Updates on Preclinical and Translational Neuroscience of Mood Disorders A Brief Historical Focus on Ketamine for the Clinician

Background The development of new-generation antidepressants comes at a time of great clinical need when the global burden of depression, suicide, and other psychiatric conditions continues to increase. Our current treatment armamentarium is limited by the time delay needed for antidepressant effects and the significant number of patients who do not show an adequate response to antidepressants. The past 2 decades of psychiatric research has revealed that ketamine, known to be used only as an anesthetic and drug of abuse and to produce experimental models of psychosis, is effective at subanesthetic doses to ameliorate clinical depression. Methods We performed a systematic search of PubMed/MEDLINE indexed reports to identify clinical and translational research done with ketamine for purposes of treating depression. Results We will first present the rationale for investigating ketamine and other N-methyl-d-aspartate receptor antagonists as a novel class of glutamate system targeting antidepressants. We will summarize putative molecular pathways underlying mood disorders and outline a brief history of investigation into ketamine as a treatment for depression. Recent clinical/translational evidence of ketamine's rapid-acting antidepressant mechanism will be critically reviewed in detail. Conclusions At the end of this review, we will opine on the role of ketamine and derivatives in clinical practice.