Low-Dose Metformin May Reduce Body Weight and BMI in Clozapine-Treated Schizophrenia

Negative symptoms of schizophrenia linked to poor clinical outcomes
Negative symptoms of schizophrenia linked to poor clinical outcomes
These study results indicate that early intervention with low doses of metformin in patients with few metabolic abnormalities may be beneficial.

Researchers have found that a low metformin dose of 500 or 1000 mg/d for 12 weeks slightly reduced the body weight and body mass index (BMI) of patients with schizophrenia who were being treated with clozapine and who had preexisting metabolic abnormalities.

Chun-Hsin Chen, MD, from the Department of Psychiatry in Taipei City Hospital, Taiwan, and colleagues screened 96 clozapine-treated patients for a 12-week, randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov identifier: NCT02751307). Of the 96 patients screened, 55 participants with preexisting metabolic abnormalities were enrolled in the study and were randomly assigned either to placebo (n = 18) or to a metformin dose of 500 mg/d (n = 18) or a metformin dose of 1000 mg/d (n = 19).

The participants underwent physical and laboratory evaluations at 4, 8, and 12 weeks. The study outcomes were any changes in metabolic traits.

The researchers found that in the 1000 mg/d group, participants’ body weights significantly decreased by a mean of 0.97 kg over the course of 12 weeks. The same was not found in the 500 mg/d metformin group, however.

“Treatment with 500 mg/d of metformin was not discovered to have a significant effect on the [body weight] of those who received it,” the investigators wrote. Although 1 possible explanation is that the 500 mg/d group had lower body weights to begin with (62.8 kg compared with 69.7 kg in the 1000 mg/d group and 71.1 kg in the placebo group), “further analysis for the overweight and obese patients in each group revealed a significant effect on [body weight] at week 12 in the metformin 1000 mg/d group, but not in the other groups. This suggests that 500 mg daily may be too low to have an effect,” they wrote.

Participants in the 500 mg/d and 1000 mg/d metformin groups also had a significant decrease in BMI after 12 weeks, with mean decreases of 0.70 and 0.50 kg/m2, respectively.

“Compared with [body weight], the BMI may be a more suitable indicator of metabolic syndrome,” the investigators wrote.

No significant changes were observed in other metabolic parameters in any of the groups, including waist circumference. Previous studies have found different results about whether metformin can reduce waist circumference in patients with schizophrenia treated with clozapine, but the researchers noted that some of these studies that did not find any change in waist circumference may have been too small to detect an effect.2-5

Summary & Clinical Applicability

Metformin at either 500 mg/d or 1000 mg/d for 12 weeks can lead to a slight decrease in the body weight or BMI of clozapine-treated patients with schizophrenia who have preexisting metabolic abnormalities.

However, exploring longer-term treatment, larger sample sizes, and factors that influence metformin treatment response are warranted in future studies.


  • The sample size was small. These results require validation in a larger sample size.
  • Participants’ diet and physical activity was not evaluated, so the researchers cannot rule out lifestyle changes as possible influencers of body weight and BMI changes.
  • Some metabolism-related hormones, such as insulin and leptin, were not measured.
  • The length of the trial was relatively short. Future studies should investigate whether longer treatment with metformin would have a more beneficial effect.
  • These results are not generalizable to those who already have a metabolic syndrome. These study results do indicate, however, that early intervention with low doses of metformin in patients with few metabolic abnormalities may be beneficial.


  1. Chiu C-C, Lu M-L, Huang M-C, et al. Effects of low dose metformin on metabolic traits in clozapine-treated schizophrenia patients: an exploratory twelve-week randomized, double-blind, placebo-controlled study. PLoS ONE. 2016;11(12):e0168347. doi:10.1371/journal.pone.0168347
  2. Carrizo E, Fernandez V, Connell L, et al. Extended release metformin for metabolic control assistance during prolonged clozapine administration: a 14 week, double-blind, parallel group, placebo-controlled study. Schizophr Res. 2009;113:19-26. doi:10.1016/j.schres.2009.05.007
  3. Hebrani P, Manteghi AA, Behdani F, et al. Double-blind, randomized, clinical trial of metformin as add-on treatment with clozapine in treatment of schizophrenia disorder. J Res Med Sci. 2015;20:364-71.
  4. Chen CH, Huang MC, Kao CF, et al. 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;74:e424-30. doi:10.4088/JCP.12m08186
  5. Siskind DJ, Leung J, Russell AW, Wysoczanski D, Kisely S. Metformin for clozapine associated obesity: a systematic review and meta-analysis. PLoS One. 2016;11:e0156208. doi:10.1371/journal.pone.0156208