Skip to main content Accessibility help

We use cookies to distinguish you from other users and to provide you with a better experience on our websites. Close this message to accept cookies or find out how to manage your cookie settings.

Close cookie message
×
Hostname: page-component-cd9895bd7-8ctnn Total loading time: 0 Render date: 2024-12-25T17:06:51.105Z Has data issue: false hasContentIssue false

11 - Managing Metabolic Adverse Effects

Published online by Cambridge University Press:  19 October 2021

Jonathan M. Meyer  and
Stephen M. Stahl
Jonathan M. Meyer
Affiliation:
University of California, San Diego
Stephen M. Stahl
Affiliation:
University of California, San Diego
Get access

Summary

The primary use of clozapine is for schizophrenia spectrum patients with a history of suicidality or treatment-resistant psychosis. Although clozapine itself imposes significant metabolic burden, this is overlaid on the twofold higher rates of metabolic disorders (type 2 diabetes mellitus, metabolic syndrome) and twofold greater standardized mortality rates for cardiovascular disease in this patient population. Multiple factors contribute to this risk profile including lifestyle (e.g. smoking, dietary habits, sedentary behavior), metabolic effects of medications, and biological aspects of schizophrenia itself detectable in treatment-naive patients. Given clozapine’s metabolic impact, combined with the reality that patients may remain on clozapine throughout their lives, ongoing management of cardiometabolic risk is integral to the care of clozapine-treated individuals. Despite this confluence of medication and disease-related risk, the use of clozapine is associated with lower mortality rates from unnatural and natural causes. Investigators compared mortality trends in 14,754 individuals with schizophrenia, schizoaffective disorder or bipolar disorder followed in London from 2007 to 2011. There was a significant association between clozapine use (n = 748) and lower mortality even after controlling for confounders including clinical monitoring and disease severity (adjusted hazard ratio 0.4; 95% CI 0.2–0.7; p = 0.001). This adds to prior data from an 11-year Finnish study which showed that clozapine markedly reduces suicide-related mortality, while no pronounced differences for ischemic heart disease mortality were found between antipsychotics.

Type
Chapter
Information
The Clozapine Handbook
Stahl's Handbooks
 , pp. 204 - 223
Publisher: Cambridge University Press
Print publication year: 2019

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Meyer, J. M. and Stahl, S. M. (2009). The metabolic syndrome and schizophrenia. Acta Psychiatrica Scandinavica, 119, 4–14.CrossRefGoogle ScholarPubMed
Nemani, K. L., Greene, M. C., Ulloa, M., et al. (2019). Clozapine, diabetes mellitus, cardiovascular risk and mortality: Results of a 21-year naturalistic study in patients with schizophrenia and schizoaffective disorder. Clinical Schizophrenia & Related Psychoses, 12, 168–176.CrossRefGoogle ScholarPubMed
Hayes, R. D., Downs, J., Chang, C. K., et al. (2015). The effect of clozapine on premature mortality: An assessment of clinical monitoring and other potential confounders. Schizophrenia Bulletin, 41, 644–655.CrossRefGoogle ScholarPubMed
Tiihonen, J., Lonnqvist, J., Wahlbeck, K., et al. (2009). 11-year follow-up of mortality in patients with schizophrenia: A population-based cohort study (FIN11 study). Lancet, 374, 620–627.CrossRefGoogle ScholarPubMed
Zimbron, J., Khandaker, G. M., Toschi, C., et al. (2016). A systematic review and meta-analysis of randomised controlled trials of treatments for clozapine-induced obesity and metabolic syndrome. European Neuropsychopharmacology, 26, 1353–1365.CrossRefGoogle ScholarPubMed
Siskind, D. J., Leung, J., Russell, A. W., et al. (2016). Metformin for clozapine associated obesity: A systematic review and meta-analysis. PLoS ONE, 11, e0156208.CrossRefGoogle ScholarPubMed
Nielsen, J., Correll, C. U., Manu, P., et al. (2013). Termination of clozapine treatment due to medical reasons: When is it warranted and how can it be avoided? Journal of Clinical Psychiatry, 74, 603–613.Google Scholar
Whelton, P. K., Carey, R. M., Aronow, W. S., et al. (2018). 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: Executive summary: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Journal of the American Society for Hypertension, 12, e1–579.CrossRefGoogle Scholar
Sebo, P., Herrmann, F. R. and Haller, D. M. (2017). Accuracy of anthropometric measurements by general practitioners in overweight and obese patients. BMC Obesity, 4, 23–29.CrossRefGoogle ScholarPubMed
Kim, S. F., Huang, A. S., Snowman, A. M., et al. (2007). Antipsychotic drug-induced weight gain mediated by histamine H1 receptor-linked activation of hypothalamic AMP-kinase. Proceedings of the National Academy of Sciences of the United States of America, 104, 3456–3459.Google Scholar
Suetani, R. J., Siskind, D., Reichhold, H., et al. (2017). Genetic variants impacting metabolic outcomes among people on clozapine: A systematic review and meta-analysis. Psychopharmacology (Berlin), 234, 2989–3008.CrossRefGoogle ScholarPubMed
Vancampfort, D., Van Damme, T., Probst, M., et al. (2017). Physical activity is associated with the physical, psychological, social and environmental quality of life in people with mental health problems in a low resource setting. Psychiatry Research, 258, 250–254.CrossRefGoogle Scholar
Citrome, L., McEvoy, J. P. and Saklad, S. R. (2016). Guide to the management of clozapine-related tolerability and safety concerns. Clinical Schizophrenia & Related Psychoses, 10, 163–177.Google Scholar
Henderson, D. C., Nguyen, D. D., Copeland, P. M., et al. (2005). Clozapine, diabetes mellitus, hyperlipidemia, and cardiovascular risks and mortality: Results of a 10-year naturalistic study. Journal of Clinical Psychiatry, 66, 1116–1121.CrossRefGoogle ScholarPubMed
Meyer, J. M. (2010). Antipsychotics and metabolics in the post-CATIE era. Current Topics in Behavioral Neurosciences, 4, 23–42.CrossRefGoogle ScholarPubMed
Bailey, C. J. (2017). Metformin: Historical overview. Diabetologia, 60, 1566–1576.Google Scholar
Siskind, D., Friend, N., Russell, A., et al. (2018). CoMET: A protocol for a randomised controlled trial of co-commencement of METformin as an adjunctive treatment to attenuate weight gain and metabolic syndrome in patients with schizophrenia newly commenced on clozapine. BMJ Open, 8, e021000.Google Scholar
Lipska, K. J., Bailey, C. J. and Inzucchi, S. E. (2011). Use of metformin in the setting of mild-to-moderate renal insufficiency. Diabetes Care, 34, 1431–1437.Google Scholar
Takeuchi, H. and Remington, G. (2013). A systematic review of reported cases involving psychotic symptoms worsened by aripiprazole in schizophrenia or schizoaffective disorder. Psychopharmacology (Berlin), 228, 175–185.Google Scholar
Fisher, D., Coleman, K. J., Arterburn, D. E., et al. (2017). Mental illness in bariatric surgery: A cohort study from the PORTAL network. Obesity (Silver Spring), 25, 850–856.CrossRefGoogle ScholarPubMed
Kouidrat, Y., Amad, A., Stubbs, B., et al. (2017). Surgical management of obesity among people with schizophrenia and bipolar disorder: A systematic review of outcomes and recommendations for future research. Obesity Surgery, 27, 1889–1895.Google Scholar
Johnson, D. E., Yamazaki, H., Ward, K. M., et al. (2005). Inhibitory effects of antipsychotics on carbachol-enhanced insulin secretion from perifused rat islets: role of muscarinic antagonism in antipsychotic-induced diabetes and hyperglycemia. Diabetes, 54, 1552–1558.CrossRefGoogle ScholarPubMed
Stroup, T. S., Gerhard, T., Crystal, S., et al. (2016). Comparative effectiveness of clozapine and standard antipsychotic treatment in adults with schizophrenia. American Journal of Psychiatry, 173, 166–173.Google Scholar
Henderson, D. C., Cagliero, E., Copeland, P. M., et al. (2007). Elevated hemoglobin A1c as a possible indicator of diabetes mellitus and diabetic ketoacidosis in schizophrenia patients receiving atypical antipsychotics. Journal of Clinical Psychiatry, 68, 533–541.Google Scholar
Lachin, J. M., Christophi, C. A., Edelstein, S. L., et al. (2007). Factors associated with diabetes onset during metformin versus placebo therapy in the diabetes prevention program. Diabetes, 56, 1153–1159.Google Scholar
Taylor, J., Stubbs, B., Hewitt, C., et al. (2017). 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, 12, e0168549.Google Scholar
Hemmingsen, B., Sonne, D. P., Metzendorf, M. I., et al. (2017). Dipeptidyl-peptidase (DPP)-4 inhibitors and glucagon-like peptide (GLP)-1 analogues for prevention or delay of type 2 diabetes mellitus and its associated complications in people at increased risk for the development of type 2 diabetes mellitus. Cochrane Database of Systematic Reviews, 5, Cd012204.Google Scholar
Gorczynski, P., Firth, J., Stubbs, B., et al. (2017). Are people with schizophrenia adherent to diabetes medication? A comparative meta-analysis. Psychiatry Research, 250, 17–24.Google Scholar
Vuk, A., Baretic, M., Osvatic, M. M., et al. (2017). Treatment of diabetic ketoacidosis associated with antipsychotic medication: Literature review. Journal of Clinical Psychopharmacology, 37, 584–589.CrossRefGoogle ScholarPubMed
Morlan-Coarasa, M. J., Arias-Loste, M. T., Ortiz-Garcia de la Foz, V., et al. (2016). Incidence of non-alcoholic fatty liver disease and metabolic dysfunction in first episode schizophrenia and related psychotic disorders: A 3-year prospective randomized interventional study. Psychopharmacology (Berlin), 233, 3947–3952.CrossRefGoogle ScholarPubMed
Merrell, M. D. and Cherrington, N. J. (2011). Drug metabolism alterations in nonalcoholic fatty liver disease. Drug Metabolism Reviews, 43, 317–334.CrossRefGoogle ScholarPubMed
Vancampfort, D., Firth, J., Schuch, F. B., et al. (2017). Sedentary behavior and physical activity levels in people with schizophrenia, bipolar disorder and major depressive disorder: A global systematic review and meta-analysis. World Psychiatry, 16, 308–315.Google Scholar
Dauwan, M., Begemann, M. J., Heringa, S. M., et al. (2016). Exercise improves clinical symptoms, quality of life, global functioning, and depression in schizophrenia: A systematic review and meta-analysis. Schizophrenia Bulletin, 42, 588–599.Google Scholar
Watkins, C. C. and Andrews, S. R. (2016). Clinical studies of neuroinflammatory mechanisms in schizophrenia. Schizophrenia Research, 176, 14–22.CrossRefGoogle ScholarPubMed
Greenwood, J. L., Joy, E. A. and Stanford, J. B. (2010). The Physical Activity Vital Sign: A primary care tool to guide counseling for obesity. Journal of Physical Activity and Health, 7, 571–576.CrossRefGoogle ScholarPubMed
Vancampfort, D., Stubbs, B., Probst, M., et al. (2016). Physical activity as a vital sign in patients with schizophrenia: Evidence and clinical recommendations. Schizophrenia Research, 170, 336–340.Google Scholar
Daumit, G. L., Dickerson, F. B., Wang, N. Y., et al. (2013). A behavioral weight-loss intervention in persons with serious mental illness. New England Journal of Medicine, 368, 1594–1602.Google Scholar
Green, C. A., Yarborough, B. J., Leo, M. C., et al. (2015). The STRIDE weight loss and lifestyle intervention for individuals taking antipsychotic medications: A randomized trial. American Journal of Psychiatry, 172, 71–81.Google Scholar
Nicol, G., Worsham, E., Haire-Joshu, D., et al. (2016). Getting to more effective weight management in antipsychotic-treated youth: A survey of barriers and preferences. Child Obesity, 12, 70–76.Google Scholar
Jakobsen, A. S., Speyer, H., Norgaard, H. C. B., et al. (2018). Dietary patterns and physical activity in people with schizophrenia and increased waist circumference. Schizophrenia Research, 199, 109–115.Google Scholar
Hjorth, P., Juel, A., Hansen, M. V., et al. (2017). Reducing the risk of cardiovascular diseases in non-selected outpatients with schizophrenia: A 30-month program conducted in a real-life setting. Archives of Psychiatric Nursing, 31, 602–609.CrossRefGoogle ScholarPubMed
Khokhar, J. Y., Dwiel, L. L., Henricks, A. M., et al. (2018). The link between schizophrenia and substance use disorder: A unifying hypothesis. Schizophrenia Research, 194, 78–85.CrossRefGoogle ScholarPubMed
Dickerson, F., Origoni, A., Schroeder, J., et al. (2018). Natural cause mortality in persons with serious mental illness. Acta Psychiatrica Scandinavica, 137, 371–379.Google Scholar
Stubbs, B., Vancampfort, D., Bobes, J., et al. (2015). How can we promote smoking cessation in people with schizophrenia in practice? A clinical overview. Acta Psychiatrica Scandinavica, 132, 122–130.CrossRefGoogle ScholarPubMed
Evins, A. E., Cather, C., Pratt, S. A., et al. (2014). Maintenance treatment with varenicline for smoking cessation in patients with schizophrenia and bipolar disorder: A randomized clinical trial. JAMA, 311, 145–154.CrossRefGoogle ScholarPubMed
Cather, C., Pachas, G. N., Cieslak, K. M., et al. (2017). Achieving smoking cessation in individuals with schizophrenia: Special considerations. CNS Drugs, 31, 471–481.Google Scholar
World Health Organization Expert Consultation.(2004). Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet, 363, 157–163.Google Scholar
American Diabetes Association. (2018). Classification and diagnosis of diabetes: Standards of medical care in diabetes – 2018. Diabetes Care, 41, S13–S27.Google Scholar
Khorassani, F., Kaufman, M., Lopez, L. V. (2018). Supratherapeutic serum clozapine concentration after transition from traditional to electronic cigarettes. Journal of Clinical Psychopharmacology, 38, 391–392.CrossRefGoogle Scholar

Save book to Kindle

To save this book to your Kindle, first ensure [email protected] is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about saving to your Kindle.

Note you can select to save to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be saved to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

Find out more about the Kindle Personal Document Service.

Available formats
×

Save book to Dropbox

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Dropbox.

Available formats
×

Save book to Google Drive

To save content items to your account, please confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your account. Find out more about saving content to Google Drive.

Available formats
×