Page 1 of 19 Antipsychotic Treatment for Borderline Personality Disorder: Are We Bordering the Line of Appropriate? Daniel Taylor, PharmD PGY2 Psychiatric Pharmacy Resident Central Texas Veterans Health Care System September 27, 2019 Learning Objectives: 1. Describe the pathophysiology of borderline personality disorder (BPD) 2. Identify current guideline recommendations for pharmacologic treatment of BPD 3. Explain the theoretical mechanism(s) of action for antipsychotic treatment in BPD 4. Assess the efficacy and safety of antipsychotic use for patients with BPD
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Page 1 of 19
Antipsychotic Treatment for Borderline Personality Disorder: Are We Bordering the
Line of Appropriate?
Daniel Taylor, PharmD
PGY2 Psychiatric Pharmacy Resident Central Texas Veterans Health Care System
September 27, 2019
Learning Objectives: 1. Describe the pathophysiology of borderline personality disorder (BPD) 2. Identify current guideline recommendations for pharmacologic treatment of BPD 3. Explain the theoretical mechanism(s) of action for antipsychotic treatment in BPD 4. Assess the efficacy and safety of antipsychotic use for patients with BPD
Page 2 of 19
Epidemiology: • Prevalence of BPD1-4
o Lifetime prevalence: 5.9% o Primary Care: 6% o Outpatient mental health clinics: 10% o Psychiatric inpatients: 15-28% o Female vs Male
▪ ~3:1 in clinical settings • Risk Factors for BPD5-9
o Environmental ▪ Childhood trauma/abuse – physical, sexual, emotional
o Genetic ▪ Increased risk noted in twin studies. ▪ Heritability of ~67% ▪ No specific causative gene identified. ▪ Epigenetic changes – DNA methylation abnormalities associated
with BPD. Pathophysiology:
• Structural Changes in the Brain10-11 – decreased brain volume o Amygdala – fear, emotional processing o Anterior Cingulate Cortex – emotion, impulse control, empathy o Hippocampus – learning and memory o Prefrontal Cortex – motivation, executive function
• Neurotransmitter effects in BPD12-13 o Serotonin – impulsive behavior & aggression regulation o Dopamine – emotion information processing, impulse control, cognition
▪ Proposed mechanism for antipsychotics in BPD is regulation of dopamine dysfunction.
o Acetylcholine – mood regulation o Norepinephrine – arousal, aggression, affective instability o Gamma-Aminobutyric Acid (GABA) – mood regulation
Presenter Conclusions: • Mood stabilizers and second generation antipsychotics were found to be beneficial for
symptom clusters of BPD. • Large variation in outcome variables and rating scales used between studies. • Standardization of outcome measures, especially use of outcome measures specific to BPD,
would be beneficial for future studies and meta-analyses. • Longer study duration is necessary to evaluate long-term effectiveness of medications in
BPD. • Larger randomized, placebo-controlled studies are needed to better evaluate efficacy and
Study Selection Process for Today’s Presentation: • Oral antipsychotic studies for patients with BPD • Published from 2014 to 2019
Page 5 of 19
Table 4: Comparison of Low and Moderate Dosages of Extended Release Quetiapine in Borderline Personality Disorder: A Randomized, Double-Blind, Placebo Controlled Trial.23 Black DW, Zanarini MC, Romine A, et al. Am J Psychiatry. 2014 Nov 1;171(11):1174-82.
Objective To determine the efficacy of low and moderate dose quetiapine for symptoms of borderline personality disorder
Inclusion
Criteria
• Diagnosis of BPD (DSM-IV)
• Zanarini scale score > 9 at baseline
Exclusion
Criteria • Medically unstable
• Current major depressive disorder, post-traumatic stress disorder, panic disorder, or obsessive-compulsive disorder
• Current substance dependence or abuse
• Any psychotic disorder, primary neurological condition, or cognitive impairment
• Previous non-response to atypical antipsychotic
• Pregnant or lactating
• Could not begin psychotherapy during the study
Intervention • Quetiapine 150 mg/day, quetiapine 300 mg/day, or placebo for 8 weeks, followed by a
1-week discontinuation phase o Quetiapine 150 mg/day:
▪ Started at 50 mg/day
▪ Increased to 150 mg/day after 1 week o Quetiapine 300 mg/day
▪ Started at 50 mg/day ▪ Increased to 150 mg/day after 1 week
▪ Increased to 300 mg/day after 4 weeks
Assessment • Patients were evaluated at baseline and weekly using both clinician and patient rated scales
• Safety: electrolytes, glucose, lipids, and prolactin at baseline and week 10. UDS and
pregnancy test at baseline. Extrapyramidal symptoms (EPS) assessed by Abnormal Involuntary Movement Scale (AIMS), Barnes Akathisia Scale and Simpson-Angus Rating Scale.
Endpoints • Primary: Zanarini Rating Scale for BPD (ZAN-BPD) total score
• Secondary: ZAN-BPD Self-Report (SR), Borderline Evaluation of Severity Over Time (BEST),
• Dropout rate of 33%, although similar between groups
• Strict exclusion criteria
• Placebo arm did not meet power
• Funded by AstraZeneca
• Previous medication use not reported
Conclusion:
• Quetiapine ER 150 mg/day appears to improve overall symptoms of BPD in the short-term.
• Quetiapine ER 150-300 mg/day appears to improve symptoms of aggression, affective and cognitive disturbance, severity of symptoms, and days lost from work in the short-term.
• Quetiapine ER 300 mg/day appears to improve irritability, physical and verbal aggression.
Table 5: A Comparative Study on Olanzapine and Aripiprazole for Symptom Management in Female Patients with Borderline Personality Disorder.24 Shafti SS, Kaviani H. Bulletin of Clinical Psychopharmacology 2015;25(1):38-43.
Design 8 week, randomized, open-label study
Objective To compare the efficacy and safety of olanzapine vs aripiprazole with regard to management of BPD.
Inclusion
Criteria
• Diagnosis of BPD (DSM-IV TR)
• Female
Exclusion
Criteria
• Major depression, bipolar disorder, psychosis, substance dependence, mental retardation, or
neurological conditions
• Concurrent psychotropic medications or psychotherapy
Intervention • Olanzapine
o Initial: 2.5 mg/day; increased by 2.5 mg/day as needed or tolerated o Max dose: 10 mg/day
• Aripiprazole
o Initial: 2.5 mg/day; increased by 2.5 mg/day as needed or tolerated
o Max dose: 10 mg/day
• Dose established by week 4 continued for remainder of study
• Secondary: Clinical Global Impression-Severity (CGI-S), Buss-Durkee Hostility Inventory
(BDHI)
Statistical Analysis
• Student t-test to compare baseline characteristics
• BPRS, CGI-S, BDHI analyzed via paired t-test (within each group) and unpaired t-test
(between groups)
• Cohen’s d and effect size correlation to analyze effect size.
• Statistical significance: p<0.05
Page 8 of 19
Results • Enrollment: n=24 o Mean age:
▪ Olanzapine group: 28 years ▪ Aripiprazole group: 26.8 years
o Female: n=24 (100%)
• Mean dose:
o Olanzapine group: 6.4 mg/day o Aripiprazole group: 7.0 mg/day
Olanzapine vs Aripiprazole Effect on Endpoints
Intra-group analysis
Measure OLANZ
Baseline
OLANZ
Week 8
Mean
Reduction
P
value
ARIP
baseline
ARIP
Week 8
Mean
Reduction
P
value
BPRS 43.8 32.5 -25.7% 0.001 44.1 35.8 -18.8% 0.04
BDHI 59.7 50.7 -15% 0.04 58.3 51.1 -12.2% NS
CGI-S 3.5 2.8 -20.9% 0.03 3.36 2.7 -19.3% NS
Between-group analysis
Measure OLANZ Baseline
ARIP Baseline P value OLANZ Week 8
ARIP Week 8 P value
BPRS 44.1 43.8 NS 35.8 32.5 NS
BDHI 58.3 59.7 NS 51.1 50.7 NS
CGI-S 3.3 3.5 NS 2.7 2.8 NS
Safety: all adverse effects reported as mild and well-tolerated.
• Aripiprazole group (n=12)
o Tremor (n=1)
o Inner restlessness (n=2) o Akathisia (n=1)
o Headache (n=1) o Insomnia (n=1)
• Olanzapine group (n=12)
o Weight gain (n=3) o Somnolence (n=4)
o Dizziness (n=2)
o Tremor (n=2)
Author’s Conclusions
• Both olanzapine and aripiprazole improved overall symptoms of BPD, as measured by BPRS.
Between group analysis did not show a significant difference in effect between olanzapine and aripiprazole groups.
• Olanzapine had more improvement on “anger and hostility” and “overall illness severity” from
baseline to 8 weeks, although this was not statistically significant compared to aripiprazole.
• Side effect profiles differed between the two antipsychotics o Olanzapine was more likely to cause weight gain, somnolence, and dizziness.
o Aripiprazole was more likely to cause akathisia, headache, and insomnia.
Page 9 of 19
Presenter
Comments & Conclusions
Strengths:
• Patients were randomized
• Compared aripiprazole to most well-studied antipsychotic in BPD
• Not funded by manufacturer; authors report no conflicts of interest
• No dropouts
Limitations:
• Open-label design
• All female
• Lack of placebo group
• Baseline characteristics not well reported
• Concomitant psychotropic medications not well reported
• Small sample size (n=24) Conclusion:
• Olanzapine and aripiprazole doses of 2.5-10mg/day appear to be effective for the short-term
management of overall BPD symptoms.
• Olanzapine may have additional benefit on symptoms of “anger and hostility” and “overall
illness severity” compared to aripiprazole when used short-term.
• Generalizability to males limited due to all female study population. • Additional studies with larger sample sizes and placebo-control groups are needed to better
evaluate effects of olanzapine vs aripiprazole for treatment of BPD.
Table 6: Efficacy and Tolerability of Asenapine Compared with Olanzapine in Borderline Personality Disorder: An Open-Label Randomized Controlled Trial.25
Bozzatello P, Rocca P, Uscinska M, Bellino S. CNS Drugs. 2017 Sep;31(9):809-819.
• Both asenapine and olanzapine improved overall psychiatric symptoms.
• No significant difference between asenapine and olanzapine for overall psychiatric symptoms,
anxiety, or functioning.
• Asenapine was found superior to olanzapine in reducing affective instability.
• Olanzapine was found superior to asenapine in reducing dissociation/paranoid ideation,
although power was not met for this endpoint.
• Neither medication caused significant improvement for symptoms of depression.
• Asenapine was associated with a lower incidence of weight gain than olanzapine, but more common extrapyramidal symptoms (akathisia) and oral hypoesthesia.
Page 11 of 19
Presenter
Comments & Conclusions
Strengths:
• Intention-to-treat (ITT) analysis
• Moderate sample size (n=51)
• Compared asenapine to most well-studied atypical antipsychotic (olanzapine) for BPD
• Not funded by manufacturer; no author conflicts of interest
Limitations:
• Open-label design
• Lack of placebo group
• Strict exclusion criteria
• Previous pharmaco- and psychotherapy not assessed
• Drop-out rate (21.7%)
• Post-hoc power analysis Conclusion:
• Both asenapine and olanzapine appear to improve overall psychiatric symptoms in the short-
term.
• Asenapine appears to be more effective than olanzapine for symptoms of affective instability
in the short-term.
• Olanzapine may be more effective for cognitive-perceptual symptoms of BPD. • Validity of study results is limited by lack of placebo group.
Table 7: Real-world effectiveness of clozapine for borderline personality disorder: results from a 2-year mirror-image study.26
Measure Pre-Clozapine Post-Clozapine Mean difference P value
Psychiatric
Hospitalizations
All BPD pts
(n=1107)
2.54 2.00 -0.54 < 0.001
BPD specific pts (n=102)
2.02 1.33 -0.69 0.0067
Psychiatric
Hospitalizations for pts
admitted in Pre-Cloz Period
All BPD pts
(n=698)
4.04 2.70 -1.34 <0.001
BPD specific
pts (n=47)
4.38 2.51 -1.87 <0.001
Psychiatric
Bed-Days
All BPD pts
(n=1107)
56 4 - <0.001
Specific BPD
pts (n=102)
3 0 - 0.008
Psychiatric
Bed-Days for pts > 1 Bed-
Day in Pre-Cloz Period
All BPD pts
(n=770)
190.08 65.95 -124.12 <0.001
Specific BPD pts (n=52)
160.49 76.34 -84.15 0.006
Intentional
Self-Harm or Overdose
All BPD pts
(n=1107)
189 (17.07) 114 (10.30) - <0.001
Specific BPD pts (n=102)
19 (18.63) 14 (13.73) - NS
Concomitant Medication Use: All BPD pts (n=1107)
Medication Pre-Clozapine (%) Post-Clozapine (%) P value
Lithium 72 (6.50) 64 (5.78) NS
TCA 208 (18.79) 257 (23.22) <0.001
SSRI 368 (33.24) 380 (34.33) NS
Other Antidepressants 195 (17.62) 181 (16.35) NS
BZDs 664 (59.98) 751 (67.84) <0.001
FGAs Low-Potency 573 (51.76) 547 (49.41) NS
Mid-Potency 398 (35.95) 309 (27.91) <0.001
High-Potency 137 (12.38) 114 (10.30) 0.035
SGAs 448 (40.47) 407 (36.77) 0.001
*Specific BPD pts = without schizophrenia, schizoaffective disorder, or bipolar disorder
Page 13 of 19
Safety (n=1107)
Adverse Event Pre-Clozapine (%) Post-Clozapine
Agranulocytosis 0 (0) 0 (0)
Cardiomyopathy 5 (0.45) 2 (0.18)
Myocarditis 0 (0) 0 (0)
Neuroleptic Malignant Syndrome 4 (0.36) 0 (0)
Diabetes Type 2 14 (1.26) 19 (1.72)
Author’s Conclusions
• There were significant decreases in number of hospitalizations, as well as number of
psychiatric inpatient bed-days in the all BPD group and specific BPD group after initiation of clozapine.
o Clozapine in the specific BPD group showed a decrease in hospitalizations similar to
studies for bipolar disorder and schizophrenia.
• There was a significant decrease in intentional self-harm or overdose after initiation of clozapine in the all BPD group but not the specific BPD group. This may be due to the small
sample size of the specific BPD group.
• Use of BZDs and TCAs increased significantly. The use of all antipsychotics decreased significantly, except for low-potency FGAs.
• Rate of serious adverse effects was not significantly different after initiating clozapine.
Presenter
Comments & Conclusions
Strengths:
• Large overall sample size (n=1107) for all BPD patient group
• Data and conclusions based solely on ICD-8, ICD-10, and prescription refill data. o Unable to classify patients by specific symptomology or symptomatic benefits of
clozapine.
• Small sample size (n=107) for the specific BPD group based on type of study.
• Did not evaluate mild to moderate side effects of clozapine or reasons for discontinuation. Conclusion:
• Clozapine appears to decrease the risk of hospitalization for patients with BPD. However, the
sample size was small for patients with only BPD (without concomitant schizophrenia or
bipolar disorder).
• Unclear whether the magnitude of effect was due to improved symptomology from treating these other conditions or whether clozapine actually benefits BPD itself.
• Further study, preferably with randomized, double-blind, placebo-controlled trials is
warranted.
Page 14 of 19
Table 8: Comparison of Studies Evaluated23-26
Quetiapine (2014)
n=95
Olanzapine vs
Aripiprazole (2015) n=24
Asenapine vs
Olanzapine (2017) n=51
Clozapine (2018)
n=1107
Type of
Study
Randomized, double-
blind, placebo-controlled trial
Randomized, open-
label trial
Randomized, open-
label trial
Retrospective,
observational, mirror-image study
Treatment
Duration
8 weeks (tx phase) 8 weeks 12 weeks 2 years
Study
Population
Mean age: ~29 yrs
Female: 70% Psych. co-morbidities
included:
• Hx of mood,
anxiety, and/or SUD
Mean age: ~27 yrs
Female: 100% Psych. co-morbidities
included:
• Not defined
Mean age: ~25 yrs
Female: 63% Psych co-morbidities
included:
• Excluded most
co-morbid Axis I disorders
Mean age: ~36 yrs
Female: 61% Psych. co-morbidities
included:
• Not defined
Findings Significant
improvement in overall BPD symptoms with
low-dose quetiapine.
• Greatest improvement from
weeks 2 to 6.
Both low- and mod-
dose quetiapine improved symptoms of
aggression.
No significant
Improvement on impulsivity or
depression vs placebo.
Both olanzapine and
aripiprazole improved overall symptoms of
BPD.
Olanzapine >
aripiprazole on “anger and hostility” and
“overall illness severity” but not
statistically significant.
Both asenapine and
olanzapine improved overall psychiatric
symptoms.
Asenapine >
olanzapine for reducing affective instability.
Olanzapine >
asenapine for dissociation/paranoid
ideation
Neither medication improved symptoms of
depression.
Significant decrease in
psychiatric admissions and bed-days with
clozapine use.
No significant
difference in serious adverse events.
Strengths/ Limitations
Strengths: Randomized, double-
blind, placebo controlled trial
Moderate sample size
Use of validated rating
scales
Extended screening period
Limitations:
Dropout rate (33%)
Strict exclusion criteria
Funded by AstraZeneca
Previous medication
use not reported
Strengths: Patients were
randomized
Not funded by manufacturer
No dropouts
Limitations: Open-label design
All female
Lack of placebo group
Baseline characteristics not well reported
Small sample size
Strengths: Moderate sample size
Compared asenapine
to most well-studied atypical antipsychotic
for BPD
Not funded by
manufacturer
Limitations:
Open-label design
Lack of placebo group
Strict exclusion criteria
Drop-out rate (21.7%)
Strengths: Analyzed clinical
outcomes (e.g. hospitalizations)
Analyzed concomitant
medication use.
Limitations:
Analysis based on ICD, and prescription refill
data.
Small sample size for
the specific BPD group.
Did not evaluate mild to moderate side
effects or reasons for
discontinuation.
Page 15 of 19
Conclusions: A. There is some weak evidence for the use of specific atypical antipsychotics for the management of
overall BPD symptoms.
B. Atypical antipsychotics appear to be effective for the management of BPD symptoms, with variable
effects on specific symptom clusters based on the antipsychotic chosen. C. Antipsychotics may be useful for the treatment of BPD when first-line psychotherapies have failed or
are unavailable. Currently, available information provides evidence to support short-term antipsychotic treatment (< 12 weeks).
D. Evaluation of risks and benefits with initiation of antipsychotic therapy is pivotal to decide whether initiation of antipsychotic therapy is appropriate in patients with BPD. Patients should be informed of
current guideline recommendations and evidence with therapeutic options being offered.
E. More research is needed to evaluate the benefits of combination therapies, including psychotherapy plus pharmacotherapy or combination pharmacotherapy.
F. More long-term studies are needed to better evaluate the benefits and risks of continuing antipsychotic therapy when patients have experienced benefit.
G. Randomized, double-blind, placebo-controlled trials are needed to evaluate the benefit of clozapine
for the treatment of severe BPD.
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