What Are We Looking for in New Antipsychotics?

Abstract

Antipsychotics are the cornerstone of treatment for psychotic and some nonpsychotic disorders. However, despite pharmacologic advances, considerable areas of need remain. This article reviews desirable properties for future antipsychotics and considers how far current agents have come in achieving those objectives. Preferably, new antipsychotics should have a "balanced" pharmacodynamic profile that addresses the need for efficacy without compromising psychiatric or physical well-being; a safe, fast, and convenient pharmacokinetic profile; a definable therapeutic window, and availability in multiple formulations. Compared with available agents, new antipsychotics should ideally have at least similar efficacy for positive symptoms, agitation, and aggression and better efficacy for negative or cognitive symptoms, relapse prevention, treatment-resistant illness, and associated problems such as depression, anxiety, and substance abuse. Improved tolerability and subjective acceptability to patients are also important in promoting adherence and continued treatment. Finally, they should have improved effectiveness in facilitating functioning, subjective well-being, quality of life, and, ultimately, recovery. Given the complexity of schizophrenia, its unknown etiology and pathophysiology, and challenges in clinical trial design and conduct, it is not surprising that it has remained difficult to develop antipsychotics with novel mechanisms. To achieve true breakthroughs, we need greater insight into the pathophysiology underlying specific disease processes and therapeutic and adverse responses. It is hoped that research on drug-specific biomarkers that can predict response in specific patient groups will advance personalized psychiatric care and improve patient outcomes.