Ketamine’s mechanism of rapid antidepressant activity: Evidence gleaned from clinical studies

Abstract

The discovery of antidepressant medications more than 50 years ago was one of the major breakthroughs in medical science. Today, the field of antidepressant drug development is experiencing a paradigm shift. Changing perceptions regarding the neurobiology of depression and the serendipitous discovery of ketamine’s rapid antidepressant effects have ushered in a new era of innovative research and novel drug development. This chapter provides a selective review of the suspected mechanisms of ketamine’s rapid antidepressant action in human subjects gleaned from multiple controlled and open-label trials. We also briefly review the underlying neurobiology of depression, potential biomarkers of ketamine response, the efficacy and safety profile of ketamine, current limitations to its widespread use, and considerations for novel drug development that hold promise for improved psychotherapeutic treatments for depressive and trauma-related disorders.