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Published: March 2007
ADR update

Clozapine: Fatal 'constipation' more common than fatal agranulocytosis

Prescriber Update 28(1): 7
March 2007

PM Ellis*, Wellington School of Medicine; RM McLean and M Harrison-Woolrych**, Intensive Medicines Monitoring Programme, University of Otago

Clozapine (Clozaril®, Clopine®) is an atypical antipsychotic that is effective for treatment-resistant schizophrenia.  It causes agranulocytosis in up to 1% of patients1 and regular monitoring of neutrophil counts is mandatory throughout treatment.  In New Zealand one death from agranulocytosis has been reported to the IMMP.  In contrast, four deaths from complications of severe constipation have been reported.  This article reminds health professionals that the gastrointestinal effects of clozapine are potentially serious.  Awareness of this issue may prevent life-threatening complications.

Clozapine-induced constipation may be fatal

Constipation is often regarded as a frequent, minor side effect of clozapine.  However, review of New Zealand reports received by the IMMP shows that clozapine-induced constipation may be associated with serious effects such as intestinal obstruction, bowel perforation and toxic megacolon.  The four deaths reported to IMMP demonstrate that these effects can be fatal.

Clozapine affects motility throughout the gut
In addition to reports of constipation associated with clozapine, IMMP has received three reports of paralytic ileus and a further three reports of oesophageal dysmotility.  These case reports suggest that clozapine may reduce gastrointestinal (GI) motility throughout the gut, resulting in complications higher in the GI tract.

Mechanism - anticholinergic, serotonergic and more

Many anticholinergic drugs can cause GI dysmotility, but clozapine has a much more potent effect through its interaction with multiple receptors, (including anticholinergic and serotonergic receptors) affecting GI activity.  This action is exacerbated by co-prescription of anticholinergic agents such as benztropine and tricyclic antidepressants.

Take-home messages

Competing interests (authors):
* None declared.
**IMMP has in the past received unconditional grants from several pharmaceutical companies, including Novartis who are one of the sponsors of clozapine in NZ.  However, pharmaceutical companies have no role in the design, analysis or interpretation of IMMP studies.

Reference
  1. Alvir JMJ, Lieberman JA, Safferman AZ, et al.  Clozapine-induced agranulocytosis.  New England Journal of Medicine 1993;329:162-167.