Treatment with metformin led to striking resolution of amenorrhea in women with schizophrenia treated with an antipsychotic drug, in a randomized, controlled study with 84 patients.

Six months of treatment with a standard metformin dosage of 500 mg b.i.d. also led to significant weight loss, lower body mass index, and reduced insulin levels and insulin resistance. It also normalized levels of prolactin and luteinizing hormone, Dr. Ren-Rong Wu said at the annual meeting of the American Psychiatric Association.

Mitchel L. Zoler/IMNG Medical Media

Dr. Ren-Rong Wu

Amenorrhea completely resolved in 28 (67%) of 42 women randomized to receive the metformin regimen after 3 months of treatment, compared with resolution in 2 (5%) of 42 women in the placebo arm, a statistically significant difference, reported Dr. Wu, a psychiatrist at the Mental Health Institute of the Second Xiangya Hospital of Central South University in Changsha, China.

“Metformin provides a new option for managing amenorrhea and weight gain” in women with schizophrenia on antipsychotic treatment, she said. The metformin regimen was safe, with an adverse-effect profile similar to that of the placebo arm.

Results from a prior study by Dr. Wu and her associates had documented the efficacy and safety of metformin for producing weight loss in patients with schizophrenia and antipsychotic-induced weight gain (JAMA 2008;299:185-93).

Based on the new results, “it’s reasonable to use metformin to treat women who develop amenorrhea on antipsychotic treatment,” commented Dr. Keming Gao, a psychiatrist and clinical director of the mood disorders program at University Hospital Case Medical Center in Cleveland. Although Dr. Wu and her associates maintained their patients on metformin for only 6 months in the reported study, in routine practice it would be reasonable to keep women who safely respond to metformin on the drug for as long as they continue on an antipsychotic regimen, Dr. Gao said in an interview.

Menstrual irregularity is a common side effect of antipsychotic treatment in women, with reports documenting an incidence of 26%-78% (Br. J. Psychiatry 2003;182:199-204). The mechanism of this effect appears to be multifactorial, with antipsychotic drugs causing weight gain and insulin resistance that triggers hyperprolactinemia; the drugs also cause the pituitary to produce elevated levels of luteinizing hormone, Dr. Wu said. Insulin resistance also may have direct effects on ovarian function, she added.

Her study enrolled 84 women with first-episode schizophrenia who had developed amenorrhea while taking clozapine, olanzapine, risperidone, or sulpiride. Patients randomized to the metformin arm started treatment with 500 mg once daily, and if after 3 days they tolerated the drug, their dosage increased to 500 mg b.i.d. Resolution of amenorrhea was the study’s primary end point.

After 6 months on treatment, women in the metformin arm lost an average 2.4 kg of weight, had an average 0.9 kg/m2 reduction in their body mass index, had an average 8.8 microIU/mL drop in their blood insulin level, and had an average 2.0 point reduction in their insulin resistance index. All these changes were statistically significant, compared with baseline levels. In contrast, women in the placebo arm had, on average, significant increases from baseline in weight and body mass index, and had no significant change in their insulin or insulin resistance.

Metformin treatment also produced an average 84.9-mcg/L cut in prolactin levels and a 3.3-IU/L drop in luteinizing hormone levels, both statistically significant changes from baseline, as well as a significant reduction in the ratio of luteinizing hormone to follicle-stimulating hormone. None of these measures changed significantly in women who received placebo.

A series of regression analyses by Dr. Wu and her associates indicated that reduction in body weight was the strongest predictor of restoration of menstrual function in metformin-treated patients, followed by reduction in prolactin level. Normalization of luteinizing hormone and reduction of insulin resistance index also appeared to play significant, independent roles in resolving amenorrhea, she said.

Dr. Wu said that she had no disclosures.