Lifestyle Intervention and Metformin for Treatment of Antipsychotic-Induced Weight Gain

Background: Lifestyle intervention has demonstrated efficacy for weight loss in obese persons and has been shown to prevent or delay the development of type 2 diabetes by 40% to 60% in different populations in controlled studies. Metformin, which inhibits hepatic glucose production, is well tolerated and prevents continual weight gain while it decreases measures of insulin resistance. Some studies found that Metformin can reduce body weight in patient with type 2 diabetes and in obese individuals who do not have diabetes.

Objective: this study objective was to test the efficacy of lifestyle intervention and Metformin alone and in combination for antipsychotic-induced weight gain and abnormalities in insulin sensitivity.

Methods: This is a 12 week randomized, double-blind, placebo-controlled trial. 128 adult patients with schizophrenia in the Mental Health Institute of the Second Xiangya hospital, Central South University in China enrolled in this study. Enrollment criteria included that participants gained more than 10 % if their pre-drug body weight within the first year of treatment with a target antipsychotic agent. Patients had to have relatively stable improvement (the total score of Positive and Negative Symptom Scale [PANSS] <= 60). In addition, participants had to be taking only 1 antipsychotic agent, whose dose had not changed by more than 25% over the past 3 months. All participants had to be under the care of their parents or another adult caregiver who monitored and recorded food intake, exercise activity, and medication intake each day of the trial to monitor adherence.  The exclusion criteria included liver or renal dysfunction, cardiovascular disease, or diabetes mellitus, if patients were pregnant or lactating, or had conditions that limited their ability to perform lifestyle modifications such as arthritis, pulmonary disease, or dietary restrictions. Patients were also excluded if they had received a psychiatric diagnosis other than schizophrenia or had a history of substance abuse. Of the 128 eligible patients, 32 patients were randomly assigned to each of the treatment groups: lifestyle plus metformin, metformin, lifestyle plus placebo, or placebo. Patients continued their antipsychotic medication and were randomly assigned to 12 weeks of placebo, 750 mg/day of metformin alone, 750 mg/day of metformin and lifestyle intervention, or lifestyle intervention only. The lifestyle interventions included psychoeducational, dietary, and exercise programs.

Results: The primary outcome included the changes weight, body mass index, waist circumference, fasting glucose, fasting insulin level, and insulin resistance index (IRI). The major secondary outcomes included the change in PANSS total scores and adverse effects. 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). At week 12, the total score of PANSS was 47.6 in the lifestyle plus metformin group, 45.3 in the metformin alone group, 46.2 in the lifestyle plus placebo group, and 46.2 in the placebo alone group (p>0.20) with no significant changes from baseline. There were no significant differences in the frequency and types of adverse effects reported among 4 treatment groups.

Strengths: This was a well designed randomized and double-blind study. Three metformin trials have been reported for prevention of weight gain or weight reduction in patients taking antipsychotic medications. All these studies suggested a significant effect of metformin in reducing weight and improving insulin sensitivity. The study’s findings are consistent with most of these controlled studies. Study analyses included both per protocol and intention-to-treat.

Weaknesses: This study was conducted in China; thus, the study was limited to 1 ethnicity; therefore the result of the study might not be true for patients outside of this population. In addition, patients in this study were young and few were obese. We don’t know whether these interventions would have same effect on obese, older, or long–term patients. This is a short term study of only 12 weeks. It is unknown whether the improved body weight and insulin sensitivity could be sustained beyond 12 weeks after patients stop taking metformin or engaging lifestyle intervention. The 750 mg/day dosing of metformin was based on safety and efficacy findings for Chinese obese nondiabetic population. This study used a fixed dose of 750mg/day of metformin, thus we don’t know the dose effect of metformin on weight loss or whether it can be effective on other populations. The measures of compliance for lifestyle intervention, particularly the food intake, were mainly reliant on patient or caregiver report.  As a result, the calculation of adherence could be inaccurate. Unblinding is possible due to the detectable odor of metformin tablets.

Conclusion: Based on the study results, I agree with the authors that all 3 intervention groups were found to have a significant advantage over placebo in improving weight gain and insulin sensitivity in patients with schizophrenia. To maintain a balanced weight is often very challenging especially so for patients with schizophrenia due to their poor diet, sedentary lifestyle, and long-time need for antipsychotic drugs. Lifestyle intervention is important because poorly managed weight not only leads to medical complications but also impairs quality of life. It should be noted that the study reported lifestyle plus metformin group had a mean decrease of waist circumference of 2.0 cm. However, if what authors reported were right, it must be a typo in table 2 that waist circumference appeared to be increased at week 12. Overall, this is a good study and will lead to more studies in the future to examine the effect of lifestyle intervention and metformin alone or in combination on weight gain induced by antipsychotic therapy.

Wu RR, Zhao JP, et al. Lifestyle Intervention and Metformin for Treatment of Antipsychotic-Induced Weight Gain. JAMA 2008; 299 (2): 185-93. 

Khanh-Ha Nguyen, Pharm.D Candidate