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.
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 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 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.
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.