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Serum Antimuscarinic Activity During Clozapine Treatment

de Leon, Jose MD*; Odom-White, Aruby MD*†; Josiassen, Richard C. PhD; Diaz, Francisco J. PhD*†; Cooper, Thomas B. MA‡§; Simpson, George M. MD

Journal of Clinical Psychopharmacology: August 2003 - Volume 23 - Issue 4 - p 336-341
doi: 10.1097/
Original Contributions

This study attempts: (1) to verify that serum antimuscarinic activity is related to clozapine dose, and more importantly to clozapine plasma concentrations; (2) to explore whether norclozapine has serum antimuscarinic activity; (3) to explore whether antimuscarinic activity is related to clozapine side effects; and (4) to compare the serum antimuscarinic activities of clozapine with those of antiparkinsonian drugs and other antipsychotics.

In 39 patients participating in a double-blind clozapine study, the [3H]QNB assay was used to measure serum antimuscarinic activity: (1) on baseline medications; (2) after a 4-week haloperidol trial; (3) after a 16-week clozapine trial of either 100, 300, or 600 mg/d; and (4) after 1 or 2 consecutive 16-week clozapine trials with remaining doses in nonresponders.

Clozapine levels predicted serum antimuscarinic activity better than clozapine dose. At the end of the 1st clozapine trial, the correlation with the levels explained 69% of the variance of serum antimuscarinic activity (r = 0.83, P < 0.001, N = 34). Clozapine levels were good predictors of serum antimuscarinic activity only in patients taking 300 or 600 mg/d. After correcting for clozapine levels, the within-subject correlation between norclozapine levels and serum antimuscarinic activity was relatively high and significant (r = 0.54, F = 26.7, df = 1.65, P < 0.001). Constipation was significantly associated with higher serum antimuscarinic activity during the 1st clozapine trial. Clozapine was associated with clearly higher antimuscarinic activity than other antipsychotics or low doses of antiparkinsonians. In vitro studies and new clinical studies are needed to verify whether norclozapine may significantly contribute to antimuscarinic activity during clozapine treatment.

*Mental Health Research Center, Eastern State Hospital, Lexington, KY;

†Department of Statistics, Universidad Nacional, Medellin;

‡Nathan Kline Institute, Orangeburg, NY;

§New York University School of Medicine, New York, NY;

∥Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA;

¶The Arthur P. Noyes Research Foundation, Norristown, PA and the Department of Psychiatry, University of Pennsylvania Medical School, Philadelphia, PA.

Received May 13, 2002; accepted after revision November 20, 2002.

Address correspondence and reprint requests to Jose de Leon, MD, Mental Health Research Center, Eastern State Hospital, 627 West Fourth Street, Lexington, KY 40508. E-mail:

© 2003 Lippincott Williams & Wilkins, Inc.