Clozapine-Associated Neuroleptic Malignant Syndrome: Two New Cases and a Review of the Literature

BACKGROUND: Clozapine has recently been found to be associated with neuroleptic malignant syndrome (NMS). Our objective is to determine if clozapine causes NMS, if the presentation of clozapine-induced NMS differs from that of traditional agents, and which set of diagnostic criteria will most readily allow diagnosis of NMS associated with clozapine. METHODS: Two new cases of clozapine-associated NMS are presented, along with previously reported cases from the literature, identified by using a MEDLINE search (1966-August 1998). From all cases, concomitant medications and washout periods were examined (if available) to assess clozapine as the likely cause of NMS. Characteristics of clozapine and traditional antipsychotic-induced NMS were compared. Different diagnostic criteria for NMS were applied to the cases to determine which were more likely to diagnose the syndrome. RESULTS: Clozapine was deemed a highly probable cause of NMS in 14 cases, a medium probability cause in five cases, and a low probability cause in eight cases. The most commonly reported clinical features were tachycardia, mental status changes, and diaphoresis. Fever, rigidity, and elevated creatine kinase were less prominent than in NMS associated with classical neuroleptics. CONCLUSIONS: Clozapine appears to cause NMS, although the presentation may be different than that of traditional antipsychotics. Levenson's original and Addonizio's modified criteria were more likely to diagnose NMS than were other criteria. Clozapine-associated NMS may present with fewer clinical features. Limitations are the lack of detailed information provided by many of the case reports and the use of "modified" diagnostic criteria for retrospective diagnosis.