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.
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.
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.
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.
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.
Clinical Pharmacology & Therapeutics
August 29, 2020
Eva G. Katz, David Hough, Teodora Doherty et al.
35 citations
Adding esketamine nasal spray to an oral antidepressant improves outcomes for people with treatment-resistant depression. During the initial treatment phase, for every 100 patients, 5 to 21 more achieve remission and 14 to 17 more show a response compared to those receiving a placebo plus an antidepressant. In maintenance therapy, 19 to 32 fewer relapses occur with esketamine. Serious or severe side effects—mainly dissociation, vertigo, and dizziness—differ little between the groups. The findings indicate a favorable balance of benefits and risks for esketamine combined with an antidepressant.
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.
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
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.
CNS Spectrums
February 1, 2018
Abigail I. Nash, M. Shawi, Jaskaran Singh et al.
In a post-hoc analysis of a Phase 2a clinical trial, adults with treatment-resistant major depressive disorder who had not responded to at least two prior antidepressants received twice-weekly intranasal esketamine (28 mg, 56 mg, or 84 mg) or placebo for one week. At all doses, patients reported a one-point average improvement on the Patient Global Impression Severity scale, while placebo patients reported no change. Clinician ratings on the Clinical Global Impression Severity scale similarly improved for esketamine groups but not for placebo. These results suggest that esketamine can produce clinically meaningful improvement in depression symptoms within one week, as reported by both clinicians and patients, consistent with prior findings using the Montgomery-Åsberg Depression Rating Scale.