Increases in C-Reactive Protein May Predict Recurrence of Clozapine-Induced Fever

OBJECTIVE To report a case of recurrent clozapine-induced fever that was associated with a rise in C-reactive protein (CRP). CASE SUMMARY A 73-year-old man with Lewy Body dementia was admitted for psychosis. He was treated with clozapine (initial dose 12.5 mg/day, titrated to 75 mg/day over 15 days). On day 15 of clozapine therapy, he developed a benign fever (maximum 38.4 °C) that was associated with a rise in the CRP level (3.96 mg/dL). The level normalized when clozapine was discontinued. However, when the patient was rechallenged with clozapine, the CRP level became elevated (4.36 mg/dL) after 3 days of therapy, with a subsequent recurrence of fever (38.7 °C). DISCUSSION We postulate that the elevation in CRP levels and the subsequent fever were caused by the effects of clozapine on the cytokine system via interleukin-6 and tumor necrosis factor-α, resulting in an inflammatory response with an acute phase reaction. This case is unique, as it is the first reported in the literature associating a recurrence of clozapine-induced fever with the known immunomodulatory effects of clozapine on cytokines and CRP level. According to the Naranjo probability scale, this adverse effect is probably associated with clozapine. CONCLUSIONS Clozapine-related fever is generally benign but difficult to assess and manage, as it can be confused with much more serious conditions. Further research is needed to study whether CRP is a useful tool in predicting and managing clozapine fever.