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.
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