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.
American Journal of Psychiatry
January 5, 2021
A. Feder, Sara Costi, S. Rutter et al.
239 citations
Repeated intravenous infusions of ketamine, given over two weeks, significantly reduced symptom severity in chronic PTSD compared to a psychoactive placebo (midazolam). At two weeks, the ketamine group scored nearly 12 points lower on the Clinician-Administered PTSD Scale, and 67% of participants responded to treatment versus 20% in the placebo group. Among responders, the median time to loss of response was 27.5 days after the infusion course. Ketamine was well tolerated with no serious adverse events. This is the first randomized controlled trial to show efficacy of repeated ketamine infusions for chronic PTSD.
Translational Psychiatry
January 10, 2022
F. Cathomas, L. Bevilacqua, Aarthi Ramakrishnan et al.
44 citations
Ketamine rapidly and lastingly reduces depression in people with treatment-resistant depression (TRD), but how it works remains unclear. TRD is linked to inflammation, and ketamine may curb inflammatory processes. Whole blood gene expression was compared between 21 healthy controls and 26 TRD patients, and again in TRD patients 24 hours after a single ketamine infusion. Before treatment, TRD patients showed activation of interferon signaling pathways. Among TRD patients, those who later responded to ketamine had higher levels of two glutamate receptor genes (GRM2 and GRIN2D) before the infusion. Ketamine response produced a distinct gene expression signature, but no evidence of anti-inflammatory changes was found. More research is needed on the peripheral immune system's role.
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.
Brain : a journal of neurology
June 30, 2025
Sara Costi, Chloe Wigg, Erdem Pulcu et al.
3 citations
Ketamine, long used as an anesthetic, was first identified in 2000 as a fast-acting antidepressant. A single dose alleviates depressive symptoms, including anhedonia, within hours, and effects last for days. Research in animals indicates ketamine rapidly influences brain regions involved in punishment and reward processing, reverses negative affective biases in memories, and promotes stress resilience. Translating these findings to humans is ongoing, with emerging evidence suggesting similar mechanisms in healthy volunteers and patients. Clinical use is limited by acute side effects and unknown long-term safety. Understanding ketamine's mechanisms may guide development of safer rapid-acting antidepressants.
medRxiv Preprint Server
April 10, 2021
Agnes Norbury, Sarah B. Rutter, Abigail B. Collins et al.
1 citation
preprint
In a small randomized clinical trial, repeated doses of ketamine improved PTSD symptoms more than midazolam. Brain scans showed that symptom improvement was linked to increased communication between the ventromedial prefrontal cortex and amygdala when viewing emotional faces, especially in those who received ketamine. Ketamine-related improvement was also predicted by decreased activity in the dorsal anterior cingulate during emotional conflict and increased resting-state connectivity between the ventromedial prefrontal cortex and anterior insula. Further analysis indicated that ketamine specifically strengthened the prefrontal cortex's ability to inhibit amygdala responses to threatening social cues, suggesting a normalization of brain circuits involved in fear regulation.
bioRxiv (Cold Spring Harbor Laboratory)
February 10, 2026
Erdem Pulcu, Sara Costi, Pilar Artiach-Hortelano et al.
A single sub-anesthetic dose of ketamine reduces activity in the lateral habenula, a small midbrain structure involved in aversive learning, when healthy volunteers expect or experience unpleasant stimuli a day later. In a randomized trial with 70 adults, those who received ketamine showed attenuated habenula responses during an aversive Pavlovian conditioning task measured with 7-Tesla functional neuroimaging. Preliminary evidence suggests that reduced habenula activity during aversive learning may weaken the emotional impact of negative memories. These results support preclinical models of how ketamine may rapidly relieve depression by acting on the human habenula.
The Journal of clinical psychiatry
April 2, 2025
Adriana Feder, Oneysha Brown, Sarah B Rutter et al.
Combining six ketamine infusions with a brief exposure-based psychotherapy, written exposure therapy (WET), produced large and durable reductions in PTSD symptoms for patients with chronic, severe PTSD. In an open-label trial, 13 of 14 patients completed treatment. PTSD symptom severity, measured by the CAPS-5, dropped from an average of 41.6 before treatment to 20.8 at 12 weeks, a large-magnitude improvement. Nine patients (69%) were treatment responders, and eight (61.5%) maintained improvement up to six months. The authors suggest the combined treatment may be effective but call for larger randomized controlled trials to confirm efficacy and synergy.