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Ann Pharmacother. 2009 Jan;43(1):143-6. doi: 10.1345/aph.1L467. Epub 2009 Jan 6.

Increases in C-reactive protein may predict recurrence of clozapine-induced fever.

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Geriatric Psychiatry Division, North Shore-Long Island Jewish Health System, The Zucker Hillside Hospital, Glen Oaks, NY 11004,USA.



To report a case of recurrent clozapine-induced fever that was associated with a rise in C-reactive protein (CRP).


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 degrees 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 degrees C).


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-alpha, 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.


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.

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