Depressive Disorder, Treatment-Resistant
Recent clinical, regulatory, research and industry developments relating to this disease.
Deep brain stimulation for refractory major depressive disorder: a comprehensive review.
Ketamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms.
Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression.
What's happening now
An analyst briefing on current research, clinical, regulatory and industry activity surrounding this disease.
- 6 clinical trials expected to report results, the earliest in Q3 2028.
- Q3 2028A Multicenter, Double-blind, Randomized, Placebo-controlled Study to Evaluate Efficacy and Safety of Seltorexant as Monotherapy in Adult and Elderly Participants With Major Depressive Disorder (MDD) and an Open-label Long-term Extension Treatment With Seltorexant
- Q4 2028A Multicenter, Double-blind, Placebo-controlled, Randomized Withdrawal Study of Solriamfetol in Subjects With Major Depressive Disorder With Excessive Daytime Sleepiness Symptoms
- Q4 2028RNA Editing as a Biomarker of Antidepressant Response in Unipolar and Bipolar Depression (EDIT-ANDRE)
- Q1 2030Prefrontal Glutamatergic Modulation by N-acetylcysteine and Mindfulness-based Cognitive Therapy for Mild Depression in Youth
- Q1 2030Sequential Multiple Assignment Randomized Trial for Bipolar Depression
Clinical MilestonesView all 15Hide
- 2026-10-13A Multicenter, Double-blind, Placebo-controlled, Randomized Withdrawal Study of Solriamfetol in Subjects With Major Depressive Disorder With Excessive Daytime Sleepiness SymptomsResults expected Q4 2028
- 2026-10-01A Multicenter, Double-blind, Randomized, Placebo-controlled Study to Evaluate Efficacy and Safety of Seltorexant as Monotherapy in Adult and Elderly Participants With Major Depressive Disorder (MDD) and an Open-label Long-term Extension Treatment With SeltorexantResults expected Q3 2028
- 2026-09-25A Double-blind, Randomized, Psychoactive Placebo-controlled Study to Evaluate the Efficacy and Safety of Intranasal Esketamine 84 mg in Addition to Comprehensive Standard of Care for the Rapid Reduction of the Symptoms of Major Depressive Disorder in Adolescent Participants With Acute Suicidal Ideation or BehaviorResults expected Q2 2031
- 2026-06-22RNA Editing as a Biomarker of Antidepressant Response in Unipolar and Bipolar Depression (EDIT-ANDRE)Results expected Q4 2028
- 2026-03-11Prefrontal Glutamatergic Modulation by N-acetylcysteine and Mindfulness-based Cognitive Therapy for Mild Depression in YouthResults expected Q1 2030
- 2026-07-13An Interventional, Open-label, Single Arm, Multicenter Study to Evaluate the Efficacy and Safety of Esketamine Nasal Spray in Korean Participants With Treatment-Resistant Depression(TRD)Completed
- 2026-06-19Precision Psychiatry: Anti-inflammatory Medication in Immuno-metabolic DepressionCompleted
- 2026-06-17A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Effects of Oral NMRA-335140 Versus Placebo in Participants With Major Depressive DisorderCompleted
- 2026-05-16Clonidine to Prevent Postictal Delirium After ElectroConvulsive Therapy: a Randomised, Placebo-controlled, Triple-blind, Single-centre Trial.Completed
- 2026-04-15A Phase III, Multicentre, Randomised, Double-blind, Placebo-controlled Study to Investigate the Efficacy, Safety, and Tolerability of COMP360 in Participants With Treatment-resistant DepressionCompleted
- 2027-05-01Dopamine D3 Receptor Occupancy in Bipolar Depression by Cariprazine (Vraylar): Evaluating Its Antidepressant BenefitWithdrawn
- 2027-03-01A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of REL-1017 As Adjunctive Treatment for Major Depressive Disorder (MDD)Withdrawn
- 2026-08-17Long-term Study to Assess the Safety and Effectiveness of NMRA-335140 in Participants With Major Depressive DisorderTerminated
- 2027-05-01ClinicalDopamine D3 Receptor Occupancy in Bipolar Depression by Cariprazine (Vraylar): Evaluating Its Antidepressant BenefitWithdrawn
- 2027-03-01ClinicalA Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Assess the Efficacy and Safety of REL-1017 As Adjunctive Treatment for Major Depressive Disorder (MDD)Withdrawn
- 2026-10-13ClinicalA Multicenter, Double-blind, Placebo-controlled, Randomized Withdrawal Study of Solriamfetol in Subjects With Major Depressive Disorder With Excessive Daytime Sleepiness SymptomsResults expected Q4 2028
- 2026-10-01ClinicalA Multicenter, Double-blind, Randomized, Placebo-controlled Study to Evaluate Efficacy and Safety of Seltorexant as Monotherapy in Adult and Elderly Participants With Major Depressive Disorder (MDD) and an Open-label Long-term Extension Treatment With SeltorexantResults expected Q3 2028
- 2026-09-25ClinicalA Double-blind, Randomized, Psychoactive Placebo-controlled Study to Evaluate the Efficacy and Safety of Intranasal Esketamine 84 mg in Addition to Comprehensive Standard of Care for the Rapid Reduction of the Symptoms of Major Depressive Disorder in Adolescent Participants With Acute Suicidal Ideation or BehaviorResults expected Q2 2031
- 2026-08-17ClinicalLong-term Study to Assess the Safety and Effectiveness of NMRA-335140 in Participants With Major Depressive DisorderTerminated
- 2026-07-13ClinicalAn Interventional, Open-label, Single Arm, Multicenter Study to Evaluate the Efficacy and Safety of Esketamine Nasal Spray in Korean Participants With Treatment-Resistant Depression(TRD)Completed
- 2026-06-22ClinicalRNA Editing as a Biomarker of Antidepressant Response in Unipolar and Bipolar Depression (EDIT-ANDRE)Results expected Q4 2028
- 2026-06-19ClinicalPrecision Psychiatry: Anti-inflammatory Medication in Immuno-metabolic DepressionCompleted
- 2026-06-17ClinicalA Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Effects of Oral NMRA-335140 Versus Placebo in Participants With Major Depressive DisorderCompleted
Therapeutic landscape
Therapies with a regulatory footing for this condition, alongside the wider set of agents co-studied with it in the literature.
Original application approval — Spravato, in combination with a SSRI or SNRI, is indicated for adults with treatment-resi… (2019)
Clinical trials
The current development programme across all trial phases.
Regulatory timeline
Drug regulatory events matched to this condition by indication — EMA.
European Medicines Agency (CC BY 4.0). Events are matched to this condition by drug indication text — approvals/updates for drugs indicated for it, not disease-specific acts.
Research activity
Key research shaping understanding of this disease, combining the latest publications with the most influential evidence.
Major themes8
- Depressive Disorder, Treatment-Resistant7
- Major Depressive Disorder4
- Deep Brain Stimulation3
- Hallucinogens3
- Psilocybin3
- Ketamine2
- Antidepressive Agents1
- Banisteriopsis1
Leading journals6
- Acta psychiatrica Scandinavica2
- Molecular psychiatry2
- Psychopharmacology2
- Brain stimulation1
- British journal of pharmacology1
- Journal of neural transmission (Vienna, Austria : 1996)1
Leading researchers8
- Nutt DJ5
- Carhart-Harris RL4
- Kaelen M4
- Feilding A3
- Roseman L3
- Rucker J3
- Bloomfield M2
- Bolstridge M2
Affiliations (unnormalised)6
- South London and Maudsley NHS Foundation Trust4
- Centre for Neuropsychopharmacology3
- The Beckley Foundation3
- The Institute of Psychiatry3
- Clinical Psychology and Clinical Effectiveness2
- Clinical Psychopharmacology Unit2
Associated genes
Genes associated with this disease in the canonical knowledge graph (Open Targets evidence). Number shows the association score.
Disease profile
A grounded synthesis of the condition — overview, causes, mechanism, risk factors and current standard of care.
Treatment-resistant depressive disorder is a form of depression defined by failure to respond to at least two antidepressant monotherapy trials or four or more different antidepressant therapies. The grounding frames it as a refractory mood disorder with substantial unmet treatment need and poor response to standard antidepressant therapy.
The grounding supports a depression-related pathophysiology but does not define a specific biological cause for treatment resistance. It highlights interest in synaptic plasticity, glutamatergic signaling, and NMDA receptor-related mechanisms, especially in relation to ketamine's rapid antidepressant effects. It also notes that animal models are used to study symptomatic and pathophysiological dimensions of depression, but that these models have important shortcomings.
The grounding supports treatment at the modality and drug-class level rather than a single standard regimen. It includes antidepressant therapy, psychotherapy, ketamine-based treatment, psychedelic-assisted approaches such as psilocybin in controlled settings, and deep brain stimulation for select refractory cases. The literature also discusses NMDA receptor antagonism and other novel synaptic mechanisms as emerging therapeutic directions.
AI-generated summary grounded in MeSH and 6 peer-reviewed sources. Informational only — not medical advice. Generated 2026-07-07.
Reference
Authoritative identity, definition & identifiers.
Failure to respond to two or more trials of antidepressant monotherapy or failure to respond to four or more trials of different antidepressant therapies. (Campbell's Psychiatric Dictionary, 9th ed.)
- Disease identity & definition — NLM Medical Subject Headings (MeSH), public domain
- Clinical trials — ClinicalTrials.gov (U.S. National Library of Medicine)
- Research activity — Europe PMC (EMBL-EBI) + OpenAlex-derived paper links
- Related entities are derived from literature co-mention (studied together) — associative, not causal.