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252 Antipsychotic Medications15. Gelenberg AJ: Th e P450 family.
Biological Therapies in Psychiatry Newsletter.Vol. 18(8), August
1995.16. Gershon S : Current therapeutic profile of lithium. Arch
Gen Psychiatry 54, 1997.17. Kupfer DJ, et al: Three year outcomes
for maintenance therapies in recurrent depression. Arch Gen18.
Leonard BE: New approaches to the treatment of depr ession . J Clin
Psychiatry 57(su ppl 4), 1996.19. Nelson JC: Safety and
tolerability of the new antidepressants. J Clin Psychiatry 5 8(sup
pl6):26 -31, 1997.20. Nemeroff CB, Devane CL , Pollock BG , et al:
Newer antidepressants and th e cytochrome P45 0 system. Am J2 1 .
Nierenberg A A, F eighner JP, Rudo lph R, et al: Venlafaxine fo r
treatment-resistant unipolar depression. J22. Quitkin FM, M cGrath
PJ , Stewart AW, et al: Atypical depre ssion, panic attacks, and
response to imipramine23. Schatzberg A F Fluoxetine i n the
treatment of comorbid anxiety and depression. J Clin Psychiatry
135-12, 1995.24. Schatzberg AF, Cole JO , Debattista C : Manual of
Clinical Psychopharmac ology. 3rd ed. Washington, D C,25. The M
edical Letter: Citalopram for depression. 40 1041), Decem ber 4,
1998.26. Wheatley DP, van Morraert M, Timmerman L, Kremer CM E: M
irtazapine: Efficacy and tolerability in com -
parison with fluoxetine in patients with moderate to severe ma
jor depressive disorder. J Clin Psychiatry59:306-3 12, 1998.27.
Wisner KL, Perel JM, Findling RL: A ntidepressant treatment during
breast feeding. Am J Psychiatry 153:
Psychiatry 47:1093-1099, 1990.
Psychiatry 153:311-320, 1996.Clin Psychopharmacol 14:4 1 9 4 2 3
, 1994.and phenelzine: A replication. Arch Gen Psychiatry
47:935-941, 1990.
American Psychiatric Press, 1997.
1132-1 137, 1996.
48. ANTIPSYCHOTIC MEDICATIONSHerbert T Nagamoto, M . D
1. What are antipsychotic medications?Antipsychotic m edications
are used to treat psychotic symp toms in patients with
schizophreniaand other conditions. Sym ptoms m ay include
hallucinations, delusions, paranoia, thought broadcast-ing,
catatonia, bizarre behavior, and associated symptoms such as
hypervigilance, agitation, and i r r -tability. Typical
antipsychotic medications also have neurologic side effects,
leading to the alternatedesignation of neuroleptics (of the
neuron). Antipsychotic medications are divided into typicalagents
which are similar to haloperidol, and atypical agents as
exemplified by clozapine, whichhave different therapeutic and
side-e ffect profiles and a different mech anism of ac tion. Th is
is arapidly evolving area of psychopharmacology, and the newer
atypical an tipsychotic agents increas-ingly are used as first-line
agents (see Question 21).2. List the different typical
antipsychotic medications by chemical class specifying relative
potency in chlorpromazine equivalents and usual range of daily
oral dose.Potency and Range of Oral Dose of Neuroleptics
APPROXIMATE AMOU NT MG) OFDRUG NEEDED TO EQUAL 100NTIPSYCHOTIC
AGE NT RANGE OF DAILY ORA LGENERIC NAME (TRADE NAME) MG OF
CHLORPROMAZINE DOSE (MG)AliphaticPiperazineChlorpromazine
(Thorazine)
Fluphenazine (Permitil ,Perphenazine (Trilafon)Prochlorperazine
(Compazine)Trifluoperazine (Stelazine)
Prolixin)
I00 25-20002 1 4 01 4-64IS 15-1505 2-40
Table continued on ollowing p ge
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Ant i psye o ic Medications 253Potency and Range o Oral Dose of
Neuroleptics (Cont.)
APPROXIMATE AMO UNT (M G) OFDRUG NEEDED TO EQUAL 100NTIPSYCHOTIC
AG ENT RANGE OF DAILY ORA LGENERIC NAME (TRADE NAME) MG OF
CHLORPROMAZINE DOSE (MG)PiperidineMesoridazine
(Serentil)Thioridazine (Mellad)
Haloperidol (Haldol)Chlorprothixene (Taractan)Thiothixene
(Navane)Molindone (Moban)Loxapine (Loxitane)
ButyrophenoneThioxanthene
DihydroindoloneDi henzoxazepine
50100
2100
41010
7540075-800
1-10030-606 4 0
15-2251-250
From Jenkins S , Gibbs T, Szymanski S: A Pocket Reference for
Psychiatrists. Washington, DC, AmericanPsychiatric Association,
1990,p 134 with permission.3. What is the mechanism of action of
typical antipsychotic medications?
Th e typical ant ipsychotic medicat ions are bel ieved to act
via central blockade of d opam ine re-ceptors. This ac tion in
limbic areas leads to antipsych otic effects; in basal gang lia, to
extrapy ramidalside effects; in the brainstem chemoreceptor t r
igger zone, to antinausea and antiemetic effects; andin the
hypothalam us (via blockad e of dopam ine inhibition of anterior
pituitary prolactin release), toincreased prolactin release.4. Name
several conditions that are indications for the use of
antipsychotic medications.
Antipsychotic medicat ions are used in a number of condit ions
to treat psychotic sym ptoms , in-cluding hallucination s,
delusions, paranoia, c omb ativeness, agitation and hostility, ins
om nia, catato-nia, hyperactivity, and poor gro oming and
self-care.
Indications or Use of ntipsychotic MedicationAcute and
maintenance treatment of schizophreniaPsychosis associated with
acute mania and major depressionPsychosis from any number of
medical causes (see chapters on schizophrenia, dementia, andAs ad
junctive treatment for agitation due to psychiatric conditions,
delirium, delirium tremens,Tics due to neurologic conditions such
as Huntingtons chorea and T ourettes syndromeFlashbacks,
nightmares, and agitation due to posttraumatic stress
disorderNausea and vom iting (prochlorperazine [Comp azine],
trimethobenzamide [Tigan ], metoclo-Gastroesophageal reflux and
diabetic gastroparesis (metoclopramide [Reglan])Adjunctive use in
anesthesia for medical and surgical procedures (droperidol
[Inapsine])
delirium)and dementia
pramide [Reglanl)
5. List the general classes of side effects of typical
antipsychotic medications.Dopaminergic side
effects*Pseudoparkinsonism
Cogwheel rigidityShuffl ing gaitParkinsonian tremorMasked
faciesacute airway obstruct ion
*Acute dystonias , such as opisthotonus, tor t icol l i s , and
t la ryngospasm, which may cause
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254 Antipsychotic MedicationsIncreased prolactin secretion that
may lead to galactorrheaTardive dyskinesia, tardive dystonia (see
question 12)Akathisia-subjective or observabJe restlessness
(thorazine shuffle)TNeuroleptic malignant syndrome NMS)
*Dry mouth*Blurred vision (accommodation problems or frank
blurred vision)*Constipation that may lead to ladynamic
ileusUrinary hesitancy or ?obstruction
Anticholinergic side effects
Memory and concentration difficulties, up to ifrank
deliriumAlpha-adrenergicblockadeHypotensionOrthostatic
hypotensionAntihistaminergic side effects*Sedation,
drowsinessWeight gainOthersgranulocytosisECG changes (prolonged QT
interval)Elevated liver function testsElevated creatine
phosphokinase (in the absence of NMS)Fetal
toxicityPhotosensitivityPigmentary retinopathy (avoid doses of
thioridazine > 800 mg/day)Seizures (decreased seizure
threshold)*Sexualdysfunction (erectile problems, impotency,
delayed, absent, or retrogradeejaculation, priapism)Skin rashes
Common side effects.?Potentially dangerous side effects.6. How
is antipsychotic potency related to side effects?In general, the
lower-potency agents, such as chlorpromazine and thioridazine, tend
to be highin sedation, orthostatic hypotension, and anticholinergic
side effects, whereas the higher-potencyagents, such as haloperidol
and fluphenazine, tend to be high in pseudoparkinsonian, akathisia,
and
acute dystonic side effects.7. Describe the treatmentof common
side effects of typical antipsychotic medications.In general,
decrease antipsychotic medications to the lowest effective dose
whenever possible tominimize side effects and avoid
polyphamacy.Pseudoparkinsonism and acute dystonias are treated with
antiparkinson agents. Benztropine(Cogentin, 1-2 mg up to 4
timedday), diphenhydramine (Benadryl, 25-50 mg up to 4
timedday),and trihexyphenidyl (Artane, 2-5 mg up to 15mg/day in
divided doses) are used for their anticholin-ergic effects to treat
acute extrapyramidal side effects. Prophylactic treatment for
approximately thefirst 10 days of treatment or after dosage
increases may be considered for adolescents and other pa-
tients who (by history) are highly susceptible to
pseudoparkinsonism and acute dystonias. Exercisecare to avoid
anticholinergic poisoning in combination with other anticholinergic
agents, particu-larly in elderly or medically debilitated patients.
The lowest effective doses are prudent, and theyshould be tapered
and discontinued as soon as possible. Amantadine (Symmetrel), which
is thoughtto potentiate dopaminergic neurotransmission, also may be
used. In the case of laryngospasm, whichmay lead to acute airway
obstruction, use Benadryl, 50 mg intravenously.Akathisia usually
responds well to dosage reduction, anticholinergic agents, or
change to a dif-ferent class of neuroleptics. Benzodiazepines and
beta-adrenergic antagonists such as propranolol
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Antipsychotic Medications 255are also effective in treating ak
athisia. It is important to differentiate akathisia d ue to
neuroleptictreatment from agitation d ue to psychosis. This
differentiation m ay be difficult, but neuroleptic do sesmay be
increased (w hich improves psychotic agitation but worsens
akathisia) o r decreased (whichimproves akathisia but worsens
psychotic agitation). Some akathisia treatments
(anticholinergics)are unlikely to affect psychotic agitation,
whereas others may improve (benzodiazepines) or havedifferential
effects (beta-adrenergic antagonists) on agitation due to
psychosis.Patients often develop tolerance to anticholinergic side
effects but they may persist. It is usuallybest to decrease dosage
or switch to a more potent agent if anticholinergic side effects
become intol-erable. Alternatively, bethanechol (Urecholine, 5-10
mg up to 4 timedday; sometimes 25 mg up to 4timedday ) may be used
to decrease dry mouth, blurred vision, constipation, and urinary
hesitancy.Hypotension and orthostatic hypotension are treated with
oral hydration, careful instructionsto the patient, dose reduction,
o r change to more po tent agents. Occasionally, intravenous
hydrationis indicated. If a vasoactive agent is required, one
should avoid agents with beta-adrenergic agonistproperties (such as
epinephrine), which may worsen hypotension via vasodilatation and
peripheralpooling. In such cases, a selective alpha-adrenergic
agonist such as metaraminol (Aram ine) shouldbe used.
8. What constitutes an adequate trial of typical antipsychotic
medications?Antipsychotic medications often induce sedation
quickly, but their specific antipsychotic effectsmay take up to 6
weeks at therape utic dos es to develop fully. Conversely, when a
stable schiz o-phrenic patient decides to stop antipsychotic
medication suddenly, it may take weeks for psychoticsymp toms to
return or for patients to decompensate. Therapeu tic doses vary
widely from patient topatient and within a given patient at various
times. In general, maintenance doses range from ap-proximately
100-700 mg/day, averaging 300 mg/day in chlorpromazine equivalents.
Acutely ill pa-tients may require higher doses, although the
current trend is toward adjunctive use ofbenzod iazepines in
acutely psychotic patients to avoid the side effects often
associated with high-dose antipsychotic m edications.In an
emergency situation, with a highly agitated or out-of-control
patient, m any an tipsychoticmedications can be given
intramuscularly. In general, the lower-po tency antipsychotics such
as chlor-prom azine or thioridazine a re given in half the am ount
of oral doses. In som e settings, particularlyemergency
departments, acutely psychotic, out-of-control patients are given
intravenous haloperidol,often in very high doses. There is a small
chance that intravenous haloperidol will induce the condi-tion
known as torsade de pointes, which may lead to ventricular
fibrillation and sudden death.Intravenous haloperidol should be
used with caution in women and patients with increased QT
inter-vals on electrocardiogram, who a re at increased risk for
developing torsade de pointes.
9. Delineate an approach to patients who donot respond well to
antipsychotic medications.For patients who d o not respond to
treatment, reassess the diagnosis particularly in the case ofsuch
illnesses as schizophrenia and bipolar affective disorder, which
may be q uite sim ilar in theacute phases. When revisiting a
patients diagnosis: 1) rule out occult medical illness that
mayworsen s ym ptom s or caus e the illness under treatment; 2 )
ule out alcohol and substance abuse,which may m imic or worsen a
number of psychiatric sym ptoms; and (3) ensu re that the patient
is re-ceiving an adequate dosage of antipsychotic for an adequate
length of time.Typical antipsychotic medications may have a
therapeutic window; thus patients out of theappropriate range may
receive too little or too much medication. Plasma levels obtained
at steadystate help to assess dosag e of som e neuroleptics (see
below; haloperidol an d fluphen azine are moststudied).Compliance
is a com mo n problem with antipsychotic medications. All too often
patients stopmedications because of legitimately troublesome side
effects and thus experience psychotic decom -pensation. To ensure
acute compliance, administer intramuscular injections or observe
the patientfor 30 minutes after oral ingestion of liquid
medications. For long-term maintenance, fluphenazineand haloperidol
are available in slow -release depot fo rms that m ay be given
intramuscu larly every2-4 weeks.
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256 Antipsychotic MedicationsEnsure that troublesome side
effects do not hinder the effectiveness of treatment, especially
inakathisia, which can m imic or exacerbate psychotic agitation.
Pseudopark insonism an d oversedationmay make patients look
artificially depressed, and neuroleptic malignant syndrome may make
pa-tients suddenly look worse (e.g., catatonic or delirious). If a
schizophrenic patient does not improve,
it is also important not to miss a treatable depression. F
inally, for patients who cannot tolerate or d onot respond to
typical neuroleptics, a trial of an atypical antipsychotic is
indicated (see below).10. How can blood levels of antipsychotic
medications he helpful in the clinical managementof patients?Th ere
is evide nce that at least so me antipsychotic medications have a
therapeutic window ofideal dosage or blood levels. Currently,
haloperidol is the most thorou ghly studied agent, with
besttherapeutic effects achieved at trough plasma levels of 5-1 2
nglml in most patients. Fluphenazinealso is well studied, with
recommended plasma levels of 1-2.8 ng/ml. For other agents,
plasmalevels are useful in ruling out subtherapeutic levels of
medication in patients who hypermetabo-lize, have poor ab sorp
tion, or are noncompliant. If a laboratory reports a therapeutic
range fo r aneuroleptic, it is reasonable to inquire how the
laboratory arrived at its recommendations. For theatypical
antipsychotic clozapine, patients sh ould have improved clinical
response at trough plasmalevels of greater than 350410 nglml.11.
Name possible problematic interactions between antipsychotic
medications and otherdrugs.Anticholinergic agents may place
patients at increased risk of anticholinergic delirium.Numerous
agents may ind uce or worsen hypotension o r orthostatic changes in
combinationwith neuroleptics, in cludin g barbiturates and non barb
iturate hyp notics , narcotics, benzodi-azepines,
angiotensin-converting enzyme inhibitors, antihypertensives,
antidepressants,
methyldopa, anesthetics, and epinep hrine.Sedation may be
worsened when antipsychotics are used w ith benzodiazepines,
sedatives, nar-cotics, cimetidine, antidepressants, and
antihistamines. In particular, chlorpromazine andmeperidine used in
comb ination may lead to hypotension and lethargy.Lithium and
antidepressan ts may w orsen extrapyramidal side effects (p
seudopark insonismand acute dystonias). For a mo re com plete
listing of drug interactions w ith antipsychotic m ed-ications,
including changes in plasma levels, see Maxmen and Ward.512. What
is tardive dyskinesia? Why is it of concern with chronic useof
antipsychotic medica-tions?Tardive dyskinesia is a syndrom e of
abnorm al involuntary movem ents such as buccolingual mas-ticatory
mov ements, choreoathetoid movem ents of the limbs or even trunk
and neck, and facial gri-macing or tics. Long before the advent of
antipsychotic m edications, such m ovements were noted
inschizophrenic patients, who probably are at increased risk of
developing the syndrom e. Tardive dysk-inesia tends to develop
after months to years of neuroleptic treatment and has been
described in pa-tients treated with all available typical agen ts.
It occurs in about 15-20 of patients receiving chronicneuroleptic
treatm ent; the inciden ce rises significantly in elderly po
pulations. Curiously, it is tem-porarily masked by increased
antipsychotic do ses and tend s to worsen acutely w ith decreased
dosage.13. How is tardive dyskinesia avoided or managed?Patients
treated with neuroleptics should be examined for abnormal
involuntary movementsbefo re initiating therapy and every 6 months
or with dosage chan ges or appearance of suspectedmovem ents.
Patients should be maintained o n the lowest effective dosage of
medication. On exami-nation, the abnormal movements are more
apparent when patients do not know that they are beingobserved or
when they are concentrating on tasks such as rapid alternating
movem ents. In addition, asyndrome of withdrawal dyskinesias may
occu r briefly on withdrawal of neuroleptics. In a small
butsignificant percentage of cases, tardive dyskinesia becomes
permanent and disfiguring.Unfortunately, there are no effective
treatments fo r tardive dyskinesia, although vitamin E (400IU 3 4
imeslday) has been shown to decrease symp toms in som e patients,
especially those wh o are
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Antipsychotic Medications 257young and have had the syndrom e
briefly. The atypical antipsychotic clozapine appears not to
causethis problem and may improve symptoms in patients who develop
tardive dys kines ia (see below)and need continued antipsychotic
treatment. Risperidone, olanzapine, and quetiapine appear to bemuch
less likely to cause tardive dyskinesia than typical
antipsychotics, though long-term u se withthese agen ts is limited
a t this time.14. Define neuroleptic malignant syndrome.Neuroleptic
malignant syndrome (NMS) is a potentially fatal side effect that
involves:Fever (up to 42C) in the absence of infectionRigidity,
which m ay be lead pipe and generalized, and o ther neurologic
signs (e.g., akinesia
Autonomic dysfunction leading to tachycardia, labile
hypertension, diaphoresis, and pallorChanges in mental status
ranging from mild obtundation through stupor and com a (in
approx-Other possible symp toms: rhabdomyolysis (with elevated
creatine phosphokinase in 40-90 ),
NM S usually occurs within 2 weeks of initiating typical
antipsycho tics or increasing dosage, butmay occur after months of
stable-dose treatment. It evolves over 24-72 hours an d lasts 5-10
dayswith oral med ications or considerably longer with depot
intramuscular med ications. NM S has an esti-mated mortality rate
of 15-20%. Prompt diagnosis and discontinuation of neuroleptics are
essential.Treatment is primarily supportive, although dantrolene
and brom ocriptine have been helpful. Therehave been isolated case
reports of NM S associated with clozapine, risperidone, and
olanzapine .
and dyskinesia)(mix of sym ptom s varies widely)imately 70 of
patients)dysarthria, dysphagia, mutism, Babinski reflex,
sialorrhea, opisthotonus
15. What is clozapine?Clozapine (Clozaril) is a tricyclic
dibenzodiazepine antipsychotic medication. It was synthesizedin the
1960s but withdrawn from the market in the U.S. after 8 of 16
patients who developed agranu-locytosis in Finland died in the
1970s. It has been used continuously in other countries since then.
In1990 it was reintroduced in the U S . after it was shown that, in
com parison to typical neuroleptics:Clozapine is more effective in
treatment-resistant schizophrenic patients for both positive
psy-chotic sym ptom s, such as delusions an d hallucinations, and
chronic negative sym ptom s, such associal withdrawal, anhedonia,
blunted affect, and poor initiative.Clozapine is unlikely to cause
dopam inergic side effects such as pseudoparkinsonism,
tardivedyskinesia, and elevated prolactin levels.
16. What are the side effectsof clozapine?The FDA m andates
weekly dispensing and C BC monitoring with initial treatment d ue
to therisk of agranulocytosis.Most cases of agranulocytosis occur
in the first 6 months of treatment. W ithweekly monitoring, the
incidence of agranulocytosis has decreased from 1-2 in the initial
stud iesto 0.38 in the first 5 years of use since U S .
reintroduction (versus 0.1 with typical antipsy-chotics). Th e FDA
now allows every other week dispensing and C BC checks in stable
patients afterthe first 6 months of treatment. There is still some
risk of death from agranulocytosis d espite thiscareful m onitoring
1 9 deaths ou t of over 180,000patients exposed to clozapine in the
U.S. as of thiswriting; an approximate 1/10,000 risk of
death).Other side effects can include dose-related seizures ( 5 at
doses above 60 0 mg/day), sedation,orthostatic hypotension,
sialorrhea, and weight gain. The risk of seizures dictates low
starting dosesand slow dose increases, and if a pa tient has been
off of clozapine for mo re than a few day s, retitra-tion back to
previous dosage.17. Why is clozapine considered the prototypic
atypical antipsychotic medication?Clozapine has been designated as
an atypical antipsychotic because of its clinical profile an
dpharmacologic actions. Clozapine affects a large number of
neurotransmitter systems. Its atypicalproperties currently are
though t to be due to its relatively high 5H T2 blocka de and weak
DU D2
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258 Antipsychotic Medicationsblockade, with more dopamine
effects in limbic systems (related to antipsychotic effects) than i
nstriatal systems (leading to motor side effects). Average doses
are 2 50450 mg/day with a range of100-900 mgiday.Clozapine has been
found useful in a number of psychotic conditions in addition to
schizophre-nia including treatment refractory bipolar affective
disorders. It remains the gold standard for effi-cacy in
antipsychotic medications, but its use is limited by side effects,
cost, and monitoringrequirements.18. What other atypical
antipsychotic medications currently are available?As of this
writing, the atypical antipsychotic medications available in the
U.S. in addition toclozapine are (in order of introduction)
risperidone (Risperdal), olanzapine (Zyprexa), and quetiap-ine
(Seroquel). All three medications appear to be effective with both
positive and negative symp-toms of schizophrenia.19. How do they
compare to clozapine in atypical characteristics?
Risperidone has dose-dependent dopaminergic effects that are low
at optimal doses of 4mg/day (range 2-1 6/day). There is increasing
pseudoparkinsonism, akathisia, and elevated prolactinwith increased
doses of risperidone, though usually less than that seen with
typical antipsychotics.Olanzapine (current range 7.5-20 mg/day)
also has some risks for akathisia and elevated pro-lactin at higher
doses, again less than that seen with typical antipsychotics. While
tardive dyskinesiacan occur with risperidone and olanzapine, the
incidence with each appears to be considerably lessthan that seen
with typical neuroleptics. Both of these medications also are
showing promise in thetreatment of other psychotic disorders, such
as treatment refractory mania. While there are isolatedcase reports
of mania induction attributed to risperidone, other data suggest
that this is not likely tobe a problem, especially if a mood
stabilizer is also used.Quetiapine (dose range 150-750 mg/day) is
the closest to clozapine in being very unlikely toinduce
dopaminergic effects such as pseudoparkinsonism and elevated
prolactin levels, but there arelimited data on its efficacy.
20. Name the other common side effects of risperidone olanzapine
and quetiapine.Risperidone can cause insomnia, agitation,
dizziness, orthostatic hypotension, and tachycardiain addition to
its dose-related dopaminergic side effects. Olanzapine can cause
somnolence, drymouth, insomnia, weight gain, dizziness, orthostatic
hypotension, and nausea in addition to lesscommon dopaminergic side
effects. Quetiapine can cause dizziness, orthostatic hypotension,
drymouth, constipation, dyspepsia, and somnolence, which can
require a slower titration than risperi-done or olanzapine, though
not as slow as clozapine. Again, quetiapine appears to not have
signifi-cant dopaminergic side effects.21. Should the atypical
antipsychotic medications he used first line in
psychosis?Clozapine, with its potential for agranulocytosis and
seizures and monitoring requirements, isnot a first-line agent.
However, other, newer atypical antipsychotics increasingly are
being used asfirst-line agents in the treatment of psychosis, with
data supporting their greater efficacy, lower sideeffects,
increased compliance, and fewer relapses when compared to typical
antipsychotics. Therealso are preliminary data that these agents
may be more effective for first-break patients, an impor-tant
consideration given that schizophrenic patients tend to experience
the greatest decline in thefirst years of their illness. Because of
their more favorable side-effect profiles, these agents also
arerecommended for elderly patients (who can be susceptible to
hypotension and tachycardia) and pa-tients with Parkinsons disease.
There is little debate that these agents are indicated for patients
whoeither cant tolerate or dont respond to typical
antipsychotics.Cost is an important consideration, as oral typical
neuroleptics cost approximately 200 peryear, as compared to
2000-3000 per year for atypicals, and more for clozapine with
monitoring.There arc a number of open trials that show overall cost
savings when atypical antipsychotics areused in schizophrenic
patients, due to decreased need for hospitalization and outpatient
visits.
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Mood-Stabilizing Agents 259However, only a smal l number of
randomized control studies are completed at this t ime; these
showmodest to significant cost savings.
BIBLIOGRAPHY1. Arnt J , SkarsfeldT Do novel an tipsychotics have
similar pharmacological characteristics?A review of the ev-2.
Baldessarini RJ, Frankenburg FR: Clozapine:A novel antipsychotic
agent. N Engl J Med 324746-754, 1991.3. Janicak PG, Davis JM ,
Preskhorn SH, Ayd FJ: Principles and P ractice of Psychoph
armacotherapy,2nd ed.4. Jenkins SC, Hansen MR (eds): A Pocket
Reference for Psychiatrists, 2nd ed. W ashington, DC , American5 .
Maxmen JS , Ward NG: Psychotropic Drugs Fast Facts, 3rd. New York,
WW Norton and Co, 2000.6. Schatzberg AF, Nemeroff CB: The American
Psychiatric Press Textbook of P sychopharm acology,2nd ed.7. Stahl
SM : Essential Psychopharmacology .New York, Cambridge University
Press, 1998.8. Van Putten T, Marder SR,W irshingWC, et al:
Neuroleptic plasma levels. Schizophr Bull 17:197-216, 1991.
idence. Neuropsychopharm 18:63-101, 1998.
Baltimore, Williams& Wilkins, 1997.Psychiatric Press ,
1995.
Washington, DC, American Psychiatric Press, 1998.
49. MOOD-STABILIZING AGENTSJames L acobson,M . D
1. What are mood -stabilizing agents?Moo d-stabil iz ing agents
a re medica t ions wi th both ant imanic and ant idepressant e f
fec ts. Th e
ideal mood stabilizer would treat acute mania and depression, as
well as prevent recurrence of bothstates. Currently available
medicat ions in this class tend to b e bet ter antimanic agen ts
than antide-pressant agents.
M ood stabi lizers a re somet im es ca l led thymoleptics. This
te rm impl ies the capaci ty to a l te remotional or mental states,
once (w rongly) thought to b e influenced by the thymus gland. Henc
e thepersistence of terms suc h as euthymic (normal mood range) and
hyperthymic (excessively elevatedmood) .2. Name som e m
ood-stabilizing agents.
Lithium (as a ca rbonate or ci trate sal t) and v alproate
(valproic acid, divalproex sodium ) are theonly FDA -approved
medica t ions in th is c lass . Both have proven ant imanic benef i
ts , and cer ta inlymay be useful in trea ting bipolar depression.
Li th ium has been shown to decrease recurrent moodepisode s. It is
widely believed that valproate also may pre vent recurrent episodes
in bipolar illness,but this has yet to be proven in controlled
research studies. Carbam azepine has clearly demon stratedantimanic
propert ies, but i t has not yet gained FD A approval for this
indicat ion.
Dose Ranges and Therapeutic Levels o Mood-Stabilizing Ag
entsMEDICATION DOSE RANGE (APPROXIMATE) THERAPEUT IC BLOOD
LEVELS*
Lithium 600-1 800 nig/day 0.5-1.5 mEq/LCarbam azepine 600-1 600
mglday 6-12 nglmlValproate acid 750-3000 mglday 50- 100 pg/ml
* Based on trough values obtained 8-12 hours after the preceding
dose of medication.Oth er medica tions current ly be in g invest
iga ted and used a s mood-stabil iz ing agen ts inc lude
lamotrigine, gabapentm, calcium channel blockers (e.g.,
verapamil), and neuroleptic medications.