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15. Gelenberg AJ: The 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 Gen Psychiatry 47:1093-1099, 1990. 18. Leonard BE: New approaches to the treatment of depression. J Clin Psychiatry 57(suppl4), 1996. 19. Nelson JC: Safety and tolerability of the new antidepressants. J Clin Psychiatry 58(suppl6):26-31, 1997. 20. Nemeroff CB, Devane CL, Pollock BG, et al: Newer antidepressants and the cytochrome P450 system. Am J Psychiatry 153:311-320, 1996. 2 1. Nierenberg AA, Feighner JP, Rudolph R, et al: Venlafaxine for treatment-resistant unipolar depression. J Clin Psychopharmacol 14:4 1 9 4 2 3 , 1994. 22. Quitkin FM, McGrath PJ, Stewart AW, et al: Atypical depression, panic attacks, and response to imipramine and phenelzine: A replication. Arch Gen Psychiatry 47:935-941, 1990. 23. SchatzbergA F Fluoxetine in the treatment of comorbid anxiety and depression. J Clin Psychiatry 135-12, 1995. 24. Schatzberg AF, Cole JO, Debattista C: Manual of Clinical Psychopharmacology. 3rd ed. Washington, DC, American Psychiatric Press, 1997. 25. The Medical Letter: Citalopram for depression. 40(1041), December 4, 1998. 26. Wheatley DP, van Morraert M, Timmerman L, Kremer CME: Mirtazapine: Efficacy and tolerability in comparison with fluoxetine in patients with moderate to severe major depressive disorder. J Clin Psychiatry 59:306-3 12, 1998. 27. Wisner KL, Perel JM, Findling RL: Antidepressant treatment during breast feeding. Am J Psychiatry 153: 1132-1 137, 1996.

48. ANTIPSYCHOTIC MEDICATIONS

Herbert T.Nagamoto, M . D
1. What are antipsychotic medications? Antipsychotic medications are used to treat psychotic symptoms in patients with schizophrenia and other conditions. Symptoms may include hallucinations, delusions, paranoia, thought broadcasting, catatonia, bizarre behavior, and associated symptoms such as hypervigilance, agitation, and irrtability. Typical antipsychotic medications also have neurologic side effects, leading to the alternate designation of neuroleptics (of the neuron). Antipsychotic medications are divided into typical agents, which are similar to haloperidol, and atypical agents, as exemplified by clozapine, which have different therapeutic and side-effect profiles and a different mechanism of action. This is a rapidly evolving area of psychopharmacology, and the newer atypical antipsychotic agents increasingly are used as first-line agents (see Question 21).
2. List the different typical antipsychotic medications by chemical class, specifying relative potency in chlorpromazineequivalents and usual range of daily oral dose.

Potency and Range of Oral Dose of Neuroleptics

ANTIPSYCHOTIC AGENT GENERIC NAME (TRADE NAME) APPROXIMATE AMOUNT (MG) OF DRUG NEEDED TO EQUAL 100 MG OF CHLORPROMAZINE RANGE OF DAILY ORAL DOSE (MG)

Aliphatic
Chlorpromazine (Thorazine)

I00
2
10 IS

25-2000
140 4-64 15-150 2-40
Table continued on following page

Piperazine
Fluphenazine (Permitil, Prolixin) Perphenazine (Trilafon) Prochlorperazine (Compazine) Trifluoperazine (Stelazine)

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Potency and Range of Oral Dose of Neuroleptics (Cont.)

ANTIPSYCHOTIC AGENT GENERIC NAME (TRADE NAME) APPROXIMATE AMOUNT (MG) OF DRUG NEEDED TO EQUAL 100 MG OF CHLORPROMAZINE RANGE OF DAILY ORAL DOSE (MG)

Piperidine
Mesoridazine (Serentil) Thioridazine (Mellad)

50 100
2

75400 75-800 1-100 30-60 640 15-225 1-250

Butyrophenone
Haloperidol (Haldol)

Thioxanthene
Chlorprothixene (Taractan) Thiothixene (Navane)

100 4 10 10

Dihydroindolone
Molindone (Moban)

Di henzoxazepine
Loxapine (Loxitane) From Jenkins S, Gibbs T, Szymanski S: A Pocket Reference for Psychiatrists. Washington, DC, American Psychiatric Association, 1990, p 134, with permission.

3. What is the mechanism of action of typical antipsychotic medications?

The typical antipsychotic medications are believed to act via central blockade of dopamine receptors. This action in limbic areas leads to antipsychotic effects; in basal ganglia, to extrapyramidal side effects; in the brainstem chemoreceptor trigger zone, to antinausea and antiemetic effects; and in the hypothalamus (via blockade of dopamine inhibition of anterior pituitary prolactin release), to increased prolactin release.

4. Name several conditions that are indications for the use of antipsychotic medications. Antipsychotic medications are used in a number of conditions to treat psychotic symptoms, including hallucinations, delusions, paranoia, combativeness, agitation and hostility, insomnia, catatonia, hyperactivity, and poor grooming and self-care.

Indications for Use of Antipsychotic Medication

Acute and maintenance treatment of schizophrenia Psychosis associated with acute mania and major depression Psychosis from any number of medical causes (see chapters on schizophrenia, dementia, and delirium) As adjunctive treatment for agitation due to psychiatric conditions, delirium, delirium tremens, and dementia Tics due to neurologic conditions such as Huntingtons chorea and Tourettes syndrome Flashbacks, nightmares, and agitation due to posttraumatic stress disorder Nausea and vomiting (prochlorperazine [Compazine], trimethobenzamide [Tigan], metoclopramide [Reglanl) Gastroesophageal reflux and diabetic gastroparesis (metoclopramide [Reglan]) Adjunctive use in anesthesia for medical and surgical procedures (droperidol [Inapsine])

5. List the general classes of side effects of typical antipsychotic medications. Dopaminergic side effects

*Pseudoparkinsonism
Cogwheel rigidity Shuffling gait Parkinsonian tremor Masked facies *Acute dystonias, such as opisthotonus, torticollis, and tlaryngospasm, which may cause acute airway obstruction

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Increased prolactin secretion that may lead to galactorrhea Akathisia-subjective or observabJe restlessness (thorazine shuffle) Tardive dyskinesia, tardive dystonia (see question 12) TNeuroleptic malignant syndrome (NMS) Anticholinergicside effects *Dry mouth *Blurred vision (accommodation problems or frank blurred vision) *Constipation that may lead to ladynamic ileus Urinary hesitancy or ?obstruction Memory and concentration difficulties, up to ifrank delirium Alpha-adrenergicblockade Hypotension Orthostatic hypotension Antihistaminergicside effects *Sedation, drowsiness Weight gain Others i Agranulocytosis ECG changes (prolonged QT interval) Elevated liver function tests Elevated creatine phosphokinase (in the absence of NMS) Fetal toxicity Photosensitivity Pigmentary retinopathy (avoid doses of thioridazine > 800 mg/day) Seizures (decreased seizure threshold) *Sexualdysfunction (erectile problems, impotency, delayed, absent, or retrograde ejaculation, 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 high in sedation, orthostatic hypotension, and anticholinergic side effects, whereas the higher-potency agents, such as haloperidol and fluphenazine, tend to be high in pseudoparkinsonian, akathisia, and acute dystonic side effects.

7. Describe the treatment of common side effects of typical antipsychotic medications. In general, decrease antipsychotic medications to the lowest effective dose whenever possible to minimize side effects and avoid polyphamacy. Pseudoparkinsonismand 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 15 mg/day in divided doses) are used for their anticholinergic effects to treat acute extrapyramidal side effects. Prophylactic treatment for approximately the first 10 days of treatment or after dosage increases may be considered for adolescents and other patients who (by history) are highly susceptible to pseudoparkinsonism and acute dystonias. Exercise care to avoid anticholinergic poisoning in combination with other anticholinergic agents, particularly in elderly or medically debilitated patients. The lowest effective doses are prudent, and they should be tapered and discontinued as soon as possible. Amantadine (Symmetrel), which is thought to potentiate dopaminergic neurotransmission, also may be used. In the case of laryngospasm, which may lead to acute airway obstruction, use Benadryl, 50 mg intravenously. Akathisia usually responds well to dosage reduction, anticholinergic agents, or change to a different class of neuroleptics. Benzodiazepines and beta-adrenergic antagonists such as propranolol

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are also effective in treating akathisia. It is important to differentiate akathisia due to neuroleptic treatment from agitation due to psychosis. This differentiation may be difficult, but neuroleptic doses may be increased (which improves psychotic agitation but worsens akathisia) or decreased (which improves akathisia but worsens psychotic agitation). Some akathisia treatments (anticholinergics) are unlikely to affect psychotic agitation, whereas others may improve (benzodiazepines) or have differential effects (beta-adrenergic antagonists) on agitation due to psychosis. Patients often develop tolerance to anticholinergic side effects, but they may persist. It is usually best to decrease dosage or switch to a more potent agent if anticholinergic side effects become intolerable. Alternatively, bethanechol (Urecholine, 5-10 mg up to 4 timedday; sometimes 25 mg up to 4 timedday) may be used to decrease dry mouth, blurred vision, constipation, and urinary hesitancy. Hypotension and orthostatic hypotension are treated with oral hydration, careful instructions to the patient, dose reduction, or change to more potent agents. Occasionally, intravenous hydration is indicated. If a vasoactive agent is required, one should avoid agents with beta-adrenergic agonist properties (such as epinephrine), which may worsen hypotension via vasodilatation and peripheral pooling. In such cases, a selective alpha-adrenergic agonist such as metaraminol (Aramine) should be used.

8. What constitutes an adequate trial of typical antipsychotic medications? Antipsychotic medications often induce sedation quickly, but their specific antipsychotic effects may take up to 6 weeks at therapeutic doses to develop fully. Conversely, when a stable schizophrenic patient decides to stop antipsychotic medication suddenly, it may take weeks for psychotic symptoms to return or for patients to decompensate. Therapeutic doses vary widely from patient to patient and within a given patient at various times. In general, maintenance doses range from approximately 100-700 mg/day, averaging 300 mg/day in chlorpromazine equivalents. Acutely ill patients may require higher doses, although the current trend is toward adjunctive use of benzodiazepines in acutely psychotic patients to avoid the side effects often associated with highdose antipsychotic medications. In an emergency situation, with a highly agitated or out-of-control patient, many antipsychotic medications can be given intramuscularly. In general, the lower-potency antipsychotics such as chlorpromazine or thioridazine are given in half the amount of oral doses. In some settings, particularly emergency 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 condition 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 intervals on electrocardiogram, who are at increased risk for developing torsade de pointes.

9. Delineate an approach to patients who do not respond well to antipsychotic medications. For patients who do not respond to treatment, reassess the diagnosis, particularly in the case of
such illnesses as schizophrenia and bipolar affective disorder, which may be quite similar in the acute phases. When revisiting a patients diagnosis: (1) rule out occult medical illness that may worsen symptoms or cause the illness under treatment; ( 2 ) rule out alcohol and substance abuse, which may mimic or worsen a number of psychiatric symptoms; and (3) ensure that the patient is receiving an adequate dosage of antipsychotic for an adequate length of time. Typical antipsychotic medications may have a therapeutic window; thus patients out of the appropriate range may receive too little or too much medication. Plasma levels obtained at steady state help to assess dosage of some neuroleptics (see below; haloperidol and fluphenazine are most studied). Compliance is a common problem with antipsychotic medications. All too often patients stop medications because of legitimately troublesome side effects and thus experience psychotic decompensation. To ensure acute compliance, administer intramuscular injections or observe the patient for 30 minutes after oral ingestion of liquid medications. For long-term maintenance, fluphenazine and haloperidol are available in slow-release depot forms that may be given intramuscularly every 2-4 weeks.

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Ensure that troublesome side effects do not hinder the effectiveness of treatment, especially in akathisia, which can mimic or exacerbate psychotic agitation. Pseudoparkinsonism and oversedation may make patients look artificially depressed, and neuroleptic malignant syndrome may make patients 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. Finally, for patients who cannot tolerate or do not 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 management of patients? There is evidence that at least some antipsychotic medications have a therapeutic window of ideal dosage or blood levels. Currently, haloperidol is the most thoroughly studied agent, with best therapeutic effects achieved at trough plasma levels of 5-1 2 nglml in most patients. Fluphenazine also is well studied, with recommended plasma levels of 1-2.8 ng/ml. For other agents, plasma levels are useful in ruling out subtherapeutic levels of medication in patients who hypermetabolize, have poor absorption, or are noncompliant. If a laboratory reports a therapeutic range for a neuroleptic, it is reasonable to inquire how the laboratory arrived at its recommendations. For the atypical antipsychotic clozapine, patients should have improved clinical response at trough plasma levels of greater than 35041 0 nglml. 11. Name possible problematic interactions between antipsychotic medications and other drugs. Anticholinergic agents may place patients at increased risk of anticholinergic delirium. Numerous agents may induce or worsen hypotension or orthostatic changes in combination with neuroleptics, including barbiturates and nonbarbiturate hypnotics, narcotics, benzodiazepines, angiotensin-converting enzyme inhibitors, antihypertensives, antidepressants, methyldopa, anesthetics, and epinephrine. Sedation may be worsened when antipsychotics are used with benzodiazepines, sedatives, narcotics, cimetidine, antidepressants, and antihistamines. In particular, chlorpromazine and meperidine used in combination may lead to hypotension and lethargy. Lithium and antidepressants may worsen extrapyramidal side effects (pseudoparkinsonism and acute dystonias). For a more complete listing of drug interactions with antipsychotic medications, including changes in plasma levels, see Maxmen and Ward.5
12. What is tardive dyskinesia? Why is it of concern with chronic use of antipsychotic medications? Tardive dyskinesia is a syndrome of abnormal involuntary movements such as buccolingual masticatory movements, choreoathetoid movements of the limbs or even trunk and neck, and facial grimacing or tics. Long before the advent of antipsychotic medications, such movements were noted in schizophrenic patients, who probably are at increased risk of developing the syndrome. Tardive dyskinesia tends to develop after months to years of neuroleptic treatment and has been described in patients treated with all available typical agents. It occurs in about 15-20% of patients receiving chronic neuroleptic treatment; the incidence rises significantly in elderly populations. Curiously, it is temporarily masked by increased antipsychotic doses and tends to worsen acutely with decreased dosage. 13. How is tardive dyskinesia avoided or managed? Patients treated with neuroleptics should be examined for abnormal involuntary movements before initiating therapy and every 6 months or with dosage changes or appearance of suspected movements. Patients should be maintained on the lowest effective dosage of medication. On examination, the abnormal movements are more apparent when patients do not know that they are being observed or when they are concentrating on tasks such as rapid alternating movements. In addition, a syndrome of withdrawal dyskinesias may occur briefly on withdrawal of neuroleptics. In a small but significant percentage of cases, tardive dyskinesia becomes permanent and disfiguring. Unfortunately, there are no effective treatments for tardive dyskinesia, although vitamin E (400 IU 3 4 timeslday) has been shown to decrease symptoms in some patients, especially those who are

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young and have had the syndrome briefly. The atypical antipsychotic clozapine appears not to cause this problem and may improve symptoms in patients who develop tardive dyskinesia (see below) and need continued antipsychotic treatment. Risperidone, olanzapine, and quetiapine appear to be much less likely to cause tardive dyskinesia than typical antipsychotics, though long-term use with these agents is limited at 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 infection Rigidity, which may be lead pipe and generalized, and other neurologic signs (e.g., akinesia and dyskinesia) Autonomic dysfunction leading to tachycardia, labile hypertension, diaphoresis, and pallor (mix of symptoms varies widely) Changes in mental status ranging from mild obtundation through stupor and coma (in approximately 70% of patients) Other possible symptoms: rhabdomyolysis (with elevated creatine phosphokinase in 40-90%), dysarthria, dysphagia, mutism, Babinski reflex, sialorrhea, opisthotonus NMS usually occurs within 2 weeks of initiating typical antipsychotics or increasing dosage, but may occur after months of stable-dose treatment. It evolves over 24-72 hours and lasts 5-10 days with oral medications or considerably longer with depot intramuscular medications. NMS has an estimated mortality rate of 15-20%. Prompt diagnosis and discontinuation of neuroleptics are essential. Treatment is primarily supportive, although dantrolene and bromocriptine have been helpful. There have been isolated case reports of NMS associated with clozapine, risperidone, and olanzapine. 15. What is clozapine? Clozapine (Clozaril) is a tricyclic dibenzodiazepine antipsychotic medication. It was synthesized in the 1960s but withdrawn from the market in the U.S. after 8 of 16 patients who developed agranulocytosis in Finland died in the 1970s. It has been used continuously in other countries since then. In 1990 it was reintroduced in the US. after it was shown that, in comparison to typical neuroleptics: Clozapine is more effective in treatment-resistant schizophrenic patients for both positive psychotic symptoms, such as delusions and hallucinations, and chronic negative symptoms, such as social withdrawal, anhedonia, blunted affect, and poor initiative. Clozapine is unlikely to cause dopaminergic side effects such as pseudoparkinsonism, tardive dyskinesia, and elevated prolactin levels.

16. What are the side effects of clozapine? The FDA mandates weekly dispensing and CBC monitoring with initial treatment due to the risk of agranulocytosis.Most cases of agranulocytosis occur in the first 6 months of treatment. With weekly monitoring, the incidence of agranulocytosis has decreased from 1-2% in the initial studies to 0.38% in the first 5 years of use since U S . reintroduction (versus 0.1% with typical antipsychotics). The FDA now allows every other week dispensing and CBC checks in stable patients after the first 6 months of treatment. There is still some risk of death from agranulocytosis despite this careful monitoring ( 1 9 deaths out of over 180,000 patients exposed to clozapine in the U.S. as of this writing; an approximate 1/10,000 risk of death). Other side effects can include dose-related seizures (5% at doses above 600 mg/day), sedation, orthostatic hypotension, sialorrhea, and weight gain. The risk of seizures dictates low starting doses and slow dose increases, and if a patient has been off of clozapine for more than a few days, retitration 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 and pharmacologic actions. Clozapine affects a large number of neurotransmitter systems. Its atypical properties currently are thought to be due to its relatively high 5HT2 blockade and weak DUD2

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blockade, with more dopamine effects in limbic systems (related to antipsychotic effects) than i n striatal systems (leading to motor side effects). Average doses are 2 5 0 4 5 0 mg/day with a range of 100-900 mgiday. Clozapine has been found useful in a number of psychotic conditions in addition to schizophrenia including treatment refractory bipolar affective disorders. It remains the gold standard for efficacy in antipsychotic medications, but its use is limited by side effects, cost, and monitoring requirements.

18. What other atypical antipsychotic medications currently are available?

As of this writing, the atypical antipsychotic medications available in the U.S. in addition to clozapine are (in order of introduction) risperidone (Risperdal), olanzapine (Zyprexa), and quetiapine (Seroquel). All three medications appear to be effective with both positive and negative symptoms 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 4 mg/day (range 2-1 6/day). There is increasing pseudoparkinsonism, akathisia, and elevated prolactin with 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 prolactin at higher doses, again less than that seen with typical antipsychotics. While tardive dyskinesia can occur with risperidone and olanzapine, the incidence with each appears to be considerably less than that seen with typical neuroleptics. Both of these medications also are showing promise in the treatment of other psychotic disorders, such as treatment refractory mania. While there are isolated case reports of mania induction attributed to risperidone, other data suggest that this is not likely to be 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 to induce dopaminergic effects such as pseudoparkinsonism and elevated prolactin levels, but there are limited 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 tachycardia in addition to its dose-related dopaminergic side effects. Olanzapine can cause somnolence, dry mouth, insomnia, weight gain, dizziness, orthostatic hypotension, and nausea in addition to less common dopaminergic side effects. Quetiapine can cause dizziness, orthostatic hypotension, dry mouth, constipation, dyspepsia, and somnolence, which can require a slower titration than risperidone or olanzapine, though not as slow as clozapine. Again, quetiapine appears to not have significant 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, is not a first-line agent. However, other, newer atypical antipsychotics increasingly are being used as first-line agents in the treatment of psychosis, with data supporting their greater efficacy, lower side effects, increased compliance, and fewer relapses when compared to typical antipsychotics. There also are preliminary data that these agents may be more effective for first-break patients, an important consideration given that schizophrenic patients tend to experience the greatest decline in the first 5 years of their illness. Because of their more favorable side-effect profiles, these agents also are recommended for elderly patients (who can be susceptible to hypotension and tachycardia) and patients with Parkinsons disease. There is little debate that these agents are indicated for patients who either cant tolerate or dont respond to typical antipsychotics. Cost is an important consideration, as oral typical neuroleptics cost approximately $200 per year, 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 are used in schizophrenic patients, due to decreased need for hospitalization and outpatient visits.

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However, only a small number of randomized control studies are completed at this time; these show modest to significant cost savings.

BIBLIOGRAPHY
1. Arnt J, Skarsfeld T Do novel antipsychotics have similar pharmacological characteristics?A review of the ev-

idence. Neuropsychopharm 18:63-101, 1998. 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 Practice of Psychopharmacotherapy,2nd ed. Baltimore, Williams & Wilkins, 1997. 4. Jenkins SC, Hansen MR (eds): A Pocket Reference for Psychiatrists, 2nd ed. Washington, DC, American Psychiatric Press, 1995. 5. 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 Psychopharmacology,2nd ed. Washington, DC, American Psychiatric Press, 1998. 7. Stahl SM: Essential Psychopharmacology.New York, Cambridge University Press, 1998. 8. Van Putten T, Marder SR,WirshingWC, et al: Neuroleptic plasma levels. Schizophr Bull 17:197-216, 1991.

49. MOOD-STABILIZING AGENTS

James L.Jacobson, M . D

1. What are mood-stabilizing agents?

Mood-stabilizing agents are medications with both antimanic and antidepressant effects. The ideal mood stabilizer would treat acute mania and depression, as well as prevent recurrence of both states. Currently available medications in this class tend to be better antimanic agents than antidepressant agents. Mood stabilizers are sometimes called thymoleptics. This term implies the capacity to alter emotional or mental states, once (wrongly) thought to be influenced by the thymus gland. Hence the persistence of terms such as euthymic (normal mood range) and hyperthymic (excessively elevated mood).

2. Name some mood-stabilizing agents.

Lithium (as a carbonate or citrate salt) and valproate (valproic acid, divalproex sodium) are the only FDA-approved medications in this class. Both have proven antimanic benefits, and certainly may be useful in treating bipolar depression. Lithium has been shown to decrease recurrent mood episodes. It is widely believed that valproate also may prevent recurrent episodes in bipolar illness, but this has yet to be proven in controlled research studies. Carbamazepine has clearly demonstrated antimanic properties, but it has not yet gained FDA approval for this indication.

Dose Ranges and Therapeutic Levels of Mood-Stabilizing Agents

MEDICATION

DOSE RANGE (APPROXIMATE)

THERAPEUTIC BLOOD LEVELS*

Lithium Carbamazepine Valproate acid

600-1 800 nig/day 600-1 600 mglday 750-3000 mglday hours after the preceding dose of medication.

0.5-1.5 mEq/L 6-12 nglml 50- 100 pg/ml

* Based on trough values obtained 8-12

Other medications currently being investigated and used as mood-stabilizing agents include lamotrigine, gabapentm, calcium channel blockers (e.g., verapamil), and neuroleptic medications.