Evidence-Based Reviews

Antiepileptic drugs for bipolar disorder: Are there any clear winners?

Current Psychiatry. 2002 January;1(1):18-24

References

1. Keck PE, Jr, McElroy SL, Strakowski SM. Anticonvulsants and antipsychotics in the treatment of bipolar disorder. J Clin Psychiatry. 1998;59(Suppl 6):74-81.

2. McElroy SL, Keck PE, Jr. Pharmacologic agents for the treatment of acute bipolar mania. Biol Psychiatry. 2000;48:539-557.

3. Post RM, Denicoff KD, Frye MA, Leverich GS. Re-evaluating carbamazepine prophylaxis in bipolar disorder. Br J Psychiatry. 1997;170:202-204.

4. Greil W, Ludwig-Mayerhofer W, Erazon-Scheichlin C, Schmidt S, Engel RR, et al. Lithium versus carbamazepine in the maintenance treatment of bipolar disorders–a randomized study. J Affect Disorders. 1997;43:151-161.

5. Denicoff KD, Smith-Jackson EE, Disney ER, Ali SO, Leverich GS, Post RM. Comparative prophylactic efficacy of lithium, carbamazepine and the combination in bipolar disorder. J Clin Psychiatry. 1997;58:470-478.

6. Suppes T, Swann AC, Dennehy EB, Habermacher ED, Mason M, Crismon ML, Toprac MG, Rush AJ, Shon SP, Altshuler KZ. Texas Medication Algorithm Project: development and feasibility testing of a treatment algorithm for patients with bipolar disorder. J Clin Psychiatry. 2001;62:439-447.

7. Pope HG, Jr, McElroy SL, Keck PE, Jr, Hudson JI. Valproate in the treatment of acute mania: a placebo-controlled study. Arch Gen Psychiatry. 1991;48:62-68.

8. Bowden CL, Brugger AM, Swann AC, Calabrese JR, Janicak PG, Petty F, et al. Efficacy of divalproex sodium vs. lithium and placebo in the treatment of mania. JAMA. 1994;271:915-924.

9. Tohen M, Baker RW, Milton DR, Risser RC, Gilmore JA, Davis AR, et al. Olanzapine versus divalproex sodium for the treatment of acute mania. Bipolar Disorders. 2001;3(Suppl 1):60-61.

10. Zajecka J. Divalproex versus olanzapine in the treatment of acute mania. Presented at the 39 th Annual Meeting of the American College of Neuropsychopharmacology. San Juan, Puerto Rico, Dec. 10-14, 2000.

11. Bowden CL, Calabrese JR, McElroy SL, Hirschfeld RMA, Petty F, Gyulai LL, Pope HG, Jr, et al. Efficacy of divalproex versus lithium and placebo in maintenance treatment of bipolar disorder. Arch Gen Psychiatry. 2000;57:481-489.

12. Tohen M, Baker RW, Altshuler LL, Zarate CA, Suppes T, Ketter T, et al. Olanzapine versus divalproex for bipolar mania: a 47-week study. Presented at the European College of Neuropsychopharmacology Meeting, Istanbul, Turkey, Oct. 15, 2001.

13. Pande AD, Crockatt JG, Janney CA, Werth JL, Tsaaroucha G. and the Gabapentin Bipolar Disorder Study Group. Bipolar Disorders. 2000;2:249-255.

14. Frye MA, Ketter TA, Kimbrell TA, et al. A placebo controlled study of lamotrigine and gabapentin monotherapy in refractory mood disorders. J Clin Psychopharmacol. 2000;24:205-212.

15. Calabrese JR, Suppes T, Bowden CL, et al. A double-blind, placebo-controlled study of lamotrigine monotherapy in rapid-cycling bipolar disorder. J Clin Psychiatry. 2000;61:841-850.

16. Bowden CL, Calabrese JR, Akthar S, Olajossy M, Montgomery S, Ascher J, et al. Lamotrigine demonstrates long-term mood stabilization in manic patients. Bipolar Disorders. 2001;3(Suppl 1):27-28.

17. Calabrese JR, Bowden CL, Sachs GS, et al. A double-blind, placebo-controlled study of lamotrigine monotherapy in outpatients with bipolar I depression. J Clin Psychiatry. 1999;60:79-88.

18. McElroy SL, Suppes T, Keck PE, Jr, Frye MA, Denicoff KD, Altshuler LL, et al. Open-label adjunctive topiramate in the treatment of bipolar disorders. Biol Psychiatry. 2000;47:1025-1033.

19. Calabrese JR. A double-blind, placebo-controlled trial of topiramate monotherapy in the treatment of acute mania. Presented at the Annual Meeting of the European College of Neuropsychopharmacology. Munich, Germany, Sept. 9-13, 2000.

20. Emrich H, Schiwy W, Silverstone T. eds. Carbamazepine and Oxcarbazepine in Psychiatry. London: CNS Publishers, 1990.

Valproate: For patients with mixed and mood episodes

The evidence seems to point to valproate as a suitable agent for patients with mixed and mood episodes.

Two earlier randomized, controlled studies^7,8 showed that the divalproex sodium formulation of valproate was superior to a placebo, leading to the indication of divalproex for treatment of acute mania in patients with bipolar disorder. Additional analyses of data from the second controlled trial⁸ indicated that patients with prominent depressive symptoms during mania (mixed episodes) responded better to divalproex than lithium. Further, multiple prior mood episodes were associated with poor lithium response but not with divalproex response.

Two recent randomized, controlled trials compared the antimanic efficacy and tolerability of divalproex and olanzapine.^9,10 The design of these two studies differed in two important ways: sample size and starting doses. This may explain the different results of the two trials.

In the first study, 248 patients received starting doses of either divalproex 750 mg/d with upward titration to therapeutic concentrations, or olanzapine 15 mg/d with titration if clinically indicated.⁹ Olanzapine was found to be superior in the mean reduction of manic symptoms and in the proportion of patients who either responded to treatment or were in remission.

In the second study, the number of patients (N=120) randomized was not sufficient to detect a statistically significant difference between treatment groups.¹⁰ Initial dosing consisted of rapid divalproex loading (20 mg/kg/d) versus olanzapine (10 mg/d) with upward titration as clinically indicated. This trial revealed no significant differences in efficacy on any outcome measure and the mean valproic acid plasma concentration was higher than in the first trial.

Differences in side effects between the two agents were similar in both studies. Olanzapine was associated with greater sedation, appetite stimulation, and weight gain, and divalproex with greater gastrointestinal symptoms. Taken together, these two studies indicate that olanzapine is at least as efficacious as divalproex in treating acute mania and that divalproex should be titrated to plasma concentrations well within the therapeutic range consistent with response and tolerability.

The efficacy of divalproex as a maintenance therapy for patients with bipolar disorder has been studied in four trials to date:

A randomized, open comparison of lithium and divalproex found generally good efficacy for both drugs across 18 months.
A second naturalistic, pharmacoeconomic, one-year open comparison also found both lithium and divalproex fairly equal in efficacy.
A large, prospective, randomized one-year maintenance trial showed little difference in relapse rates among patients receiving divalproex (24%), lithium (31%), and a placebo (38%).¹¹
A recently completed one-year comparison of relapse rates between divalproex and olanzapine showed little difference between the two drugs.¹²

The overall results suggest that divalproex helps prevent mood episodes in patients with bipolar disorder, but the data are less substantial and conclusive than from placebo-controlled trials of lithium.

The antidepressant effects of divalproex in treating acute bipolar depression have not been studied in randomized controlled trials. Impressions from case reports and case series suggest that divalproex may exert some antidepressant activity, but that this action may be less robust than its antimanic effects.

Divalproex is now available in a once-daily extended release (ER) formulation. This appears to have improved tolerability, especially regarding gastrointestinal side effects. (Clinical experience suggests that the immediate release formulation of divalproex can also be given once daily.) The ER formulation is not bioequivalent to its immediate-release counterpart; it produces plasma concentrations of approximately 80% of those achieved with immediate release. Thus, switching a patient to the ER formulation might require a dose increase.

Lamotrigine for bipolar depression

Several recent randomized controlled trials indicate that lamotrigine has important thymoleptic properties.^14-17

Three studies addressed the efficacy of lamotrigine in treating patients with acute bipolar mania. In two small trials, lamotrigine did not display superior efficacy over placebo in reducing manic symptoms.¹⁴ A third trial revealed differences between lithium and lamotrigine in reducing manic symptoms, but this study lacked sufficient power to detect potential differences in efficacy.

Two placebo-controlled maintenance studies of lamotrigine were recently reported.^15,16 The first found no significant differences in relapse rates in patients with rapid cycling bipolar I and II disorders randomized to lamotrigine or placebo after initial stabilization on lamotrigine.¹⁵ However, in a post hoc analysis among bipolar II (but not bipolar I) patients, lamotrigine was significantly more efficacious than placebo in time-to-study dropout and considerably better (P=0.07) in time to need for additional medication.

In the second randomized, placebo-controlled trial, patients with bipolar I disorder who had recently experienced a manic episode were treated with lamotrigine 100-200 mg/d during an open-label phase (8-16 weeks) while other psychotropic agents were tapered and discontinued.¹⁶ Patients (N = 171) who remained stable were then randomized to lamotrigine 200-400 mg/d, lithium, or placebo for up to 18 months.