Assessment of Treatment Algorithms Including Amantadine, Metformin, and Zonisamide for the Prevention of Weight Gain With Olanzapine: A Randomized Controlled Open-Label Study

Objective: This 22-week, open-label study, conducted between November 2006 and September 2008 in a community setting, was designed to determine if weight gain during olanzapine treatment can be prevented or mitigated with adjunctive treatment algorithms that include amantadine, metformin, and zonisamide.

Method: Outpatients with schizophrenia or schizoaffective disorder (DSM-IV-TR criteria) were randomly assigned to olanzapine alone (n = 50), olanzapine plus algorithm A (olanzapine + A [amantadine 200 mg/d with possible switches to metformin 1,000-1,500 mg/d and then to zonisamide 100-400 mg/d; n = 76]), or olanzapine plus algorithm B (olanzapine + B [metformin 1,000-1,500 mg/d with possible switches to amantadine 200 mg/d and then to zonisamide 100-400 mg/d; n = 73]). Brief weight management education was provided at baseline. The primary outcome measure was comparison of mean weight gain between olanzapine and pooled olanzapine + A and olanzapine + B results.

Results: Least squares mean ± SE weight gain was 2.76 ± 0.75 kg for olanzapine, 2.40 ± 0.65 kg for olanzapine + A, and 0.65 ± 0.63 kg for olanzapine + B. Mean weight gain during olanzapine treatment did not differ significantly from pooled results for olanzapine + A and olanzapine + B (P = .065). Participants treated with olanzapine + B experienced significantly less mean weight gain than olanzapine-treated participants (P = .036).

Conclusions: Pooled treatment algorithm results were not significantly different from olanzapine monotherapy in mitigating weight gain. However, participants who received treatment with metformin with possible progression to amantadine and then zonisamide had significantly less mean weight gain than participants treated with olanzapine alone. Progression of some participants through the algorithm indicated that a single therapy solution may not be adequate for every patient. Patients treated with olanzapine should receive regular weight monitoring.

Trial Registration: clinicaltrials.gov Identifier: NCT00401973

J Clin Psychiatry

Submitted: August 3, 2009; accepted September 28, 2010.

Online ahead of print: May 17, 2011 (doi:10.4088/JCP.09m05580).

Corresponding author: Vicki Poole Hoffmann, PharmD, Lilly USA, LLC, Lilly Corporate Center, Indianapolis, IN 46285 (vph@lilly.com).