Antipsychotic drugs at 75: the past, present, and future of psychosis management

Abstract

Introduction: The discovery of chlorpromazine in 1950 marked a turning point in psychiatry, and, for the first time, effective pharmacological treatments for psychosis became widely used. Over the following decades, antipsychotics became the cornerstone of schizophrenia treatment, yet their fundamental mechanism—dopamine D2 receptor antagonism—has remained largely unchanged. Now, 75 years on, novel drug classes and advances in mechanistic understanding are reshaping the field. Sources of data: This review synthesizes findings from clinical trials, neurobiological research, and pharmacological studies, highlighting the evolution of antipsychotic treatment. Areas of agreement: Antipsychotics reduce positive symptoms, but their efficacy for negative and cognitive symptoms is limited. Clozapine remains the gold standard for treatment-resistant schizophrenia. Areas of controversy: The typical/atypical distinction is increasingly seen as outdated. The dopamine hypothesis, while central, does not fully explain schizophrenia. Growing points: Emerging nondopaminergic treatments—such as the muscarinic agonist xanomeline-trospium—offer new therapeutic avenues. Areas timely for developing research: Further research is needed to determine the clinical utility of nondopaminergic drugs, refine stratified treatment approaches, and integrate precision psychiatry into psychosis management.