One of the most-studied indications in psychedelic and consciousness research, from antidepressant mechanisms to assisted-therapy trials.
Synthesized from 25 studies in the library · AI-generated, grounded in the abstracts below
Found by searching the library for Depression, major depressive disorder, MDD, depressive disorder, treatment-resistant depression, then ranked by relevance.
The research consistently shows that several interventions produce meaningful antidepressant effects: ketamine yields rapid relief in treatment-resistant depression, psilocybin-assisted therapy produces large reductions in depressive symptoms that can persist for months, and mindfulness-based cognitive therapy reduces relapse in people with three or more prior episodes. Effects are directionally consistent across trials, but most studies are small, several are open-label or use active or waiting-list controls rather than inert placebo, and long-term durability beyond 6-12 months is largely untested.
Direction is which way each study's own result points, not our rating of the study.
| Study | Design | Sample size | Direction | Finding |
|---|---|---|---|---|
| A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression 2006 | RCT (double-blind crossover) | 18 | Supports | A single 0.5 mg/kg ketamine infusion significantly improved depression versus placebo within 110 minutes, remaining significant through one week. |
| Prevention of relapse/recurrence in major depression by mindfulness-based cognitive therapy. 2000 | RCT | 145 | Mixed | MBCT significantly reduced relapse risk over 60 weeks in patients with three or more prior episodes but did not reduce relapse in those with only two episodes. |
| Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial 2016 | RCT (double-blind crossover) | 51 | Supports | High-dose psilocybin produced large decreases in depressed mood and anxiety, with about 80% of participants showing clinically significant improvement sustained at 6 months. |
| Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial 2016 | RCT (double-blind, placebo-controlled crossover) | 29 | Supports | Single-dose psilocybin with psychotherapy produced immediate and sustained reductions in depression and anxiety, with roughly 60-80% showing clinically significant reductions at 6.5 months. |
| Synaptic Dysfunction in Depression: Potential Therapeutic Targets 2012 | review | Supports | Argues that ketamine rapidly induces synaptogenesis and reverses stress-induced synaptic deficits, supporting a synaptogenic hypothesis of depression and treatment response. | |
| Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. 2016 | open-label feasibility trial | 12 | Supports | Two psilocybin doses were well tolerated and associated with marked reductions in depressive symptoms at one week and three months. |
| Mindfulness-Based Cognitive Therapy for Depression: Replication and Exploration of Differential Relapse Prevention Effects. 2004 | RCT | 73 | Mixed | MBCT reduced relapse from 78% to 36% in patients with three or more prior episodes but was associated with a higher relapse rate (50% vs 20%) in those with only two episodes. |
| Trial of Psilocybin versus Escitalopram for Depression 2021 | RCT | No effect | At week 6, psilocybin did not differ significantly from escitalopram on the primary depression outcome, though secondary outcomes generally favored psilocybin without correction for multiple comparisons. | |
| Mindfulness-based cognitive therapy for depression 2006 | theoretical | Unclear | Describes the development of MBCT, a theory-driven psychological intervention incorporating mindfulness training to reduce relapse in recurrent major depression. | |
| Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder 2020 | RCT (waiting-list controlled) | 24 | Supports | Psilocybin with supportive psychotherapy produced large, statistically significant reductions in depression severity versus a waiting list, with 71% response at week 1 and 54% remission at week 4. |
| Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial 2013 | RCT (two-site, active placebo) | 73 | Supports | Ketamine produced greater MADRS improvement than midazolam at 24 hours (7.95-point difference), with 64% versus 28% response rates. |
| Mindfulness-Based Cognitive Therapy for Depression: A New Approach to Preventing Relapse 2003 | review | Supports | Presents MBCT as a new approach to preventing relapse in recurrent depression by combining cognitive therapy with mindfulness practices. | |
| Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. 2022 | phase 2 double-blind RCT | 233 | Supports | A single 25 mg psilocybin dose significantly reduced MADRS scores at week 3 versus a 1 mg control (-12.0 vs -5.4), while 10 mg did not differ significantly from control. |
| Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. 2017 | open-label trial | 20 | Supports | Two psilocybin doses produced large reductions in depressive symptoms (Cohen's d 2.2 at week 1) that remained significant at 3 and 6 months (d 1.5 and 1.4). |
| A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression 2010 | RCT (double-blind crossover, add-on) | 18 | Supports | A single 0.5 mg/kg ketamine infusion significantly improved depressive symptoms versus placebo within 40 minutes, remaining significant through day 3. |
| LSD treatment affects working memory-related brain function in patients with major depressive disorder 2026 | RCT (double-blind, parallel-group) | 43 | Supports | High-dose LSD increased working-memory-related brain responses versus low dose, but these responses correlated with task performance and perceptual changes, not with treatment response. |
| Psilocybin use, mental health treatment utilization, and unmet treatment need among US individuals with depression. 2026 | observational cross-sectional | 6793 | Mixed | Past-year psilocybin use was not associated with any conventional mental health treatment utilization but was associated with greater perceived unmet treatment need (52.0% vs 33.9%). |
| Therapists’ Perspectives on the Psychotherapeutic Support in Psilocybin Treatment for Major Depressive Disorder: Insights from a Randomized Controlled Trial 2026 | qualitative | 9 | Supports | Therapists described psilocybin treatment as beneficial for psychotherapy and the psychedelic experience as facilitating therapeutic processes, while noting it remains undetermined whether psychotherapeutic support is essential. |
| Effects of Repeated Ketamine Infusions on Suicidal Ideation in Treatment-Resistant Depression and Associated Changes in Selected Plasma Biomarkers 2026 | secondary analysis of open-label trial | Mixed | Repeated ketamine infusions were associated with modest reductions in suicide-related item scores on MADRS and QIDS-SR-16, but Columbia Suicide Severity Rating Scale decreases were not statistically significant and no biomarker associations survived correction. | |
| Mystical Experiences Mediate the Effects of Psilocybin-Assisted Psychotherapy + Mindfulness-Based Stress Reduction on Trait Mindfulness and Depression Symptoms: Mechanistic Results from a Randomized Controlled Trial 2026 | RCT (mechanistic) | 25 | Supports | MBSR plus group psilocybin-assisted therapy showed significant between-group effects favoring the psilocybin arm on mindfulness gains, with mystical experience proposed as the mediating mechanism. |
| Connectedness as a Mechanism of Change in Psilocybin-Assisted Cognitive Behavioral Therapy for Major Depressive Disorder 2026 | open-label trial analysis | 15 | Mixed | Connectedness increased significantly from baseline to post-treatment (Hedges' g 0.62) and predicted improved depressive outcomes at follow-up, but the increase was not sustained at three months. |
| KETAMINE VERSUS ELECTROCONVULSIVE THERAPY FOR SEVERE TREATMENT-RESISTANT DEPRESSION: A SYSTEMATIC REVIEW AND META-ANALYSIS OF EFFICACY, SPEED OF RESPONSE, COGNITIVE OUTCOMES, AND SAFETY 2026 | systematic review and meta-analysis | 1388 | Mixed | Pooled response and remission did not differ significantly between intravenous ketamine and ECT, though heterogeneity was high and omitting one large trial produced a significant ECT advantage. |
| Voided REM Sleep (V-REM): A Candidate Biomarker Linking Treatment-Resistant PTSD and Major Depressive Disorder 2026 | theoretical | Unclear | Proposes 'Voided REM sleep' as a candidate biomarker linking treatment-resistant PTSD and major depressive disorder, arguing it would not require determining whether the anomaly causes or results from treatment resistance. | |
| Multimodal predictors of response to intravenous ketamine in treatment-resistant depression: toward personalized treatment in major depressive and bipolar disorders. 2026 | systematic review | Unclear | Identifies a broad set of candidate predictors of intravenous ketamine response across clinical, biomarker, metabolic, genetic, neurophysiological, and cognitive domains, but argues most remain exploratory and require prospective validation. | |
| Symptom-level and network analyses of ketamine treatment in treatment-resistant depression: A pooled analysis of two randomized controlled trials. 2026 | post hoc pooled analysis of RCTs | 132 | Supports | Ketamine produced broad early symptom improvement, with adjusted control-minus-ketamine differences of about 1.1 points on apparent sadness, pessimistic thoughts, and suicidal thoughts at 240 minutes. |
This synthesis reads the 15 most-cited and 10 most recent studies whose primary subject is Depression, up to 25 in all. The most-cited set anchors the established evidence, and the recent set surfaces work that is too new to have gathered citations yet.
A study qualifies only when Depression or a known alias appears in its title or keywords, so broad reviews that mention it only in passing are left out. Each study is read from its abstract, strongest evidence first, and the summary reports the direction of the results along with any conflicts and gaps.
The full method, including what a person does and does not review, is on the methods page.
Latest monthly recap: September 2026 →
10,336 articles · 3,583 from the last two years · 9,789,796 participants across 5,293 studies reporting sample size
Data updated
Studies whose primary subject is both the compound and depression, with reviews counted by the study design extracted from each abstract. Registered trials are from ClinicalTrials.gov, and each count links to that compound's full trial pipeline. This maps how much research exists, not how well anything works.
| Compound | Studies | Meta-analyses and systematic reviews | Registered trials | Highest phase | From the last two years |
|---|---|---|---|---|---|
| Ketamine | 1,746 studies | 208 meta-analyses and systematic reviews | 317 registered trials | up to Phase 4 | 731 from the last two years |
| Esketamine | 594 studies | 84 meta-analyses and systematic reviews | 75 registered trials | up to Phase 4 | 344 from the last two years |
| Psilocybin | 505 studies | 86 meta-analyses and systematic reviews | 100 registered trials | up to Phase 3 | 220 from the last two years |
| LSD | 58 studies | 9 meta-analyses and systematic reviews | 8 registered trials | up to Phase 2 | 21 from the last two years |
| MDMA | 54 studies | 6 meta-analyses and systematic reviews | 1 registered trial | No phase listed | 19 from the last two years |
| Ayahuasca | 46 studies | 4 meta-analyses and systematic reviews | 2 registered trials | up to Phase 2 | 11 from the last two years |
| DMT | 36 studies | 4 meta-analyses and systematic reviews | 11 registered trials | up to Phase 2 | 16 from the last two years |
4,134 studies whose primary subject is depression since 2002
| Year | Studies |
|---|---|
| 2002 | 1 |
| 2003 | 4 |
| 2004 | 2 |
| 2005 | 3 |
| 2006 | 7 |
| 2007 | 10 |
| 2008 | 13 |
| 2009 | 19 |
| 2010 | 39 |
| 2011 | 34 |
| 2012 | 24 |
| 2013 | 24 |
| 2014 | 68 |
| 2015 | 73 |
| 2016 | 115 |
| 2017 | 130 |
| 2018 | 206 |
| 2019 | 124 |
| 2020 | 169 |
| 2021 | 247 |
| 2022 | 344 |
| 2023 | 466 |
| 2024 | 512 |
| 2025 | 761 |
| 2026 | 739 |
bonndoc October 26, 2026 Yara Mecdad
Autophagy is a fundamental cellular process critical for maintaining homeostasis and has emerging relevance in stress adaptation and affective disorders. This thesis investigated how autophagy flux is modulated by acute stress, chronic stress-associated depression, pharmacological interventions, and psychedelic compounds across human, mouse, organotypic and cellular models. In humans, acute...
Journal of Affective Disorders October 26, 2026 Ying-Jay Liou, Li-Kai Cheng, Wei-Chen Lin et al.
Several studies have reported entropy reductions in regions of the brain associated with affective-regulatory and reward- and motivation-related processes in patients with major depressive disorder. However, whether low-dose ketamine modulates this reduction remains unclear. We analyzed resting-state functional magnetic resonance imaging data from two single-infusion low-dose ketamine trials....
JAMA October 26, 2026 David Feifel, Mathieu Seynaeve, Wiesław Jerzy Cubała et al.
Psychedelics represent a potential breakthrough for treatment-resistant depression; however, the prolonged in-clinic monitoring required for compounds such as psilocybin and lysergic acid diethylamide is a logistical hurdle to widespread use. Intranasal mebufotenin (5-methoxy-N,N-dimethyltryptamine), a 5-hydroxytryptamine 1A (5-HT1A) and 5-HT2A agonist associated with brief psychedelic...
Psychological Reports October 24, 2026 Radiah Maria Belak, Nicholas J. Moberly
Death anxiety may operate as a transdiagnostic process underlying anxiety and depressive symptoms. This study used the Death-Implicit Association Task (D-IAT) to index implicit self-death associations (ISDA) and evaluated a brief mindfulness intervention using a concurrent multiple-baseline design with maintenance across four students with prior anxiety/depressive diagnoses. Across 20 daily...
Research Square October 23, 2026 Clara De Oliveira Lapa, Mario F Juruena, Danilo Costa Pereira et al. preprint
Abstract Background Intranasal esketamine is an approved therapy for treatment-resistant depression and is recognized for its rapid and effective antidepressant effects. Although ketamine-associated cystitis has been documented in recreational users, the urinary safety profile of therapeutic esketamine remains incompletely characterized. Functional lower urinary tract disturbances suggestive of...
Trials October 23, 2026 Tamsin Ford, Rachel Childs, Rachel Hayes et al.
Abstract: Background: Mindfulness-based cognitive therapy (MBCT) is a group intervention recommended by NICE for adults who have experienced recurrent depression but is untested for adolescents. MBCT aims to teach people to recognise early indicators of depression, to avoid repetitive thinking patterns that make relapse more likely, and to respond to stressors in ways that protect mental...
Psychiatric Services October 22, 2026 Michael Lebenbaum, Benoit H. Mulsant, Sagar V Parikh et al.
OBJECTIVE: Electroconvulsive therapy (ECT) is a highly effective intervention for treatment-resistant depression; however, its use has been limited partly because of concerns about cognitive side effects. Evidence for the sustained (>1 month) efficacy of ketamine versus ECT for treatment-resistant depression has only recently been demonstrated. This study aimed to examine the...
Zenodo (CERN European Organization for Nuclear Research) October 21, 2026 preprint
Ketamine shows moderate efficacy as a rapid-acting treatment for treatment-resistant depression, including bipolar depression, with evidence supporting its use mainly in treatment-resistant cases. Monitoring and cautious patient selection are necessary due to limited long-term safety data.
World Journal of Psychiatry October 21, 2026 Xiao-ge Han, Qibin Chen, Su Min et al.
BACKGROUNDEvidence for adjunctive subanesthetic-dose esketamine during electroconvulsive therapy (ECT) in adolescents with major depressive disorder (MDD) is limited.Suicidal ideation is a critical early treatment target in this population.We hypothesized that adjunctive subanesthetic-dose esketamine during ECT would accelerate the reduction in suicidal ideation and improve early clinical...
Current Biology October 19, 2026 John H. Krystal
Ketamine's robust antidepressant effects often appear twenty-four hours after a single dose. A new study now provides evidence suggesting that this timepoint coincides with a quieting of habenula activation and reductions in aversive learning in healthy subjects.
Not yet recruiting Phase 1/2 50 participants Indiana University
Not yet recruiting Phase 2 150 participants VA Office of Research and Development
Not yet recruiting Phase 2 30 participants University of California, Los Angeles
Not yet recruiting Phase 2 150 participants University of New Mexico
Not yet recruiting Phase 1 32 participants MycoMedica Life Sciences PBC