CNS Drugs

, Volume 32, Issue 12, pp 1103–1112 | Cite as

Metformin for Weight Gain Associated with Second-Generation Antipsychotics in Children and Adolescents: A Systematic Review and Meta-Analysis

  • Pierre EllulEmail author
  • Richard Delorme
  • Samuele Cortese
Systematic Review



Weight gain is a potentially concerning side effect of second-generation antipsychotics (SGAs). Metformin, a biguanide with antihyperglycemic effects, is used to manage weight gain in adults treated with SGAs.


The objective of this study was to perform the first systematic review and meta-analysis of randomized controlled trials (RCTs) assessing the effects of metformin on weight gain in children and adolescents treated with SGAs.


Based on a pre-registered protocol (PROSPERO–CRD42017074839), we searched the PubMed, EMBASE, PsychoINFO, BIOSIS, Science Direct, Cochrane Central, and electronic databases through March 2018 (with no restrictions on language, date, or type of publication) for RCTs that assessed the effect of metformin or placebo on body weight in children or adolescents (< 18 years of age) treated with selected SGAs (risperidone, aripiprazole, olanzapine, and clozapine) for any psychiatric disorder. We also contacted relevant drug manufacturers for possible additional pertinent studies/data. A random effects model was used and the quality of the included RCTs was assessed using the Cochrane Risk of Bias tool.


Five RCTs (205 participants in total) were included in the meta-analysis. We found a significant weight decrease in the metformin group compared with placebo after 4, 12, and 16 weeks of treatment {mean difference − 0.98 kg (95% confidence interval [CI] − 1.26, − 0.69); − 1.83 kg (95% CI − 2.47, − 1.18); and − 3.23 kg (95% CI − 5.59, − 0.86), respectively}. A weight decrease at weeks 2 and 8 did not reach statistical significance. The decrease in body mass index (BMI) paralleled that of weight, with a significant effect at weeks 4, 12, and 16. Overall, four studies were rated as unclear, and one study was rated as high, risk of bias.


Meta-analytical evidence shows that metformin might decrease weight in children/adolescents treated with SGAs but additional high-quality evidence is needed. Clinicians need to be aware that this use of metformin is currently off-label.



The authors would like to thank the following authors who kindly provided additional unpublished information/data: E. Anagnostou and colleagues, Department of Pediatrics, University of Toronto, Toronto, ON, Canada; C.U. Correll and colleagues, Hofstra Northwell School of Medicine, New York, NY, USA; S. Arman and colleagues, Department of Psychiatry, Isfahan University of Medical Sciences, Iran; M.A. Riddle and colleagues, Division of Child and Adolescent Psychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; L. Sikich and colleagues, Division of Child and Adolescent Psychiatry, School of Medicine, University of Maryland, Baltimore, MD, USA.

Compliance with Ethical Standards


No funding was received for the preparation of this manuscript.

Conflicts of interest

Pierre Ellul and Richard Delorme declare no conflicts of interest. Samuele Cortese has received fees from the Association for Child and Mental Health (ACAMH; a non-profit organization) and Healthcare Convention for educational activity on attention-deficit hyperactivity disorder.

Supplementary material

40263_2018_571_MOESM1_ESM.pptx (37 kb)
Supplementary material 1 (PPTX 37 KB)


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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Pierre Ellul
    • 1
    Email author
  • Richard Delorme
    • 1
    • 2
  • Samuele Cortese
    • 3
    • 4
    • 5
    • 6
    • 7
  1. 1.Child and Adolescent Psychiatry DepartmentRobert Debré Hospital, APHPParisFrance
  2. 2.Human Genetics and Cognitive FunctionsInstitut PasteurParisFrance
  3. 3.Center for Innovation in Mental Health, Academic Unit of PsychologyUniversity of SouthamptonSouthamptonUK
  4. 4.Clinical and Experimental Sciences (CNS and Psychiatry), Faculty of MedicineUniversity of SouthamptonSouthamptonUK
  5. 5.Solent NHS TrustSouthamptonUK
  6. 6.New York University Child Study CenterNew YorkUSA
  7. 7.Division of Psychiatry and Applied Psychology, School of MedicineUniversity of NottinghamNottinghamUK

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