Clozapine and Fever: A Case of Continued Therapy With Clozapine

Clozapine is a major atypical antipsychotic drug used in treatment-resistant schizophrenia (Patel and Allin. Ther Adv Psychopharmacol 2011;1:25-29). It interferes with dopamine binding to D1, D2, D3, and D5 receptors but has high affinity to D4. It also has an anticholinergic effect and antagonizes α-adrenergic, histaminergic, and serotoninergic receptors (Oerther and Ahlenius. J Pharmacol Exp Ther 2000;292:731-736). Clozapine has proved effective in treating positive and negative symptoms in patients with refractory schizophrenia, thus accounting for its frequent use. Despite its effectiveness, this drug is not without its adverse effects. The most well known is agranulocytosis. There are, however, many others, such as myocarditis, aspiration pneumonia, ileus, fever, hyperglycemia, hyperlipidemia, hypertriglycemia, tachycardia, and weight gain, among others (Bruijnzeel et al. Asian J Psychiatr 2014;11:3-7). Fever induced by clozapine is a common phenomenon (Lowe et al. Ann Pharmacother 2007;41:1700-1704), which usually occurs in the first 4 weeks of treatment, and its prevalence oscillates from 0.5% and 55%, depending on the study (Jeong et al. Schizophr Res 2002;56:191-193; Young et al. Schizophr Bull 1998;24:381-390). The fever lasts for 2.5 days on average, and unless the treatment is discontinued, it generally abates between day 8 and 16 of treatment (Kohen et al. Ann Pharmacother 2009;43:143-146). There are several different theories about the physiopathological mechanism; it could be a variation of malignant neuroleptic syndrome, an infection secondary to neutropenia, and allergic reaction or the emergence of the immunomodulating effect of clozapine. Some case reports in the bibliography have shown that patients in treatment with clozapine can develop a mild leukocytosis, but the presence of other concurrent symptoms, which indicate infection, is not common (Tham and Dickson. J Clin Psychiatry 2002;63:880-884). The theory of an allergic reaction is unsupported because of the fact that the fever does not recur after reintroducing clozapine. So we question, "What would be the attitudes to follow when we find clozapine-induced fever (Nielsen et al. J Clin Psychiatry 2013;74:603-613)?" The management of patients with clozapine-induced fever should include a complete blood picture, liver and renal function tests, a creatine kinase test urine culture, and a chest x-ray. A nasopharyngeal aspirate can also be useful to exclude infection (Pui-yin Chung et al. Can J Psychiatry 2008;53:857-862). On the other hand, some drugs have been suggested for treatment of fever induced by clozapine. The use of acetaminophen, in the treatment of the fever induced by clozapine, is supported by many studies (Jeong et al. Schizophr Res 2002;56:191-193). In one of these, clozapine was suspended and restarted successfully after 1 week. However, in some studies, such as the case report of Tremeau et al (Clin Neuropharmacol 1997;20:168-170), clozapine was reduced instead of discontinued. In other studies, the recommendation is continuating clozapine treatment (Martin and Williams. J Psychiatry Neurosci 2013;38:E9-E10).