Metformin: A Potential Agent for Attenuating Antipsychotic-Induced Weight Gain and Amenorrhea

Metformin: A Potential Agent for Attenuating Antipsychotic-Induced Weight Gain and Amenorrhea
Metformin: A Potential Agent for Attenuating Antipsychotic-Induced Weight Gain and Amenorrhea

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.

The researchers found that significantly more patients in the metformin group resumed menstruation, compared to patients in the placebo group (66.7% versus 4.8%, P<0.001). Metformin also assisted in reducing weight and improving insulin resistance. BMI decreased by a mean of 0.93 in the metformin group, compared to mean decrease in BMI of 0.85 in the control group. The insulin-resistance index decreased significantly in the metformin group, but there was no comparably significant change in the placebo group.

There were significant decreases in mean prolactin levels in the metformin group, but not in the placebo group. Decreases in the mean LH and testosterone levels and the LH/FSH levels in the metformin group were significantly greater than those in the placebo group. Importantly, there were no significant differences in the frequency and type of adverse events reported between the two groups.

The researchers commented, "Weight gain, metabolic abnormalities, prolactin elevation, and amenorrhea are important side effects of antipsychotics. Metformin provides a new option for managing these complications." They noted that metformin might be particularly useful in managing these complications in patients who present with coexisting amenorrhea, weight gain, and metabolic syndrome. They concluded, "This study has shown clearly that the addition of metformin to antipsychotics is a potential treatment to restore antipsychotic-induced amenorrhea in female patients with schizophrenia."

REFERENCES
1. Tandon R. Recent advances in the antipsychotic treatment of schizophrenia. Available at: http://medicaidmentalhealth.org/files/Guidelines/Advances%20Antipsychotic%20Treatment%20of%20Schizophrenia2012011708339782.pdf. Accessed: November 7, 2012.

2. Kane JM. Addressing side effects from antipsychotic treatment in schizophrenia. J Clin Psychiatry. 2011;72(2):e07.

3. Wieck A, Haddad PM. Antipsychotic-induced hyperprolactinemia in women: Pathophysiology, severity, and consequences. Br J Psychiatry. 2003;182:199–204.

4. Alvarez-Jimenez M, Gonzalez-Blanch C, Crespo-Facorro B, et al. Antipsychotic-induced weight gain in chronic and first-episode psychotic disorders: A systematic critical reappraisal. CNS Drugs. 2008;22:547–562.

5. Colton CW, Manderscheid RW. Congruencies in increased mortality rates, years of potential life lost, and causes of death among public mental health clients in eight states. Prev Chronic Dis. 2006;3:A42.

6. Wu RR, Jin H, Gao K, et al. Metformin for treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia: A double-blind, randomized, placebo-controlled study. Am J Psychiatry. 2012;169(8):813–821.

7. Wu RR, Zhao JP, Guo XF, et al. Metformin addition attenuates olanzapine-induced weight gain in drug-naïve first-episode schizophrenia patients: A double-blind, placebo-controlled study. Am J Psychiatry. 2008;165:352–358.

8. Wu RR, Zhao JP, Jim H, et al. Lifestyle intervention and metformin for treatment of antipsychotic-induced weight gain: A randomized controlled trial. JAMA. 2008;299:185–193.

9. Palomba S, Falbo A, Zullo F, et al. Evidence-based and potential benefits of metformin in the polycystic ovary syndrome: a comprehensive review. Endocr Rev. 2009;19:207–208.

10. Wang D, Chen JJ, Yu L. Clinical study of metformin in young obese women with amenorrhea. Journal of Jiangsu University. 2007;17:498–502.

11. Qu S, Hui L, Gao CR. Therapeutic effect of metformin in obese women with amenorrhea. Chinese Journal of Endocrinology and Metabolism. 2003;19:207–208.

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