Effects of adjunctive metformin on metabolic traits in nondiabetic clozapine-treated patients with schizophrenia and the effect of metformin discontinuation on body weight: a 24-week, randomized, double-blind, placebo-controlled study

J Clin Psychiatry. 2013 May;74(5):e424-30. doi: 10.4088/JCP.12m08186.


Objective: Many studies have shown that metformin can decrease body weight and improve metabolic abnormalities in patients with schizophrenia. Whether or not the beneficial effects can be sustained after discontinuation of metformin needs to be evaluated. We conducted a 24-week randomized, double-blind, placebo-controlled study to evaluate the effect of metformin on metabolic features in clozapine-treated patients with schizophrenia and followed their body weight after stopping the intervention for at least 24 weeks.

Method: The study was conducted between September 2008 and July 2011. We recruited patients with DSM-IV diagnosis of schizophrenia or schizoaffective disorder who had been taking clozapine for more than 3 months, were overweight or obese, or fulfilled at least 1 criteria of metabolic syndrome. Eligible patients were randomized to receive metformin 1,500 mg/d or placebo. We followed metabolic features at baseline and at weeks 2, 4, 8, 16, and 24 and rechecked body weight when the patients stopped the trial after at least 24 weeks.

Results: A total of 55 subjects (28 in the metformin and 27 in the placebo group) were enrolled. There were no significant differences in all baseline characteristics between the 2 groups, except that patients in the metformin group had higher fasting plasma glucose levels (P = .03). After the 24-week intervention, body weight (P < .0001), body mass index (P < .0001), fasting plasma glucose (P < .0001), high-density lipoprotein cholesterol (P = .03), insulin level (P = .01), and homeostasis model assessment index (P = .02) had significant changes in the metformin group. At the end of the intervention, 8 patients (28.57%) lost more than 7% of their body weight in the metformin group. Mean body weight returned to baseline after patients stopped the intervention in the metformin group.

Conclusions: Metformin can significantly reduce body weight and reverse metabolic abnormalities in clozapine-treated patients with schizophrenia and preexisting metabolic abnormalities. However, the beneficial effects of metformin on body weight disappeared after discontinuing this medication.

Trial registration: ClinicalTrials.gov NCT01300637.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Body Weight / drug effects*
  • Clozapine / adverse effects
  • Clozapine / therapeutic use*
  • Double-Blind Method
  • Female
  • Follow-Up Studies
  • Humans
  • Male
  • Metabolic Syndrome / chemically induced
  • Metabolic Syndrome / diagnosis
  • Metabolic Syndrome / drug therapy
  • Metformin / administration & dosage
  • Metformin / pharmacology*
  • Middle Aged
  • Obesity / chemically induced
  • Obesity / diagnosis
  • Obesity / drug therapy
  • Overweight / chemically induced
  • Overweight / diagnosis
  • Overweight / drug therapy
  • Psychotic Disorders / drug therapy
  • Psychotic Disorders / metabolism
  • Schizophrenia / drug therapy*
  • Schizophrenia / metabolism
  • Time Factors
  • Treatment Outcome


  • Metformin
  • Clozapine

Associated data

  • ClinicalTrials.gov/NCT01300637