Why Is Clozapine Uniquely Effective in Treatment-Resistant Schizophrenia? A Review and Proposal

A great deal is known about the use, benefits, and side effects of clozapine in treatment-resistant schizophrenia (TRS). However, why clozapine is more effective than other antipsychotics in TRS remains unclear. In this article, we address this question. Patients with TRS show glutamate abnormalities, and clozapine has widespread effects on glutamate. However, these actions have not been proven to be different from those of other antipsychotics. Immune dysfunction is also reported in TRS, and clozapine has anti-inflammatory actions, but these have not been correlated with clinical improvement. Currently, there is a great deal of interest in muscarinic abnormalities in psychosis. Unlike most antipsychotics, clozapine has important effects on muscarinic receptors, particularly M₁ and M₄, and its major metabolite, N-desmethylclozapine, is a full agonist at M₁. These effects are likely crucial to clozapine's effectiveness. In addition, clozapine's lower dopamine D₂ receptor occupancy has been postulated to allow gradual resolution of dopamine receptor supersensitivity in the minority of patients with TRS who initially respond to antipsychotics but become resistant following long-term dopamine blockade. However, this hypothesis remains controversial. Clozapine's multireceptor profile enables it to have beneficial actions on the nonpsychotic symptoms common in TRS; its ability to bind to histamine H₁, serotonin 5-HT_1A, and GABA_B (gamma-aminobutyric acid B) receptors offers an explanation for its anxiolytic actions, while effects on 5-HT_1A, 5-HT_2A, and 5-HT₇ receptors likely underlie its antidepressant properties. Clozapine shares these properties with olanzapine and quetiapine, but its affinity for muscarinic receptors may be the mechanism by which it is more effective in TRS.