Similarly, orthostatic hypotension can be managed with a reduced dosage of clozapine or slower titration. Increased fluid intake, compression stockings, and, if necessary, fludrocortisone also can be initiated.20
Rare, potentially fatal events. Myocarditis, pericarditis, and cardiomyopathy are among the rare but potentially fatal adverse effects of clozapine. A recent study reported the incidence of myocarditis with clozapine at a range of 0.015% to 1.3%; cardiomyopathy was even more rare.23 Pulmonary embolism and deep venous thrombosis also are very rare possibilities; keep them in mind, however, when patients taking clozapine report new cardiovascular symptoms.
Patients with clozapine-induced cardiovascular effects most commonly report shortness of breath (60%), palpitations (36%), cough (16%), fatigue (16%), and chest pain (8%).7,24
Clozapine’s “black-box” warning specifically recommends discontinuing clozapine and consulting cardiology when myocarditis or cardiomyopathy is suspected. In 50% of cases, myocarditis symptoms present in the first few weeks of clozapine treatment.23 The manufacturer states that myocarditis usually presents in the first 2 months, and cardiomyopathy after 8 weeks of treatment; however, either can present at any time.8Figure 2 provides a clinical reference for monitoring a clozapine patient for cardiomyopathy.24
Laboratory findings that support a diagnosis of clozapine-related myocarditis include:
- elevated C-reactive protein
- elevated troponin I or T
- elevated creatine kinase-MB
- peripheral eosinophilia.8,25
ECG, echocardiography, and cardiac MRI can be helpful in diagnosis, in consultation with a cardiologist.
Neurologic side effectsSeizures are listed in the “black-box” warning for clozapine. Seizure incidence with clozapine is 5% per year, with higher incidence at dosages ≥600 mg/d.8 Because clozapine-induced seizures are dosage-dependent, slow titration can mitigate this risk. Tonic-clonic seizures are the most common type associated with clozapine.
The manufacturer recommends caution when using clozapine in patients with a known seizure disorder, alcohol use disorder, or other CNS pathology.8 Patients with a seizure disorder may be at increased risk of experiencing clozapine-induced seizures, but this is not an absolute contraindication.26 Smoking cessation increases clozapine blood levels by an average of 57.4%, further increasing seizure risk.26,27
Discontinuing clozapine is unnecessary when a patient experiences a seizure. Instead, you can:
- halve the dosage prescribed at the time of the seizure (or at least reduce to the last seizure-free dosage)
- consider any medications or medical problems that might have contributed to a lower seizure threshold
- consider prophylaxis with an antiepileptic medication (eg, valproic acid has efficacy for both myoclonic and tonic-clonic seizures).20,26
Sedation is the most common side effect of clozapine.1 Patients experiencing severe sedation should not drive or operate heavy machinery. To reduce sedation, consider instructing the patient to take all or most of the clozapine dosage at bedtime. A critical review of modafinil for sedation caused by antipsychotics in schizophrenia found only 1 open-label study that showed any positive effects; the authors concluded that further study is needed.28
Cognitive and motor slowing are possible neurologic side effects of clozapine. Caution patients about the risk of participating in activities that require cognitive or motor performance until the individual effects of clozapine are known.8
Tardive dyskinesia. Clozapine carries some risk of tardive dyskinesia, although that risk is lower than with other antipsychotics. Similarly, all antipsychotics including clozapine are associated with a risk of NMS. In the rare case of clozapine-induced NMS, stop clozapine immediately and initiate supportive therapy. Clozapine-induced NMS is not an absolute contraindication to re-challenging a patient with clozapine, however, if doing so is clinically appropriate.20
Cerebrovascular events. In older people with dementia, the use of antipsychotics—including clozapine—has been shown to increase the risk of cerebrovascular events. Because most antipsychotics are not FDA-approved for treating psychosis associated with dementia (only pimavanserin is FDA-approved for symptoms of psychosis in Parkinson’s disease), a risk-benefit analysis should be documented when prescribing any antipsychotic in this population. In practice, clozapine’s benefits may outweigh the mortality risks in specific situations.29,30
CASE Sialorrhea puts progress at risk
Ms. B, age 40, has a history of treatment-resistant schizophrenia and is starting clozapine because of residual psychosis during trials of other antipsychotics. She develops severe persistent drooling, mostly at night, during clozapine titration. Sugar-free candy, multiple bed pillows, and changing the dosing schedule do not significantly improve the sialorrhea.
As a result, Ms. B is embarrassed to continue her usual activities. She asks to stop clozapine, even though her psychotic symptoms have improved and she is functioning at her highest level in years.
Ms. B already is taking trihexyphenidyl, 5 mg, 3 times daily, to manage extrapyramidal symptoms related to haloperidol decanoate treatment. After discussing other medication options for sialorrhea, she agrees to a trial of glycopyrrolate, 1 mg, twice daily. She experiences significant improvement and continues taking clozapine.