Pharmacological Reviews
June 26, 2018
P. Zanos, R. Moaddel, Patrick J. Morris et al.
1,272 citations
Ketamine, in clinical use since 1970, is best known as a dissociative anesthetic but also has analgesic, anti-inflammatory, and antidepressant effects. This review covers its therapeutic uses by dose, route, and time course, along with side effects from short-term or prolonged exposure and recreational use. Ketamine is rapidly metabolized into norketamine, dehydronorketamine, hydroxyketamine, and hydroxynorketamine (HNK). While anesthetic and analgesic actions stem from inhibition of N-methyl-D-aspartate receptors, other targets include GABA, dopamine, serotonin, sigma, opioid, and cholinergic receptors, plus ion channels. HNK metabolites show antidepressant efficacy in preclinical studies, suggesting broader clinical relevance. Understanding these targets may help develop new drugs with ketamine's benefits but fewer side effects.
Biochemical Pharmacology
December 1, 2021
E. Hess, L. Riggs, M. Michaelides et al.
167 citations
Ketamine, an anesthetic, produces rapid antidepressant effects in people with treatment-resistant depression when given at sub-anesthetic doses, leading to FDA approval of esketamine. The mechanisms behind these effects remain under investigation, with evidence suggesting that ketamine's metabolites, such as (2R,6R)-hydroxynorketamine (HNK), may play a key role. HNK shows antidepressant potential in preclinical tests without ketamine's dissociative or abuse-related side effects. The review discusses how ketamine and its metabolites influence glutamate signaling through NMDARs and AMPARs, synaptic changes via BDNF, opioid receptor interactions, and enhancement of serotonin, norepinephrine, and dopamine signaling. Targeting these pathways could yield new rapid-acting antidepressants with fewer side effects.
Annual Review of Clinical Psychology
February 9, 2021
L. Riggs, T. Gould
87 citations
Traditional antidepressants can take weeks to work and often fail for many patients. In contrast, a single low dose of ketamine can relieve depression symptoms within hours, even in people who have not responded to other treatments. Ketamine is thought to repair damaged neural circuits by boosting glutamate signaling and promoting the release of neurotrophic factors that strengthen synaptic connections. This review covers the history of antidepressant development leading up to the ketamine discovery, critically evaluates proposed mechanisms for ketamine's rapid effects, and discusses how these insights are guiding current drug discovery.