Fourth-Generation Antipsychotics: novel mechanism of action and clinical indication

Abstract

Fourth-generation or novel-mechanism antipsychotics are characterized by distinctive pharmacological profiles that are largely dopamine-sparing or dopamine-independent in their mechanisms of action. Unlike traditional agents that primarily target D₂ receptors, these compounds modulate serotonergic, muscarinic, sigma, and trace amine-associated receptor pathways. These mechanisms represent a paradigm shift toward circuit-level modulation in antipsychotic drug development. Fourth-generation antipsychotics achieve antipsychotic effectiveness while improving cognition and tolerability. Their dopamine-independent actions promote restoration of neural network balance and neuroplasticity. This article summarizes pimavanserin, roluperidone, KarXT, emraclidine, brilaroxazine, and ulotaront, and highlights their clinical relevance for improving negative and cognitive symptoms with minimal risk of extrapyramidal symptoms, metabolic disturbances, and prolactin elevation