American Journal of Psychiatry
May 21, 2019
Vanina Popova, Ella J. Daly, Madhukar 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 J. 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.
World Psychiatry
September 15, 2023
Roger S. McIntyre, Mohammad Alsuwaidan, Bernhard T. Baune et al.
712 citations
At least 30% of people with depression meet the common definition of treatment-resistant depression (TRD): inadequate response to two or more antidepressants despite adequate trials and adherence. Many cases are actually pseudo-resistant due to insufficient treatment or non-adherence. No consensus definition with proven predictive utility for clinical decisions exists, leading to varied prevalence estimates and inconsistent care. Intravenous ketamine and intranasal esketamine are effective for TRD. Some second-generation antipsychotics (e.g., aripiprazole, quetiapine XR) help as adjuncts in partial responders, but only the olanzapine-fluoxetine combination has been studied in FDA-defined TRD. Repetitive transcranial magnetic stimulation and electroconvulsive therapy are established effective interventions. Evidence for extending trials, switching, or combining antidepressants is mixed, and manual-based psychotherapies are not effective alone but help when added to antidepressants.
JAMA Psychiatry
December 27, 2017
Ella J. Daly, Jaskaran B. 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.
American Journal of Psychiatry
April 8, 2016
Jaskaran Singh, Maggie Fedgchin, Ella Daly et al.
530 citations
In adults with treatment-resistant depression, intravenous ketamine (0.5 mg/kg) given two or three times per week produced a substantial and similar reduction in depression scores over 15 days compared to placebo. The twice-weekly ketamine group showed an average 18.4-point drop on the Montgomery-Åsberg Depression Rating Scale, versus 5.7 points for placebo; the thrice-weekly group showed a 17.7-point drop, versus 3.1 points for placebo. Headache, anxiety, dissociation, nausea, and dizziness were common side effects, but dissociative symptoms were temporary and lessened with repeated doses.
Journal of Psychopharmacology
November 30, 2016
Richard C. Shelton, Peter S. Hendricks
14 citations
No Summary
CNS Spectrums
July 29, 2022
Ibrahim Turkoz, Oliver Lopena, Giacomo Salvadore et al.
6 citations
In adults with major depressive disorder and active suicidal ideation with intent who did not show early improvement, adding esketamine nasal spray to standard care increased the likelihood of achieving a response (63.9% vs 48.0%) and remission (35.1% vs 24.4%) after four weeks compared to placebo plus standard care. The odds of response were nearly double with esketamine. Similar benefits appeared for those who had not responded after one week. The findings suggest that continuing esketamine treatment for the full four weeks can be beneficial even when early response is absent.
JAMA Network Open
May 7, 2026
Peter S. Hendricks, Sara Lappan, Richard C. Shelton et al.
4 citations
A single 25 mg dose of psilocybin, combined with psychotherapy, led to a higher percentage of cocaine-abstinent days, a greater likelihood of complete abstinence, and a longer time before the first cocaine lapse over 180 days compared with an active placebo (100 mg diphenhydramine) in a randomized, quadruple-blind trial. Among 40 participants with cocaine use disorder, 33 were men, 33 were Black, and most had low income. Psilocybin appeared safe, with no serious adverse events, and may offer a treatment for cocaine use disorder in underrepresented populations.
Expert Opin Investig Drugs
May 26, 2026
Mina Takahashi, Richard C. Shelton
A review of a two-step approach for bipolar depression with acute suicidal ideation and behavior: an initial intravenous ketamine protocol for rapid symptom relief, followed by maintenance with D-cycloserine and lurasidone to prolong therapeutic effects. The strategy is mechanistically informed but uncertainties remain about which components drive efficacy, optimal dosing, and duration of benefits. Further studies are needed to refine maintenance strategies and translate insights into clinical practice.