Randomized, Placebo-Controlled Trial of Olanzapine as Maintenance ...

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Am J Psychiatry 163:2, February 2006. 247. Article ajp.psychiatryonline.org. Randomized, Placebo-Controlled Trial of Olanzapine as. Maintenance Therapy in ...
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Randomized, Placebo-Controlled Trial of Olanzapine as Maintenance Therapy in Patients With Bipolar I Disorder Responding to Acute Treatment With Olanzapine Mauricio Tohen, M.D., Dr.P.H. Joseph R. Calabrese, M.D. Gary S. Sachs, M.D. Michael D. Banov, M.D. Holland C. Detke, Ph.D. Richard Risser, M.S. Robert W. Baker, M.D. James C.-Y. Chou, M.D. Charles L. Bowden, M.D.

Objective: In a placebo-controlled, double-blind study, the authors investigated the efficacy and safety of olanzapine as monotherapy in relapse prevention in bipolar I disorder. Method: Patients achieving symptomatic remission from a manic or mixed episode of bipolar I disorder (Young Mania Rating Scale [YMRS] total score ≤12 and 21-item Hamilton Depression Rating Scale [HAM-D] score ≤8) at two consecutive weekly visits following 6–12 weeks of open-label acute treatment with 5–20 mg/day of olanzapine were randomly assigned to double-blind maintenance treatment with olanzapine (N=225) or placebo (N=136) for up to 48 weeks. The primary measure of efficacy was time to symptomatic relapse into any mood episode (YMRS score ≥15, HAM-D score ≥15, or hospitalization). Results: Time to symptomatic relapse into any mood episode was significantly longer among patients receiving olanzapine (a median of 174 days, compared

with a median of 22 days in patients receiving placebo). Times to symptomatic relapse into manic , depressive, and mixed episodes were all significantly longer among patients receiving olanzapine than among patients receiving placebo. The relapse rate was significantly lower in the olanzapine group (46.7%) than in the placebo group (80.1%). During olanzapine treatment, the most common emergent event was weight gain; during the open-label phase, patients who received olanzapine gained a mean of 3.1 kg (SD=3.4). In double-blind treatment, placebo patients lost a mean of 2.0 kg (SD=4.4) and patients who continued to take olanzapine gained an additional 1.0 kg (SD=5.2). Conclusions: C o m p a re d t o p l ac e b o, olanzapine delays relapse into subsequent mood episodes in bipolar I disorder patients who responded to open-label acute treatment with olanzapine for a manic or mixed episode. (Am J Psychiatry 2006; 163:247–256)

B

ipolar I disorder is a recurrent disorder requiring acute and maintenance therapy. Despite therapeutic intervention, relapse rates for patients who are receiving treatment range from 40% to 60%, even after a first lifetime episode (1, 2), with as many as one-half of patients experiencing a second mood episode within a year of recovery (3). These findings strongly suggest that treatment efficacy in relapse prevention requires further study. Although lithium remains the standard treatment in the prevention of relapse in bipolar disorder, several studies have compared the efficacy of other treatment interventions with lithium in relapse prevention. In a double-blind study comparing divalproex to lithium and placebo over a 12-month maintenance period, time to development of any mood episode did not differ significantly between the two treatment groups or between either treatment group and the placebo group (4). In patients with recent manic/ hypomanic symptoms, lamotrigine and lithium were reported to be significantly superior to placebo in prolong-

Am J Psychiatry 163:2, February 2006

ing the time to intervention for any mood episode (5). Similarly, in patients with recent depressive symptoms, both lamotrigine and lithium were significantly more effective than placebo at prolonging time to intervention for a mood episode (6). Further review of the literature revealed few placebocontrolled relapse prevention studies with other psychotropic agents. Several atypical antipsychotics have shown efficacy in treatment of acute mania (olanzapine, aripiprazole, quetiapine, risperidone, ziprasidone) (7–11), but maintenance-phase studies in relapse prevention are lacking, although preliminary results presented at scientific meetings indicated the efficacy of aripiprazole, compared to placebo, in prolonging time to relapse during a 26-week study of patients with recent manic symptoms (12). Accordingly, the objective of the present study was to compare olanzapine with placebo in the prevention of relapse among bipolar I disorder patients who responded to open-label acute olanzapine treatment. ajp.psychiatryonline.org

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OLANZAPINE MAINTENANCE THERAPY IN BIPOLAR DISORDER TABLE 1. Disposition of Bipolar I Disorder Patients in the 6–12-Week Open-Label Acute Treatment Phase and the 48-Week Double-Blind Maintenance Phase of a Study of Olanzapine in Relapse Prevention Double-Blind Maintenance Phase Patients Receiving Olanzapine in the Open-Label Acute Treatment Phase (N=731)

a

Patients Receiving Placebo (N=136)

N

%

N

%

N

%

pa

361

49.4

370

50.6

48 105 72

21.3 46.7 32.0

9 109 18

6.6 80.1 13.2