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Clinical trials landscape

TL;DR — The active MDD pipeline is mechanistically diverse: glutamatergic and opioid targets, inflammation enrichment, accelerated and personalized stimulation, psychedelics, digital monitoring, and biomarker-guided care. Every NCT identifier below was re-fetched from the live ClinicalTrials.gov v2 API on 2026-08-30, including an active-status MDD query and exact-record checks. Registry status is a snapshot, not evidence of efficacy. The main development problems are high placebo response, unblinding, short follow-up, outcome switching, and poor representativeness. Trials should distinguish acute symptom change, remission, function, suicidality, durability, and treatment burden.

Selected active studies

NCT Intervention/question Phase/status at query Why it matters
NCT06511908 (2R,6R)-hydroxynorketamine phase 2, recruiting non-dissociative ketamine-pathway test
NCT06136546 infliximab for cognitive dysfunction/inflammation phase 2, recruiting biomarker-enriched immunology
NCT05437588 exosomal miRNAs for suicidality/outcome recruiting biomarker validation
NCT05616559 precision package for first-episode depression recruiting treatment allocation utility
NCT05415397 celecoxib for immunometabolic depression phase 3, active not recruiting anti-inflammatory enrichment
NCT06793397 CYB003 psilocin analog phase 3, recruiting psychedelic development
NCT06236880 GM-2505 phase 2, recruiting novel compound
NCT07226661 SPN-821 phase 2, recruiting novel pharmacology
NCT06547489 zelquistinel phase 2, recruiting NMDA-related modulation
NCT07043738 imaging- vs scalp-targeted accelerated TMS not yet recruiting tests value of scanning
NCT06392867 iTBS intensity-response recruiting dose optimization
NCT07528157 personalized vs non-personalized iTBS not yet recruiting target personalization
NCT05773755 sensing-enabled DBS recruiting adaptive invasive stimulation
NCT07042217 tDCS plus mindfulness recruiting combined scalable stimulation
NCT07775586 home wearable rTMS not yet recruiting access and safety model
NCT06732089 digital interventions in TRD recruiting scalable support
NCT06801925 GPT-4o/RAG voice PHQ-9 screening invitation-only AI screening validity
NCT06110897 resistance exercise dose recruiting non-drug dose-response
NCT04337242 blended vs face-to-face therapy active not recruiting delivery equivalence
NCT07282366 stigma video intervention not yet recruiting public-health outcome

Pipeline by hypothesis

Hypothesis Examples Decisive test
Glutamatergic plasticity without dissociation HNK, zelquistinel active comparator, durability
Inflammatory subgroup infliximab, celecoxib prespecified biomarker interaction
Personalized circuit targeting imaging-guided iTBS/DBS added benefit over standard target
Psychedelic analog CYB003 credible blinding and long-term safety
Digital monitoring wearables/voice prospective utility, privacy, drift
Lifestyle dose resistance exercise, diet adherence and functional endpoints

Why depression trials fail

Failure mode Effect Prevention
High/variable placebo response reduced separation site training, prospective severity, central review
Functional unblinding expectancy inflation assess guesses; credible control
Outcome switching false-positive emphasis public protocol/SAP
Enriched samples poor generalizability pragmatic eligibility and reporting
Short follow-up unknown durability continuation and post-treatment observation
Missing data estimand ambiguity prespecified intercurrent-event strategy
Multiple biomarkers overfitting locked classifier and external validation

Completed landmarks informing the pipeline

Ketamine proof-of-concept established rapid action (Berman 2000, PMID 10686270; Zarate 2006, PMID 16894061). Esketamine phase 3 showed modest mean separation plus characteristic adverse effects (Popova 2019, PMID 31109201). SNT's double-blind trial made accelerated circuit-guided stimulation a major replication target (Cole 2022, PMID 34711062). Psilocybin trials showed promise while exposing the blinding problem (Carhart-Harris 2021, PMID 33852780; Goodwin 2022, PMID 36322843).

Trial-design landscape

Pipeline breadth is not the same as evidentiary diversity. Many trials reuse short symptom endpoints, enriched samples, and highly selected sites.

Design feature Why sponsors use it Scientific cost
Placebo lead-in or response enrichment Increases assay sensitivity Reduces generalizability and may inflate maintenance effects
Newly initiated background antidepressant Standardizes combination trials Conflates background-drug and investigational-drug trajectories
Randomized withdrawal Efficient relapse-prevention design Enriches responders/tolerators and can misclassify withdrawal
Sham device Controls attention and procedure Sensory differences can unblind TMS/tDCS/ECT allocation
Psychological support around a drug Improves safety and engagement Makes drug and context difficult to separate
Six-to-eight-week endpoint Limits cost and attrition Misses durability, withdrawal, recurrence, and functional recovery
Symptom-scale primary outcome Regulatory precedent Small mean differences can obscure response distributions and burden

The live ClinicalTrials.gov snapshot should be interpreted as a registry state on 2026-08-30, not proof that a study is enrolling locally or will report. Registry outcome switching and nonpublication remain part of the evidence landscape.

Additional live-search evidence ledger

The records below were added after full PubMed E-utilities retrieval on 2026-08-30. The ledger states the evidentiary role of each record and preserves the design limitation that should travel with its citation.

  • Kalfas M 2025 — Incidence and Nature of Antidepressant Discontinuation Symptoms: A Systematic Review and Meta-Analysis. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Kalfas M 2025, PMID 40632531)

  • Hieronymus F 2026 — Assessing the presence of biasing and non-biasing unblinding in a randomized controlled trial of a home-use tDCS device: An exploratory analysis. Randomized comparison; population, control credibility, duration, and missingness bound transportability. (Hieronymus F 2026, PMID 41796776)

  • Nelson JC 2009 — Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Nelson JC 2009, PMID 19687129)

  • Reddy S 2024 — Efficacy of Deep Brain Stimulation for Treatment-Resistant Depression: Systematic Review and Meta-Analysis. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Reddy S 2024, PMID 39197490)

  • Naudet F 2011 — Antidepressant response in major depressive disorder: a meta-regression comparison of randomized controlled trials and observational studies. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Naudet F 2011, PMID 21687681)

  • Apaydin EA 2016 — A systematic review of St. John's wort for major depressive disorder. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Apaydin EA 2016, PMID 27589952)

  • Leucht C 2012 — Amitriptyline versus placebo for major depressive disorder. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Leucht C 2012, PMID 23235671)

  • Memon RI 2020 — Effectiveness and Safety of Ketamine for Unipolar Depression: a Systematic Review. Systematic review; useful for mapping consistency and gaps, not automatically a pooled causal estimate. (Memon RI 2020, PMID 32852658)

  • Seshadri A 2024 — Efficacy of intravenous ketamine and intranasal esketamine with dose escalation for Major depression: A systematic review and meta-analysis. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Seshadri A 2024, PMID 38537759)

  • Bahji A 2021 — Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Bahji A 2021, PMID 33022440)

  • Elmosalamy A 2025 — Intravenous ketamine versus esketamine for depression: a systematic review and meta-analysis. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Elmosalamy A 2025, PMID 41244961)

  • Shi ZM 2025 — Intravenous ketamine versus electroconvulsive therapy for major depressive disorder or bipolar depression: A meta-analysis of randomized controlled trials. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Shi ZM 2025, PMID 39549887)

  • Terao I 2024 — Comparative efficacy, tolerability and acceptability of intravenous racemic ketamine with intranasal esketamine, aripiprazole and lithium as augmentative treatments for treatment-resistant unipolar depression: A systematic review and network meta-analysis. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Terao I 2024, PMID 37949235)

  • Shim SR 2026 — Ketamine Infusions and Rapid Reduction of Suicidal and Depressive Symptoms in Major Depressive Episode: A Systematic Review and Meta-Analysis. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Shim SR 2026, PMID 42090166)

  • Terao I 2025 — Comparative efficacy and safety of intravenous racemic ketamine, repetitive transcranial magnetic stimulation and electroconvulsive therapy for Stage 2 or higher treatment-resistant depression: A systematic review and network meta-analysis. Meta-analysis; pooled estimates depend on eligibility, heterogeneity, and reporting bias. (Terao I 2025, PMID 40590032)

  • Erritzoe D 2024 — Effect of psilocybin versus escitalopram on depression symptom severity in patients with moderate-to-severe major depressive disorder: observational 6-month follow-up of a phase 2, double-blind, randomised, controlled trial. Randomized evidence; control credibility, duration, missingness, and eligibility bound transportability. (Erritzoe D 2024, PMID 39764567)

  • Parikh SV 2024 — Efficacy and safety of zuranolone co-initiated with an antidepressant in adults with major depressive disorder: results from the phase 3 CORAL study. Randomized evidence; control credibility, duration, missingness, and eligibility bound transportability. (Parikh SV 2024, PMID 37875578)

  • Clayton AH 2023 — Zuranolone in Major Depressive Disorder: Results From MOUNTAIN-A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial. Randomized evidence; control credibility, duration, missingness, and eligibility bound transportability. (Clayton AH 2023, PMID 36811520)

  • Kishi T 2024 — Theta burst stimulation for depression: a systematic review and network and pairwise meta-analysis. Meta-analysis; heterogeneity, comparator choice, and reporting bias govern interpretation. (Kishi T 2024, PMID 38844532)

  • Yang X 2024 — Vortioxetine for depression in adults: A systematic review and dose-response meta-analysis of randomized controlled trials. Meta-analysis; heterogeneity, comparator choice, and reporting bias govern interpretation. (Yang X 2024, PMID 38957929)

Open questions

  • Which active trials include durable functional outcomes rather than symptom endpoints only?
  • Will biomarker enrichment demonstrate a treatment interaction rather than general prognosis?
  • Can home neuromodulation maintain safety and protocol fidelity?
  • How should trials measure expectancy and functional unblinding?

References

  1. Berman RM, et al. Antidepressant effects of ketamine. Biological Psychiatry. 2000. PMID 10686270
  2. Zarate CA Jr, et al. NMDA antagonist in TRD. Archives of General Psychiatry. 2006. PMID 16894061
  3. Popova V, et al. Esketamine nasal spray in TRD. American Journal of Psychiatry. 2019. PMID 31109201
  4. Cole EJ, et al. Stanford Neuromodulation Therapy RCT. American Journal of Psychiatry. 2022. PMID 34711062
  5. Carhart-Harris R, et al. Psilocybin versus escitalopram. New England Journal of Medicine. 2021. PMID 33852780
  6. Goodwin GM, et al. Single-dose psilocybin in TRD. New England Journal of Medicine. 2022. PMID 36322843
  7. Kalfas M, et al. Incidence and Nature of Antidepressant Discontinuation Symptoms: A Systematic Review and Meta-Analysis. JAMA psychiatry. 2025;82:896-904. PMID 40632531
  8. Hieronymus F, et al. Assessing the presence of biasing and non-biasing unblinding in a randomized controlled trial of a home-use tDCS device: An exploratory analysis. Journal of affective disorders. 2026;405:121553. PMID 41796776
  9. Nelson JC, et al. Atypical antipsychotic augmentation in major depressive disorder: a meta-analysis of placebo-controlled randomized trials. The American journal of psychiatry. 2009;166:980-91. PMID 19687129
  10. Reddy S, et al. Efficacy of Deep Brain Stimulation for Treatment-Resistant Depression: Systematic Review and Meta-Analysis. Biological psychiatry. Cognitive neuroscience and neuroimaging. 2024;9:1239-1248. PMID 39197490
  11. Naudet F, et al. Antidepressant response in major depressive disorder: a meta-regression comparison of randomized controlled trials and observational studies. PloS one. 2011;6:e20811. PMID 21687681
  12. Apaydin EA, et al. A systematic review of St. John's wort for major depressive disorder. Systematic reviews. 2016;5:148. PMID 27589952
  13. Leucht C, et al. Amitriptyline versus placebo for major depressive disorder. The Cochrane database of systematic reviews. 2012;12:CD009138. PMID 23235671
  14. Memon RI, et al. Effectiveness and Safety of Ketamine for Unipolar Depression: a Systematic Review. The Psychiatric quarterly. 2020;91:1147-1192. PMID 32852658
  15. Seshadri A, et al. Efficacy of intravenous ketamine and intranasal esketamine with dose escalation for Major depression: A systematic review and meta-analysis. Journal of affective disorders. 2024;356:379-384. PMID 38537759
  16. Bahji A, et al. Comparative efficacy of racemic ketamine and esketamine for depression: A systematic review and meta-analysis. Journal of affective disorders. 2021;278:542-555. PMID 33022440
  17. Elmosalamy A, et al. Intravenous ketamine versus esketamine for depression: a systematic review and meta-analysis. Therapeutic advances in psychopharmacology. 2025;15:20451253251394127. PMID 41244961
  18. Shi ZM, et al. Intravenous ketamine versus electroconvulsive therapy for major depressive disorder or bipolar depression: A meta-analysis of randomized controlled trials. Journal of affective disorders. 2025;371:45-53. PMID 39549887
  19. Terao I, et al. Comparative efficacy, tolerability and acceptability of intravenous racemic ketamine with intranasal esketamine, aripiprazole and lithium as augmentative treatments for treatment-resistant unipolar depression: A systematic review and network meta-analysis. Journal of affective disorders. 2024;346:49-56. PMID 37949235
  20. Shim SR, et al. Ketamine Infusions and Rapid Reduction of Suicidal and Depressive Symptoms in Major Depressive Episode: A Systematic Review and Meta-Analysis. JAMA psychiatry. 2026;83:714-731. PMID 42090166
  21. Terao I, et al. Comparative efficacy and safety of intravenous racemic ketamine, repetitive transcranial magnetic stimulation and electroconvulsive therapy for Stage 2 or higher treatment-resistant depression: A systematic review and network meta-analysis. PCN reports : psychiatry and clinical neurosciences. 2025;4:e70136. PMID 40590032
  22. Erritzoe D, et al. Effect of psilocybin versus escitalopram on depression symptom severity in patients with moderate-to-severe major depressive disorder: observational 6-month follow-up of a phase 2, double-blind, randomised, controlled trial. EClinicalMedicine. 2024;76:102799. PMID 39764567
  23. Parikh SV, et al. Efficacy and safety of zuranolone co-initiated with an antidepressant in adults with major depressive disorder: results from the phase 3 CORAL study. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2024;49:467-475. PMID 37875578
  24. Clayton AH, et al. Zuranolone in Major Depressive Disorder: Results From MOUNTAIN-A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial. The Journal of clinical psychiatry. 2023;84:22m14445. PMID 36811520
  25. Kishi T, et al. Theta burst stimulation for depression: a systematic review and network and pairwise meta-analysis. Molecular psychiatry. 2024;29:3893-3899. PMID 38844532
  26. Yang X, et al. Vortioxetine for depression in adults: A systematic review and dose-response meta-analysis of randomized controlled trials. Psychiatry and clinical neurosciences. 2024;78:536-545. PMID 38957929