American Journal of Psychiatry
March 17, 2021
R. Mcintyre, J. Rosenblat, C. Nemeroff et al.
694 citations
Ketamine and esketamine are the first non-monoamine-based antidepressants with rapid-onset efficacy for adults with treatment-resistant depression, offering hope to those who do not recover fully with standard antidepressants. However, concerns remain about their safety, tolerability, and appropriate placement in treatment algorithms. An international group of mood disorder experts synthesizes evidence on efficacy, safety, and tolerability, and provides guidance for clinical implementation, including practice parameters at point of care. Areas of consensus and future research directions are discussed.
American Journal of Psychiatry
October 3, 2017
S. Wilkinson, Elizabeth D. Ballard, M. Bloch et al.
680 citations
A single dose of ketamine rapidly reduces suicidal thoughts within one day and for up to one week in depressed patients with suicidal ideation. The effect is moderate to large and partially independent of changes in depressive symptoms. The analysis combined data from 167 participants across 10 studies comparing ketamine to a placebo (saline or midazolam). Ketamine significantly improved clinician-rated and self-reported suicidal ideation, though not on one self-report measure (the Beck Depression Inventory). The authors call for further research on long-term safety and suicide risk reduction before clinical use.
Neuron
March 1, 2019
J. Krystal, C. Abdallah, G. Sanacora et al.
443 citations
Ketamine represents a new class of rapid-acting antidepressants effective for treatment-resistant mood disorders. Its development grew from a revised understanding of depression's biology. Research into how ketamine works is providing fresh insights into antidepressant mechanisms and challenging established views on the neurobiology of depression. The drug's fast, strong, and lasting effects on depressive symptoms appear ready to change how depression is treated.
Molecular Psychiatry
October 3, 2018
M. Fava, M. Freeman, M. Flynn et al.
438 citations
Intravenous ketamine at 0.5 mg/kg and 1.0 mg/kg produces rapid antidepressant effects in adults with treatment-resistant depression, with most improvement seen one day after a single 40-minute infusion. Lower doses (0.1 mg/kg and 0.2 mg/kg) did not show consistent benefit. The study compared four ketamine doses against an active placebo (midazolam) in 99 outpatients across six U.S. sites. Higher doses caused more dissociative symptoms and temporary blood pressure increases, but infusions were generally well tolerated. The findings indicate a range of effective subanesthetic doses, with no clear advantage for doses below 0.5 mg/kg.
New England Journal of Medicine
May 24, 2023
A. Anand, S. Mathew, G. Sanacora et al.
263 citations
For treatment-resistant major depression without psychosis, intravenous ketamine is at least as effective as electroconvulsive therapy (ECT). In a randomized trial with 403 patients, 55.4% of those receiving ketamine and 41.2% of those receiving ECT showed a 50% or greater reduction in depression scores over three weeks. ECT was linked to a notable decline in memory recall after three weeks (average decrease of 9.7 points on a memory test vs. 0.9 points with ketamine), with gradual recovery during follow-up. Quality-of-life improvements were similar between groups. Ketamine caused dissociation, while ECT led to musculoskeletal side effects.
European Archives of Psychiatry and Clinical Neuroscience
February 20, 2020
G. C. Leal, I. D. Bandeira, F. S. Correia-Melo et al.
257 citations
A single intravenous infusion of arketamine (0.5 mg/kg) rapidly reduced depression severity in seven people with treatment-resistant depression. The Montgomery–Åsberg Depression Rating Scale score fell from an average of 30.7 before infusion to 10.4 after one day, a mean drop of 20.3 points. Dissociative side effects were nearly absent. The findings suggest arketamine may produce fast-onset and sustained antidepressant effects with a favorable safety profile, as previously observed in animals, but controlled trials are needed to confirm.
Neuropsychopharmacology
February 24, 2020
C. Abdallah, L. Averill, R. Gueorguieva et al.
181 citations
Ketamine produces rapid antidepressant effects within 24 hours, thought to involve mTORC1 activation. In a double-blind crossover trial, 20 depressed patients received either rapamycin (an mTORC1 inhibitor) or placebo before ketamine. Rapamycin did not block ketamine's 24-hour antidepressant effects. Over two weeks, rapamycin prolonged ketamine's benefits: response rates were 41% with rapamycin versus 13% with placebo, and remission rates were 29% versus 7%. These findings question whether systemic or local mTORC1 blockade matters and suggest rapamycin may extend ketamine's effects, potentially informing mechanisms of depression relapse.
American Journal of Psychiatry
March 3, 2021
J. Dwyer, A. Landeros-Weisenberger, Jessica A. Johnson et al.
163 citations
A single intravenous dose of ketamine (0.5 mg/kg) significantly reduced depressive symptoms in adolescents with major depressive disorder compared with an active placebo (midazolam) 24 hours after infusion, with a large effect size. The improvement appeared to persist for up to 14 days on one depression scale but not another. More participants responded to ketamine during the first three days (76%) than to midazolam (35%). Ketamine caused temporary dissociative symptoms but no serious adverse events. This first controlled trial in adolescents suggests ketamine is well tolerated and has short-term efficacy for treatment-resistant depression.
JAMA psychiatry
October 19, 2022
T. Rhee, S. Shim, B. Forester et al.
139 citations
A systematic review and meta-analysis of six clinical trials involving 340 patients with major depressive episodes found that electroconvulsive therapy (ECT) was more effective than ketamine for reducing depression severity in the acute phase, with a standardized mean difference of -0.69 favoring ECT. No significant differences were observed between the two treatments for cognition, memory, or serious adverse events. Ketamine carried lower risks of headache and muscle pain, while ECT carried lower risks of blurred vision, vertigo, diplopia, and dissociative symptoms. The findings suggest ECT may be superior, but treatment decisions should be individualized.
Contemporary Clinical Trials
February 1, 2019
S. Mathew, S. Wilkinson, Murat Altinay et al.
54 citations
Electroconvulsive therapy (ECT) and ketamine show similar response rates for treatment-resistant depression, but a head-to-head comparison in a large, well-powered trial has been lacking. This protocol describes a non-inferiority trial randomizing 400 patients with treatment-resistant depression to receive either ECT thrice weekly or intravenous ketamine twice weekly for 3-5 weeks. The primary outcome is the proportion of responders based on a patient-reported depression scale. The study is designed to determine whether ketamine retains at least 90% of ECT's treatment effect. Results will inform patient choice, clinical practice, and insurance policies.
European Neuropsychopharmacology
June 2, 2021
A. Feeney, R. Hock, Marlene P. Freeman et al.
33 citations
A single intravenous infusion of ketamine may reduce suicidal ideation in patients with treatment-resistant depression for up to 30 days, but early effects diminish rapidly. In a double-blind randomized trial, 40 patients received ketamine and 16 received midazolam placebo; all had clinically significant suicidal ideation at baseline. By day 30, the ketamine group had a lower mean suicide score (2.03) than the placebo group (3.00). However, among those whose suicidal ideation initially resolved by day 3, there was no significant difference between groups in later scores. Recurrence of suicidal ideation was common in both groups. The findings suggest a possible role for ketamine as an adjunct to standard treatments.