Case: You’re a ‘freak’
A local mental health agency refers Mr. Z, age 23, to our inpatient psychiatry service because of increasing suicidality and psychosis. He began receiving care from the mental health agency 3 years ago, after a psychiatrist diagnosed paranoid schizophrenia.
At presentation, Mr. Z is delusionally preoccupied with a brief relationship he had with a young woman at college 2 years ago. He feels embarrassed about his conduct toward her during a psychotic episode and her subsequent response. He believes strangers are ridiculing him, and he hears voices calling him a “freak” and making crude references to the encounter. He is also contemplating suicide and endorses a suicide plan.
Mr. Z was hospitalized for 1 month last year with schizophrenia symptoms. He is medically healthy and does not abuse alcohol or drugs.
We admit Mr. Z because of his suicidality. Four weeks later, he remains suicidal and hears voices telling him to “rape” and “kill.” Successive 2-week trials of risperidone, 1 mg/d titrated to 5 mg/d, and quetiapine, 200 mg/d titrated to 700 mg/d, cause intolerable akathisia. We try adding propranolol, 20 mg every 8 hours, to alleviate akathisia, but to no avail. Previous trials of olanzapine, 30 mg/d, and haloperidol, dosage unknown, were unsuccessful or caused akathisia.
The authors’ observations
Substantial evidence supports clozapine’s efficacy in treatment-resistant schizophrenia, and this second-generation antipsychotic (SGA) also might reduce suicidality.1,2 Clinicians often combine antipsychotics, switch to an antidepressant, or add a mood stabilizer for treatment-resistant schizophrenia,3 but little evidence supports these options.
Mr. Z had failed at least 4 antipsychotic trials. We consider clozapine for patients with severe psychosis who have failed 2 or 3 antipsychotic trials or cannot tolerate these medications. Severity of psychosis and presence of suicidality warrant use of clozapine in treatment-resistant cases.
If Mr. Z had tolerated risperidone or quetiapine, we would have waited as long as 8 weeks before switching to clozapine. In inpatients, improvement should be seen 2 to 4 weeks after starting an antipsychotic.
Perform blood tests weekly during the first 6 months of clozapine therapy and bi-weekly thereafter to check for abnormally low white blood cell counts that might suggest agranulocytosis.
How clozapine might cause myocarditis
Myocarditis is a potentially fatal inflammation of the myocardium that can result from a viral infection, toxins, medications, or hypersensitive immune reactions.
Data on myocarditis prevalence are scarce because no relatively noninvasive assessment tools exist. Among 2,200 patients with unexplained heart failure occurring over 5
An FDA-mandated “black box” in clozapine’s package insert describes an “increased risk of fatal myocarditis, especially during—but not limited to—the first month of therapy.”6 Proposed explanations of how clozapine causes myocarditis include:
- direct toxic effect on cardiac myocytes related to impaired clozapine metabolism in some patients7,8
- myocardial damage mediated by clozapine blockade of a muscarinic M2 receptor subtype9
- selenium deficiency or presence of reactive clozapine nitrenium metabolites contributing to myocardial toxicity.10,11
The common presence of peripheral eosinophilia on autopsy—including diffuse eosinophilic infiltrates in myocardial and perivascular areas—might suggest a hypereosinophilic syndrome or a type II hypersensitive immune reaction mediated by clozapine.7,12 Similar immune-mediated conditions of acute, progressive myocarditis have been noted after exposure to other medications such as penicillin or sulfonamides.13
Noting that clozapine increases inflammatory cytokines, some authors believe TNF-alpha and other inflammatory cytokines contribute to myocarditis.14
TREATMENT: New regimen
After discussing clozapine’s risks and benefits with Mr. Z and his parents, we start the medication at 25 mg/d to gauge tolerability, then titrate to 300 mg/d over 10 days. Mr. Z tolerates clozapine well, with some sedation and sialorrhea. A blood test taken 7 days after we start clozapine shows a normal white blood cell count.
After 10 days on clozapine, Mr. Z’s delusions and hallucinations are considerably less intense. He is no longer suicidal and visits his former college with his parents without thinking about his past acquaintance. We discharge him on clozapine, 300 mg/d, and refer him to the local mental health agency.
Two days later, Mr. Z’s parents report that since discharge their son has had extreme fatigue, shortness of breath, leg edema, and chest pain. We advise them to immediately take their son to the ER for cardiac workup.