Pharmacology and Therapeutics
May 1, 2023
J. Johnston, I. Henter, C. Zarate
106 citations
Ketamine shows rapid antidepressant effects in treatment-resistant depression, but side effects and misuse risk limit its use. Its two enantiomers, (S)- and (R)-ketamine, work through different mechanisms: (S)-ketamine affects mTORC1 signaling, while (R)-ketamine affects ERK signaling. Preclinical studies suggest divergent pathways, and clinical research indicates (R)-ketamine has a milder side effect profile and reduces depression scores. However, recent randomized controlled trials found (R)-ketamine had no significant antidepressant efficacy compared to placebo, so caution is needed when interpreting its therapeutic potential. Further research is required to optimize dosing, route, and administration for each enantiomer.
Drug Discovery Today
February 1, 2023
J. Johnston, Maximillian Greenwald, I. Henter et al.
64 citations
Stress triggers inflammation in the brain, a pattern also seen in the blood of people with depression. This stress-induced inflammation may contribute to treatment-resistant depression. The rapid-acting antidepressant ketamine works partly by reducing inflammation through effects on the HPA axis, the kynurenine pathway, or by suppressing cytokines. Understanding the link between ketamine, inflammation, and stress could reveal how ketamine works and lead to new rapid-acting antidepressants that target inflammation.
October 23, 2018
B. Kadriu, Subha Subramanian, Z. Deng et al.
preprint
Major depressive disorder (MDD) is common, debilitating, and linked to suicide risk. Standard antidepressants can take weeks to work and have low remission rates, with about a third of patients not fully responding. Newer therapies targeting the glutamatergic system, such as ketamine, offer rapid antidepressant effects and high remission rates. This chapter reviews evidence for several novel therapeutics—ketamine, esketamine, nitrous oxide, scopolamine, GLYX-13, and buprenorphine—as well as interventional techniques like sleep deprivation. Ketamine and esketamine also rapidly reduce suicidal thoughts, making them useful in emergencies. Pivotal drug trials using rodents, neuroimaging, and electrophysiological studies are also reviewed to understand the neurocircuitry underlying MDD.