Drug targeting in psychiatric disorders — how to overcome the loss in translation?

In spite of major efforts and investment in development of psychiatric drugs, many clinical trials have failed in recent decades, and clinicians still prescribe drugs that were discovered many years ago. Although multiple reasons have been discussed for the drug development deadlock, we focus here on one of the major possible biological reasons: differences between the characteristics of drug targets in preclinical models and the corresponding targets in patients. Importantly, based on technological advances in single-cell analysis, we propose here a framework for the use of available and newly emerging knowledge from single-cell and spatial omics studies to evaluate and potentially improve the translational predictivity of preclinical models before commencing preclinical and, in particular, clinical studies. We believe that these recommendations will improve preclinical models and the ability to assess drugs in clinical trials, reducing failure rates in expensive late-stage trials and ultimately benefitting psychiatric drug discovery and development. Several challenges hamper the translation of preclinical drug discovery efforts into safe and effective therapies for psychiatric disorders. In their Perspective, Khodosevich and colleagues highlight differences between drug targets in animal models and those in patients as a key reason for failed clinical studies. They present a framework that integrates single-cell and spatial omics data to overcome this loss in translation, which they hope will assist the development of new drugs for diseases such as schizophrenia and major depressive disorder.