World Psychiatry
September 15, 2023
Roger S. McIntyre, Mohammad Alsuwaidan, Bernhard T. Baune et al.
712 citations
At least 30% of people with depression meet the common definition of treatment-resistant depression (TRD): inadequate response to two or more antidepressants despite adequate trials and adherence. Many cases are actually pseudo-resistant due to insufficient treatment or non-adherence. No consensus definition with proven predictive utility for clinical decisions exists, leading to varied prevalence estimates and inconsistent care. Intravenous ketamine and intranasal esketamine are effective for TRD. Some second-generation antipsychotics (e.g., aripiprazole, quetiapine XR) help as adjuncts in partial responders, but only the olanzapine-fluoxetine combination has been studied in FDA-defined TRD. Repetitive transcranial magnetic stimulation and electroconvulsive therapy are established effective interventions. Evidence for extending trials, switching, or combining antidepressants is mixed, and manual-based psychotherapies are not effective alone but help when added to antidepressants.
American Journal of Psychiatry
April 16, 2018
Carla M. Canuso, Jaskaran B. 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.
JAMA
August 31, 2023
Charles L Raison, Gerard Sanacora, Joshua Woolley et al.
493 citations
A single 25-mg dose of synthetic psilocybin, administered with psychological support, produced a clinically significant and sustained reduction in depressive symptoms and functional disability over 43 days in adults with major depressive disorder. In a phase 2 trial of 104 participants, those receiving psilocybin showed a mean 12.3-point greater improvement on the Montgomery-Asberg Depression Rating Scale at day 43 compared with those receiving a niacin placebo. Psilocybin also improved daily functioning and led to more sustained response, though not remission. No serious adverse events occurred, but psilocybin was associated with more overall and severe adverse events.
Annual Review of Medicine
October 23, 2014
Chadi G. Abdallah, Gerard Sanacora, Ronald S. Duman et al.
420 citations
Ketamine, a glutamate-based antidepressant, can rapidly alleviate depression within hours of treatment. Replicated evidence shows its rapid and potent effects in treatment-resistant depression. Preclinical and biomarker studies have begun to explain the mechanism behind these rapid effects, offering new insights into depression's biology and identifying potential treatment targets. This article discusses ketamine's efficacy, safety, and tolerability, summarizes depression's neurobiology, reviews the mechanisms of ketamine's rapid antidepressant effects, and considers prospects for next-generation rapid-acting antidepressants.
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.
Psychotherapy and Psychosomatics
January 1, 2017
Samuel T. Wilkinson, Dashaun Wright, Madonna K. Fasula et al.
120 citations
Ketamine provides rapid but short-lived antidepressant effects. In an open-label trial, patients with treatment-resistant depression received a 2-week course of intravenous ketamine alongside a 10-week course of cognitive behavioral therapy (CBT). Of 16 participants, 8 responded to ketamine and 7 achieved remission in the first 2 weeks. Among responders, 25% relapsed by the end of CBT, and the median time to relapse was 12 weeks after ketamine. Among remitters, 2 of 7 maintained remission through 8 weeks after ketamine. Ketamine nonresponders did not benefit from CBT. The combination may help sustain ketamine's effects, but randomized controlled trials are needed.
Psychotherapy and Psychosomatics
January 1, 2021
Samuel t. Wilkinson, Taeho greg Rhee, Jutta Joormann et al.
102 citations
Cognitive behavioral therapy (CBT) may help sustain the antidepressant effects of ketamine in people with treatment-resistant depression. In a trial, 42 patients with treatment-resistant depression received six intravenous ketamine infusions over three weeks. The 28 who responded were then randomized to CBT or treatment as usual for 14 weeks. On one depression scale, the CBT group showed significantly greater sustained improvement, with a moderate-to-large effect size. A smaller subset of ketamine responders also improved in emotional cognitive accuracy, while nonresponders did not. The findings are preliminary and need confirmation in larger trials.
Proceedings of the National Academy of Sciences of the United States of America
November 27, 2023
J. Krystal, Alfred P. Kaye, S. Jefferson et al.
66 citations
Ketamine represents a new type of antidepressant that works quickly, helps people whose depression has not responded to other treatments, and reduces the chance of relapse. Its development came from a new understanding of depression's biology, and studying how ketamine works has deepened knowledge of depression and related conditions. Twenty-five years after the first findings on ketamine for depression were presented, this review examines what has been learned and suggests future ways to improve rapid-acting antidepressant therapy.
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.
JAMA network open
June 3, 2024
Manish Kumar Jha, Samuel T Wilkinson, Kamini Krishnan et al.
29 citations
In people with treatment-resistant depression who do not have psychosis, intravenous ketamine works as well as electroconvulsive therapy (ECT) overall. Among outpatients with moderately severe or severe depression, ketamine produced greater improvement in depressive symptoms than ECT. In contrast, inpatients with very severe depression improved more with ECT early in treatment, though by the end of the three-week course both treatments were similarly effective. Higher premorbid intelligence and a diagnosis of posttraumatic stress disorder were linked to greater improvement with ECT, but not with ketamine. These findings may help patients and clinicians decide between the two treatments.
American Journal of Psychiatry
September 10, 2025
Gerard Sanacora, Muhammad Ahmed, Brianne Brown et al.
24 citations
Over nearly five years of real-world use in the United States, esketamine's safety profile remains consistent with clinical trial findings and product labeling. Among 58,483 patients completing 1,486,213 outpatient sessions, sedation occurred in 34.7% of sessions, dissociation in 41.0%, and increased blood pressure in 0.9%. Serious adverse events were rare, reported in less than 0.1% of sessions in the REMS program and 0.18% in the US-GMS database. Suicide rates were lower than background rates, and 210 incidences of all-cause abuse or misuse were reported. No new safety signals were identified.
Drug discovery today
December 1, 2023
Taeho Greg Rhee, Pasha A Davoudian, Gerard Sanacora et al.
20 citations
Psychiatric disorders are the leading cause of disability globally, and interest in psychedelic substances as potential treatments has recently revived. This review examines the therapeutic potential and safety concerns of psilocybin, DMT, LSD, and MDMA, including their possible interactions with psychotherapy. It covers active and recently completed clinical trials drawn from published literature, conference abstracts, clinical trial registries, and press releases. The review suggests that these compounds may offer new avenues for treating psychiatric disorders, though safety considerations remain important.
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.
The international journal of neuropsychopharmacology
December 1, 2024
Craig Chepke, Richard Shelton, Gerard Sanacora et al.
7 citations
Esketamine nasal spray, approved for treatment-resistant depression and major depressive disorder with suicidal thoughts, rarely causes respiratory depression after marketing. Analysis of 47 months of postapproval safety data found 50 cases of respiratory depression among patients, with 8 strongly linked to the drug. The estimated incidence is 1 case per 20,000 treatment sessions. Symptoms are manageable and resolve with minor support. Monitoring, including pulse oximetry, is recommended during postdose observation.
American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics
June 17, 2025
Clio E Franklin, Murat Altinay, Kala Bailey et al.
2 citations
For treatment-resistant mood disorders, intensive interventions such as electroconvulsive therapy, transcranial magnetic stimulation, ketamine, and esketamine are commonly used, but how genetics influences response to these therapies remains unclear. A review of the current literature finds that most studies have examined single variants in candidate genes, particularly COMT and BDNF, yet none have been consistently reproducible. Genome-wide association studies are few and mostly underpowered, with only one exceeding 1000 participants, yielding few statistically significant single nucleotide polymorphisms outside COMT and BDNF. Large-scale data collection is needed to establish genetic predictors and differentiate responses among treatments, a goal being pursued by the worldwide Gen-ECT-ic consortium.
Psychiatry research
May 1, 2025
Gerard Sanacora, Brian S Barnett, Bo Hu et al.
2 citations
Patients with treatment-resistant depression who preferred ketamine over electroconvulsive therapy (ECT) were more likely to respond to treatment, regardless of which treatment they actually received. Matching patients to their preferred treatment improved response rates for ketamine but not for ECT, and reduced adverse events for ECT-treated patients. Ketamine was the more popular choice overall. The findings suggest that aligning treatment with patient preference can influence effectiveness, safety, and possibly adherence, but these effects vary by treatment modality and context.
Focus (American Psychiatric Publishing)
April 1, 2025
Sophie I Elliott, Rachel B Katz, Robert B Ostroff et al.
2 citations
For severe treatment-resistant depression, both electroconvulsive therapy (ECT) and ketamine are effective, but it remains unclear which is superior. Two noninferiority trials and three meta-analyses show efficacy for both treatments yet report contradictory findings about which works better. Discrepancies may stem from differences in patient selection, outcome measures, treatment delivery, and site experience. Each treatment has unique risks and benefits that should be weighed for individual patients. The authors aim to help clinicians choose the optimal treatment by evaluating the latest evidence and patient-specific factors.
Contemp Clin Trials
March 2, 2026
Samuel T. Wilkinson, Sandhya Prashad, Rachel Dalthorp et al.
1 citation
The EQUIVALENCE trial protocol describes a non-inferiority, comparative effectiveness study designed to test whether intranasal esketamine is no less effective than intravenous ketamine for treating treatment-resistant depression. The study will compare the two treatments head-to-head in patients who have not responded to prior antidepressant therapies. The protocol outlines the trial's design, including randomization, dosing regimens, outcome measures, and statistical analysis plan. By directly comparing these two forms of ketamine, the trial aims to provide evidence on whether the more convenient intranasal route can match the efficacy of the intravenous formulation, potentially offering a more accessible treatment option.
Neurologic clinics
February 1, 2026
Mina Ansari, Sophie I Elliott, Sophie E Holmes et al.
1 citation
Placebo effects in depression treatment trials are substantial and can obscure the true efficacy of new drugs, especially for psychedelic-like compounds. Expectancy, the therapeutic setting, and trial design all interact to shape patient outcomes. This review examines these factors and discusses emerging methods to mitigate, measure, or harness placebo effects in future research on rapid-acting antidepressants and psychedelic therapies.
The Journal of clinical psychiatry
May 4, 2026
Samuel T Wilkinson, Brandon M Kitay, Matthew Macaluso et al.
Adding cognitive behavioral therapy to esketamine treatment reduces suicidal ideation more than esketamine alone in people with major depression and suicidal thoughts. In a randomized trial of 93 patients, 72% completed the study, meeting feasibility goals. Those who received 16 weeks of CBT plus esketamine showed greater improvement on three measures of suicidal ideation than those receiving esketamine with usual care: a mean difference of -1.91 on the Beck Scale for Suicidal Ideation, -0.33 on the Clinician Global Improvement Scale for Suicide Severity, and -3.77 on the depression rating scale. No difference was found on the Columbia-Suicide Severity Rating Scale or in suicide-related events.