Neurobiological Mechanisms of Ketamine: Depression, Suicide, Trauma, and Chronic Stress Pathologies

Ketamine's discovery as a rapid antidepressant has transformed drug development and understanding of chronic stress pathology. This review covers the history of NMDA receptor modulators leading to ketamine's psychiatric use, its rapid antidepressant and antisuicidal effects, a model of synaptic loss and dysconnectivity underlying chronic stress pathology, clinically relevant biomarkers and mechanisms, and how ketamine may both reverse chronic stress pathology and serve as a research tool. The authors discuss outstanding questions and the ongoing debate between optimism and concern about ketamine's widespread use.

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Abstract

The serendipitous discovery of ketamine's robust antidepressant effects has served as a major catalyst to usher in new era of drug development and a paradigm shift in our understanding of the neurobiology of chronic stress pathology (CSP). This review provides a selective synthesis of (1) the historical foundations of N-methyl-D-aspartate receptor modulators and the path to discovering ketamine's use in psychiatry; (2) ketamine's clinical efficacy, specifically its rapid-acting antidepressant and rapid-acting antisuicidal effects; (3) a model of synaptic loss and dysconnectivity thought to underlie CSP; (4) clinically relevant biomarkers and mechanisms of action; and (5) how ketamine may be both an effective treatment to reverse and normalize CSP as well as a tool to further our understanding of depression, trauma, suicidality, and CSP. We conclude with a brief discussion of outstanding questions and the continued struggle between optimism and concern regarding ketamine's widespread utility as a pharmacologic agent. [ Psychiatr Ann . 2020;50(2):48–53.]