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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.

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3. In what conditions are mood stabilizers used? Bipolar I disorder

Bipolar I1 disorder Cyclothymia Schizoaffective disorder Intermittent explosive disorder Mania due to medical conditions (e.g., stroke, temporal lobe syndrome, cancer) Major depressive disorder (adjunctive treatment or prophylaxis in recurrent disorder)

4. What assessment is necessary before initiation of treatment with mood-stabilizingagents? A general medical assessment, including history, physical examination, and laboratory evaluation focusing on organ systems potentially affected by each agent, is important prior to starting these
medications.

Moodstabilizing Agents: Side Effects and Laboratory Tests

MEDICATION ORGAN SYSTEM AFFECTED POTENTIAL SIDE EFFECTS LABORATORY TESTS

Lithium

Cardiac Hematologic Renal

Conduction disturbance Sinus node dysfunction Elevated white blood cell count Diabetes insipidus/development of renal failure

EKG Complete blood count with differential Electrolytes, blood urea nitrogen (BUN), creatinine, urinalysis (specific gravity) Pregnancy test Thyroid-stimulating hormone (TSH) Complete blood count with differential Blood count Platelet countibleeding time Hepatic enzymes Pregnancy test EKG Complete blood count with differential Platelet count Hepatic enzymes Bilirubin BUNkreatinine

Reproductive (women) Thyroid Valproate Hematologic

Fetal abnormalities Hypothyroidism/goi ter Anemia Leukopenia Thrombocytopenia

Hepatic Reproductive (women) Carbamaze pine Cardiac Hematologic

Hepatic dysfunction or failure Fetal abnormality Arrhythmia Agranulocytosis Aplastic anemia Thrombocytopenia Hepatitis Jaundice Syndrome of inappropriate secretion of antidiuretic hormone Hyponatremia Fetal abnormality

Hepatic Renal

Reproductive (women)

Electrolytes Pregnancy -~ tests

Once treatment is initiated and efficacy is established, periodic blood level monitoring of the mood stabilizer, review of potential side effects, physical examination, and laboratory monitoring for side effects are recommended. The patients general health and reliability should be taken into account in deciding the frequency of monitoring (generally no less than every 3 months). For example, in a healthy, reliable 35-year-old patient whose bipolar illness is well controlled, monitoring of medication, blood levels, and laboratory tests screening for side effects every 3

Mood-Stabilizing Agents

26 I

months is probably adequate in the absence of newly developed symptoms attributable to the medication. In a 50-year-old patient with bipolar disorder, a history of alcohol abuse, liver damage, and treatment noncompliance, blood level monitoring and screening laboratory tests may be needed every 2-4 weeks to ensure compliance and to decrease the risk of serious side effects.

5. Describe an acute manic episode. The acute manic phase of bipolar illness is heralded by the rapid onset of a persistently elevated, expansive, or irritable mood accompanied by a cluster of symptoms such as inflated self-esteem, grandiosity, decreased need for sleep, increased talking, racing thoughts, easy distractibility, increased motor behavior, increased goal-directed activity, and increased involvement in high-risk, pleasure-seeking activities. The symptoms cause marked impairment in functioning and may have profound effects on others (e.g., intrusive, aggressive behavior, high risk-taking activities, impulsive spending). Additionally, frank psychotic symptoms may be present (e.g., delusions, hallucinations). Hospitalization often is necessary.

6. Discuss the pharmacologic management of an acute manic episode.

Medication is the primary mode of treatment. Lithium and valproate are the principal agents for mania, with response rates reported as high as 80% in bipolar I disorder. After appropriate medical and laboratory evaluation, lithium can be initiated at 300 mg orally 3 times/day (no parenteral form is available), then titrated according to side effects, clinical response, and blood level. A blood level of 0.8-1.2 m E q k generally is required to treat acute mania. A steady-state, stable blood level generally is achieved in about 5 days and is measured 10-12 hours after the lithium dose (e.g., in the morning before the first dose of the day). Changes in dosage require monitoring of lithium levels at least every 5-7 days after the change. Some patients require (and tolerate) levels up to 1.5 mEq/L, although higher levels are not advisable because of the risk of toxicity. Treatment with lithium alone may have a relatively slow response rate (up to 2 weeks after a therapeutic blood level is established); hence adjunctive medication treatment usually is required. Valproate, used alternately or adjunctively, often provides more rapid antimanic response (e.g., 3-5 days). Valproate is the preferred treatment in rapid cycling and mixed bipolar states, as well as in mania caused by many medical conditions and in patients Intolerant of lithium (e.g., due to allergy). Valproate may be initiated at 250 mg orally 3 timedday, or an oral-loading regimen may be used (e.g., 20 mg/kg/ day in divided doses). Carbamazepine also is effective in acute mania, although it may be slightly less effective than lithium. Treatment is started at 200-600 mg/day in divided doses and titrated as tolerated, usually to 800-1000 mg/day, striving for blood levels of 6-12 ng/ml. Blood levels should be monitored at least weekly initially, with the specimen drawn about 10 hours after the previous dose. Sedation and ataxia early in treatment may slow the upward titration and attainment of therapeutic blood levels. Dermatologic reactions also may occur early in treatment. If psychotic symptoms are present, the addition of a neuroleptic (antipsychotic) medication may be essential. Neuroleptics generally result in rapid improvement (days as opposed to weeks) in agitation, thought disorder, and sleep. For example, haloperidol, 5-20 mg/day in divided doses, is a typical regimen. However, bipolar patients are at an increased risk of neuroleptic malignant syndrome and tardive dyskinesia. In addition, a syndrome of combined lithium-neuroleptic neurotoxicity (e.g., confusion, encephalopathy, delirium, ataxia, nystagmus, extrapyramidal side effects) can occur. Hence, these medications have to be monitored closely. Atypical antipsychotic medications (e.g., olanzepine, risperidine, quetinpine, clozapine) are becoming the preferred choice due to lower risks of side effects. However, mood cycling and/or switching have been reported. Benzodiazepines also are widely used in treating acute mania. Both clonazepam and lorazepam are effective in decreasing hyperactivity, controlling agitation, decreasing anxiety, and improving sleep during a manic episode. Both are effective orally (clonazepam, 4-20 mg/day; lorazepam, 4-30 mg/day in divided doses). Lorazepam may be given intramuscularly in severely

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agitated, noncompliant patients who require acute sedation (up to 4 mg IM). Benzodiazepines may decrease the total required dose of neuroleptic medications, resulting in a lowered risk of neuroleptic-related side effects. In addition, sedative-hypnotic agents often are needed to promote adequate sleep. Hypomania may be managed with lithium or valproate and benzodiazepines. Doses can be lower than for mania, and treatment may forestall an incipient manic episode.

7. Describe bipolar depression. Major depressive episodes in patients with bipolar type I and type 11 disorders are likely to occur more frequently than manic episodes (see Chapter 12). Such episodes are characterized by at least 2 weeks of depressed mood, loss of interest or pleasure in activities, weight loss or gain, insomnia or hypersomnia, psychomotor agitation or slowing, fatigue, loss of energy, feelings of worthlessness, difficulty in thinking, indecisiveness, and recurrent thoughts of death (often with suicidal ideas or attempts). Such patients are significantly distressed, and their functioning is impaired. Bipolar depressions often are characterized by hypersomnia, profound anergy, early age of onset, and/or postpartum onset. A family history of bipolar illness may be present.
8. Discuss the pharmacologic management of bipolar depression. While one may be inclined to treat manifest depression with antidepressant medications, careful attention is necessary to discern a history of bipolarity, because antidepressants may adversely affect the course of illness in bipolar individuals. All antidepressants can induce switching from depression to mania, with rates of switching as high as 50%. In addition, in bipolar illness, antidepressants may induce rapid mood cycling and mixed mood states (mania and depression co-existing), as well as precipitate difficult-to-treat, severe depressive states. Hence, treatment of bipolar depression should first make use of mood-stabilizing agents. Lithium alone may be used to treat bipolar depression; the response rate is 60-70%. However, response may be slow (6-8 weeks). Blood levels may need to be higher (> 1.2 mEqlL) than in mania. Thyroid augmentation (e.g., thyroxine) may be helpful, even if the patient has normal thyroid levels. Valproate and carbamazepine also can be effective in treating bipolar depression. These medications should be initiated slowly to achieve antidepressant effectiveness, as rapid titration (as used in treating mania) may result in mood stabilization in a depressed state. If depression persists despite a mood-stabilizer regimen, antidepressants may be added. When indicated (e.g., severe, life-threatening depression or depression unresponsive to mood stabilizers and psychotherapy), buproprion (75 mg 2 times/day-l50 mg 2-3 timedday) or tranylcypromine, a monoamine oxidase (MAO) inhibitor (1 0 mg 2 times/day-20 mg 3 timedday) may be good choices; some studies have shown decreased rates of switching relative to other antidepressants. Buproprion may induce seizures; therefore, dosing schedules and total dose must be closely monitored. Tranylcypromine and all MA0 inhibitors may interact with other antidepressants, carbamazepine, pressor agents, and food high in the amino acid tyramine to produce a potentially lethal hypertensive crisis. Monitor M A 0 inhibitors closely, and pay particular attention to patient education about diet restrictions. Short-half-life serotonin reuptake inhibitors such as sertraline and paroxetine also may be reasonable choices; rates of switching may be relatively lower than with tricyclic antidepressants (TCAs). Other antidepressants (e.g., TCAs) clearly are effective in treating bipolar depression, but should be avoided because they have relatively increased rates of switching. Antidepressants should be used for the briefest period necessary to treat the depression, then gradually withdrawn. Recent trials of lamotrigine and gabapentin (both anticonvulsants) have shown promise in treating bipolar depression and, perhaps, in stabilizing mood. While data is not yet conclusive, many anecdotal reports and a few controlled studies are supportive. Lamotrigine must be titrated very gradually due to the risk of Stevens-Johnson syndrome and of toxic dermal necrolysis. This risk is increased in the presence of concurrent valproate treatment.

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Electroconvulsive therapy clearly is effective in bipolar depression and at times is the preferred treatment (see Question 16).
9. Why are long-term maintenance strategies important in bipolar disorders? Bipolar disorder is a chronic, relapsing, and remitting illness. At this time there is no cure. In addition, recurrent episodes predispose toward more frequent and severe episodes (a phenomenon known as kindling). Therefore, long-term management is critical, and life-long treatment is extremely likely.

10. What are the goals of maintenance treatment? The goals of maintenance treatment are to decrease the psychosocial impact of the illness (such as job loss, economic ruin, and loss of relationships), suicide risk, and frequency and severity of recurrence; to improve compliance to treatment regimens, and to achieve the most effective treatment regimen with the fewest possible side effects. Many people with bipolar illness also have significant impairment from mood fluctuation and other symptoms between identifiable episodes of illness (subsyndromal symptoms), which also can be improved with continuous pharmacologic intervention and psychotherapeutic efforts.
11. How is long-term maintenance executed? Lithium maintenance decreases the frequency and severity of both manic and major depressive episodes. When lithium is stopped abruptly, more than 50% of patients relapse within 6 months. Maintenance therapy with lithium should focus on maintaining the blood level range that was effective in treating acute illness. Lower-dose maintenance has been associated with an increased relapse rate. Long-term lithium maintenance requires monitoring of lithium blood levels (which may change with age, diet, use of other medications, concurrent illness, and state of hydration) and periodic ( e g , every 6 months) assessment of thyroid (TSH) and renal function (BUN and creatinine; 24-hour creatinine clearance in patients with evidence of altered functioning). Neither valproate nor carbamazepine has been carefully studied in the long-term management of bipolar illness. Some studies (none carefully controlled) suggest that these agents may be useful in decreasing the intensity of recurrent manic episodes. However, when lithium alone is ineffective for maintenance or acute treatment, the addition of either valproate or carbamazepine often is beneficial. Interepisode management may require intermittent use of benzodiazepines during periods of sleep deprivation (e.g., at times of increased acute stress) to decrease the risk of precipitating a manic episode. Antidepressants should be avoided in long-term management, when possible, because of the risk of inducing rapid-cycling disorders. Neuroleptics also should be avoided because of the increased risk of tardive dyskinesia and neuroleptic malignant syndrome in patients with bipolar disorder. However, some bipolar patients and all patients with schizoaffective disorder require neuroleptic medications in maintenance regimens. The lowest effective dose should be established to minimize the risk of side effects. Clozapine may be a good choice, because of lower risk of tardive dyskinesia and emerging reports of mood stabilization. However, clozapine should not be the neuroleptic of first choice because of the risk of potentially fatal agranulocytosis. Atypical antipsychotic agents (e.g., olanzapine, risperidone) are becoming the preferred agents. 12. Describe the clinically pertinent pharmacodynamicsof the mood-stabilizing agents. Pharmacodynamic properties are helpful in understanding various clinically pertinent phenomena. For example, with a patient taking lithium, peak blood levels are more likely to be associated with transient side effects (e.g., tremor), and a decrease in total body water (i.e., dehydration) increases blood level and blood level-sensitive side effects (e.g., diarrhea). When valproate or carbamazepine is used, competition for protein-binding sites and hepatic metabolic pathways affects the doses of concurrently used medications (see Question 13).

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Mood-Stabilizing Agents
Pharmacodynamics of Mood-Stabilizing Agents

MEDICATION

PEAK BLOOD LEVEL (HR)

METABOLISM

HALF-LIFE (HR)

PROTEIN BINDING

Lithium Valproate (Divalproex sodi um) Carbamazepine

1-2

Renal excretion Hepatic

14-30

2 3-8
4-8

6-16

No (distributed in total body water) Yes

Hepatic

18-55

Yes

13. Discuss some significant drug interactions of the mood-stabilizingagents. Lithium. Blood levels of lithium are increased by thiazide diuretics and nonsteroidal antiinflammatory agents through renal mechanisms. Intracellular concentrations of lithium may be increased by neuroleptic agents. Dehydration also increases lithium levels. Calcium channel blockers may cause increased neurotoxicity. Valproate. Valproate levels are decreased by inducers of microsomal enzymes, such as carbamazepine, and increased by inhibitors of microsomal enzymes, such as fluoxetine and paroxetine. Valproate increases the blood levels of protein-bound drugs, including phenobarbital, phenytoin, tricyclic antidepressants, digoxin, and warfarin and increases blood levels of lamotrigine. Carbamazepine. Carbamazepine, an inducer of microsomal enzymes, decreases its own levels (autoinduction) as well as the levels of other drugs, including neuroleptics, benzodiazepines, other anticonvulsants, TCAs, and hormonal contraceptives. However, competition for protein-binding sites may increase blood levels initially when carbamazepine is added to ongoing treatment regimens.
14. Discuss the clinical presentation and management of lithium toxicity. Lithium toxicity typically occurs at blood levels 2 2.0 m E q L Some individuals may experience toxicity at lower doses. Neuroleptics may synergistically cause increased neurotoxicity even at therapeutic blood levels. Patients with lithium toxicity may experience lethargy, clumsiness, nausea, vomiting, diarrhea, marked tremulousness, blurred vision, and confusion. Findings on physical exam may include nystagmus, increased deep tendon reflexes, and altered mental status. Such manifestations may progress to include seizures, coma, and cardiac arrhythmias. This progression is more likely to occur in patients with lithium levels > 2.5 m E q L Permanent CNS damage may ensue. Lithium toxic& is a medical emergency and should be managed in an intensive care setting. Fluid and electrolyte monitoring, treatment of arrhythmias and respiratory compromise, and prevention of further gastrointestinal absorption may be required. Hemodialysis is the most effective way of acutely reducing the blood lithium level. The best treatment of lithium toxicity is prevention, which often is achieved through patient education. Patients need to know the symptoms of lithium toxicity, drugs that may interact with lithium, and the necessity of careful monitoring of blood lithium levels. In addition they need to be aware that avoidable circumstances (such as dehydration and use of nonsteroidal anti-inflammatory agents) may increase lithium levels. Lithium Toxicity
SYMPTOMS SIGNS

Lethargy, fatigue Clumsiness Weakness Muscle cramping Nausea Vomiting Marked tremor Blurred vision Confusion

Nystagmus Ataxia Increased deep tendon reflexes Altered mental status Cardiac arrhythmia

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15. Discuss the management of side effects of mood-stabilizing agents.

Side Effect Munagement Strategy
Check blood level; decrease dose if clinically possible Take medication with meals Change to slow-release preparation Give majority of dose at bedtime; decrease if clinically possible As above, and add a beta blocker (e.g., propranolol, 10-20 mg up to 3 timedday) Monitor, usually resolves with time Decrease dose if severe Monitor electrolytes Consider adding nonthiazide diuretic Nephrology consultation Lower lithium dose; monitor blood level more frequently Consider change to alternate mood stabilizer Monitor thyroid functions Add T4 If moderate-to-severe, consider change to alternate mood-stabilizing agents Topical antibiotics and retenoic acid Advise about dietlexercise; lower dose, if possible May resolve with time Give drug with meals Change preparations Decrease dose As above Give bulk of dose at bedtime As above Add a beta blocker B complex vitamins Folic acid Zinc (50 mg/day) and selenium (50 yg/day) Decrease dose Monitor hepatic enzymes Decrease dose Monitor platelet and granulocyte counts; if significantly diminished, taper valproate and switch to alternate agent Potentially fatal Discontinue valproate Urgent medical consultation Usually transient Decrease dose Give medication with meals Bulk of dose at bedtime Consider extended-release preparations Table continued on,following page

Lithium
Gastrointestinal distress (nausea, vomiting, diarrhea Poor concentration, confusion, sedation Tremor Increased white blood count Polydipsia, polyuria (nephrogenic diabetes insipidus) Renal insufficiency

Hypothyroidism Psoriasis Acne Weight gain

Valproate
Gastrointestinal distress (change in appetite, nausea, vomiting, diarrhea)

Sedation Tremor Hair loss (usually transient)

Minor hepatic transaminase elevation Asymptomatic thrombocytopenia or leukopenia

Pancreatitis, agranulocytosis, severe transaminase elevation or hepatic failure

Carbamazepine
Gastrointestinal distress

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Side Effect Management Strategy
As above, may require reduced dose Observe Antihistamines to control itching with mild rash Medical or derrnatologic consultation to determine if drug should be discontinued (discontinue if associated with fever, wheezing respiration, or blisterlike skin lesions) Increase frequency of monitoring white blood cells Discontinue if leukopenia persists or worsens Increase frequency of monitoring platelet counts Discontinue if thrombocytopenia persists Monitor electrolytes Change mood stabilizers, if hyponatremia persists May be fatal; discontinue drug Urgent medical consultation Discontinue medication

Carbamazepine (cont.)
Blurred vision, fatigue, ataxia, sedation, skin rash

Mild leukopenia Mild thrombocytopenia Hyponatremia Agranulocytosis, aplastic anemia, exfoliative dermatitis, or severe elevation of hepatic enzymes

16. When is electroconvulsive therapy (ECT) used in bipolar disorders?

ECT is effective in treating both acute manic and depressive phases of bipolar illness. Efficacy rates equal or exceed those o f lithium, and often with a more rapid onset of action. Although ECT generally is reserved for cases in which standard agents are not effective, it should be considered as a primary treatment when rapid response is necessary or when standard treatments are contraindicated. ECT may be the primary treatment in manic delirium (a severe mania with identifiable delirium that may include hyperthermia), mania with neuroleptic malignant syndrome, and mania during pregnancy or other medical contraindications to mood-stabilizing medications (e.g., renal impairment, history of allergy to mood-stabilizing agents). ECT also may be used earlier in the course of treatment in patients with psychotic depression and when the risk of slower response may severely compromise the patients health (e.g., ongoing serious suicide attempts, deteriorating nutritional status). Lithium generally is discontinued before starting ECT because of an increased risk of delirium and intractable seizures when ECT and lithium are combined.

Indications tor ECT as Prinrarv Treatment in Binolar Illness

Manic delirium Mania or bipolar depression with neuroleptic malignant syndrome Medical contraindications to using mood stabilizers Psychotic bipolar manic or depressive episodes Severely compromised health (e.g., serious, ongoing suicide attempts)

17. How does age affect the use of mood-stabilizingmedications? Metabolic differences in children, adolescents, and geriatric populations require altered dosing
strategies. Hepatic metabolism generally is less efficient in these groups, and lower doses of carbamazepine and valproate are used to establish therapeutic blood levels. In elderly patients, renal function often is diminished; hence a lower dose of lithium is typical. In addition, elderly patients often take other medications (carefully review drug interactions) and are more sensitive to potential neurotoxic effects (blood levels should be maintained at the lower end of the therapeutic range).

18. What other medications are used for mood stabilization?

Although they are not widely used, evidence suggests that calcium channel blockers may be effective as mood stabilizers. For example, verapamil (120-360 mg/day) has been beneficial in bipolar

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illness. It probably works well in the same group of patients who respond best to lithium (bipolar type I). Newer anticonvulsant medications (e.g., lamotrigine, topiramate, gabapentin) also are being investigated for mood-stabilizing properties. Some studies demonstrate that atypical antipsychotic agents, especially clozapine and olanzapine, are mood stabilizing. Long-acting depointramuscular injections of neuroleptic medications (e.g., fluphenazine decanoate, haloperidol decanoate) sometimes are the only effective treatment for patients who are not compliant with oral medication and whose illnesses are severe enough to warrant this approach. In patients whose mood or behavioral instability is caused by an underlying medical condition (e.g., thyroid disease, brain tumor), identification and aggressive treatment of underlying illnesses may cure the secondary mood disorder. Intermittent explosive disorder and impulsive aggressive behavior in brain-injured patients also may respond to beta blockers (e.g., propranolol in widely variable doses has been used effectively).

19. How do mood-stabilizingmedications work? The mode of action is not yet known for any of the mood-stabilizing medications. Current research efforts are trying to determine the basic cellular mechanisms that correlate with clinical processes. For example, lithium attenuates neuronal signal transduction mediated by G-proteins, which may be associated with increasing mood stability. Current research also focuses on lithium inhibition of neurotransmitter-receptor-coupled adenylate or cyclase activity, cyclic adenosine monophosphate formation, and metabolism of phosphoinositide in relation to its effect on other significant second-messenger systems. Also under investigation are attenuation of dopamine receptor turnover and function, effects on serotonin synthesis and function and binding of certain serotonin receptors, interactions with protein kinase C, ion-channel function, intracellular calcium mobilization, and impact on gene expression. With regard to anticonvulsant-type mood stabilizers (e.g., valproate, carbamazepine, lamotrigine, gabapentin), effects on voltage-gated sodium and calcium ion channels, ligand gated ion channels (e.g., GABA receptorkhannel), NMDNglutamate receptor are being investigated.
BIBLIOGRAPHY
1. American Psychiatric Association: Practice guidelines for the treatment of patients with bipolar disorder. Am J Psychiatry lS(Suppl), December, 1994. 2. Bowden CL, et al: Efficiency of divalproex vs. lithium and placebo in the treatment of mania. The Depakote Mania Study Group. JAMA 271:918-924, 1994. 3. Bowden CL, et al (eds): Practical Guidelines for the Management of Bipolar Disorder. Monograph on Treatment. Deerfield, IL, Discovery International, 1992. 4. Calabrese J, et al: A double-blind placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. J Clin Psychiatry 60(2):79-80, 1999. S. Freeman M, Stoll A: Mood-stabilizer combinations: A review of safety and efficacy. Am J Psychiatry 15S(1): 12-21, 1998. 6. Gerner RH, et al: Algorithm for patient management of acute manic states: Lithium, valproate, or carbamazepine? J Clin Psychophatmacol 12576-635, 1992. 7. Goodwin FK, Jamison KR: Manic-Depressive Illness. New York, Oxford University Press, 1990. 8. Janicak P, Levy N: Rational copharmacy for acute mania. Psychiatric Ann 28(4):204-212, 1998. 9. Jefferson J (Chairperson): Lithium: The present and the future (report on symposium). J Clin Psychiatry 156:4148, 1995. 10. McElroy SL, et al: Valproate in the treatment of bipolar disorder. Literature review and clinical guidelines. J Clin Psychopharmacol 12(Suppl):42S-S2S, 1992. 1 1 , Nemeroff C (ed): Lithium in the treatment of manic-depressive illness: An update. J Clin Psychiatry S9(suppl), 1998. 12. Solomon D, et al: The course of illness and maintenance treatments for patients with bipolar disorder. J Clin Psychiatry 56:5-13, 1995. 13. Suppes T, et al: Risk of recurrence following discontinuation of lithium treatment in bipolar disorder. Arch Gen Psychiatry 48:1082-1088, 1991. 14. Sussman N (ed): Anticonvulsants in Psychiatry. Roundtable Series, 64. London, Royal Society of Medicine Press. 1999.