Nature
April 24, 2016
P. Zanos, R. Moaddel, Patrick J. Morris et al.
1,602 citations
A metabolite of ketamine, (2R,6R)-hydroxynorketamine (HNK), produces rapid and sustained antidepressant-like effects in mice without the side effects associated with ketamine itself. These effects do not rely on blocking NMDA receptors but instead involve early and ongoing activation of AMPA receptors. This finding points to a new mechanism for developing faster-acting antidepressants with fewer unwanted effects.
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.
Journal of affective disorders
March 15, 2025
Polymnia Georgiou, Cristan A Farmer, Gustavo C Medeiros et al.
24 citations
Baseline levels of stress-related hormones (CRF, ACTH, and cortisol) did not significantly influence how well ketamine worked as an antidepressant in people with treatment-resistant depression. However, higher levels of ACTH and CRF were associated with longer overall duration of depressive episodes, suggesting these hormones might serve as biomarkers for chronic depression. Additionally, people who developed depression at a younger age tended to have more severe depressive symptoms, indicating that earlier onset may lead to greater cumulative stress on the brain and body. The study involved 42 participants in a randomized, placebo-controlled, crossover trial.
Biological psychiatry
March 15, 2025
Anna Onisiforou, Andria Michael, Markos Apostolakis et al.
14 citations
Opioid use disorder (OUD) has reached epidemic levels, and current medications, while lifesaving, fail to address negative affect and cognitive impairment, leading to high relapse rates even years after drug cessation. Ketamine, an anesthetic and rapid-acting antidepressant, shows promise for treating OUD, including managing acute withdrawal symptoms, negative affect during protracted abstinence, and preventing return to opioid use. This review examines preclinical and clinical research on ketamine and its metabolites as novel therapeutic strategies. Evidence demonstrates that ketamine and its metabolites can modulate pathophysiological processes in OUD, suggesting a promising role in treatment and relapse prevention.