Metformin for treatment of antipsychotic-induced weight gain: A randomized, placebo-controlled study

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Abstract

Objectives

To evaluate the efficacy of metformin for treatment of antipsychotic-induced weight gain.

Methods

Seventy-two patients with first-episode schizophrenia who gained more than 7% of their predrug weight were randomly assigned to receive 1000 mg/d of metformin or placebo in addition to their ongoing treatment for 12 weeks using a double-blind study design. The primary outcome was change in body weight. The secondary outcomes included changes in body mass index, fasting glucose and insulin, and insulin resistance index.

Results

Of the 72 patients who were randomly assigned, 66 (91.6%) completed treatments. The body weight, body mass index, fasting insulin and insulin resistance index decreased significantly in the metformin group, but increased in the placebo group during the 12-week follow-up period. Significantly more patients in the metformin group lost their baseline weight by more than 7%, which was the cutoff for clinically meaningful weight loss. Metformin was tolerated well by majority patients.

Conclusion

Metformin was effective and safe in attenuating antipsychotic-induced weight gain and insulin resistance in first-episode schizophrenia patients. Patients displayed good adherence to metformin.

Introduction

Almost all antipsychotics can induce weight gain. Citrome reported that the proportions of patients who gained at least 7%, 15% or 25% of their baseline weight with long-term exposure to antipsychotic were 64%, 32% and 12%, respectively (Citrome et al., 2011). So, weight gain has become a main concern for the antipsychotic treatment because weight gain not only influence medication adherence but also are associated with substantial medical morbidity (Smith et al., 2005). For example, people with severe mental illness die up to 3 decades earlier than the general population. Heart disease is a leading cause of death in these patients (Colton and Manderscheid, 2006, Miller et al., 2006). One of the major risk factors for heart disease and early death in these patients is weight gain.

The mechanisms which produce weight gain in many antipsychotics are not well understood, but are associated with central histamine H1 antagonism, increased appetite, and/or the direct impairment of metabolic regulation through the alteration of insulin sensitivity (Kroeze et al., 2003, Matsui-Sakata et al., 2005). At present, there is a relative dearth of interventions to control or reverse antipsychotic-induced weight gain. A variety of pharmacological agents have been studied in an attempt to reverse antipsychotic-induced weight gain (Henderson et al., 2005, Hester and Thrower, 2004), but current evidence is insufficient to support any particular pharmacological treatment.

Metformin is the most widely prescribed insulin sensitizer for the management of type 2 diabetes. Some studies found that metformin can improve weight gain and insulin resistance that were induced by antipsychotics in schizophrenia patients, and reduce metabolic syndrome or type 2 diabetes (Kitabchi et al., 2005, Klein et al., 2006, Rasouli et al., 2007, Wu et al., 2008b).

To our knowledge, there have been few double-blind, placebo-controlled studies to assess the efficacy of metformin for antipsychotic-induced weight gain among patients with schizophrenia. In this article, we report a 12-week randomized, double-blind, placebo-controlled trial that tested the efficacy of metformin attenuating antipsychotic-induced weight gain in first episode schizophrenia patients.

Section snippets

Participants

Patients aged 18 through 60 years with a first psychotic episode of schizophrenia diagnosed in accordance with criteria set out in the Diagnostic and Statistical Manual of Mental Disorders—Fourth Edition (DSM-IV) were eligible for our study (American Psychiatric Association, 1994). The diagnosis of schizophrenia was determined by the Structured Clinical Interview of DSM-IV Axis I Disorders, Clinical Version, during the screening phase (First et al., 1997). Other enrollment criteria included that

Demographic and basic descriptive data

Seventy-two patients entered the trial. Six withdrew from the study within the first 4 weeks because of nausea (two metformin patients and one placebo patient) and hospitalization for exacerbation of psychosis (two metformin patients and one placebo patient). This resulted in 66 (91.7%) patients who were included in the study. The two treatment groups did not differ significantly in demographic or clinical characteristics and baseline measurements (Table 1, Table 2).

The findings presented in

Discussion

This randomized placebo-controlled study represents an attempt to explore the effectiveness of metformin on preventing further weight exacerbation or causing weight loss in patients with schizophrenia who had experienced substantial weight gain during the first year of treatment with antipsychotic agents. In this 12-week study, we found body weight and body mass index decreased significantly in the metformin group and increased in the placebo group. Accordingly, significantly more patients in

Role of funding source

This article was supported by research grant from the Scientific Research Fund of Liaoning Science and Technology Agency, China (No. 2011225020).

I have not signed an agreement with any sponsor of the study reported in this article that has a clause which prevents me from publishing both positive and negative results, from collaborating with other investigators to pool data across sites, or that forbids me from publishing without the approval of the sponsor.

Contributors

  • 1.

    Guarantor of integrity of the entire study: Man Wang and Jian-hua Tong

  • 2.

    Study concepts and design: Man Wang and Jian-hua Tong and Gang Zhu

  • 3.

    Literature research: Gang Zhu and Guang-ming Liang

  • 4.

    Clinical studies: Man Wang and Gang Zhu and Guang-ming Liang and Hong-fei Yan and Xiu-zhen Wang

  • 5.

    Experimental studies/data analysis: Jian-hua Tong and Gang Zhu

  • 6.

    Statistical analysis: Man Wang and Jian-hua Tong

  • 7.

    Manuscript preparation: Man Wang and Gang Zhu and Guang-ming Liang and Hong-fei Yan and Xiu-zhen Wang

  • 8.

Conflicts of interest

Dr. Man Wang reported no biomedical financial interests or potential conflicts of interest in relation to the work described in the manuscript.

Dr. Jian-hua Tong reported no biomedical financial interests or potential conflicts of interest in relation to the work described in the manuscript.

Dr. Gang Zhu reported no biomedical financial interests or potential conflicts of interest in relation to the work described in the manuscript.

Dr. Guang-ming Liang reported no biomedical financial interests

Acknowledgments

This article was supported by research grant from the Scientific Research Fund of Liaoning Science and Technology Agency, China (No. 2011225020).

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