Ketamine: 50 Years of Modulating the Mind

Abstract

Ketamine was introduced into clinical practice in the 1960s and continues to be both clinically useful and scientifically fascinating. With considerably diverse molecular targets and neurophysiological properties, ketamine's effects on the central nervous system remain incompletely understood. Investigators have leveraged the unique characteristics of ketamine to explore the invariant, fundamental mechanisms of anesthetic action. Emerging evidence indicates that ketamine-mediated anesthesia may occur via disruption of corticocortical information transfer in a frontal-to-parietal ("top down") distribution. This proposed mechanism of general anesthesia has since been demonstrated with anesthetics in other pharmacological classes as well. Ketamine remains invaluable to the fields of anesthesiology and critical care medicine, in large part due to its ability to maintain cardiorespiratory stability while providing effective sedation and analgesia. Furthermore, there may be an emerging role for ketamine in treatment of refractory depression and Post-Traumatic Stress Disorder. In this article, we review the history of ketamine, its pharmacology, putative mechanisms of action and current clinical applications.

Keywords: anesthesia; consciousness; depression; functional connectivity; ketamine; neuropharmacology; post-traumatic stress disorder.

Figure 1

Dr. Edward Domino as a young faculty at the University of Michigan. Dr. Domino is now in his 90s, an Emeritus Professor, and still active as a scientist in the field of neuropharmacology. Photograph provided courtesy of the University of Michigan Bentley Historical Library.

Figure 2

Structure of Ketamine.

Figure 3

Measures of directed connectivity after induction with Ketamine, adapted from Blain-Moraes et al. (2014). Graphical depiction of dominant feedback connectivity in the waking state that is neutralized after ketamine induction. Please see original article (Blain-Moraes et al., 2014) for additional information.