Ketamine treatment for depression: a review

Abstract

This manuscript reviews the clinical evidence regarding single-dose intravenous (IV) administration of the novel glutamatergic modulator racemic (R,S)-ketamine (hereafter referred to as ketamine) as well as its S-enantiomer, intranasal esketamine, for the treatment of major depressive disorder (MDD). Initial studies found that a single subanesthetic-dose IV ketamine infusion rapidly (within one day) improved depressive symptoms in individuals with MDD and bipolar depression, with antidepressant effects lasting three to seven days. In 2019, esketamine received FDA approval as an adjunctive treatment for treatment-resistant depression (TRD) in adults. Esketamine was approved under a risk evaluation and mitigation strategy (REMS) that requires administration under medical supervision. Both ketamine and esketamine are currently viable treatment options for TRD that offer the possibility of rapid symptom improvement. The manuscript also reviews ketamine’s use in other psychiatric diagnoses—including suicidality, obsessive–compulsive disorder, post-traumatic stress disorder, substance abuse, and social anxiety disorder—and its potential adverse effects. Despite limited data, side effects for antidepressant-dose ketamine—including dissociative symptoms, hypertension, and confusion/agitation—appear to be tolerable and limited to around the time of treatment. Relatively little is known about ketamine’s longer-term effects, including increased risks of abuse and/or dependence. Attempts to prolong ketamine’s effects with combined therapy or a repeat-dose strategy are also reviewed, as are current guidelines for its clinical use. In addition to presenting a novel and valuable treatment option, studying ketamine also has the potential to transform our understanding of the mechanisms underlying mood disorders and the development of novel therapeutics.

Depression in Adolescence and Brain-Derived Neurotrophic Factor

“…Recently, ketamine, a glutamate modulator, has attracted great attention due to its rapid antidepressant effect in adults ( Frizzo, 2019 ). Ketamine also appears to be effective in reducing anhedonia and suicidality in adolescent MDD patients, making ketamine a potentially valuable new treatment option for adolescents ( Dwyer et al, 2021 ; Yavi et al, 2022 ). An increase in BDNF mRNA or protein levels in the hippocampus and prefrontal cortex by ketamine treatment has been reported in animal models of depression ( Autry et al, 2011 ), and results from clinical studies of an increase in serum BDNF with ketamine treatment have also been reported in MDD patients ( Strasburger et al, 2017 ; Arosio et al, 2021 ).…”

An open-label study evaluating the safety, behavioral, and electrophysiological outcomes of low-dose ketamine in children with ADNP syndrome

“…The informed consent procedure included extensive discussion of potential risks of ketamine, including sedation, headache, nausea, elevated blood pressure and heart rate, and perceptual disturbances. 27 While this study involved only a single dose, caregivers were also informed that repeated ketamine use has been associated with structural and functional brain changes, 28 cognitive problems, and increased inflammatory cytokines. 29 Ten participants were screened, and all met criteria for inclusion and were enrolled between August 2020 and May 2021.…”

Application of Intranasal Administration in the Delivery of Antidepressant Active Ingredients

“…The U.S. FDA approved the intranasal S-enantiomer of ketamine (Esketamine) in 2019 for the treatment of MDD in adults. The S-enantiomer of ketamine is more potent on NMDAR than the R-enantiomer and racemic ketamine [ 127 , 128 ]. R-enantiomer of ketamine exhibits more potent and longer-lasting antidepressant effects [ 129 ].…”