Letters to the Editor
Atypical Neuroleptic Malignant Syndrome With Clozapine and Subsequent Haloperidol Treatment
Dear Editor:
Clozapine can cause neuroleptic malignant syndrome (NMS), with a presentation that may be atypical in that it may occur without rigidity, fever, or changes in creatine kinase (CK) (1). We report a patient who developed atypical NMS while taking clozapine, followed by a similar syndrome while taking haloperidol.
Mr A, aged 22 years, had a 5-year history of disorganized schizophrenia.
He had previously failed trials of olanzapine, valproic acid, and risperidone.
During an admission for exacerbated symptoms, a trial of clozapine was
initiated. Prior to initiation, his white blood cell count (WBC) was slightly
elevated, at 13.3 109/L. Neutrophils, blood pressure (BP), and heart rate
(HR) were normal. The clozapine was started at 25 mg daily and titrated
to 325 mg daily over 16 days, while his risperidone dosage of 5 mg daily
was tapered off completely. Atypically, he had mild hypertension (maximum
156/96) on clozapine, which persisted. On day 17 of clozapine treatment,
he declined his medication and was observed to be more disorganized. The
following day, he vomited and was diaphoretic, agitated, and delirious,
yet afebrile. He became more hypertensive and tachycardic, with marked
elevations in his WBC (31.8 109/L), neutrophils (24.8 109/L), and CK (1442
IU/L). There was no rigidity or evidence of an infectious process. We discontinued
the clozapine, and he received haloperidol 5 mg, and lorazepam 2 mg, daily.
His WBC, neutrophils, BP, and HR all normalized within 24 hours. Over the
following week, his delirium resolved and his CK dropped to 361 IU/L. After
5 days on haloperidol, his WBC, neutrophils, and CK suddenly rose again
(17 109/L, 12.8 109/L, and 598 IU/L, respectively). He remained normotensive
but became tachycardic. We discontinued haloperidol, and his vital signs
and laboratory values subsequently normalized. Following a 1-week period
of no antipsychotic (AP) treatment, Mr A was started on olanzapine without
any further adverse effects.
To our knowledge, this is the first report of an atypical NMS occurring with clozapine and then repeated with another agent. It is possible that the return of this patient’s NMS symptoms might have been caused by residual clozapine in his system. However, the resolution of his laboratory abnormalities and symptoms, followed by their recurrence 5 days later, makes this unlikely. Certain individuals may be sensitive to clozapine and its low affinity for dopamine receptors (2), and this may underlie an incomplete NMS presentation. A multifactorial contribution from neurotransmitters may also explain the basis of atypical NMS (3). Haloperidol is a relatively specific dopamine blocker and the recurrence of NMS while Mr A was taking this medication lends more support to the dopaminergic theory. Nonetheless, this case highlights the possibility that patients taking clozapine may develop atypical NMS. Once NMS is present, subsequent AP medication should be introduced with caution.
References
1. Karagianis JL, Phillips LC, Hogan KP, LeDrew KK. Clozapine-associated neuroleptic malignant syndrome: two new cases and a review of the literature. Ann Pharmacother 1999;33: 623–30.
2. Kapur S, Seeman P. Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics? A new hypothesis. Am J Psychiatry 2001;3:360–9.
3. Amore M, Zazzeri N, Beradi D. Atypical neuroleptic malignant syndrome associated with clozapine treatment. Neuropsychobiology 1997;35:197–9.
Mitchell Spivak
Beverly Adams
David Crockford
Calgary, Alberta
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