Efficacy of metformin for treatment and prevention of antipsychotic-induced overweight and obesity in women: an open-label, randomized, prospective placebo-controlled study

Background: The prevalence of obesity and metabolic abnormalities is increased patients with mental disorders receiving psychopharmacotherapy, which significantly impairs their treatment adherence.

Aims: To evaluate the efficacy and safety of metformin in prevention and treatment obesity and overweight in patients with mental disorders receiving antipsychotics.

Materials and methods: This was an open-label, prospective, randomized, placebo-controlled study of female patients with mental disorders (age, 18 to 50). The patients were randomized into two groups in a 2:1 ratio: the treatment group received metformin and the control group received placebo. Metformin was administered at a starting dose of 500 mg daily, with subsequent up-titration every 2 weeks when necessary, up to 2000 mg daily. The treatment duration was 6 months.

Results: Baseline BMI in the treatment group (N=62) was 27,3 [24,0; 30,4] kg/m²; it decreased to 26,0 [22,5; 30,5] kg/m², p < 0.0001, Wilсoxon test) after 6 months of treatment. The patients receiving metformin decreased their body weight by 3 [-6; 0] kg, or  -4,0 [-8; 0] %. In the placebo group (N=30), the baseline BMI was 27,5 [24,0; 32,0] kg/m² and increased to 28,2 [25,8; 34,0] kg/m² at 6 month (p=0.001, Wilсoxon test), or 3 [1; 6] kg. After 6 months of treatment, the difference in BMI between the metformin and placebo groups was significant (26,0 и 28,2 kg/m², respectively, р=0,027, Mann-Withney test). Six (6) of 62 patients treated with metformin had side effects and were switched to an equivalent dose of prolonged release metformin, with reduction of side effects in 5 of them.

Conclusions: The use of metformin in patients with mental disorders receiving antipsychotics allows for reduction or stabilization of body weight in 80% of cases, with ≥5% decrease of body weight in 44% of patients. It is recommended to start metformin at a dose of 500 mg daily with subsequent up-titration of up to 2000 mg if necessary.

1. Shatsberg AF, Koul DO, DeBattista Ch. Rukovodstvo po klinicheskoi psikhofarmakologii. Moscow: Medpress-inform; 2019. P. 175-180. (In Russ.).

2. Holt RI, Peveler RC. Obesity, serious mental illness and antipsychotic drugs. Diabetes ObesMetab. 2009;11(7):665-679. doi: https://doi.org/10.1111/j.1463-1326.2009.01038.x

3. Allison DB, Mentore JL, Heo M, et al. Antipsychotic-induced weight gain: comprehensive research synthesis. Am J Psychiatry. 1999;156(11):1686-1696. doi: https://doi.org/10.1176/ajp.156.11.1686

4. Gor’kov VA, Oleichik IV, Rayushkin VA, Churilov YuYu. Atipichnye neiroleptiki gruppy benzamidov. Farmateka. 2000;2:15-19. (In Russ.).

5. Oleichik IV, Baranov PA. Sovremennye podkhody k lecheniyu shizofrenii i rasstroistv shizofrenicheskogo spectra. Klinicheskaya farmakologiya i terapiya. 2012;21(4):52-58. (In Russ.).

6. Fiedorowicz J, Miller D, Jeffrey R, et al. Systematic Review and Meta-analysis of Pharmacological Interventions for Weight Gain from Antipsychotics and Mood Stabilizers. Curr Psychiatry Rev. 2012;8(1):25-36. doi: https://doi.org/10.2174/157340012798994867

7. Spelman LM, Walsh PI, Sharifi N, et al. Impaired glucose tolerance in first-episode drug-naive patients with schizophrenia. Diabet Med. 2007;24:481-485. doi: https://doi.org/10.1111/j.1464-5491.2007.02092

8. Prasenjit R, Khess C. Level of Insulin Resistance in Schizophrenia Patients and Its Association with Treatment with Antipsychotics. J Neuropsychopharmacol Mental Health. 2016;1(1):125-128.

9. Koro CE, Fedder DO, L’Italien GJ, et al. Assessment of independent effect of olanzapine and risperidone on risk of diabetes among patients with schizophrenia: population based nested case-control study. BMJ. 2002;325(7358):243. doi: https://doi.org/10.1136/bmj.325.7358.243

10. Ostroumova OD, Akimovа ES, Kochetkov AI. Drug-induced hyperglycemia. Clin Pharmacol Ther. 2019;28(2):61-69. (In Russ.). doi: https://doi.org/10.32756/0869-5490-2019-2-61-69

11. Weiden P, Mackell J, McDonnell D. Obesity as a risk factor for antipsychotic noncompliance. Schizophrenia Res. 2004;66:51-57. doi: https://doi.org/10.1016/S0920-9964(02)00498-X

12. bid obesity treatment in adults. 3rd revision (Morbid obesity treatment in adults). Obesity ahd Metabolism. 2018;15(1):53-70. (In Russ.). doi: https://doi.org/10.14341/omet2018153-70doi: 10.14341/OMET2018153-70

13. Pasquali R, Casanueva F, Haluzik M, et al. European Society of Endocrinology Clinical Practice Guideline: Endocrine work-up in obesity. European Journal of Endocrinology. 2020;182(1):G1-G32. doi: https://doi.org/10.1530/EJE-19-0893

14. Cooper SJ, Reynolds GP, Barnes T, et al. BAP guidelines on the management of weight gain, metabolic disturbances and cardiovascular risk associated with psychosis and antipsychotic drug treatment. J Psychopharmacol. 2016;30(8):717-748. doi: https://doi.org/10.1177/0269881116645254

15. De Hert M, Eramo A, Landsberg W, et al. Efficacy and safety of aripiprazole once-monthly in obese and nonobese patients with schizophrenia: a post hoc analysis. Neuropsychiatr Dis Treat. 2015 May 27;11:1299-306. doi: 10.2147/NDT.S80479.

16. Desilets AR, Dhakal-Karki S, Dunican KC. Role of Metformin for Weight Management in Patients Without Type 2 Diabetes. The Annals of Pharmacotherapy. 2008 June;(42): 817-826 doi: 10.1345/aph.1K656.

17. Levri KM, Slaymaker E, Last A, et al. Metformin as Treatment for Overweight and Obese Adults: A Systematic Review. Ann Fam Med. 2005;3(5):457-461. doi: https://doi.org/10.1370/afm.343

18. Domecq JP, Prutsky G, Leppin A, et al. Drugs Commonly Associated With Weight Change: A Systematic Review and Meta-analysis. J Clin Endocrinol Metab. 2015 Feb; 100(2): 363-370. doi: 10.1210/jc.2014-3421.

19. Saenz A, et al. Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2005;(3):CD002966. doi: https://doi.org/10.1002/14651858.CD002966.pub3

20. Giugliano D, Quatraro A, Consoli G, et al. Metformin for obese, insulin-treated diabetic patients: improvement in glycaemic control and reduction of metabolic risk factors. Eur J Clin Pharmacol. 1993;44:107-112. doi: https://doi.org/10.1007/BF00315466

21. Venditti EM, Edelstein SL, et al. Long-Term Weight Loss With Metformin or Lifestyle Intervention in the Diabetes Prevention Program Outcomes Study. Ann Intern Med. 2019;170(10):682-690. doi: https://doi.org/10.7326/M18-1605

22. Terada T, Boulé NG. Does metformin therapy influence the effects of intensive lifestyle intervention? Exploring the interaction between first line therapies in the Look AHEAD trial. Metabolism Clinical and Experimental. 2019;94:39-46. doi: https://doi.org/10.1016/j.metabol.2019.01.004

23. Vatopoulou A, Tziomalos K. Management of obesity in adolescents with polycystic ovary syndrome. Expert Opin Pharmacother. 2020;21(2):207-211. doi: https://doi.org/10.1080/14656566.2019.1701655

24. Teede H, Tassone EC, Piltonen T, et al. Effect of the combined oral contraceptive pill and/or metformin in the management of polycystic ovary syndrome: A systematic review with meta‐analyses. Clinical Endocrinology. 2019;91:479-489. doi: https://doi.org/10.1111/cen.14013

25. Asanka de Silva V, Suraweera C, Ratnatunga S, et al. Metformin in prevention and treatment of antipsychotic induced weight gain: a systematic review and meta-analysis. BMC Psychiatry. 2016;(16):341. doi: https://doi.org/10.1186/s12888-016-1049-5.

26. Mizuno Y, Suzuki T, Nakagawa A, et al. Pharmacological Strategies to Counteract Antipsychotic-Induced Weight Gain and Metabolic Adverse Effects in Schizophrenia: A Systematic Review and Meta-analysis. Schizophr Bull. 2014;40(6):1385-1403. doi: https://doi.org/10.1093/schbul/sbu030

27. Zhuo C, Xu Y, Liu S, et al. Topiramate and Metformin Are Effective Add-On Treatments in Controlling Antipsychotic-Induced Weight Gain: A Systematic Review and Network Meta-Analysis. Front Pharmacol. 2018;9(2):207-211. doi: https://doi.org/10.3389/fphar.2018.01393

28. Baptista T, Martínez J. Metformin for Prevention of Weight Gain and Insulin Resistance With Olanzapine: A Double-Blind Placebo-Controlled Trial. Can J Psychiatry. 2006;51(3):192-196. doi: https://doi.org/10.1177/070674370605100310

29. Kraal AZ, Ward KM, Ellingrod VL. Sex Differences in Antipsychotic Related Metabolic Functioning in Schizophrenia Spectrum Disorders. Psychopharmacol Bull. 2017;47(2):8-21.

30. Aichhorn W, Gasser M, Weiss E, et al. Gender Differences in Pharmacokinetics and Side Effects of Second Generation Antipsychotic Drugs. Curr Neuropharmacol. 2005;3(1):73-85. doi: https://doi.org/10.2174/1570159052773440

31. Dedov II, Shestakova MV, et al. Sakharnyi diabet: diagnostika, lechenie, profilaktika. Moscow: Meditsinskoe informatsionnoe agentstvo; 2011. (In Russ.).

32. Fleishhacker WW, Siu CO, Boden R, et al. Metabolic risk factors in first-episode schizophrenia: baseline prevalence and course analysed from the European First-Episode Schizophrenia Trial. International Journal of Neuropsychopharmacology, 2013;16(5):987-995. doi: https://doi.org/10.1017/S1461145712001241

33. Korneeva MN, Poddubskaya EA, Mardanov BU, Dudinskaya EN. Rannie narusheniya uglevodnogo obmena v kardiologicheskoi praktike: posobie. Moscow: FGBU Gosudarstvennyi nauchno-issledovatel’skii tsentr profilakticheskoi meditsiny; 2017. 29 p. (In Russ.).

34. The DECODE Study Group. Age- and Sex-Specific Prevalences of Diabetes and Impaired Glucose Regulation in 13 European Cohorts. Diabetes Care. 2003;26(1):61-69. doi: https://doi.org/10.2337/diacare.26.1.61

35. Anagnostou E, Aman MG, Handen BL, 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(9):928-937. doi: https://doi.org/10.1001/jamapsychiatry.2016.1232