European journal of psychotraumatology
December 1, 2026
Maud Rothärmel, Lila Mekaoui, François Kazour et al.
1 citation
In a retrospective study of 22 adults with treatment-resistant depression and comorbid post-traumatic stress disorder who received esketamine nasal spray, trauma re-experiencing episodes occurred during treatment sessions. For 16 patients (72.7%) these episodes disappeared as sessions progressed. Treatment was stopped for 6 patients (27.3%) due to re-experiencing. Among those who continued esketamine, depression response rate was 45.5% and remission 22.7%; PTSD improvement rate was 45.5% and remission 18.2%. The findings suggest esketamine can be safely administered in this comorbid population and that trauma re-experiencing does not prevent clinical improvement.
Journal of affective disorders
November 1, 2026
Lindsay L Benster, Jordan N Kohn, Benjamin Wade et al.
In a real-world comparison of two FDA-approved treatments for treatment-resistant depression, intranasal esketamine led to faster improvement than repetitive transcranial magnetic stimulation (rTMS). Over 90 days, esketamine patients responded a median of 36 days versus 49 days for rTMS, and suicidal ideation resolved more quickly (median 9 vs. 26 days). However, by about 90 days, overall response and remission rates were similar between the groups (68.8% and 45.2% for esketamine; 59.4% and 40.1% for rTMS), suggesting a difference in speed rather than ultimate effectiveness. For rTMS, slower response was predicted by comorbid anxiety and benzodiazepine use, while former tobacco use predicted faster response. No such predictors were found for esketamine.
Journal of affective disorders
November 1, 2026
Dian-Jeng Li, Tien-Wei Hsu, Te-Chang Changchien et al.
Patients with major depressive disorder who are prescribed esketamine have higher rates of comorbid substance use disorders compared to those treated with antidepressants or repetitive transcranial magnetic stimulation. Among esketamine users, those with a substance use disorder face greater risks of self-harm, suicide attempt, emergency visits, hospitalization, and mortality. The findings indicate a prescription bias toward patients with comorbid substance use disorders and highlight the need for careful monitoring and specialized care for this population.
Psychiatry research
September 1, 2026
Isis Lunsky, Gilmar Gutierrez, Xena Wang et al.
Postpartum depression (PPD) is common and harmful if untreated, with few effective prevention strategies. Ketamine and esketamine are rapid-acting antidepressants showing promise for PPD. This review searched five databases for peer-reviewed randomized controlled trials, pilot studies, and observational studies examining ketamine or esketamine for PPD prevention during pregnancy or postpartum, for both cesarean and vaginal deliveries. A network meta-analysis and narrative synthesis were used. Thirty-six studies were identified; five included vaginal delivery, thirty included cesarean section, and one did not specify delivery mode. Results suggested that ketamine and esketamine were well tolerated and may reduce PPD risk. However, data quality was low to very low, so results should be interpreted cautiously. More high-quality studies are needed.
Journal of affective disorders
August 1, 2026
João Paulo Atidio, Rodrigo Simonini Delfino, Igor Saque Garios et al.
In patients with treatment-resistant depression receiving subcutaneous esketamine over six weeks, depressive symptoms improved significantly, with MADRS scores dropping by an average of 2.82 points per week. Those also taking benzodiazepines had higher depression scores throughout treatment, while lamotrigine and lithium showed no significant effect on outcomes. No medication altered the rate of improvement over time. The findings suggest benzodiazepine use may blunt the antidepressant response to esketamine, but further prospective research is needed.
Brain research bulletin
August 1, 2026
Rui Dong, Jiaxin Liu, Yumei Shen et al.
In a mouse model of trigeminal neuralgia (TN) that also shows anxiety-like behavior, esketamine (ES) given for five days dose-dependently reduced pain and anxiety. TN caused damage to neurons in the hippocampus and increased levels of the necroptosis pathway proteins RIPK1, RIPK3, and MLKL. ES treatment reversed these changes, protecting neurons and restoring dendritic spines. Adding a necroptosis activator blocked ES's effects, confirming that ES works by inhibiting the RIPK1/RIPK3/MLKL pathway. The findings highlight necroptosis as a key mechanism linking TN pain to emotional disorders and suggest ES could be repurposed as a treatment for both pain and anxiety in TN.
Journal of affective disorders
August 1, 2026
Ching-Hua Julie Lee, Yunzhe Qian, Weiqun Yu et al.
Compared with injectable ketamine, esketamine was linked to higher risks of suicidal ideation (24% increase), generalized anxiety disorder (55% increase), insomnia (25% increase), and cardiac arrest (57% increase). Compared with oral antidepressants in treatment-resistant depression, esketamine was associated with lower risks of suicidal ideation (11% decrease), suicide attempt (29% decrease), and generalized anxiety disorder (18% decrease), but a higher risk of cardiac arrest (109% increase). Injectable ketamine showed a more favorable safety and effectiveness profile than esketamine. Head-to-head clinical trials are needed to validate these findings.
Zenodo (CERN European Organization for Nuclear Research)
July 17, 2026
Bartosz Niciński, Magdalena Kloc, Ewa Wiench, Natasza Millan, Aleksandra Blicharz, Wojciech Kozdraś, Lidia Kozaczko, Gabriela Szewczyk, Elżbieta Bukowczan, Alicja Zając, Damian Broda, Alicja Benecka
Major depressive disorder is a common and burdensome condition, and many patients do not fully recover after standard antidepressant treatment, prompting interest in rapid-acting interventions that target brain pathways beyond serotonin, norepinephrine, and dopamine. This review examines ketamine, esketamine, and classic psychedelics for depression, especially treatment-resistant depression. Ketamine and esketamine have the strongest evidence, with ketamine showing rapid antidepressant and anti-suicidal effects, and intranasal esketamine being the first NMDA receptor antagonist approved for treatment-resistant depression. Psilocybin-assisted therapy has shown promising results but remains investigational and requires a structured therapeutic framework. Evidence for LSD, DMT, and mescaline is preliminary. These treatments highlight the roles of glutamatergic modulation, serotonergic mechanisms, and neuroplasticity. Key unresolved issues include maintaining effects over time, identifying which patients benefit most, and safe delivery outside specialized settings.
Journal of affective disorders
July 16, 2026
Sara Massetti, Sanne Y Smith-Apeldoorn, Jolien K E Veraart et al.
Ketamine and its enantiomer esketamine are effective in only 30-35% of patients with treatment-resistant depression. Increased serum brain-derived neurotrophic factor (BDNF) after a single intravenous dose has been proposed as a biomarker of antidepressant response, but effects under different treatment schedules are unclear. In a randomized, placebo-controlled trial of six-week, low-dose, oral esketamine (90 mg/day, three 30 mg intakes), depression severity and serum BDNF were measured in 54 patients at baseline, end of treatment, and after a four-week washout. BDNF levels did not significantly differ between esketamine and placebo groups during treatment or washout. An increase in BDNF occurred regardless of treatment condition.
Open MIND
July 13, 2026
Vassilis Martiadis, Fabiola Raffone
In patients receiving routine esketamine treatment for depression, the reduction in suicidal thoughts over six months is not fully explained by concurrent improvement in depressive symptoms, suggesting a partly independent anti-suicidal effect. This pattern also holds for deliberate self-harm in the subgroup with comorbid borderline personality disorder, a population previously excluded from clinical trials. Early improvement in depression predicts later reduction in suicidal ideation, but a direct, non-mediated path remains. Change in trait impulsivity was explored as an alternative mediator of these effects.
New England Journal of Medicine
October 4, 2023
Andreas Reif, Istvan Bitter, Jozefien Buyze et al.
197 citations
In treatment-resistant depression, esketamine nasal spray combined with an SSRI or SNRI led to remission in 27.1% of patients at week 8, compared to 17.6% for extended-release quetiapine plus an SSRI or SNRI. Over 32 weeks, 21.7% of patients on esketamine had no relapse after remission versus 14.1% on quetiapine. The open-label, single-blind, randomized trial included 676 patients. Adverse events matched known safety profiles. Esketamine was superior to quetiapine for achieving remission and preventing relapse.
Neuropsychopharmacology
May 12, 2023
Naim Zaki, Li Chen, Rosanne Lane et al.
122 citations
Adults with treatment-resistant depression who continued esketamine nasal spray plus an oral antidepressant in a long-term extension study (SUSTAIN-3) showed sustained improvement in depression ratings over up to 4.5 years. Among 1148 participants, common side effects included headache, dizziness, nausea, dissociation, somnolence, and nasopharyngitis. Depression scores dropped during the initial four-week induction phase and remained low during maintenance; about 46% of participants were in remission at the maintenance phase endpoint. No new safety concerns emerged with long-term, intermittent dosing.
American Journal of Psychiatry
March 17, 2021
R. Mcintyre, J. Rosenblat, C. Nemeroff et al.
694 citations
Ketamine and esketamine are the first non-monoamine-based antidepressants with rapid-onset efficacy for adults with treatment-resistant depression, offering hope to those who do not recover fully with standard antidepressants. However, concerns remain about their safety, tolerability, and appropriate placement in treatment algorithms. An international group of mood disorder experts synthesizes evidence on efficacy, safety, and tolerability, and provides guidance for clinical implementation, including practice parameters at point of care. Areas of consensus and future research directions are discussed.
Journal of Affective Disorders
September 23, 2020
A. Bahji, G. Vázquez, C. Zarate
404 citations
A systematic review and meta-analysis of 24 randomized controlled trials with 1,877 participants compared racemic ketamine and esketamine for unipolar and bipolar major depression. Racemic ketamine showed greater treatment response (rate ratio 3.01 versus 1.38) and remission rates (rate ratio 3.70 versus 1.47) than esketamine, and had lower dropout rates (rate ratio 0.76 versus 1.37). Intravenous ketamine appears more efficacious than intranasal esketamine for depression.
The Journal of Clinical Psychiatry
May 11, 2020
Dong-Jing Fu, Dawn F. Ionescu, Xiang Li et al.
367 citations
In adults hospitalized for major depressive disorder with active suicidal thoughts, adding esketamine nasal spray to standard treatment (antidepressants and hospitalization) reduced depression symptoms more than placebo plus standard treatment within 24 hours, with benefits persisting over four weeks. The difference in suicidal ideation severity between groups was not statistically significant. Common side effects of esketamine included dizziness, dissociation, headache, nausea, and drowsiness.
The Journal of Clinical Psychiatry
April 20, 2020
Ewa Wajs, Leah Aluisio, Richard Holder et al.
288 citations
In a year-long open-label study of 802 adults with treatment-resistant depression, esketamine nasal spray combined with a new oral antidepressant showed a manageable safety profile and sustained improvement in depressive symptoms. Common side effects included dizziness, dissociation, nausea, and headache, mostly mild or moderate and resolving the same day. Two deaths occurred, neither linked to the drug. Cognitive performance remained stable or improved. Depression scores dropped during the first four weeks and stayed lower through the maintenance phase.
Drug Design Development and Therapy
December 1, 2019
Jing Wang, Jie Huang, Shuang Yang et al.
214 citations
A single 0.5 mg/kg dose of esketamine is generally safe and tolerated in Chinese patients undergoing painless gastroscopy. Compared with 1 mg/kg racemic ketamine, esketamine provides a shorter recovery time (9 minutes vs. 13 minutes) and orientation recovery time (11.5 minutes vs. 17 minutes). Adverse event rates were 75.0% for esketamine and 87.5% for racemic ketamine, with dizziness, agitation, nausea, vomiting, headache, and fatigue as main reactions; no serious adverse events occurred. Clearance of esketamine was similar between groups (18.1 and 18.4 mL/min·kg), but in the racemic group esketamine cleared faster than R-ketamine. Gender did not affect pharmacokinetics.
Journal of Affective Disorders
November 14, 2019
F. S. Correia-Melo, G. C. Leal, F. Vieira et al.
188 citations
In adults with treatment-resistant depression, a single intravenous infusion of esketamine (0.25 mg/kg) was non-inferior to ketamine (0.5 mg/kg) for achieving remission 24 hours later. Among 63 participants, 29.4% in the esketamine group and 24.1% in the ketamine group showed remission, a difference of 5.3% that fell within the predefined non-inferiority margin. Depression scores on the Montgomery-Åsberg Depression Rating Scale improved similarly in both groups, and side effects were mild and comparable. The findings suggest that esketamine at half the dose of ketamine offers equivalent short-term efficacy and safety.
The International Journal of Neuropsychopharmacology
July 9, 2019
Maggie Fedgchin, Madhukar Trivedi, Ella J Daly et al.
593 citations
In a phase 3 trial of 346 adults with moderate-to-severe treatment-resistant depression, adding esketamine nasal spray (56 or 84 mg twice weekly) to a new oral antidepressant for 4 weeks did not significantly reduce depression scores compared to adding placebo nasal spray. The 84 mg dose failed to separate from placebo on the primary outcome, and the 56 mg dose could not be formally tested due to the statistical hierarchy. However, the magnitude of improvement with both esketamine doses exceeded what is typically considered clinically meaningful for approved antidepressants. Common side effects included nausea, dissociation, dizziness, vertigo, and headache. The authors conclude the results provide supportive evidence for esketamine's safety and efficacy in treatment-resistant depression.
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.
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.
American Journal of Psychiatry
April 16, 2018
Carla M. Canuso, Jaskaran B. Singh, Maggie Fedgchin et al.
666 citations
Adding intranasal esketamine to standard care rapidly reduced depression symptoms in people at imminent suicide risk. In a double-blind trial, 68 participants received either esketamine (84 mg) or placebo twice weekly for four weeks. Depression scores improved significantly more with esketamine at 4 hours and 24 hours after the first dose, but not at 25 days. Suicidal thoughts improved at 4 hours but not later. Clinician-rated suicide risk did not differ between groups at any time. Common side effects of esketamine included nausea, dizziness, dissociation, unpleasant taste, and headache. The findings suggest esketamine may offer rapid but temporary relief for severe depression with suicide risk.
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.
European Archives of Psychiatry and Clinical Neuroscience
April 18, 2016
Kenji Hashimoto, Takeharu Kakiuchi, Hiroyuki Ohba et al.
125 citations
Esketamine, but not R-ketamine, reduces dopamine D2/3 receptor binding availability in the monkey striatum, indicating that esketamine triggers dopamine release in this brain region. This dopamine release may underlie the psychotomimetic side effects of esketamine. R-ketamine, in contrast, does not affect striatal dopamine D2/3 binding, consistent with its proposed safer profile as a rapid antidepressant. The findings suggest a neurochemical difference between the two ketamine enantiomers that could explain their distinct side-effect profiles.