1. ¹Schizophrenia Program and the PET Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada
2. ²Neuroimaging Research Section, Centre for Addiction and Mental Health, Toronto, ON, Canada
3. ³Department of Pharmacology, University of Toronto, Toronto, ON, Canada
4. ⁴Department of Psychiatry, University of Toronto, Toronto, ON, Canada

Correspondence: Dr S Kapur, Centre for Addiction and Mental Health, ARF Site, 33 Russell Street, Toronto, ON, Canada M5S 2S1, Tel: +1 416 979 6890, Fax: +1 416 260 4206, E-mail: shitij_kapur@camh.net

Received 14 June 2006; Revised 16 October 2006; Accepted 17 October 2006; Published online 13 December 2006.

Abstract

There is growing interest in N-desmethylclozapine (NDMC), the major metabolite of clozapine, as a unique antipsychotic because it acts in vitro as a 5-HT₂ antagonist and as a partial agonist to dopamine D₂ and muscarinic receptors. To explore this, we compared NDMC to a typical (haloperidol), atypical (clozapine), and partial-agonist atypical (aripiprazole) antipsychotic in preclinical models. The comparison was carried out using: brain D₂ and 5-HT₂ receptor occupancy; animal models predictive of antipsychotic efficacy (amphetamine-induced hyperlocomotion (AIL) and conditioned avoidance response (CAR) models); measures predictive of side effects (catalepsy and prolactin elevation); and molecular markers predictive of antipsychotic action (striatal Fos induction). NDMC (10–60 mg/kg/s.c.) showed high 5-HT₂ (64–79%), but minimal D₂ occupancy (<15% at 60 mg/kg) 1 h after administration. In contrast to other antipsychotics, NDMC was not very effective in reducing AIL or CAR and showed minimal induction of Fos in the nucleus accumbens. However, like atypical antipsychotics, it showed no catalepsy, prolactin elevation, and minimal Fos in the dorsolateral striatum. It seems unlikely that NDMC would show efficacy as a stand-alone antipsychotic, however, its freedom from catalepsy and prolactin elevation, and its unique pharmacological profile (muscarinic agonism) may make it feasible to use this drug as an adjunctive treatment to existing antipsychotic regimens.