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Depression

One of the most-studied indications in psychedelic and consciousness research, from antidepressant mechanisms to assisted-therapy trials.

State of the evidence

Synthesized

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.

Psilocybin and ketamine/esketamine show rapid and often sustained antidepressant effects in treatment-resistant depression and cancer-related depression, with several randomized trials reporting large improvements within days to weeks. However, the evidence is tempered by small sample sizes, open-label designs in some studies, and mixed durability at longer follow-ups. Mindfulness-based cognitive therapy (MBCT) reduces relapse in recurrent depression, but the evidence for psilocybin and ketamine is still emerging and not yet definitive.

Evidence by study

Direction is which way each study's own result points, not our rating of the study.

What the directions mean
Supports:
the study found the intervention worked, or its hypothesis held.
Opposes:
it found the opposite, no benefit or a harm.
No effect:
no significant difference either way.
Mixed:
effects in both directions within the same study.
Unclear:
the abstract does not report a direction.
A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression 2006
Supports

Ketamine produced significant improvement in depression within 110 minutes, sustained for 7 days, compared to placebo.

RCT Sample size: 18

Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial 2016
Supports

High-dose psilocybin produced large decreases in depression and anxiety, sustained at 6 months with about 80% showing clinically significant improvement.

RCT Sample size: 51

Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial 2016
Supports

Psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression, with 60-80% maintaining clinically significant reductions at 6.5 months.

RCT Sample size: 29

Synaptic Dysfunction in Depression: Potential Therapeutic Targets 2012
Supports

Reviews evidence that ketamine rapidly induces synaptogenesis and reverses stress-related synaptic deficits, supporting a synaptogenic hypothesis of depression treatment.

theoretical

Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. 2016
Supports

Psilocybin (10 and 25 mg) with psychological support was feasible and associated with reduced depressive symptoms up to 3 months.

open-label trial Sample size: 12

Mindfulness-Based Cognitive Therapy for Depression: Replication and Exploration of Differential Relapse Prevention Effects. 2004
Supports

MBCT reduced relapse from 78% to 36% in patients with 3+ previous episodes, but was less effective in those with only 2 episodes.

RCT Sample size: 73

Trial of Psilocybin versus Escitalopram for Depression 2021
No effect

Psilocybin did not show a significant difference in antidepressant effects compared to escitalopram at week 6 on the primary outcome.

RCT

Mindfulness-based cognitive therapy for depression 2006
Supports

Describes the development of MBCT, a theory-driven intervention incorporating mindfulness training to reduce relapse in recurrent major depression.

theoretical

Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder 2020
Supports

Psilocybin therapy (20 and 30 mg/70 kg) produced significant antidepressant effects compared to a waiting list control in MDD.

RCT Sample size: 27

Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial 2013
Supports

Ketamine showed greater improvement than midazolam at 24 hours, with response rates of 64% vs 28%.

RCT Sample size: 73

Mindfulness-Based Cognitive Therapy for Depression: A New Approach to Preventing Relapse 2003
Supports

Describes MBCT as a new approach to preventing relapse in depression.

theoretical

Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. 2022
Supports

Psilocybin 25 mg significantly reduced MADRS scores at week 3 vs 1 mg control, but sustained response at 12 weeks was not supported.

RCT Sample size: 233

Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. 2017
Supports

Psilocybin produced large reductions in depressive symptoms at 1 and 5 weeks, with effects remaining significant at 6 months.

open-label trial Sample size: 20

A Randomized Add-on Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Bipolar Depression 2010
Supports

Ketamine significantly improved depressive symptoms within 40 minutes, with effects lasting through day 3.

RCT Sample size: 18

Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study 2019
Supports

Esketamine nasal spray plus antidepressant showed significantly greater improvement in MADRS score at day 28 compared to antidepressant plus placebo.

RCT Sample size: 227

Trauma re-experiencing episodes during esketamine treatment in patients with treatment-resistant depression and comorbid PTSD: a retrospective case series. 2026
Mixed

Trauma re-experiencing occurred during esketamine sessions; in 72.7% episodes resolved, but 27.3% discontinued treatment; favorable outcomes when continued.

retrospective case series Sample size: 22

Changes in anxiety, quality of life, and functioning following psilocybin-assisted therapy in veterans with treatment-resistant depression. 2026
Supports

Psilocybin produced sustained improvements in anxiety, quality of life, and functioning through 12 months, though effects were no longer significant after accounting for depression improvement.

open-label trial Sample size: 15

Increased morning cortisol after ketamine treatment for suicidal depression: Exploratory report from a randomized trial. 2026
Supports

Ketamine increased morning cortisol 24 hours post-infusion, with a small correlation with decreased suicidal ideation, suggesting enhanced stress-resilience.

RCT

Prescribing bias and adverse outcomes of esketamine in major depression comorbid substance. 2026
Opposes

Esketamine users had higher risks of comorbid SUD and, within the esketamine cohort, SUD was associated with higher risks of self-harm, suicide attempt, and hospitalization.

retrospective cohort Sample size: 30670

Comparing transcranial magnetic stimulation and esketamine treatment response trajectories in resistant depression. 2026
Supports

Esketamine showed faster time-to-response than rTMS over 90 days, but cumulative response rates were similar; suicidal ideation improved more rapidly with esketamine.

retrospective analysis Sample size: 372

Effects of ketamine on sleep and circadian rhythmicity in major depressive disorder and bipolar disorder: A systematic review. 2026
Supports

Ketamine is associated with favorable effects on subjective sleep quality and preliminary evidence that sleep disturbances may predict antidepressant response.

systematic review Sample size: 1694

Ketamine and esketamine for the prevention of postpartum depression: A systematic review and network meta-analysis, with an integrated evidence synthesis. 2026
Supports

Ketamine and esketamine may reduce risk of developing postpartum depression, but data quality was low to very low.

systematic review and network meta-analysis

Ketamine-related neural changes in treatment-resistant depression: A multimodal synthesis of fMRI and PET studies. 2026
Unclear

Ketamine-related neural changes were frequently reported in subcortical regions and default-mode, ventral attention, and visual networks, but results are hypothesis-generating due to heterogeneity.

systematic review

Clinical correlates of anhedonia non-response to ketamine in treatment-resistant depression. 2026
Mixed

47.1% of patients were anhedonia non-responders to ketamine; non-responders were more likely to be single and had fewer depressive episodes and lower prior substance use disorder.

retrospective analysis Sample size: 34

The role of therapeutic alliance in psilocybin treatment for treatment-resistant depression: A post hoc path analysis. 2026
Supports

Therapeutic alliance had indirect effects on depression outcomes via psychedelic experience measures, but direct effects were not significant.

post hoc path analysis Sample size: 79

Points of agreement

  • Both psilocybin and ketamine/esketamine produce rapid antidepressant effects, often within hours to days.
  • Multiple RCTs show that psilocybin and ketamine reduce depression in treatment-resistant populations.
  • Psilocybin's effects are often sustained for weeks to months, with some studies reporting benefits at 6 months.
  • MBCT reduces relapse in recurrent depression, particularly in patients with 3 or more prior episodes.

Conflicts

  • One trial (15938) found no significant difference between psilocybin and escitalopram at 6 weeks, while other trials show large effects for psilocybin vs placebo.
  • Sustained response at 12 weeks was not supported in one psilocybin trial (2362), whereas other studies report sustained effects at 6 months.
  • Esketamine was associated with higher risks of comorbid SUD and adverse outcomes in one retrospective study (28670), contrasting with its overall positive efficacy in RCTs.
  • Anhedonia non-response to ketamine was observed in 47% of patients in one study (28912), indicating variability in response.

Gaps

  • Durability of effects beyond 6-12 months is not well studied for psilocybin and ketamine.
  • Most psilocybin studies have small sample sizes and many are open-label, limiting generalizability.
  • Comparative effectiveness against standard antidepressants is understudied, with only one head-to-head trial (15938).
  • Blinding is challenging in psychedelic trials due to subjective effects, potentially biasing results.
  • Optimal dosing, number of sessions, and long-term safety (e.g., trauma re-experiencing, SUD risks) require further investigation.
  • Mechanisms of action (e.g., neural changes, HPA axis effects) are not fully understood and need harmonized multimodal studies.
Browse these studies in the library
How we analyze this

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.

Ask your own question in the Research Synthesis Tool

Latest monthly recap: June 2026 →

6,444 articles · 2,753 from the last two years · 7,396,650 participants across 2,976 studies reporting sample size

Common study designs

review 1181 systematic review 370 observational cohort 288 randomized controlled trial 754 theoretical or philosophical paper 247

Research

Synthesize the evidence → Search all →

Trauma re-experiencing episodes during esketamine treatment in patients with treatment-resistant depression and comorbid PTSD: a retrospective case series.

European Journal of Psychotraumatology December 1, 2026 Maud Rothärmel, Lila Mekaoui, François Kazour et al. 1 citation

In a retrospective study of 22 adults with treatment-resistant depression and comorbid post-traumatic stress disorder who received esketamine nasal spray, trauma re-experiencing episodes occurred during treatment sessions. For 16 patients (72.7%) these episodes disappeared as sessions progressed. Treatment was stopped for 6 patients (27.3%) due to re-experiencing. Among those who continued esketamine, depression response rate was 45.5% and remission 22.7%; PTSD improvement rate was 45.5% and remission 18.2%. The findings suggest esketamine can be safely administered in this comorbid population and that trauma re-experiencing does not prevent clinical improvement.

DOI: 10.1080/20008066.2025.2609425 (opens in new tab) Full text (opens in new tab) Treatment-resistant depression Esketamine nasal spray Post-traumatic stress disorder Real-life data +2

Comparing transcranial magnetic stimulation and esketamine treatment response trajectories in resistant depression.

Journal of Affective Disorders November 1, 2026 Lindsay L Benster, Jordan N Kohn, Benjamin Wade et al.

In a real-world comparison of two FDA-approved treatments for treatment-resistant depression, intranasal esketamine led to faster improvement than repetitive transcranial magnetic stimulation (rTMS). Over 90 days, esketamine patients responded a median of 36 days versus 49 days for rTMS, and suicidal ideation resolved more quickly (median 9 vs. 26 days). However, by about 90 days, overall response and remission rates were similar between the groups (68.8% and 45.2% for esketamine; 59.4% and 40.1% for rTMS), suggesting a difference in speed rather than ultimate effectiveness. For rTMS, slower response was predicted by comorbid anxiety and benzodiazepine use, while former tobacco use predicted faster response. No such predictors were found for esketamine.

DOI: 10.1016/j.jad.2026.122107 (opens in new tab) Full text (opens in new tab) Esketamine Treatment-resistant depression Rtms

Prescribing bias and adverse outcomes of esketamine in major depression comorbid substance.

Journal of Affective Disorders November 1, 2026 Dian‐jeng Li, Tien-Wei Hsu, Te-Chang Changchien et al.

Patients with major depressive disorder who are prescribed esketamine have higher rates of comorbid substance use disorders compared to those treated with antidepressants or repetitive transcranial magnetic stimulation. Among esketamine users, those with a substance use disorder face greater risks of self-harm, suicide attempt, emergency visits, hospitalization, and mortality. The findings indicate a prescription bias toward patients with comorbid substance use disorders and highlight the need for careful monitoring and specialized care for this population.

DOI: 10.1016/j.jad.2026.122106 (opens in new tab) Full text (opens in new tab) Esketamine Major depressive disorder Substance use disorder Mortality +1

Increased morning cortisol after ketamine treatment for suicidal depression: Exploratory report from a randomized trial.

Journal of Affective Disorders November 1, 2026 Tse-Hwei Choo, Hanga C Galfalvy, John G Keilp et al.

A midazolam-controlled trial of intravenous ketamine for suicidal depressed patients found that ketamine rapidly reduced suicidal ideation within 24 hours. An exploratory analysis measured saliva cortisol awakening response at baseline and 24 hours after infusion. Waking cortisol significantly increased 24 hours after ketamine treatment. The increase in waking cortisol from baseline to post-infusion showed a small to medium, nonsignificant correlation with decreased suicidal ideation. These preliminary results, pending replication, align with evidence that moderate cortisol increases may enhance stress-resilience.

DOI: 10.1016/j.jad.2026.122175 (opens in new tab) Full text (opens in new tab) Depression Ketamine Cortisol Resilience +2

Changes in anxiety, quality of life, and functioning following psilocybin-assisted therapy in veterans with treatment-resistant depression.

Journal of Affective Disorders November 1, 2026 Carlton M Kelly, Mathieu Fradet, Catherine Bostian et al.

A single 25-mg dose of psilocybin with psychological support was associated with sustained improvements in anxiety, quality of life, functioning, and PTSD symptoms in 15 veterans with treatment-resistant depression. Anxiety scores dropped 59% from baseline at three weeks and remained lower through 12 months. Quality of life increased 24% and functional impairment decreased 46% at three weeks, though these effects were no longer statistically significant after accounting for concurrent improvements in depression. PTSD symptom reductions were observed at all timepoints. Acute subjective experiences did not correlate with treatment response. The study is limited by its small sample and open-label design.

DOI: 10.1016/j.jad.2026.122063 (opens in new tab) Full text (opens in new tab) Anxiety Psilocybin Treatment-resistant depression Posttraumatic stress disorder +1

Effects of ketamine on sleep and circadian rhythmicity in major depressive disorder and bipolar disorder: A systematic review.

Journal of Affective Disorders September 15, 2026 Rutger Boesjes, Claudia Oosterveld, Jeanine Kamphuis et al. 1 citation

Ketamine and its enantiomers show rapid antidepressant effects for major depressive disorder and bipolar disorder, but responses vary widely. This systematic review of 26 studies (1694 participants) found that ketamine treatment is linked to improved subjective sleep quality. Preliminary evidence suggests that baseline sleep disturbances and early sleep improvements may predict antidepressant response. Some studies also indicate beneficial effects on objective sleep and circadian rhythmicity, but this finding is tentative due to few published articles. The authors call for more research on objective circadian measures and potential synergy with chronotherapies.

DOI: 10.1016/j.jad.2026.121915 (opens in new tab) Full text (opens in new tab) Depression Ketamine Major depressive disorder Bipolar disorder +3

Effectiveness of Mindfulness-Based Cognitive Therapy (MBCT) on depression and anxiety in older adults: A systematic review and meta-analysis.

Journal of behavior therapy and experimental psychiatry September 1, 2026 Jieping Ding, Zafar Mehnaz Ali, Ateya Megahed Ibrahim et al.

Mindfulness-Based Cognitive Therapy (MBCT) may reduce depressive symptoms in adults aged 60 years and older compared with control conditions. A meta-analysis of three randomized controlled trials involving 178 participants found that MBCT was associated with significantly lower depressive symptom severity (pooled effect size Hedges g = -0.92, 95% confidence interval -1.30 to -0.55, with no heterogeneity). Evidence for anxiety and quality-of-life outcomes was limited and could not be pooled, and no trials reported relapse or recurrence. The authors note the evidence base remains small and heterogeneous, calling for larger, methodologically rigorous trials with standardized outcomes and longer follow-up.

DOI: 10.1016/j.jbtep.2026.102105 (opens in new tab) Full text (opens in new tab) Anxiety Depression Meta-analysis Mindfulness-based cognitive therapy +2

Ketamine-related neural changes in treatment-resistant depression: A multimodal synthesis of fMRI and PET studies.

Journal of Affective Disorders September 1, 2026 Nesreen Sedeek, Carley Rivers, Lucas Williamson et al.

Ketamine's rapid antidepressant effects in treatment-resistant depression are linked to changes in brain activity, but previous studies have been hard to compare due to differences in imaging techniques, analysis methods, and timing. A review combining fMRI and PET studies found that ketamine-related effects commonly appear in subcortical brain regions, with more variable effects in cortical areas like the prefrontal and anterior cingulate cortices. Network-level patterns suggest involvement of the default-mode, ventral attention, and visual systems. These findings are hypothesis-generating and highlight the need for future studies that harmonize methods to directly connect circuit changes to molecular mechanisms and clinical outcomes.

DOI: 10.1016/j.jad.2026.121891 (opens in new tab) Full text (opens in new tab) Ketamine Brain networks Multimodal synthesis PET +2

Ketamine and esketamine for the prevention of postpartum depression: A systematic review and network meta-analysis, with an integrated evidence synthesis.

Psychiatry Research September 1, 2026 Isis Lunsky, Gilmar Gutierrez, Xena Wang et al.

Postpartum depression (PPD) is common and harmful if untreated, with few effective prevention strategies. Ketamine and esketamine are rapid-acting antidepressants showing promise for PPD. This review searched five databases for peer-reviewed randomized controlled trials, pilot studies, and observational studies examining ketamine or esketamine for PPD prevention during pregnancy or postpartum, for both cesarean and vaginal deliveries. A network meta-analysis and narrative synthesis were used. Thirty-six studies were identified; five included vaginal delivery, thirty included cesarean section, and one did not specify delivery mode. Results suggested that ketamine and esketamine were well tolerated and may reduce PPD risk. However, data quality was low to very low, so results should be interpreted cautiously. More high-quality studies are needed.

DOI: 10.1016/j.psychres.2026.117221 (opens in new tab) Full text (opens in new tab) Esketamine Perinatal mental health Postpartum depression Psychopharmacology

Clinical correlates of anhedonia non-response to ketamine in treatment-resistant depression.

Journal of Affective Disorders August 15, 2026 Michał Walaszek, Wiesław Jerzy Cubała, Zofia Kachlik et al.

Anhedonia, a core symptom of major depressive disorder linked to poor outcomes, may be reduced by ketamine. In a retrospective analysis of 34 inpatients with treatment-resistant depression receiving short-term ketamine as an add-on to standard care, 16 patients (47.1%) did not respond to treatment, defined as less than a 50% reduction on the Snaith-Hamilton Pleasure Scale. Non-responders were more likely to be single, had fewer lifetime depressive episodes, and lower rates of prior substance use disorder. These factors suggest that psychosocial and demographic characteristics influence anhedonia treatment outcomes, supporting a personalized approach to mood disorder treatment.

DOI: 10.1016/j.jad.2026.121762 (opens in new tab) Full text (opens in new tab) Ketamine Treatment-resistant depression Anhedonia Psychopharmacology

Clinical trials

All Depression trials →