Section Free - Video Lectures

09. Managing Cardiac and Metabolic Adverse Effects of Clozapine

Published on June 1, 2023 Certification expiration date: June 1, 2026

Brian Miller, M.D., Ph.D., M.P.H.

Professor - Augusta University

Key Points

Myocarditis risk is higher during clozapine initiation.
Monitor CRP, CK, and troponin I weekly for the first 6–8 weeks to mitigate myocarditis risk.
Stop clozapine immediately for any cardiorespiratory complaints that occur during titration.
Tachycardia and orthostasis are common but manageable adverse effects of clozapine.
Lifestyle modifications and adjunctive pharmacologic treatments can help mitigate the metabolic syndrome risk of clozapine.
Topiramate and metformin can be used prophylactically in collaboration with the patient.

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Slides and Transcript

Slide 1 of 27

So now, we're going to talk about the management of cardiac and metabolic adverse effects of clozapine.

Managing Cardiac and Metabolic Adverse Effects of Clozapine Slide 1 of 27

Slide 2 of 27

So, we mentioned that myocarditis is a black box warning of clozapine. There's also a risk of cardiomyopathy. So, the myocarditis usually occurs within the first six to eight weeks of treatment. By contrast, the highest risk of cardiomyopathy with clozapine occurs later on the order of about nine months.

References:

Sandarsh, S., Bishnoi, R. J., Shashank, R. B., Miller, B. J., Freudenreich, O., & McEvoy, J. P. (2021). Monitoring for myocarditis during treatment initiation with clozapine. Acta Psychiatrica Scandinavica, 144(2), 194–200.

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Slide 3 of 27

So it's important to note that heavy alcohol consumption is a risk factor for clozapine-induced myocarditis or cardiomyopathy.

References:

Sandarsh, S., Bishnoi, R. J., Shashank, R. B., Miller, B. J., Freudenreich, O., & McEvoy, J. P. (2021). Monitoring for myocarditis during treatment initiation with clozapine. Acta Psychiatrica Scandinavica, 144(2), 194–200.

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Slide 4 of 27

So symptoms of myocarditis or cardiomyopathy can include fever, tachycardia, fatigue, dyspnea, chest pain, and flu-like symptoms.

References:

Sandarsh, S., Bishnoi, R. J., Shashank, R. B., Miller, B. J., Freudenreich, O., & McEvoy, J. P. (2021). Monitoring for myocarditis during treatment initiation with clozapine. Acta Psychiatrica Scandinavica, 144(2), 194–200.

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Slide 5 of 27

Some of the signs that we might see include eosinophilia, increases in C-reactive protein, CK and/or troponin I. We might see ST-segment depression on EKG or an enlarged heart on echocardiography.

References:

Sandarsh, S., Bishnoi, R. J., Shashank, R. B., Miller, B. J., Freudenreich, O., & McEvoy, J. P. (2021). Monitoring for myocarditis during treatment initiation with clozapine. Acta Psychiatrica Scandinavica, 144(2), 194–200.

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Slide 6 of 27

My general rule of thumb is for patients to stop clozapine immediately for any cardiorespiratory complaints that are prominent during titration. This may even require medical hospitalization.

References:

Sandarsh, S., Bishnoi, R. J., Shashank, R. B., Miller, B. J., Freudenreich, O., & McEvoy, J. P. (2021). Monitoring for myocarditis during treatment initiation with clozapine. Acta Psychiatrica Scandinavica, 144(2), 194–200.

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Slide 7 of 27

To mitigate the risk of myocarditis, it is recommended in addition to the CBC to get weekly C-reactive protein, CK, and troponin I.

References:

Sandarsh, S., Bishnoi, R. J., Shashank, R. B., Miller, B. J., Freudenreich, O., & McEvoy, J. P. (2021). Monitoring for myocarditis during treatment initiation with clozapine. Acta Psychiatrica Scandinavica, 144(2), 194–200.

Managing Cardiac and Metabolic Adverse Effects of Clozapine Slide 7 of 27

Slide 8 of 27

And in fact, in a study that we conducted here at our university, we found evidence for presumptive myocarditis in four out of 76 patients who are initiated on clozapine. And the key distinguishing factor was all four of these patients had newly detectable troponin I levels.

References:

Sandarsh, S., Bishnoi, R. J., Shashank, R. B., Miller, B. J., Freudenreich, O., & McEvoy, J. P. (2021). Monitoring for myocarditis during treatment initiation with clozapine. Acta Psychiatrica Scandinavica, 144(2), 194–200.

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Slide 9 of 27

So, at baseline, troponin I was nondetectable and all of the patients who had presumptive myocarditis with clozapine initiation experienced a bump in their troponin within the first weeks of therapy. So, certainly, a potentially scary and, and life-threatening side effect that we want to be vigilant and monitoring for.

References:

Sandarsh, S., Bishnoi, R. J., Shashank, R. B., Miller, B. J., Freudenreich, O., & McEvoy, J. P. (2021). Monitoring for myocarditis during treatment initiation with clozapine. Acta Psychiatrica Scandinavica, 144(2), 194–200.

Managing Cardiac and Metabolic Adverse Effects of Clozapine Slide 9 of 27

Slide 10 of 27

Tachycardia is one of the most common side effects that we see from clozapine affecting anywhere from 25% to 50% of patients. We want to always ask our patients about their level of caffeine intake and if we do that sometimes we're not surprised by the tremendously high quantities of caffeine consumption in some of our patients.

References:

Lally, J., Docherty, M. J., & MacCabe, J. H. (2015). Pharmacological interventions for clozapine-induced sinus tachycardia. Cochrane Database of Systematic Reviews.

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Slide 11 of 27

If a patient has repeated measurements of a heart rate above 100, then I strongly consider adjunctive treatment typically using a cardioselective beta-blocker such as atenolol at a dose of 12.5 to 25 mg daily especially in younger patients in their 20s should not have a heart rate greater than 100 and I don't want them tachy-ing away for years and years. So I will try to be aggressive about adjunctive atenolol for those patients with tachycardia.

References:

Lally, J., Docherty, M. J., & MacCabe, J. H. (2015). Pharmacological interventions for clozapine-induced sinus tachycardia. Cochrane Database of Systematic Reviews.

Managing Cardiac and Metabolic Adverse Effects of Clozapine Slide 11 of 27

Slide 12 of 27

Orthostasis is also extremely common. It affects about 20% of our patients. As we are titrating clozapine, I recommend if they complain of dizziness, lightheadedness to hold the dose until that improves and also go even more slowly with the rate of titration.

References:

Ronaldson K. J. (2017). Cardiovascular disease in clozapine-treated patients: evidence, mechanisms and management. CNS Drugs, 31(9), 777–795.

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Slide 13 of 27

I advise my patients to be slow and deliberate when changing positions, not to just jump up out of bed but to give themselves a moment to sit up and adjust on the side of the bed before getting up. It's also important for patients to maintain good hydration status. In general, especially on the inpatient side, a lot of our patients with schizophrenia come in and they're really mildly dehydrated and so that puts them at increased risk for orthostasis. And in some significant cases, sometimes we use support or TED hose to address the orthostasis.

References:

Ronaldson K. J. (2017). Cardiovascular disease in clozapine-treated patients: evidence, mechanisms and management. CNS Drugs, 31(9), 777–795.

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Slide 14 of 27

Although clozapine does not have a black box warning for metabolic syndrome, we know that overall its metabolic effects and risk of metabolic syndrome are essentially on par with olanzapine as being the two antipsychotics that have the overall greatest risk of metabolic syndrome.

References:

Allison, D. B., Mentore, J. L., Heo, M., Chandler, L. P., Cappelleri, J. C., Infante, M. C., & Weiden, P. J. (1999). Antipsychotic-induced weight gain: A comprehensive research synthesis. The American Journal of Psychiatry, 156(11), 1686–1696.

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Slide 15 of 27

Toby Pillinger from the United Kingdom published what's called kind of a heat map study that looked at the risk of different cardiometabolic parameters with different antipsychotics finding large effect sizes for increases in weight, body mass index, blood glucose, total cholesterol, and triglycerides with clozapine treatment.

References:

Pillinger, T., McCutcheon, R. A., Vano, L., Mizuno, Y., Arumuham, A., Hindley, G., Beck, K., Natesan, S., Efthimiou, O., Cipriani, A., & Howes, O. D. (2020). Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: A systematic review and network meta-analysis. The Lancet Psychiatry, 7(1), 64-77.

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So how do we go about addressing that risk? Well, I like to use my initial patient history as a risk assessment in terms of do they at baseline have a personal or family history of diabetes, hypertension, hyperlipidemia.

References:

Sandarsh, S., Bishnoi, R. J., Shashank, R. B., Miller, B. J., Freudenreich, O., & McEvoy, J. P. (2021). Monitoring for myocarditis during treatment initiation with clozapine. Acta Psychiatrica Scandinavica, 144(2), 194–200.

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Slide 17 of 27

And then the question is what do we do about that? We know that many patients with clozapine are going to experience weight gain and its metabolic sequelae. So we collaborate on the decision of when and if to start adjunctive treatment. Lifestyle modifications including improvements in nutrition and exercise are discussed with every patient using both behavioral activation and motivational interviewing strategies.

References:

Sandarsh, S., Bishnoi, R. J., Shashank, R. B., Miller, B. J., Freudenreich, O., & McEvoy, J. P. (2021). Monitoring for myocarditis during treatment initiation with clozapine. Acta Psychiatrica Scandinavica, 144(2), 194–200.

Managing Cardiac and Metabolic Adverse Effects of Clozapine Slide 17 of 27

Slide 18 of 27

I tell patients, for example, if they're not exercising, nobody expects them to go out and run a marathon, but if you're starting with no exercise, a five-minute walk a day or five-minute walk once a week is better than no exercise at all. Ten minutes is better than five and 15 is better than 10, etc.

References:

Sandarsh, S., Bishnoi, R. J., Shashank, R. B., Miller, B. J., Freudenreich, O., & McEvoy, J. P. (2021). Monitoring for myocarditis during treatment initiation with clozapine. Acta Psychiatrica Scandinavica, 144(2), 194–200.

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Slide 19 of 27

And then in terms of nutrition, things that we suggest, one of the most common would be to try to substitute high sugar beverages, reducing intake of sodas and juices. Even if you can just replace one of those, with water a day, that can make a benefit. Here in the South where people eat a lot of fried foods, we try to talk about, maybe switching from fried to baked or grilled as simple nutritional interventions to try to help there.

References:

Sandarsh, S., Bishnoi, R. J., Shashank, R. B., Miller, B. J., Freudenreich, O., & McEvoy, J. P. (2021). Monitoring for myocarditis during treatment initiation with clozapine. Acta Psychiatrica Scandinavica, 144(2), 194–200.

Managing Cardiac and Metabolic Adverse Effects of Clozapine Slide 19 of 27

Slide 20 of 27

In terms of pharmacologic treatments, there are two first-line pharmacologic treatments for clozapine-associated weight gain. One of them is metformin which can be dosed initially at 500 mg twice a day. There's also evidence for adjunctive topiramate starting at 25 mg twice a day, increasing by 50 mg a week up to a maximum dose of 400 mg per day.

References:

Sandarsh, S., Bishnoi, R. J., Shashank, R. B., Miller, B. J., Freudenreich, O., & McEvoy, J. P. (2021). Monitoring for myocarditis during treatment initiation with clozapine. Acta Psychiatrica Scandinavica, 144(2), 194–200.

Managing Cardiac and Metabolic Adverse Effects of Clozapine Slide 20 of 27

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Slide 21 of 27

So one of the questions is should we be using prophylactic metformin or topiramate? And the answer to that is it depends and again I really try to make a collaborative decision with the patient. Sometimes, it's hard to get a patient to take one medicine, not to mention multiple medications. Based on their overall risk, personal and family history, we make patients aware of the risk of weight gain and some patients will choose to just monitor things carefully and then consider adjunctive medications, whereas others prefer to start the adjuncts prophylactically.

References:

Sandarsh, S., Bishnoi, R. J., Shashank, R. B., Miller, B. J., Freudenreich, O., & McEvoy, J. P. (2021). Monitoring for myocarditis during treatment initiation with clozapine. Acta Psychiatrica Scandinavica, 144(2), 194–200.
Correll, C. U., Maayan, L., Kane, J., De Hert, M., & Cohen, D. (2016). Efficacy for psychopathology and body weight and safety of topiramate-antipsychotic cotreatment in patients with schizophrenia spectrum disorders. The Journal of Clinical Psychiatry, 77(06), e746-e756.
De Silva, V. A., Suraweera, C., Ratnatunga, S. S., Dayabandara, M., Wanniarachchi, N., & Hanwella, R. (2016). Metformin in prevention and treatment of antipsychotic induced weight gain: A systematic review and meta-analysis. BMC Psychiatry, 16(1).

Managing Cardiac and Metabolic Adverse Effects of Clozapine Slide 21 of 27

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So we do know that, for example, patients with schizophrenia and a family history of diabetes are themselves at approximately a three- to four-fold increased risk of developing diabetes themselves. So in a patient with a relevant family history of diabetes, we might be more aggressive with these adjunctive pharmacologic treatments.

References:

Sandarsh, S., Bishnoi, R. J., Shashank, R. B., Miller, B. J., Freudenreich, O., & McEvoy, J. P. (2021). Monitoring for myocarditis during treatment initiation with clozapine. Acta Psychiatrica Scandinavica, 144(2), 194–200.
Correll, C. U., Maayan, L., Kane, J., De Hert, M., & Cohen, D. (2016). Efficacy for psychopathology and body weight and safety of topiramate-antipsychotic cotreatment in patients with schizophrenia spectrum disorders. The Journal of Clinical Psychiatry, 77(06), e746-e756.
De Silva, V. A., Suraweera, C., Ratnatunga, S. S., Dayabandara, M., Wanniarachchi, N., & Hanwella, R. (2016). Metformin in prevention and treatment of antipsychotic induced weight gain: A systematic review and meta-analysis. BMC Psychiatry, 16(1).

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Slide 23 of 27

The evidence shows that, in patients with schizophrenia, clozapine and topiramate together not only improved weight and metabolic parameters but there were actually some improvements in symptomatology as well. So there may be an added benefit there with adjunctive topiramate. And similarly, we know that adding metformin to an antipsychotic can be associated with an average weight loss of several kilograms. And any weight loss that we see in our patients is beneficial in terms of reducing their cardiovascular risk.

References:

Sandarsh, S., Bishnoi, R. J., Shashank, R. B., Miller, B. J., Freudenreich, O., & McEvoy, J. P. (2021). Monitoring for myocarditis during treatment initiation with clozapine. Acta Psychiatrica Scandinavica, 144(2), 194–200.
Correll, C. U., Maayan, L., Kane, J., De Hert, M., & Cohen, D. (2016). Efficacy for psychopathology and body weight and safety of topiramate-antipsychotic cotreatment in patients with schizophrenia spectrum disorders. The Journal of Clinical Psychiatry, 77(06), e746-e756.
De Silva, V. A., Suraweera, C., Ratnatunga, S. S., Dayabandara, M., Wanniarachchi, N., & Hanwella, R. (2016). Metformin in prevention and treatment of antipsychotic induced weight gain: A systematic review and meta-analysis. BMC Psychiatry, 16(1).

Managing Cardiac and Metabolic Adverse Effects of Clozapine Slide 23 of 27

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So in summary, myocarditis risk is highest during the initiation of clozapine. It's recommended that you monitor C-reactive protein, CK and troponin I weekly for at least the first six to eight weeks to mitigate that risk.

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Slide 25 of 27

Clozapine should be stopped immediately for any significant cardiorespiratory complaints that occur during titration. Tachycardia and orthostasis are common but manageable potential adverse effects of clozapine.

Managing Cardiac and Metabolic Adverse Effects of Clozapine Slide 25 of 27

Slide 26 of 27

Lifestyle modifications such as nutrition and exercise and adjunctive pharmacologic treatment with topiramate or metformin can help mitigate metabolic syndrome risk with clozapine. And that can be potentially used prophylactically in collaboration with the patient.

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Slide 27 of 27

Managing Cardiac and Metabolic Adverse Effects of Clozapine Slide 27 of 27

Next Section

10. Managing Other Common Adverse Effects of Clozapine

Learning Objectives:

After completing this activity, the learner will be able to:

Recognize the different approved and off-label indications of clozapine.
Assess and successfully manage any potential side effects of clozapine.
Identify the clinical scenarios in which clozapine should be prescribed and confidently do so.

Original Release Date: June 1, 2023

Review and Re-release Date: March 1, 2024

Expiration Date: June 1, 2026

Expert: Brian Miller, M.D.

Medical Editor: Paz Badía, M.D.

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None of the faculty, planners, and reviewers for this educational activity have relevant financial relationships to disclose during the last 24 months with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.

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