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Bipolar Disorder Currentp SYCHIATRY Antiepileptic drugs for Paul E. Keck, Jr, MD Susan L. McElroy, MD Biological Psychiatry Program, Department of Psychiatry University of Cincinnati College of Medicine, Cincinnati, Ohio Carbamazepine and valproate are effective in treating various aspects of bipolar disorder. Now seven more antiepileptics present possible additional options. The following literature review can help you decide a course of therapy. 18 VOL. 1, NO. 1/JANUARY 2002 bipolar disorder Are there any clear winners? he newer antiepileptic drugs pose a sometimes cacy of carbamazepine in patients with acute bipolar I mania. bewildering range of options for bipolar Carbamazepine was superior to placebo and comparable to disorder treatment. Which work best for acute chlorpromazine and lithium. Pooled data reveal an overall bipolar I mania? Which are best suited for response rate (defined as the proportion of patients experi- Tmaintenance in patients with mixed episodes, or for those encing > 50% reduction in manic symptoms) of 50% for car- with a history of rapid cycling? What about prevention of bamazepine, 56% for lithium, and 61% for chlorpromazine depressive episodes? And how do the antiepileptics compare (differences in overall response rates are not significant). with lithium? Until recently, the efficacy of carbamazepine as a For many patients with bipolar disorder, lithium is still maintenance therapy for bipolar disorder was controversial.3 the drug of choice. For others, however, an increasing body of However, two recent large randomized, controlled evidence supports the efficacy of some antiepileptics and maintenance studies that compared carbamazepine with atypical antipsychotics. lithium validated use of the agent for that purpose.4,5 The mood-stabilizing properties of two antiepileptic In the first study, 144 patients received either drug and agents, carbamazepine and valproate, were demonstrated were followed for up to 2 1/2 years.4 The study showed no some years ago in randomized controlled trials in patients significant differences between the two groups in time-to- with bipolar disorder. Since then, there has been considerable mood episode recurrence or hospitalization. However, interest in the potential thymoleptic properties of the new significantly more patients receiving carbamazepine required antiepileptic drugs.1 In recent years gabapentin, lamotrigine, treatment discontinuation for side effects and additional topiramate, oxcarbazepine, zonisamide, tiagabine, and leve- medications for breakthrough symptoms than did the tiracetam have been approved in the United States for the patients receiving lithium. treatment of various types of epilepsy. These medications Patients without both comorbid disorders and mood- have diverse pharmacological properties that distinguish incongruent delusions responded better to lithium, whereas them from earlier agents and from one another. those with mixed episodes and bipolar II disorder or NOS Do these new agents have anything to offer patients? For appeared to respond better to carbamazepine. the most part, the evidence is not yet in hand, but we will In the second trial, 52 patients with bipolar I or II examine what's available, starting with the most recent trial disorders received either lithium or carbamazepine for one data regarding the efficacy of valproate and carbamazepine. year, crossed over to the alternate drug the second year, and received both drugs during the third year.5 No significant Carbamazepine for bipolar mania differences were reported in relapse rates during the first year Five randomized, controlled trials2 have shown the effi- between lithium (31%) and carbamazepine (37%), or in the VOL. 1, NO. 1/JANUARY 2002 19 Currentp SYCHIATRY Antiepileptic drugs for bipolar disorder percentage of patients who experienced a moderate Paul Keck, MD ment in depressive symptoms) ranged from 32% to or better response: 33% on lithium, 31% on 34%, although many patients who participated had carbamazepine, and 55% on the combination. On a treatment-resistant bipolar depression. variety of other measures, lithium was superior to Based on the studies reviewed above, carba- carbamazepine. But patients with a history of rapid mazepine is considered a second-line agent for cycling responded significantly better to the bipolar mania and maintenance treatment with combination (56%) than to lithium (28%) or very limited data regarding its antidepressant carbamazepine (19%) alone. effects.6 As in the previous study, a higher proportion of patients receiving carbamazepine withdrew after Susan McElroy, MD Valproate: For patients experiencing side effects. Both studies found that with mixed and mood episodes while carbamazepine is efficacious, lithium is The evidence seems to point to valproate as a superior overall. But since neither study included a suitable agent for patients with mixed and mood placebo group, carbamazepine's efficacy in episodes. maintenance treatment cannot be determined. Two earlier randomized, controlled studies7,8 Carbamazepine also was evaluated in three showed that the divalproex sodium formulation of randomized, controlled trials in patients with valproate was superior to a placebo, leading to the bipolar depression.2 These small trials suggest that indication of divalproex for treatment of acute carbamazepine's antidepressant activity may be less robust mania in patients with bipolar disorder. Additional analyses than its antimanic effects. Response rates (>50% improve- of data from the second controlled trial8 indicated that Comparing the known efficacy of antiepileptic agents in bipolar disorder Drug Mania Depression Maintenance Comments New Depakote Valproate ER formulation 2 new maintenance Carbamazepine studies v. lithium Key — 2 negative placebo- efficacy demonstrated in Gabapentin controlled studies in mania > 2 placebo-controlled trials Antidepressant activity in efficacy demonstrated in Lamotrigine ✖ several controlled trials one placebo-controlled or two large, active comparator trials Topiramate Dose-related weight loss efficacy in two small or one large Improved tolerability & Oxcarbazepine active comparator trial pharmacokinetics efficacy only in open trials and ND ND May produce weight loss in Zonisamide case series some patients ✖ conflicting evidence of efficacy ND ND More data needed regarding in available studies Tiagabine ✖ tolerability and efficacy — lack of efficacy demonstrated in ND ND ND Data needed regarding randomized, controlled trials Levetiracetam efficacy and tolerability ND no data presently available 20 VOL. 1, NO. 1/JANUARY 2002 Currentp SYCHIATRY Currentp SYCHIATRY patients with prominent depressive symptoms during mania 2. A second naturalistic, pharmacoeconomic, one-year (mixed episodes) responded better to divalproex than lithi- open comparison also found both lithium and dival- um. Further, multiple prior mood episodes were associated proex fairly equal in efficacy. with poor lithium response but not with divalproex response. 3. A large, prospective, randomized one-year maintenance Two recent randomized, controlled trials compared the trial showed little difference in relapse rates among antimanic efficacy and tolerability of divalproex and patients receiving divalproex (24%), lithium (31%), and olanzapine.9,10 The design of these two studies differed in two a placebo (38%).11 important ways: sample size and starting doses. This may 4. A recently completed one-year comparison of relapse explain the different results of the two trials. rates between divalproex and olanzapine showed little In the first study, difference between the two drugs.12 248 patients received start- Findings suggest that The overall results suggest that divalproex helps prevent ing doses of either divalproex divalproex helps mood episodes in patients with bipolar disorder, but the data 750 mg/d with upward titration prevent mood episodes are less substantial and conclusive than from placebo-con- to therapeutic concentrations, or in patients with trolled trials of lithium. olanzapine 15 mg/d with titration if bipolar disorder, but The antidepressant effects of divalproex in treating acute 9 clinically indicated. Olanzapine was the data are not bipolar depression have not been studied in randomized found to be superior in the mean controlled trials. Impressions from case reports and case reduction of manic symptoms and in conclusive 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 series suggest that divalproex may exert some antidepressant upward titration as clinically indicated. This trial revealed no activity, but that this action may be less robust than its significant differences in efficacy on any outcome measure antimanic effects. and the mean valproic acid plasma concentration was higher Divalproex is now available in a once-daily extended than in the first trial. release (ER) formulation. This appears to have improved Differences in side effects between the two agents were tolerability, especially regarding gastrointestinal side effects. similar in both studies. Olanzapine was associated with (Clinical experience suggests that the immediate release greater sedation, appetite stimulation, and weight gain, and formulation of divalproex can also be given
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