Olanzapine May Be Better Than Divalproex in Acute Mania

Laurie Barclay, MD

July 10, 2003

July 10, 2003 — Olanzapine is better overall for the treatment of acute mania than divalproex, but there are no differences in relapse rates, according to the results of a 47-week randomized trial published in the July issue of the American Journal of Psychiatry. These results are in contrast to those of a 12-week randomized trial, previously reported on Medscape, which suggested that divalproex was as good as olanzapine but with fewer adverse effects.

"Few double-blind trials have compared longer-term efficacy and safety of medications for bipolar disorder," write Mauricio Tohen, MD, DrPH, from Lilly Research Laboratories in Indianapolis, Indiana, and colleagues. "Examining data from only the first few weeks of medication use may lead to incorrectly concluding that medications with more rapid onset of action are more efficacious than those with slower onset. Also important, longer-term studies allow better assessment of whether and how quickly patients reach endpoints such as full syndromal remission."

In this double-blind study, 251 patients with manic or mixed episodes of bipolar disorder received flexibly dosed olanzapine (5-20 mg/day) or divalproex (500-2,500 mg/day). Patients were also permitted to use lorazepam for agitation, but no other psychoactive medication.

Over 47 weeks, mean improvement in Young Mania Rating Scale score was significantly greater for the olanzapine group than for the divalproex group. Median time to symptomatic remission was 14 days for olanzapine and 62 days for divalproex (P = .05). However, there were no significant differences between treatments in the rates of symptomatic mania remission over the 47 weeks (56.8% for olanzapine and 45.5% for divalproex) and subsequent relapse into mania or depression (42.3% and 56.5%, respectively).

Somnolence, dry mouth, increased appetite, weight gain, akathisia, and high alanine aminotransferase levels were significantly more common during olanzapine treatment, whereas nausea and nervousness were significantly more common with divalproex.

Study limitations include flexible dosing within large ranges; olanzapine initially administered at a therapeutic dose but divalproex started at a subtherapeutic dose with gradual titration upward; broad ranges rather than precise values reported for valproate concentrations; withdrawal of most patients before completing 47 weeks of treatment; and high severity of illness precluding generalization to less severely ill patients in nonacademic clinical settings.

"In this 47-week study of acute bipolar mania, symptomatic remission occurred sooner and overall mania improvement was greater for olanzapine than for divalproex, but rates of bipolar relapse did not differ," the authors write. "Although the primary efficacy outcome of this trial favored olanzapine, both olanzapine and divalproex demonstrated efficacy for bipolar mania. In selecting pharmacological treatment, the clinician should consider both safety and efficacy as well as patient-specific considerations."

Lilly Research Laboratories sponsored this study.

Am J Psychiatry. 2003;160:1263-1271

Reviewed by Gary D. Vogin, MD

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