Antipsychotic drug‐treated patients best suited for metformin therapy

In the paper by Curtis et al. (1) and the accompanying editorial comment (2), we are pleased that this Journal renewed the discussion of metformin to reduce or control antipsychotic drug (APD)-induced weight gain and glucose dysregulation. We systematically reviewed the literature on this topic 2 years ago (3, 4) and would like to make a few additional comments to optimize its use in this setting. In 2010, 12 trials (4) (please see our review for references) had described metformin use among patients with APD-associated weight gain and glucose dysregulation. Eight were randomized, double-blind, placebo-controlled, parallel group trials; three trials were open-label; and one was a double-blind, placebo-controlled, same-group sequential trial. Metformin was effective in limiting or reversing weight gain and glucose dysregulation in medication-na€ıve young-adult, first-episode psychosis patients. No gender differences were apparent. It was not effective in older patients with long-term exposure to APDs. The effect of metformin in individuals less than 18 years old was less clear due to insufficient data. Data limited drawing conclusions about potential racial differences. A recent study further substantiates (5) the beneficial effects of metformin treatment in young patients newly exposed to APDs. In this double-blind study, 72 patients with first-episode schizophrenia who gained more than 7% of their predrug weight were randomly assigned to receive 1000 mg/day of metformin or placebo in addition to APDs (clozapine, olanzapine, risperidone, or sulpiride; mean duration of exposure 7–8 months) for 12 weeks. Body weight, BMI, fasting insulin, and insulin resistance index decreased significantly in the metformin group, but increased in the placebo group during 12 weeks of follow-up. Significantly more metformin-treated patients (40.6%) than placebo-treated patients (8.8%) lost more than 7% of baseline weight. Studies of metformin for APD-associated weight gain and glucose dysregulation and findings from the Diabetes Prevention Program to help identify APD-treated patients most likely to benefit from metformin treatment (3, 4). Three key factors to consider are i) vulnerability to weight gain and/or glucose dysregulation. Family or personal history of these problems would be the major ‘individual’ indicators, and metabolic liability of the APD used would be the ‘iatrogenic’ indicator of such vulnerability; ii) Existing overweight/obesity and/or glucose dysregulation, which would dictate whether an individual merits metformin treatment following the American Diabetes Association (ADA) recommendations; and iii) Age and previous exposure to APD treatment that will help determine who would be likely to benefit and who would not. Following ADA guidelines (6), all obese patients with evidence of glucose dysregulation would be candidates for metformin treatment irrespective of APD treatment. Obese patients with schizophrenia without current evidence of glucose dysregulation but with a strong family history of obesity and/ or diabetes mellitus would also be potential candidates for metformin therapy. In addition, young adults with psychosis newly exposed to APDs who show a pattern of rapid weight gain and/or glucose dysregulation would be prime candidates for metformin. Young, drug-na€ıve, normal weight to overweight adults are particularly sensitive to weight gain and glucose dysregulation after initiation of an APD. APDs with high metabolic liability are best avoided in this population, but they may develop metabolic side effects even with low metabolic liability APDs. Metformin may be three times as effective in limiting or reversing weight gain in this population as in older patients with chronic exposure to APDs (4). Initiation of metformin sooner than later is likely to give the best results. We refer interested readers to a point system we have previously suggested (3) to facilitate identification of patients most likely to benefit from metformin treatment. The existing data do not justify the use of metformin for preventive purposes or in the pediatric population. Use of metformin is this setting will be off-label. Due to the heightened risk of lactic acidosis, it should not be used in patients with renal impairment. The duration of metformin therapy could range from several weeks to several years depending upon patient’s risk factors and response. Metformin is not a substitute to healthy lifestyle interventions. Metformin is a viable option in selected group of patients receiving APD treatment but has not received sufficient clinical attention. Psychiatrists may be uncomfortable prescribing it, and general physicians may not be aware of this option. Their collaboration will likely improve patient care.