A r t ic le
M e tfo rm in fo r Tre a tm e n t o f A n tip sy c h o tic -In d u c e d A m e n o rrh e a a n d W e ig h t G a in in W o m e n W ith F irst-E p iso d e S c h iz o p h re n ia : A D o u b le -B lin d , R a n d o m iz e d , P la c e b o -C o n tro lle d S tu d y Ren-Rong Wu, M.D., Ph.D. Hua Jin, M.D. Keming Gao, M.D., Ph.D. Elizabeth W. Twamley, Ph.D. Jian-Jun Ou, M.D. Ping Shao, M.D. Juan Wang, M.D. Xiao-Feng Guo, M.D., Ph.D. John M. Davis, M.D. Philip K. Chan, M.S. Jing-Ping Zhao, M.D., Ph.D.
O b je c tiv e : D ata on the treatm ent of antipsychotic-induced am enorrhea, particularly w hen occurring w ith w eight gain, are lim ited. The authors investigated the efficacy and safety of m etform in in the treatm ent of antipsychotic-induced am enorrhea and w eight gain in w om en w ith first-episode schizophrenia. M e th o d : Eighty-four w om en (ages 18–40 years) w ith first-episode schizophrenia w ho suffered from am enorrhea during antipsychotic treatm ent w ere random ly assigned, in a double-blind study design, to receive 1000 m g/day of m etform in or placebo in addition to their antipsychotic treatm ent for 6 m onths. The prim ary outcom e m easures w ere restoration of m enstruation and change in body w eight and body m ass index (BM I). Secondary outcom e m easures w ere changes in levels of prolactin, luteinizing horm one (LH), follicle-stim ulating horm one (FSH), estradiol, and testosterone; in fasting levels of insulin and glucose; in LH/FSH ratio; and in
insulin resistance index. Repeated m ixed m odels w ith repeated-m easures re gression analyses and binary logistic re gression w ere used in the analysis. R e s u lts : A total of 76 patients com pleted the 6-m onth trial. Significantly m ore patients in the m etform in group (N=28, 66.7% ) than in placebo group (N=2, 4.8% ) resum ed their m enstruation. Am ong patients treated w ith m etform in, BM I decreased by a m ean of 0.93 and the insulin resistance index by 2.04. In contrast, patients w ho received placebo had a m ean increase in BM I of 0.85. The prolactin, LH, and testosterone levels and LH/FSH ratio decreased significantly in the m etform in group at m onths 2, 4, and 6, but these levels did not change in the placebo group. C o n c lu s io n s : M etform in w as effective in reversing antipsychotic-induced adverse events, including restoration of m enstruation, prom otion of w eight loss, and im provem ent in insulin resistance in fem ale patients w ith schizophrenia. (A m J P sy c h ia try 2 0 1 2 ; 1 6 9 :8 1 3 –8 2 1 )
t is well documented that antipsychotics can cause endocrine adverse events such as amenorrhea, galactorrhea, and weight gain. Indeed, some studies of patients receiving antipsychotics have found that more than 18% have abnormal hormone levels and that up to 36.7% may have an increase in body weight of more than 7% over baseline (1, 2). These antipsychotic-related endocrine adverse events have become a major concern in the treatment of female patients with psychosis because amenorrhea and weight gain not only influence medication adherence but also are associated with substantial medical morbidity, such as ovarian dysfunction, infertility, diabetes mellitus, and heart disease (1, 3, 4). Moreover, amenorrhea and weight gain could contribute to more than 50% of nonadherence in antipsychotic-treated female patients (5–7). Clinical studies indicate that antipsychotics may vary in their propensity to induce amenorrhea and weight gain.
For example, risperidone causes the highest rate of amenorrhea in female patients with schizophrenia, while many other second-generation agents have relatively low rates (8). Studies also suggest that weight gain is greatest with clozapine and olanzapine, intermediate with quetiapine and risperidone, and lowest with ziprasidone and aripiprazole (9, 10). The mechanisms by which many antipsychotics produce weight gain are not well understood, but they may be associated with central histamine H1 antagonism, increased appetite, or the direct impairment of metabolic regulation through the alteration of insulin sensitivity (11, 12). Metformin can improve antipsychotic-induced weight gain and insulin resistance in schizophrenia patients and reduce metabolic syndrome or type 2 diabetes (13–16). In 1994, metformin was administrated for the first time in obese women with polycystic ovarian syndrome and was reported to reduce hyperinsulinemia, decrease an-
This article is featured in this m onth’s AJP A u d io , is discussed in an E d ito ria l by D r. Sm ith (p. 774), and is an article that provides C lin ic a l G u id a n c e (p. A10) A m J Psych ia try 1 6 9 :8 , Au gu st 2 0 1 2
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M e tform in for T r e atm e nt of A nt ips y chot ic -Induc e d A m e norrh e a and W e ight G a in
drogen and prolactin levels, and regularize menses; these findings have been further verified in extended studies (17–19). Polycystic ovarian syndrome and antipsychoticinduced weight gain or amenorrhea may have common characteristics. Researchers in China have found that metformin can restore menstruation in obese women with amenorrhea by restoring sex hormone levels and decreasing insulin resistance. In a 6-month trial of metformin in 24 young obese women with amenorrhea, 79.2% resumed menstruation (20); the women’s abnormal sex hormone levels and insulin resistance also improved significantly. Another study showed similar results (21). Antipsychotic-induced amenorrhea has received little attention. Dopamine agonists (e.g., bromocriptine) are used in general medicine for amenorrhea resulting in abnormalities that produce elevated prolactin levels and have been used for antipsychotic-induced amenorrhea (22), both with limited success. Since metformin restores menstruation in polycystic ovarian syndrome and in obese women with amenorrhea, we postulated that a trial in antipsychotic-induced amenorrhea was warranted. There is evidence that metformin may also increase dopaminergic tone and affect other hormones in women with polycystic ovarian syndrome (18, 23). Metformin is the most prescribed insulin sensitizer for the management of type 2 diabetes and may constitute the treatment of choice. Recently, interest in metformin’s mechanism of action has been stimulated by the recognition of its pleiotropic actions on several tissues, including skeletal muscles, adipose tissue, endothelium, and the ovary, although the liver is its primary target organ (19). For example, metformin has been shown to decrease weight in patients with antipsychotic-induced obesity (15, 16). Metformin appears to affect ovarian function in a dual mode, through the alleviation of the excessive effect of insulin on the ovary and direct effects on ovary (explored in cultures of ovarian cells) (18). To our knowledge, there has never been a double-blind placebo-controlled study to assess the efficacy of metformin for antipsychotic-induced amenorrhea and weight gain among female patients with schizophrenia. We report a 6-month randomized, double-blind, placebo-controlled trial that tested the efficacy of metformin in reversing antipsychotic-induced amenorrhea and attenuating antipsychotic-induced weight gain in female patients with first-episode schizophrenia.
M e th o d
S tu d y D e sig n This was a double-blind, randomized, placebo-controlled study. Participants were randomly assigned to receive metformin (1000 mg/day) or placebo for up to 6 months. The dosage of 1000 mg/day of metformin was based on safety and efficacy findings for obese Chinese women with amenorrhea (20, 21). Randomization was carried out using a computer-generated table to assign patients to one of the two treatment groups in blocks of four to ensure approximately equal numbers of participants in the two groups. To ensure concealment of the randomization, a research pharmacist who was independent of the investigators at a separate facility provided the study medications in coded containers of identical-appearing capsules of metformin or placebo supplied by the manufacturer.
P h a rm a c o lo g ic a l In te rv e n tio n For the first 3 days, participants took 250 mg of metformin or placebo twice a day, one before lunch and one before dinner. From day 4 onward, they took 500 mg of metformin or placebo twice a day. Any antipsychotics that patients were taking before enrollment in the study remained at the same dosage throughout the course of the study. Only trihexyphenidyl for extrapyramidal symptoms and lorazepam for insomnia or agitation were considered concomitant medications and were allowed as needed during the study period. Participants’ adherence to the study medication for each visit was defined as having taken more than 80% of the study drug dose prescribed for that period. If a participant was nonadherent, both the patient and the caregiver were counseled on the importance of taking the prescribed study medication.
M e a su re s
P a rtic ip a n ts Female patients 18–40 years old with first-episode schizophrenia were recruited from the schizophrenia outpatient clinic of the Mental Health Institute of the Second Xiangya Hospital, Central South University, China, between February 2008 and July 2010. The study was approved by the hospital’s ethics committee, and all participants provided written informed consent in accordance with National Health and Medical Research Council guidelines.
The diagnosis of schizophrenia was determined by the Structured Clinical Interview for DSM-IV Axis I Disorders, Clinician Version (24). To be eligible for the study, patients had to be relatively stable during the screening phase, as indicated by a total score