Introduction:
A second-generation antipsychotic medication called Clozapine is sometimes shadowed by its unfavorable side-effect profile but helps prevent rehospitalization, relapse, and suicidality linked to treatment-resistant schizophrenia. This drug is a well-known side effect of agranulocytosis but also carries a severe but rare adverse cardiovascular risk of myocarditis. Clozapine-induced myocarditis has a mortality rate of 10 to 50 percent, commonly present within the first month of Clozapine initiation. It is difficult to distinguish it from a benign inflammatory response to Clozapine. The least common potentially fatal side effect of Clozapine use is myocarditis, which can develop during the initial four weeks after starting the medication.
What Is Clozapine?
Clozapine is a medication given to a mentally compromised patient. It is a benzodiazepine drug primarily used to treat people with schizophrenia and schizoaffective disorders who have had an inadequate response to other antipsychotics or have been unable to tolerate other drugs due to extrapyramidal side effects.
Risk Factor: Studies found a significant link between Clozapine-induced myocarditis and cumulative-dose exposure during Clozapine titration. Clozapine should be titrated slowly at increased 25 mg (milligrams) doses daily over 4 to 6 weeks. Myocarditis was affected by sodium valproate, and coronary artery disease was not a risk factor.
What Is the Pathophysiology of Myocarditis?
A viral infection generally causes myocarditis; however, hypersensitivity to myocarditis occurs in response to medication. The mechanisms behind Clozapine-induced myocarditis are not completely understood. Still, a widely accepted theory is that a directly cardiotoxic metabolite of Clozapine forms through altered metabolism and damages myocardial tissue. The reason for patients experiencing a mild, self-limiting, and chronic inflammatory response is due to the hypersensitive reaction of Clozapine during the initial period. The mechanism of myocardial injury works on the theory of catecholamines which inhibit Clozapine and norepinephrine transporter.
What Is the Clinical Sign of Myocarditis?
The difference between the onset of a benign inflammatory response to Clozapine and Clozapine-induced myocarditis is challenging. Patients typically report flu-like symptoms such as fever, myalgia, dyspnea, gastrointestinal distress, or exhaustion when myocarditis first manifests. But in some cases, the patients may be asymptomatic, and the initial presentation is highly variable, like symptoms of cardiac involvement, such as chest pain, peripheral edema, hypotension, and tachycardia, which may not develop for several days. Therefore clinically active signs can help clinicians to make a timely and accurate diagnosis.
How Does Clozapine Cause Cardiac Toxicity?
Clozapine can rarely cause myocarditis and cardiomyopathy. A study says that Clozapine exposure to over twenty-five thousand people revealed that these occurred in approximately seven in thousand patients treated and resulted in death in three to four in ten thousand patients exposed. Although myocarditis occurs almost within the first eight weeks of treatment, cardiomyopathy can occur much later. The first signs of illness are fever, followed by symptoms associated with upper respiratory tract, gastrointestinal or urinary tract infection. C-reactive protein also increases with the onset of fever, and a rise in troponin, a cardiac enzyme, occurs up to five days later. Monitoring guidelines advise checking C-reactive protein and troponin should weekly for the first four weeks after Clozapine intake and observing the patient’s signs and symptoms of illness. A recent study found that the risk of Clozapine-induced myocarditis increases with an increasing rate of Clozapine dose.
What Are the Adverse Effects of Clozapine?
Clozapine may cause serious and fatal adverse effects such as low levels of neutrophils, low blood pressure upon changing position, including flow heart rate and fainting, seizures, inflammation of the heart, and risk of death when used in older adults with mental illness related to psychosis. While increasing the dose slowly, the risk of seizures and orthostatic hypotension may decrease. Common side effects include constipation, bed-wetting, night-time drooling, sedation, muscle stiffness, tremors, orthostatic hypotension, high blood sugar, and weight gain. In addition, there are some sexual problems, like retrograde ejaculation, that have been reported while taking Clozapine. Despite the risk of various side effects, many side effects can be managed while taking Clozapine.
How to Monitor Cardiovascular Complications Associated With Clozapine?
The importance of comprehensive monitoring tools for spotting cardiovascular side effects of Clozapine has been proven. However, protocols largely concentrate on maintaining a high uncertainty index for early symptom detection. Discussions about including cardiac indicators and inflammatory markers into these regimens for weekly blood tests are ongoing.
How to Diagnose Myocarditis?
There are various tests to diagnose myocarditis, including :
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Typically, a diagnostic blood test is performed to look for indicators of an infection, inflammation, or heart attack. In addition, a cardiac enzyme test can check for proteins related to heart muscle damage.
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Electrocardiogram- This is a quick and painless test that shows the heartbeat.
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Chest X-Ray- It shows the size and shape of the lungs and heart.
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Cardiac MRI- MRI or magnetic resonance imaging test uses magnetic fields and radio waves to create detailed heart images.
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Echocardiogram- It shows the heart size and how well blood flows to the heart and the heart valves.
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Cardiac Catheterization and Heart Muscle Biopsy- The dye is injected via catheter to enhance the heart's visibility on X-rays.
How Is Myocarditis Treated?
There are several treatments which include:
Medications
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Heart medicines like diuretics, beta-blockers, and angiotensin-converting enzymes.
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Medications to treat chronic conditions.
Surgeries and Procedures
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IV (intravenous) medications.
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Ventricular assist devices.
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Intra-aortic balloon pump.
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Extracorporeal membrane oxygenation.
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Heart transplant.
Clozapine myocarditis is treated with supportive and empirical measures. If drug-induced myocarditis is suspected after the diagnosis, the inciting agent should be stopped immediately. It has been demonstrated that administering beta blockers, diuretics, and angiotensin-converting enzyme inhibitors during an acute myocardial insult will support myocardial function. Inflammatory markers, including ESR (erythrocyte sedimentation rate) and CRP )C-reactive protein) trending levels have been proposed as recovery indicators.
Although discontinuing Clozapine results in a direct association between the degree of reduced systolic function and the degree of recovery, mortality is still 12.5 to 24 percent. The time it takes for cardiac functional recovery to start after a medication has been stopped varies. Clozapine discontinuation should be done in careful coordination with psychiatry monitoring as a recurrence of schizophrenia may result, which could cause serious risks to patients.
Conclusion:
As per studies, it is proven that Clozapine-induced myocarditis is a life-threatening condition in which myocarditis is increased with the increased dose of Clozapine with increasing age. Therefore, physicians need to prescribe the medication dose as per the age and severity because it may cause the death of a person. It is a fatal condition, and signs can be seen within the first four weeks of dose intake. Close monitoring reduces mortality and undiagnosed Clozapine-induced myocarditis. Therefore close supervision and frequent monitoring may help treat resistant patients who continue to experience severe psychosis.
