Ketamine and the Future of Rapid-Acting Antidepressants

Summary

Traditional antidepressants can take weeks to work and often fail for many patients. In contrast, a single low dose of ketamine can relieve depression symptoms within hours, even in people who have not responded to other treatments. Ketamine is thought to repair damaged neural circuits by boosting glutamate signaling and promoting the release of neurotrophic factors that strengthen synaptic connections. This review covers the history of antidepressant development leading up to the ketamine discovery, critically evaluates proposed mechanisms for ketamine's rapid effects, and discusses how these insights are guiding current drug discovery.

Study at a glance

Abstract

The therapeutic onset of traditional antidepressants is delayed by several weeks and many depressed patients fail to respond to treatment altogether. In contrast, subanesthetic ketamine can rapidly alleviate symptoms of depression within hours of a single administration, even in patients who are considered treatment-resistant. Ketamine is thought to exert these effects by restoring the integrity of neural circuits that are compromised in depression. This hypothesis stems in part from preclinical observations that ketamine can strengthen synaptic connections by increasing glutamate-mediated neurotransmission and promoting rapid neurotrophic factor release. An improved understanding of how ketamine, and other novel rapid-acting antidepressants, give rise to these processes will help foster future therapeutic innovation. Here, we review the history of antidepressant treatment advances that preceded the ketamine discovery, critically examine mechanistic hypotheses for how ketamine may exert its antidepressant effects, and discuss the impact this knowledge has had on ongoing drug discovery efforts.