Molecular Mechanism and Clinical Relevance of Ketamine as Rapid-Acting Antidepressant

Preclinical Research The emergence of rapid-acting antidepressants such as ketamine has motivated studies aiming to reveal the molecular mechanism of the ketamine antidepressant effect and to enable the clinical application of rapid-acting antidepressants. Here, we provide an overview of studies addressing the antidepressant effects of ketamine in depressed patients and animal models of depression and we compare the reduction of depressive symptoms in humans with the reduction in immobility time in the forced swim test in rodents after acute ketamine treatment. We also discuss different theories and potential biochemical pathways involved in the rapid antidepressant response to ketamine including the modulation of glutamatergic neurotransmission and intracellular hub-kinase activation. Finally, we summarize recent brain-region specific studies and we suggest that the activation of the ventral hippocampus-medial prefrontal cortex-dorsal raphae nuclei (vHC-mPFC-DRN) neuronal pathway may mediate the antidepressant effect of ketamine. Although substantial progress has been made, further brain-region specific animal studies and longitudinal clinical trials are necessary for the understanding and successful application of novel rapid-acting antidepressants. Drug Dev Res 77 : 414-422, 2016. © 2016 Wiley Periodicals, Inc.