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Metformin for Weight Loss and Metabolic Control in Overweight Outpatients With Schizophrenia and Schizoaffective Disorder
L. Fredrik Jarskog, M.D.; Robert M. Hamer, Ph.D.; Diane J. Catellier, Dr.P.H.; Dawn D. Stewart, M.S.; Lisa LaVange, Ph.D.; Neepa Ray, M.S.; Lauren H. Golden, M.D.; Jeffrey A. Lieberman, M.D.; T. Scott Stroup, M.D., M.P.H.; for the METS Investigators
Am J Psychiatry 2013;170:1032-1040. doi:10.1176/appi.ajp.2013.12010127
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Dr. Jarskog has served as a consultant for AstraZeneca, has received research grant support from GlaxoSmithKline, Novartis, Roche, and Sunovion, and has served on a data and safety monitoring board for Janssen. Dr. Hamer has served on an advisory board for, consulted with, served on a data and safety monitoring board/data monitoring committee with, or participated as an expert witness in patent lawsuits involving Abbott, Acadia, Allergan, Alpharma, Anesta, AstraZeneca, Barr, Biolinerx, Caraco, Cenerx, Cephalon, Edo, Epix, Eurand, Fidopharm, Forest, Johnson & Johnson, Lilly, Lundbeck, Marial, Mylan, NeuroPharmaBoost, Novartis, Pfizer, Proctor and Gamble, Roche, Solvay, Sun, Teva, Titan, and Velcera. Dr. LaVange has received an honorarium from GlaxoSmithKline and research grant support from Sanofi-Aventis. Dr. Lieberman serves on the advisory boards of Bioline, Intracellular Therapies, and PsychoGenics; he receives research grant support from Allon, F. Hoffman-La Roche, GlaxoSmithKline, Eli Lilly, Merck, Novartis, Pfizer, PsychoGenics, Sepracor (Sunovion), and Targacept; and he holds a patent with Repligen. Dr. Stroup has served as a consultant for Janssen and Eli Lilly. All other authors report no financial relationships with commercial interests.

ClinicalTrials.gov identifier: NCT00816907.

Supported by NIMH contract N01MH-90001 to Drs. Stroup and Lieberman.

The Metformin in the Treatment of Antipsychotic-Induced Weight Gain in Schizophrenia (METS) Study investigators and sites were as follows: Lawrence Adler, M.D., Clinical Insights, Glen Burnie, Md.; Michael Barber, M.D., Baylor College of Medicine, Houston; Matthew Byerly, M.D., University of Texas-Southwestern, Dallas; Jose M. Canive, M.D., New Mexico VA Health Care System, Albuquerque, N.Mex.; Ira Glick, M.D., Stanford University, Palo Alto, Calif.; David C. Henderson, M.D., Massachusetts General Hospital/Freedom Trail Clinic, Boston; L. Fredrik Jarskog, M.D. (during subject enrollment period), New York State Psychiatric Institute/Columbia University, New York; J. Steven Lamberti, M.D., University of Rochester Medical Center, Rochester, N.Y.; Ahsan Khan, M.D., Clinical Research Institute, Wichita, Kan.; Joseph P. McEvoy, M.D., Duke University, Durham, N.C.; Herbert Meltzer, M.D., Vanderbilt University, Nashville; Alexander Miller, M.D., University of Texas Health Science Center at San Antonio; Del D. Miller, M.D., University of Iowa, Iowa City; Henry A. Nasrallah, M.D., University of Cincinnati; Stephen Olson, M.D., University of Minnesota, Minneapolis; Jayendra K. Patel, M.D., University of Massachusetts Medical School, Worcester; and Bruce L. Saltz, M.D., Mental Health Advocates, Boca Raton, Fla.

From the Departments of Psychiatry and Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill; North Carolina Psychiatric Research Center, Raleigh; Departments of Psychiatry and Medicine, Columbia University, College of Physicians and Surgeons, New York; and New York State Psychiatric Institute, New York.

Presented at the 65th annual meeting of the Society of Biological Psychiatry, New Orleans, May 20–22, 2010, and the 49th annual meeting of the American College of Neuropsychopharmacology, Miami Beach, Fla., Dec. 5–9, 2010.

Address correspondence to Dr. Jarskog (jarskog@med.unc.edu).

Copyright © 2013 by the American Psychiatric Association

Received January 26, 2012; Revised December 05, 2012; Revised January 27, 2013; Accepted February 25, 2013.

Objective  The purpose of this study was to determine whether metformin promotes weight loss in overweight outpatients with chronic schizophrenia or schizoaffective disorder.

Method  In a double-blind study, 148 clinically stable, overweight (body mass index [BMI] ≥27) outpatients with chronic schizophrenia or schizoaffective disorder were randomly assigned to receive 16 weeks of metformin or placebo. Metformin was titrated up to 1,000 mg twice daily, as tolerated. All patients continued to receive their prestudy medications, and all received weekly diet and exercise counseling. The primary outcome measure was change in body weight from baseline to week 16.

Results  Fifty-eight (77.3%) patients who received metformin and 58 (81.7%) who received placebo completed 16 weeks of treatment. Mean change in body weight was −3.0 kg (95% CI=−4.0 to −2.0) for the metformin group and −1.0 kg (95% CI=−2.0 to 0.0) for the placebo group, with a between-group difference of −2.0 kg (95% CI=−3.4 to −0.6). Metformin also demonstrated a significant between-group advantage for BMI (−0.7; 95% CI=−1.1 to −0.2), triglyceride level (−20.2 mg/dL; 95% CI=−39.2 to −1.3), and hemoglobin A1c level (−0.07%; 95% CI=−0.14 to −0.004). Metformin-associated side effects were mostly gastrointestinal and generally transient, and they rarely led to treatment discontinuation.

Conclusions  Metformin was modestly effective in reducing weight and other risk factors for cardiovascular disease in clinically stable, overweight outpatients with chronic schizophrenia or schizoaffective disorder over 16 weeks. A significant time-by-treatment interaction suggests that benefits of metformin may continue to accrue with longer treatment. Metformin may have an important role in diminishing the adverse consequences of obesity and metabolic impairments in patients with schizophrenia.

Abstract Teaser
Figures in this Article

The difference in life expectancy for patients with schizophrenia compared with the general population is more than 20 years (1), and cardiovascular disease accounts for at least 50% of this excess mortality (2). While the basis for increased cardiovascular disease in schizophrenia is multifactorial, adverse metabolic side effects of antipsychotic medications include increased risk for weight gain, hyperlipidemia, and impaired glucose metabolism (36). Studies suggest that antipsychotic-induced metabolic side effects can increase both the 10-year risk of cardiovascular disease (7) and mortality from cardiovascular disease (8). Given the magnitude of the problem, surprisingly little evidence from randomized trials is available to guide the management of antipsychotic-induced weight gain and related metabolic deficits (9).

Among treatments approved by the U.S. Food and Drug Administration (FDA) for weight loss, options for persons with schizophrenia are very limited. Sympathomimetics, such as diethylpropion, phentermine, and a recently approved combination of phentermine and topiramate, are relatively contraindicated given the potential risk for psychosis exacerbation. In a 16-week study, orlistat, a pancreatic lipase inhibitor, produced no significant weight loss in overweight patients with schizophrenia (10). The safety and efficacy of other weight loss agents, including lorcaserin, a newly approved 5-HT2c agonist, and a combination of naltrexone and bupropion currently under development, are unknown in schizophrenia. Among agents without an FDA indication for weight loss, several recent meta-analyses indicate that metformin, topiramate, sibutramine, fenfluramine, and reboxetine have modest efficacy for antipsychotic-induced weight gain (9, 11), although only metformin and topiramate are currently marketed in the United States.

Metformin is a well-tolerated biguanide antihyperglycemic approved for treatment of type 2 diabetes mellitus. Metformin normalizes blood glucose levels by blocking hepatic gluconeogenesis and increasing peripheral insulin sensitivity (12). Since metformin does not increase insulin production, it is rarely associated with hypoglycemia (13). Metformin is known to cause modest weight loss in people with prediabetes and with type 2 diabetes (14, 15). Contributing mechanisms for weight loss are thought to include appetite suppression and slowing of gastric emptying related to stimulation of glucagon-like peptide−1 secretion (13, 16).

Studies of the use of metformin to produce weight loss or to prevent antipsychotic-induced weight gain in nondiabetic patients with schizophrenia have demonstrated positive (1721), suggestive (22), and negative (2325) results. A meta-analysis of available studies (N=7) found weight loss of approximately 3 kg with metformin over 3 to 4 months (9), primarily in narrowly defined populations, including children (19, 24), adults with first-episode schizophrenia (17, 18, 20, 21), and predominantly nonobese individuals (17, 18, 2225). The present study is the first, to our knowledge, to examine whether metformin is effective for weight loss in a typical sample of overweight adults with a chronic psychotic illness.

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Setting and Study Design

The study was conducted between March 2009 and February 2010 at 17 U.S. academic, Veterans Affairs, and private research clinic sites affiliated with the National Institute of Mental Health-funded Schizophrenia Trials Network (see the acknowledgment section for a list of the research sites). In this double-blind randomized study, stable outpatients with schizophrenia or schizoaffective disorder with a body mass index (BMI) ≥27 received 16 weeks of adjunctive metformin or placebo. The primary outcome measure was between-group change in body weight over 16 weeks. It was hypothesized that metformin would produce greater weight loss compared with placebo.

Study treatments were randomly assigned using a central computerized system, and eligible participants received double-blind over-encapsulated metformin or placebo in a 1:1 ratio. Randomization was stratified by site in blocks of four. All participants received a standardized behavioral intervention focused on improving diet and exercise habits. An institutional review board approved the study at each research site.

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Participants

Eligible participants were 18 to 65 years old; met criteria for schizophrenia or schizoaffective disorder, as determined by the Structured Clinical Interview for DSM-IV; had a duration of illness ≥1 year; had a BMI ≥27; had outpatient status; and were receiving one or a combination of two FDA-approved antipsychotics with no change in antipsychotic agents for 2 months and no change in dosage for 1 month prior to study entry. Concomitant medications were allowed if dosages were unchanged for 1 month prior to entry. Women of childbearing potential were required to use an acceptable method of birth control. All participants provided written informed consent.

Exclusion criteria included inpatient status; a Clinical Global Impressions scale severity rating (CGI-S) ≥6 (severely or very severely ill); diabetes mellitus; a fasting glucose level >125 mg/dL; current or previous treatment with metformin; current treatment with insulin or an oral hypoglycemic; treatment with more than two antipsychotics; use of any prescription or nonprescription medication for weight loss within the past month; pregnancy or breastfeeding; an uncorrected thyroid disorder; and any serious and unstable medical illness. Rarely, metformin has been associated with lactic acidosis (3 in 100,000 patient-years), a condition that often co-occurs with a serious medical condition and that can be potentiated by excessive alcohol intake (13). To minimize the risk of lactic acidosis, individuals were excluded if they had congestive heart failure, renal impairment (serum creatinine levels ≥1.5 mg/dL for men and ≥1.4 for women; estimated glomerular filtration rate <55 mL/min/1.73 m2), hepatic disease (ALT, AST, GGT levels >1.5 times the upper limit of normal; total bilirubin level >1.2 times the upper limit of normal), metabolic acidosis (serum CO2 level below the lower limit of normal), iodinated contrast material in the past month, or alcohol abuse or dependence in the past month.

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Intervention

Study treatments were double-blind, with identical capsules containing metformin (500 mg) or placebo. After randomization, participants began treatment with one 500-mg metformin capsule or matching placebo twice daily, to be taken with morning and evening meals for the first week. If well tolerated, the study medication was then increased to one capsule in the morning and two capsules in the evening for the following week and then increased to the final dosage of two capsules twice daily at week 3. The maximum total daily dose for metformin was 2,000 mg. During the titration period, the dosage could be reduced or the drug discontinued for tolerability concerns. Following a reduction or interruption in the dosage, study medication would be retitrated in one-capsule increments per week up to two capsules twice daily or continued at the maximum tolerated dosage.

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Behavioral Intervention

All participants received weekly diet and exercise counseling during the study. The intervention was adapted from a weight-reduction program developed for patients with severe mental illnesses (26). The intervention included eight 20- to 30-minute lessons and seven interim telephone calls to reinforce lessons. (For details, see the data supplement that accompanies the online edition of this article.)

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Outcome Measures

The primary outcome measure was change in body weight from baseline to week 16. Secondary outcome measures included change from baseline to week 16 in BMI, waist circumference, waist-hip ratio, and levels of fasting total cholesterol, non-high-density lipoprotein (non-HDL) cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, glucose, insulin, and hemoglobin A1c (HbA1c). Additional safety outcomes included the frequency and severity of adverse events (assessed using a side effects scale adapted from the Clinical Antipsychotic Trials of Intervention Effectiveness study [3]), vital signs, laboratory measures (for estimated glomerular filtration rate and creatinine, ALT, AST, and lactate levels), and CGI-S ratings. Weight and vital signs were assessed at screening, at baseline, weekly during the first 2 weeks of treatment, and then every 2 weeks until week 16 or treatment discontinuation. Laboratory blood tests were obtained at screening, baseline, and weeks 4, 8, 12, and 16; CGI-S ratings were determined at screening, at baseline, and monthly until week 16.

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Statistical Analysis

Participants who were screened but not randomly assigned were not included in efficacy or safety analyses. Efficacy was assessed for participants who received at least one dose of study medication and had at least one postbaseline weight measure (i.e., the intent-to-treat population). A linear mixed-model analysis was used to compare treatment groups with respect to least-squares-mean estimates of change in body weight from baseline to week 16. The mixed model used data from all visits for which the participant was receiving the study drug and included fixed effects for treatment group, visit, and treatment-by-visit interaction and random effects for participant and site. Only visits that occurred after participants discontinued the study drug and did not restart it were excluded from the analysis. A similar approach was used to compare continuous secondary efficacy and safety outcome variables. Graphical representation of change in primary outcome over the follow-up period was based on least-squares-mean estimates of change for each group and associated 95% confidence intervals.

Safety analyses were performed for participants who received at least one dose of the study drug and included any event occurring between the time of the first dose and within 30 days of discontinuation of the study drug.

The target sample size of 148 participants was estimated to yield 80% power to detect a 2-kg (SD=4) difference in weight change between the treatment groups, assuming a two-tailed test with an alpha level of 0.05 (18, 19, 27).

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Randomization and Baseline Characteristics

A total of 193 individuals consented to participate in the study, and 148 were found eligible and randomly assigned to receive metformin or placebo. Of these, 75 received metformin and 71 received placebo. Two participants in the placebo arm withdrew before receiving study medication. Fifty-eight (77.3%) participants who received metformin and 58 (81.7%) who received placebo completed 16 weeks of treatment. (The CONSORT flowchart is presented in the online data supplement.) The baseline demographic and clinical characteristics of the intent-to-treat population are summarized in Table 1. For the baseline distribution of antipsychotic medications and concomitant medications commonly associated with weight gain, see Table S1 in the data supplement.

 
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TABLE 1.Baseline Demographic and Clinical Characteristics of Overweight Outpatients With Schizophrenia or Schizoaffective Disorder Treated With Metformin or Placebo
Table Footer Note

a Antipsychotics categorized a priori as higher-risk agents for weight gain are clozapine, olanzapine, paliperidone, quetiapine, and risperidone.

Table Footer Note

b Antipsychotics categorized a priori as lower-risk agents for weight gain are aripiprazole, fluphenazine, haloperidol, loxitane, perphenazine, thiothixene, and ziprasidone.

Table Footer Note

c Data are for patients receiving a combination of one higher- and one lower-risk agent.

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Weight and BMI

Least-squares-mean body weight change across the 16-week treatment period was −3.0 kg (95% confidence interval [CI]=−4.0 to −2.0) for the metformin group and −1.0 kg (95% CI=−2.0 to 0.0) for the placebo group, with a between-group difference of −2.0 kg (95% CI=−3.4 to −0.6; p=0.007) (Figure 1, Table 2). The between-group difference demonstrated a significant time-by-treatment interaction (p=0.007). In the active treatment arm, the mean final daily dose of metformin was 1,887 mg (SD=292). Over 16 weeks, participants who received metformin experienced a 2.8% weight reduction, compared with a 1.0% reduction among those who received placebo. Thirteen (17.3%) participants who received metformin, compared with seven (9.8%) who received placebo, lost more than 5% of their baseline weight. BMI changed by −1.0 (95% CI=−1.3 to −0.7) in the metformin group and by −0.3 (95% CI=−0.7 to 0.0) in the placebo group, with a between-group difference of −0.7 (95% CI=−1.1 to −0.1; p=0.006).

 
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FIGURE 1.Weight Change Across 16 Weeks of Treatment With Metformin or Placebo in Overweight Outpatients With Schizophrenia or Schizoaffective Disordera

a Error bars represent 95% confidence intervals. Significantly different between groups, p=0.007.

 
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TABLE 2.Mean Change From Baseline to 16 Weeks for Primary and Secondary Outcome Variables Among Overweight Outpatients With Schizophrenia or Schizoaffective Disorder Treated With Metformin or Placebo
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Lipid Measures

Triglyceride levels changed by −7.0 mg/dL (95% CI=−20.4 to 6.3) in the metformin group and by 13.2 mg/dL (95% CI=−0.3 to 26.7) in the placebo group, with a between-group difference of −20.2 mg/dL (95% CI=−39.2 to −1.3; p=0.037) and a significant time-by-treatment interaction (p=0.04). Between-group differences for metformin and placebo fell short of statistical significance for levels of non-HDL cholesterol (−9.0 mg/dL, 95%=CI=−18.3 to 0.2; p=0.054) and total cholesterol (−9.2 mg/dL, 95% CI=−18.6 to 0.3; p=0.057). Similarly, no differences emerged for HDL and LDL cholesterol levels (Table 2).

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Indices of Glucose Metabolism

Changes in fasting glucose and insulin levels did not differ between the metformin and placebo groups (Table 2). Mean HbA1c levels changed by −0.06% (95% CI=−0.11 to −0.01) in the metformin group and 0.011% (95% CI=−0.04 to 0.06) in the placebo group, with a between-group difference of −0.07% (95% CI=−0.14 to −0.004; p=0.04) and a significant time-by-treatment interaction (p=0.039).

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Adherence to Treatment

In the intent-to-treat population, 94.9% of participants in the metformin group and 96.0% in the placebo group demonstrated adherence to study medication across all study visits either all (81%–100%) or most (61%–80%) of the time, based on pill counts, patient report, and any other available information, with no between-group differences. For the behavioral intervention, 84.9% of participants receiving metformin and 89.7% of those receiving placebo exhibited reasonable-to-excellent adherence based on patient report and rater assessment, with no between-group differences.

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Adverse Events and Safety Assessments

Ten serious adverse events (metformin group, N=3; placebo group, N=7) were reported. None were attributed to metformin. A systematic inquiry about seven side effects commonly associated with metformin and rated at severity levels of “moderate” or “severe” is summarized in Table 3. Only diarrhea was reported significantly more frequently with metformin (33.3%) than placebo (16.9%). The side effects were generally transient. Eleven of the 75 (14.7%) participants receiving metformin and eight of the 71 (11.3%) participants receiving placebo discontinued the study treatment because of intolerability. Two participants in the metformin group discontinued treatment because of abdominal symptoms. In all, 17 participants discontinued metformin and 13 discontinued placebo before the end of the 16-week treatment period.

 
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TABLE 3.Adverse Events From Systematic Inquiry in Overweight Outpatients With Schizophrenia or Schizoaffective Disorder Treated With Metformin or Placebo

Safety assessments for vital signs, for levels of ALT, AST, and creatinine, and for estimated glomerular filtration rate revealed no change in both groups. Lactate levels demonstrated a small increase in the metformin group (mean=0.240 mmol/L, 95% CI=0.06–0.42) compared with the placebo group (mean=−0.07 mmol/L, 95% CI=−0.24 to 0.11), with a mean group difference of 0.31 mmol/L (95% CI=0.06–0.56; p=0.02).

Recent illicit drug use was reported in at least one study visit by 10 participants in the metformin group (cocaine, opiate, or cannabis use) and eight in the placebo group (cocaine, opiate, or cannabis use). No between-group differences emerged.

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Exploratory Analyses

We explored the effect of age and baseline BMI using a median split and the effect of sex, antipsychotic medication, smoking status, and presence or absence of nausea, vomiting, or diarrhea (during the first 2 weeks of study treatment) as categorical variables on metformin-placebo weight change. A priori, antipsychotic medications were categorized as having “higher” or “lower” risk for causing weight gain (see Table 1 footnotes), based on published data (3, 6, 28, 29). Exploratory analyses revealed significant metformin-placebo weight reductions in the following groups: younger-age participants (<44 years old), participants with a baseline BMI <33.38, men, and nonsmokers (Table 4).

 
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TABLE 4.Exploratory Moderators of Metformin-Placebo Weight Change in Overweight Outpatients With Schizophrenia or Schizoaffective Disorder
Table Footer Note

a Analyzed using a median split.

Table Footer Note

b Participants receiving one higher- and one lower-risk agent (N=16) were not included in this analysis. (For a list of higher- and lower-risk agents, see Table 1 footnotes.)

Table Footer Note

c Data refer to the presence or absence of nausea, vomiting, or diarrhea within the first 2 weeks of study medication.

In this study, treatment with metformin over 16 weeks, along with weekly diet and exercise counseling, was associated with significantly more weight loss (2.0 kg) than placebo in overweight adult outpatients with chronic schizophrenia or schizoaffective disorder. The weight change corresponds to a BMI reduction of 1.0 with metformin and an advantage of −0.7 for metformin over placebo. Unlike previous studies, this study placed no restrictions on the timing of weight gain, the chronicity of psychosis, or the presence of comorbid psychiatric conditions. Furthermore, patients could be on a regimen of any single antipsychotic medication or any combination of two antipsychotic medications as well as stable dosages of other concomitant medications. The only medical exclusions were for diabetes and conditions that could increase risk for metformin-induced lactic acidosis. Taken together, these factors suggest that the results are generalizable and applicable to a broad group of patients.

An increase of one BMI unit has previously been identified as an important threshold for triggering an intervention to address weight gain in patients receiving antipsychotic medication (30). While this study suggests that metformin can reasonably be expected to lead to loss of one BMI unit, it is also clear that the magnitude of needed weight loss in this population often exceeds the demonstrated effects of 16 weeks of metformin. It would be important to determine whether metformin-associated weight loss in overweight patients receiving antipsychotics can extend beyond 16 weeks, as suggested by the linear time-by-treatment interaction. Continued weight loss with metformin is also supported by a study of 84 mostly nonobese female patients with first-episode schizophrenia and amenorrhea that demonstrated significant weight loss with 6 months of metformin compared with placebo (20), as well as evidence of modest weight loss for up to 12 months in patients with prediabetes and type 2 diabetes (14, 15).

Other approaches to promote weight loss among people diagnosed with schizophrenia are limited. Topiramate is the only adjunctive agent other than metformin marketed in the United States that has demonstrated significant weight loss (approximately 2.5 kg) in a meta-analysis (9). The other main pharmacological approach to weight loss in this population is to switch to an antipsychotic with lower weight-gain liability. Studies have demonstrated comparable modest weight loss using this method (31, 32). Although switching in these studies was generally safe and did not lead to widespread relapses, switching antipsychotics must be undertaken with considerable care and close clinical monitoring. Taken together, the evidence suggests that metformin represents one of the few safe and modestly effective approaches for overweight patients receiving antipsychotics who are also committed to making healthy lifestyle changes consistent with weight loss.

Among previous studies of metformin for antipsychotic-induced weight gain, many have focused on adults with first-episode schizophrenia. In 128 Chinese adults with first-episode schizophrenia (the largest previous study) who had gained >10% of their baseline weight since starting antipsychotics, metformin was associated with a mean weight loss of 4.7 kg after 12 weeks of treatment together with a daily behavioral intervention, while the behavioral intervention alone produced a mean weight loss of 1.4 kg (18). Comparing those findings with our data suggests that metformin may be somewhat more effective for weight loss in patients with first-episode psychosis. In adults with chronic multiepisode psychosis, previous metformin studies have been smaller with mostly nonobese participants. Two studies found no significant metformin-placebo weight change: the first examined 40 inpatients (mean BMI, approximately 23) starting olanzapine (25), and the second examined 80 inpatients and outpatients (mean BMI, approximately 25.5) who were stable on olanzapine (23). A study of 61 chronic patients receiving clozapine (mean BMI, approximately 28) found a small metformin-placebo difference over 14 weeks, but only in a completer analysis (22). The present study represents the largest study to date of metformin in antipsychotic-treated patients (N=146) and extends previous findings to a more typical group of substantially overweight patients receiving antipsychotics.

Although our cohort was not selected for lipid abnormalities, their mean baseline levels of triglycerides, non-HDL cholesterol, LDL cholesterol, and HDL cholesterol were at or near unhealthy levels (33). For triglycerides, the metformin-placebo difference was −20 mg/mL. While this effect reflected, in part, a triglyceride increase in the placebo arm, the pattern is consistent with the effects of metformin on triglycerides in type 2 diabetes (14, 34), and the significant time-by-treatment interaction suggests the potential for continued improvement. In the largest previous study of metformin in first-episode schizophrenia, lipids were not measured (18). In a study of patients receiving clozapine, no differential effect of metformin was found on lipids (22). Our study provides evidence that metformin may improve cardiovascular disease risk in overweight patients with schizophrenia.

No changes in fasting glucose or insulin levels were demonstrated between the metformin and placebo groups, although a small between-group difference was found for HbA1c levels (−0.07%), which also revealed a significant time-by-treatment interaction. These results contrast with findings from a study of patients with first-episode schizophrenia in which metformin was associated with a 50% reduction of fasting insulin levels compared with placebo (18). This could reflect distinct pathophysiological, pharmacogenetic, and dietary differences between the two populations studied. Although mean glucose and insulin levels did not change in our study, the benefits of metformin in preventing the onset of diabetes in prediabetic individuals (15) suggest that diabetes prevention is another potential long-term benefit for overweight patients with schizophrenia who are receiving metformin.

In exploratory analyses, younger age (<44 years old), lower BMI (<33), male sex, and nonsmoking status were significantly associated with metformin-associated weight loss. The evidence that younger patients who are not morbidly obese appear to exhibit greater metformin-placebo weight loss appears to be consistent with previous studies of metformin in first-episode psychosis that found somewhat more weight loss than we observed in the present study (18, 20). The lack of significant metformin-associated weight loss in female patients is likely confounded by the relatively small percentage of women (approximately 30%). Smoking has been associated with lower body mass and reduced appetite (35), and given that appetite suppression has been linked to metformin (16), the appetite-suppressing effects of smoking may have reduced the potential for metformin-induced weight loss. While these associations could represent important predictors of weight loss response to metformin, they must be interpreted cautiously given that the study was not powered to test these post hoc analyses.

Metformin was generally well tolerated by participants. No serious adverse events were attributed to metformin. While the frequency of adverse events was relatively high, the difference between metformin and placebo was generally small. Gastrointestinal symptoms were more common in the metformin group, but most of these were transient, and only diarrhea was substantially more common in the metformin group compared with the placebo group. Of the 19 participants who discontinued the study medication because of unacceptable side effects, 11 received metformin and eight received placebo.

The study did not follow participants after discontinuation of metformin, and therefore it remains unknown whether and when any weight lost might be regained. Furthermore, because an important goal was to obtain results with broad generalizability, the study did not standardize antipsychotic treatment or exclude concomitant medications with a risk for weight gain. However, weight change in participants receiving antipsychotics associated with higher compared with lower risk for causing weight gain did not differ between the metformin and placebo groups. Another potential confounder was the lack of standardization of caloric intake and physical activity. Analysis of adherence to the behavioral intervention suggested that adherence was high and similar between the groups. However, it is uncertain how well patients in clinical practice can modify their diet and activity level in a manner similar to that achieved in this study and whether less frequent behavioral counseling could also be effective.

This double-blind randomized controlled trial demonstrates the efficacy of metformin to achieve weight loss in overweight outpatients with schizophrenia or schizoaffective disorder. While the benefit of metformin on weight was modest, there are few alternatives for this patient population. For example, switching antipsychotic agents may not be appropriate for patients already receiving an agent with lower risk for causing weight gain or for patients for whom risks to clinical stability are considerable, such as for those receiving clozapine. Metformin represents a safe and reasonable option for overweight patients who are motivated to lose weight. It should be further emphasized that weight loss with any pharmacological intervention is more likely when accompanied by concurrent modifications of diet and physical activity levels.

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Allison  DB;  Mentore  JL;  Heo  M;  Chandler  LP;  Cappelleri  JC;  Infante  MC;  Weiden  PJ:  Antipsychotic-induced weight gain: a comprehensive research synthesis.  Am J Psychiatry 1999; 156:1686–1696
[PubMed]
 
Daumit  GL;  Goff  DC;  Meyer  JM;  Davis  VG;  Nasrallah  HA;  McEvoy  JP;  Rosenheck  R;  Davis  SM;  Hsiao  JK;  Stroup  TS;  Lieberman  JA:  Antipsychotic effects on estimated 10-year coronary heart disease risk in the CATIE schizophrenia study.  Schizophr Res 2008; 105:175–187
[CrossRef] | [PubMed]
 
Henderson  DC;  Nguyen  DD;  Copeland  PM;  Hayden  DL;  Borba  CP;  Louie  PM;  Freudenreich  O;  Evins  AE;  Cather  C;  Goff  DC:  Clozapine, diabetes mellitus, hyperlipidemia, and cardiovascular risks and mortality: results of a 10-year naturalistic study.  J Clin Psychiatry 2005; 66:1116–1121
[CrossRef] | [PubMed]
 
Maayan  L;  Vakhrusheva  J;  Correll  CU:  Effectiveness of medications used to attenuate antipsychotic-related weight gain and metabolic abnormalities: a systematic review and meta-analysis.  Neuropsychopharmacology 2010; 35:1520–1530
[CrossRef] | [PubMed]
 
Joffe  G;  Takala  P;  Tchoukhine  E;  Hakko  H;  Raidma  M;  Putkonen  H;  Eronen  M;  Räsänen  P:  Orlistat in clozapine- or olanzapine-treated patients with overweight or obesity: a 16-week randomized, double-blind, placebo-controlled trial.  J Clin Psychiatry 2008; 69:706–711
[CrossRef] | [PubMed]
 
Björkhem-Bergman  L;  Asplund  AB;  Lindh  JD:  Metformin for weight reduction in non-diabetic patients on antipsychotic drugs: a systematic review and meta-analysis.  J Psychopharmacol 2011; 25:299–305
[CrossRef] | [PubMed]
 
Shaw  RJ;  Lamia  KA;  Vasquez  D;  Koo  SH;  Bardeesy  N;  Depinho  RA;  Montminy  M;  Cantley  LC:  The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin.  Science 2005; 310:1642–1646
[CrossRef] | [PubMed]
 
Kirpichnikov  D;  McFarlane  SI;  Sowers  JR:  Metformin: an update.  Ann Intern Med 2002; 137:25–33
[CrossRef] | [PubMed]
 
DeFronzo  RA;  Goodman  AM; the Multicenter Metformin Study Group:  Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus.  N Engl J Med 1995; 333:541–549
[CrossRef] | [PubMed]
 
Knowler  WC;  Barrett-Connor  E;  Fowler  SE;  Hamman  RF;  Lachin  JM;  Walker  EA;  Nathan  DM; Diabetes Prevention Program Research Group:  Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.  N Engl J Med 2002; 346:393–403
[CrossRef] | [PubMed]
 
Mannucci  E;  Ognibene  A;  Cremasco  F;  Bardini  G;  Mencucci  A;  Pierazzuoli  E;  Ciani  S;  Messeri  G;  Rotella  CM:  Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic subjects.  Diabetes Care 2001; 24:489–494
[CrossRef] | [PubMed]
 
Wu  RR;  Zhao  JP;  Guo  XF;  He  YQ;  Fang  MS;  Guo  WB;  Chen  JD;  Li  LH:  Metformin addition attenuates olanzapine-induced weight gain in drug-naive first-episode schizophrenia patients: a double-blind, placebo-controlled study.  Am J Psychiatry 2008; 165:352–358
[CrossRef] | [PubMed]
 
Wu  RR;  Zhao  JP;  Jin  H;  Shao  P;  Fang  MS;  Guo  XF;  He  YQ;  Liu  YJ;  Chen  JD;  Li  LH:  Lifestyle intervention and metformin for treatment of antipsychotic-induced weight gain: a randomized controlled trial.  JAMA 2008; 299:185–193
[CrossRef] | [PubMed]
 
Klein  DJ;  Cottingham  EM;  Sorter  M;  Barton  BA;  Morrison  JA:  A randomized, double-blind, placebo-controlled trial of metformin treatment of weight gain associated with initiation of atypical antipsychotic therapy in children and adolescents.  Am J Psychiatry 2006; 163:2072–2079
[CrossRef] | [PubMed]
 
Wu  RR;  Jin  H;  Gao  K;  Twamley  EW;  Ou  JJ;  Shao  P;  Wang  J;  Guo  XF;  Davis  JM;  Chan  PK;  Zhao  JP:  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; 169:813–821
[CrossRef] | [PubMed]
 
Wang  M;  Tong  JH;  Zhu  G;  Liang  GM;  Yan  HF;  Wang  XZ:  Metformin for treatment of antipsychotic-induced weight gain: a randomized, placebo-controlled study.  Schizophr Res 2012; 138:54–57
[CrossRef] | [PubMed]
 
Carrizo  E;  Fernández  V;  Connell  L;  Sandia  I;  Prieto  D;  Mogollón  J;  Valbuena  D;  Fernández  I;  de Baptista  EA;  Baptista  T:  Extended release metformin for metabolic control assistance during prolonged clozapine administration: a 14 week, double-blind, parallel group, placebo-controlled study.  Schizophr Res 2009; 113:19–26
[CrossRef] | [PubMed]
 
Baptista  T;  Rangel  N;  Fernández  V;  Carrizo  E;  El Fakih  Y;  Uzcátegui  E;  Galeazzi  T;  Gutiérrez  MA;  Servigna  M;  Dávila  A;  Uzcátegui  M;  Serrano  A;  Connell  L;  Beaulieu  S;  de Baptista  EA:  Metformin as an adjunctive treatment to control body weight and metabolic dysfunction during olanzapine administration: a multicentric, double-blind, placebo-controlled trial.  Schizophr Res 2007; 93:99–108
[CrossRef] | [PubMed]
 
Arman  S;  Sadramely  MR;  Nadi  M;  Koleini  N:  A randomized, double-blind, placebo-controlled trial of metformin treatment for weight gain associated with initiation of risperidone in children and adolescents.  Saudi Med J 2008; 29:1130–1134
[PubMed]
 
Baptista  T;  Martínez  J;  Lacruz  A;  Rangel  N;  Beaulieu  S;  Serrano  A;  Arapé  Y;  Martinez  M;  de Mendoza  S;  Teneud  L;  Hernández  L:  Metformin for prevention of weight gain and insulin resistance with olanzapine: a double-blind placebo-controlled trial.  Can J Psychiatry 2006; 51:192–196
[PubMed]
 
Brar  JS;  Ganguli  R;  Pandina  G;  Turkoz  I;  Berry  S;  Mahmoud  R:  Effects of behavioral therapy on weight loss in overweight and obese patients with schizophrenia or schizoaffective disorder.  J Clin Psychiatry 2005; 66:205–212
[CrossRef] | [PubMed]
 
Pavo  I;  Jermendy  G;  Varkonyi  TT;  Kerenyi  Z;  Gyimesi  A;  Shoustov  S;  Shestakova  M;  Herz  M;  Johns  D;  Schluchter  BJ;  Festa  A;  Tan  MH:  Effect of pioglitazone compared with metformin on glycemic control and indicators of insulin sensitivity in recently diagnosed patients with type 2 diabetes.  J Clin Endocrinol Metab 2003; 88:1637–1645
[CrossRef] | [PubMed]
 
Nussbaum  AM;  Stroup  TS:  Paliperidone for treatment of schizophrenia.  Schizophr Bull 2008; 34:419–422
[CrossRef] | [PubMed]
 
Rummel-Kluge  C;  Komossa  K;  Schwarz  S;  Hunger  H;  Schmid  F;  Lobos  CA;  Kissling  W;  Davis  JM;  Leucht  S:  Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-analysis.  Schizophr Res 2010; 123:225–233
[CrossRef] | [PubMed]
 
Marder  SR;  Essock  SM;  Miller  AL;  Buchanan  RW;  Casey  DE;  Davis  JM;  Kane  JM;  Lieberman  JA;  Schooler  NR;  Covell  N;  Stroup  S;  Weissman  EM;  Wirshing  DA;  Hall  CS;  Pogach  L;  Pi-Sunyer  X;  Bigger  JT  Jr;  Friedman  A;  Kleinberg  D;  Yevich  SJ;  Davis  B;  Shon  S:  Physical health monitoring of patients with schizophrenia.  Am J Psychiatry 2004; 161:1334–1349
[CrossRef] | [PubMed]
 
Stroup  TS;  McEvoy  JP;  Ring  KD;  Hamer  RH;  LaVange  LM;  Swartz  MS;  Rosenheck  RA;  Perkins  DO;  Nussbaum  AM;  Lieberman  JA; Schizophrenia Trials Network:  A randomized trial examining the effectiveness of switching from olanzapine, quetiapine, or risperidone to aripiprazole to reduce metabolic risk: comparison of antipsychotics for metabolic problems (CAMP).  Am J Psychiatry 2011; 168:947–956
[CrossRef] | [PubMed]
 
Newcomer  JW;  Campos  JA;  Marcus  RN;  Breder  C;  Berman  RM;  Kerselaers  W;  L’italien  GJ;  Nys  M;  Carson  WH;  McQuade  RD:  A multicenter, randomized, double-blind study of the effects of aripiprazole in overweight subjects with schizophrenia or schizoaffective disorder switched from olanzapine.  J Clin Psychiatry 2008; 69:1046–1056
[CrossRef] | [PubMed]
 
Grundy  SM;  Cleeman  JI;  Merz  CN;  Brewer  HB  Jr;  Clark  LT;  Hunninghake  DB;  Pasternak  RC;  Smith  SC  Jr;  Stone  NJ; Coordinating Committee of the National Cholesterol Education Program:  Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines.  J Am Coll Cardiol 2004; 44:720–732
[CrossRef] | [PubMed]
 
Schernthaner  G;  Matthews  DR;  Charbonnel  B;  Hanefeld  M;  Brunetti  P; Quartet Study Group:  Efficacy and safety of pioglitazone versus metformin in patients with type 2 diabetes mellitus: a double-blind, randomized trial.  J Clin Endocrinol Metab 2004; 89:6068–6076
[CrossRef] | [PubMed]
 
Albanes  D;  Jones  DY;  Micozzi  MS;  Mattson  ME:  Associations between smoking and body weight in the US population: analysis of NHANES II.  Am J Public Health 1987; 77:439–444
[CrossRef] | [PubMed]
 
References Container

FIGURE 1. Weight Change Across 16 Weeks of Treatment With Metformin or Placebo in Overweight Outpatients With Schizophrenia or Schizoaffective Disordera

a Error bars represent 95% confidence intervals. Significantly different between groups, p=0.007.

Anchor for Jump
TABLE 1.Baseline Demographic and Clinical Characteristics of Overweight Outpatients With Schizophrenia or Schizoaffective Disorder Treated With Metformin or Placebo
Table Footer Note

a Antipsychotics categorized a priori as higher-risk agents for weight gain are clozapine, olanzapine, paliperidone, quetiapine, and risperidone.

Table Footer Note

b Antipsychotics categorized a priori as lower-risk agents for weight gain are aripiprazole, fluphenazine, haloperidol, loxitane, perphenazine, thiothixene, and ziprasidone.

Table Footer Note

c Data are for patients receiving a combination of one higher- and one lower-risk agent.

Anchor for Jump
TABLE 2.Mean Change From Baseline to 16 Weeks for Primary and Secondary Outcome Variables Among Overweight Outpatients With Schizophrenia or Schizoaffective Disorder Treated With Metformin or Placebo
Anchor for Jump
TABLE 3.Adverse Events From Systematic Inquiry in Overweight Outpatients With Schizophrenia or Schizoaffective Disorder Treated With Metformin or Placebo
Anchor for Jump
TABLE 4.Exploratory Moderators of Metformin-Placebo Weight Change in Overweight Outpatients With Schizophrenia or Schizoaffective Disorder
Table Footer Note

a Analyzed using a median split.

Table Footer Note

b Participants receiving one higher- and one lower-risk agent (N=16) were not included in this analysis. (For a list of higher- and lower-risk agents, see Table 1 footnotes.)

Table Footer Note

c Data refer to the presence or absence of nausea, vomiting, or diarrhea within the first 2 weeks of study medication.

+

References

Tiihonen  J;  Lönnqvist  J;  Wahlbeck  K;  Klaukka  T;  Niskanen  L;  Tanskanen  A;  Haukka  J:  11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study).  Lancet 2009; 374:620–627
[CrossRef] | [PubMed]
 
Osby  U;  Correia  N;  Brandt  L;  Ekbom  A;  Sparén  P:  Mortality and causes of death in schizophrenia in Stockholm county, Sweden.  Schizophr Res 2000; 45:21–28
[CrossRef] | [PubMed]
 
Lieberman  JA;  Stroup  TS;  McEvoy  JP;  Swartz  MS;  Rosenheck  RA;  Perkins  DO;  Keefe  RS;  Davis  SM;  Davis  CE;  Lebowitz  BD;  Severe  J;  Hsiao  JK; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators:  Effectiveness of antipsychotic drugs in patients with chronic schizophrenia.  N Engl J Med 2005; 353:1209–1223
[CrossRef] | [PubMed]
 
Correll  CU;  Manu  P;  Olshanskiy  V;  Napolitano  B;  Kane  JM;  Malhotra  AK:  Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents.  JAMA 2009; 302:1765–1773
[CrossRef] | [PubMed]
 
Kahn  RS;  Fleischhacker  WW;  Boter  H;  Davidson  M;  Vergouwe  Y;  Keet  IP;  Gheorghe  MD;  Rybakowski  JK;  Galderisi  S;  Libiger  J;  Hummer  M;  Dollfus  S;  López-Ibor  JJ;  Hranov  LG;  Gaebel  W;  Peuskens  J;  Lindefors  N;  Riecher-Rössler  A;  Grobbee  DE; EUFEST study group:  Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trial.  Lancet 2008; 371:1085–1097
[CrossRef] | [PubMed]
 
Allison  DB;  Mentore  JL;  Heo  M;  Chandler  LP;  Cappelleri  JC;  Infante  MC;  Weiden  PJ:  Antipsychotic-induced weight gain: a comprehensive research synthesis.  Am J Psychiatry 1999; 156:1686–1696
[PubMed]
 
Daumit  GL;  Goff  DC;  Meyer  JM;  Davis  VG;  Nasrallah  HA;  McEvoy  JP;  Rosenheck  R;  Davis  SM;  Hsiao  JK;  Stroup  TS;  Lieberman  JA:  Antipsychotic effects on estimated 10-year coronary heart disease risk in the CATIE schizophrenia study.  Schizophr Res 2008; 105:175–187
[CrossRef] | [PubMed]
 
Henderson  DC;  Nguyen  DD;  Copeland  PM;  Hayden  DL;  Borba  CP;  Louie  PM;  Freudenreich  O;  Evins  AE;  Cather  C;  Goff  DC:  Clozapine, diabetes mellitus, hyperlipidemia, and cardiovascular risks and mortality: results of a 10-year naturalistic study.  J Clin Psychiatry 2005; 66:1116–1121
[CrossRef] | [PubMed]
 
Maayan  L;  Vakhrusheva  J;  Correll  CU:  Effectiveness of medications used to attenuate antipsychotic-related weight gain and metabolic abnormalities: a systematic review and meta-analysis.  Neuropsychopharmacology 2010; 35:1520–1530
[CrossRef] | [PubMed]
 
Joffe  G;  Takala  P;  Tchoukhine  E;  Hakko  H;  Raidma  M;  Putkonen  H;  Eronen  M;  Räsänen  P:  Orlistat in clozapine- or olanzapine-treated patients with overweight or obesity: a 16-week randomized, double-blind, placebo-controlled trial.  J Clin Psychiatry 2008; 69:706–711
[CrossRef] | [PubMed]
 
Björkhem-Bergman  L;  Asplund  AB;  Lindh  JD:  Metformin for weight reduction in non-diabetic patients on antipsychotic drugs: a systematic review and meta-analysis.  J Psychopharmacol 2011; 25:299–305
[CrossRef] | [PubMed]
 
Shaw  RJ;  Lamia  KA;  Vasquez  D;  Koo  SH;  Bardeesy  N;  Depinho  RA;  Montminy  M;  Cantley  LC:  The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin.  Science 2005; 310:1642–1646
[CrossRef] | [PubMed]
 
Kirpichnikov  D;  McFarlane  SI;  Sowers  JR:  Metformin: an update.  Ann Intern Med 2002; 137:25–33
[CrossRef] | [PubMed]
 
DeFronzo  RA;  Goodman  AM; the Multicenter Metformin Study Group:  Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus.  N Engl J Med 1995; 333:541–549
[CrossRef] | [PubMed]
 
Knowler  WC;  Barrett-Connor  E;  Fowler  SE;  Hamman  RF;  Lachin  JM;  Walker  EA;  Nathan  DM; Diabetes Prevention Program Research Group:  Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.  N Engl J Med 2002; 346:393–403
[CrossRef] | [PubMed]
 
Mannucci  E;  Ognibene  A;  Cremasco  F;  Bardini  G;  Mencucci  A;  Pierazzuoli  E;  Ciani  S;  Messeri  G;  Rotella  CM:  Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic subjects.  Diabetes Care 2001; 24:489–494
[CrossRef] | [PubMed]
 
Wu  RR;  Zhao  JP;  Guo  XF;  He  YQ;  Fang  MS;  Guo  WB;  Chen  JD;  Li  LH:  Metformin addition attenuates olanzapine-induced weight gain in drug-naive first-episode schizophrenia patients: a double-blind, placebo-controlled study.  Am J Psychiatry 2008; 165:352–358
[CrossRef] | [PubMed]
 
Wu  RR;  Zhao  JP;  Jin  H;  Shao  P;  Fang  MS;  Guo  XF;  He  YQ;  Liu  YJ;  Chen  JD;  Li  LH:  Lifestyle intervention and metformin for treatment of antipsychotic-induced weight gain: a randomized controlled trial.  JAMA 2008; 299:185–193
[CrossRef] | [PubMed]
 
Klein  DJ;  Cottingham  EM;  Sorter  M;  Barton  BA;  Morrison  JA:  A randomized, double-blind, placebo-controlled trial of metformin treatment of weight gain associated with initiation of atypical antipsychotic therapy in children and adolescents.  Am J Psychiatry 2006; 163:2072–2079
[CrossRef] | [PubMed]
 
Wu  RR;  Jin  H;  Gao  K;  Twamley  EW;  Ou  JJ;  Shao  P;  Wang  J;  Guo  XF;  Davis  JM;  Chan  PK;  Zhao  JP:  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; 169:813–821
[CrossRef] | [PubMed]
 
Wang  M;  Tong  JH;  Zhu  G;  Liang  GM;  Yan  HF;  Wang  XZ:  Metformin for treatment of antipsychotic-induced weight gain: a randomized, placebo-controlled study.  Schizophr Res 2012; 138:54–57
[CrossRef] | [PubMed]
 
Carrizo  E;  Fernández  V;  Connell  L;  Sandia  I;  Prieto  D;  Mogollón  J;  Valbuena  D;  Fernández  I;  de Baptista  EA;  Baptista  T:  Extended release metformin for metabolic control assistance during prolonged clozapine administration: a 14 week, double-blind, parallel group, placebo-controlled study.  Schizophr Res 2009; 113:19–26
[CrossRef] | [PubMed]
 
Baptista  T;  Rangel  N;  Fernández  V;  Carrizo  E;  El Fakih  Y;  Uzcátegui  E;  Galeazzi  T;  Gutiérrez  MA;  Servigna  M;  Dávila  A;  Uzcátegui  M;  Serrano  A;  Connell  L;  Beaulieu  S;  de Baptista  EA:  Metformin as an adjunctive treatment to control body weight and metabolic dysfunction during olanzapine administration: a multicentric, double-blind, placebo-controlled trial.  Schizophr Res 2007; 93:99–108
[CrossRef] | [PubMed]
 
Arman  S;  Sadramely  MR;  Nadi  M;  Koleini  N:  A randomized, double-blind, placebo-controlled trial of metformin treatment for weight gain associated with initiation of risperidone in children and adolescents.  Saudi Med J 2008; 29:1130–1134
[PubMed]
 
Baptista  T;  Martínez  J;  Lacruz  A;  Rangel  N;  Beaulieu  S;  Serrano  A;  Arapé  Y;  Martinez  M;  de Mendoza  S;  Teneud  L;  Hernández  L:  Metformin for prevention of weight gain and insulin resistance with olanzapine: a double-blind placebo-controlled trial.  Can J Psychiatry 2006; 51:192–196
[PubMed]
 
Brar  JS;  Ganguli  R;  Pandina  G;  Turkoz  I;  Berry  S;  Mahmoud  R:  Effects of behavioral therapy on weight loss in overweight and obese patients with schizophrenia or schizoaffective disorder.  J Clin Psychiatry 2005; 66:205–212
[CrossRef] | [PubMed]
 
Pavo  I;  Jermendy  G;  Varkonyi  TT;  Kerenyi  Z;  Gyimesi  A;  Shoustov  S;  Shestakova  M;  Herz  M;  Johns  D;  Schluchter  BJ;  Festa  A;  Tan  MH:  Effect of pioglitazone compared with metformin on glycemic control and indicators of insulin sensitivity in recently diagnosed patients with type 2 diabetes.  J Clin Endocrinol Metab 2003; 88:1637–1645
[CrossRef] | [PubMed]
 
Nussbaum  AM;  Stroup  TS:  Paliperidone for treatment of schizophrenia.  Schizophr Bull 2008; 34:419–422
[CrossRef] | [PubMed]
 
Rummel-Kluge  C;  Komossa  K;  Schwarz  S;  Hunger  H;  Schmid  F;  Lobos  CA;  Kissling  W;  Davis  JM;  Leucht  S:  Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: a systematic review and meta-analysis.  Schizophr Res 2010; 123:225–233
[CrossRef] | [PubMed]
 
Marder  SR;  Essock  SM;  Miller  AL;  Buchanan  RW;  Casey  DE;  Davis  JM;  Kane  JM;  Lieberman  JA;  Schooler  NR;  Covell  N;  Stroup  S;  Weissman  EM;  Wirshing  DA;  Hall  CS;  Pogach  L;  Pi-Sunyer  X;  Bigger  JT  Jr;  Friedman  A;  Kleinberg  D;  Yevich  SJ;  Davis  B;  Shon  S:  Physical health monitoring of patients with schizophrenia.  Am J Psychiatry 2004; 161:1334–1349
[CrossRef] | [PubMed]
 
Stroup  TS;  McEvoy  JP;  Ring  KD;  Hamer  RH;  LaVange  LM;  Swartz  MS;  Rosenheck  RA;  Perkins  DO;  Nussbaum  AM;  Lieberman  JA; Schizophrenia Trials Network:  A randomized trial examining the effectiveness of switching from olanzapine, quetiapine, or risperidone to aripiprazole to reduce metabolic risk: comparison of antipsychotics for metabolic problems (CAMP).  Am J Psychiatry 2011; 168:947–956
[CrossRef] | [PubMed]
 
Newcomer  JW;  Campos  JA;  Marcus  RN;  Breder  C;  Berman  RM;  Kerselaers  W;  L’italien  GJ;  Nys  M;  Carson  WH;  McQuade  RD:  A multicenter, randomized, double-blind study of the effects of aripiprazole in overweight subjects with schizophrenia or schizoaffective disorder switched from olanzapine.  J Clin Psychiatry 2008; 69:1046–1056
[CrossRef] | [PubMed]
 
Grundy  SM;  Cleeman  JI;  Merz  CN;  Brewer  HB  Jr;  Clark  LT;  Hunninghake  DB;  Pasternak  RC;  Smith  SC  Jr;  Stone  NJ; Coordinating Committee of the National Cholesterol Education Program:  Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines.  J Am Coll Cardiol 2004; 44:720–732
[CrossRef] | [PubMed]
 
Schernthaner  G;  Matthews  DR;  Charbonnel  B;  Hanefeld  M;  Brunetti  P; Quartet Study Group:  Efficacy and safety of pioglitazone versus metformin in patients with type 2 diabetes mellitus: a double-blind, randomized trial.  J Clin Endocrinol Metab 2004; 89:6068–6076
[CrossRef] | [PubMed]
 
Albanes  D;  Jones  DY;  Micozzi  MS;  Mattson  ME:  Associations between smoking and body weight in the US population: analysis of NHANES II.  Am J Public Health 1987; 77:439–444
[CrossRef] | [PubMed]
 
References Container
+
+

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1.
Weight loss over the course of 16 weeks of metformin treatment in overweight people with schizophrenia and schizoaffective disorder followed which pattern?
2.
Compared to placebo, metformin improved which fasting metabolic measure in overweight people with schizophrenia and schizoaffective disorder?
3.
What side effect was most common in people who received metformin?
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The American Psychiatric Publishing Textbook of Psychopharmacology, 4th Edition > Chapter 40.  >
The American Psychiatric Publishing Textbook of Psychiatry, 5th Edition > Chapter 26.  >
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