Antipsychotics are the cornerstone of treatment for patients with schizophrenia and other psychotic conditions.1 However, these agents frequently cause amenorrhea and weight gain in female patients, side effects which compromise medication adherence in women2 and are also associated with substantial medical morbidity, such as ovarian dysfunction, infertility, diabetes mellitus, and heart disease.3–5 Minimizing these side effects is therefore critical to managing antipsychotic treatment.

Wu and colleagues investigated the efficacy and safety of metformin for treatment of antipsychotic-induced amenorrhea and weight gain in 84 women with first-episode schizophrenia who suffered from amenorrhea resulting from treatment with antipsychotics.6 Subjects were randomized to receive either 1,000mg/day of metformin (N=42) or placebo (N=42) for a six-month period, in addition to their antipsychotic regimen (risperidone (Risperdal), sulpiride, clozapine (Clozaril), or olanzapine (Zyprexa)).

The researchers chose to investigate metformin because of its recognized role in addressing both weight gain and amenorrhea in a variety of populations. For example, metformin has been shown to decrease weight and improve insulin resistance in patients with antipsychotic-induced obesity.7,8 Several studies have found it effective in restoring regular menstruation by reducing hyperinsulinemia in women with polycystic ovary syndrome (PCOS)9 and decreasing insulin resistance in obese women with amenorrhea.10,11

PCOS and antipsychotic-induced weight gain and amenorrhea have common characteristics and pathways that are mediated through elevated androgen and prolactin levels. While the mechanism of antipsychotic-induced weight gain is not fully understood, it appears to be associated with central histamine H1 antagonism, increased appetite, or the direct impairment of metabolic regulation through the alteration of insulin sensitivity. According to the authors, “There are clearly analogies between PCOS and antipsychotic-induced weight gain and amenorrhea.” These analogies suggest that an agent effective in improving weight gain and amenorrhea in PCOS might also be effective in improving these symptoms when they are side effects of antipsychotics.

The primary outcome measures of the study were restoration of menstruation and reduction in body weight and body mass index (BMI). Secondary outcome measures were changes in levels of prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol and testosterone; fasting levels of insulin and glucose; LH/FSH ratio; and insulin-resistance index.