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.
Journal of affective disorders • November 1, 2026 • Tse-Hwei Choo, Hanga C Galfalvy, John G Keilp et al.
A midazolam-controlled trial of intravenous ketamine for suicidal depressed patients found that ketamine rapidly reduced suicidal ideation within 24 hours. An exploratory analysis measured saliva cortisol awakening response at baseline and 24 hours after infusion. Waking cortisol significantly increased 24 hours after ketamine treatment. The increase in waking cortisol from baseline to post-infusion showed a small to medium, nonsignificant correlation with decreased suicidal ideation. These preliminary results, pending replication, align with evidence that moderate cortisol increases may enhance stress-resilience.
Journal of affective disorders • November 1, 2026 • Carlton M Kelly, Mathieu Fradet, Catherine M Bostian et al.
A single 25-mg dose of psilocybin with psychological support was associated with sustained improvements in anxiety, quality of life, functioning, and PTSD symptoms in 15 veterans with treatment-resistant depression. Anxiety scores dropped 59% from baseline at three weeks and remained lower through 12 months. Quality of life increased 24% and functional impairment decreased 46% at three weeks, though these effects were no longer statistically significant after accounting for concurrent improvements in depression. PTSD symptom reductions were observed at all timepoints. Acute subjective experiences did not correlate with treatment response. The study is limited by its small sample and open-label design.
Journal of affective disorders • September 15, 2026 • Rutger Boesjes, Claudia Oosterveld, Jeanine Kamphuis et al. • 1 citation
Ketamine and its enantiomers show rapid antidepressant effects for major depressive disorder and bipolar disorder, but responses vary widely. This systematic review of 26 studies (1694 participants) found that ketamine treatment is linked to improved subjective sleep quality. Preliminary evidence suggests that baseline sleep disturbances and early sleep improvements may predict antidepressant response. Some studies also indicate beneficial effects on objective sleep and circadian rhythmicity, but this finding is tentative due to few published articles. The authors call for more research on objective circadian measures and potential synergy with chronotherapies.
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 • September 1, 2026 • Nesreen Sedeek, Carley Rivers, Lucas Williamson et al.
Ketamine's rapid antidepressant effects in treatment-resistant depression are linked to changes in brain activity, but previous studies have been hard to compare due to differences in imaging techniques, analysis methods, and timing. A review combining fMRI and PET studies found that ketamine-related effects commonly appear in subcortical brain regions, with more variable effects in cortical areas like the prefrontal and anterior cingulate cortices. Network-level patterns suggest involvement of the default-mode, ventral attention, and visual systems. These findings are hypothesis-generating and highlight the need for future studies that harmonize methods to directly connect circuit changes to molecular mechanisms and clinical outcomes.
Journal of affective disorders • August 15, 2026 • Michał Walaszek, Wiesław Jerzy Cubała, Zofia Kachlik et al.
Anhedonia, a core symptom of major depressive disorder linked to poor outcomes, may be reduced by ketamine. In a retrospective analysis of 34 inpatients with treatment-resistant depression receiving short-term ketamine as an add-on to standard care, 16 patients (47.1%) did not respond to treatment, defined as less than a 50% reduction on the Snaith-Hamilton Pleasure Scale. Non-responders were more likely to be single, had fewer lifetime depressive episodes, and lower rates of prior substance use disorder. These factors suggest that psychosocial and demographic characteristics influence anhedonia treatment outcomes, supporting a personalized approach to mood disorder treatment.
Journal of affective disorders • August 1, 2026 • Guy M Goodwin, Scott T Aaronson, Oscar Alvarez et al. • 2 citations
In people with treatment-resistant depression receiving 25 mg psilocybin with monitoring and support, the therapeutic alliance before dosing had only weak correlations with improvement in depression scores at three weeks. Stronger correlations were seen with the intensity of the psychedelic experience itself, particularly emotional breakthrough and visual restructuring. Path analysis suggested that therapeutic alliance helped facilitate the psychedelic experience, but it was the psychedelic experience—not the alliance—that had stronger direct effects on clinical outcomes. The alliance's direct effect on antidepressant response was limited or absent.
The New England journal of medicine • November 3, 2022 • Guy M Goodwin, Scott T Aaronson, Oscar Alvarez et al. • 1,095 citations
A single 25 mg dose of psilocybin, but not 10 mg, reduced depression scores more than a 1 mg control dose over three weeks in adults with treatment-resistant depression. In this phase 2 trial, 233 participants were randomly assigned to 25 mg, 10 mg, or 1 mg of synthetic psilocybin with psychological support. The 25 mg group showed an average 12-point drop on the MADRS depression scale versus a 5.4-point drop in the 1 mg group, a significant difference. The 10 mg group did not differ significantly from control. Response and remission rates at three weeks supported the primary result, but sustained response at 12 weeks was not significantly different.
New England Journal of Medicine • April 14, 2021 • Robin Carhart‐Harris, Bruna Giribaldi, Rosalind Watts et al. • 1,372 citations
In a selected group of patients, psilocybin did not show a significantly greater antidepressant effect than escitalopram based on depression scores at week 6. Secondary outcomes generally favored psilocybin, but these analyses were not corrected for multiple comparisons. The authors call for larger and longer trials to compare psilocybin with established antidepressants.
JAMA Psychiatry • November 4, 2020 • Mary P Cosimano, Alan K. Davis, Frederick S. Barrett et al. • 1,269 citations
Two doses of psilocybin (20 and 30 mg per 70 kg) combined with supportive psychotherapy produced large, rapid antidepressant effects in adults with major depressive disorder who were not taking other antidepressants. In a randomized waiting list-controlled trial with 24 completers, depression scores on the GRID-Hamilton scale dropped from a mean of 22.8 at baseline to 8.0 one week after the second session, compared with 23.8 at the same time point in the delayed-treatment group. Seventy-one percent of participants showed a clinically significant response at week 1, and 58% met remission criteria. Effects persisted through the four-week follow-up.
American Journal of Psychiatry • May 21, 2019 • 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.
Psychopharmacology (Berl) • November 8, 2017 • 978 citations
In an open-label trial, twenty patients with severe, treatment-resistant major depression received two oral doses of psilocybin (10 mg and 25 mg, one week apart) in a supportive setting. Depressive symptoms dropped markedly within the first five weeks, with large effect sizes (Cohen's d = 2.2 at week 1 and 2.3 at week 5). Nine patients responded and four achieved remission at week 5. Improvements remained significant at three and six months (Cohen's d = 1.5 and 1.4). No one sought conventional antidepressants within five weeks. The quality of the acute psychedelic experience predicted symptom reductions at five weeks. Tolerability was good, and psilocybin appears promising for unresponsive depression, though double-blind trials are needed.
Journal of Psychopharmacology • November 30, 2016 • Annie Umbricht, Mary P Cosimano, Roland R. Griffiths et al. • 2,174 citations
In cancer patients with life-threatening diagnoses and symptoms of depression or anxiety, a high dose of psilocybin (22 or 30 mg/70 kg) produced large decreases in depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety, compared with a very low placebo-like dose (1 or 3 mg/70 kg). At 6-month follow-up, about 80% of participants continued to show clinically significant decreases in depressed mood and anxiety. Participants attributed improvements in attitudes about life, mood, relationships, and spirituality to the high-dose experience, with over 80% endorsing moderately or greater increased well-being or life satisfaction. The mystical-type experience during the session mediated the effect of dose on therapeutic outcomes.
Journal of Psychopharmacology • November 30, 2016 • Stephen Ross, Anthony Bossis, Jeffrey Guss et al. • 1,699 citations
A single moderate dose of psilocybin (0.3 mg/kg), combined with psychotherapy, produced immediate and sustained improvements in anxiety and depression among 29 patients with cancer-related psychological distress. At the 6.5-month follow-up, approximately 60–80% of participants continued to show clinically significant reductions in depression or anxiety. Psilocybin also decreased demoralization and hopelessness, improved spiritual wellbeing, quality of life, and attitudes toward death. The therapeutic effects on anxiety and depression were mediated by the psilocybin-induced mystical experience.
Lancet Psychiatry • May 17, 2016 • 1,546 citations
In an open-label trial, 12 patients with moderate-to-severe treatment-resistant depression received two doses of psilocybin (10 mg and 25 mg, one week apart) in a supportive setting. The psychedelic effects peaked 2-3 hours after dosing and subsided within 6 hours. No serious adverse events occurred; transient anxiety, confusion, nausea, and headache were noted. Depressive symptoms, measured with the Quick Inventory of Depressive Symptoms, were markedly reduced one week after the high dose (mean reduction of 11.8 points) and remained lower at three months (mean reduction of 9.2 points). Improvements in anxiety and anhedonia were also observed. The results provide preliminary support for psilocybin's safety and efficacy in treatment-resistant depression, warranting further controlled trials.
American Journal of Psychiatry • August 28, 2013 • 1,207 citations
A single intravenous infusion of ketamine produced greater improvement in depression severity 24 hours later than the active placebo midazolam in patients with treatment-resistant major depression. In a randomized controlled trial of 73 participants, the ketamine group scored 7.95 points lower on the Montgomery-Åsberg Depression Rating Scale than the midazolam group. Response rates were 64% for ketamine and 28% for midazolam, with an odds ratio of 2.18 favoring ketamine. The findings support NMDA receptor modulation as a mechanism for rapid improvement in severe, chronic depression, though more information on durability and safety is needed before clinical use.
Science • October 4, 2012 • 1,613 citations
Depression involves shrinkage of brain regions that regulate mood and cognition, such as the prefrontal cortex and hippocampus, along with reduced neuronal synapses in those areas. Typical antidepressants can reverse some of these deficits but work slowly and have limited effectiveness. Ketamine, a drug that blocks N-methyl-D-aspartate receptors, rapidly (within hours) improves symptoms in patients who do not respond to standard antidepressants. In basic studies, ketamine quickly promotes the formation of new synapses and reverses the synaptic damage caused by chronic stress. These findings suggest that maintaining healthy mood circuit connections is central to depression and its treatment, forming the basis of a synaptogenic hypothesis.
Archives of General Psychiatry • August 1, 2010 • 969 citations
A single intravenous dose of ketamine, an N-methyl-D-aspartate-receptor antagonist, produced rapid antidepressant effects in patients with treatment-resistant bipolar depression. Depressive symptoms improved within 40 minutes and remained significantly better than placebo through day 3. The largest drug effect occurred at day 2. Seventy-one percent of subjects responded to ketamine versus 6% to placebo. One subject in each group developed manic symptoms. Ketamine was generally well tolerated, with dissociative symptoms only at the 40-minute point.
August 21, 2006 • 1,332 citations
The authors developed mindfulness-based cognitive therapy (MBCT), a theory-driven psychological intervention to reduce relapse in recurrent major depression. MBCT centrally incorporates mindfulness training, drawing heavily on the mindfulness-based stress reduction (MBSR) program created by Jon Kabat-Zinn and colleagues. MBSR integrates traditional Buddhist mindfulness meditation practices into a structured eight-week program, originally designed for hospital patients with various medical conditions who had no prior meditation experience.
Archives of General Psychiatry • August 1, 2006 • 3,762 citations
A single intravenous dose of ketamine, an N-methyl-D-aspartate receptor antagonist, produced rapid and robust antidepressant effects in treatment-resistant major depression. Improvement was significant within 110 minutes and remained so for one week. The effect size was very large after 24 hours and moderate to large after one week. Among 17 subjects, 71% met response and 29% met remission criteria the day after infusion; 35% maintained response for at least one week. These findings suggest a role for glutamatergic modulation in achieving rapid relief from depression.
Journal of Consulting and Clinical Psychology • January 1, 2004 • 1,401 citations
Mindfulness-based cognitive therapy (MBCT) added to usual care reduced relapse from 78% to 36% in recovered depressed patients with three or more previous episodes, replicating earlier findings. In patients with only two recent episodes, relapse rates were 20% with usual care and 50% with MBCT. MBCT was most effective at preventing relapses not preceded by life events. Relapses in the two-episode group were more often linked to significant life events. The two-episode group reported less childhood adversity and later first depression onset, suggesting distinct populations. MBCT is an effective way to prevent relapse in patients with three or more previous episodes.