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Update on Bipolar Disorder: How to Better Predict

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Update on Bipolar Disorder: How to Better Predict Currentp SYCHIATRY Update on bipolar disorder: How to better predict Paul E. Keck, Jr., MD Erik B. Nelson, MD Susan L. McElroy, MD Biological Psychiatry Program, Department of Psychiatry University of Cincinnati College of Medicine, Cincinnati, Ohio What does current evidence show regarding maintenance treatment with lithium, divalproex, carbamazepine, lamotrigine, or other agents? How well can you predict response? Which therapy will stop subsyndromal symptoms? The answers are here. © John Ritter/Graphistock 40 VOL. 1, NO. 4 / APRIL 2002 response to maintenance therapy hat are we trying to accomplish in the Compared with clinical trials of agents for acute bipolar maintenance treatment of patients mania (and mixed episodes), there are relatively few ran- with bipolar disorder? Given that the domized controlled trials of medications for the maintenance disorder recurs in more than 90% of patients who experience phase of bipolar disorder. Some naturalistic studies have pro- W1 a manic episode, there are 5 important goals: vided data on relapse rates associated with treatment with a 1. Prevention of recurrent episodes; variety of different agents. Even fewer studies have examined 2. Amelioration of subsyndromal symptoms; psychosocial interventions designed specifically to reduce 3. Reduction of suicide risk; relapse rates. 4. Compliance enhancement; But new data are beginning to emerge regarding the 5. Optimization of interpersonal, social, and vocational efficacy of divalproex, lamotrigine, and olanzapine as main- functioning. tenance therapies. A number of clinical predictors of There is a great premium on preventing mood episode response to these agents have begun to be identified, as well recurrence in patients with bipolar disorder. Mood episodes as to lithium and carbamazepine. Eliciting these characteris- themselves produce substantial morbidity, but morbidity is tics is important when making recommendations to patients not confined to these episodes alone. about available drug therapies. Full recovery of functioning often lags In addition, effective maintenance many months behind remission of symp- New data are emerging treatment often requires combinations toms.2 Recurrent mood episodes also may lead regarding the efficacy of of mood-stabilizing, antidepressant, and to progressive loss of function between episodes. divalproex, lamotrigine, antipsychotic agents to control or elimi- Mood episodes also carry risks of mortality from nate subsyndromal and breakthrough suicide, violence, and impulsive risk taking. and olanzapine symptoms. Clearly, mood-stabilizing medications form the as maintenance In this review, we will cover the cornerstone of maintenance treatment,3, 4 along with therapies available new data on pharmacologic a strong therapeutic alliance between patient and maintenance treatments of bipolar disor- clinician and targeted psychosocial therapies. In der and their clinical implications. the Expert Consensus Guidelines for medication treatment of bipolar I disorder, maintenance treatment was What the studies show recommended for ≥ 1 year following an initial manic or Lithium has been the mainstay of therapy for bipolar disorder mixed episode; longer (indefinite) treatment was recom- for more than 35 years. Most randomized, controlled trials of mended for patients with a family history of bipolar disorder lithium maintenance therapy were conducted in the 1960s or if ≥ 2 episodes occurred.3 and 1970s5 (Table 1). Unfortunately, these studies had several VOL. 1, NO. 4 / APRIL 2002 41 Currentp SYCHIATRY Update on bipolar disorder design limitations that inflated the expectations of lithium’s extending time to manic relapse.7,8 Both studies enrolled efficacy as a maintenance treatment.6 These included discon- patients who were currently or had recently been manic and tinuation designs in which patients stabilized on lithium had been stabilized in open-label treatment that included were abruptly switched to placebo; exaggerated early placebo study medications. relapse rates; enrollment of both unipolar and bipolar In the first study, comparing 1-year relapse rates among patients; lack of specific diagnostic criteria; and reported patients randomized to lithium, divalproex, or placebo, lithi- results only for patients completing studies. Pooled data from these Previous studies had design limitations that inflated the trials indicated that lithium expectations of lithium’s efficacy as maintenance therapy reduced the risk of relapse fourfold compared with placebo at 6 months and 1 year.5 um extended time to recurrence of mania by 55% compared Two contemporary randomized, placebo-controlled with placebo.7 In the second, an 18-month trial comparing maintenance studies utilizing more rigorous designs provid- lithium, lamotrigine, and placebo, lithium significantly ed further evidence of lithium’s superiority over placebo in increased the time to intervention for recurrence of mania Table 1 What works in maintenance treatment of bipolar disorder (ranked by number of randomized, controlled trials) Medication Trial results Strong evidence Some evidence RCTs (n) Lithium Equal to divalproex 4-fold reduction of relapse risk (15) and lamotrigine; equal vs. placebo at 6, 12 months; to or better than more efficacious in mania than carbamazepine; better in depression; higher lithium than placebo level correlated with lower relapse rates, but more side effects Carbamazepine No significant benefit May be more efficacious in (7) vs. lithium; better than mania than in depression; may placebo be less tolerable than lithium; no data on serum levels Divalproex Equal to lithium and May be more efficacious in (4) olanzapine; better than mania than in depression; may placebo be more tolerable than lithium; data on serum levels pending Lamotrigine Better than placebo More efficacious in depression Dosage 200-400 mg/d (2) than in mania Olanzapine Equal to divalproex Data on dosage and differential (1) efficacy related to dosage pending Clozapine Better than treatment Efficacy in treatment-resistant (1) as usual mania (bipolar schizoaffective disorder, bipolar type) 42 VOL. 1, NO. 4 / APRIL 2002 Currentp SYCHIATRY Currentp SYCHIATRY 8 compared with placebo. The overall manic relapse Paul E. Keck, Jr, MD In the second comparison study, 167 patients rates were 17% for lithium-treated patients and initially randomized and responding to divalproex 41% for those on placebo. However, lithium did or olanzapine in a 3-week acute bipolar mania not significantly extend time to depressive relapse trial continued in a double-blind 44-week exten- or intervention for depressive relapse, respectively, sion study.12 There were no significant differences in either study. Moreover, in the first study, patients in relapse into mania between the two groups who received lithium tended to have greater sub- (olanzapine 41%, divalproex 50%, p = 0.4) or time threshold depressive symptoms.8 to manic relapse (olanzapine 270 days, divalproex These findings were consistent with earlier 74 days, p = 0.4). There was no significant differ- placebo-controlled studies of lithium maintenance ence in tolerability between the two. treatment and a recent crossover comparison trial Erik B. Nelson, MD Two open-label studies compared valproate with carbamazepine.9 Lithium was also recently with lithium. In an 18-month study conducted in compared with carbamazepine in a 2.5-year main- France, patients randomized to the valpromide tenance multisite study in Europe.10 There was no formulation of valproate displayed a 20% lower significant difference in efficacy between the two relapse rate than those receiving lithium.13 The in time to hospitalization, the primary outcome second open-label comparison trial found compa- measure. On other outcome measures, including rable efficacy between lithium and divalproex in a time to relapse or need for additional medication, 1-year naturalistic pharmacoeconomic study that lithium was superior to carbamazepine. allowed additional medications as needed for Pooled results from a number of naturalistic studies, recurrent symptoms.14 which mirror clinical practice, indicated that approximately one-third of patients maintained on lithium had good func- Carbamazepine has been evaluated in a limited number of tional outcomes without relapses and only minimal symp- studies for maintenance treatment of bipolar disorder. The toms.11 In general, these studies found higher rates of relapse results of many early randomized, controlled maintenance with longer durations of follow-up. trials were criticized on methodologic grounds.15 But two recent comparison trials with lithium, as noted earlier, pro- Valproate maintenance treatment has been studied in two vided clinically important data regarding carbamazepine’s randomized, controlled trials (one vs. placebo,7 and one vs. prophylactic efficacy.9, 10 Several additional clinically relevant olanzapine12) and two open-label comparison studies against observations emerged from analyses of secondary outcome lithium.13,14 In the placebo-controlled trial, which also includ- measures in these two trials. ed a lithium comparison group described earlier, there was In the first study, 52 patients with bipolar I or II disorder no significant difference in the time to development of any received lithium or carbamazepine for 1 year, crossed over to mood episode among the three treatment groups.7 However, the alternate drug the second year, and received both drugs divalproex was superior to placebo on a number of other
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