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.
American Journal of Psychiatry
April 16, 2018
Carla M. Canuso, Jaskaran 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.
The International Journal of Neuropsychopharmacology
July 9, 2019
Maggie Fedgchin, Madhukar H. Trivedi, Ella 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.
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.
Biological Psychiatry
November 4, 2015
Jaskaran Singh, Maggie Fedgchin, Ella Daly et al.
466 citations
A single 40-minute intravenous infusion of esketamine at either 0.20 mg/kg or 0.40 mg/kg produced a rapid and robust antidepressant effect in patients with treatment-resistant depression, with significant improvement in depression scores within two hours. The higher and lower doses were similarly effective, but the lower dose may offer better tolerability. Common side effects included headache, nausea, and transient dissociation that resolved within four hours.
The International Journal of Neuropsychopharmacology
August 26, 2020
Dawn F. Ionescu, Dong-Jing Fu, Xin Qiu et al.
411 citations
In severely depressed adults with active suicidal thoughts and intent, adding esketamine nasal spray to standard care (hospitalization and new antidepressants) produced a greater reduction in depressive symptoms than placebo plus standard care. At 24 hours, depression scores dropped an average of 15.7 points with esketamine versus 12.4 points with placebo. Improvement was also seen at 4 hours. Both groups showed rapid decreases in suicidality severity, but the difference between them was not statistically significant. Common side effects of esketamine included dizziness, dissociation, nausea, and headache.
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.
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.
The International Journal of Neuropsychopharmacology
November 1, 2011
Giacomo Salvadore, Jan Willem van der Veen, Yan Zhang et al.
105 citations
Pretreatment levels of certain amino-acid neurotransmitters in the prefrontal cortex predict how well patients with major depressive disorder respond to a single intravenous infusion of ketamine. In fourteen drug-free patients, a lower ratio of glutamine to glutamate in the dorsomedial/dorsal anterolateral prefrontal cortex was associated with greater improvement in depressive symptoms 230 minutes after ketamine administration. Higher glutamate levels in the ventromedial prefrontal cortex correlated with greater improvement in anxiety symptoms. The findings suggest that the presence of reduced glial cells, reflected by the lower glutamine-to-glutamate ratio, may indicate which patients are more likely to benefit from ketamine treatment.
Translational Psychiatry
September 20, 2016
Daniel M. Rotroff, Daniel Corum, Alison A. Motsinger‐Reif et al.
99 citations
Sub-anesthetic doses of ketamine and its S-enantiomer, esketamine, rapidly reduce depression symptoms in patients with treatment-resistant major depressive disorder. A pharmacometabolomics approach mapped global metabolic effects in 33 patients receiving ketamine and 20 receiving esketamine, with esketamine retested after a second infusion four days later. Both drugs altered metabolites related to tryptophan metabolism (e.g., indole-3-acetate and methionine) and the urea cycle (e.g., citrulline, arginine, and ornithine) two hours post-infusion. Changes in glutamate and circulating phospholipids were significantly associated with decreases in depression severity. These findings provide new insights into the mechanisms underlying the rapid antidepressant effects of these therapies.
Bipolar Disorders
September 18, 2013
Allison C. Nugent, Nancy Diazgranados, Paul J. Carlson et al.
86 citations
In people with bipolar disorder who are depressed, a single ketamine infusion alters brain glucose metabolism in regions linked to mood disorders. Those who improved most showed the largest metabolic increase in the right ventral striatum. Ketamine also lowered metabolism in the left hippocampus compared with placebo. Higher baseline activity in the subgenual anterior cingulate cortex predicted a stronger antidepressant response to ketamine. These metabolic changes may help explain how ketamine works.
Journal of Affective Disorders
November 14, 2020
Stacie Hudgens, Lysbeth Floden, Michael Blackowicz et al.
77 citations
For patients with treatment-resistant depression (TRD)—those who have not responded to at least two different antidepressants in their current episode—meaningful improvement on two common depression scales was defined using a clinician-rated severity anchor. On the Patient Health Questionnaire (PHQ-9), a decrease of 6 points was the most appropriate meaningful change threshold. By Day 28, 86.5% of patients receiving esketamine nasal spray plus an antidepressant reached or exceeded this threshold, compared to 70% of those receiving placebo plus an antidepressant. On the Montgomery-Åsberg Depression Rating Scale (MADRS), a decrease of 10 points was the most appropriate threshold, with 78.2% of esketamine-treated patients versus 65.0% of placebo-treated patients meeting it. These anchor-based thresholds help interpret individual-level treatment response in TRD.
Psychopharmacology
February 1, 2018
Randall L. Morrison, Maggie Fedgchin, Jaskaran Singh et al.
72 citations
Intranasal esketamine temporarily impairs cognitive performance and increases mental effort and sleepiness in healthy participants. At 40 minutes after dosing, performance on five cognitive tests (Detection, Identification, One-Card Learning, One Back, and Groton Maze Learning) was significantly worse compared with placebo. These effects resolved by 2 hours postdose, with no differences between esketamine and placebo at 2, 4, or 6 hours. Participants reported greater mental effort at 40 minutes and increased sleepiness at 40 minutes and 2 hours, which also returned to placebo levels later. Common mild adverse events included dizziness, nausea, attention disturbance, and fatigue.
Scientific Reports
July 28, 2020
Qingqin S. Li, Ewa Wajs, Rachel Ochs-Ross et al.
49 citations
A genome-wide association study in 527 people of European ancestry with major depressive disorder identified a significant genetic locus in the IRAK3 gene and a significant gene-level association in NME7 linked to the antidepressant efficacy of esketamine nasal spray, measured as percentage change in symptom severity. Polygenic risk score analysis showed the strongest association with esketamine efficacy came from genetic loading for depressive symptoms, though this did not reach study-wide significance. Suggestive signals were enriched in pathways related to neuronal and synaptic function, immune signaling, and glucocorticoid receptor/stress response.
JAMA Psychiatry
July 2, 2025
Adam Janik, Xin Qiu, Rosanne Lane et al.
40 citations
In adults with treatment-resistant depression who had not responded to at least two prior oral antidepressants, esketamine nasal spray taken alone (without an oral antidepressant) reduced depressive symptoms more than a placebo. Over four weeks, both a 56 mg and an 84 mg dose of esketamine produced significantly greater improvements on the Montgomery-Åsberg Depression Rating Scale than placebo, with effects apparent as early as 24 hours after the first dose. Common side effects included nausea, dissociation, dizziness, and headache. The findings suggest that esketamine monotherapy could offer a new treatment option for patients who cannot tolerate or do not respond to oral antidepressants.
The International Journal of Neuropsychopharmacology
June 6, 2025
Naim Zaki, Li Nancy Chen, Rosanne Lane et al.
32 citations
In a long-term extension study (SUSTAIN-3) involving 1,148 adults with treatment-resistant depression, esketamine nasal spray combined with an oral antidepressant was evaluated for safety and efficacy over up to 79 months (median 45.8 months). Common adverse events included headache (36.9%), dizziness (33.9%), and nausea (33.6%). Nine participants died, with causes including COVID-19 and suicide. Depressive symptoms, measured by the MADRS, improved during the initial induction phase (average reduction of 12.8 points) and this improvement was maintained during the optimization/maintenance phase. At the end of maintenance, 49.6% of participants were in remission. No new safety concerns emerged, and depression improvement generally persisted for those continuing treatment.
Health and Quality of Life Outcomes
May 8, 2023
Carol Jamieson, Vanina Popova, Ella Daly et al.
18 citations
Patients with treatment-resistant depression who received esketamine nasal spray plus an oral antidepressant reported greater improvements in health-related quality of life and daily functioning after 28 days compared to those who received a placebo nasal spray plus an antidepressant. At day 28, a lower percentage of patients in the esketamine group reported problems across all five dimensions of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The esketamine group also showed larger average improvements in health status index and overall health rating, as well as greater reductions in functional disability.
Journal of the American Academy of Child and Adolescent Psychiatry
March 7, 2025
Colette Kosik-Gonzalez, Dong-Jing Fu, Li Nancy Chen et al.
14 citations
In a phase 2b trial, adolescents aged 12 to 17 with major depressive disorder at imminent risk for suicide received either esketamine nasal spray (28, 56, or 84 mg) or a psychoactive placebo (oral midazolam) twice weekly for four weeks, alongside standard care including hospitalization, an antidepressant, and psychotherapy. Pooled esketamine doses (56 and 84 mg) reduced depressive symptoms more than midazolam at 24 hours after the first dose, though individual doses did not reach statistical significance. Suicidality severity improved across all groups. Common side effects included dizziness, nausea, and dissociation.
The International Journal of Neuropsychopharmacology
December 14, 2022
David Williamson, Ibrahim Turkoz, Ewa Wajs et al.
11 citations
Dissociation encompasses distinct phenomena, some linked to esketamine treatment and potentially overlapping with psychosis symptoms. In a post hoc analysis of data from an open-label, phase 3 study of esketamine plus a newly initiated oral antidepressant in patients with treatment-resistant depression, dissociation was reported as an adverse event in 14.3% (109/764) of patients. CADSS scores generally aligned with investigator-reported dissociation severity, but no cutoff point reliably distinguished presence from absence of dissociation events. Hallucinations occurred in 5 patients, and no delusions were reported, indicating psychotic symptoms were uncommon.
The International Journal of Neuropsychopharmacology
November 1, 2024
Randall L. Morrison, Jaskaran Singh, Ella Daly et al.
9 citations
In patients with treatment-resistant depression, adding esketamine nasal spray to a newly initiated oral antidepressant did not harm cognitive function over the short or long term. Across three short-term double-blind studies (747 patients aged 18–64 years) and one long-term maintenance study (137 patients aged 65 or older), cognitive performance on tests of psychomotor function, attention, and memory either remained stable or slightly improved from baseline to the end of treatment. At the start, patients showed mild-to-moderate cognitive impairment. The correlation between depression severity and cognitive performance was weak. The analysis found no evidence that esketamine worsens cognition in treatment-resistant depression.
British Journal of Pharmacology
May 13, 2025
Brian Lord, Sirak Simavorian, Ian Fraser et al.
2 citations
A selective GluN2A antagonist, JNJ-78911118, blocks GluN1/2A receptors with an IC50 of 44 nM and shows selectivity over other NMDA receptor subtypes. It increases prefrontal cortex monoamine levels in wild-type but not GluN2A knockout mice, blocks hippocampal long-term potentiation, and boosts dendritic complexity, synapse number, and mEPSC frequency in rat cortical neurons. In rats, no Olney's lesions occurred, but acute increases in heart rate and blood pressure were detected. The molecule reproduces effects of known rapidly acting antidepressants on neurotransmitter levels and synaptic plasticity, offering a tool to study GluN2A biology.
Clinical and Translational Science
April 1, 2026
Matthijs W Van Hoogdalem, Dong-Jing Fu, Wayne C. Drevets et al.
Esketamine nasal spray is the first glutamate-modulating antidepressant approved as a monotherapy for adults with treatment-resistant depression. It acts rapidly by blocking NMDA receptors on inhibitory interneurons, which disinhibits glutamate release and alters synaptic plasticity. Administered at 56 mg or 84 mg, it reaches peak concentration in 20–40 minutes with about 50% bioavailability. This review covers its regulatory approval, mechanism of action, pharmacokinetics, and clinical trial data for efficacy and safety in treatment-resistant depression and major depressive disorder with acute suicidal ideation or behavior.