American Journal of Psychiatry
May 21, 2019
Vanina Popova, Ella Daly, Madhukar H. Trivedi et al.
879 citations
Switching to esketamine nasal spray plus a new antidepressant led to a significantly greater reduction in depression severity after 28 days than switching to a new antidepressant alone in adults with treatment-resistant depression. The average improvement on the Montgomery-Åsberg Depression Rating Scale was 4 points greater with esketamine (95% CI -7.31 to -0.64). Earlier improvements were also seen. Common side effects included dissociation, nausea, vertigo, dysgeusia, and dizziness, which typically appeared shortly after dosing and resolved within 1.5 hours. Seven percent of esketamine patients discontinued due to adverse events versus 0.9% in the comparator group. The findings support esketamine as a rapidly acting option for this difficult-to-treat population.
JAMA Psychiatry
June 5, 2019
Ella Daly, Madhukar H. Trivedi, Adam Janik et al.
766 citations
For adults with treatment-resistant depression who achieved stable remission or response after 16 weeks of esketamine nasal spray plus an oral antidepressant, continuing esketamine plus the antidepressant delayed relapse significantly more than switching to placebo plus the antidepressant. Among those in stable remission, 26.7% relapsed on esketamine versus 45.3% on placebo, a 51% reduction in relapse risk. Among stable responders, 25.8% relapsed on esketamine versus 57.6% on placebo, a 70% reduction. Common side effects of esketamine included transient taste disturbance, vertigo, dissociation, drowsiness, and dizziness.
JAMA Psychiatry
December 27, 2017
Ella Daly, Jaskaran Singh, Maggie Fedgchin et al.
708 citations
In adults with treatment-resistant depression, intranasal esketamine at doses of 28 mg, 56 mg, and 84 mg produced a rapid, dose-related reduction in depressive symptoms compared to placebo, as measured by the Montgomery-Åsberg Depression Rating Scale. The improvement appeared to persist for more than two months even when dosing frequency was reduced. Adverse events leading to discontinuation occurred in 5% of esketamine-treated participants during the double-blind phase and in 2% during the open-label phase, with no such events in the placebo group.
Psychopharmacology Bulletin
March 4, 2024
Timothy Whitaker, Kimberly F Farrand, Michael E. Thase
249 citations
No approved therapy exists for suicidal ideation and behavior (SI/B) in Major Depressive Disorder (MDD), though ketamine shows rapid antidepressant effects. While FDA-approved esketamine reduced suicidality indicators, its effects did not significantly surpass placebo. Racemic ketamine, a mixture of esketamine and arketamine, may better alleviate SI/B. In an open-label study, 17 hospitalized MDD patients with acute SI/B received intranasal racemic ketamine (SLS-002). Treatment significantly reduced depression and suicidality scores on four clinical scales, including the Montgomery-Åsberg Depression Rating Scale and Sheehan-Suicidality Tracking Scale. SLS-002 was well tolerated with an acceptable safety profile, supporting continued development.
The Journal of Clinical Psychiatry
August 14, 2023
Michael E. Thase
9 citations
After decades of limited progress in treating major depressive disorder (MDD), especially for patients unresponsive to standard antidepressants, the serendipitous discovery of ketamine's antidepressant effects has renewed optimism. This has spurred development of related drugs like S-ketamine and oral NMDA antagonists showing promise in late-stage trials. An extended-release combination of bupropion (105 mg) and dextromethorphan (45 mg) reduced MADRS total scores in recipients. Neurosteroids such as brexanolone and zuranolone represent another class, modulating GABA neurotransmission, a pathway long used for insomnia and anxiety. Psychedelic drugs, after nearly 50 years of legal restrictions, are also being investigated, with psilocybin under study for treatment-resistant depression.
JAMA Psychiatry
March 25, 2026
Wiesław Jerzy Cubała, Malek Bajbouj, Michael Bauer et al.
3 citations
A single day of treatment with an inhaled synthetic formulation of mebufotenin (GH001) significantly reduced depression symptoms in adults with treatment-resistant depression compared to placebo. In a randomized, double-blind trial of 81 patients, those receiving up to three escalating doses of GH001 showed an average 15.5-point greater improvement on the Montgomery-Åsberg Depression Rating Scale by day 8 than those on placebo. Remission rates were 57.5% for GH001 and 0% for placebo. No severe or serious adverse events occurred. The findings suggest GH001 may be a rapid-acting, well-tolerated treatment option for treatment-resistant depression.
Biological Psychiatry Global Open Science
July 1, 2025
Stephen A Murata, Zachary B Madaj, Colt D Capan et al.
1 citation
Higher baseline levels of anthranilic acid (AA), a metabolite in the kynurenine pathway, predicted remission in patients with treatment-resistant depression receiving intravenous ketamine. In an open-label trial of 74 patients, 52% achieved remission after three infusions. Composite ratios of AA to intercellular adhesion molecule-1 and AA to tryptophan improved predictive accuracy over AA alone. The findings suggest that immunometabolic biomarkers could guide personalized ketamine treatment.
Psychopharmacology Bulletin
June 5, 2026
Michael E. Thase, Brian Brennan, Rachael Macisaac et al.
In patients with treatment-resistant depression, a single-day individualized dosing regimen of inhaled GH001 (synthetic mebufotenin) produced rapid and large improvements in depressive symptoms compared with placebo in a Phase 2b trial, with 57.5% achieving remission at Day 8 versus 0% on placebo. A post hoc analysis of 40 patients who received GH001 found no meaningful correlation between the number of prior lifetime antidepressant treatment failures and improvement on the Montgomery-Åsberg Depression Rating Scale at Day 8 or among 6-month open-label extension completers. Remission rates at Day 8 were similar across subgroups with 2, 3, 4, or 5 or more prior failures (range 53.9%-63.6%) and were maintained at Month 6 (range 61.5%-85.7%). The efficacy of GH001 appears largely independent of how many prior antidepressant treatments a patient has tried.
The Journal of Clinical Psychiatry
May 4, 2026
Samuel T. Wilkinson, Brandon Kitay, Matthew Macaluso et al.
Adding cognitive behavioral therapy to esketamine treatment reduces suicidal ideation more than esketamine alone in people with major depression and suicidal thoughts. In a randomized trial of 93 patients, 72% completed the study, meeting feasibility goals. Those who received 16 weeks of CBT plus esketamine showed greater improvement on three measures of suicidal ideation than those receiving esketamine with usual care: a mean difference of -1.91 on the Beck Scale for Suicidal Ideation, -0.33 on the Clinician Global Improvement Scale for Suicide Severity, and -3.77 on the depression rating scale. No difference was found on the Columbia-Suicide Severity Rating Scale or in suicide-related events.