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Original Research

A 12-Month Randomized, Open-Label Study of the Metabolic Effects of Olanzapine and Risperidone in Psychotic Patients: Influence of Valproic Acid Augmentation

Herbert Y. Meltzer, MD; Stefania Bonaccorso, MD, PhD; William V. Bobo, MD, MPH; Yuejin Chen, MD, PhD; and Karuna Jayathilake, MS

Published: July 12, 2011

Article Abstract

Objective: Longitudinal data comparing the metabolic effects of olanzapine and risperidone with or without valproic acid supplementation in schizophrenic and bipolar patients are lacking.

Method: This study compares the metabolic effects of olanzapine and risperidone in a prospective, randomized, open-label trial in 160 patients with DSM-IV-TR schizophrenia, schizoaffective disorder, or bipolar disorder after 1, 3, 6, and 12 months’ treatment. The study was conducted between 2000 and 2006. The primary analysis compared all patients randomized to olanzapine or risperidone; the primary outcome measure was changes in triglycerides (TG), and TG/high density lipoprotein cholesterol (HDL-C) ratio, a risk factor for ischemic cardiovascular disease. Secondary analyses included the effect of concomitant valproic acid.

Results: Significantly greater increases in weight (F4,434 = 4.7), body mass index (BMI) (F4,424 = 5.1), glycosylated hemoglobin (HgbA1c) (F4,427 = 4.3), total cholesterol (F4,429 = 4.4), TG (F4,426 = 5.9), and TG/HDL-C ratio (F4,426 = 4.3) (P < .005 for all drug × time interaction effects) were observed at all but the initial time points in the olanzapine- compared to the risperidone patients. Olanzapine/+valproic acid produced significantly greater increases in HgbA1c, BMI, weight, TG, and TG/HDL-C than olanzapine/-valproic acid at 3 and 6 months, while risperidone/+valproic acid produced significantly smaller increases in HgbA1c, BMI, and weight at 1, 3, and 6 months than risperidone/-valproic acid. The olanzapine/+valproic acid group had significantly greater BMI, and weight at 1, 3, and 6 months, and greater HgbA1c at 3 and 6 months, compared with the risperidone/+valproic acid group. There were too few patients treated with mood stabilizers other than valproic acid to analyze effects of any other mood stabilizer separately. Metabolic effects did not differ significantly by diagnostic category (schizophrenia/schizoaffective disorder vs bipolar disorder).

Conclusion: Further study of the metabolic effects of adjunctive valproic acid is indicated, as valproic acid may produce markedly different metabolic effects when combined with various antipsychotic drugs.

Trial Registration: Identifier: NCT00179062

J Clin Psychiatry

Submitted: January 22, 2010; accepted August 3, 2010.

Online ahead of print: July 12, 2011 (doi:10.4088/JCP.10m05997).

Corresponding author: Herbert Y. Meltzer, MD, 1601 23rd Ave South, Ste 3035, Nashville, TN 37212-8645 (

Volume: 72

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