) Early studies oftenincluded combinations of BPD and SPD subjects(Goldberg et al 1986 Serban amp Siegel 1984 Soloff et al 1986c ) and studies recruiting a range of allpersonality disorders ultimately include BPD as themost frequent diagnosis (Coccaro amp Kavoussi
1997 Hollander et al 2003)Cliniciansshouldexercisecautioninattemptingtoapplyresearch1047297ndingstoseverelyillBPDpatientsasmany RCTs recruited only outpatients who further
were excluded if they expressed acute suicidality (Frankenburg amp Zanarini 2002 Tritt et al 2005Zanarini amp Frankenburg 2003 Zanarini et al
2004b ) or had made a recent suicide attempt(Bogenschutz amp Nurnberg 2004) In additionsmall sample sizes predominated and most studieslasted 3 months The few trials lasting $6 monthssuffered from high drop-out rates (Frankenburg amp
Zanarini 2002 Zanarini amp Frankenburg 2001) or concomitant recruitment of subjects without BPD(Battaglia et al 1999 Montgomery et al 1983Verkes et al 1998) Moreover RCTs with BPDsubjects appear to be prone to highplacebo responserates (Lieb et al 2004 Salzman et al 1995)meaning that open-label trial data should be inter-preted with caution
APA practice guidelines (APA 2001) recom-mended a symptom-targeted approach in pharma-cotherapy of BPD This leaves open the possibility for patients to improve in some but not all symptomdimensions Some clinicians have based their de-cision to implement polypharmacy on this butthere is actually little evidence as to the effectivenessof this strategy The only study on combined pharmacotherapy in BPD (Zanarini et al 2004b )found no superior ef 1047297cacy for combination treat-ment compared to one medication alone Using asfew medications as possible to target central areas of
clinical dysfunction together with evidence-based psychotherapy is usually the optimal treatmentstrategy In light of this although the 2001 guide-lines suggest a prominent role for serotonergicpharmacotherapy recent reviews have questioned this and instead emphasized anticonvulsants and antipsychotics (Abraham amp Calabrese 2008 Mercer et al 2009)
TRICYCLIC ANTIDEPRESSANTS (TCA S)
Disturbances of serotonin have been associated
with BPD impulsive aggression self-harm and suicidality (Coccaro et al 1995 Evenden 1999Malone et al 1996 Pitchot et al 2005) Low CSFlevels of serotonin metabolites have been associated
with suicide attempts and completion (Samuelssonet al 2006 Traskman et al 1981) impulsivityaggression (Mehlman et al 1994 Virkkunen et al
1994) lifetime aggressiveness and suicidal lethality (Placidi et al 2001) Impulsive aggression withsuicidality has been linked to blunted prolactinresponses to the serotonergic probe fen1047298uramine(Coccaro et al 1989) PET scans of personality-
disordered subjects high in impulsive aggressionhave demonstrated reduced response to fen1047298ur-amine in orbitofrontal ventromedial and cingulateregions (Siever et al 1999)
Nevertheless early research on TCAs for BPDproved disappointing (Montgomery et al 1983Soloff et al 1989) Amitryptiline has been associ-ated with paradoxical increases in suicidality para-noia and behavioural dysregulation attributed tolsquogeneralized disinhibition of cognitive and affec-tive controlsrsquo (Soloff et al 1986a 1987) Indeedborderline patients have dif 1047297culty cognitively
236 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
resolving con1047298ict among stimulus dimensions(Posner et al 2002) and prefrontal hypofunctioncan be seen after a serotonergic stimulus in subjects
with prominent impulsive aggression (New et al
2002) Thus medications with adverse cognitivesequelae including anticholinergic side-effects may contribute to worsening impulsivity As mentioned in prior reviews the use of TCAs in treating BPD isdiscouraged (Abraham amp Calabrese 2008 Mercer et al 2009) Their use is also associated with po-tentially signi1047297cant risk of overdose
MONOAMINE OXIDASE INHIBITORS (MAOIS)
Despite hesitancyinprescribingMAOIstopatients with prominent impulsivity or self-injurious behav-iour some recommend these medications for BPDpatientswhocantakethemsafelyandreliablyInterestin MAOIs for BPD is rooted in their differential ef-1047297cacy for conditions such as hysteroid dysphoria or atypical depression viewed as being related to oneother and BPD (Kayser et al 1985 Liebowitz ampKlein 1981) In a crossover trial with multiplemedication phases only tranylcypromine was as-sociated with higher patient-rated improvementscores and completion rates (Cowdry amp Gardner1988)
Similarly relative prominence of BPD symptomspredicted superiority of phenelzine (Parsons et al
1989) Phenelzine is bene1047297cial in the treatment of hostility anxiety and borderline symptoms (Soloff et al 1993) In some patients it could cause un-
comfortable excitement and emotional reactivity (Cornelius et al 1993) Thus although there isevidence for their ef 1047297cacy many patients may nottolerate these medications Other associated risksof MAOIs include toxicity in overdose and po-tentially fatal hypertensive crises or serotoninsyndrome
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIS)
SSRIs are thought to potentiate serotonergicneuromodulation but demonstrate more favour-able side-effect pro1047297les Fluoxetine reduced anger in BPD independent of any antidepressant ef-fect (Salzman et al 1995) It also improved verbaland impulsive aggression irritability and overallfunctioning (Coccaro amp Kavoussi 1997) Simi-larly a RCT with paroxetine demonstrated ef 1047297cacy in preventing recurrent suicidal behaviour but nosigni1047297cant effect on depression hopelessness or anger (Verkes et al 1998) By contrast there waslittle added bene1047297t from 1047298uoxetine when added to
dialectical behavioural therapy (DBT) (Simpsonet al 2004)
On the other hand 1047298uvoxamine decreased af-fective lability but not scores of impulsivity or ag-gression (Rinne et al 2002) Although SSRIsdecrease impulsivity and aggression in BPD patients
with comorbid intermittent explosive disorder (IED Coccaro amp Kavoussi 1997 New et al 2004)data from BPD subjects without comorbid IED areinconsistent (Rinne et al 2002) Previous reviewshave emphasized that effect sizes for antidepressantpharmacotherapy vary widely between classes and trials (Ingenhoven et al 2010 Lieb et al 2010Mercer et al 2009) Nevertheless current evidence-based practice recommends use of SSRIs due topotential bene1047297ts on impulsive aggression that may outweigh associated risks There has been no evi-dence that antidepressants alleviate the chronicemptiness shameful self-concept and intrapsychicpain in BPD
FIRST-GENERATION ANTIPSYCHOTICS
An early interest in antipsychotic medications for treating BPD probably arose from a conception of BPD as a variant of schizophrenia (eg Deutsch1942) Antipsychotics have demonstrated partialef 1047297cacy re1047298ecting underlying abnormalities in do-paminergic signalling Borderline subjects demon-strate high levels of the dopamine metabolitehomovallinic acid in both plasma and cerebrospinal1047298uid (Siever et al unpublished data) Prior to more
widespread use of SSRIs antipsychotics demon-strated ef 1047297cacy in decreasing psychotic-like symptoms(Goldberg et al 1986 Soloff et al 1986b ) depression(Soloff et al 1986b ) irritability (Cornelius et al
1993) and general symptom severity (Cowdry ampGardner 1988 Soloff et al 1986b )
A recent Cochrane review suggests haloperidol isef 1047297cacious in reducing anger in BPD and treatment
with 1047298upenthixol decanoate reduced suicidal be-haviour (Lieb et al 2010) By contrast evidence for ef 1047297cacy of neuroleptics on affective symptomspsychosis and anxiety remains inconsistent The
dosage of antipsychotic medication for evidence-based treatment of BPD is usually lower thanschizophrenia High drop-out rates are noted and risk of extrapyramidal symptoms may further limitthe utility of neuroleptics
SECOND-GENERATION ANTIPSYCHOTICS
Classical neuroleptics have largely been superseded by atypical antipsychotics whose broader therapeuticbene1047297ts may be explained by activity beyond the D2
receptor As mentioned in prior reviews olanzapine
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 237
has proven bene1047297cial in treatment of BPD patientsrsquoanxiety anger interpersonal sensitivity and para-noia but not depression (Zanarini amp Frankenburg2001) as well as improving general clinical func-tioning and BPD symptomatology (Bogenschutz ampNurnberg 2004) A recent large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulzet al 2008) although the authors suggested thatpatients may have been underdosed A study comparing olanzapine to haloperidol showed nobetween-group differences except with respect toside-effects with more weight gain associated witholanzapine and more extra-pyramidal side-effects
with haloperidol (Shafti amp Shahveisi 2010) Adding 1047298uoxetine to olanzapine did not elicit
further bene1047297t except that subjects receiving bothmedications gained less weight than those receiving only olanzapine (Zanarini et al 2004b ) The addi-tion of olanzapine to DBT reduced depressionanxiety and impulsive aggression but the magni-
tude and timing of these bene1047297ts relative to DBT was dif 1047297cult to interpret (Soler et al 2005)
Aripiprazolehas a novelmechanismof action(partialagonist at the dopamine D2 receptor and serotonin 5-HT1A receptor antagonist at the 5-HT2A receptor) Itmay be more favourable than other atypicals withrespect to metabolic side-effects A longer half-lifemay be more effective for patients susceptible to non-adherence In non-suicidal BPD patients aripipra-zole was effective in reducing aggression anxietydepression psychosis interpersonal symptoms self-injurious behaviour and subjective distress There
were no signi1047297cant differences between groups in weight gain (Nickel et al 2006) An 18-month open-label follow-up showed sustained improvements and continued tolerability (Nickel et al 2007)
Previously open-label trials suggested possibleef 1047297cacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al 2004 2006) Theside-effect and psychopharmacological pro1047297les of ziprasidone indicated lesser metabolic risks and an-tidepressant and anxiolytic effects thought to beindependent of antidopaminergic activity (Keck et al 1998 Tandon 2000 Wilner et al 2002)
Despite such promise a recent RCT with ziprasi-done was negative (Pascual et al 2008) Thusevidence-based practice supports use of aripiprazolebut not ziprasidone in treating BPD
In meta-analyses the class of antipsychotics had moderate effect in treating aggression but no sig-ni1047297cant effect on depression although aripiprazoleand olanzapine may be exceptions (Lieb et al 2010Mercer et al 2009) For aypicals metabolic side-effects may limit clinical utility Because 29-53of borderline patients ful1047297l criteria for an eating disorder at some point in their lives (Lieb et al
2004) and a signi1047297cant number suffer from obesity (Frankenburg amp Zanarini 2006) iatrogenic meta-bolic risks must be regarded as serious Althoughevidence-based practices have advanced in treating aggression associated with BPD chronic emptinessaffective lability and interpersonal dysfunction lack effective evidence-based medication treatments
MOOD STABILIZERS AND ANTICONVULSANTS
Due to BPD patientsrsquo affective dysregulation and comorbidity with bipolar disorder some have clas-si1047297ed BPD within the bipolar spectrum (Akiskal2004 Smith et al 2004) although most continue todistinguish between the two particularly withregard to interpersonal dysfunction (Bolton ampGunderson 1996 Henry et al 2001 Paris 2004)Mood stabilizers are indeed becoming a more in-tegral component of evidence-based treatmentpractices for BPD
Lithium is bene1047297cial in treating BPD particularly in terms of quieting affective instability (Links et al
1990 Rifkin et al 1972) Lithium toxicity andor non-compliance may be problematic due to BPDpatientsrsquo characteristic impulsive self-destructivebehaviour
However anticonvulsants are more often rec-ommended for treatment of rapid-cycling bipolar disorder the variant most closely resembling BPDCarbamazepine demonstrated lsquodramaticrsquo reductionsin behavioural dyscontrol and improvements inglobal functioning anxiety anger euphoria im-
pulsivity and suicidality but it was associated with worsening melancholic depression (Gardner ampCowdry 1986a b ) and therapeutic bene1047297ts could not be replicated in in-patients (de la Fuente ampLotstra 1994)
Although high drop-out rates were reported withdivalproex (Hollander et al 2001) it subsequently demonstrated bene1047297ts on interpersonal sensitivityanger and aggression in euthymic borderline wo-men with bipolar II (Frankenburg amp Zanarini2002) Divalproex reduced aggression irritabilityand overall disease severity in patients with Cluster
B personality disorders and prominent impulsiveaggression (Hollander et al 2003) Differentialtreatment response in Cluster B subjects was en-hanced by baseline trait impulsivity and state ag-gression although not affective instability (Hollander et al 2005)
Lamotrigine extends periods of euthymia in bi-polar patients (eg Goodwin et al 2004) Potentialbene1047297ts also include pro-cognitive activity as pre-viously demonstrated in normal volunteers(Aldenkamp et al 2002) Lamotrigine effectively reduced BPD patientsrsquo anger (Tritt et al 2005) and
238 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
242 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 243
antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
patients SPD patients often demonstrate cognitivede1047297cits in working memory particularly sustained attention and executive functioning (Bergida ampLenzenweger 2006 McClure et al 2007a Parc ampMcTigue 1997) as well as signi1047297cant abnormalitiesin empathic understanding (Langdon amp Coltheart2004 Pickup 2006 Ripoll et al unpublished data)Unlike schizophrenic patients there is greater preservation of frontal volume in SPD (Siever ampDavis 2004)
Overall clinical trials for SPD have been com-plicated by comorbidity particularly with other personality disorders Most early RCTs on BPDalso included SPD patients (Goldberg et al 1986Serban amp Siegel 1984 Soloff et al 1986c ) be-cause both SPD and BPD were considered rooted in lsquoborderlinersquo schizophrenia but psychoticsymptoms in SPD and BPD are clinically distin-guishable
The conceptualization of SPD within theschizophrenia spectrum supports treatment withantipsychotic medications Antipsychotics appear
tobeusefulinthetreatmentofSPDparticularlyinterms of psychotic-like symptoms (Goldberg et al
1986 Koenigsberg e t a l 2003) Open-labelstudies have suggested a role for antidepressantsin treating self-injury psychotic-like and de-pressive symptomatology (Jensen amp Andersen1989 Markovitz et al 1991) but the evidence is
weaker Recent RCTs targeting cognitive de1047297citsin SPD compared performance on neuro-psychological tasks before and after treatment
with medication or placebo Both pergolidea dopaminergic agonist active at both the D1 and
D2 receptor (McClure et al 2010) and the nor-adrenergic a2A agonist guanfacine (McClure et al
2007b ) improved SPD patientsrsquo cognitive per-formance on distinct neuropsychological mea-sures Whether this improvement extends tooverall clinical functioning in SPD remains sub-
ject to future investigationIn sumSPDpatients respondto low-dose atypical
antipsychotics targeting psychotic-like symptomsand general functioning First-generation antipsy-
chotic medication and antidepressants may alsoplay a role although the evidence is not as reliableEvidence-based practice requires weighing risk of extrapyramidal side-effects or tardive dyskinesia against potential bene1047297ts Cognitive enhancementvia noradrenergic a2A or dopaminergic agonismmay be future avenues of research given that by analogy with schizophrenia the cognitive impair-ment in SPD may be responsible for the overalldysfunction observed in the disorder Researchefforts to understand neurobiological substratesof social cognitive dysfunction have heretofore
mainly focused on BPD and schizophrenia Be-cause SPD involves social isolation relationalparanoia and empathic de1047297cits research on phar-macotherapeutic effects on social cognition may also be fruitful
A NTISOCIAL PERSONALITY DISORDER
(A SPD)
Peer-reviewed trials of AsPD include studieson groups of individuals likely to have been antiso-cial based on histories of repeated violence and
criminality and an absence of other stated causes for these behaviours Lithium has been associated withdecreases in serious rule infractions in incarcerated males (Sheard 1971 Sheard et al 1976) Prisonerstreated with phenytoin committed fewer aggressiveacts and evidenced decreased tension-anxiety and depression-dejection (although not anger-hostility)and improvements in aggression appeared to belimited to impulsive (not pre-meditated) aggres-sion (Barratt et al 1991 1997) At presentevidenced-based pharmacotherapy for AsPD isrestricted to treatment of impulsive aggressionFuture neurobiological research in AsPD and psychopathy will probably increase our un-derstanding of the dysfunctional emotional em-pathy often seen in this disorder (Blair 2005) and
whether this may be susceptible to psychophar-macological intervention
BPD
Most RCTs on personality disorders focused onBPD which consists of several domains of dys-function affective instability impulsivity and an-ger transient psychotic or dissociative symptomsand intense unstable relationships (Lieb et al
2004 Zanarini et al 1990) BPD patients oftendemonstrate high comorbidity (Zanarini et al
2004a c ) and make numerous suicide attempts and parasuicidal gestures conferring signi1047297cantly higher risk for completed suicide (Welch amp Linehan2000)
Early studies employed a distinct nosology incharacterizing subjects some of whom actually had
what might be called BPD today (Rifkin et al 1972)In studies on suicidal or parasuicidal subjects themajority often have BPD (Battaglia et al 1999Montgomery amp Montgomery 1982 Montgomery et al 1983 Verkes et al 1998) Early studies oftenincluded combinations of BPD and SPD subjects(Goldberg et al 1986 Serban amp Siegel 1984 Soloff et al 1986c ) and studies recruiting a range of allpersonality disorders ultimately include BPD as themost frequent diagnosis (Coccaro amp Kavoussi
1997 Hollander et al 2003)Cliniciansshouldexercisecautioninattemptingtoapplyresearch1047297ndingstoseverelyillBPDpatientsasmany RCTs recruited only outpatients who further
were excluded if they expressed acute suicidality (Frankenburg amp Zanarini 2002 Tritt et al 2005Zanarini amp Frankenburg 2003 Zanarini et al
2004b ) or had made a recent suicide attempt(Bogenschutz amp Nurnberg 2004) In additionsmall sample sizes predominated and most studieslasted 3 months The few trials lasting $6 monthssuffered from high drop-out rates (Frankenburg amp
Zanarini 2002 Zanarini amp Frankenburg 2001) or concomitant recruitment of subjects without BPD(Battaglia et al 1999 Montgomery et al 1983Verkes et al 1998) Moreover RCTs with BPDsubjects appear to be prone to highplacebo responserates (Lieb et al 2004 Salzman et al 1995)meaning that open-label trial data should be inter-preted with caution
APA practice guidelines (APA 2001) recom-mended a symptom-targeted approach in pharma-cotherapy of BPD This leaves open the possibility for patients to improve in some but not all symptomdimensions Some clinicians have based their de-cision to implement polypharmacy on this butthere is actually little evidence as to the effectivenessof this strategy The only study on combined pharmacotherapy in BPD (Zanarini et al 2004b )found no superior ef 1047297cacy for combination treat-ment compared to one medication alone Using asfew medications as possible to target central areas of
clinical dysfunction together with evidence-based psychotherapy is usually the optimal treatmentstrategy In light of this although the 2001 guide-lines suggest a prominent role for serotonergicpharmacotherapy recent reviews have questioned this and instead emphasized anticonvulsants and antipsychotics (Abraham amp Calabrese 2008 Mercer et al 2009)
TRICYCLIC ANTIDEPRESSANTS (TCA S)
Disturbances of serotonin have been associated
with BPD impulsive aggression self-harm and suicidality (Coccaro et al 1995 Evenden 1999Malone et al 1996 Pitchot et al 2005) Low CSFlevels of serotonin metabolites have been associated
with suicide attempts and completion (Samuelssonet al 2006 Traskman et al 1981) impulsivityaggression (Mehlman et al 1994 Virkkunen et al
1994) lifetime aggressiveness and suicidal lethality (Placidi et al 2001) Impulsive aggression withsuicidality has been linked to blunted prolactinresponses to the serotonergic probe fen1047298uramine(Coccaro et al 1989) PET scans of personality-
disordered subjects high in impulsive aggressionhave demonstrated reduced response to fen1047298ur-amine in orbitofrontal ventromedial and cingulateregions (Siever et al 1999)
Nevertheless early research on TCAs for BPDproved disappointing (Montgomery et al 1983Soloff et al 1989) Amitryptiline has been associ-ated with paradoxical increases in suicidality para-noia and behavioural dysregulation attributed tolsquogeneralized disinhibition of cognitive and affec-tive controlsrsquo (Soloff et al 1986a 1987) Indeedborderline patients have dif 1047297culty cognitively
236 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
resolving con1047298ict among stimulus dimensions(Posner et al 2002) and prefrontal hypofunctioncan be seen after a serotonergic stimulus in subjects
with prominent impulsive aggression (New et al
2002) Thus medications with adverse cognitivesequelae including anticholinergic side-effects may contribute to worsening impulsivity As mentioned in prior reviews the use of TCAs in treating BPD isdiscouraged (Abraham amp Calabrese 2008 Mercer et al 2009) Their use is also associated with po-tentially signi1047297cant risk of overdose
MONOAMINE OXIDASE INHIBITORS (MAOIS)
Despite hesitancyinprescribingMAOIstopatients with prominent impulsivity or self-injurious behav-iour some recommend these medications for BPDpatientswhocantakethemsafelyandreliablyInterestin MAOIs for BPD is rooted in their differential ef-1047297cacy for conditions such as hysteroid dysphoria or atypical depression viewed as being related to oneother and BPD (Kayser et al 1985 Liebowitz ampKlein 1981) In a crossover trial with multiplemedication phases only tranylcypromine was as-sociated with higher patient-rated improvementscores and completion rates (Cowdry amp Gardner1988)
Similarly relative prominence of BPD symptomspredicted superiority of phenelzine (Parsons et al
1989) Phenelzine is bene1047297cial in the treatment of hostility anxiety and borderline symptoms (Soloff et al 1993) In some patients it could cause un-
comfortable excitement and emotional reactivity (Cornelius et al 1993) Thus although there isevidence for their ef 1047297cacy many patients may nottolerate these medications Other associated risksof MAOIs include toxicity in overdose and po-tentially fatal hypertensive crises or serotoninsyndrome
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIS)
SSRIs are thought to potentiate serotonergicneuromodulation but demonstrate more favour-able side-effect pro1047297les Fluoxetine reduced anger in BPD independent of any antidepressant ef-fect (Salzman et al 1995) It also improved verbaland impulsive aggression irritability and overallfunctioning (Coccaro amp Kavoussi 1997) Simi-larly a RCT with paroxetine demonstrated ef 1047297cacy in preventing recurrent suicidal behaviour but nosigni1047297cant effect on depression hopelessness or anger (Verkes et al 1998) By contrast there waslittle added bene1047297t from 1047298uoxetine when added to
dialectical behavioural therapy (DBT) (Simpsonet al 2004)
On the other hand 1047298uvoxamine decreased af-fective lability but not scores of impulsivity or ag-gression (Rinne et al 2002) Although SSRIsdecrease impulsivity and aggression in BPD patients
with comorbid intermittent explosive disorder (IED Coccaro amp Kavoussi 1997 New et al 2004)data from BPD subjects without comorbid IED areinconsistent (Rinne et al 2002) Previous reviewshave emphasized that effect sizes for antidepressantpharmacotherapy vary widely between classes and trials (Ingenhoven et al 2010 Lieb et al 2010Mercer et al 2009) Nevertheless current evidence-based practice recommends use of SSRIs due topotential bene1047297ts on impulsive aggression that may outweigh associated risks There has been no evi-dence that antidepressants alleviate the chronicemptiness shameful self-concept and intrapsychicpain in BPD
FIRST-GENERATION ANTIPSYCHOTICS
An early interest in antipsychotic medications for treating BPD probably arose from a conception of BPD as a variant of schizophrenia (eg Deutsch1942) Antipsychotics have demonstrated partialef 1047297cacy re1047298ecting underlying abnormalities in do-paminergic signalling Borderline subjects demon-strate high levels of the dopamine metabolitehomovallinic acid in both plasma and cerebrospinal1047298uid (Siever et al unpublished data) Prior to more
widespread use of SSRIs antipsychotics demon-strated ef 1047297cacy in decreasing psychotic-like symptoms(Goldberg et al 1986 Soloff et al 1986b ) depression(Soloff et al 1986b ) irritability (Cornelius et al
1993) and general symptom severity (Cowdry ampGardner 1988 Soloff et al 1986b )
A recent Cochrane review suggests haloperidol isef 1047297cacious in reducing anger in BPD and treatment
with 1047298upenthixol decanoate reduced suicidal be-haviour (Lieb et al 2010) By contrast evidence for ef 1047297cacy of neuroleptics on affective symptomspsychosis and anxiety remains inconsistent The
dosage of antipsychotic medication for evidence-based treatment of BPD is usually lower thanschizophrenia High drop-out rates are noted and risk of extrapyramidal symptoms may further limitthe utility of neuroleptics
SECOND-GENERATION ANTIPSYCHOTICS
Classical neuroleptics have largely been superseded by atypical antipsychotics whose broader therapeuticbene1047297ts may be explained by activity beyond the D2
receptor As mentioned in prior reviews olanzapine
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 237
has proven bene1047297cial in treatment of BPD patientsrsquoanxiety anger interpersonal sensitivity and para-noia but not depression (Zanarini amp Frankenburg2001) as well as improving general clinical func-tioning and BPD symptomatology (Bogenschutz ampNurnberg 2004) A recent large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulzet al 2008) although the authors suggested thatpatients may have been underdosed A study comparing olanzapine to haloperidol showed nobetween-group differences except with respect toside-effects with more weight gain associated witholanzapine and more extra-pyramidal side-effects
with haloperidol (Shafti amp Shahveisi 2010) Adding 1047298uoxetine to olanzapine did not elicit
further bene1047297t except that subjects receiving bothmedications gained less weight than those receiving only olanzapine (Zanarini et al 2004b ) The addi-tion of olanzapine to DBT reduced depressionanxiety and impulsive aggression but the magni-
tude and timing of these bene1047297ts relative to DBT was dif 1047297cult to interpret (Soler et al 2005)
Aripiprazolehas a novelmechanismof action(partialagonist at the dopamine D2 receptor and serotonin 5-HT1A receptor antagonist at the 5-HT2A receptor) Itmay be more favourable than other atypicals withrespect to metabolic side-effects A longer half-lifemay be more effective for patients susceptible to non-adherence In non-suicidal BPD patients aripipra-zole was effective in reducing aggression anxietydepression psychosis interpersonal symptoms self-injurious behaviour and subjective distress There
were no signi1047297cant differences between groups in weight gain (Nickel et al 2006) An 18-month open-label follow-up showed sustained improvements and continued tolerability (Nickel et al 2007)
Previously open-label trials suggested possibleef 1047297cacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al 2004 2006) Theside-effect and psychopharmacological pro1047297les of ziprasidone indicated lesser metabolic risks and an-tidepressant and anxiolytic effects thought to beindependent of antidopaminergic activity (Keck et al 1998 Tandon 2000 Wilner et al 2002)
Despite such promise a recent RCT with ziprasi-done was negative (Pascual et al 2008) Thusevidence-based practice supports use of aripiprazolebut not ziprasidone in treating BPD
In meta-analyses the class of antipsychotics had moderate effect in treating aggression but no sig-ni1047297cant effect on depression although aripiprazoleand olanzapine may be exceptions (Lieb et al 2010Mercer et al 2009) For aypicals metabolic side-effects may limit clinical utility Because 29-53of borderline patients ful1047297l criteria for an eating disorder at some point in their lives (Lieb et al
2004) and a signi1047297cant number suffer from obesity (Frankenburg amp Zanarini 2006) iatrogenic meta-bolic risks must be regarded as serious Althoughevidence-based practices have advanced in treating aggression associated with BPD chronic emptinessaffective lability and interpersonal dysfunction lack effective evidence-based medication treatments
MOOD STABILIZERS AND ANTICONVULSANTS
Due to BPD patientsrsquo affective dysregulation and comorbidity with bipolar disorder some have clas-si1047297ed BPD within the bipolar spectrum (Akiskal2004 Smith et al 2004) although most continue todistinguish between the two particularly withregard to interpersonal dysfunction (Bolton ampGunderson 1996 Henry et al 2001 Paris 2004)Mood stabilizers are indeed becoming a more in-tegral component of evidence-based treatmentpractices for BPD
Lithium is bene1047297cial in treating BPD particularly in terms of quieting affective instability (Links et al
1990 Rifkin et al 1972) Lithium toxicity andor non-compliance may be problematic due to BPDpatientsrsquo characteristic impulsive self-destructivebehaviour
However anticonvulsants are more often rec-ommended for treatment of rapid-cycling bipolar disorder the variant most closely resembling BPDCarbamazepine demonstrated lsquodramaticrsquo reductionsin behavioural dyscontrol and improvements inglobal functioning anxiety anger euphoria im-
pulsivity and suicidality but it was associated with worsening melancholic depression (Gardner ampCowdry 1986a b ) and therapeutic bene1047297ts could not be replicated in in-patients (de la Fuente ampLotstra 1994)
Although high drop-out rates were reported withdivalproex (Hollander et al 2001) it subsequently demonstrated bene1047297ts on interpersonal sensitivityanger and aggression in euthymic borderline wo-men with bipolar II (Frankenburg amp Zanarini2002) Divalproex reduced aggression irritabilityand overall disease severity in patients with Cluster
B personality disorders and prominent impulsiveaggression (Hollander et al 2003) Differentialtreatment response in Cluster B subjects was en-hanced by baseline trait impulsivity and state ag-gression although not affective instability (Hollander et al 2005)
Lamotrigine extends periods of euthymia in bi-polar patients (eg Goodwin et al 2004) Potentialbene1047297ts also include pro-cognitive activity as pre-viously demonstrated in normal volunteers(Aldenkamp et al 2002) Lamotrigine effectively reduced BPD patientsrsquo anger (Tritt et al 2005) and
238 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
242 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 243
antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
patients SPD patients often demonstrate cognitivede1047297cits in working memory particularly sustained attention and executive functioning (Bergida ampLenzenweger 2006 McClure et al 2007a Parc ampMcTigue 1997) as well as signi1047297cant abnormalitiesin empathic understanding (Langdon amp Coltheart2004 Pickup 2006 Ripoll et al unpublished data)Unlike schizophrenic patients there is greater preservation of frontal volume in SPD (Siever ampDavis 2004)
Overall clinical trials for SPD have been com-plicated by comorbidity particularly with other personality disorders Most early RCTs on BPDalso included SPD patients (Goldberg et al 1986Serban amp Siegel 1984 Soloff et al 1986c ) be-cause both SPD and BPD were considered rooted in lsquoborderlinersquo schizophrenia but psychoticsymptoms in SPD and BPD are clinically distin-guishable
The conceptualization of SPD within theschizophrenia spectrum supports treatment withantipsychotic medications Antipsychotics appear
tobeusefulinthetreatmentofSPDparticularlyinterms of psychotic-like symptoms (Goldberg et al
1986 Koenigsberg e t a l 2003) Open-labelstudies have suggested a role for antidepressantsin treating self-injury psychotic-like and de-pressive symptomatology (Jensen amp Andersen1989 Markovitz et al 1991) but the evidence is
weaker Recent RCTs targeting cognitive de1047297citsin SPD compared performance on neuro-psychological tasks before and after treatment
with medication or placebo Both pergolidea dopaminergic agonist active at both the D1 and
D2 receptor (McClure et al 2010) and the nor-adrenergic a2A agonist guanfacine (McClure et al
2007b ) improved SPD patientsrsquo cognitive per-formance on distinct neuropsychological mea-sures Whether this improvement extends tooverall clinical functioning in SPD remains sub-
ject to future investigationIn sumSPDpatients respondto low-dose atypical
antipsychotics targeting psychotic-like symptomsand general functioning First-generation antipsy-
chotic medication and antidepressants may alsoplay a role although the evidence is not as reliableEvidence-based practice requires weighing risk of extrapyramidal side-effects or tardive dyskinesia against potential bene1047297ts Cognitive enhancementvia noradrenergic a2A or dopaminergic agonismmay be future avenues of research given that by analogy with schizophrenia the cognitive impair-ment in SPD may be responsible for the overalldysfunction observed in the disorder Researchefforts to understand neurobiological substratesof social cognitive dysfunction have heretofore
mainly focused on BPD and schizophrenia Be-cause SPD involves social isolation relationalparanoia and empathic de1047297cits research on phar-macotherapeutic effects on social cognition may also be fruitful
A NTISOCIAL PERSONALITY DISORDER
(A SPD)
Peer-reviewed trials of AsPD include studieson groups of individuals likely to have been antiso-cial based on histories of repeated violence and
criminality and an absence of other stated causes for these behaviours Lithium has been associated withdecreases in serious rule infractions in incarcerated males (Sheard 1971 Sheard et al 1976) Prisonerstreated with phenytoin committed fewer aggressiveacts and evidenced decreased tension-anxiety and depression-dejection (although not anger-hostility)and improvements in aggression appeared to belimited to impulsive (not pre-meditated) aggres-sion (Barratt et al 1991 1997) At presentevidenced-based pharmacotherapy for AsPD isrestricted to treatment of impulsive aggressionFuture neurobiological research in AsPD and psychopathy will probably increase our un-derstanding of the dysfunctional emotional em-pathy often seen in this disorder (Blair 2005) and
whether this may be susceptible to psychophar-macological intervention
BPD
Most RCTs on personality disorders focused onBPD which consists of several domains of dys-function affective instability impulsivity and an-ger transient psychotic or dissociative symptomsand intense unstable relationships (Lieb et al
2004 Zanarini et al 1990) BPD patients oftendemonstrate high comorbidity (Zanarini et al
2004a c ) and make numerous suicide attempts and parasuicidal gestures conferring signi1047297cantly higher risk for completed suicide (Welch amp Linehan2000)
Early studies employed a distinct nosology incharacterizing subjects some of whom actually had
what might be called BPD today (Rifkin et al 1972)In studies on suicidal or parasuicidal subjects themajority often have BPD (Battaglia et al 1999Montgomery amp Montgomery 1982 Montgomery et al 1983 Verkes et al 1998) Early studies oftenincluded combinations of BPD and SPD subjects(Goldberg et al 1986 Serban amp Siegel 1984 Soloff et al 1986c ) and studies recruiting a range of allpersonality disorders ultimately include BPD as themost frequent diagnosis (Coccaro amp Kavoussi
1997 Hollander et al 2003)Cliniciansshouldexercisecautioninattemptingtoapplyresearch1047297ndingstoseverelyillBPDpatientsasmany RCTs recruited only outpatients who further
were excluded if they expressed acute suicidality (Frankenburg amp Zanarini 2002 Tritt et al 2005Zanarini amp Frankenburg 2003 Zanarini et al
2004b ) or had made a recent suicide attempt(Bogenschutz amp Nurnberg 2004) In additionsmall sample sizes predominated and most studieslasted 3 months The few trials lasting $6 monthssuffered from high drop-out rates (Frankenburg amp
Zanarini 2002 Zanarini amp Frankenburg 2001) or concomitant recruitment of subjects without BPD(Battaglia et al 1999 Montgomery et al 1983Verkes et al 1998) Moreover RCTs with BPDsubjects appear to be prone to highplacebo responserates (Lieb et al 2004 Salzman et al 1995)meaning that open-label trial data should be inter-preted with caution
APA practice guidelines (APA 2001) recom-mended a symptom-targeted approach in pharma-cotherapy of BPD This leaves open the possibility for patients to improve in some but not all symptomdimensions Some clinicians have based their de-cision to implement polypharmacy on this butthere is actually little evidence as to the effectivenessof this strategy The only study on combined pharmacotherapy in BPD (Zanarini et al 2004b )found no superior ef 1047297cacy for combination treat-ment compared to one medication alone Using asfew medications as possible to target central areas of
clinical dysfunction together with evidence-based psychotherapy is usually the optimal treatmentstrategy In light of this although the 2001 guide-lines suggest a prominent role for serotonergicpharmacotherapy recent reviews have questioned this and instead emphasized anticonvulsants and antipsychotics (Abraham amp Calabrese 2008 Mercer et al 2009)
TRICYCLIC ANTIDEPRESSANTS (TCA S)
Disturbances of serotonin have been associated
with BPD impulsive aggression self-harm and suicidality (Coccaro et al 1995 Evenden 1999Malone et al 1996 Pitchot et al 2005) Low CSFlevels of serotonin metabolites have been associated
with suicide attempts and completion (Samuelssonet al 2006 Traskman et al 1981) impulsivityaggression (Mehlman et al 1994 Virkkunen et al
1994) lifetime aggressiveness and suicidal lethality (Placidi et al 2001) Impulsive aggression withsuicidality has been linked to blunted prolactinresponses to the serotonergic probe fen1047298uramine(Coccaro et al 1989) PET scans of personality-
disordered subjects high in impulsive aggressionhave demonstrated reduced response to fen1047298ur-amine in orbitofrontal ventromedial and cingulateregions (Siever et al 1999)
Nevertheless early research on TCAs for BPDproved disappointing (Montgomery et al 1983Soloff et al 1989) Amitryptiline has been associ-ated with paradoxical increases in suicidality para-noia and behavioural dysregulation attributed tolsquogeneralized disinhibition of cognitive and affec-tive controlsrsquo (Soloff et al 1986a 1987) Indeedborderline patients have dif 1047297culty cognitively
236 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
resolving con1047298ict among stimulus dimensions(Posner et al 2002) and prefrontal hypofunctioncan be seen after a serotonergic stimulus in subjects
with prominent impulsive aggression (New et al
2002) Thus medications with adverse cognitivesequelae including anticholinergic side-effects may contribute to worsening impulsivity As mentioned in prior reviews the use of TCAs in treating BPD isdiscouraged (Abraham amp Calabrese 2008 Mercer et al 2009) Their use is also associated with po-tentially signi1047297cant risk of overdose
MONOAMINE OXIDASE INHIBITORS (MAOIS)
Despite hesitancyinprescribingMAOIstopatients with prominent impulsivity or self-injurious behav-iour some recommend these medications for BPDpatientswhocantakethemsafelyandreliablyInterestin MAOIs for BPD is rooted in their differential ef-1047297cacy for conditions such as hysteroid dysphoria or atypical depression viewed as being related to oneother and BPD (Kayser et al 1985 Liebowitz ampKlein 1981) In a crossover trial with multiplemedication phases only tranylcypromine was as-sociated with higher patient-rated improvementscores and completion rates (Cowdry amp Gardner1988)
Similarly relative prominence of BPD symptomspredicted superiority of phenelzine (Parsons et al
1989) Phenelzine is bene1047297cial in the treatment of hostility anxiety and borderline symptoms (Soloff et al 1993) In some patients it could cause un-
comfortable excitement and emotional reactivity (Cornelius et al 1993) Thus although there isevidence for their ef 1047297cacy many patients may nottolerate these medications Other associated risksof MAOIs include toxicity in overdose and po-tentially fatal hypertensive crises or serotoninsyndrome
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIS)
SSRIs are thought to potentiate serotonergicneuromodulation but demonstrate more favour-able side-effect pro1047297les Fluoxetine reduced anger in BPD independent of any antidepressant ef-fect (Salzman et al 1995) It also improved verbaland impulsive aggression irritability and overallfunctioning (Coccaro amp Kavoussi 1997) Simi-larly a RCT with paroxetine demonstrated ef 1047297cacy in preventing recurrent suicidal behaviour but nosigni1047297cant effect on depression hopelessness or anger (Verkes et al 1998) By contrast there waslittle added bene1047297t from 1047298uoxetine when added to
dialectical behavioural therapy (DBT) (Simpsonet al 2004)
On the other hand 1047298uvoxamine decreased af-fective lability but not scores of impulsivity or ag-gression (Rinne et al 2002) Although SSRIsdecrease impulsivity and aggression in BPD patients
with comorbid intermittent explosive disorder (IED Coccaro amp Kavoussi 1997 New et al 2004)data from BPD subjects without comorbid IED areinconsistent (Rinne et al 2002) Previous reviewshave emphasized that effect sizes for antidepressantpharmacotherapy vary widely between classes and trials (Ingenhoven et al 2010 Lieb et al 2010Mercer et al 2009) Nevertheless current evidence-based practice recommends use of SSRIs due topotential bene1047297ts on impulsive aggression that may outweigh associated risks There has been no evi-dence that antidepressants alleviate the chronicemptiness shameful self-concept and intrapsychicpain in BPD
FIRST-GENERATION ANTIPSYCHOTICS
An early interest in antipsychotic medications for treating BPD probably arose from a conception of BPD as a variant of schizophrenia (eg Deutsch1942) Antipsychotics have demonstrated partialef 1047297cacy re1047298ecting underlying abnormalities in do-paminergic signalling Borderline subjects demon-strate high levels of the dopamine metabolitehomovallinic acid in both plasma and cerebrospinal1047298uid (Siever et al unpublished data) Prior to more
widespread use of SSRIs antipsychotics demon-strated ef 1047297cacy in decreasing psychotic-like symptoms(Goldberg et al 1986 Soloff et al 1986b ) depression(Soloff et al 1986b ) irritability (Cornelius et al
1993) and general symptom severity (Cowdry ampGardner 1988 Soloff et al 1986b )
A recent Cochrane review suggests haloperidol isef 1047297cacious in reducing anger in BPD and treatment
with 1047298upenthixol decanoate reduced suicidal be-haviour (Lieb et al 2010) By contrast evidence for ef 1047297cacy of neuroleptics on affective symptomspsychosis and anxiety remains inconsistent The
dosage of antipsychotic medication for evidence-based treatment of BPD is usually lower thanschizophrenia High drop-out rates are noted and risk of extrapyramidal symptoms may further limitthe utility of neuroleptics
SECOND-GENERATION ANTIPSYCHOTICS
Classical neuroleptics have largely been superseded by atypical antipsychotics whose broader therapeuticbene1047297ts may be explained by activity beyond the D2
receptor As mentioned in prior reviews olanzapine
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 237
has proven bene1047297cial in treatment of BPD patientsrsquoanxiety anger interpersonal sensitivity and para-noia but not depression (Zanarini amp Frankenburg2001) as well as improving general clinical func-tioning and BPD symptomatology (Bogenschutz ampNurnberg 2004) A recent large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulzet al 2008) although the authors suggested thatpatients may have been underdosed A study comparing olanzapine to haloperidol showed nobetween-group differences except with respect toside-effects with more weight gain associated witholanzapine and more extra-pyramidal side-effects
with haloperidol (Shafti amp Shahveisi 2010) Adding 1047298uoxetine to olanzapine did not elicit
further bene1047297t except that subjects receiving bothmedications gained less weight than those receiving only olanzapine (Zanarini et al 2004b ) The addi-tion of olanzapine to DBT reduced depressionanxiety and impulsive aggression but the magni-
tude and timing of these bene1047297ts relative to DBT was dif 1047297cult to interpret (Soler et al 2005)
Aripiprazolehas a novelmechanismof action(partialagonist at the dopamine D2 receptor and serotonin 5-HT1A receptor antagonist at the 5-HT2A receptor) Itmay be more favourable than other atypicals withrespect to metabolic side-effects A longer half-lifemay be more effective for patients susceptible to non-adherence In non-suicidal BPD patients aripipra-zole was effective in reducing aggression anxietydepression psychosis interpersonal symptoms self-injurious behaviour and subjective distress There
were no signi1047297cant differences between groups in weight gain (Nickel et al 2006) An 18-month open-label follow-up showed sustained improvements and continued tolerability (Nickel et al 2007)
Previously open-label trials suggested possibleef 1047297cacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al 2004 2006) Theside-effect and psychopharmacological pro1047297les of ziprasidone indicated lesser metabolic risks and an-tidepressant and anxiolytic effects thought to beindependent of antidopaminergic activity (Keck et al 1998 Tandon 2000 Wilner et al 2002)
Despite such promise a recent RCT with ziprasi-done was negative (Pascual et al 2008) Thusevidence-based practice supports use of aripiprazolebut not ziprasidone in treating BPD
In meta-analyses the class of antipsychotics had moderate effect in treating aggression but no sig-ni1047297cant effect on depression although aripiprazoleand olanzapine may be exceptions (Lieb et al 2010Mercer et al 2009) For aypicals metabolic side-effects may limit clinical utility Because 29-53of borderline patients ful1047297l criteria for an eating disorder at some point in their lives (Lieb et al
2004) and a signi1047297cant number suffer from obesity (Frankenburg amp Zanarini 2006) iatrogenic meta-bolic risks must be regarded as serious Althoughevidence-based practices have advanced in treating aggression associated with BPD chronic emptinessaffective lability and interpersonal dysfunction lack effective evidence-based medication treatments
MOOD STABILIZERS AND ANTICONVULSANTS
Due to BPD patientsrsquo affective dysregulation and comorbidity with bipolar disorder some have clas-si1047297ed BPD within the bipolar spectrum (Akiskal2004 Smith et al 2004) although most continue todistinguish between the two particularly withregard to interpersonal dysfunction (Bolton ampGunderson 1996 Henry et al 2001 Paris 2004)Mood stabilizers are indeed becoming a more in-tegral component of evidence-based treatmentpractices for BPD
Lithium is bene1047297cial in treating BPD particularly in terms of quieting affective instability (Links et al
1990 Rifkin et al 1972) Lithium toxicity andor non-compliance may be problematic due to BPDpatientsrsquo characteristic impulsive self-destructivebehaviour
However anticonvulsants are more often rec-ommended for treatment of rapid-cycling bipolar disorder the variant most closely resembling BPDCarbamazepine demonstrated lsquodramaticrsquo reductionsin behavioural dyscontrol and improvements inglobal functioning anxiety anger euphoria im-
pulsivity and suicidality but it was associated with worsening melancholic depression (Gardner ampCowdry 1986a b ) and therapeutic bene1047297ts could not be replicated in in-patients (de la Fuente ampLotstra 1994)
Although high drop-out rates were reported withdivalproex (Hollander et al 2001) it subsequently demonstrated bene1047297ts on interpersonal sensitivityanger and aggression in euthymic borderline wo-men with bipolar II (Frankenburg amp Zanarini2002) Divalproex reduced aggression irritabilityand overall disease severity in patients with Cluster
B personality disorders and prominent impulsiveaggression (Hollander et al 2003) Differentialtreatment response in Cluster B subjects was en-hanced by baseline trait impulsivity and state ag-gression although not affective instability (Hollander et al 2005)
Lamotrigine extends periods of euthymia in bi-polar patients (eg Goodwin et al 2004) Potentialbene1047297ts also include pro-cognitive activity as pre-viously demonstrated in normal volunteers(Aldenkamp et al 2002) Lamotrigine effectively reduced BPD patientsrsquo anger (Tritt et al 2005) and
238 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
242 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 243
antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
criminality and an absence of other stated causes for these behaviours Lithium has been associated withdecreases in serious rule infractions in incarcerated males (Sheard 1971 Sheard et al 1976) Prisonerstreated with phenytoin committed fewer aggressiveacts and evidenced decreased tension-anxiety and depression-dejection (although not anger-hostility)and improvements in aggression appeared to belimited to impulsive (not pre-meditated) aggres-sion (Barratt et al 1991 1997) At presentevidenced-based pharmacotherapy for AsPD isrestricted to treatment of impulsive aggressionFuture neurobiological research in AsPD and psychopathy will probably increase our un-derstanding of the dysfunctional emotional em-pathy often seen in this disorder (Blair 2005) and
whether this may be susceptible to psychophar-macological intervention
BPD
Most RCTs on personality disorders focused onBPD which consists of several domains of dys-function affective instability impulsivity and an-ger transient psychotic or dissociative symptomsand intense unstable relationships (Lieb et al
2004 Zanarini et al 1990) BPD patients oftendemonstrate high comorbidity (Zanarini et al
2004a c ) and make numerous suicide attempts and parasuicidal gestures conferring signi1047297cantly higher risk for completed suicide (Welch amp Linehan2000)
Early studies employed a distinct nosology incharacterizing subjects some of whom actually had
what might be called BPD today (Rifkin et al 1972)In studies on suicidal or parasuicidal subjects themajority often have BPD (Battaglia et al 1999Montgomery amp Montgomery 1982 Montgomery et al 1983 Verkes et al 1998) Early studies oftenincluded combinations of BPD and SPD subjects(Goldberg et al 1986 Serban amp Siegel 1984 Soloff et al 1986c ) and studies recruiting a range of allpersonality disorders ultimately include BPD as themost frequent diagnosis (Coccaro amp Kavoussi
1997 Hollander et al 2003)Cliniciansshouldexercisecautioninattemptingtoapplyresearch1047297ndingstoseverelyillBPDpatientsasmany RCTs recruited only outpatients who further
were excluded if they expressed acute suicidality (Frankenburg amp Zanarini 2002 Tritt et al 2005Zanarini amp Frankenburg 2003 Zanarini et al
2004b ) or had made a recent suicide attempt(Bogenschutz amp Nurnberg 2004) In additionsmall sample sizes predominated and most studieslasted 3 months The few trials lasting $6 monthssuffered from high drop-out rates (Frankenburg amp
Zanarini 2002 Zanarini amp Frankenburg 2001) or concomitant recruitment of subjects without BPD(Battaglia et al 1999 Montgomery et al 1983Verkes et al 1998) Moreover RCTs with BPDsubjects appear to be prone to highplacebo responserates (Lieb et al 2004 Salzman et al 1995)meaning that open-label trial data should be inter-preted with caution
APA practice guidelines (APA 2001) recom-mended a symptom-targeted approach in pharma-cotherapy of BPD This leaves open the possibility for patients to improve in some but not all symptomdimensions Some clinicians have based their de-cision to implement polypharmacy on this butthere is actually little evidence as to the effectivenessof this strategy The only study on combined pharmacotherapy in BPD (Zanarini et al 2004b )found no superior ef 1047297cacy for combination treat-ment compared to one medication alone Using asfew medications as possible to target central areas of
clinical dysfunction together with evidence-based psychotherapy is usually the optimal treatmentstrategy In light of this although the 2001 guide-lines suggest a prominent role for serotonergicpharmacotherapy recent reviews have questioned this and instead emphasized anticonvulsants and antipsychotics (Abraham amp Calabrese 2008 Mercer et al 2009)
TRICYCLIC ANTIDEPRESSANTS (TCA S)
Disturbances of serotonin have been associated
with BPD impulsive aggression self-harm and suicidality (Coccaro et al 1995 Evenden 1999Malone et al 1996 Pitchot et al 2005) Low CSFlevels of serotonin metabolites have been associated
with suicide attempts and completion (Samuelssonet al 2006 Traskman et al 1981) impulsivityaggression (Mehlman et al 1994 Virkkunen et al
1994) lifetime aggressiveness and suicidal lethality (Placidi et al 2001) Impulsive aggression withsuicidality has been linked to blunted prolactinresponses to the serotonergic probe fen1047298uramine(Coccaro et al 1989) PET scans of personality-
disordered subjects high in impulsive aggressionhave demonstrated reduced response to fen1047298ur-amine in orbitofrontal ventromedial and cingulateregions (Siever et al 1999)
Nevertheless early research on TCAs for BPDproved disappointing (Montgomery et al 1983Soloff et al 1989) Amitryptiline has been associ-ated with paradoxical increases in suicidality para-noia and behavioural dysregulation attributed tolsquogeneralized disinhibition of cognitive and affec-tive controlsrsquo (Soloff et al 1986a 1987) Indeedborderline patients have dif 1047297culty cognitively
236 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
resolving con1047298ict among stimulus dimensions(Posner et al 2002) and prefrontal hypofunctioncan be seen after a serotonergic stimulus in subjects
with prominent impulsive aggression (New et al
2002) Thus medications with adverse cognitivesequelae including anticholinergic side-effects may contribute to worsening impulsivity As mentioned in prior reviews the use of TCAs in treating BPD isdiscouraged (Abraham amp Calabrese 2008 Mercer et al 2009) Their use is also associated with po-tentially signi1047297cant risk of overdose
MONOAMINE OXIDASE INHIBITORS (MAOIS)
Despite hesitancyinprescribingMAOIstopatients with prominent impulsivity or self-injurious behav-iour some recommend these medications for BPDpatientswhocantakethemsafelyandreliablyInterestin MAOIs for BPD is rooted in their differential ef-1047297cacy for conditions such as hysteroid dysphoria or atypical depression viewed as being related to oneother and BPD (Kayser et al 1985 Liebowitz ampKlein 1981) In a crossover trial with multiplemedication phases only tranylcypromine was as-sociated with higher patient-rated improvementscores and completion rates (Cowdry amp Gardner1988)
Similarly relative prominence of BPD symptomspredicted superiority of phenelzine (Parsons et al
1989) Phenelzine is bene1047297cial in the treatment of hostility anxiety and borderline symptoms (Soloff et al 1993) In some patients it could cause un-
comfortable excitement and emotional reactivity (Cornelius et al 1993) Thus although there isevidence for their ef 1047297cacy many patients may nottolerate these medications Other associated risksof MAOIs include toxicity in overdose and po-tentially fatal hypertensive crises or serotoninsyndrome
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIS)
SSRIs are thought to potentiate serotonergicneuromodulation but demonstrate more favour-able side-effect pro1047297les Fluoxetine reduced anger in BPD independent of any antidepressant ef-fect (Salzman et al 1995) It also improved verbaland impulsive aggression irritability and overallfunctioning (Coccaro amp Kavoussi 1997) Simi-larly a RCT with paroxetine demonstrated ef 1047297cacy in preventing recurrent suicidal behaviour but nosigni1047297cant effect on depression hopelessness or anger (Verkes et al 1998) By contrast there waslittle added bene1047297t from 1047298uoxetine when added to
dialectical behavioural therapy (DBT) (Simpsonet al 2004)
On the other hand 1047298uvoxamine decreased af-fective lability but not scores of impulsivity or ag-gression (Rinne et al 2002) Although SSRIsdecrease impulsivity and aggression in BPD patients
with comorbid intermittent explosive disorder (IED Coccaro amp Kavoussi 1997 New et al 2004)data from BPD subjects without comorbid IED areinconsistent (Rinne et al 2002) Previous reviewshave emphasized that effect sizes for antidepressantpharmacotherapy vary widely between classes and trials (Ingenhoven et al 2010 Lieb et al 2010Mercer et al 2009) Nevertheless current evidence-based practice recommends use of SSRIs due topotential bene1047297ts on impulsive aggression that may outweigh associated risks There has been no evi-dence that antidepressants alleviate the chronicemptiness shameful self-concept and intrapsychicpain in BPD
FIRST-GENERATION ANTIPSYCHOTICS
An early interest in antipsychotic medications for treating BPD probably arose from a conception of BPD as a variant of schizophrenia (eg Deutsch1942) Antipsychotics have demonstrated partialef 1047297cacy re1047298ecting underlying abnormalities in do-paminergic signalling Borderline subjects demon-strate high levels of the dopamine metabolitehomovallinic acid in both plasma and cerebrospinal1047298uid (Siever et al unpublished data) Prior to more
widespread use of SSRIs antipsychotics demon-strated ef 1047297cacy in decreasing psychotic-like symptoms(Goldberg et al 1986 Soloff et al 1986b ) depression(Soloff et al 1986b ) irritability (Cornelius et al
1993) and general symptom severity (Cowdry ampGardner 1988 Soloff et al 1986b )
A recent Cochrane review suggests haloperidol isef 1047297cacious in reducing anger in BPD and treatment
with 1047298upenthixol decanoate reduced suicidal be-haviour (Lieb et al 2010) By contrast evidence for ef 1047297cacy of neuroleptics on affective symptomspsychosis and anxiety remains inconsistent The
dosage of antipsychotic medication for evidence-based treatment of BPD is usually lower thanschizophrenia High drop-out rates are noted and risk of extrapyramidal symptoms may further limitthe utility of neuroleptics
SECOND-GENERATION ANTIPSYCHOTICS
Classical neuroleptics have largely been superseded by atypical antipsychotics whose broader therapeuticbene1047297ts may be explained by activity beyond the D2
receptor As mentioned in prior reviews olanzapine
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 237
has proven bene1047297cial in treatment of BPD patientsrsquoanxiety anger interpersonal sensitivity and para-noia but not depression (Zanarini amp Frankenburg2001) as well as improving general clinical func-tioning and BPD symptomatology (Bogenschutz ampNurnberg 2004) A recent large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulzet al 2008) although the authors suggested thatpatients may have been underdosed A study comparing olanzapine to haloperidol showed nobetween-group differences except with respect toside-effects with more weight gain associated witholanzapine and more extra-pyramidal side-effects
with haloperidol (Shafti amp Shahveisi 2010) Adding 1047298uoxetine to olanzapine did not elicit
further bene1047297t except that subjects receiving bothmedications gained less weight than those receiving only olanzapine (Zanarini et al 2004b ) The addi-tion of olanzapine to DBT reduced depressionanxiety and impulsive aggression but the magni-
tude and timing of these bene1047297ts relative to DBT was dif 1047297cult to interpret (Soler et al 2005)
Aripiprazolehas a novelmechanismof action(partialagonist at the dopamine D2 receptor and serotonin 5-HT1A receptor antagonist at the 5-HT2A receptor) Itmay be more favourable than other atypicals withrespect to metabolic side-effects A longer half-lifemay be more effective for patients susceptible to non-adherence In non-suicidal BPD patients aripipra-zole was effective in reducing aggression anxietydepression psychosis interpersonal symptoms self-injurious behaviour and subjective distress There
were no signi1047297cant differences between groups in weight gain (Nickel et al 2006) An 18-month open-label follow-up showed sustained improvements and continued tolerability (Nickel et al 2007)
Previously open-label trials suggested possibleef 1047297cacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al 2004 2006) Theside-effect and psychopharmacological pro1047297les of ziprasidone indicated lesser metabolic risks and an-tidepressant and anxiolytic effects thought to beindependent of antidopaminergic activity (Keck et al 1998 Tandon 2000 Wilner et al 2002)
Despite such promise a recent RCT with ziprasi-done was negative (Pascual et al 2008) Thusevidence-based practice supports use of aripiprazolebut not ziprasidone in treating BPD
In meta-analyses the class of antipsychotics had moderate effect in treating aggression but no sig-ni1047297cant effect on depression although aripiprazoleand olanzapine may be exceptions (Lieb et al 2010Mercer et al 2009) For aypicals metabolic side-effects may limit clinical utility Because 29-53of borderline patients ful1047297l criteria for an eating disorder at some point in their lives (Lieb et al
2004) and a signi1047297cant number suffer from obesity (Frankenburg amp Zanarini 2006) iatrogenic meta-bolic risks must be regarded as serious Althoughevidence-based practices have advanced in treating aggression associated with BPD chronic emptinessaffective lability and interpersonal dysfunction lack effective evidence-based medication treatments
MOOD STABILIZERS AND ANTICONVULSANTS
Due to BPD patientsrsquo affective dysregulation and comorbidity with bipolar disorder some have clas-si1047297ed BPD within the bipolar spectrum (Akiskal2004 Smith et al 2004) although most continue todistinguish between the two particularly withregard to interpersonal dysfunction (Bolton ampGunderson 1996 Henry et al 2001 Paris 2004)Mood stabilizers are indeed becoming a more in-tegral component of evidence-based treatmentpractices for BPD
Lithium is bene1047297cial in treating BPD particularly in terms of quieting affective instability (Links et al
1990 Rifkin et al 1972) Lithium toxicity andor non-compliance may be problematic due to BPDpatientsrsquo characteristic impulsive self-destructivebehaviour
However anticonvulsants are more often rec-ommended for treatment of rapid-cycling bipolar disorder the variant most closely resembling BPDCarbamazepine demonstrated lsquodramaticrsquo reductionsin behavioural dyscontrol and improvements inglobal functioning anxiety anger euphoria im-
pulsivity and suicidality but it was associated with worsening melancholic depression (Gardner ampCowdry 1986a b ) and therapeutic bene1047297ts could not be replicated in in-patients (de la Fuente ampLotstra 1994)
Although high drop-out rates were reported withdivalproex (Hollander et al 2001) it subsequently demonstrated bene1047297ts on interpersonal sensitivityanger and aggression in euthymic borderline wo-men with bipolar II (Frankenburg amp Zanarini2002) Divalproex reduced aggression irritabilityand overall disease severity in patients with Cluster
B personality disorders and prominent impulsiveaggression (Hollander et al 2003) Differentialtreatment response in Cluster B subjects was en-hanced by baseline trait impulsivity and state ag-gression although not affective instability (Hollander et al 2005)
Lamotrigine extends periods of euthymia in bi-polar patients (eg Goodwin et al 2004) Potentialbene1047297ts also include pro-cognitive activity as pre-viously demonstrated in normal volunteers(Aldenkamp et al 2002) Lamotrigine effectively reduced BPD patientsrsquo anger (Tritt et al 2005) and
238 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
242 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 243
antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
resolving con1047298ict among stimulus dimensions(Posner et al 2002) and prefrontal hypofunctioncan be seen after a serotonergic stimulus in subjects
with prominent impulsive aggression (New et al
2002) Thus medications with adverse cognitivesequelae including anticholinergic side-effects may contribute to worsening impulsivity As mentioned in prior reviews the use of TCAs in treating BPD isdiscouraged (Abraham amp Calabrese 2008 Mercer et al 2009) Their use is also associated with po-tentially signi1047297cant risk of overdose
MONOAMINE OXIDASE INHIBITORS (MAOIS)
Despite hesitancyinprescribingMAOIstopatients with prominent impulsivity or self-injurious behav-iour some recommend these medications for BPDpatientswhocantakethemsafelyandreliablyInterestin MAOIs for BPD is rooted in their differential ef-1047297cacy for conditions such as hysteroid dysphoria or atypical depression viewed as being related to oneother and BPD (Kayser et al 1985 Liebowitz ampKlein 1981) In a crossover trial with multiplemedication phases only tranylcypromine was as-sociated with higher patient-rated improvementscores and completion rates (Cowdry amp Gardner1988)
Similarly relative prominence of BPD symptomspredicted superiority of phenelzine (Parsons et al
1989) Phenelzine is bene1047297cial in the treatment of hostility anxiety and borderline symptoms (Soloff et al 1993) In some patients it could cause un-
comfortable excitement and emotional reactivity (Cornelius et al 1993) Thus although there isevidence for their ef 1047297cacy many patients may nottolerate these medications Other associated risksof MAOIs include toxicity in overdose and po-tentially fatal hypertensive crises or serotoninsyndrome
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
(SSRIS)
SSRIs are thought to potentiate serotonergicneuromodulation but demonstrate more favour-able side-effect pro1047297les Fluoxetine reduced anger in BPD independent of any antidepressant ef-fect (Salzman et al 1995) It also improved verbaland impulsive aggression irritability and overallfunctioning (Coccaro amp Kavoussi 1997) Simi-larly a RCT with paroxetine demonstrated ef 1047297cacy in preventing recurrent suicidal behaviour but nosigni1047297cant effect on depression hopelessness or anger (Verkes et al 1998) By contrast there waslittle added bene1047297t from 1047298uoxetine when added to
dialectical behavioural therapy (DBT) (Simpsonet al 2004)
On the other hand 1047298uvoxamine decreased af-fective lability but not scores of impulsivity or ag-gression (Rinne et al 2002) Although SSRIsdecrease impulsivity and aggression in BPD patients
with comorbid intermittent explosive disorder (IED Coccaro amp Kavoussi 1997 New et al 2004)data from BPD subjects without comorbid IED areinconsistent (Rinne et al 2002) Previous reviewshave emphasized that effect sizes for antidepressantpharmacotherapy vary widely between classes and trials (Ingenhoven et al 2010 Lieb et al 2010Mercer et al 2009) Nevertheless current evidence-based practice recommends use of SSRIs due topotential bene1047297ts on impulsive aggression that may outweigh associated risks There has been no evi-dence that antidepressants alleviate the chronicemptiness shameful self-concept and intrapsychicpain in BPD
FIRST-GENERATION ANTIPSYCHOTICS
An early interest in antipsychotic medications for treating BPD probably arose from a conception of BPD as a variant of schizophrenia (eg Deutsch1942) Antipsychotics have demonstrated partialef 1047297cacy re1047298ecting underlying abnormalities in do-paminergic signalling Borderline subjects demon-strate high levels of the dopamine metabolitehomovallinic acid in both plasma and cerebrospinal1047298uid (Siever et al unpublished data) Prior to more
widespread use of SSRIs antipsychotics demon-strated ef 1047297cacy in decreasing psychotic-like symptoms(Goldberg et al 1986 Soloff et al 1986b ) depression(Soloff et al 1986b ) irritability (Cornelius et al
1993) and general symptom severity (Cowdry ampGardner 1988 Soloff et al 1986b )
A recent Cochrane review suggests haloperidol isef 1047297cacious in reducing anger in BPD and treatment
with 1047298upenthixol decanoate reduced suicidal be-haviour (Lieb et al 2010) By contrast evidence for ef 1047297cacy of neuroleptics on affective symptomspsychosis and anxiety remains inconsistent The
dosage of antipsychotic medication for evidence-based treatment of BPD is usually lower thanschizophrenia High drop-out rates are noted and risk of extrapyramidal symptoms may further limitthe utility of neuroleptics
SECOND-GENERATION ANTIPSYCHOTICS
Classical neuroleptics have largely been superseded by atypical antipsychotics whose broader therapeuticbene1047297ts may be explained by activity beyond the D2
receptor As mentioned in prior reviews olanzapine
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 237
has proven bene1047297cial in treatment of BPD patientsrsquoanxiety anger interpersonal sensitivity and para-noia but not depression (Zanarini amp Frankenburg2001) as well as improving general clinical func-tioning and BPD symptomatology (Bogenschutz ampNurnberg 2004) A recent large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulzet al 2008) although the authors suggested thatpatients may have been underdosed A study comparing olanzapine to haloperidol showed nobetween-group differences except with respect toside-effects with more weight gain associated witholanzapine and more extra-pyramidal side-effects
with haloperidol (Shafti amp Shahveisi 2010) Adding 1047298uoxetine to olanzapine did not elicit
further bene1047297t except that subjects receiving bothmedications gained less weight than those receiving only olanzapine (Zanarini et al 2004b ) The addi-tion of olanzapine to DBT reduced depressionanxiety and impulsive aggression but the magni-
tude and timing of these bene1047297ts relative to DBT was dif 1047297cult to interpret (Soler et al 2005)
Aripiprazolehas a novelmechanismof action(partialagonist at the dopamine D2 receptor and serotonin 5-HT1A receptor antagonist at the 5-HT2A receptor) Itmay be more favourable than other atypicals withrespect to metabolic side-effects A longer half-lifemay be more effective for patients susceptible to non-adherence In non-suicidal BPD patients aripipra-zole was effective in reducing aggression anxietydepression psychosis interpersonal symptoms self-injurious behaviour and subjective distress There
were no signi1047297cant differences between groups in weight gain (Nickel et al 2006) An 18-month open-label follow-up showed sustained improvements and continued tolerability (Nickel et al 2007)
Previously open-label trials suggested possibleef 1047297cacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al 2004 2006) Theside-effect and psychopharmacological pro1047297les of ziprasidone indicated lesser metabolic risks and an-tidepressant and anxiolytic effects thought to beindependent of antidopaminergic activity (Keck et al 1998 Tandon 2000 Wilner et al 2002)
Despite such promise a recent RCT with ziprasi-done was negative (Pascual et al 2008) Thusevidence-based practice supports use of aripiprazolebut not ziprasidone in treating BPD
In meta-analyses the class of antipsychotics had moderate effect in treating aggression but no sig-ni1047297cant effect on depression although aripiprazoleand olanzapine may be exceptions (Lieb et al 2010Mercer et al 2009) For aypicals metabolic side-effects may limit clinical utility Because 29-53of borderline patients ful1047297l criteria for an eating disorder at some point in their lives (Lieb et al
2004) and a signi1047297cant number suffer from obesity (Frankenburg amp Zanarini 2006) iatrogenic meta-bolic risks must be regarded as serious Althoughevidence-based practices have advanced in treating aggression associated with BPD chronic emptinessaffective lability and interpersonal dysfunction lack effective evidence-based medication treatments
MOOD STABILIZERS AND ANTICONVULSANTS
Due to BPD patientsrsquo affective dysregulation and comorbidity with bipolar disorder some have clas-si1047297ed BPD within the bipolar spectrum (Akiskal2004 Smith et al 2004) although most continue todistinguish between the two particularly withregard to interpersonal dysfunction (Bolton ampGunderson 1996 Henry et al 2001 Paris 2004)Mood stabilizers are indeed becoming a more in-tegral component of evidence-based treatmentpractices for BPD
Lithium is bene1047297cial in treating BPD particularly in terms of quieting affective instability (Links et al
1990 Rifkin et al 1972) Lithium toxicity andor non-compliance may be problematic due to BPDpatientsrsquo characteristic impulsive self-destructivebehaviour
However anticonvulsants are more often rec-ommended for treatment of rapid-cycling bipolar disorder the variant most closely resembling BPDCarbamazepine demonstrated lsquodramaticrsquo reductionsin behavioural dyscontrol and improvements inglobal functioning anxiety anger euphoria im-
pulsivity and suicidality but it was associated with worsening melancholic depression (Gardner ampCowdry 1986a b ) and therapeutic bene1047297ts could not be replicated in in-patients (de la Fuente ampLotstra 1994)
Although high drop-out rates were reported withdivalproex (Hollander et al 2001) it subsequently demonstrated bene1047297ts on interpersonal sensitivityanger and aggression in euthymic borderline wo-men with bipolar II (Frankenburg amp Zanarini2002) Divalproex reduced aggression irritabilityand overall disease severity in patients with Cluster
B personality disorders and prominent impulsiveaggression (Hollander et al 2003) Differentialtreatment response in Cluster B subjects was en-hanced by baseline trait impulsivity and state ag-gression although not affective instability (Hollander et al 2005)
Lamotrigine extends periods of euthymia in bi-polar patients (eg Goodwin et al 2004) Potentialbene1047297ts also include pro-cognitive activity as pre-viously demonstrated in normal volunteers(Aldenkamp et al 2002) Lamotrigine effectively reduced BPD patientsrsquo anger (Tritt et al 2005) and
238 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
242 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 243
antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
has proven bene1047297cial in treatment of BPD patientsrsquoanxiety anger interpersonal sensitivity and para-noia but not depression (Zanarini amp Frankenburg2001) as well as improving general clinical func-tioning and BPD symptomatology (Bogenschutz ampNurnberg 2004) A recent large RCT demonstrated no effect of olanzapine on BPD symptoms (Schulzet al 2008) although the authors suggested thatpatients may have been underdosed A study comparing olanzapine to haloperidol showed nobetween-group differences except with respect toside-effects with more weight gain associated witholanzapine and more extra-pyramidal side-effects
with haloperidol (Shafti amp Shahveisi 2010) Adding 1047298uoxetine to olanzapine did not elicit
further bene1047297t except that subjects receiving bothmedications gained less weight than those receiving only olanzapine (Zanarini et al 2004b ) The addi-tion of olanzapine to DBT reduced depressionanxiety and impulsive aggression but the magni-
tude and timing of these bene1047297ts relative to DBT was dif 1047297cult to interpret (Soler et al 2005)
Aripiprazolehas a novelmechanismof action(partialagonist at the dopamine D2 receptor and serotonin 5-HT1A receptor antagonist at the 5-HT2A receptor) Itmay be more favourable than other atypicals withrespect to metabolic side-effects A longer half-lifemay be more effective for patients susceptible to non-adherence In non-suicidal BPD patients aripipra-zole was effective in reducing aggression anxietydepression psychosis interpersonal symptoms self-injurious behaviour and subjective distress There
were no signi1047297cant differences between groups in weight gain (Nickel et al 2006) An 18-month open-label follow-up showed sustained improvements and continued tolerability (Nickel et al 2007)
Previously open-label trials suggested possibleef 1047297cacy of ziprasidone in BPD patients during acute exacerbations (Pascual et al 2004 2006) Theside-effect and psychopharmacological pro1047297les of ziprasidone indicated lesser metabolic risks and an-tidepressant and anxiolytic effects thought to beindependent of antidopaminergic activity (Keck et al 1998 Tandon 2000 Wilner et al 2002)
Despite such promise a recent RCT with ziprasi-done was negative (Pascual et al 2008) Thusevidence-based practice supports use of aripiprazolebut not ziprasidone in treating BPD
In meta-analyses the class of antipsychotics had moderate effect in treating aggression but no sig-ni1047297cant effect on depression although aripiprazoleand olanzapine may be exceptions (Lieb et al 2010Mercer et al 2009) For aypicals metabolic side-effects may limit clinical utility Because 29-53of borderline patients ful1047297l criteria for an eating disorder at some point in their lives (Lieb et al
2004) and a signi1047297cant number suffer from obesity (Frankenburg amp Zanarini 2006) iatrogenic meta-bolic risks must be regarded as serious Althoughevidence-based practices have advanced in treating aggression associated with BPD chronic emptinessaffective lability and interpersonal dysfunction lack effective evidence-based medication treatments
MOOD STABILIZERS AND ANTICONVULSANTS
Due to BPD patientsrsquo affective dysregulation and comorbidity with bipolar disorder some have clas-si1047297ed BPD within the bipolar spectrum (Akiskal2004 Smith et al 2004) although most continue todistinguish between the two particularly withregard to interpersonal dysfunction (Bolton ampGunderson 1996 Henry et al 2001 Paris 2004)Mood stabilizers are indeed becoming a more in-tegral component of evidence-based treatmentpractices for BPD
Lithium is bene1047297cial in treating BPD particularly in terms of quieting affective instability (Links et al
1990 Rifkin et al 1972) Lithium toxicity andor non-compliance may be problematic due to BPDpatientsrsquo characteristic impulsive self-destructivebehaviour
However anticonvulsants are more often rec-ommended for treatment of rapid-cycling bipolar disorder the variant most closely resembling BPDCarbamazepine demonstrated lsquodramaticrsquo reductionsin behavioural dyscontrol and improvements inglobal functioning anxiety anger euphoria im-
pulsivity and suicidality but it was associated with worsening melancholic depression (Gardner ampCowdry 1986a b ) and therapeutic bene1047297ts could not be replicated in in-patients (de la Fuente ampLotstra 1994)
Although high drop-out rates were reported withdivalproex (Hollander et al 2001) it subsequently demonstrated bene1047297ts on interpersonal sensitivityanger and aggression in euthymic borderline wo-men with bipolar II (Frankenburg amp Zanarini2002) Divalproex reduced aggression irritabilityand overall disease severity in patients with Cluster
B personality disorders and prominent impulsiveaggression (Hollander et al 2003) Differentialtreatment response in Cluster B subjects was en-hanced by baseline trait impulsivity and state ag-gression although not affective instability (Hollander et al 2005)
Lamotrigine extends periods of euthymia in bi-polar patients (eg Goodwin et al 2004) Potentialbene1047297ts also include pro-cognitive activity as pre-viously demonstrated in normal volunteers(Aldenkamp et al 2002) Lamotrigine effectively reduced BPD patientsrsquo anger (Tritt et al 2005) and
238 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
242 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 243
antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
242 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 243
antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
242 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 243
antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
242 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 243
antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
an 18-month follow-up demonstrated maintenanceof this anti-aggressive effect (Leiberich et al 2008)More recently BPD patients without comorbid bipolar disorder but with prominent affective in-stability demonstrated reduced affective lability and
impulsivity but no change in other BPD symp-toms when treated with lamotrigine (Reich et al
2009) Documented effects on impulsivity angerand affective lability in BPD thus make lamo-trigine an attractive pharmacotherapeutic option
Table 4 Continued
Study Diagnosis N M edication(s) Dosage(s)
Design
duration
Results in active drug
group(s)
Mean dose 1924 mgd at
endpoint Paroxetine
Began with 20 mgd with
flexible increases by 10
mg every week tomaximum of 50 mgd
Mean dose 442 mgd at
endpoint
social functioning
Possibly more rapid
effect of venlafaxine
Kasper et al
(2005)
Social
phobia
358 males and
females (100
generalized
type)
Escitalopram Began with 10 mgd with
possible increase to 20
mgd after 4 6 or 8 wk
for unsatisfactory
response Mean dose
176 mgd at endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 54
response rate vs 39 in
placebo group
Liebowitz
et al
(2005b )
Social
phobia
271 males and
females (100
generalized
type)
Venlafaxine ER Began with 75 mgd for first
week with increase to
150 mg in 2nd week and
to maximum of 225 mg in
3rd week if clinicallyindicated
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning 44
response rate vs 30 in
placebo group
Liebowitz
et al
(2005a )
Social
phobia
413 males and
females (100
generalized
type)
Venlafaxine
ER
paroxetine
Venlafaxine ER Began with
75 mgd-225 mgd with
flexible 75 mg increases
each week to maximum
of 225 mgd Mean dose
2017 mgd at endpoint
Paroxetine Began with
20 mgd with flexible
10 mg increases to
maximum of 50 mgd
Mean dose 46 mgd at
endpoint
Parallel design 12 wk Reduction of social anxiety
and improvement in
social functioning
compared with placebo
for both medication
groups Both medications
equally efficacious
566 response rate for
venlafaxine 625 for
paroxetine and 361
for placebo group
Stein et al(2005)
Socialphobia
386 males andfemales (100
generalized
type)
Venlafaxine Comparison of low-dose(fixed) to higher-dose
(flexible) All began with
75 mgd and if
randomized to higher-
dose increased to 150
mgd after first week
with further flexible
increase to 225 mgd
after 2nd week
Parallel design 24 wk Reduction in social phobiaand improvement in
social functioning in both
dosage groups 31
remission rate for both
venlafaxine groups
combined vs 16 in
placebo group
Montgomery
et al (2005)
Social
phobia
517 males and
females (100
generalized
type)
Escitalopram During open-label phase
began with 10 mgd with
possible increase to 20
mgd at wk 2 4 or 8 CGI
responders entered
relapse prevention phase
with last dose continued
for remainder
12-wk open-label
phase followed by
24-wk fixed-
dose relapse
prevention
(parallel design
double-blind RCT)
Relapse rate 22 vs 50
in placebo group Median
time to relapse was 407d
vs 144d for placebo
group No direct
comparison made
between doses
For abbreviations in table see notes to Table 3
242 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 243
antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
Nevertheless the latter study reported higher ratesof skin rash than reported elsewhere Due to thislife-threatening risk clinicians should monitor patients closely and titrate the dose slowly
Although topiramatersquos utility in bipolar disorder is controversial it is ef 1047297cacious for BPD Top-iramate reduced anger in female BPD subjects(Nickel et al 2004) and a similar RCT reported thiseffect in males with BPD (Nickel et al 2005) A separate RCT conducted with female BPD patientstaking topiramate also demonstrated improve-ments in somatization anxiety health-related quality of life overall stress interpersonal sensi-tivity hostility and other facets of interpersonalfunctioning (Loew et al 2006) Although no drop-outs were due to side-effects cognitive impairmentreduced appetite and weight loss were commonly reported
Open-labelfollow-upstudiestotheseinitialRCTsdemonstrated maintenance of therapeutic gains and
additional weight loss associated with topiramateand the authors therefore encouraged longer-termuse (Loew amp Nickel 2008 Nickel amp Loew2008) The authors admit that the patients studied
were not the most severe Because cognitive side-effects of topiramate may more adversely affect se-verely impulsive or suicidal BPD patients a carefulriskbene1047297t analysis should be undertaken beforeprescribing
Overall mood stabilizers and anticonvulsants areeffective in treating BPD particularly symptoms of impulsivity and aggression As a class they also
demonstrate a moderate effect in treating depressionin BPD (Ingenhoven et al 2010 Mercer et al
2009) Although they are an important componentof evidence-based practice patients should beclosely monitored because some may not toleratethese medications The relatively slow titrationschedules and the necessity of drawing plasma levels to reach an optimal dose may limit clinicaleffectiveness particularly in a population oftencharacterized by impulsive non-compliance Al-though impulsivity and aggression appear to re-spond to treatment there is little evidence of any
effect from mood stabilizers in improving in-terpersonal dysfunction or disturbances of iden-tity Future research should focus more closely onthese domains
OTHER MEDICATIONS
Although there have been case reports of im-provement in BPD patients treated with alprazolam(Faltus 1984) theclass of benzodiazepines has beenassociated with disinhibition worsening impulsiv-ity suicidal ideation and behavioural dyscontrol in
BPD (Cowdry amp Gardner 1988) Benzodiazepinesare vehemently discouraged due to these risks as
well as elevated risks of dependence Patients may abuse benzodiazepines to self-medicate intrapsychicpain interfering with progress in psychotherapy and adversely affecting cognition
The omega-3 fatty acid ethyl-eicosapentaenoicacid (E-EPA) decreased aggression and depressioninwomenwithmoderatetosevereBPD(ZanariniampFrankenburg 2003) A similar anti-aggressive effect
was observedin two other RCTswithhealthy subjects(Hamazaki et al 1996 2002) Omega-3 fatty acidsmay act by inhibiting protein kinase C a mechanismthought to be involved in lithium and valproic acid pharmacotherapy (Peet amp Stokes 2005)
Clonidine a presynaptic a2 noradrenergic ago-nist has been studied in a trial comparing two dosesgiven to BPD patients amidst states of lsquoacute aver-sive inner tensionrsquo Although tension dissociativesymptoms self-injurious urges and suicidal idea-
tion decreased for both doses there was no differ-ence between the two doses (Philipsen et al 2004a )Ziegenhorn et al (2009) conducted an RCT of clonidine with BPD subjects with prominentsymptoms of hyperarousal Most of them thereforealso met criteria for comorbid PTSD which limited generalizability of 1047297ndings In the total sample clo-nidine treatment improved hyperarousal subjectivequality of sleep and anxiety but not borderline-speci1047297c symptoms and these bene1047297ts were not seenin the minuscule non-PTSD subsample Althoughclonidine and similar agents have been ef 1047297cacious in
the treatment of PTSD (eg Southwick et al 1999Strawn amp Geracioti 2008) their role in treating BPD remains unclear
A subset of borderline patients engage in self-injurious behaviour or more indirect forms of self-destructiveness (eg bulimia substance abuse)
which may re1047298ect disturbances in endogenousopioids Some BPD patients become disinhibited and aggressive after receiving opiate medications(Saper 2000) and morphine administration in-creased self-injurious behaviour in one patient withBPD (Thurauf amp Washeim 2000) Naloxone used
during acute states of aversive tension and dissoci-ation in BPD demonstrated no signi1047297cant bene1047297t(Philipsen et al 2004b ) Naltrexone has been used successfully in open-label trials to treat self-harm(Griengl et al 2001 McGee 1997 Roth et al
1996) and dissociation (Bohus et al 1999) There-fore evidence for treatment of BPD with medicationsacting upon opioid receptors remains inconsistentTreatment with full agonists or antagonists may becomplicated by differences between chronic effectson post-synaptic receptor density on the one handand distinct acute effects of receptor agonism or
focuspsychiatryonlineorg FOCUS Spring 2013 Vol XI No 2 243
antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
antagonism ontheother (Prossin et al 2010Stanley ampSiever 2010) The potential for abuse of full opioid agonists may pose too great a risk for an effectivetreatment For both these reasons future trials withpartial opioid agonists may be more effective in re-ducing self-injury interpersonal dysfunction and intrapsychic pain
A VOIDANT PERSONALITY DISORDER
(A VPD)
AvPD is a common personality disorder (Loranger et al 1994) existing as a comorbid condition in upto one-third of all patients with anxiety disorders(Alden et al 2002) Up to 56 of AvPD patientscontinue to meet criteria after 2 years (Skodol et al
2005) Nevertheless distinguishing between thisand generalized social phobia has been dif 1047297cult dueto similarities in diagnostic criteria as well as fre-quently reported comorbidity No neurobiological
evidence indicates how the aetiology and psychopa-thology of AvPD differs from social phobia
At present clinicians should lsquoextrapolate from data which are primarily related to anxiety disordershellipto apply treatment strategieshellip that have primarily been developed for social phobia rsquo (Herpertz et al
2007) Evidence-based treatment for AvPD would thereby include venlafaxine and SSRIs as 1047297rst-lineagents A potential caveat is mentioned for sertra-line if symptoms began in childhood or adoles-cence in which case lesser ef 1047297cacy was reported (van Ameringen et al 2004) Gabapentin (Pande
et al 1999) and pregabalin (Pande et al 2004)have also demonstrated ef 1047297cacy in social phobiaSecond-line agents would include reversible MAOIsbrofaromine and moclobemide for which there ispresently less robust evidence and the irreversibleMAOI phenelzine which entails risk of serious side-effects
OTHER PERSONALITY DISORDERSMALADAPTIVE TRAITS
Pharmacological research is strikingly absent from
other personality disorders In these cases medicationis particularly indicated in the treatment of comorbid Axis I disorders particularly mood and anxiety dis-orders that frequently co-occur with narcissistichistrionic and dependent personality disordersSSRIs may be of particular clinical bene1047297t relative toTCAs given their more favourable side-effect pro1047297leand the possibility of an independent effect on per-sonality factors (Ekselius amp von Knorring 1998Reich et al 2002) With the advent of thenext DSMa greater emphasis on a dimensional diagnostic ap-proach to personality disorders will probably cast
greater importance upon pharmacotherapeutic inter-ventions targeting dimensions common to a variety of current Axis II diagnoses
One such dimension of personality dysfunction isimpulsive aggression Recent trials with levetir-acetamand oxcarbazepinefor impulsive aggressionrecruited individuals with IED without signi1047297cantcomorbidity (eg Mattes 2005 2008) whileother trials recruited subjects with personality disorders and a history of impulsive aggression (eg Coccaro et al 2009 Hollander et al 2003)Coccaro et al (2009) found an anti-aggressiveeffect of 1047298uoxetine in patients with IED and per-sonality disorders Several anticonvulsants (mostnotably divalproex oxcarbazepine and phenyt-oin) have also demonstrated evidence in treating impulsive aggression across diagnoses (Huband et al 2010)
FUTURE DIRECTIONS
Although the past two decades of research haveushered a paradigm shift in personality disordersmost research has been limited to BPD and SPDFuture research should be directed towards thetreatment of other Axis II diagnoses and dimen-sions of dysfunction across diagnoses Althoughresearch has made great strides towards under-standing impulsivity and aggression similar neu-robiological substrates should be sought for other dimensionsofpersonalityOnlybyclarifyingthesegaps in the evidence base can clinicians anticipate
more effective evidence-based psychopharmaco-logical practices for the treatment of personality disorders
FurthereffortstounderstandtowhatextentAvPDdiffers from generalized social phobia are warrantedThis may require understanding distinctions be-tween these diagnoses in neurobiology of fear and socialinhibitionandinthedevelopmentaltrajectory of each disorder For SPD the effects of pro-cognitive interventions should be evaluated withrespect to social isolation and overall function-ing More comprehensive efforts are needed to
understand the underlying neurobiology of SPDto improve evidence-based practices Further char-acterization of the interpersonal dysfunction and cognitive sensory-gating abnormalities seen in SPD
will probably improve the effect of treatment ongeneral functioning Efforts at understanding theneurobiology of schizophrenia and its prodrome willalso assist in de1047297ning targets for pharmacotherapyClarifying the respective roles of genes and envi-ronment in shaping the course of the schizophrenia spectrum will also uncover future pharmacother-apeutic targets
244 Spring 2013 Vol XI No 2 F O C U S T H E J O U R N A L O F L I F E L O N G L E A R N I N G I N P S Y C H I A T R Y
Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
Within BPD research has detailed more extensiveevidence-based practices for treating impulsive ag-gression Anticonvulsants and atypical anti-psychotics areacquiring more prominentroles in thetreatment of BPD relative to SSRIs Neverthelessgreaterserotonergicspeci1047297citywillprobablyimprovethe ef 1047297cacy of treatments For example selective5-HT2A antagonism but not 5-HT2C antagonismhas been shown to decrease impulsivity (Higginset al 2003 Winstanley et al 2004)
Futureresearch will also focus on treating affectiveinstability intrapsychic pain dissociation and in-terpersonal dysfunction associated with BPD BPDhas been conceptualized as related to disturbed at-tachment (Fonagy amp Luyten 2009) and dysfunc-tional representations of self and other (Bender ampSkodol 2007) with other symptoms seen as se-quelae to this core feature Oxytocin vasopressinand opioids may therefore be of particular rele-vance for treating BPD (Stanley amp Siever 2010)
given the developmental role of these neuro-peptides in attachment and the relationship be-tween attachment security and stable socialcognitive representations of self and other (Fonagy amp Luyten 2009) Although these domains havebeen exclusively treated with psychotherapy re-search in the neurobiology of af 1047297liative behaviour (eg Depue amp Morrone-Strupinsky 2005) as well asself-injury and dissociation (Mauchnik amp Schmahl2010) may eventually provide novel pharmacother-apeutic targets
For all personality disorders integrating psycho-
pharmacology with neurobiological effects of psy-chotherapy may produce synergistic and long-lasting bene1047297ts Evidence-based practice continues to recom-mend an approach that includes both psychotherapy and pharmacotherapy Although experienced therapistsrsquo contributions to personality theory and empirical research often continue to be at odds withone another future research should attempt toconnect theory with empirically-validated psycho-pharmacological targets By understanding the neu-robiology underlying increasingly complex behaviorpharmacotherapy can be optimized and targeted to
personality dimensions previously considered sus-ceptible only to psychotherapy
R E F E R E N C E S
Abraham PF Calabrese JR (2008) Evidence-based pharmacologic treatment of
borderline personality disorder a shift from SSRIs to anticonvulsants and atypical
antipsychotics Journal of Affective Disorders 111 21ndash30
Akiskal HS (2004) Demystifying borderline personality critique of the concept
and unorthodox reflections on its natural kinship with the bipolar spectrum Acta
Psychiatrica Scandinavica 110 401ndash407
Alden LE Paosa JM Taylor CT Ryder AG (2002) Avoidant personality disorder
current status and future directions Journal of Personality Disorders 16 1ndash29
Aldenkamp AP Arends J Boorsma HPR Diepman L et al (2002) Randomized
double-blind parallel-group study comparing cognitive effects of a low-dose
lamotrigine with valproate and placebo in healthy volunteers Epilepsia 43 19ndash26
Allgulander C (1999) Paroxetine in social anxiety disorder a randomized
placebo-controlled study Acta Psychiatrica Scandinavica 100 193ndash198
Allgulander C Mangano R Zhang J Dahl AA et al (2004) Efficacy of venlafaxine
ER in patients with social anxiety disorder a double-blind placebo-controlled
parallel-group comparison with paroxetine Human Psychopharmacology 19
387ndash396
APA (1994) Diagnostic and Statistical Manual of Mental Disorders 4th edn
Washington DC American Psychiatric Association
APA (2001) Practice guideline for the treatment of patients with borderline per-sonality disorder American Journalof Psychiatry 158 (October supplement) 1ndash52
Baldwin D Bobes J Stein DJ Scharwachter I et al (1999) Paroxetine in social
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine
Montgomery SA Montgomery D (1982) Pharmacological prevention of suicidal
behavior Journal of Affective Disorders 4 291ndash298
Montgomery SA Nil R Durr-Pal N Loft H et al (2005) A 24-week randomized
double-blind placebo-controlled study of escitalopram for the prevention of gen-
eralized social anxiety disorder Journal of Clinical Psychiatry 66 1270ndash1278
Montgomery SA Roy D Montgomery DB (1983) The prevention of recurrent
suicidal acts British Journal of Clinical Pharmacology 15 183Sndash188S
New AS Hazlett EA Buchsbaum MS Goodman M et al (2002) Blunted pre-
frontal cortical 18fluorodeoxyglucose positron emission tomography response to
meta-chlorophenylpiperazine in impulsive aggression Archives of General Psy-
chiatry 59 621ndash629
New AS Trestman R Mitropoulou V Benishay DS et al (1997) Serotonergic
function and self-injurious behavior in personality disorder patients Psychiatry Research 69 17ndash26
New AS Trestman R Mitropoulou V Goodman M et al (2004) Low prolactin
response to fenfluramine in impulsive aggression Journal of Psychiatric Re-
search 38 223ndash230
Nickel MK Loew TH (2008) Treatment of aggression with topiramate in male
borderline patients part II 18-month follow-up European Psychiatry 23 115ndash
117
Nickel MK Loew TH Pedrosa Gil F (2007) Aripiprazole in treatment of border-
line patients part II an 18-month follow-up Psychopharmacology 191 1023ndash
1026
Nickel MK Muehlbacher M Nickel C Kettler C et al (2006) Aripiprazole in the
treatment of patients with borderline personality disorder a double-blind
placebo-controlled study American Journal of Psychiatry 163 833ndash838
Nickel MK Nickel C Kaplan P Lahmann C et al (2005) Treatment of aggression
with topiramate in male borderline patients a double-blind placebo-controlled
study Biological Psychiatry 57 495ndash499
Nickel MK Nickel C Mitterlehner FO Tritt K et al (2004) Topiramate treatment of aggression in female borderline personality disorder patients a double-blind
placebo-controlled study Journal of Clinical Psychiatry 65 1515ndash1519
Noyes R Moroz G Davidson JR Liebowitz MR et al (1997) Moclobemide in
social phobia a controlled dose-response trial Journal of Clinical Psychophar-
macology 17 247ndash254
Ogiso Y Moriya N Ikuta N Maher-Nishizono A et al (1993) Relationship be-
tween clinical symptoms and EEG findings in borderline personality disorder
Japanese Journal of Psychiatry and Neurology 47 37ndash46
Oquendo MA Krunic A Parsey RV Milak M et al (2005) Positron emission
tomography of regional brain metabolic responses to a serotonergic challenge
in major depressive disorder with and without borderline personality disorder
Neuropsychopharmacology 30 1163ndash1172
Pande AC Davidson JR Jefferson JW Janney CA et al (1999) Treatment of
social phobia with gabapentin a placebo-controlled study Journal of Clinical
Psychopharmacology 19 341ndash348
Pande AC Feltner DE Jefferson JW Davidson JR et al (2004) Efficacy of the
novel anxiolytic pregabalin in social anxiety disorder Journal of Clinical Psycho-
pharmacology 24 141ndash149
Parc S McTigue K (1997) Working memory and the syndromes of schizotypal
personality Schizophrenia Research 29 213ndash220
Paris J (2004) Borderline or bipolar Distinguishing borderline personality
disorder from bipolar spectrum disorders Harvard Review of Psychiatry 1 2
140ndash145
Paris J (2005) Borderline personality disorder Canadian Medical Association
Journal 172 1579ndash1583
Parsons B Quitkin FM McGrath PJ Stewart JW et al (1989) Phenelzine
imipramine and placebo in borderline patients meeting criteria for atypical de-pression Psychopharmacological Bulletin 25 524ndash534
Pascual JC Oller S Soler J Barrachina J et al (2004) Ziprasidone in the acute
treatment of borderline personality disorder in psychiatric emergency services
Journal of Clinical Psychiatry 65 1281ndash1283
Pascual JC Madre M Soler J Barrachina J et al (2006) Injectable atypical
antipsychotics for agitation in borderline personality disorder Pharmacopsychia-
try 39 117ndash118
Pascual JCSoler J PuigdemontD Perez-EgeaR etal (2008) Ziprasidone in the
treatment of borderline personality disorder a double-blind placebo-controlled
randomized study Journal of Clinical Psychiatry 69 603ndash608
Peet M Stokes C (2005) Omega-3 fatty acids in the treatment of psychiatric
disorders Drugs 65 1051ndash1059
Philipsen A Richter H Schmahl C Peters J et al (2004a ) Clonidine in acute
aversive inner tension and self-injurious behavior in female patients with border-
line personality disorder Journal of Clinical Psychiatry 65 1414ndash1419
Philipsen A Schmahl C Lieb K (2004b ) Naloxone in the treatment of acute
dissociative states in female patients with borderline personality disorder Phar- macopsychiatry 37 196ndash199
Pickup GJ (2006) Theory of mind and its relation to schizotypy Cognitive Neu-
ropsychiatry 11 177ndash192
Pitchot W Hansenne M Pinto E Reggers J etal (2005) 5-Hydroxytryptamine1A
receptors major depression and suicidal behavior Biological Psychiatry 58
854ndash858
Placidi GP Oquendo MA Malone KM Huang YY et al (2001) Aggressivity
suicide attempts and depression relationship to cerebrospinal fluid monoamine