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A Randomized Controlled Trial

Ren-Rong Wu, MD; Jing-Ping Zhao, MD, PhD; Hua Jin, MD; Ping Shao, MD; Mao-Sheng Fang, MD; Xiao-Feng Guo, MD; Yi-Qun He, MD; Yi-Jun Liu, MD; Jin-Dong Chen, MD; Le-Hua Li, MD

JAMA. 2008;299(2):185-193.

Context  Weight gain, a common adverse effect of antipsychotic medications, is associated with medical comorbidities in psychiatric patients.

Objective  To test the efficacy of lifestyle intervention and metformin alone and in combination for antipsychotic-induced weight gain and abnormalities in insulin sensitivity.

Design, Setting, and Patients  A randomized controlled trial (October 2004-December 2006) involving 128 adult patients with schizophrenia in the Mental Health Institute of the Second Xiangya Hospital, Central South University, China. Participants who gained more than 10% of their predrug weight were assigned to 1 of 4 treatment groups.

Interventions  Patients continued their antipsychotic medication and were randomly assigned to 12 weeks of placebo, 750 mg/d of metformin alone, 750 mg/d of metformin and lifestyle intervention, or lifestyle intervention only.

Main Outcome Measures  Body mass index, waist circumference, insulin levels, and insulin resistance index.

Results  All 128 first-episode schizophrenia patients maintained relatively stable psychiatric improvement. The lifestyle-plus-metformin group had mean decreases in body mass index (BMI) of 1.8 (95% confidence interval [CI], 1.3-2.3), insulin resistance index of 3.6 (95% CI, 2.7-4.5), and waist circumference of 2.0 cm (95% CI, 1.5-2.4 cm). The metformin-alone group had mean decreases in BMI of 1.2 (95% CI, 0.9-1.5), insulin resistance index of 3.5 (95% CI, 2.7-4.4), and waist circumference of 1.3 cm (95% CI, 1.1-1.5 cm). The lifestyle-plus-placebo group had mean decreases in BMI of 0.5 (95% CI, 0.3-0.8) and insulin resistance index of 1.0 (95% CI, 0.5-1.5). However, the placebo group had mean increases in BMI of 1.2 (95% CI, 0.9-1.5), insulin resistance index of 0.4 (95% CI, 0.1-0.7), and waist circumference of 2.2 cm (95% CI, 1.7-2.8 cm). The lifestyle-plus-metformin treatment was significantly superior to metformin alone and to lifestyle plus placebo for weight, BMI, and waist circumference reduction.

Conclusions  Lifestyle intervention and metformin alone and in combination demonstrated efficacy for antipsychotic-induced weight gain. Lifestyle intervention plus metformin showed the best effect on weight loss. Metformin alone was more effective in weight loss and improving insulin sensitivity than lifestyle intervention alone.

Trial Registration  clinicaltrials.gov Identifier: NCT00451399

Author Affiliations: Mental Health Institute of the Second Xiangya Hospital, Central South University, Changsha, Hunan, China (Drs Wu, Zhao, Shao, Fang, Guo, He, Liu, Chen, and Li) and Department of Psychiatry, University of California, San Diego (Dr Jin).

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