May 2026
Depression
What May 2026's 25 new studies found, synthesized from the papers below. All Depression research →
The synthesis
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.
In May 2026, research on depression focused heavily on ketamine and esketamine for treatment-resistant depression (TRD), with consistent evidence of rapid antidepressant and anti-suicidal effects, though durability and blinding remain key caveats. Psilocybin-assisted therapy also showed sustained antidepressant benefits up to 12 months in TRD, while a small RCT found ketamine not superior to midazolam, highlighting the impact of functional unblinding. Overall, novel rapid-acting treatments show promise but require better-controlled long-term studies.
Confidence in the evidence
Moderate- Multiple RCTs, systematic reviews, and meta-analyses provide converging evidence for rapid antidepressant effects of ketamine and psilocybin in TRD.
- Sample sizes are often modest (e.g., n=63, n=35, n=45), and several studies are open-label, retrospective, or animal models, limiting generalizability.
- Functional unblinding due to dissociative side effects is a recognized methodological issue in ketamine trials, reducing confidence in effect estimates.
- Long-term follow-up data are available for psilocybin (12 months) but limited for ketamine, and optimal dosing strategies remain unclear.
How we rate confidence
Confidence reflects the strength of the underlying evidence, not whether the result is favorable. It weighs the number and size of studies, their design (randomized trials count for more than observational or single-case work), how consistently they point the same way, and their risk of bias.
Tiers run from Insufficient to High. High is rare in this field: small, early, or open-label studies land lower even when their direction is encouraging.
Evidence by study
Direction is each study's finding relative to your question: Supports, Opposes, No effect, Mixed, or Unclear.
| Study | Design | Sample size | Direction | Finding |
|---|---|---|---|---|
| Preliminary Non-Randomized Clinical Trial of Subcutaneous Esketamine in Treatment-Resistant Depression: Exploring Adjunctive Effects of Ketamine-Assisted Psychotherapy 2026 | non-randomized clinical trial | — | Supports | Subcutaneous esketamine with adjunctive psychotherapy shows potential for TRD, but structured psychotherapeutic support remains largely unexplored. |
| Microbiota-Derived SCFAs Mediate the Synergistic Antidepressant Effects of Dajianzhong Decoction and Ketamine via FFAR2-NLRP3-IL-1β Signaling. 2026 | preclinical (animal model) | — | Supports | Dajianzhong Decoction prolongs ketamine's antidepressant effects in mice via gut microbiota-derived SCFAs and FFAR2-NLRP3-IL-1β signaling. |
| The Use of Ketamine for Depression in Cancer Patients: A Systematic Review of Efficacy, Safety, and Clinical Applications. 2026 | systematic review | 14 | Supports | Ketamine provides rapid relief from depressive symptoms in cancer patients, with additional benefits for anxiety and pain, but long-term safety data are limited. |
| Differences in how NMDA antagonists modulate negative affective biases in male rats may serve as a predictor of clinical efficacy in major depressive disorder. 2026 | preclinical (animal model) | — | Unclear | NMDA antagonists modulate negative affective biases in male rats, which may predict clinical efficacy in MDD. |
| The Serotonin 2B (5‐ HT2B ) Receptor: A Narrative Review of Preclinical and Clinical Evidence on the Safety Considerations and Therapeutic Potential for the Treatment of Depression 2026 | narrative review | — | Mixed | The 5-HT2B receptor has both central antidepressant potential and peripheral cardiac risks (valvular heart disease), with insufficiently characterized cumulative exposure risks for psychedelics. |
| Ketamine: Is It Superior to Midazolam for Depression? 2026 | RCT | 63 | No effect | Serial intravenous ketamine was not significantly more effective than midazolam in reducing depressive symptoms, but the study was underpowered and had high unblinding rates. |
| Long-Term Efficacy of Psilocybin with Adjunct Psychotherapy in Treatment-Resistant Major Depression (EPIsoDE): 6- and 12-Month Naturalistic Follow-Up of a Phase 2b Trial. 2026 | RCT (naturalistic follow-up) | 126 | Supports | Psilocybin with adjunct psychotherapy showed sustained antidepressant effects at 6 and 12 months in TRD, with significant HAMD17 reductions from baseline. |
| Improving access to novel treatments for treatment-resistant depression: The potential role of specialist clinics in Australia 2026 | review/opinion | — | Unclear | Novel TRD treatments (ketamine, psilocybin, TMS) have low uptake in public services; specialist clinics are proposed to improve access. |
| A novel sequential ketamine and D-cycloserine/lurasidone therapy for bipolar depression with acute suicidal ideation. 2026 | narrative review | — | Supports | Sequential ketamine followed by D-cycloserine/lurasidone shows mechanistic rationale for rapid anti-suicidal effects in bipolar depression, but uncertainties remain about efficacy drivers and dosing. |
| Pharmacotherapeutic Options in Drug-Resistant Bipolar Depression: From Molecular Mechanisms to Rational Polypharmacotherapy. 2026 | review | — | Mixed | Atypical neuroleptics show limited efficacy in TRBD; ketamine and other augmentation strategies are discussed but evidence is mixed. |
| Early suicidal ideation change and suicidality-associated emergency department utilization after ketamine or esketamine treatment in treatment-resistant depression. 2026 | observational | — | Supports | Early suicidal ideation change and reduced emergency department utilization are observed after ketamine/esketamine treatment in TRD. |
| Shorter to be effective: subanesthetic-dose ketamine infusion reduces the global and regional path length of brain functional connectivity in patients with treatment-resistant depression and suicidal ideation. 2026 | observational | — | Supports | Subanesthetic ketamine infusion reduces global and regional brain functional connectivity path length in TRD patients with suicidal ideation. |
| Innovations in Depression Diagnosis and Treatment: A Review of Biological, Cognitive, and Psychosocial Advances. 2026 | review | — | Supports | Advances include FDA-approved neurosteroids for postpartum depression and psychedelic-assisted psychotherapy for TRD, with a shift toward precision psychiatry. |
| Effect of ketamine intervention on hemodynamic responses in patients with treatment-resistant depression. 2026 | RCT (secondary analysis) | 45 | Supports | Ketamine alters hemodynamic responses in brain regions involved in sensory-cognitive integration and mood regulation, associated with anti-suicidal effects. |
| Treatment-emergent psychiatric adverse events in patient-reported outcomes during ketamine use for major depressive disorder: a retrospective analysis. 2026 | retrospective analysis | — | Unclear | Treatment-emergent psychiatric adverse events are reported during ketamine use for MDD, but details are not provided in the abstract. |
| The multilevel exploration test, a novel paradigm to measure exploratory behavior in depression animal models and the involvement of the PL-ZI circuit. 2026 | preclinical (animal model) | — | Supports | A novel paradigm (MET) shows that depressed mice have reduced exploratory behavior, which is restored by ketamine and PL-ZI circuit stimulation. |
| Corrigendum to "Intranasal esketamine in treatment-resistant depression: long-term dosing patterns and clinical outcomes in a 5-year observational study". 2026 | corrigendum | — | Unclear | This is a corrigendum to a 5-year observational study on intranasal esketamine dosing patterns and clinical outcomes; no new findings are reported. |
| Short-term effects of oral ketamine for the treatment of depression: A systematic review and meta-analysis of randomized controlled trials. 2026 | systematic review and meta-analysis | — | Supports | Short-term effects of oral ketamine for depression are supported by a systematic review and meta-analysis of RCTs. |
| Interdisciplinary, Delphi-driven consensus guidelines on the use of intravenous ketamine infusions for depressive disorders from the American Society of Ketamine Physicians, Psychotherapists, and Practitioners (ASKP3). 2026 | consensus guidelines | — | Unclear | Delphi-driven consensus guidelines on intravenous ketamine infusions for depressive disorders were developed by ASKP3. |
| Short-Term and Late-Term Effects of Psilocybin on Symptoms in Major Depression 2026 | RCT | 35 | Supports | A single 25 mg psilocybin dose with psychotherapy significantly reduced MADRS scores at day 8 compared to placebo, with effects sustained up to 365 days. |
| Changes in depression symptom network structure following ketamine treatment in treatment-resistant depression. 2026 | observational | — | Unclear | Changes in depression symptom network structure occur following ketamine treatment in TRD. |
| Toward Integrating Intranasal Esketamine with Traumatic-Memory Psychotherapy in Treatment-Resistant Depression: A Narrative Review and Feasibility-Oriented Protocol Proposal. 2026 | narrative review | — | Supports | Intranasal esketamine may facilitate traumatic-memory psychotherapy in TRD, but evidence is mainly from pilot studies and case reports. |
| [Ketamine and esketamine in treatment-resistant depression - Pharmacological effects and augmented psychotherapy]. 2026 | review | — | Supports | Esketamine nasal spray is approved for TRD; ketamine-augmented psychotherapy may leverage a 'therapeutic window' of enhanced plasticity, but functional unblinding is a methodological concern. |
| Microdosing psilocybin for major depressive disorder: study protocol for a phase II double-blind placebo-controlled randomised partial crossover trial - CORRIGENDUM. 2026 | study protocol (corrigendum) | — | Unclear | This is a corrigendum to a phase II trial protocol on microdosing psilocybin for MDD; no results are reported. |
| Structural imaging predictors of ketamine response in treatment-resistant depression: a machine learning approach. 2026 | observational (machine learning) | 99 | Supports | A machine learning model using structural MRI predicted ketamine response in TRD with 72.2% balanced accuracy; frontal gray matter volume predicted response, cerebellar volume predicted non-response. |
Subcutaneous esketamine with adjunctive psychotherapy shows potential for TRD, but structured psychotherapeutic support remains largely unexplored.
non-randomized clinical trial
Dajianzhong Decoction prolongs ketamine's antidepressant effects in mice via gut microbiota-derived SCFAs and FFAR2-NLRP3-IL-1β signaling.
preclinical (animal model)
Ketamine provides rapid relief from depressive symptoms in cancer patients, with additional benefits for anxiety and pain, but long-term safety data are limited.
systematic review · Sample size: 14
NMDA antagonists modulate negative affective biases in male rats, which may predict clinical efficacy in MDD.
preclinical (animal model)
The 5-HT2B receptor has both central antidepressant potential and peripheral cardiac risks (valvular heart disease), with insufficiently characterized cumulative exposure risks for psychedelics.
narrative review
Serial intravenous ketamine was not significantly more effective than midazolam in reducing depressive symptoms, but the study was underpowered and had high unblinding rates.
RCT · Sample size: 63
Psilocybin with adjunct psychotherapy showed sustained antidepressant effects at 6 and 12 months in TRD, with significant HAMD17 reductions from baseline.
RCT (naturalistic follow-up) · Sample size: 126
Novel TRD treatments (ketamine, psilocybin, TMS) have low uptake in public services; specialist clinics are proposed to improve access.
review/opinion
Sequential ketamine followed by D-cycloserine/lurasidone shows mechanistic rationale for rapid anti-suicidal effects in bipolar depression, but uncertainties remain about efficacy drivers and dosing.
narrative review
Atypical neuroleptics show limited efficacy in TRBD; ketamine and other augmentation strategies are discussed but evidence is mixed.
review
Early suicidal ideation change and reduced emergency department utilization are observed after ketamine/esketamine treatment in TRD.
observational
Subanesthetic ketamine infusion reduces global and regional brain functional connectivity path length in TRD patients with suicidal ideation.
observational
Advances include FDA-approved neurosteroids for postpartum depression and psychedelic-assisted psychotherapy for TRD, with a shift toward precision psychiatry.
review
Ketamine alters hemodynamic responses in brain regions involved in sensory-cognitive integration and mood regulation, associated with anti-suicidal effects.
RCT (secondary analysis) · Sample size: 45
Treatment-emergent psychiatric adverse events are reported during ketamine use for MDD, but details are not provided in the abstract.
retrospective analysis
A novel paradigm (MET) shows that depressed mice have reduced exploratory behavior, which is restored by ketamine and PL-ZI circuit stimulation.
preclinical (animal model)
This is a corrigendum to a 5-year observational study on intranasal esketamine dosing patterns and clinical outcomes; no new findings are reported.
corrigendum
Short-term effects of oral ketamine for depression are supported by a systematic review and meta-analysis of RCTs.
systematic review and meta-analysis
Delphi-driven consensus guidelines on intravenous ketamine infusions for depressive disorders were developed by ASKP3.
consensus guidelines
A single 25 mg psilocybin dose with psychotherapy significantly reduced MADRS scores at day 8 compared to placebo, with effects sustained up to 365 days.
RCT · Sample size: 35
Changes in depression symptom network structure occur following ketamine treatment in TRD.
observational
Intranasal esketamine may facilitate traumatic-memory psychotherapy in TRD, but evidence is mainly from pilot studies and case reports.
narrative review
Esketamine nasal spray is approved for TRD; ketamine-augmented psychotherapy may leverage a 'therapeutic window' of enhanced plasticity, but functional unblinding is a methodological concern.
review
This is a corrigendum to a phase II trial protocol on microdosing psilocybin for MDD; no results are reported.
study protocol (corrigendum)
A machine learning model using structural MRI predicted ketamine response in TRD with 72.2% balanced accuracy; frontal gray matter volume predicted response, cerebellar volume predicted non-response.
observational (machine learning) · Sample size: 99
Points of agreement
- Ketamine and esketamine produce rapid antidepressant effects in treatment-resistant depression, including reductions in suicidal ideation.
- Psilocybin-assisted therapy shows sustained antidepressant benefits in TRD, with effects lasting up to 12 months.
- Functional unblinding due to dissociative side effects is a recognized methodological challenge in ketamine trials.
- Gut microbiota and neuroplasticity mechanisms are implicated in ketamine's antidepressant effects.
Conflicts
- One RCT found ketamine not superior to midazolam (active placebo), while many other studies report positive effects, possibly due to unblinding and small sample size.
- Long-term safety data for ketamine are limited, whereas psilocybin has more robust long-term follow-up data.
- The role of psychotherapy augmentation with ketamine/esketamine is supported theoretically but lacks strong empirical evidence.
Gaps
- Durability of ketamine's antidepressant effects beyond short-term follow-up is insufficiently studied.
- Optimal dosing strategies for ketamine and psilocybin in TRD are not established.
- Blinding integrity in ketamine trials is poor; better active placebos or blinding methods are needed.
- Long-term safety of ketamine and psychedelics, especially cardiac risks with 5-HT2B agonists, is not well characterized.
- Most studies focus on TRD; evidence in bipolar depression, adolescent depression, and other subtypes is limited.
- Mechanisms linking gut microbiota to ketamine response in humans are not directly tested.