A secondary care randomised controlled trial from China has shown that metformin combined with lifestyle intervention is effective in reversing antipsychotic-induced weight gain in patients with schizophrenia.

Obesity (BMI >30) is associated with a two- to threefold increase in the risk of CVD,¹ and is thought to be a major risk factor in patients with schizophrenia (30% of patients with severe mental illness in our practice were obese).

The study recruited 128 patients aged 18-45 who had a new diagnosis of schizophrenia and had gained more than 10% of their body weight within the first year of antipsychotic treatment. Participants were randomly assigned to 12 weeks of placebo, metformin alone (750mg daily), metformin and lifestyle intervention, or lifestyle intervention and placebo.

There was a significant fall in BMI, waist circumference and insulin resistance index in all three treatment groups. The measurements in the placebo group continued to increase.

Combination treatment was the most effective therapy (mean decrease in BMI of 1.8), and metformin alone (decrease of 1.2) was significantly more effective than lifestyle intervention alone (decrease of 0.5).

The average weight loss with lifestyle intervention and metformin (4.7kg) compares favourably with the mean weight loss after three months' treatment with sibutramine and lifestyle intervention (2.78kg).² Metformin alone achieved an average weight loss of 3.2kg.

Atypical antipsychotic drugs in particular cause considerable weight gain. A recent study found that after two years patients on olanzapine had gained an average of 15.4kg, compared with 7.5kg for those on haloperidol.³

However, these results should be interpreted with caution: four atypical antipsychotics were used, with different propensities for causing weight gain. The numbers in each treatment arm were quite small (32) and the study does not state whether the benefits were sustained. Patients were closely monitored by a caregiver, which may have produced unusually high levels of adherence with medication and/or the intensive lifestyle intervention. Systematic reviews have also found no evidence that metformin is effective in reducing weight, either in women with polycystic ovary syndrome⁴ or in adults with obesity.⁵

Combination therapy with an atypical antipsychotic and metformin may be an attractively simple solution but more data from larger, long-term, preferably primary care-based trials are required to test this approach. In the meantime, we should be closely monitoring weight gain and cardiovascular risk in patients newly started on atypical antipsychotics, bearing in mind that the Framingham risk score underestimates risk in obese patients with the metabolic syndrome.