American Journal of Psychiatry
August 28, 2013
James W. Murrough, Dan V. Iosifescu, Lee C. Chang et al.
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.
JAMA Psychiatry
March 1, 2017
Gerard Sanacora, Mark A. Frye, William M. Mcdonald et al.
577 citations
Ketamine can produce rapid and robust antidepressant effects in patients with mood and anxiety disorders that were previously resistant to treatment. However, existing studies have relatively small sample sizes, lack longer-term data on efficacy, and provide limited data on safety. Despite these limitations, ketamine is increasingly used off-label for mood and other psychiatric disorders. This review and consensus statement provides an overview of the data, highlights limitations, and offers suggestions to facilitate evidence-based clinical decision-making and patient safety.
Drug and Alcohol Dependence
January 15, 2014
E. Dakwar, C. Anerella, Carl L. Hart et al.
125 citations
In a small study of eight cocaine-dependent individuals, ketamine infusions produced mystical-type experiences that helped explain increased motivation to quit cocaine a day later. Participants received two doses of ketamine (0.41 mg/kg and 0.71 mg/kg) and a control drug lorazepam (2 mg) in random order. Ketamine, especially the higher dose, caused significantly stronger mystical-type effects than lorazepam. The intensity of those mystical effects, but not dissociative symptoms, predicted greater motivation to stop using cocaine 24 hours after infusion. The findings suggest that psychological experiences during ketamine treatment may contribute to its anti-addiction benefits, though larger studies are needed.
The Journal of Clinical Psychiatry
May 26, 2020
George I. Papakostas, Naji C. Salloum, Rebecca S. Hock et al.
107 citations
Adjunctive intranasal esketamine is more effective than placebo for treating major depressive disorder. Pooling five randomized, double-blind trials with 774 patients, esketamine outperformed placebo on depression rating scale score change, response, and remission. The effect was statistically significant across different study samples and baseline antidepressant regimens. Esketamine appears to be an effective treatment strategy for patients who are treatment-resistant or acutely suicidal.
Depression and Anxiety
December 30, 2018
Naji C. Salloum, Maurizio Fava, Marlene P. Freeman et al.
49 citations
In a double-blind trial, 99 people with treatment-resistant depression received either a single intravenous dose of ketamine (0.1, 0.2, 0.5, or 1.0 mg/kg) or midazolam (0.045 mg/kg). Among them, 45 had high baseline anxiety and 54 did not. No significant difference in depression improvement was found between the ketamine and midazolam groups for either anxious or nonanxious participants at 1 or 3 days after infusion. The results suggest that ketamine may work similarly for both anxious and nonanxious treatment-resistant depression, unlike some traditional antidepressants.
Journal of Clinical Psychopharmacology
April 25, 2020
Marlene P. Freeman, Rebecca S. Hock, George I. Papakostas et al.
45 citations
Higher body mass index (BMI) and obesity are linked to a stronger acute antidepressant effect from a single intravenous dose of ketamine in patients with treatment-resistant depression. In a randomized, double-blind, placebo-controlled trial, patients with obesity showed a significantly greater reduction in depression symptoms 24 hours after ketamine infusion compared to those with normal BMI. Overweight patients also showed a trend toward greater improvement. Similar but weaker effects were observed at 72 hours. The findings suggest that obesity may enhance the rapid antidepressant response to ketamine, which could have clinical relevance for the many patients with both major depressive disorder and obesity.
The Journal of Clinical Psychiatry
November 14, 2022
Anna Feeney, Bettina B. Hoeppner, Marlene P. Freeman et al.
9 citations
Among people with treatment-resistant depression, those taking oral benzodiazepines alongside a single intravenous infusion of ketamine showed less improvement in depression scores 24 hours later if they were on higher benzodiazepine doses. The same pattern was not seen in those who received a midazolam placebo. By day 3 after the infusion, benzodiazepine use no longer affected depression scores. The findings suggest that higher doses of benzodiazepines may temporarily weaken ketamine's rapid antidepressant effect.
JAMA Psychiatry
December 1, 2023
Sanjay J. Mathew, Manish K. Jha, Amit Anand
8 citations
Electroconvulsive therapy (ECT) and ketamine are both used to treat treatment-resistant depression (TRD), but recent reports highlight important considerations when comparing them. This viewpoint examines key issues from several recent studies, including differences in how quickly each treatment works, their side effects, and the practical challenges of administering them. ECT remains highly effective but requires anesthesia and can cause memory problems, while ketamine offers rapid relief but its long-term effects and optimal dosing are still being studied. The authors suggest that neither treatment is clearly superior for all patients, and the choice depends on individual circumstances and preferences.
Translational Psychiatry
July 4, 2026
Krisha Shah, Rubén Herzog, Alan C. Swann et al.
Ketamine rapidly reduces depression in some people with treatment-resistant depression, but the brain mechanisms are not fully understood. This analysis of a randomized, double-blind trial compared ketamine to midazolam in 30 older veterans with treatment-resistant depression. Using EEG data and a measure called O-information, which captures how brain regions interact in groups of three or more, the study found that ketamine caused dynamic changes in these interactions over time. The strongest effects occurred in alpha brain waves one hour after infusion, with changes shifting to theta waves by 24 hours and partially returning in beta and gamma waves by day 7.
The Journal of Clinical Psychiatry
September 3, 2025
Kristina T. Kumpf, Samuel T. Wilkinson, Bo Hu et al.
In a multisite randomized trial comparing cognitive effects of intravenous ketamine and electroconvulsive therapy (ECT) in patients with treatment-resistant depression, those receiving six ketamine treatments showed superior cognitive functioning after a three-week treatment course compared with those receiving nine ECT sessions. No significant differences in cognitive task performance were associated with response to either treatment. Among responders followed for up to six months, no group differences emerged. Subjective memory measures were mixed: both groups improved on the Squire Memory Complaint Questionnaire, with ketamine recipients reporting greater functional gains, while ketamine-treated patients reported improvements on a global self-evaluation of memory but ECT-treated patients reported a decline. Within the ketamine group, improvements in executive functioning and cognitive flexibility survived adjustment for changes in depression, suggesting partial independence of cognitive and mood effects.