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.
European journal of psychotraumatology • December 1, 2026 • V Ursule Taujanskaite, Sunjeev K Kamboj
A 6-item short form of the Clinician Administered Dissociative States Scale (CADSS-SF) was developed using data from three studies of nitrous oxide in 229 healthy volunteers, then validated in 80 separate participants. The single-factor scale, composed of derealization and depersonalization items, showed excellent model fit and internal consistency (omega = 0.87), correlated strongly with the full 19-item CADSS (r ≥ 0.88), and moderately with a measure of psychotomimesis (r = 0.63). The CADSS-SF enables rapid, repeated assessment of dissociation during drug intoxication without disrupting the experience, but primarily captures derealization and depersonalization and requires further validation beyond drug-induced dissociation in healthy populations.
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 • 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 • 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.
Neuropharmacology • September 15, 2026 • Taisiia Prosvirova, Wiktoria Podolecka, Jacek Wrobel et al.
Ketamine rapidly reorganizes fast brain rhythms differently across cortical networks. In freely moving rats, neocortical gamma power increased broadly, while the olfactory bulb showed suppressed gamma alongside robust high-frequency oscillations (HFO; 130-180 Hz). Local blockade of non-NMDA glutamate receptors in the olfactory bulb suppressed ketamine-enhanced HFO in the bulb, ventral striatum, and prefrontal cortex without affecting neocortical gamma, indicating separate circuit mechanisms. Within the bulb, a kainate receptor antagonist markedly reduced HFO, while AMPA receptor blockade had minimal effect. Blocking GABA-A receptors reduced HFO power while increasing gamma power, showing that fast inhibition is necessary for HFO expression. The findings suggest that tonic kainate-dependent depolarization recruits interneurons to generate an inhibitory network rhythm that drives HFO propagation through olfactory-limbic circuits.
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.
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.
JAMA Psychiatry • June 5, 2019 • 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 • 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.
Pharmacological Reviews • June 26, 2018 • P. Zanos, R. Moaddel, Patrick J. Morris et al. • 1,272 citations
Ketamine, in clinical use since 1970, is best known as a dissociative anesthetic but also has analgesic, anti-inflammatory, and antidepressant effects. This review covers its therapeutic uses by dose, route, and time course, along with side effects from short-term or prolonged exposure and recreational use. Ketamine is rapidly metabolized into norketamine, dehydronorketamine, hydroxyketamine, and hydroxynorketamine (HNK). While anesthetic and analgesic actions stem from inhibition of N-methyl-D-aspartate receptors, other targets include GABA, dopamine, serotonin, sigma, opioid, and cholinergic receptors, plus ion channels. HNK metabolites show antidepressant efficacy in preclinical studies, suggesting broader clinical relevance. Understanding these targets may help develop new drugs with ketamine's benefits but fewer side effects.
American Journal of Psychiatry • April 16, 2018 • 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.
Molecular Psychiatry • March 13, 2018 • P. Zanos, T. Gould • 1,112 citations
A single low dose of the anesthetic ketamine can rapidly and lastingly relieve depression, but its abuse potential and dissociative side effects limit widespread use. This review examines proposed molecular mechanisms for ketamine's antidepressant action, including inhibition of specific N-methyl-D-aspartate receptors (NMDARs), effects on GABAergic interneurons, and suppression of burst firing in the lateral habenula. It also discusses downstream pathways involving brain-derived neurotrophic factor (BDNF), eukaryotic elongation factor 2 (eEF2), mTOR, and GSK-3, as well as the roles of ketamine's (R)-ketamine enantiomer and the metabolite (2R,6R)-hydroxynorketamine. These mechanisms likely work together to trigger lasting changes in synaptic plasticity that underlie the antidepressant effects.
JAMA Psychiatry • December 27, 2017 • 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 • October 3, 2017 • S. Wilkinson, Elizabeth D. Ballard, M. Bloch et al. • 680 citations
A single dose of ketamine rapidly reduces suicidal thoughts within one day and for up to one week in depressed patients with suicidal ideation. The effect is moderate to large and partially independent of changes in depressive symptoms. The analysis combined data from 167 participants across 10 studies comparing ketamine to a placebo (saline or midazolam). Ketamine significantly improved clinician-rated and self-reported suicidal ideation, though not on one self-report measure (the Beck Depression Inventory). The authors call for further research on long-term safety and suicide risk reduction before clinical use.
Nature • April 24, 2016 • P. Zanos, R. Moaddel, Patrick J. Morris et al. • 1,602 citations
A metabolite of ketamine, (2R,6R)-hydroxynorketamine (HNK), produces rapid and sustained antidepressant-like effects in mice without the side effects associated with ketamine itself. These effects do not rely on blocking NMDA receptors but instead involve early and ongoing activation of AMPA receptors. This finding points to a new mechanism for developing faster-acting antidepressants with fewer unwanted effects.
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.
CNS Neuroscience & Therapeutics • April 10, 2013 • G. Mion, Thierry Villevieille • 690 citations
For over 50 years, ketamine has been a safe anesthetic with potent pain-relieving properties. Its active form is S(+)-ketamine, and it is mainly metabolized into norketamine, an active metabolite. During dissociative anesthesia, sensory inputs reach the brain but are not perceived in some association areas. Ketamine also enhances the descending serotonin pathway for pain relief and has antidepressant effects. Pain relief persists at plasma concentrations ten times lower than those needed for hypnosis. By blocking the NMDA receptor, ketamine reduces the wind-up phenomenon and hyperalgesia, including opioid-induced hyperalgesia.
Science • August 19, 2010 • Nanxin Li, Boyoung Lee, Rongjian Liu et al. • 2,875 citations
Ketamine, a drug that blocks NMDA receptors, rapidly activates the mTOR pathway in the prefrontal cortex of rats, increasing synaptic signaling proteins and the number and function of new spine synapses. Blocking mTOR signaling prevented ketamine from inducing synaptogenesis and behavioral antidepressant-like responses in depression models. These effects reverse the synaptic deficits caused by stress and may explain ketamine's fast antidepressant action in treatment-resistant depressed patients, which contrasts with the weeks or months needed for standard medications.
Journal of Neuroscience • April 15, 1997 • Bita Moghaddam, Barbara W. Adams, Anita Verma et al. • 1,813 citations
Low doses of the NMDA receptor antagonist ketamine (10, 20, and 30 mg/kg) increase glutamate outflow in the rat prefrontal cortex (PFC), suggesting enhanced glutamatergic neurotransmission at non-NMDA receptors. An anesthetic dose (200 mg/kg) decreases glutamate levels, while an intermediate dose (50 mg/kg) has no effect. Ketamine at 30 mg/kg also increases dopamine release in the PFC, an effect blocked by intra-PFC application of the AMPA/kainate receptor antagonist CNQX. Systemic pretreatment with the AMPA/kainate receptor antagonist LY293558 ameliorates ketamine-induced dopamine release and impairment of spatial delayed alternation, a PFC-sensitive cognitive task. Ketamine may disrupt PFC dopaminergic neurotransmission and cognitive functions partly by increasing glutamate release and stimulating postsynaptic non-NMDA glutamate receptors.
Archives of General Psychiatry • March 1, 1994 • 3,339 citations
Ketamine, a drug that blocks a specific brain receptor called NMDA, produces a broad set of effects in healthy people that resemble schizophrenia and dissociative states. In a randomized, double-blind, placebo-controlled study with 19 healthy adults, ketamine caused behaviors similar to both positive and negative symptoms of schizophrenia, altered perceptions, and impaired performance on tests of attention, verbal fluency, and cognitive flexibility. It disrupted delayed recall of words while sparing immediate and postdistraction recall. Ketamine also increased blood pressure and dose-dependently raised cortisol and prolactin levels, but did not affect a measure of general mental status. These findings suggest that NMDA receptor dysfunction may contribute to psychotic disorders.