¹National Institute of Mental Health, Intramural Research Program, Clinical Brain Disorders Branch, Bethesda, MD, USA

Correspondence: Dr DR Weinberger, Clinical Brain Disorders Branch, NIMH, National Institutes of Health, 10 Center Drive, 4S-235 (MSC 1379), Bethesda, MD 20892-1379, USA. Tel: +1 301 402 7956; Fax: +1 301 480 7795; E-mail: weinberd@intra.nimh.nih.gov

²Current address: Department of Psychiatry, University of Hamburg, Martinistr. 52, 20246 Hamburg, Germany.

³Current address: Stanley Foundation Research Programs, 5430 Grosvenor Lane, Suite 200 Bethesda, MD 20814, USA.

Received 20 February 2002; Revised 15 April 2003; Accepted 16 April 2003; Published online 11 June 2003.

Abstract

Clozapine is the prototypical atypical antipsychotic. In vitro, clozapine antagonizes a broad range of receptors, including dopamine, serotonin and muscarinic acetylcholine receptors. In vivo, receptor occupancy studies have shown moderate dopamine D₂ receptor blockade as well as high serotonin 5HT₂ receptor blockade for clozapine. Using [I-123]IQNB SPECT, we explored the influence of clozapine on muscarinic receptors in vivo. Eight schizophrenia patients underwent a total of 12 [I-123]IQNB SPECT scans after treatment with low to moderate doses of clozapine (mean 210 mg/day, range 50–450 mg/day). Muscarinic receptor availability was determined for basal ganglia, cortex, thalamus, and pons. A group of 12 age- and sex-matched unmedicated schizophrenia patients was used for comparison. Compared to unmedicated patients, [I-123]IQNB binding was lower in all regions in subjects treated with clozapine and decreased with increasing dose. In patients treated with a daily clozapine dose of at least 200 mg (mean 27588 mg/day), these differences were highly significant (p<0.003) with mean reductions of muscarinic receptor availability of 45% for basal ganglia, 58% for cortex, 66% for pons, and 79% for thalamus. These preliminary data indicate that reduction of muscarinic receptor availability by clozapine can be measured in vivo and that moderate daily doses are associated with moderate to high reductions of muscarinic receptor availability. These results may explain, at least in part, the lack of extrapyramidal side effects as well as some side effects seen with clozapine.