Tandon and Kane1 provide a thoughtful review of the neuropharmacological profile of the atypical antipsychotic drug, clozapine, in the February 1993 issue of the ARCHIVES. They propose that the in vivo partial agonist effect of clozapine may be relevant for the beneficial effect of clozapine in the treatment of patients with refractory schizophrenia. They derive support for this possibility from the cholinergic-dopaminergic imbalance model of schizophrenia wherein an overactive muscarinic system may diminish the expression of positive psychotic symptoms presumably caused by dopaminergic hyperfunction.2 Other pharmacological evidence not reviewed by the authors also supports a role for the muscarinic system in the atypical therapeutic effects of clozapine; muscarinic antagonists attenuate the increase in accumbens and striatum dopamine metabolism produced by clozapine but not by haloperidol.3
Although the cholinergic-dopaminergic model adequately explains the therapeutic effect of clozapine on positive symptoms, it does not explain improvement of negative symptoms.
Keshavan M. Muscarinic Effects of Clozapine and Negative Symptoms. Arch Gen Psychiatry. 1993;50(10):835. doi:10.1001/archpsyc.1993.01820220091014