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Review Article

Beyond White Blood Cell Monitoring: Screening in the Initial Phase of Clozapine Therapy

Dan Cohen, MD, PhD; Jan P. A. M. Bogers, MD; Daniel van Dijk, MD; Bert Bakker, MD; and Peter F. J. Schulte, MD, PhD

Published: October 15, 2012

Article Abstract

Objective: Clozapine is the preferred option for treatment-resistant schizophrenia. However, since 1975, clozapine has been known to cause agranulocytosis. In the clozapine screening guidelines, white blood cell count is mandatory. In the past 20 years, after its reintroduction, 3 other serious side effects, namely, diabetic ketoacidosis, gastrointestinal hypomotility, and myocarditis have been documented but have so far failed to be incorporated in the screening guidelines. The objective of this review is to determine whether an update of the screening guidelines for serious side effects with clozapine is evidence based.

Data Sources: The English-language literature, available via MEDLINE or PubMed, on the incidence of 4 clozapine-related side effects, using clozapine, agranulocytosis, diabetic ketoacidosis, and gastrointestinal hypomotility as keywords, that have been published over the period 1976-2010, was collected.

Study Selection: 16 studies that provided incidence rates or data from which these rates could be calculated were included.

Data Extraction: We compared 1-year incidence rates, mortality rates in the whole study population and in the affected cases. When rates reflected longer periods of observation, the given rate was recalculated to obtain a 1-year incidence rate.

Results: The incidence of clozapine-induced agranulocytosis varies between 3.8′ °-8.0′ °. The mortality rate is 0.1′ °-0.3′ °, and the case-fatality rate is 2.2′ °-4.2′ °. In diabetic ketoacidosis, the incidence was calculated at 1.2′ °-3.1′ °, and the case-fatality rate was 20%-31%. In gastrointestinal hypomotility, the incidence was 4′ °-8′ °, and the case-fatality rate was 15%-27.5%. The discrepancy in incidence rates between Australia (7′ °-34′ °) and the rest of the world (0.07′ °-0.6′ °) impairs a general approach of this side effect.

Conclusions: In 2 of the 3 studied side effects, diabetic ketoacidosis and gastrointestinal hypomotility, reduction of mortality to the level of agranulocytosis is both necessary and feasible. In order to obtain this outcome, the screening guidelines need to be modified; early detection of treatment-emergent hyperglycemia, that might—via diabetes mellitus—develop into diabetic ketoacidosis, requires obligatory monthly measurement of fasting plasma glucose. To prevent gastrohypomotility, and complications therefrom, the clinician should be required to choose between either weekly monitoring or standard coprescription of laxatives for prevention. The reported incidence of myocarditis (high in Australia, low in the rest of the world) is too divergent to allow for an overall recommendation outside Australia.

J Clin Psychiatry 2012;73(10):1307-1312

Submitted: March 1, 2011; accepted May 7, 2012 (doi:10.4088/JCP.11r06977).

Corresponding author: Dan Cohen, MD, PhD, Department of Severe Mental Illness, Mental Health Care Organization North-Holland North, Hectorlaan 19, 1702 CL Heerhugowaard, The Netherlands (

Volume: 73

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