Archives of General Psychiatry
August 1, 2006
Carlos A. Zarate, Jaskaran Singh, Paul J. Carlson et al.
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.
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 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.
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.
CNS Neuroscience & Therapeutics
April 12, 2013
Giacomo Salvadore, Jaskaran Singh
80 citations
A single intravenous subanesthetic dose of ketamine, an NMDA receptor antagonist, rapidly reduces depressive symptoms and suicidal thoughts in patients with treatment-resistant mood disorders. Emerging evidence suggests that ketamine's antidepressant effects depend on increasing AMPA signaling and rapidly inducing synaptogenesis. However, critical questions remain about safe and effective use, including optimal dose, administration method, and biomarkers of response. This review summarizes clinical evidence, preclinical and human studies on ketamine's mechanisms and predictors of antidepressant response, and identifies knowledge gaps to guide future research toward developing more effective, fast-acting antidepressants.
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.
International Journal of Neuropsychopharmacology
May 5, 2020
Ziad S. Saad, D. Hibar, M. Fedgchin et al.
43 citations
A genetic variant in the mu-opioid receptor (OPRM1 A118G) did not alter the antidepressant response to esketamine plus an oral antidepressant in people with treatment-resistant depression. In the placebo-plus-antidepressant group, carriers of the G allele showed greater improvement in depression scores on day 2, with a similar trend at day 28, suggesting that endogenous opioids may contribute to the placebo response. No genetic effect was observed on dissociative side effects from esketamine.
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 Journal of Clinical Psychiatry
July 16, 2021
Ibrahim Turkoz, Ella Daly, Jaskaran Singh et al.
21 citations
For patients with treatment-resistant depression who did not show a response within the first week of treatment, a full four-week induction course of esketamine nasal spray plus an oral antidepressant may still provide benefit. In a pooled analysis of two phase 3 trials, among those not meeting early response criteria at day 2 or days 2 and 8, the odds of a response by day 28 were about 1.6 times higher with esketamine plus antidepressant compared to antidepressant plus placebo. The findings suggest that lack of early improvement does not preclude later benefit from the full induction course.
The International Journal of Neuropsychopharmacology
April 7, 2020
Michel Nijs, Ewa Wajs, Leah Aluisio et al.
21 citations
For patients with treatment-resistant depression, adjusting how often they use esketamine nasal spray based on their symptoms can help maintain or improve treatment response. In an open-label study of 778 patients, those who responded to twice-weekly esketamine during a 4-week induction phase then had their treatment frequency reduced to weekly. After four weeks of weekly treatment, 26% of 580 responders continued to improve, 50% maintained benefit, and 24% worsened. When frequency was further reduced to every other week, 19% improved, 49% maintained benefit, and 32% worsened. For patients who lost remission after reducing frequency, increasing back to weekly led to 47% improving, 43% staying the same, and 10% worsening. These results suggest that personalizing esketamine treatment frequency can optimize outcomes.
Psychiatry Research
March 15, 2023
Ibrahim Turkoz, J. Craig Nelson, Samuel T. Wilkinson et al.
19 citations
A post hoc analysis of two pooled 4-week phase 3 trials examined predictors of response and remission in patients with treatment-resistant depression receiving esketamine nasal spray plus a new oral antidepressant compared to a new oral antidepressant plus placebo nasal spray. Younger age, being employed, having fewer failed antidepressants in the current episode, and early reduction in Clinical Global Impression-Severity score at day 8 predicted better outcomes. Those on esketamine had 68% higher odds of response and 55% higher odds of remission. In the esketamine group, response was more likely in employed patients, those without baseline anxiety, and those with early symptom improvement.
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 Psychopharmacology
February 25, 2022
Francis M. Dijkstra, Aurora JAE van de Loo, Smedra Abdulahad et al.
16 citations
A single 84 mg dose of intranasal esketamine did not impair next-morning driving performance in patients with mild-to-moderate major depressive disorder or persistent depressive disorder, and same-day driving was not impaired after twice-weekly administration over three weeks. Alcohol, used as a positive control, significantly worsened driving (increased weaving by 1.83 cm), while esketamine showed no such effect. Twenty-seven patients completed on-road driving tests on a public highway. The findings suggest that esketamine, at this dose, does not compromise driving ability the morning after or on the same day of repeated use.
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.
CNS Spectrums
April 1, 2020
Leslie Citrome, Allitia DiBernardo, Jaskaran Singh
In people with treatment-resistant depression, adding esketamine nasal spray to an oral antidepressant is more effective than an antidepressant plus placebo for both acute and long-term treatment. For every 8 patients treated, one additional patient achieves a 50% or greater reduction in depressive symptoms; for every 6 patients, one additional patient achieves remission. Common side effects include dissociation, vertigo, nausea, dizziness, and dysgeusia, each occurring in roughly 1 in 5 to 1 in 4 patients. Discontinuation due to side effects is uncommon. Patients are about 3 times more likely to achieve remission than to stop treatment due to a side effect.
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.