Journal of Affective Disorders
September 23, 2020
A. Bahji, G. Vázquez, C. Zarate
404 citations
A systematic review and meta-analysis of 24 randomized controlled trials with 1,877 participants compared racemic ketamine and esketamine for unipolar and bipolar major depression. Racemic ketamine showed greater treatment response (rate ratio 3.01 versus 1.38) and remission rates (rate ratio 3.70 versus 1.47) than esketamine, and had lower dropout rates (rate ratio 0.76 versus 1.37). Intravenous ketamine appears more efficacious than intranasal esketamine for depression.
Journal of Affective Disorders
February 18, 2014
D. Luckenbaugh, M. Niciu, D. Ionescu et al.
282 citations
In treatment-resistant inpatients with major depressive or bipolar disorder, the dissociative side effects of a single ketamine infusion predicted a more robust and sustained antidepressant response. Greater dissociation measured 40 minutes after infusion correlated with greater improvement in depression scores at 230 minutes and 7 days later. In contrast, psychotomimetic symptoms, manic symptoms, and changes in blood pressure or pulse were not significantly linked to antidepressant efficacy. The findings suggest that dissociation, rather than other side effects, may be a marker or mediator of ketamine's antidepressant action, though further prospective research is needed.
Journal of Affective Disorders
November 14, 2019
F. S. Correia-Melo, G. C. Leal, F. Vieira et al.
188 citations
In adults with treatment-resistant depression, a single intravenous infusion of esketamine (0.25 mg/kg) was non-inferior to ketamine (0.5 mg/kg) for achieving remission 24 hours later. Among 63 participants, 29.4% in the esketamine group and 24.1% in the ketamine group showed remission, a difference of 5.3% that fell within the predefined non-inferiority margin. Depression scores on the Montgomery-Åsberg Depression Rating Scale improved similarly in both groups, and side effects were mild and comparable. The findings suggest that esketamine at half the dose of ketamine offers equivalent short-term efficacy and safety.
Journal of Affective Disorders
November 1, 2020
R. Mcintyre, Isabelle P. Carvalho, L. Lui et al.
186 citations
Ketamine is a rapid and effective treatment for adults with treatment-resistant depression, but different formulations and routes of delivery vary in effect size. A meta-analysis of studies found that intranasal ketamine or esketamine had a large effect on depression symptoms at 24 hours and again at 7-20 days. Intravenous ketamine or esketamine showed a large but not statistically significant effect at 2-6 days. Oral ketamine had a moderate effect at 21-28 days. No conclusions about which formulation or route is best could be drawn because direct comparisons are lacking. More studies with larger samples are needed, especially for oral ketamine.
Journal of Affective Disorders
January 1, 2019
D. Ionescu, Kate H Bentley, M. Eikermann et al.
179 citations
Repeated doses of ketamine did not reduce depression or suicidal ideation more than placebo in outpatients with severe, treatment-resistant depression and chronic suicidal thoughts. Twenty-six medicated adults received six infusions of ketamine or saline over three weeks. Neither depression severity nor suicidal ideation differed between groups during the infusion phase. At three months, two patients in each group had remitted from depression. The authors suggest that the standard 0.5 mg/kg dose may be insufficient for this severely ill outpatient population.
Journal of Affective Disorders
February 3, 2023
Guy M Goodwin, Scott T Aaronson, Oscar Alvarez et al.
168 citations
Three weeks after a single dose, 25 mg of psilocybin, and to a lesser extent 10 mg, improved patient-reported measures of depression severity, anxiety, affect, and functioning in people with treatment-resistant depression. These findings extend the primary results from the largest randomized clinical trial of psilocybin for TRD, highlighting outcomes that matter to patients.
Journal of Affective Disorders
February 17, 2018
M. Niciu, Bridget J. Shovestul, Brittany A. Jaso et al.
134 citations
Depersonalization—a feeling of detachment from one's own body or thoughts—was the dissociative symptom most strongly linked to ketamine's antidepressant effect in patients with treatment-resistant depression. Analyzing data from 126 patients with major depressive or bipolar disorder who received a single ketamine infusion, researchers found that higher scores on the depersonalization subscale of the Clinician-Administered Dissociative States Scale consistently predicted greater improvement in depression ratings across multiple time points. Derealization (feeling the world is unreal) showed a weaker and less consistent association, while amnesia was unrelated to antidepressant response. The finding suggests that depersonalization and antidepressant response may share neurobiological mechanisms, though off-target effects cannot be ruled out.
Journal of Affective Disorders
January 1, 2022
L. Mcinnes, Jimmy J Qian, Rishab Gargeya et al.
60 citations
In a retrospective analysis of 537 patients receiving ketamine intravenous therapy for depression in 178 U.S. community practices, 53.6% showed a response (at least 50% reduction in depression scores) and 28.9% achieved remission within 14-31 days after the induction phase. Among patients with suicidal ideation at baseline, 73.0% reported a reduction. A small portion of patients worsened: 8.4% experienced increased depressive symptoms and 6.0% reported increased suicidal ideation. Response rates were similar across levels of baseline depression severity. Patients who responded had about an 80% chance of sustaining that response at 4 weeks and about 60% at 8 weeks, even without maintenance infusions.
Journal of Affective Disorders
July 1, 2022
T. D. Hull, Matteo Malgaroli, A. Gazzaley et al.
59 citations
At-home ketamine-assisted therapy with remote monitoring produced rapid and significant improvements in depression and anxiety. Among 1247 patients, 62.8% showed at least 50% improvement on the depression scale and 62.9% on the anxiety scale, with remission rates of 32.6% and 31.3%, respectively. Deterioration was rare (0.9% for depression, 0.6% for anxiety). Three patient subpopulations emerged: those who improved steadily (79.3%), those with delayed improvement (9.3%), and a chronic group (11.4%) who were more likely to report dissociation at the fourth session. Side effects at the second session predicted delayed improvement. Only six patients discontinued early due to side effects or adverse events, indicating that screening and monitoring kept risks low.
Journal of Affective Disorders
May 1, 2019
Wei Zheng, Xiaohong Li, Xiao-Min Zhu et al.
57 citations
An updated meta-analysis of 17 randomized controlled trials involving 1,035 people with major depressive disorder found that adding ketamine alone to electroconvulsive therapy does not improve depressive symptoms compared with other anesthetic agents at any time point. Combining ketamine with other anesthetics showed a short-term advantage in reducing depressive symptoms early in treatment, but this benefit did not persist after the full course of ECT or at the end of the study. Most subgroup analyses confirmed the lack of significant effect. Ketamine alone increased blood pressure more than other anesthetics. Results for neurocognitive function were mixed.
Journal of Affective Disorders
January 26, 2024
Ludwig Honk, Cecilia U.D. Stenfors, Simon B. Goldberg et al.
41 citations
Using data from nearly 10,000 adults in the US and UK, psychedelic use over a two-month period was not linked to changes in psychotic symptoms overall. However, among people with a personal or family history of bipolar disorder, psychedelic use was associated with an increase in symptoms. Conversely, those with a personal history of psychotic disorders experienced a decrease in symptoms. These findings suggest that the effects of psychedelics on psychotic symptoms depend on an individual's psychiatric history.
Journal of Affective Disorders
November 8, 2023
I. Terao, Takahiro Tsuge, Kaori Endo et al.
32 citations
For treatment-resistant unipolar depression, intravenous racemic ketamine, intranasal esketamine, aripiprazole, and lithium are all more effective than placebo. Intravenous racemic ketamine is significantly more effective and acceptable than intranasal esketamine and aripiprazole. Unlike intranasal esketamine and aripiprazole, intravenous racemic ketamine does not differ from placebo in tolerability. Lithium and intravenous racemic ketamine show no significant differences in efficacy, tolerability, or acceptability. The sample size for intravenous racemic ketamine was small, and a larger head-to-head trial is needed to clarify whether intravenous racemic ketamine or lithium is superior.
Journal of Affective Disorders
March 1, 2023
Debora de A. Simoes Moreira, Luís Eduardo Gauer, Guilherme Teixeira et al.
25 citations
A systematic review and meta-analysis of eight randomized controlled trials or cohort studies comparing ketamine with electroconvulsive therapy (ECT) for treatment-resistant depression found no evidence that ketamine is superior to ECT in reducing depressive symptom severity or in achieving response to therapy. Among side effects, patients treated with ketamine had a statistically significant lower risk of muscle pain compared with those receiving ECT. The analysis also noted trends toward more dissociative symptoms with ketamine and less nausea and headache, but these differences were not statistically significant. The authors caution that the small number of eligible studies, high heterogeneity, and risk of bias limit the strength of these conclusions.
Journal of Affective Disorders
January 6, 2023
G. Ahmed, Y. Elserogy, G. M. A. Elfadl et al.
24 citations
Ketamine infusions reduce suicidal ideation and depression in people with treatment-resistant depression, regardless of other psychiatric or personality disorders. In a randomized double-blind trial with 36 patients, those receiving two weekly ketamine infusions showed significantly greater decreases on the Hamilton Depression Rating Scale and Suicide Probability Scale than those given a placebo. The presence of other psychiatric symptoms did not influence the magnitude of improvement. Receiving ketamine was the only significant factor predicting better suicide and depression scores. The study lacked data on quality of life and cognition and had a small sample size.
Journal of Affective Disorders
April 1, 2023
A. Zavaliangos-Petropulu, S. Mcclintock, Jacqueline Khalil et al.
16 citations
Ketamine treatment improves cognitive function in people with treatment-resistant depression, and these improvements last at least five weeks. In a study of 66 patients receiving four ketamine infusions, significant gains occurred in inhibition, working memory, processing speed, and overall fluid cognition after the first and fourth infusions. Processing speed and overall fluid cognition remained improved at a five-week follow-up, even though depressive symptoms had largely returned to baseline by then. Baseline working memory and changes in inhibition were moderately linked to antidepressant response, but cognitive improvements were statistically independent of mood changes, suggesting ketamine acts on overlapping but distinct brain systems.
Journal of Affective Disorders
July 18, 2025
Mary E. Kittur, Mingyao Liu, Brett D. M. Jones et al.
12 citations
Psilocybin therapy shows promise for rapid and lasting clinical benefits when paired with psychological support, but the field lacks standardized therapeutic guidelines. A systematic review of 22 recent trials across conditions like depression, substance use, and obsessive-compulsive disorders found broad consistency in the structure of therapy sessions—before, during, and after psilocybin administration. However, trials varied widely in therapeutic intensity, diagnostic adaptations, and use of evidence-based psychotherapies. Fewer than half reported standardization measures such as manualized procedures, specific training, or adherence monitoring. These gaps undermine replicability and generalizability, and until support protocols are clearly defined, mechanistic understanding and clinical adoption will remain limited.
Journal of Affective Disorders
January 1, 2024
Liliana Patarroyo-Rodriguez, Vanessa M. Pazdernik, Jennifer L. Vande Voort et al.
12 citations
Sleep disturbances affect 94% of patients with treatment-resistant depression, with middle and early insomnia being the most common. Patients who experience hypersomnia (excessive sleep) before treatment show higher response rates and greater improvement in depressive symptoms after receiving intravenous ketamine or intranasal esketamine. Additionally, 15% of patients have an atypical depression phenotype, and most of them also achieve a positive response with greater symptom reduction. A trend toward faster response is seen in both the hypersomnia and atypical depression groups. These sleep-related features may help predict which patients will benefit from ketamine-based treatments.
Journal of Affective Disorders
March 1, 2021
R. Mcintyre, Nelson B Rodrigues, Orly Lipsitz et al.
10 citations
The McIntyre and Rosenblat Rapid Response Scale (MARRRS) is a brief self-report measure of depression symptom severity that is sensitive to change with the rapid-acting antidepressant ketamine. In 64 adults with treatment-resistant depression receiving intravenous ketamine, the MARRRS showed high internal consistency and strong convergent validity with the established 16-Item Quick Inventory Depressive Symptoms Self-Report. The scale detected symptom changes across four infusions and loaded onto two factors: dysphoria and psychic anxiety. The findings suggest that outcome measures validated for rapid-acting treatments are needed to inform treatment progress and decisions.
Journal of Affective Disorders
September 1, 2025
M. Olivola, Filippo Mazzoni, Barbara Tarantino et al.
8 citations
A six-month observational study of 36 patients with treatment-resistant depression found that those with poor mentalization abilities at the start had more severe depressive symptoms throughout treatment with esketamine. Greater cognitive rigidity appeared protective, possibly by stabilizing emotions and reducing negative thinking. The findings suggest esketamine may help break cognitive inflexibility and improve mentalization, supporting a personalized approach to treatment-resistant depression.
Journal of Affective Disorders
December 1, 2017
Shona Neehoff, P. Glue
8 citations
Several possible explanations could account for the differing results observed in two assessments of the CADSS (Clinician-Administered Dissociative States Scale) performance.
Journal of Affective Disorders
August 1, 2023
Mu-Hong Chen, Ya-Mei Bai, Hui-Ju Wu et al.
7 citations
A single low-dose ketamine infusion (0.5 mg/kg) compared to a low-dose midazolam control (0.045 mg/kg) resulted in higher serum levels of the anti-aging hormone klotho three days after treatment in 48 patients with treatment-resistant depression and strong suicidal ideation. However, ketamine did not significantly increase klotho levels from baseline, and changes in klotho were not associated with changes in depressive or suicidal symptoms. Higher baseline klotho levels predicted a poorer antidepressant response to ketamine. The findings suggest klotho may be involved in ketamine's antidepressant mechanism, but further molecular studies are needed.
Journal of Affective Disorders
April 1, 2023
Olivier Payette, P. Lespérance, V. D. Jodoin et al.
7 citations
For people with treatment-resistant depression who did not benefit from transcranial magnetic stimulation (TMS), intravenous racemic ketamine may offer some help. In a small case series of 21 patients, a course of six ketamine infusions over two weeks was safe and produced few side effects. Average depression scores, measured by the MADRS scale, fell from 27.6 (moderate depression) to 18.6 (mild depression), a mean improvement of 34.5%. Four patients (19%) responded to treatment, and two of those (9.5%) achieved remission. The study was uncontrolled and retrospective, so results are preliminary.
Journal of Affective Disorders
December 17, 2025
Faheem Ahmed Khan, Nuruliarizki Shinta Pandupuspitasari, Tewin Tencomnao et al.
2 citations
Psilocybin, a hallucinogenic substance from certain mushrooms, shows promise as a treatment for various mental health conditions. This meta-analysis and systematic review evaluated its therapeutic function, finding it reduces symptoms of anxiety and major depressive disorder (standardized mean difference = -1.438) and mood disorders (standardized mean difference = -1.476). The benefits appear linked to psilocybin's regulation of serotonin 5-HT2A receptors, improving neuroplasticity and emotional integration. Sustained improvements often occur after a single session. While results are resistant to publication bias, the review highlights the need to address hurdles to clinical adoption and tailor treatments for specific groups.
Journal of Affective Disorders
September 16, 2025
Sami George Sabbah, Sophie Li, Sabrina Wong et al.
2 citations
Psilocybin is linked to dynamic and temporally distinct neuroplastic changes that are associated with clinical improvement in depression. However, many studies reused overlapping datasets, had high exploratory flexibility, and risk of bias, which limits the generalizability of the results. Future research should use independent datasets, pre-registered imaging endpoints, and longitudinal designs to better understand the mechanisms of psychedelic therapy for depression.
Journal of Affective Disorders
October 31, 2025
André Do, Laurence Cloutier, Lydia Hébert‐tremblay et al.
1 citation
The therapeutic value of psilocybin for treating depression in bipolar disorder remains uncertain, as its efficacy and safety have not been established. Future research is necessary to determine whether psilocybin can be a viable treatment option for bipolar depression.