48. Antipsychotic Medications

8/12/2019 48. Antipsychotic Medications

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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.

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48. Antipsychotic Medications