Objective: The effects of olanzapine and divalproex for the treatment of mania were compared in a large randomized clinical trial. Method: A 3-week, randomized ...
Article
Olanzapine Versus Divalproex in the Treatment of Acute Mania Mauricio Tohen, M.D., Dr.P.H. Robert W. Baker, M.D. Lori L. Altshuler, M.D. Carlos A. Zarate, M.D. Trisha Suppes, M.D., Ph.D. Terrence A. Ketter, M.D. Denai R. Milton, M.S. Richard Risser, M.S. Julie A. Gilmore, Ph.D. Alan Breier, M.D. Gary A. Tollefson, M.D., Ph.D.
Objective: The effects of olanzapine and divalproex for the treatment of mania were compared in a large randomized clinical trial. Method: A 3-week, randomized, doubleblind trial compared flexibly dosed olanzapine (5–20 mg/day) to divalproex (500– 2500 mg/day in divided doses) for the treatment of patients hospitalized for acute bipolar manic or mixed episodes. The Young Mania Rating Scale and the Hamilton Depression Rating Scale were used to quantify manic and depressive symptoms, respectively. Safety was assessed with several measures. Results: The protocol defined baselineto-endpoint improvement in the mean total score on the Young Mania Rating Scale as the primary outcome variable. The mean Young Mania Rating Scale score decreased by 13.4 for patients treated with olanzapine (N=125) and 10.4 for those treated with divalproex (N=123). A priori categorizations defined response and remission rates: 54.4% of olanzapine-treated patients responded ( ≥ 50% reduction in Young Mania Rating Scale score), compared to 42.3% of divalproex-treated pa-
tients; 47.2% of olanzapine-treated patients had remission of mania symptoms (endpoint Young Mania Rating Scale ≤12), compared to 34.1% of divalproex-treated patients. The decrease in Hamilton depression scale score was similar in the two treatment groups. Completion rates for the 3-week study were similar in both groups. The most common treatmentemergent adverse events (incidence >10%) occurring more frequently during treatment with olanzapine were dry mouth, increased appetite, and somnolence. For divalproex, nausea was more frequently observed. The average weight gain with olanzapine treatment was 2.5 kg, compared to 0.9 kg with divalproex treatment. Conclusions: The olanzapine treatment group had significantly greater mean improvement of mania ratings and a significantly greater proportion of patients achieving protocol-defined remission, compared with the divalproex treatment group. Significantly more weight gain and cases of dry mouth, increased appetite, and somnolence were reported with olanzapine, while more cases of nausea were reported with divalproex. (Am J Psychiatry 2002; 159:1011–1017)
B
ipolar disorder affects approximately 1% of the U.S. population (1, 2). It represents a major public health concern, and the search for more effective and safe treatments is ongoing. In 1972, lithium was approved by the U.S. Food and Drug Administration (FDA) for the treatment of acute mania. More than 20 years elapsed before the next drug, divalproex, was approved. More recently, olanzapine, a thiobenzodiazepine previously approved for treatment of psychotic disorders, was the third drug approved by the FDA for treatment of acute mania. Both divalproex (3, 4) and olanzapine (5, 6) have demonstrated acute antimanic efficacy in two placebo-controlled, parallel-group trials. Although placebo-controlled trials are instrumental in demonstrating efficacy of a drug, active comparison studies address more directly the relative benefits of efficacious treatments. The primary objective of the study reported here was to compare the efficacy of olanzapine versus divalproex in the treatment of acute mania over a 3-week period. Herein, we report the results Am J Psychiatry 159:6, June 2002
of a multicenter, double-blind, randomized, parallel-group study comparing olanzapine to divalproex.
Method Patients Patients aged 18 to 75 with a diagnosis of bipolar I disorder, manic or mixed episode, with or without psychotic features, were enrolled in this study. Clinical diagnoses were confirmed with the Structured Clinical Interview for DSM-IV, Patient Version. After the protocol was explained to them, patients provided written informed consent to participate in the study. A minimum total score of 20 on the Young Mania Rating Scale (7) was required at both the screening visit and on the day of random assignment to study groups (baseline). Patients with any of the following criteria were excluded: serious and unstable medical illness, DSM-IV substance dependence within the past 30 days (except nicotine or caffeine), documented history of intolerance to olanzapine or divalproex, and treatment with lithium, an anticonvulsant, or an antipsychotic medication within 24 hours of random assignment to study groups.
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OLANZAPINE VERSUS DIVALPROEX
Study Design
Statistical Methods
This was a 3-week, double-blind, parallel-group study with a double-blind continuation phase of 44 weeks. This manuscript reports findings only for the 3-week acute phase. Patients were hospitalized at baseline and for at least the first week of doubleblind treatment. All psychotropic medications (except benzodiazepines) were tapered and discontinued during the screening period. Patients were randomly assigned to receive either olanzapine (5–20 mg/day) or divalproex (500–2500 mg/day). The initial daily doses were 15 mg/day of olanzapine and 750 mg/day of divalproex, consistent with the recommendations of the manufacturers. Investigators made dose adjustments primarily on the basis of clinical response but also on plasma levels and adverse events. Patients who did not tolerate the minimum dose level for treatment (5 mg/day olanzapine or 500 mg/day divalproex) were discontinued from participation in the study. Plasma levels were obtained to evaluate whether divalproex trough levels were maintained within the targeted therapeutic range of 50–125 µg/ml. Assessment of olanzapine plasma levels has not been shown to be helpful in its clinical use. To maintain the blind, all patients randomly assigned to receive olanzapine had blood drawn, and sham “divalproex” plasma level results were reported. Despite the use of this procedure, all investigators at the clinical sites and at Lilly Research Laboratories remained blind to subjects’ treatment assignments. Blood was drawn from all patients on days 5, 7, and 21 and shipped to an independent reference laboratory; a coordinator at the reference laboratory was unblinded to treatment assignment. Divalproex levels below 35 µg/ml were reported as “well below target level,” levels from 35 to 49 µg/ml as “below target level,” levels from 126 to 150 µg/ml as “above target level,” and levels above 150 µg/ml as “well above target level.” For each report sent by the laboratory of an out-oftarget-range plasma level for a divalproex-treated patient, a similar sham out-of-target-range report for divalproex was sent for a randomly selected olanzapine-treated patient at a different research center. Thus, if the investigator decided to change the medication dose on the basis of the “sham” divalproex plasma level for a patient taking olanzapine, increments or decrements affected only the number of placebo tablets given to that patient. This method ensured maintenance of the blind procedure. Concomitant lorazepam use was restricted to a maximum dose of 2 mg/day, and administration was not allowed within 8 hours of the administration of a symptom rating scale. Benztropine was permitted to treat extrapyramidal symptoms up to a maximum of 2 mg/day throughout the course of the study. Benztropine was not allowed as prophylaxis for extrapyramidal symptoms.
Patient data were analyzed on an intent-to-treat basis. Patients with a baseline and at least one postbaseline measurement were included in the analysis of mean improvement with the last observation carried forward. Efficacy and extrapyramidal symptoms rating scale scores were evaluated by using analysis of variance. Rank-transformed data were analyzed, as appropriate, when significant nonnormality was found in the analysis of raw data. The models included terms for the fixed effects of treatment, investigator, and the treatmentby-investigator interaction. Models for analyses of subgroup data included terms for investigator, treatment, the subgroup, and the treatment-by-subgroup interaction. The Kruskal-Wallis test was used to compare effects of the treatments on each Young Mania Rating Scale item. Fisher’s exact test was used to analyze treatment effects for completion rate, reason for discontinuation, categorical efficacy, treatment-emergent adverse events, and abnormalities in vital signs, ECG, and laboratory test results. Time to discontinuation, time to response, and time to symptomatic remission were assessed by using Kaplan-Meier estimated survival curves, and the curves for each treatment group were compared with the log-rank test. The primary objective of the study was to assess the noninferiority of olanzapine compared to divalproex in the reduction (from baseline to endpoint) of manic symptoms as measured by the Young Mania Rating Scale total score (with the last observation carried forward) after 3 weeks of acute therapy. The assessment of noninferiority was planned as a one-tailed comparison (one-tailed 95% confidence interval [CI]) evaluating whether olanzapine was no worse than divalproex in reducing manic symptoms by a predefined amount. In this trial, olanzapine was considered noninferior only if the reduction in the Young Mania Rating Scale score was no more than 1.9 points less than the reduction associated with divalproex. This a priori margin of noninferiority was equivalent to 20% of the reduction in manic symptoms (9.5 points on the Young Mania Rating Scale) reported previously for divalproex therapy (3). The protocol was designed for approximately 325 patients per group to be enrolled. This number of subjects was needed to provide 80% power that the lower limit of the 95% one-sided CI for the difference in mean change in Young Mania Rating Scale total scores between the two treatment groups was greater than or equal to –1.9. The calculation assumed that 5% of patients would not have a postbaseline visit, that the expected mean change from baseline was –10.3 in the olanzapine group and –9.5 in the divalproex group, and that the common standard deviation was 13. A standard assessment of a statistical difference in symptom reduction by means of a twotailed test of significance was planned with p
