Background: Atypical antipsychotic agents have raised concerns because of their association with weight gain and other metabolic disturbances. More than three fourths of patients taking these medications experienced an increase of 7 percent or more over their weight at baseline. Weight gain can decrease medication adherence and aggravate health risks, perhaps contributing to the prevalence of heart disease in persons with severe mental illness.

Weight gain may be mediated via changes in diet or through metabolic dysregulation. Lifestyle interventions have been shown to help regulate weight in this population. In addition, there is evidence that metformin (Glucophage) has a beneficial effect on weight in patients with type 2 diabetes and in obese patients without diabetes. Wu and colleagues compared the effectiveness of several interventions in reducing the weight gain associated with the use of antipsychotic agents by patients with schizophrenia.

The Study: Patients 18 to 45 years of age with schizophrenia were eligible for participation in this 12-week, randomized, placebo-controlled trial if they had gained more than 10 percent of their pre-drug body weight within one year of initiating atypical antipsychotic treatment. Patients could be on only one antipsychotic medication, with a dose that had not changed more than 25 percent over the preceding three months. All participants were otherwise generally healthy and under the care of parents or formal adult care.

Patients were randomized to receive metformin alone (750 mg per day), placebo alone, lifestyle intervention plus metformin, or lifestyle intervention and placebo. Lifestyle intervention consisted of the following: a psychoeducational approach with an emphasis on the role of eating and exercise on weight management; a dietary intervention recommended by the American Heart Association; and exercise programs initiated at the study site and continued at home. Exercise adherence was measured at various intervals using treadmill test performance. Patients provided baseline information that included height and weight parameters, and symptom severity information using validated scales. Laboratory examinations at baseline included fasting blood glucose, insulin, and lactic acid levels; liver and renal function tests; blood counts; and electrocardiography. All baseline tests were repeated at the end of the 12-week study.

Results: Of the 128 eligible patients, 118 completed the study: 30 patients in the lifestyle intervention plus metformin group, 30 patients in the metformin alone group, 29 patients in the lifestyle intervention plus placebo group, and 29 patients in the placebo alone group. Weight decreased in each treatment group and increased in the placebo group.

Lifestyle intervention plus metformin resulted in a 7.3 percent weight loss (mean 4.7 kg [10 lb, 6 oz]; 95% confidence interval [CI], 3.4 to 5.7 kg [7 lb, 8 oz to 12 lb, 9 oz]). Metformin alone produced a 4.9 percent weight loss (mean 3.2 kg [7 lb, 1 oz]; 95% CI, 2.5 to 3.9 kg [5 lb, 8 oz to 8 lb, 9 oz]). Lifestyle intervention plus placebo produced a 2.2 percent weight loss (mean 1.4 kg [3 lb, 1 oz]; 95% CI, 0.7 to 2.0 kg [1 lb, 8 oz to 4 lb, 6 oz]). Patients on placebo alone experienced a 4.8 percent weight gain (mean 3.1 kg [6 lb, 13 oz]; 95% CI, 2.4 to 3.8 kg [5 lb, 5 oz to 8 lb, 6 oz]). All interventions were superior to placebo regarding fasting blood glucose and insulin levels, and insulin resistance index.

Conclusion: All interventions were better than placebo alone for producing weight loss in patients with schizophrenia who had gained weight from atypical antipsychotic medications. The combination of lifestyle intervention and metformin may be particularly effective in reducing weight gain associated with these medications.