Cardiovascular Health in Severe Mental Illness: Potential Role for Metformin

Sri Mahavir Agarwal, MBBS, MD, PhD; Nicolette Stogios, HBSc

J Clin Psychiatry 2022;83(2):22ac14419

To cite: Agarwal SM, Stogios N. Cardiovascular health in severe mental illness: potential role for metformin. J Clin Psychiatry. 2022;83(2):22ac14419.
To share: https://doi.org/10.4088/JCP.22ac14419

^aSchizophrenia Division, Centre for Addiction and Mental Health (CAMH), Toronto, Canada
^bInstitute of Medical Science, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada
^cDepartment of Psychiatry, University of Toronto, Toronto, Canada
*Corresponding author: Sri Mahavir Agarwal, MBBS, MD, PhD, Centre for Addiction and Mental Health, 1051 Queen St W, Toronto, ON, M6J 1H3 ([email protected]).

Severe mental illnesses (SMI) such as schizophrenia and bipolar disorder are associated with very high rates of metabolic disorders, including obesity, diabetes, and metabolic syndrome.^1–3 The etiology of this comorbidity is multifactorial, encompassing genetic predisposition, environmental factors such as poor nutrition and sedentary lifestyles, and medication side effects. Antipsychotic drugs, used routinely in the treatment of SMI, contribute significantly to this risk.^4,5 Indeed, a recent large Danish cohort study found that patients with schizophrenia are inherently 3 times more likely to have type 2 diabetes than the general population, and this risk was exacerbated by antipsychotics, both first and second generation, by a further 3 times.⁶ Much of this risk is accrued early, with rates of obesity approaching 50% and prediabetes in excess of 15% within less than 6 months of starting treatment.⁷

Patients with schizophrenia spectrum disorders have a 20% lower life expectancy and die 15–20 years earlier than the general population, largely due to the several-fold increased risk of cardiovascular disease and type 2 diabetes.^8–10 As such, schizophrenia is associated with more disability than cancer and many other physical illnesses.^11,12

Beyond increased cardiovascular mortality, weight gain negatively impacts self-esteem and quality of life^13–15 and is the most distressing side effect reported by callers to mental health helplines.¹⁶ Furthermore, antipsychotic-induced metabolic effects contribute to medication noncompliance¹⁶ and have also been correlated with worse cognition,^17,18 a core symptom domain that has yet to be effectively addressed by treatment.

In 2004, the American Diabetes Association/American Psychiatric Association consensus document was published, which detailed, for the first time, metabolic monitoring guidelines for antipsychotic use.¹⁹ Other guidelines have since been published; however, modifications have been limited in most of them, with monitoring and lifestyle changes remaining the methods of choice for addressing metabolic risk.¹⁶ While lifestyle interventions such as diet and exercise or other methods like cognitive behavioral therapy may show some efficacy,^20,21 more recent large-scale studies have raised questions about the clinical and cost-effectiveness of this approach.^22,23 These factors have perhaps contributed to the low rates of treatment for metabolic comorbidities in SMI.^7,24–27

It is generally accepted that achieving clinically meaningful weight loss (ie, 5% of body weight) carries many benefits, including reduced rates of cardiovascular disease²⁸ and type 2 diabetes,^29,30 and improved quality of life.³¹ Therefore, an early adoption of adjunctive pharmacologic interventions is warranted to address this concerning problem. Intervening earlier may also produce more favorable results, as it is easier to prevent weight gain than to precipitate weight loss and associated metabolic perturbations.³²

Metformin, a biguanide antihyperglycemic and first-line pharmacologic treatment for type 2 diabetes, is now recommended in the Mental Health section of the Canadian Obesity Guidelines,³³ as well as guidelines from the World Health Organization³⁴ and UK,¹⁶ for the treatment of antipsychotic-induced weight gain in conjunction with lifestyle modification. The major mechanism of action involves suppression of hepatic glucose production (via adenosine monophosphate–activated protein kinase [AMPK] activation), in addition to increased glucose utilization in the gut.³⁵ Sixty years of clinical experience and trial data have yielded almost no serious safety concerns, except for the very rare occurrence of lactic acidosis in the context of severe liver, heart, or kidney dysfunction, and/or extreme overdose.³⁵

Metformin should be started with 500 mg twice a day or 850 mg once a day, with meals; dosage should be increased in increments of 500 mg weekly or 850 mg every 2 weeks, up to 2,000 mg/d, given in divided doses.³⁶ Higher doses may be used if tolerated/required; clinical trials have examined doses as high as 2,550 mg/d.^35,37 Gastrointestinal adverse effects are common with metformin and include nausea, vomiting, abdominal discomfort, flatulence, and diarrhea. These can be minimized by using gradual dose up-titration, administration of the drug with meals, and use of a time-release/extended-release formulation. Adverse effects are often temporary, and prescribers should work with patients to find an optimum dose. Annual monitoring of creatinine and serum B₁₂ levels (metformin can impair vitamin B₁₂ absorption) is recommended.³⁸

Metformin has been studied extensively for treating antipsychotic-related weight gain and has the most evidence supporting efficacy and safety in this role.^39,40 Efficacy may be higher earlier in the course of illness (average weight loss: 5.18 kg) as compared to patients with more long-standing illness (average weight loss: 2.22 kg). Furthermore, in line with its use as a first-line antidiabetic agent, metformin in patients with schizophrenia has been associated with adaptive changes in fasting insulin levels and insulin resistance in normoglycemic individuals.³⁹ It has also been shown to improve dysglycemia and insulin sensitivity in patients with comorbid diabetes or prediabetes.⁴¹ Improvements have been found in other metabolic parameters as well, including triglycerides (mean change: −21.01 mg/dL) and total cholesterol levels (mean change: −14.40 mg/dL).⁴² These effects would have significant implications in improving the overall cardiometabolic profile of patients. Notably, no significant differences in side effects or dropout frequency in comparison to placebo have been reported.^40,42

In a recent Cochrane meta-analysis (Agarwal et al, under review; see protocol⁴³), metformin was found to be effective in preventing weight gain as well (average weight difference: 4.03 kg), especially in combination with agents with a high metabolic liability, such as olanzapine. Again, no significant difference in side effects or dropout frequency in the metformin arm versus placebo was noted. More recent work supports metformin’s efficacy in preventing weight gain when started together with clozapine.^44,45 Metformin also reduces the risk of developing diabetes and is associated with modest weight loss among high-risk patients with prediabetes.^35,46

Alternative pharmacologic agents have also been investigated to ameliorate antipsychotic-induced weight gain. A combination of olanzapine and samidorphan (OLZ/SAM) is now available in the United States for the treatment of schizophrenia or bipolar disorder in adults.⁴⁷ This agent offers the therapeutic efficacy of olanzapine while also mitigating olanzapine-induced weight gain through opioid receptor antagonism; it is presently the only FDA-approved drug for this specific indication. A recent evidence-based review of the pharmacokinetics, safety, and efficacy of OLZ/SAM indicates that the effectiveness of the agent is equivalent to that of olanzapine, along with the advantage of lesser weight gain.⁴⁷ This single-tablet combination also has the added benefit of reducing pill burden. However, although OLZ/SAM has been demonstrated to mitigate some of the increase in waist circumference generally observed with olanzapine alone, thus denoting less of an increase in the mass of “metabolically active” fat tissue, it has not been found to improve any laboratory parameters. Other compounds that have demonstrated promising preliminary findings for treatment of antipsychotic-induced weight gain include bupropion⁴⁸; miricorilant, which is a novel selective glucocorticoid modulator⁴⁹; topiramate⁵⁰; and glucagon-like peptide-1 receptor agonists.⁵¹ The evidence for these agents is still quite limited, and their role in prevention of antipsychotic-induced weight gain has not been comprehensively studied.

To summarize, monitoring alone is clearly not enough, and the field must move to actively mitigate the onset and progression of metabolic abnormalities. Relatively inexpensive options such as adjunctive metformin are a good start. It is time we get to it.

Published online: March 9, 2022.
Potential conflicts of interest: None.
Funding/support: Dr Agarwal is supported in part by an Academic Scholars Award from the Department of Psychiatry, University of Toronto, and the Centre for Addiction and Mental Health (CAMH) Discovery Fund.

The ASCP Corner, edited by Leslie L. Citrome, MD, MPH, is a collection of brief peer-reviewed, evidence-based articles, authored by American Society of Clinical Psychopharmacology members, that examine the practice of psychopharmacology through the lens of clinical experience. The information contained herein only represents the opinion of the author(s).

References (51)

De Hert M, van Winkel R, Van Eyck D, et al. Prevalence of diabetes, metabolic syndrome and metabolic abnormalities in schizophrenia over the course of the illness: a cross-sectional study. Clin Pract Epidemiol Ment Health. 2006;2(1):14. PubMed CrossRef
Mukherjee S, Decina P, Bocola V, et al. Diabetes mellitus in schizophrenic patients. Compr Psychiatry. 1996;37(1):68–73. PubMed CrossRef
Dixon L, Weiden P, Delahanty J, et al. Prevalence and correlates of diabetes in national schizophrenia samples. Schizophr Bull. 2000;26(4):903–912. PubMed CrossRef
De Hert M, Detraux J, van Winkel R, et al. Metabolic and cardiovascular adverse effects associated with antipsychotic drugs. Nat Rev Endocrinol. 2011;8(2):114–126. PubMed CrossRef
Ballon JS, Pajvani U, Freyberg Z, et al. Molecular pathophysiology of metabolic effects of antipsychotic medications. Trends Endocrinol Metab. 2014;25(11):593–600. PubMed CrossRef
Rajkumar AP, Horsdal HT, Wimberley T, et al. Endogenous and antipsychotic-related risks for diabetes mellitus in young people with schizophrenia: a Danish population-based cohort study. Am J Psychiatry. 2017;174(7):686–694. PubMed CrossRef
Correll CU, Robinson DG, Schooler NR, et al. Cardiometabolic risk in patients with first-episode schizophrenia spectrum disorders: baseline results from the RAISE-ETP study. JAMA Psychiatry. 2014;71(12):1350–1363. PubMed CrossRef
Hennekens CH, Hennekens AR, Hollar D, et al. Schizophrenia and increased risks of cardiovascular disease. Am Heart J. 2005;150(6):1115–1121. PubMed CrossRef
Colton CW, Manderscheid RW. Congruencies in increased mortality rates, years of potential life lost, and causes of death among public mental health clients in eight states. Prev Chronic Dis. 2006;3(2):A42. PubMed
Rahman T, Lauriello J. Schizophrenia: an overview. Focus Am Psychiatr Publ. 2016;14(3):300–307. PubMed CrossRef
Saha S, Chant D, McGrath J. A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch Gen Psychiatry. 2007;64(10):1123–1131. PubMed CrossRef
Global Burden of Disease Study 2013 Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;386(9995):743–800. PubMed CrossRef
Werner FM, Coveñas R. Safety of antipsychotic drugs: focus on therapeutic and adverse effects. Expert Opin Drug Saf. 2014;13(8):1031–1042. PubMed CrossRef
Vrbová K, Kamarádová D, Látalová K, et al. Self-stigma and adherence to medication in patients with psychotic disorders–cross-sectional study. Neuroendocrinol Lett. 2014;35(7):645–652. PubMed
Faulkner G, Cohn T, Remington G, et al. Body mass index, waist circumference and quality of life in individuals with schizophrenia. Schizophr Res. 2007;90(1–3):174–178. PubMed CrossRef
Cooper SJ, Reynolds GP, Barnes T, et al; With expert co-authors (in alphabetical order). 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. PubMed CrossRef
Bora E, Akdede BB, Alptekin K. The relationship between cognitive impairment in schizophrenia and metabolic syndrome: a systematic review and meta-analysis. Psychol Med. 2017;47(6):1030–1040. PubMed CrossRef
Li C, Zhan G, Rao S, et al. Metabolic syndrome and its factors affect cognitive function in chronic schizophrenia complicated by metabolic syndrome. J Nerv Ment Dis. 2014;202(4):313–318. PubMed CrossRef
American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004;27(2):596–601. PubMed CrossRef
Álvarez-Jiménez M, Hetrick SE, González-Blanch C, et al. Non-pharmacological management of antipsychotic-induced weight gain: systematic review and meta-analysis of randomised controlled trials. Br J Psychiatry. 2008;193(2):101–107. PubMed CrossRef
Bruins J, Jörg F, Bruggeman R, et al. The effects of lifestyle interventions on (long-term) weight management, cardiometabolic risk and depressive symptoms in people with psychotic disorders: a meta-analysis. PLoS One. 2014;9(12):e112276. PubMed CrossRef
Holt RI, Hind D, Gossage-Worrall R, et al. Structured lifestyle education to support weight loss for people with schizophrenia, schizoaffective disorder and first episode psychosis: the STEPWISE RCT. Health Technol Assess. 2018;22(65):1–160. PubMed CrossRef
Speyer H, Christian Brix Nørgaard H, Birk M, et al. The CHANGE trial: no superiority of lifestyle coaching plus care coordination plus treatment as usual compared to treatment as usual alone in reducing risk of cardiovascular disease in adults with schizophrenia spectrum disorders and abdominal obesity. World Psychiatry. 2016;15(2):155–165. PubMed CrossRef
Nasrallah HA, Meyer JM, Goff DC, et al. Low rates of treatment for hypertension, dyslipidemia and diabetes in schizophrenia: data from the CATIE schizophrenia trial sample at baseline. Schizophr Res. 2006;86(1-3):15–22. PubMed CrossRef
Goldberg RW, Kreyenbuhl JA, Medoff DR, et al. Quality of diabetes care among adults with serious mental illness. Psychiatr Serv. 2007;58(4):536–543. PubMed CrossRef
Kreyenbuhl J, Dickerson FB, Medoff DR, et al. Extent and management of cardiovascular risk factors in patients with type 2 diabetes and serious mental illness. J Nerv Ment Dis. 2006;194(6):404–410. PubMed CrossRef
Frayne SM, Halanych JH, Miller DR, et al. Disparities in diabetes care: impact of mental illness. Arch Intern Med. 2005;165(22):2631–2638. PubMed CrossRef
Avenell A, Broom J, Brown TJ, et al. Systematic review of the long-term effects and economic consequences of treatments for obesity and implications for health improvement. Health Technol Assess. 2004;8(21):iii–iv, 1–182. PubMed CrossRef
Knowler WC, Fowler SE, Hamman RF, et al; 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(9702):1677–1686. PubMed CrossRef
Tuomilehto J, Lindström J, Eriksson JG, et al; Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344(18):1343–1350. PubMed CrossRef
Chen CK, Chen YC, Huang YS. Effects of a 10-week weight control program on obese patients with schizophrenia or schizoaffective disorder: a 12-month follow up. Psychiatry Clin Neurosci. 2009;63(1):17–22. PubMed CrossRef
Dayabandara M, Hanwella R, Ratnatunga S, et al. Antipsychotic-associated weight gain: management strategies and impact on treatment adherence. Neuropsychiatr Dis Treat. 2017;13:2231–2241. PubMed CrossRef
Wharton S, Lau DCW, Vallis M, et al. Obesity in adults: a clinical practice guideline. CMAJ. 2020;192(31):E875–E891. PubMed CrossRef
World Health Organization. Guidelines for the Management of Physical Health Conditions in Adults With Severe Mental Disorders. Geneva: World Health Organization; 2018.
Flory J, Lipska K. Metformin in 2019. JAMA. 2019;321(19):1926–1927. PubMed CrossRef
Hendrick V, Dasher R, Gitlin M, et al. Minimizing weight gain for patients taking antipsychotic medications: the potential role for early use of metformin. Ann Clin Psychiatry. 2017;29(2):120–124. PubMed
UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352(9131):854–865. PubMed CrossRef
Andrade C. Use of metformin for cardiometabolic risks in psychiatric practice: need-to-know safety issues. J Clin Psychiatry. 2016;77(11):e1491–e1494. PubMed CrossRef
de Silva VA, Suraweera C, Ratnatunga SS, et al. Metformin in prevention and treatment of antipsychotic induced weight gain: a systematic review and meta-analysis. BMC Psychiatry. 2016;16(1):341. PubMed CrossRef
Agarwal SM, Stogios N, Ahsan Z, et al. S90. a systematic review and meta-analysis of pharmacological interventions for reduction of weight gain in people with schizophrenia: 2019 update. Schizophr Bull. 2020;46(suppl 1):S68–S68. CrossRef
Agarwal SM, Panda R, Costa-Dookhan KA, et al. Metformin for early comorbid glucose dysregulation and schizophrenia spectrum disorders: a pilot double-blind randomized clinical trial. Transl Psychiatry. 2021;11(1):219. PubMed CrossRef
Kanagasundaram P, Lee J, Prasad F, et al. Pharmacological interventions to treat antipsychotic-induced dyslipidemia in schizophrenia patients: a systematic review and meta analysis. Front Psychiatry. 2021;12:642403. PubMed CrossRef
Agarwal SM, Ahsan ZA, Lockwood JT, et al. Pharmacological interventions for prevention of weight gain in people with schizophrenia. Cochrane Database Syst Rev. 2019;2019(6):CD013337. CrossRef
Siskind D, Russell AW, Suetani S, et al. CoMET: a randomised controlled trial of co-commencement of metformin versus placebo as an adjunctive treatment to attenuate weight gain in patients with schizophrenia newly commenced on clozapine. Ther Adv Psychopharmacol. 2021;11:20451253211045248. PubMed CrossRef
Spokes J, Hollingworth S, Winckel K, et al. Metformin reduces 12-month change in body weight among people newly commenced on clozapine: a retrospective naturalistic cohort study. Ther Adv Psychopharmacol. 2021;11:20451253211000609. PubMed CrossRef
Knowler WC, Barrett-Connor E, Fowler SE, et al; Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393–403. PubMed CrossRef
Citrome L, Graham C, Simmons A, et al. An evidence-based review of OLZ/SAM for treatment of adults with schizophrenia or bipolar I disorder. Neuropsychiatr Dis Treat. 2021;17:2885–2904. PubMed CrossRef
Weizman S, Shelef A, Bloemhof Bris E, et al. A double-blind, placebo-controlled trial of bupropion add-on to olanzapine or risperidone in overweight individuals with schizophrenia. J Clin Psychopharmacol. 2021;41(6):629–631. PubMed CrossRef
Hunt HJ, Donaldson K, Strem M, et al. Effect of miricorilant, a selective glucocorticoid receptor modulator, on olanzapine-associated weight gain in healthy subjects: a proof-of-concept study. J Clin Psychopharmacol. 2021;41(6):632–637. PubMed CrossRef
Goh KK, Chen CH, Lu ML. Topiramate mitigates weight gain in antipsychotic-treated patients with schizophrenia: meta-analysis of randomised controlled trials. Int J Psychiatry Clin Pract. 2019;23(1):14–32. PubMed CrossRef
Siskind D, Hahn M, Correll CU, et al. Glucagon-like peptide-1 receptor agonists for antipsychotic-associated cardio-metabolic risk factors: a systematic review and individual participant data meta-analysis. Diabetes Obes Metab. 2019;21(2):293–302. PubMed CrossRef