THE CLOZAPINE LEGACY: FUTURE DIRECTIONS IN TREATMENT-RESISTANT SCHIZOPHRENIA AND PARKINSON'S DISEASE PSYCHOSIS

ABSTRACT Clozapine is an exceptionally potent atypical antipsychotic medication that was developed in the 1950s and is notable for a low affinity for the dopamine D2 receptor. Following multiple fatal cases of agranulocytosis, the drug was withdrawn from the market but later reinstated with strict laboratory monitoring. Despite the risks, clozapine is regarded as the most effective medication in two different types of psychosis: treatment-resistant schizophrenia and psychosis in Parkinson’s disease. Although the landmark studies demonstrating the effectiveness of clozapine in both conditions were published decades ago, it remains strikingly underutilized, possibly due to risk of serious adverse effects, clinician reluctance and lack of experience and administrative complexity. It is unlikely that clozapine will ever fully escape these barriers, and continued delays in initiating effective treatment will therefore continue to undermine care. Gladly, novel treatment alternatives are emerging for both disorders. Over the past two decades, focus has shifted from dopaminergic strategies towards pharmacological agents targeting other neurotransmitter receptors that have a role in psychosis. In particular, pimavanserin, a serotonin receptor antagonist/inverse agonist, has been approved for psychosis in Parkinson’s disease, and glutamate modulating compounds have been shown to enhance the effectiveness of clozapine in treatment-resistant schizophrenia. Moreover, agonists of acetylcholine receptors may hold theoretical promise for improving outcomes across both conditions. This narrative review explores the future direction that treatment of both disorders may take.