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 1, 2019
Silvia Muttoni, Maddalena Ardissino, Christopher John
265 citations
Depression and anxiety are common and disabling, yet existing treatments often fall short. A review of seven clinical trials involving 130 patients found that, when used in a supportive setting, the psychedelics ayahuasca, psilocybin, and LSD produced immediate and lasting reductions in depression and anxiety symptoms over several months. The treatments were well tolerated; the most common side effects were temporary anxiety, headaches, nausea, and mild increases in heart rate and blood pressure. The authors note that the number of studies and patients is small, but the evidence suggests psychedelic-assisted therapy is a promising alternative for patients who do not respond to standard care.
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 1, 2023
Kwonmok Ko, Emma I Kopra, Anthony J. Cleare et al.
144 citations
A systematic review and meta-analysis of 14 studies (7 randomized controlled trials) examined the effects of classic psychedelics (psilocybin, ayahuasca, LSD) on depressive symptoms. The review found significant reductions in depressive symptoms at 1 day, 1 week, and 3-5 weeks after treatment with psychological support. Results at 6-8 weeks were less conclusive. Small sample sizes in most studies and lack of long-term follow-up data limited statistical power and interpretation. The findings suggest an association between psychedelic therapy and short-term symptom reduction, but more rigorous trials with larger, diverse samples are needed.
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
April 1, 2023
Otto Simonsson, Peter S. Hendricks, Richard Chambers et al.
124 citations
Using nationally representative US adult data (N = 2822), most people who have used classic psychedelics (59.1%) never had a challenging, difficult, or distressing experience. However, 8.9% reported functional impairment lasting more than one day from such an experience, and 2.6% sought medical, psychiatric, or psychological help afterward. Co-use of lithium or other mood stabilizers, and certain set and setting factors—including no preparation, disagreeable physical environment, negative mindset, no psychological support, a dose perceived as too large, and a major life event prior—were associated with greater difficulty. Negative mindset, no psychological support, and a major life event prior were also linked to overall risk of harm.
Journal of Affective Disorders
November 14, 2020
Stacie Hudgens, Lysbeth Floden, Michael Blackowicz et al.
77 citations
For patients with treatment-resistant depression (TRD)—those who have not responded to at least two different antidepressants in their current episode—meaningful improvement on two common depression scales was defined using a clinician-rated severity anchor. On the Patient Health Questionnaire (PHQ-9), a decrease of 6 points was the most appropriate meaningful change threshold. By Day 28, 86.5% of patients receiving esketamine nasal spray plus an antidepressant reached or exceeded this threshold, compared to 70% of those receiving placebo plus an antidepressant. On the Montgomery-Åsberg Depression Rating Scale (MADRS), a decrease of 10 points was the most appropriate threshold, with 78.2% of esketamine-treated patients versus 65.0% of placebo-treated patients meeting it. These anchor-based thresholds help interpret individual-level treatment response in TRD.
Journal of Affective Disorders
February 15, 2023
Sarah Shnayder, Rezvan Ameli, Ninet Sinaii et al.
67 citations
Psilocybin-assisted therapy improved psycho-social-spiritual well-being in cancer patients with major depressive disorder, as measured by the NIH-HEALS. In a Phase II open-label trial, 30 participants received 25 mg of psilocybin with group preparation and integration sessions. NIH-HEALS scores increased significantly after treatment, with gains in all three factors: Connection (12.7%), Reflection & Introspection (7.7%), and Trust & Acceptance (22.4%). Improvements appeared by day 1 and persisted through 8 weeks. The study lacked a control group, relied on self-reports, and had a small, limited sample, restricting generalizability. The results suggest that Connection, Reflection & Introspection, and Trust & Acceptance are key elements of psycho-social-spiritual healing in this context.
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
January 15, 2016
Megha M Vasavada, Amber M Leaver, Randall Espinoza et al.
58 citations
In patients with major depressive disorder, differences in brain white matter structure before ketamine treatment may predict who will respond to the drug 24 hours later. Using diffusion imaging in 10 patients, those who showed more than 50% symptom improvement had greater fractional anisotropy in the cingulum and forceps minor pathways compared to non-responders. Non-responders also had lower fractional anisotropy and higher radial and mean diffusivity in these pathways compared to healthy controls, and they had an earlier age of depression onset and longer current episode. These preliminary findings suggest that the structural integrity of emotion-related brain networks may influence ketamine's antidepressant effect.
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
August 1, 2023
Richard J. Zeifman, Anne C Wagner, Candice M Monson et al.
56 citations
In a double-blind randomized controlled trial comparing psilocybin therapy (two 25 mg sessions plus daily placebo for six weeks) with escitalopram (two 1 mg psilocybin sessions plus 10-20 mg daily escitalopram for six weeks) among 59 individuals with major depressive disorder, reductions in experiential avoidance mediated improvements in well-being, depression severity, suicidal ideation, and trait anxiety only in the psilocybin group. Exploratory analyses indicated that these improvements (except for suicidal ideation) occurred serially through increased connectedness. Experiences of ego dissolution and psychological insight predicted reductions in experiential avoidance. The findings support reduced experiential avoidance as a mechanism underlying psilocybin therapy's positive outcomes.
Journal of Affective Disorders
July 1, 2024
Ashok Seshadri, Larry J. Prokop, Balwinder Singh
50 citations
A systematic review and meta-analysis of 12 randomized controlled trials found that intravenous ketamine reduces depression symptoms in treatment-resistant depression at doses as low as 0.2 mg/kg, with increasing response at 0.5 mg/kg but no additional benefit at 1 mg/kg. Intranasal esketamine doses of 56–84 mg were more effective than 28 mg. Higher intravenous doses above 0.5 mg/kg did not lead to greater treatment response. The overall quality of evidence was low, limited by few studies, and publication bias was high.
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
July 1, 2023
Allison A. Feduccia, Gabby Agin-Liebes, Collin M Price et al.
38 citations
Psychedelic substances are being studied in drug development programs, with clinical trials showing evidence for safe and effective use of psychedelic therapies for mental health conditions. With anticipated FDA approval of MDMA-assisted therapy for PTSD in 2023 and psilocybin therapy for depression disorders soon after, the medical community should become informed on best practices and participate in developing standards of care. Gold standards in medicine distinguish treatments as the highest quality for comparison. This article reviews the origins of psychedelic-assisted therapy, minimum requirements for safe use, criteria for gold standards in mental health, and nuances in establishing gold standards in psychedelic medicine to guide clinical decision making.
Journal of Affective Disorders
July 15, 2023
Matthew B. Wall, Cynthia Lam, Natalie Ertl et al.
36 citations
Psilocybin-assisted therapy for depression alters the brain's response to music, suggesting an elevated responsiveness to music after treatment that is related to subjective drug effects during dosing. Nineteen patients with treatment-resistant depression underwent two psilocybin dosing sessions. Brain scans before and after treatment showed increased activity in the superior temporal cortex when listening to music, and decreased activity in the medial frontal lobes during rest. These changes in music-related brain activity correlated with the intensity of subjective effects felt during the psilocybin sessions. The findings imply that psychedelic therapy may enhance emotional responsiveness to music, which could be relevant for treating depression.
Journal of Affective Disorders
March 1, 2025
Guy M. Goodwin, Scott T Aaronson, Oscar Alvarez et al.
35 citations
In treatment-resistant depression, a single dose of 25 mg of psilocybin produced stronger correlations between certain psychedelic experiences and depression improvement three weeks later than lower doses. The intensity of psychedelic effects was dose-related, but scores for different doses overlapped considerably. At the 25 mg dose, dimensions of oceanic boundlessness and visual restructuralization, along with emotional breakthrough, showed the strongest correlations with reduced depression scores. The study does not establish causation and requires replication. The overlap in experience intensity across doses suggests unblinding to dose is less likely. Correlations between psychedelic experience and outcome indicate specificity in psilocybin's mechanism of action.
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
July 1, 2024
Cameron N Calder, Angela T H Kwan, Kayla M Teopiz et al.
31 citations
Ketamine is effective for adults with treatment-resistant depression. A systematic review of 21 placebo-controlled randomized trials with 2042 participants calculated the number needed to treat (NNT) for racemic ketamine: 7 at 4 hours, 3 from one day to one week, and 9 at four weeks. Esketamine had an NNT of 2 at one day and 11 at four weeks. Numbers needed to harm indicated low risk. The NNTs under 10 across observation intervals are considered highly clinically meaningful for this difficult-to-treat disorder. Limitations include potential functional unblinding and selective reporting bias.
Journal of Affective Disorders
April 1, 2023
Nadav Liam Modlin, Tammy M Miller, James J Rucker et al.
30 citations
Psilocybin therapies show promise for conditions like major depressive disorder, end-of-life anxiety, and obsessive-compulsive disorder. However, little attention has been paid to intrapersonal and interpersonal factors that influence a patient's readiness for such interventions. This paper proposes that readiness assessment should include both intrapersonal and interpersonal factors to improve safety, patient care, and treatment outcomes. Although no reliable and valid instrument currently exists, the authors suggest three areas of focus—patient presentation, therapeutic alliance, and patient safety—to establish readiness and optimize and personalize psilocybin therapy.