Open questions — major depressive disorder¶
Last curated: 2026-08-30
Stable IDs persist if wording changes. Tier 1 questions could change practice and are designable now; Tier 2 questions require enabling methods, longer horizons, or stronger preliminary evidence.
Tier 1 — practice-changing and designable now¶
OQ-1 — What is the clinically relevant antidepressant benefit within severity strata?¶
Large network evidence establishes average superiority to placebo, while FDA and patient-level analyses find benefit concentrated at higher severity (Cipriani 2018, PMID 29477251; Kirsch 2008, PMID 18303940; Fournier 2010, PMID 20051569). An individual-participant meta-analysis using absolute outcomes, functioning, and prespecified severity interactions could resolve the practical magnitude.
OQ-2 — Which STAR*D cumulative remission estimate answers patient decisions?¶
The original theoretical 67% cumulative remission conflicts with a protocol-faithful reanalysis using different denominators and criteria (Rush 2006, PMID 17074942; Pigott 2023, PMID 37491091). A transparent multi-estimand reanalysis should publish every denominator, attrition state, and sustained-remission outcome.
OQ-3 — What is the best second-step treatment after a first adequate failure?¶
Switching, combination, lithium or antipsychotic augmentation, psychotherapy, TMS, and rapid-acting treatments lack a definitive pragmatic head-to-head sequence (Nuñez 2022, PMID 34986373; Scott 2023, PMID 35861202). A platform trial could randomize within preference/safety strata.
OQ-4 — Who should receive initial psychotherapy–medication combination?¶
Combination improves response over either treatment alone (RR about 1.25–1.27), but added burden may not be justified universally (Cuijpers 2020, PMID 31922679). Prespecified effect-modifier analysis should target chronicity, severity, preference, and comorbidity.
OQ-5 — How should long-term antidepressant tapering be individualized?¶
Withdrawal incidence and duration estimates are heterogeneous. A 2025 RCT-only synthesis found a small average week-1 symptom increment (SMD 0.31, 95% CI 0.23–0.39) but large symptom-specific odds for dizziness and vertigo, while the earlier mixed-design review reported more frequent and prolonged syndromes (Kalfas 2025, PMID 40632531; Davies 2019, PMID 30292574). Trials should compare hyperbolic/proportional taper schedules, stratify by exposure duration and drug half-life, and prospectively adjudicate withdrawal, relapse, and nocebo.
OQ-6 — Which continuation strategy best prevents post-ECT relapse?¶
Relapse remains common after successful ECT; lithium may help but evidence is limited (Jelovac 2013, PMID 23774532; Lambrichts 2021, PMID 33506961). A factorial comparison of pharmacologic and continuation-ECT strategies is feasible.
OQ-7 — Does personalized accelerated TMS outperform standard targeting and scheduling?¶
SNT produced a large effect in a small controlled trial, but individualized targeting, acceleration, and high dose were bundled (Cole 2022, PMID 34711062). Multisite factorial or dismantling trials should isolate components and measure one-year durability.
OQ-8 — What is the optimal ketamine/esketamine maintenance schedule and stopping rule?¶
Randomized withdrawal supports maintenance among esketamine responders, while repeated IV ketamine evidence remains smaller (Daly 2019, PMID 31166571; Phillips 2019, PMID 30922101). Head-to-head interval and taper trials should include cognition, urinary outcomes, misuse, and function.
OQ-9 — Does psilocybin retain benefit after expectancy and functional unblinding are measured?¶
Trials show symptom benefit, but the escitalopram comparison missed its primary endpoint and psychedelic allocation is conspicuous (Carhart-Harris 2021, PMID 33852780; Goodwin 2022, PMID 36322843). Trials need repeated treatment guesses, independent raters, credible active controls, and long-term adverse-event capture.
OQ-10 — Can an inflammatory marker prospectively select an effective treatment?¶
Inflammation is associated with depression in subsets, but marker results conflict: drug-naïve synthesis found a large TNF-α difference while CRP and interferon-γ confidence intervals included no effect, and cytokine-response meta-analysis has not validated a selector (Islam 2023, PMID 37625799; Liu 2020, PMID 31427752). Biomarker-enriched randomized trials must prespecify assay, threshold, and a treatment-by-marker interaction—not within-arm change.
OQ-11 — Which interventions reduce suicide attempts or deaths after acute care transitions?¶
Cohort predictors have limited individual precision (Li 2022, PMID 35101521). Cluster-randomized health-system trials of rapid follow-up, safety planning, means intervention, and outreach can measure attempts and mortality.
OQ-12 — Can measurement-based care scale without widening disparities?¶
Rating-guided care improved outcomes in a randomized trial (Guo 2015, PMID 26315978), while global minimally adequate treatment remains uncommon (Thornicroft 2017, PMID 27908899). Implementation trials should measure clinician action, patient burden, language access, and equity.
OQ-21 — Which screening pathway improves outcomes rather than only detection?¶
PHQ-9 ≥10 has sensitivity and specificity near 0.85 against semistructured interviews, and a PHQ-2→PHQ-9 sequence can reduce full-form administration by 57%, but neither establishes that population screening improves remission, function, or mortality (Negeri 2021, PMID 34610915; Levis 2020, PMID 32515813). Cluster trials should randomize complete pathways—screen, diagnostic assessment, treatment capacity, and follow-up—and measure false-positive burden and equity.
OQ-22 — Can bipolar conversion risk be predicted well enough to change initial MDD treatment?¶
Register cohorts place long-term bipolar conversion near 6–9%, with family bipolarity, hospitalization, and psychotic depression producing hazard ratios around 1.7–2.7, but no validated threshold establishes a different first-line decision (Rhee 2023, PMID 37427550; Musliner 2018, PMID 29498031). A prospective multi-country model must report calibration, decision curves, and harms from false bipolar labeling.
OQ-23 — Can antidepressant choice optimize a patient-weighted harm profile?¶
Target-trial emulation found small average six-month weight differences across common agents—escitalopram +0.41 kg and bupropion −0.22 kg relative to sertraline—while sexual, sleep, withdrawal, and overdose outcomes remain measured in separate evidence systems (Petimar 2024, PMID 38950403; Zhou 2023, PMID 37422714). A pragmatic trial should use a preference-weighted composite without allowing one symptom scale to erase harm.
OQ-24 — What supervision intensity preserves task-shared psychotherapy effects at scale?¶
LMIC individual-participant meta-analysis found symptom benefit (Hedges g −0.32, 95% CI −0.38 to −0.26), response OR 2.11, and remission OR 1.87, but trial supervision may exceed routine capacity (Karyotaki 2022, PMID 35319740). A noninferiority implementation trial can randomize supervision dose while measuring fidelity, worker burden, deterioration, and reach.
OQ-25 — Which part of accelerated TMS produces the rapid effect?¶
Theta-burst synthesis supports left-DLPFC iTBS and bilateral cTBS+iTBS protocols, while personalized accelerated SNT bundles functional targeting, high pulse dose, multiple daily sessions, and expectancy (Kishi 2024, PMID 38844532; Cole 2022, PMID 34711062). A factorial dismantling platform should isolate target, spacing, total dose, and acceleration with a credible sham and long follow-up.
Tier 2 — important, but enabling work is needed¶
OQ-13 — Can MDD be partitioned into stable, treatment-relevant phenotypes?¶
STAR*D contained 1,030 symptom profiles among 3,703 people (Fried 2015, PMID 25451401). Stable longitudinal phenotyping must precede claims that cross-sectional clusters are disease subtypes.
OQ-14 — Which human mechanism is necessary for ketamine response?¶
Rapid controlled effects established a glutamatergic/plasticity paradigm (Berman 2000, PMID 10686270; Zarate 2006, PMID 16894061), but dissociation, opioid involvement, AMPA signaling, and metabolites remain unresolved.
OQ-15 — Which GWAS loci converge on perturbable cell types?¶
The 102-variant GWAS implicates synaptic/prefrontal biology but not individual treatment targets (Howard 2019, PMID 30718901). Fine-mapping, ancestry diversity, and functional validation are prerequisites.
OQ-16 — Can biomarkers demonstrate clinical utility rather than association?¶
Prospective biomarker synthesis found no clinically ready marker (Kennis 2020, PMID 31745238). Locked, external multi-site validation must precede randomized biomarker-guided care.
OQ-17 — How much MDD mortality is mediated by treatable medical pathways?¶
Mental disorders show roughly doubled all-cause mortality while GBD attributes almost no direct YLLs to them. A 2025 synthesis estimated depression-associated all-cause RR 2.10 (95% CI 1.87–2.35), suicide RR 9.89 (7.59–12.88), and natural-cause RR 1.63 (1.51–1.75), but heterogeneity approached 100% (Walker 2015, PMID 25671328; GBD 2019, PMID 35026139; Chan 2025, PMID 40948054). Linked causal cohorts and target-trial emulations are needed to partition disease, treatment, substance, socioeconomic, and care-access pathways.
OQ-18 — How portable are depression polygenic scores across ancestries and health systems?¶
Polygenic architecture is established, but discovery samples and prediction accuracy are ancestry-skewed (Howard 2019, PMID 30718901; Flint 2023, PMID 36702864). Multi-ancestry calibration and utility thresholds are needed before clinical use.
OQ-19 — What outcomes define recovery after TRD?¶
Lived-experience research emphasizes function, relationships, identity, and hope beyond symptom scores (Kerr 2023, PMID 37734244). A co-produced core outcome set should integrate treatment burden and durable participation.
OQ-20 — Which scalable psychotherapy components preserve efficacy?¶
Behavioral activation and CBT components show comparable network effects, while internet delivery raises engagement and support questions (Ciharova 2021, PMID 34264703; Furukawa 2021, PMID 33957075). Component trials require therapist clustering and deterioration reporting.
Dots not yet connected¶
These junctions were re-searched in PubMed on 2026-08-30. Most remain positively stated evidence gaps; where a direct preliminary study now exists, the row identifies the narrower replication or utility question that remains.
| # | Dot A | Dot B | The missing junction | Powers |
|---|---|---|---|---|
| D-1 | 1,030 STAR*D symptom profiles | antidepressant network averages | symptom-profile-by-drug interaction using individual trial data | OQ-1, OQ-13 |
| D-2 | inflammation-defined subgroup | iTBS response | external validation and a prespecified treatment-by-marker interaction after an exploratory 54-person clustering study (Pedraz-Petrozzi 2026, PMID 42364721) | OQ-7, OQ-10 |
| D-3 | ketamine/esketamine rapid response | psychotherapy learning | a well-powered timing/dismantling trial after small randomized CBT studies produced mixed measure-level results (Wilkinson 2021, PMID 34186531; Wilkinson 2026, PMID 42095692) | OQ-8, OQ-14 |
| D-4 | psilocybin experiential intensity | functional unblinding | mediation separating pharmacology, expectancy, and support | OQ-9 |
| D-5 | pharmacogenomic interaction avoidance | antidepressant withdrawal burden | whether genotype-informed exposure predicts taper difficulty | OQ-5, OQ-16 |
| D-6 | polygenic cross-disorder liability | mixed-features specifier | prospective bipolar conversion within DSM-MDD mixed features | OQ-13, OQ-18 |
| D-7 | post-ECT relapse | digital sleep/activity monitoring | whether within-person digital change gives actionable early warning | OQ-6, OQ-16 |
| D-8 | patient-defined recovery | regulatory symptom endpoints | a co-primary endpoint accepted in pivotal trials | OQ-19 |
| D-9 | treatment-gap geography | measurement-based care | low-resource implementation with equity as a primary outcome | OQ-12 |
| D-10 | suicide-attempt polygenic liability | dynamic intent/access-to-means assessment | incremental prospective utility over clinical formulation | OQ-11, OQ-18 |
| D-11 | insulin resistance | exercise network efficacy | metabolic enrichment of exercise response | OQ-10 |
| D-12 | antidepressant sexual dysfunction | combination-treatment superiority | net-benefit models incorporating preference-weighted sexual outcomes | OQ-4, OQ-19 |
| D-13 | PHQ screening accuracy | global treatment-gap data | whether screening adds benefit when treatment capacity is constrained | OQ-12, OQ-21 |
| D-14 | register-based bipolar conversion | antidepressant activation/withdrawal phenotypes | whether dynamic medication response improves calibrated conversion prediction | OQ-5, OQ-22 |
| D-15 | task-shared psychotherapy efficacy | patient-defined treatment burden | supervision and delivery models optimized for both fidelity and acceptability | OQ-19, OQ-24 |
| D-16 | cause-specific mortality excess | intervention-specific observational mortality reductions | a target-trial emulation separating treatment selection from causal survival benefit | OQ-17 |