Advertisement

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 Ellul
  • Richard Delorme
  • Samuele Cortese
Systematic Review

Abstract

Background

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.

Objective

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.

Methods

Based on a pre-registered protocol (PROSPERO–CRD42017074839), we searched the PubMed, EMBASE, PsychoINFO, BIOSIS, Science Direct, Cochrane Central, and ClinicalTrials.gov 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.

Results

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.

Conclusion

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.

Notes

Acknowledgements

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

Funding

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)

References

  1. 1.
    Kurlan R. Clinical practice. Tourette’s syndrome. N Engl J Med. 2010;363:2332–8.CrossRefPubMedGoogle Scholar
  2. 2.
    McCracken JT, McGough J, Shah B, Cronin P, Hong D, Aman MG, et al. Risperidone in children with autism and serious behavioral problems. N Engl J Med. 2002;347:314–21.CrossRefPubMedGoogle Scholar
  3. 3.
    Birnbaum ML, Saito E, Gerhard T, Winterstein A, Olfson M, Kane JM, et al. Pharmacoepidemiology of antipsychotic use in youth with ADHD: trends and clinical implications. Curr Psychiatry Rep. 2013;15:382.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Olfson M, Blanco C, Liu S-M, Wang S, Correll CU. National trends in the office-based treatment of children, adolescents, and adults with antipsychotics. Arch Gen Psychiatry. 2012;69:1247–56.CrossRefPubMedGoogle Scholar
  5. 5.
    Prah P, Petersen I, Nazareth I, Walters K, Osborn D. National changes in oral antipsychotic treatment for people with schizophrenia in primary care between 1998 and 2007 in the United Kingdom. Pharmacoepidemiol Drug Saf. 2012;21:161–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Bernardo M, Coma A, Ibáñez C, Zara C, Bari JM, Serrano-Blanco A. Antipsychotic polypharmacy in a regional health service: a population-based study. BMC Psychiatry. 2012;12:42.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Jaracz J, Tetera-Rudnicka E, Kujath D, Raczyńska A, Stoszek S, Czernaś W, et al. The prevalence of antipsychotic polypharmacy in schizophrenic patients discharged from psychiatric units in Poland. Pharmacol Rep. 2014;66:613–7.CrossRefPubMedGoogle Scholar
  8. 8.
    Verdoux H, Pambrun E, Tournier M, Bezin J, Pariente A. Antipsychotic long-acting injections: a community-based study from 2007 to 2014 of prescribing trends and characteristics associated with initiation. Schizophr Res. 2016;178:58–63.CrossRefPubMedGoogle Scholar
  9. 9.
    Bak M, Fransen A, Janssen J, van Os J, Drukker M. Almost all antipsychotics result in weight gain: a meta-analysis. PLoS ONE. 2014;9:e94112.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Burghardt KJ, Seyoum B, Mallisho A, Burghardt PR, Kowluru RA, Yi Z. Atypical antipsychotics, insulin resistance and weight; a meta-analysis of healthy volunteer studies. Prog Neuropsychopharmacol Biol Psychiatry. 2018;83:55–63.CrossRefPubMedGoogle Scholar
  11. 11.
    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;302:1765–73.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Almandil NB, Liu Y, Murray ML, Besag FMC, Aitchison KJ, Wong ICK. Weight gain and other metabolic adverse effects associated with atypical antipsychotic treatment of children and adolescents: a systematic review and meta-analysis. Paediatr Drugs. 2013;15:139–50.CrossRefPubMedGoogle Scholar
  13. 13.
    Tirosh A, Shai I, Afek A, Dubnov-Raz G, Ayalon N, Gordon B, et al. Adolescent BMI trajectory and risk of diabetes versus coronary disease. N Engl J Med. 2011;364:1315–25.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Sabin MA, Ford AL, Holly JMP, Hunt LP, Crowne EC, Shield JPH. Characterisation of morbidity in a UK, hospital based, obesity clinic. Arch Dis Child. 2006;91:126–30.CrossRefPubMedGoogle Scholar
  15. 15.
    Juonala M, Magnussen CG, Berenson GS, Venn A, Burns TL, Sabin MA, et al. Childhood adiposity, adult adiposity, and cardiovascular risk factors. N Engl J Med. 2011;365:1876–85.CrossRefPubMedGoogle Scholar
  16. 16.
    Morrison JA, Friedman LA, Gray-McGuire C. Metabolic syndrome in childhood predicts adult cardiovascular disease 25 years later: the Princeton Lipid Research Clinics Follow-up Study. Pediatrics. 2007;120:340–5.CrossRefPubMedGoogle Scholar
  17. 17.
    US Preventive Services Task Force, Grossman DC, Bibbins-Domingo K, Curry SJ, Barry MJ, Davidson KW, et al. Screening for Obesity in Children and Adolescents: US Preventive Services Task Force Recommendation Statement. JAMA. 2017;317:2417–26Google Scholar
  18. 18.
    Curtis J, Newall HD, Samaras K. The heart of the matter: cardiometabolic care in youth with psychosis. Early Interv Psychiatry. 2012;6:347–53.CrossRefPubMedGoogle Scholar
  19. 19.
    Nolt VD, Kibler AV, Wilkening GL, Fabian TJ. Second-Generation antipsychotic utilization and metabolic parameter monitoring in an inpatient pediatric population: a retrospective analysis. Pediatr Drugs. 2017;19:139–46.CrossRefGoogle Scholar
  20. 20.
    O’Connor EA, Evans CV, Burda BU, Walsh ES, Eder M, Lozano P. Screening for obesity and intervention for weight management in children and adolescents: evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2017;317:2427–44.CrossRefPubMedGoogle Scholar
  21. 21.
    Baptista T. Body weight gain induced by antipsychotic drugs: mechanisms and management. Acta Psychiatr Scand. 1999;100:3–16.CrossRefPubMedGoogle Scholar
  22. 22.
    TODAY Study Group, Zeitler P, Hirst K, Pyle L, Linder B, Copeland K, et al. A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med. 2012;366:2247–56Google Scholar
  23. 23.
    European Medicines Agency. -Human medicines—EMEA-002249-PIP01-17. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/pips/EMEA-002249-PIP01-17/pip_001818.jsp&mid=WC0b01ac058001d129. Accessed 29 July 2018.
  24. 24.
    Diabetes Prevention Program Research Group. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 2009;374:1677–86.CrossRefPubMedCentralGoogle Scholar
  25. 25.
    Baur LA, Hazelton B, Shrewsbury VA. Assessment and management of obesity in childhood and adolescence. Nat Rev Gastroenterol Hepatol. 2011;8:635–45.CrossRefPubMedGoogle Scholar
  26. 26.
    McDonagh MS, Selph S, Ozpinar A, Foley C. Systematic review of the benefits and risks of metformin in treating obesity in children aged 18 years and younger. JAMA Pediatr. 2014;168:178–84.CrossRefPubMedGoogle Scholar
  27. 27.
    Mead E, Atkinson G, Richter B, Metzendorf M-I, Baur L, Finer N, et al. Drug interventions for the treatment of obesity in children and adolescents. Cochrane Database Syst Rev. 2016;(11):CD012436.Google Scholar
  28. 28.
    de Silva VA, Suraweera C, Ratnatunga SS, Dayabandara M, Wanniarachchi N, Hanwella R. Metformin in prevention and treatment of antipsychotic induced weight gain: a systematic review and meta-analysis. BMC Psychiatry. 2016;16:341.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Wu R-R, Zhang F-Y, Gao K-M, Ou J-J, Shao P, Jin H, et al. Metformin treatment of antipsychotic-induced dyslipidemia: an analysis of two randomized, placebo-controlled trials. Mol Psychiatry. 2016;21:1537–44.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Taylor J, Stubbs B, Hewitt C, Ajjan RA, Alderson SL, Gilbody S, et al. The Effectiveness of Pharmacological and Non-Pharmacological Interventions for Improving Glycaemic Control in Adults with Severe Mental Illness: a Systematic Review and Meta-Analysis. PLoS One. 2017;12:e0168549.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    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;35:1520–30.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Andrade C. Metformin as a possible intervention for cardiometabolic risks in pediatric subjects exposed to antipsychotic drugs. J Clin Psychiatry. 2016;77:1362–4.CrossRefPubMedGoogle Scholar
  33. 33.
    Walkup JT, Cottingham E. Antipsychotic-Induced Weight Gain and Metformin. J Am Acad Child Adolesc Psychiatry. 2017;56:808–10.CrossRefPubMedGoogle Scholar
  34. 34.
    Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Cochrane Handbook for Systematic Reviews of Interventions. http://handbook-5-1.cochrane.org/. Accessed 18 May 2018.
  36. 36.
    Cortese S. Meta-analyses in child and adolescent psychiatry: getting closer to clinical practice. J Am Acad Child Adolesc Psychiatry. 2018;57:229–30.CrossRefPubMedGoogle Scholar
  37. 37.
    Sonuga-Barke EJS, Brandeis D, Cortese S, Daley D, Ferrin M, Holtmann M, et al. Nonpharmacological interventions for ADHD: systematic review and meta-analyses of randomized controlled trials of dietary and psychological treatments. Am J Psychiatry. 2013;170:275–89.CrossRefPubMedGoogle Scholar
  38. 38.
    Anagnostou E, Aman MG, Handen BL, Sanders KB, Shui A, Hollway JA, et al. Metformin for treatment of overweight induced by atypical antipsychotic medication in young people with autism spectrum disorder: a randomized clinical trial. JAMA Psychiatry. 2016;73:928–37.CrossRefPubMedGoogle Scholar
  39. 39.
    Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–60.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    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;163:2072–9.CrossRefPubMedGoogle Scholar
  41. 41.
    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;29:1130–4.PubMedGoogle Scholar
  42. 42.
    Strategies to reduce antipsychotic-associated weight gain in youth (PREVENT). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT00617240. Accessed 7 May 2018.
  43. 43.
    Reducing weight gain and improving metabolic function in children being treated with antipsychotics (IMPACT). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT00806234. Accessed 7 May 2018.
  44. 44.
    Siskind DJ, Leung J, Russell AW, Wysoczanski D, Kisely S. Metformin for clozapine associated obesity: a systematic review and meta-analysis. PLoS One. 2016;11:e0156208.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Zheng W, Li X-B, Tang Y-L, Xiang Y-Q, Wang C-Y, de Leon J. Metformin for weight gain and metabolic abnormalities associated with antipsychotic treatment: meta-analysis of randomized placebo-controlled trials. J Clin Psychopharmacol. 2015;35:499–509.CrossRefPubMedGoogle Scholar
  46. 46.
    Zheng W, Zhang Q-E, Cai D-B, Yang X-H, Ungvari GS, Ng CH, et al. Combination of metformin and lifestyle intervention for antipsychotic-related weight gain: a meta-analysis of randomized controlled trials. Pharmacopsychiatry. Epub 27 Feb 2018.  https://doi.org/10.1055/s-0044-101466.
  47. 47.
    Handen BL, Anagnostou E, Aman MG, Sanders KB, Chan J, Hollway JA, et al. A randomized, placebo-controlled trial of metformin for the treatment of overweight induced by antipsychotic medication in young people with autism spectrum disorder: open-label extension. J Am Acad Child Adolesc Psychiatry. 2017;56(849–856):e6.Google Scholar
  48. 48.
    Hasnain M, Vieweg WVR, Fredrickson SK. Metformin for atypical antipsychotic-induced weight gain and glucose metabolism dysregulation: review of the literature and clinical suggestions. CNS Drugs. 2010;24:193–206.CrossRefPubMedGoogle Scholar
  49. 49.
    Hasnain M, Fredrickson SK, Vieweg WVR. Metformin for obesity and glucose dysregulation in patients with schizophrenia receiving antipsychotic drugs. J Psychopharmacol. 2011;25:715–21.CrossRefPubMedGoogle Scholar
  50. 50.
    Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334:574–9.CrossRefPubMedGoogle Scholar
  51. 51.
    Minamii T, Nogami M, Ogawa W. Mechanisms of metformin action: in and out of the gut. J Diabetes Investig. 2018;9(4):701–3.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Lee A, Morley JE. Metformin decreases food consumption and induces weight loss in subjects with obesity with type II non-insulin-dependent diabetes. Obes Res. 1998;6:47–53.CrossRefPubMedGoogle Scholar
  53. 53.
    Dayabandara M, Hanwella R, Ratnatunga S, Seneviratne S, Suraweera C, de Silva VA. Antipsychotic-associated weight gain: management strategies and impact on treatment adherence. Neuropsychiatr Dis Treat. 2017;13:2231–41.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Borenstein M, Hedges LV, Higgins JPT, Rothstein HR. Introduction to meta-analysis. Chichester: Wiley; 2009 [cited 5 Sep 2016].  https://doi.org/10.1002/9780470743386.
  55. 55.
    Solmi M, Murru A, Pacchiarotti I, Undurraga J, Veronese N, Fornaro M, et al. Safety, tolerability, and risks associated with first- and second-generation antipsychotics: a state-of-the-art clinical review. Ther Clin Risk Manag. 2017;13:757–77.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    TODAY Study Group. Safety and tolerability of the treatment of youth-onset type 2 diabetes: the TODAY experience. Diabetes Care. 2013;36:1765–71.CrossRefPubMedCentralGoogle Scholar
  57. 57.
    Chang Y-T, Tsai H-L, Kung Y-T, Yeh Y-S, Huang C-W, Ma C-J, et al. Dose-Dependent relationship between metformin and colorectal cancer occurrence among patients with type 2 diabetes: a nationwide cohort study. Transl Oncol. 2018;11:535–41.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Bradley MC, Ferrara A, Achacoso N, Ehrlich SF, Quesenberry CP, Habel LA. A cohort study of metformin and colorectal cancer risk among patients with diabetes mellitus. Cancer Epidemiol Biomark Prev. 2018;27:525–30.CrossRefGoogle Scholar
  59. 59.
    Simard P, Presse N, Roy L, Dorais M, White-Guay B, Räkel A, et al. Association between metformin adherence and all-cause mortality among new users of metformin: a nested case-control study. Ann Pharmacother. 2018;52:305–13.CrossRefPubMedGoogle Scholar
  60. 60.
    Morrison JA, Cottingham EM, Barton BA. Metformin for weight loss in pediatric patients taking psychotropic drugs. Am J Psychiatry. 2002;159:655–7.CrossRefPubMedGoogle Scholar
  61. 61.
    Shin L, Bregman H, Breeze JL, Noyes N, Frazier JA. Metformin for weight control in pediatric patients on atypical antipsychotic medication. J Child Adolesc Psychopharmacol. 2009;19:275–9.CrossRefPubMedGoogle Scholar
  62. 62.
    Wink LK, Adams R, Pedapati EV, Dominick KC, Fox E, Buck C, et al. Brief report: metformin for antipsychotic-induced weight gain in youth with autism spectrum disorder. J Autism Dev Disord. 2017;47:2290–4.CrossRefPubMedGoogle Scholar
  63. 63.
    Metformin for weight control in adolescents taking atypical antipsychotics. ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT00845936. Accessed 30 July 2018.
  64. 64.
    Metformin for Overweight & OBese ChILdren and Adolescents With BDS Treated With SGAs (MOBILITY). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT02515773. Accessed 30 July 2018.
  65. 65.
    Improving metabolic parameters of antipsychotic child treatment with ziprasidone, aripiprazole, and clozapine (ZAC). ClinicalTrials.gov. https://clinicaltrials.gov/ct2/show/NCT00617058. Accessed 30 July 2018.
  66. 66.
    Hendrick V, Dasher R, Gitlin M, Parsi M. Minimizing weight gain for patients taking antipsychotic medications: the potential role for early use of metformin. Ann Clin Psychiatry. 2017;29:120–4.PubMedGoogle Scholar
  67. 67.
    American Psychiatric Association. Choosing Wisely. https://www.psychiatry.org/psychiatrists/practice/quality-improvement/choosing-wisely. Accessed 29 July 2018.

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Pierre Ellul
    • 1
  • 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

Personalised recommendations