Hyperammonemia

Episodes of mania or hypomania distinguish bipolar disorder from unipolar depression, and a history of mania distinguishes bipolar I from bipolar II disorder (alternating major depression and hypomania). A manic episode is characterized by persistently elevated, expansive, or irritable mood lasting at least 1 week (or any duration if hospitalization is required). Typical symptoms include inflated self-esteem, decreased need for sleep, talkativeness, flight of ideas, distractibility, increased goal-oriented behavior, and indulgence in dangerous or foolish behaviors. (1)

Both psychiatrists and primary care clinicians manage bipolar illness, and the new Mood Disorder Questionnaire may be useful for making the diagnosis in either setting. (2) Three agents--lithium, valproate, and olanzapine--have been approved by the Food and Drug Administration (FDA) as monotherapy for patients diagnosed with acute mania. Although valproate and olanzapine were first indicated fur epilepsy and schizophrenia, respectively, all three medications are considered foundational treatments.

Lithium

Lithium is viewed as the gold-standard mood stabilizer and the template for other agents being investigated for potential mood-stabilizing properties. Four placebo controlled studies and seven controlled antipsychotic comparison studies clearly established lithium's efficacy in treating acute mania. (3,4) Even so, several mania subtypes respond suboptimally to lithium (Table 1), including patients with:

* rapid cycling (four or more episodes of mania, hypomania, or depression in the preceding 12 months)

* dysphoric mania (with at least several depressive symptoms)

* mixed mania (meets formal criteria for depression and mania simultaneously)

* comorbid substance abuse

* negative family history of bipolar disorder

* more than three prior lifetime affective episodes

* a classic manic-depressive interval. (5)

For acute mania, clinical guidelines suggest titrating lithium to a therapeutic level of 0.8 to 1.2 mmol/L, at which a typical antimanic response occurs within 1 to 2 weeks. Adolescents and young adults may require and tolerate higher levels, whereas elderly patients may require lower dosages. Common side effects include polyuria and polydipsia (related to decreased renal response to antidiuretic hormone), cognitive dulling, tremor, GI distress, weight gain, acne, and hypothyroidism. Higher lithium levels are clearly more effective than lower levels but are associated with increased side effects, (6) which can deter patient compliance.

Lithium toxicity may he triggered by acute volume changes (dehydration, diarrhea, vomiting) or pharmacokinetic drug-drug interactions involving renal excretion (diuretics, NSAIDs, ACE inhibitors). Lithium has a narrow therapeutic index (beneficial versus toxic effect), and hemodialysis is the only reliable method to rapidly remove excess lithium. Long-term lithium treatment may be associated with renal insufficiency, which may be important to consider when managing patients with diabetes or hypertension.

Valproate

Divalproex sodium (valproate, valproic acid) was the first anticonvulsant approved as a mood stabilizer. Controlled studies of valproate in almost 400 patients with acute mania have included:

* one single-site placebo-controlled study (7)

* one multi-site, placebo-controlled, parallel-design study with lithium as an active comparison (8)

* one placebo-controlled study using valproate as an adjunct to typical neuroleptic therapy (9)

* six controlled, active comparison studies to lithium, (10,11) haloperidol, (12) carbamazepine, (13) and olanzapine. (14,15)

Post hoc analyses of the Bowden et al 1994 study (8) suggested that although there was no difference in response rate between divalproex and lithium for patients with euphoric mania, having two or more depressive symptoms in the manic episode (dysphoric mania) was a robust predictor of lithium nonresponse. (16) Furthermore, having had more than four prior depressive or 11 prior manic episodes was associated with a poor response to lithium; this relationship was not evident with valproate treatment. (17)

Antimanic response is generally associated with a valproate serum level >45 to 50 mg/L. In a study by Pope et al, (7) most valproate-treated patients responded 1 to 4 days alter achieving a serum level of [greater than or equal to] 50 mg/L. Divalproex loading at 20 mg/kg/d for rapid stabilization of acute mania (11,12,15) is as effective as haloperidol or olanzapine and is associated with less need for adjunctive benztropine. (12)

Starting valproate, In the outpatient setting, obtain a baseline hepatic panel and complete blood cell count before starting a patient on divalproex. An appropriate starting dosage is 250 mg tid, with increases of 250 to 500 mg every several days to a therapeutic threshold (serum level >50 mg/L). Once steady state has been achieved, consolidate the dosage to once daily in the evening to make it easier for patients to adhere to treatment. Common side effects include GI distress, tremor, sedation, benign elevated hepatic transaminase levels, leukopenia, thrombocytopenia, hair loss, increased appetite, and weight gain.

The relationship between valproate and polycystic ovarian syndrome is unclear. (18,19) Rare serious side effects with valproate--as noted in FDA black-box warnings--include hepatic failure, pancreatitis, and hyperammonemia encephalopathy associated with urea cycle disorders. Additional warnings include sedation in the elderly and thrombocytopenia. Valproate also has an FDA black-box warning of teratogenicity category D (neural tube defects such as spina bifida) (Table 2).

Olanzapine

Olanzapine is the first antipsychotic approved as a mood-stabilizing agent. Controlled studies of olanzapine in acute mania have included two multi-site, placebo-controlled studies; (20,21) one multi-site, placebo-controlled add-on study of manic patients unresponsive to lithium or valproate; (22) and four controlled comparison studies to lithium, (23) haloperidol, (24) and valproate. (14,15) In sum, more than 750 manic patients have been treated with olanzapine in controlled evaluations.

Monotherapy. FDA approval was based on two placebo-controlled studies in patients hospitalized for mania. These studies are similar in design, with the only exception being study duration (3 versus 4 weeks) and starting dosage (10 versus 15 mg/d, respectively).

In the first study, (20) the response rate--50% reduction in Young Mania Rating Scale (YMRS) baseline score--was 49% for olanzapine at a mean dosage of 15 mg/d (n=70) compared with 24% for placebo (n=69).

In the second study, (21) the response rate (same definition) and remission rate (final YMRS score [less than or equal to] 12) were 65% and 61%, respectively, with olanzapine (n=55), compared with 43% and 36% with placebo (n=60). Differences were statistically significant after 1 week and throughout this 4-week trial. Further analyses showed no difference in antimanic response to olanzapine, whether patients had rapid versus nonrapid cycling, pure mania versus mixed states, or psychotic versus nonpsychotic mania. These subanalyses are valuable, as rapid cycling and mixed mania have been shown to predict lithium nonresponse. (5)

Adjunctive therapy. Olanzapine has also been evaluated as an add-on agent for mania partially responsive to conventional mood-stabilizing agents. (22) In a 6-week double-blind study, 344 patients who had not responded to at least 2 weeks of therapeutic levels of lithium or divalproex received adjunctive olanzapine or placebo. Response was defined as a 50% reduction in baseline YMRS score. Two-thirds (67.7%) of patients responded to add-on olanzapine (mean 10.4 mg/d), compared with 44.7% of patients who responded to add-on placebo (i.e., lithium or divalproex monotherapy).

Comparison studies. Four studies have evaluated the efficacy of olanzapine versus lithium, a typical antipsychotic, or divalproex sodium in treating acute mania.

In the lithium comparison study, (23) 15 manic patients were randomized to olanzapine (mean dosage 10 mg/d) and another 15 to lithium (mean dosage 800 mg/d) for 4 weeks. Manic symptoms were reduced equally in the two groups, as rated with the YMRS or Brief Psychiatric Rating Scale (BPRS), but olanzapine was more effective in reducing illness severity, as measured by the Clinical Global Impression scale. This study was limited by its sample size, lack of placebo arm, and low lithium dosage.

In a comparison study with a typical antipsychotic, (24) 234 manic patients received a flexible dosage of olanzapine, 5 to 20 mg/d, and 219 patients received haloperidol, 3 to 15 mg/d, for 6 weeks. Although similar percentages in each group achieved symptom remission, more patients treated with olanzapine improved on measures of health-related quality of life.

In one study comparing olanzapine and divalproex, (14) 125 hospitalized manic patients received olanzapine, 15 mg/d, and 123 received divalproex, 750 mg/d. During the 3-week randomized study, dosages were increased as clinically indicated to olanzapine, mean 17.4 mg/d, and divalproex, mean 1,401 mg/d. Response was defined as a 50% reduction in symptoms, based on YMRS score, and remission as a YMRS score [less than or equal to] 12. For patients taking olanzapine, response and remission rates were 54.4% and 47.2%, respectively, compared with 42.3% and 34.1%, respectively, for patients taking divalproex (P=0.058 and P=0.039). Side effects more common with olanzapine included increased appetite, somnolence, and dry mouth; nausea was more common with divalpoex.

In a smaller 4-week study with an 8-week extension, (15) 63 hospitalized manic patients received a loading dosage of divalproex, 20/mg/kg/d, and 57 patients received a starting dosage of olanzapine, 10 mg/d. After 12 weeks, final mean dosages were divalproex, 2,115 mg/d, and olanzapine, 15 mg/d. Response rates by similar YMRS criteria were 53% for divalproex and 62% for olanzapine (not a significant difference).

Summary. Controlled data suggest that olanzapine achieves an antimanic response at a starting dosage of 10 to 15 mg/d as monotherapy or 10 mg/d as adjunctive therapy. Side effects associated with olanzapine have included sedation, dry mouth, orthostatic hypotension, dizziness, increased appetite, and weight gain.

In the primary care or psychiatry practice, lithium, divalproex, and olanzapine are foundational agents for treating bipolar disorder. Lithium--the gold standard--has been in clinical use for more than 30 years. Its antimanic efficacy is usually achieved in 1 to 2 weeks at a therapeutic blood level of 0.8 to 1.2 mmol/L.

Divalproex--the first anticonvulsant mood stabilizer--has been FDA-approved since 1995. It can be given as a loading dose for rapid mania stabilization, with a therapeutic threshold >45 to 50 mg/L.

Olanzapine--the first antipsychotic mood stabilizer--has been FDA-approved since 2000. With olanzapine, there are no established blood levels associated with antimanic response and thus no need for blood level monitoring. For treating mania, recommended dosages are 10 to 15 mg/d as monotherapy and 10 mg/d as adjunctive therapy.

References

(1.) American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th edition, text revision (DSM-IV-TR). Washington, DC: American Psychiatric Press, 2000.

(2.) Hirschfeld RM, Holzer C. Calabrese JR. et al. Validity of the mood disorder questionnaire: a general population study. Am J Psychiatry 2003;160:178-80.

(3.) Goodwin FK, Jamison KR. Manic-depressive illness. New York: Oxford University Press, 1990.

(4.) Hirschfeld RM, Bowden CL, Gitlin MJ, et al. Practice guideline for the treatment of patients with bipolar disorder (rev). Am J Psychiatry 2002;159(4 suppl)1-50.

(8.) Bowden CL, Brugger AM, Swann AC, et al. Efficacy of divalproex vs lithium and placebo in the treatment of mania. The Depakote Mania Study Group. JAMA 1994;271:918-24.

(5.) Frye MA, Altshuler LL. Selection of initial treatment for bipolar disorder, manic phase. Mod Probl Pharmacopsychiatry 1997:25:88-113.

(6.) Gelenberg AJ, Kane JM, Keller MB, et al. Comparison of standard and low serum levels of lithium for maintenance treatment of bipolar disorder. N Engl J Med 1989;321:1489-93.

(7.) Pope HG, Jr., McElroy SL, Keek PE, Jr., Hudson JI. Valproate in the treatment of acute mania. A placebo-controlled study. Arch Gen Psychiatry 1991;48:62-8.

(9.) Muller-Oerlinghausen B, Retzow A, Henn FA, Giedke H, Walden J. Valproate as an adjunct to neuroleptic medication for the treatment of acute episodes of mania a prospective, randomized, double-blind, placebo-controlled, multicenter study. European Valproate Mania Study Group. J Clin Psychopharmacol 2000;20:195-203.

(10). Freeman TW, Clothier JL, Pazzaglia P, Lesem MD, Swann AC. A double-blind comparison of valproate and lithium in the treatment of acute mania. Am J Psychiatry 1992;149:108-11.

(11.) Hirschfeld RM, Allen MH, McEvoy JP, Keck PE, Jr., Russell JM. Safety and tolerability of oral loading divalproex sodium in acutely manic bipolar patients. J Clin Psychiatry 1999;60:815-18.

(12.) McElroy SL, Keck PE, Jr., Stanton SP, Tugrul KC, Bennerr JA, Strakowski SM. A randomized comparison of divalproex oral loading versus haloperidol in the initial treatment of acute psychotic mania. J Clin Psychiatry 1996;57:142-6.

(13.) Vasudev K, Goswami U, Kohli K. Carbamazepine and valproate monotherapy: feasibility, relative safety and efficacy, and therapeutic drug monitoring in mania disorder. Psychopharmacology (Berl) 2000;150:15-23.

(14.) Tohen M, Baker RW, Altshuler LL, et al. Olanzapine versus divalproex in the treatment of acute mania Am J Psychiatry 2002;159:1011-7.

(15.) Zajecka JM, Weisler R, Sachs G, et al. A comparison of the efficacy, safety, and tolerability of divalproex sodium and olanzapine in the treatment of bipolar disorder. J Clin Psychiatry (in press).

(16.) Swann AC, Bowden CL, Morris D, et al. Depression during mania. Treatment response to lithium or divalproex. Arch Gen Psychiatry 1997;54:37-42.

(17.) Swann AC, Bowden CL, Calabrese JR, Dilsaver SC, Morris DD. Differential effect of number of previous episodes of affective disorder on response to lithium or divalproex in acute mania. Am J Psychiatry 1999;156:1264-6.

(18.) Rasgon NL, Altshuler LI, Gudeman D, et al. Medication status and polycystic ovary syndrome in women with bipolar disorder: a preliminary report. J Clin Psychiatry 2000;61:173-8.

(19.) O'Donovan C, Kusumakar V, Graves GR, Bird DC. Menstrual abnormalities and polycystic ovary syndrome in women taking valproate for bipolar mood disorder. J Clin Psychiatry 2002;63:322-30.

(20.) Tohen M, Sanger TM, McElroy SL, et al. Olanzapine versus placebo in the treatment of acute mania. Olanzapine HGEH Study Group. Am J Psychiatry 1999;156:702-9.

(21.) Tohen M, Jacobs TG, Grundy SL, et al. Efficacy of olanzapine in acute bipolar mania: a double-blind, placebo-controlled study. The Olanzapine HGGW Study Group. Arch Gen Psychiatry 2000;57:841-9.

(22.) Tohen M. Chengappa KN. Suppes T, et al. Efficacy of olanzapine in combination with valproate or lithium in the treatment of mania in patients partially nonresponsive to valproate or lithium monotherapy. Arch Gen Psychiatry 2002;59:62-9.

(23.) Berk M, Ichim L, Brook S. Olanzapine compared to lithium in mania: a double blind randomized controlled trial. Int Clin Psychopharmacol 1999;14:339-43.

(24.) Shi L, Namjoshi MA, Zhang F, et al. Olanzapine versus haloperidol in the treatment of acute mania: clinical outcomes, health-related quality of life and work status. Int Clin Psychopharmacol 2002;17:227-37.

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