Better Biomarkers, Faster Drugs, Stronger Models: Progress Towards Precision Psychiatry.

New treatments for major depressive disorder are moving beyond traditional monoamine-targeting antidepressants toward options like κ-opioid antagonists, ketamine, and neurosteroids. These advances, combined with smartphone-based experience sampling and brain imaging, enable more precise diagnosis and symptom-specific measurement. This convergence heralds 'precision psychiatry'—selecting optimal treatments for individual patients. Anhedonia exemplifies this shift, evolving from a mere depression criterion to a transdiagnostic condition understood neurobiologically and targeted by novel pharmacotherapies. Functional testing of reward circuits in developing κ-opioid antagonists for anhedonia illustrates how other treatments, including psychedelics, may fit into future precision psychiatric care.

Study at a glance

Abstract

The 21st century has brought novel therapies and new therapeutic targets for major depressive disorder (MDD). Until recently all antidepressant medications targeted monoamines-serotonin, norepinephrine, and dopamine- and their regulatory systems. But growing evidence has suggested that individuals who fail to respond to a monoaminergic treatment are likely to fail to respond to other monoaminergic options. The emergence in recent years of treatment targets beyond the monoaminergic systems (e.g. κ-opioid antagonists, ketamine and other NMDA modulators, neurosteroids) has cultivated hopes for not only greater efficacy in treating depression, but also improved precision in targeting specific phenotypes and symptoms. Concurrently, an expanding repertoire of diagnostic and assessment tools-such as smartphone-based experience sampling and brain imaging-is moving the field toward more reliable and symptom-specific measurement with greater descriptive and prescriptive power. Taken together, these diagnostic tools and treatment options herald a new era of "precision psychiatry"-the selection and implementation of an optimal treatment for an individual patient's particular needs. Anhedonia offers an example of the new precision psychiatry. Anhedonia has moved from merely one among several criteria for depression to a transdiagnostic psychopathology which can be understood neurobiologically, assessed quantitatively, and centered as a primary target in research and development of novel pharmacotherapies. We describe functional testing of reward circuits in the development of kappa-opioid antagonists for anhedonia. This offers a lens for understanding how and under what circumstances other novel treatments, such as psychedelics, might find a place in the future landscape of precision psychiatric care.