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.
Depression and Anxiety
March 25, 2014
Rebecca B Price, Dan V. Iosifescu, James W. Murrough et al.
342 citations
A single subanesthetic dose of intravenous ketamine reduced explicit suicidal thoughts and implicit associations between self and escape in adults with treatment-resistant major depression more than the active placebo midazolam. Twenty-four hours after infusion, 53% of ketamine-treated patients scored zero on all three explicit suicide measures, compared with 24% of the midazolam group. The reductions in explicit suicidal cognition were largest in those with higher baseline suicidal thoughts and were partly explained by decreases in other depressive symptoms. The findings suggest ketamine may offer rapid relief from suicidal cognition beyond what a psychoactive placebo provides.
The International Journal of Neuropsychopharmacology
March 17, 2009
Sanjay J. Mathew, James W. Murrough, Marije Aan Het Rot et al.
295 citations
A single intravenous dose of ketamine (0.5 mg/kg) produced rapid antidepressant effects in patients with treatment-resistant major depression, with 65% responding at 24 hours and 54% at 72 hours. Pretreatment with lamotrigine did not reduce ketamine's mild side effects or improve its antidepressant action. In a subsequent randomized trial, riluzole (100-200 mg/day) failed to prevent relapse over 32 days; 80% of riluzole-treated patients relapsed versus 50% on placebo, leading to early termination. Ketamine appears well-tolerated and rapidly effective, but better strategies to sustain its benefits are needed.
The International Journal of Neuropsychopharmacology
October 8, 2013
Colin N. Haile, James W. Murrough, Dan V. Iosifescu et al.
251 citations
In patients with treatment-resistant depression, ketamine increased blood levels of brain-derived neurotrophic factor (BDNF) in those who responded to the drug, compared to non-responders, 240 minutes after infusion. Higher BDNF levels were strongly linked to lower depression scores at multiple time points up to 72 hours. No such associations appeared in patients given the anesthetic midazolam. The findings support BDNF as a marker of ketamine's antidepressant effects.
The Journal of Clinical Psychiatry
September 2, 2014
Le-Ben Wan, Cara F. Levitch, Andrew M. Perez et al.
232 citations
Ketamine given intravenously at 0.5 mg/kg over 40 minutes was safe and well tolerated in a large group of patients with treatment-resistant depression. Across 205 infusions in 97 participants, the antidepressant response rate was 67%. Only about 2% of infusions were stopped due to adverse effects, and the overall dropout rate was 3%. Common temporary side effects in the first four hours included drowsiness, dizziness, poor coordination, blurred vision, and feeling strange or unreal. About one third of participants had changes in blood pressure or heart rate. There were small but significant increases in psychotomimetic and dissociative symptoms, but no lasting psychotic effects, medical complications, or increased substance use among those followed long-term.
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.
Translational Psychiatry
February 17, 2015
James W. Murrough, Katherine A. Collins, Jessica Fields et al.
111 citations
A single low dose of ketamine increases brain activity in the right caudate when people with treatment-resistant depression view happy faces, reversing a baseline deficit compared with healthy volunteers. Twenty patients with treatment-resistant depression not taking other antidepressants underwent fMRI before and 24 hours after receiving intravenous ketamine (0.5 mg per kg of body weight). Twenty matched healthy controls were scanned once. Before ketamine, depressed patients showed reduced neural responses to happy faces in the right caudate. After ketamine, responses to happy faces increased in a similar region. Greater connectivity of the right caudate during positive emotion perception was linked to greater improvement in depression severity. No effects were seen for sad faces.
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.
Molecular Psychiatry
September 7, 2022
Rebecca B Price, Nicholas Kissel, Andrew Baumeister et al.
80 citations
Ketamine given intravenously rapidly reduces depressive symptoms, with effects lasting at least a week. In an analysis of 17 randomized controlled trials with 809 participants, the benefit over placebo was larger for patients who had already failed two or more prior antidepressant trials. However, no patient-level clinical or demographic characteristics—such as age, sex, or diagnosis—could predict who would respond best, limiting the ability to personalize ketamine prescriptions. The findings confirm ketamine's broad effectiveness for depression but show that precision medicine approaches cannot yet guide treatment decisions.
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.
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.
Contemporary clinical trials communications
December 1, 2019
Brittany O'Brien, Charles E. Green, Rayan K. Al Jurdi et al.
10 citations
Over eleven million U.S. Veterans are 65 or older, and nearly 20% of that group experiences clinically significant depression. Existing medications often work poorly for late-life depression, especially when it is treatment-resistant. Ketamine offers a potentially rapid-acting option, but few studies have tested it in older adults. This ongoing trial uses an adaptive randomization design to compare the safety, tolerability, efficacy, and durability of three different low doses of intravenous ketamine against a single dose of an active placebo (midazolam) in older depressed veterans. As the study proceeds, Bayesian adaptive randomization shifts the odds of assignment toward the more promising dose conditions.
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.
The British journal of psychiatry : the journal of mental science
May 13, 2025
Shabnam Hossein, Manivel Rengasamy, Aiyedun Uzamere et al.
3 citations
Ketamine infusion most strongly alleviates sadness both immediately and during the first week after treatment, whereas improvements in suicidal thoughts emerge only after three to four weeks. In a secondary analysis of 152 adults with treatment-resistant depression (38.8% with suicidal ideation at baseline), those randomized to a single 40-minute intravenous infusion of ketamine (0.5 mg/kg) showed greater early improvement in sadness-related symptoms compared with saline. Network analyses revealed that ketamine increased connectivity among depressive symptoms, strengthening interrelationships between residual symptoms. The findings suggest that different depressive symptoms respond to ketamine with distinct time courses and possibly different mechanisms.
Brain, behavior, and immunity
April 4, 2025
Manivel Rengasamy, Benjamin Panny, Zakary Hutchinson et al.
3 citations
In adults with treatment-resistant depression, a single ketamine infusion did not produce detectable changes in blood markers of neurotrophic and inflammatory factors compared with a saline placebo, nor were those markers linked to depression improvement over five days. Among 133 participants, only one subgroup—those with a body-mass index below 25—showed an association: rising levels of interleukin-1 receptor antagonist in the first day after ketamine correlated with less reduction in depression symptoms. The results do not support the idea that peripheral neurotrophic or inflammatory factors mediate ketamine's rapid antidepressant effects, though central nervous system activity may still be involved.
Journal of Psychopathology and Clinical Science
April 1, 2025
Shabnam Hossein, Mary L Woody, Benjamin Panny et al.
3 citations
Ketamine rapidly improves symptoms of treatment-resistant depression (TRD), but because TRD varies widely among patients, markers are needed to personalize treatment. This study measured brain functional connectivity during positive mood processing in 152 adults with TRD before they received either ketamine or a saline placebo. Two connectivity-based subgroups emerged: Subgroup A (110 patients) and Subgroup B (42 patients). Ketamine improved depression uniformly across both subgroups. However, among patients given saline, those in Subgroup B were more likely to show a placebo response 24 hours later than those in Subgroup A. Thus, brain connectivity patterns predicted placebo response but not ketamine response.
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.
Molecular Psychiatry
November 1, 2024
H Nur Eken, Crystal Spotts, Benjamin Panny et al.
1 citation
A combination of ketamine infusion and a digital training program called automated self-association training (ASAT) produced more positive implicit self-associations immediately after treatment in adults with treatment-resistant depression, compared to control groups that received only one active component. These changes in implicit self-worth tracked with concurrent depression symptom improvement across all groups and specifically predicted longer-term depression relief at 30 days for the combined treatment group. The findings indicate that shifting implicit self-esteem during a post-ketamine 'plasticity window' is a key mechanism behind the combined treatment's antidepressant effect, confirming the intended cognitive target.
Journal of psychopharmacology (Oxford, England)
July 13, 2026
Todd D Gould, Sanjay J. Mathew, Maurizio Fava et al.
A new pharmacological model called event-driven pharmacology (EDP) is described, in which a plastogen—a drug that induces lasting neural plasticity—produces sustained effects after only transient binding, unlike traditional drugs that require continuous receptor occupancy. Plastogens such as ketamine and classical psychedelics can trigger metaplasticity, priming synapses to respond to later stimuli long after the drug has left the body. Dosing such drugs to maintain constant target occupancy may paradoxically reduce benefits and increase side effects. The EDP model calls for new drug development, dosing strategies, and biomarkers to harness the therapeutic potential of plastogens for depression and other synaptic disorders.
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.
Journal of Affective Disorders
June 18, 2025
Julia Myerson, Katrina A Rufino, Sanjay J. Mathew et al.
Electroconvulsive therapy (ECT) shows stronger antidepressant effects than intravenous ketamine for severe depression. In a retrospective chart review of 146 patients aged 18 to 74 with major depressive episodes, 94 received ketamine infusions twice weekly and 52 received ECT two to three times weekly. Overall, 45.2% of participants showed clinical symptom change on the Montgomery-Asberg Depression Rating Scale. ECT had a response rate of 67.3% and remission rate of 60.0%, compared to 45.7% and 46.1% for ketamine. Chi-square tests indicated a significant association between treatment type and symptom improvement, favoring ECT.