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Editorials   |    
Metformin for Antipsychotic-Related Weight Gain and Metabolic Abnormalities: When, for Whom, and for How Long?
Christoph U. Correll, M.D.; Linmarie Sikich, M.D.; Gloria Reeves, M.D.; Mark Riddle, M.D.
Am J Psychiatry 2013;170:947-952. doi:10.1176/appi.ajp.2013.13060771
View Author and Article Information

Funded in part by NIMH grant 1R01MH080274-01A2 (principal investigator, Dr. Riddle), the University of North Carolina (principal investigator, Dr. Sikich), and North Shore-Long Island Jewish Medical Center (principal investigator, Dr. Correll).

Dr. Correll has served as a consultant and/or advisor to and has received honoraria from Actelion, Alexza, the American Academy of Child and Adolescent Psychiatry, Bristol-Myers Squibb, Cephalon, Eli Lilly, Genentech, Gerson Lehrman Group, IntraCellular Therapies, Lundbeck, Medavante, Medscape, Merck, NIMH, Janssen/Johnson and Johnson, Otsuka, Pfizer, ProPhase, Roche, Sunovion, Takeda, Teva, and Vanda; and he has received grant support and/or donation of medication from Bristol-Myers Squibb, the Feinstein Institute for Medical Research, Janssen/Johnson and Johnson, and NIMH. Dr. Sikich has received research grant support from or has participated in clinical trials sponsored by Autism Speaks, Bristol-Myers Squibb, Curemark, Forest, Foundation of Hope, Merck, NIMH, Otsuka Research Institute, Seaside Pharmaceuticals, Sunovion, and SynapDx; she has served as a consultant to ABT Associates and Sanofi-Aventis and has received software for a computer intervention in schizophrenia from Posit Science; she also serves on the data safety and monitoring boards for the National Institute of Child Health and Human Development Rare Diseases Network and the Research Foundation for Mental Hygiene. Dr. Riddle has received research grant support from NIMH and a donation of medication from Bristol-Myers Squibb and serves on the data safety and monitoring boards for the Best Pharmaceuticals for Children Act. Dr. Reeves has received research grant support from NIMH and a donation of medication from Bristol-Myers Squibb. Dr. Freedman has reviewed this editorial and found no evidence of influence from these relationships.

From the Department of Psychiatry Research, Zucker Hillside Hospital, North Shore-Long Island Jewish Health System, Glen Oaks, N.Y.; Hofstra North Shore-Long Island Jewish School of Medicine, Hempstead, N.Y.; the Feinstein Institute for Medical Research, Manhasset, N.Y.; University of North Carolina at Chapel Hill, Chapel Hill, N.C.; University of Maryland School of Medicine, Baltimore; and Johns Hopkins University School of Medicine, Baltimore.

Address correspondence to Dr. Correll (ccorrell@lij.edu).

Copyright © 2013 by the American Psychiatric Association

The seriously mentally ill have significantly more cardiovascular risk factors, receive less appropriate medical care, and die on average 15 to 30 years earlier than the general population, mostly because of cardiovascular disorders (1). Reasons for this physical health disparity are complex and include unhealthy lifestyle behaviors, illness-related effects (including poverty, negative symptoms, depression, etc.), unclear genetic links between mental and medical disorders, and adverse medication effects, particularly of antipsychotics (1). Antipsychotics are key to managing schizophrenia spectrum disorders (2) and are prescribed for various other psychiatric conditions (3). However, their benefit-to-risk ratio is challenged by weight gain and metabolic abnormalities (1). Several strategies help minimize adverse cardiometabolic effects of antipsychotics: healthy lifestyle interventions (4), switching to lower-risk antipsychotics (5), and the addition of medications that may lower body weight and/or lipid and glucose parameters (6). Interestingly, each of these strategies reduces body weight to a similar, relatively limited extent of roughly 3 kg over 3 to 6 months (46).

Among pharmacologic interventions, metformin, which is indicated for the treatment of diabetes in those 10 years and older, has been studied the most (69). In contrast to several weight-loss agents that have been removed from the market because of potentially serious adverse events, metformin has a well-established safety profile in both adults and youths. The most frequent side effects are nausea, vomiting, and diarrhea. Lactic acidosis is extremely rare, especially in nonelderly populations and in those with creatinine levels <1.4. The potential risk of neuropathy as a result of chronic vitamin malabsorption is easily minimized by daily multivitamin supplementation. However, previous metformin studies targeting antipsychotic-induced weight gain have generally been small (32 to 84 participants, median=55) (612), leading to relatively wide confidence intervals (Figure 1) and precluding mediator and moderator analyses.

 
Anchor for JumpAnchor for Jump
FIGURE 1.Randomized Controlled Trials Comparing Metformin With Placebo

a Data represent the mean difference in body weight (kg), using the inverse variance statistical method in a random-effects model.

b Metformin was concurrently started with antipsychotic treatment.

c Metformin was added to ongoing antipsychotic treatment that caused weight gain.

In this issue of the Journal, the study by Jarskog et al. (13) is the largest study to date of metformin in antipsychotic-treated patients (N=146). It compared 16 weeks of 1,000 mg of metformin twice daily (mean final dose=1,887 mg [SD=292]) with placebo in antipsychotic-treated adults. Additionally, all participants received a standardized healthy lifestyle intervention, deliverable in usual care settings. Generalizability was enhanced by including patients with a body mass index (BMI) ≥27 (mean=34.6 [SD=5.9]) independent of timing and amount of prior weight gain, different levels of chronicity of psychosis, comorbid psychiatric conditions, and treatment with two antipsychotics or psychiatric comedications, excluding only diabetic individuals. Furthermore, for the first time, exploratory moderator and mediator analyses of metformin’s efficacy were performed. Metformin was associated with a −3.0-kg weight loss (95% confidence interval [CI]=−4.0 to −2.0) that was significantly greater than the small weight reduction of −1.0 kg (95% CI=−2.0 to 0.0) in the placebo group. This weight reduction translated into a −0.7 (95% CI=−1.1 to −0.2) greater BMI reduction compared with placebo. However, the mean percent weight loss was only 2.8% of baseline weight with metformin compared with 1.0% with placebo, and only 17.3% and 9.8% of participants, respectively, lost ≥5% of their baseline body weight. A linear time-by-treatment interaction suggests that weight loss could possibly continue beyond 16 weeks. Additionally, the fact that the placebo group lost 1 kg over 4 months suggests that healthy lifestyle intervention can reduce some weight in motivated patients, like those participating in research. Metformin was also associated with significantly lower triglyceride and hemoglobin A1C levels than placebo. The latter findings indicate that the weight reduction with metformin was associated with important additional benefits regarding lipid and glucose metabolism, which are closely related to the risk for diabetes and cardiovascular disease (1). Notably, metformin was well tolerated. Furthermore, younger age (<44 years old), lower BMI (<33), male sex, and nonsmoking status were associated with greater weight loss with metformin. The authors noted the inadequate power for these post hoc analyses, which likely contributed to the failure to discern significant benefits in women, who comprised only 30% of the study sample.

From this (13) and 10 other published studies (712, 1417) comparing metformin with placebo in 685 antipsychotic-treated patients over a mean of 15.5 weeks, we can conclude that 1) metformin significantly reduces body weight; 2) weight loss is statistically and clinically significant but relatively modest (−3.1 kg; 95% CI=−4.5 to −1.6 [Figure 1]); 3) despite the relatively modest weight loss, significant benefits are observed for at least some lipid and glucose parameters; 4) metformin is well tolerated; and 5) weight seems to be regained after stopping metformin (9). However, weight loss was highly heterogeneous (p<0.00001). Weight reduction appears most pronounced in first-episode studies (8, 10). Moreover, it is unclear whether there is a difference between metformin’s efficacy in prevention studies, in which metformin was started at the same time as the antipsychotics, and intervention studies, in which metformin was added to a stable antipsychotic regimen after significant weight gain occurred. Although weight loss with these two intervention strategies was similar, two of the three prevention trials, conducted in Chinese first-episode patients (8, 10), had among the most favorable outcomes, whereas the third trial, conducted in South America (12), showed no benefit. Thus, it remains unclear to what extent these findings reflect moderating effects of age, illness/treatment phase, or ethnicity versus inherent differences in prevention versus intervention approaches.

Similarly, a meta-analysis of 17 controlled trials (N=810) of healthy lifestyle intervention in antipsychotic-treated adults confirmed superior weight loss with healthy lifestyle intervention after a mean of 19.6 weeks (−3.1 kg; 95% CI=−4.4 to −1.7), with similar effects for prevention and intervention studies (4). On average, 3.6 months after stopping the healthy lifestyle intervention, benefits endured regarding weight but not BMI. In a recent, large study not included in that meta-analysis, only 3.2 kg (95% CI=−5.1 to −1.2) were lost at 18 months in 279 patients with mixed psychiatric disorders receiving tailored group or individual healthy lifestyle intervention compared with nutrition/exercise information, followed by monthly health classes (18). Interestingly, in this unique, long-term study, participants continued to demonstrate progressive weight loss throughout the 18-month study period in contrast to studies of nonpsychiatric populations in which weight loss generally plateaus after 6 months. The authors speculated that it may take individuals with serious mental illness longer to fully engage in healthy lifestyle intervention.

Only one trial has compared metformin alone, placebo plus healthy lifestyle intervention, and metformin plus healthy lifestyle intervention (11). In that study, significant advantages for reducing body weight and improving glucose- and insulin-related outcomes were observed for combined metformin plus healthy lifestyle intervention compared with either healthy lifestyle intervention alone or metformin alone. It is unclear whether the limited benefit of healthy lifestyle intervention in this study reflects the relatively short duration of the study or the limited engagement of severely ill patients in healthy lifestyle intervention (12). Such comparisons warrant further study, especially since in the general population, studied in the Diabetes Prevention Program (19), the opposite appears to be true, in that healthy lifestyle intervention was superior to metformin. Moreover, it is concerning that no healthy lifestyle intervention study (4) and only two small metformin studies (14, 17) have been conducted in antipsychotic-treated youths, a population increasingly receiving antipsychotics (3) and particularly vulnerable to antipsychotic-related cardiometabolic effects (1). Importantly, the relative efficacy and effectiveness of adding metformin versus switching to antipsychotics with lower weight gain potential, which has been shown to be effective (5), is another pressing question. Some of these gaps are being addressed in an ongoing National Institute of Mental Health-funded study of youths between 8 and 19 years old with psychotic, mood, and autism spectrum disorders who gained clinically significant weight on antipsychotics. For the first time, addition of metformin plus healthy lifestyle intervention, switch to a lower-risk antipsychotic plus healthy lifestyle intervention, and healthy lifestyle intervention alone will be directly compared (http://clinicaltrials.gov/show/NCT00806234). Findings are expected in 2014.

In summary, metformin augmentation of antipsychotics is an evidence-based option to reduce antipsychotic-associated cardiometabolic effects. However, the overall weight loss is modest compared with the weight generally gained on antipsychotics (1, 4, 6), and metformin should likely only be added after a clinical trial of a psychosocial intervention for weight loss has proven to be ineffective. Such interventions include psychoeducation focused on nutritional counseling, caloric expenditure, and portion control; behavioral self-management including motivational enhancement; goal setting; regular weigh-ins; self-monitoring of daily food and activity levels; and dietary and physical activity modifications (20). More placebo-controlled trials of metformin, at least in adults, are not likely to advance our knowledge regarding strategies to control antipsychotic-associated weight gain, unless they last at least 6 months, are sufficiently large to identify mediators and moderators, and/or have a discontinuation phase. Conversely, studying metformin in comparison to or combined with other strategies is much needed. Additional comparators may include antipsychotic switching, topiramate, which is the second most effective medication for antipsychotic-related weight gain (6), or metformin plus topiramate in patients insufficiently benefiting from metformin. Furthermore, the two recently approved antiobesity medications, lorcarserin and phentermine plus topiramate-extended release, should not only be compared with placebo but also with metformin in antipsychotic-treated patients. Finally, not all antipsychotic-treated patients benefit sufficiently from metformin. It is essential to identify the best candidates for metformin. Future studies should ideally include patients with different durations of illness and ethnicities, stratifying randomization by first- versus multiepisode schizophrenia and Asian compared with non-Asian race, so that these moderators can be assessed. Similarly, a study comparing prevention versus intervention approaches would be informative. It is hoped that future studies will help clinicians make individualized management decisions for antipsychotic-treated patients that maximize psychiatric benefits while minimizing adverse health consequences.

De Hert  M;  Detraux  J;  van Winkel  R;  Yu  W;  Correll  CU:  Metabolic and cardiovascular adverse effects associated with antipsychotic drugs.  Nat Rev Endocrinol 2012; 8:114–126
[CrossRef]
 
Kane  JM;  Correll  CU:  Past and present progress in the pharmacologic treatment of schizophrenia.  J Clin Psychiatry 2010; 71:1115–1124
[CrossRef] | [PubMed]
 
Olfson  M;  Blanco  C;  Liu  SM;  Wang  S;  Correll  CU:  National trends in the office-based treatment of children, adolescents, and adults with antipsychotics.  Arch Gen Psychiatry 2012; 69:1247–1256
[CrossRef] | [PubMed]
 
Caemmerer  J;  Correll  CU;  Maayan  L:  Acute and maintenance effects of non-pharmacologic interventions for antipsychotic associated weight gain and metabolic abnormalities: a meta-analytic comparison of randomized controlled trials.  Schizophr Res 2012; 140:159–168
[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]
 
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]
 
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]
 
Chen  CH;  Huang  MC;  Kao  CF;  Lin  SK;  Kuo  PH;  Chiu  CC;  Lu  ML:  Effects of adjunctive metformin on metabolic traits in non-diabetic clozapine-treated patients with schizophrenia and the effect of metformin discontinuation on body weight: a 24-week, randomized, double-blind, placebo-controlled study.  J Clin Psychiatry 2013; 74:e424–e430
 
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]
 
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]
 
Jarskog  LF;  Hamer  RM;  Catellier  DJ;  Stewart  DD;  LaVange  L;  Ray  N;  Golden  LH;  Lieberman  JA;  Stroup  TS; for the METS Investigators:  Metformin for weight loss and metabolic control in overweight outpatients with schizophrenia and schizoaffective disorder.  Am J Psychiatry 2013; 170:1032–1040
 
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;  Rangel  N;  Fernandez  V;  Carrizo  E;  El Fakih  Y;  Uzcategui  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]
 
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]
 
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]
 
Daumit  GL;  Dickerson  FB;  Wang  NY;  Dalcin  A;  Jerome  GJ;  Anderson  CA;  Young  DR;  Frick  KD;  Yu  A;  Gennusa  JV  3rd;  Oefinger  M;  Crum  RM;  Charleston  J;  Casagrande  SS;  Guallar  E;  Goldberg  RW;  Campbell  LM;  Appel  LJ:  A behavioral weight-loss intervention in persons with serious mental illness.  N Engl J Med 2013; 368:1594–1602
[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]
 
Dixon  LB;  Dickerson  F;  Bellack  AS;  Bennett  M;  Dickinson  D;  Goldberg  RW;  Lehman  A;  Tenhula  WN;  Calmes  C;  Pasillas  RM;  Peer  J;  Kreyenbuhl  J:  Schizophrenia Patient Outcomes Research Team (PORT).  The 2009 schizophrenia PORT psychosocial treatment recommendations and summary statements. Schizophr Bull 2010 Jan; 36:48–70
 
References Container

FIGURE 1. Randomized Controlled Trials Comparing Metformin With Placebo

a Data represent the mean difference in body weight (kg), using the inverse variance statistical method in a random-effects model.

b Metformin was concurrently started with antipsychotic treatment.

c Metformin was added to ongoing antipsychotic treatment that caused weight gain.

+

References

De Hert  M;  Detraux  J;  van Winkel  R;  Yu  W;  Correll  CU:  Metabolic and cardiovascular adverse effects associated with antipsychotic drugs.  Nat Rev Endocrinol 2012; 8:114–126
[CrossRef]
 
Kane  JM;  Correll  CU:  Past and present progress in the pharmacologic treatment of schizophrenia.  J Clin Psychiatry 2010; 71:1115–1124
[CrossRef] | [PubMed]
 
Olfson  M;  Blanco  C;  Liu  SM;  Wang  S;  Correll  CU:  National trends in the office-based treatment of children, adolescents, and adults with antipsychotics.  Arch Gen Psychiatry 2012; 69:1247–1256
[CrossRef] | [PubMed]
 
Caemmerer  J;  Correll  CU;  Maayan  L:  Acute and maintenance effects of non-pharmacologic interventions for antipsychotic associated weight gain and metabolic abnormalities: a meta-analytic comparison of randomized controlled trials.  Schizophr Res 2012; 140:159–168
[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]
 
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]
 
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]
 
Chen  CH;  Huang  MC;  Kao  CF;  Lin  SK;  Kuo  PH;  Chiu  CC;  Lu  ML:  Effects of adjunctive metformin on metabolic traits in non-diabetic clozapine-treated patients with schizophrenia and the effect of metformin discontinuation on body weight: a 24-week, randomized, double-blind, placebo-controlled study.  J Clin Psychiatry 2013; 74:e424–e430
 
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]
 
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]
 
Jarskog  LF;  Hamer  RM;  Catellier  DJ;  Stewart  DD;  LaVange  L;  Ray  N;  Golden  LH;  Lieberman  JA;  Stroup  TS; for the METS Investigators:  Metformin for weight loss and metabolic control in overweight outpatients with schizophrenia and schizoaffective disorder.  Am J Psychiatry 2013; 170:1032–1040
 
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;  Rangel  N;  Fernandez  V;  Carrizo  E;  El Fakih  Y;  Uzcategui  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]
 
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]
 
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]
 
Daumit  GL;  Dickerson  FB;  Wang  NY;  Dalcin  A;  Jerome  GJ;  Anderson  CA;  Young  DR;  Frick  KD;  Yu  A;  Gennusa  JV  3rd;  Oefinger  M;  Crum  RM;  Charleston  J;  Casagrande  SS;  Guallar  E;  Goldberg  RW;  Campbell  LM;  Appel  LJ:  A behavioral weight-loss intervention in persons with serious mental illness.  N Engl J Med 2013; 368:1594–1602
[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]
 
Dixon  LB;  Dickerson  F;  Bellack  AS;  Bennett  M;  Dickinson  D;  Goldberg  RW;  Lehman  A;  Tenhula  WN;  Calmes  C;  Pasillas  RM;  Peer  J;  Kreyenbuhl  J:  Schizophrenia Patient Outcomes Research Team (PORT).  The 2009 schizophrenia PORT psychosocial treatment recommendations and summary statements. Schizophr Bull 2010 Jan; 36:48–70
 
References Container
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