Not yet independently audited
This page was written from verified sources but has not yet passed the independent citation audit. Treat its claims as provisional.
Open questions — major depressive disorder¶
Last curated: 2026-10-29
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. CoMPACT is recruiting and compares personalized accelerated iTBS at the left dorsolateral prefrontal cortex, the left inferior parietal lobule, or sham, with five sessions daily for five days and estimated enrollment 78 (Faghani Jadidi 2026, PMID 42890690; NCT06895863, overall status RECRUITING, last update posted 2026-08-26, no results section on 2026-10-22). That design separates two cortical targets under one accelerated schedule. It does not randomize dose, spacing, and acceleration separately.
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.
The NHS feasibility trial adds a public-healthcare setting, but its full text reports failed blinding and identifies expectancy as a contributor to the observed group difference. The remaining test must therefore distinguish feasibility from efficacy under credible masking (Rucker 2026, PMID 42562964).
The question now covers short-acting psychedelics as well as psilocybin. A phase 2b trial of single-dose intranasal mebufotenin found a day-29 MADRS difference of −5.3 versus a 0.3-mg comparator. Most participants were ready for discharge within 2 hours, but follow-up lasted only 8 weeks (Feifel 2026, PMID 42931733; NCT05870540). A short session does not solve the masking problem: a subperceptual low dose is not an experientially matched control. The trial's blinding data sit in the embargoed full text and were not read on 2026-10-29.
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. CoMPACT (NCT06895863) is a recruiting three-arm test of cortical target under a fixed accelerated schedule; see OQ-7. It does not close this question.
OQ-26 — Which exercise prescription and supervision model is justified across depression severity?¶
A full-text commentary disputes CANMAT 2023’s severity restrictions and the basis for its exercise dose, intensity and structure recommendations (Gierc 2026, PMID 42411994). Pragmatic trials should compare feasible structured/supervised prescriptions, prespecify severity interactions and active comparators, and measure adherence, function, adverse events and sustained benefit. A commentary does not itself establish a replacement prescription.
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. For 2-year relapse in 564 patients, 9 baseline modalities (MRI, genetics, blood, microbiome, cognition) added nothing over a few clinical risk factors; the best balanced accuracy was 64.43% (Teutenberg 2026, PMID 42905697). The sharper question is whether repeated measurement of the same markers adds what a single baseline measurement does not.
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 2026-10-07. Each absence is limited to its named query; relevant preliminary studies are identified where found. The query strings and independent audit are in LOG.md.
| # | Dot A | Dot B | The missing junction | Powers |
|---|---|---|---|---|
| D-1 | In 3,703 STAR*D outpatients there were 1,030 unique symptom profiles; 864 (83.9%) occurred in five or fewer people, 501 (48.6%) in one person, and the most common profile had a frequency of 1.8% (Fried 2015, PMID 25451401). | A network meta-analysis of 522 trials and 116,477 participants ranked 21 antidepressants from group-level data, with efficacy odds ratios versus placebo from 2.13 (95% CrI 1.89-2.41) for amitriptyline to 1.37 (1.16-1.63) for reboxetine (Cipriani 2018, PMID 29477251). | Patient-level STARD and CO-MED analyses have since shown differential drug effects on individual symptoms: bupropion monotherapy improved hypersomnia more than venlafaxine in STARD levels 2/2A (n=686; difference 0.384, family-wise adjusted p=0.007) (Strobl 2025, PMID 40449742). A separate symptom-oriented medication-versus-psychotherapy allocation metric did not improve treatment allocation (Kappelmann 2020, PMID 32498707). The remaining junction is a prospective test of whether baseline symptom profiles improve choice among antidepressants and patient outcomes. A PubMed search for symptom-profile, antidepressant, and randomized treatment-selection terms returned 22 records on 2026-10-07; none of the titles described that decision trial. Query in LOG.md. | 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 | In a phase 2 trial, week-3 MADRS change was -12.0 after 25 mg psilocybin (n=79), -7.9 after 10 mg (n=75), and -5.4 after 1 mg (n=79); 25 mg versus 1 mg differed by -6.6 points (95% CI -10.2 to -2.9) (Goodwin 2022, PMID 36322843). | In the 25 mg arm (n=79), pre-dose therapeutic alliance correlated with week-3 MADRS change at r=-0.178, compared with Emotional Breakthrough r=-0.637, Oceanic Boundlessness r=-0.508, and Visual Restructuralization r=-0.516. Path analysis found no nominally significant direct effect of alliance on the week-3 score and one indirect effect through Visual Restructuralization (beta=-0.15) (Goodwin 2026, PMID 41881122). In a separate head-to-head sample (n=55), expectancy was higher for psilocybin than for escitalopram; escitalopram expectancy predicted escitalopram response, and psilocybin expectancy did not predict psilocybin response (Szigeti 2024, PMID 38247730). | Dose, experience, alliance, and expectancy have each been related to outcome. The cited analyses do not separate the effects of pharmacology, expectancy, and the psychological support given in every arm. On 2026-10-07 a PubMed search for psilocybin, depression, mediation, and expectancy, unblinding, suggestibility, or psychological support returned 1 record, a perspective on headache and chronic pain (Schindler 2023, PMID 37652000). Query string in LOG.md. | OQ-9 |
| D-5 | In PRIME Care (n=1,944), pharmacogenomic guidance raised the share of prescriptions with no predicted drug-gene interaction from 25.7% to 59.3% (OR 4.32, 95% CI 3.47-5.39). Remission over 24 weeks was higher by OR 1.28 (95% CI 1.05-1.57; risk difference 2.8 percentage points) and was not higher at the week-24 snapshot (risk difference 1.5 percentage points, 95% CI -2.4 to 5.3) (Oslin 2022, PMID 35819423). | One week after stopping an antidepressant, DESS scores were higher by SMD 0.31 (95% CI 0.23-0.39; 11 studies, 3,915 participants), about one extra symptom, in a review of 50 studies and 17,828 participants (Kalfas 2025, PMID 40632531). | CYP2C19 increased metabolizers had a higher hazard of a CPIC SSRI prescription being stopped (HR 1.17, 95% CI 1.08-1.27, among 5,808 patients and 8,571 orders, of which 51% of pre-testing orders were discontinued) (Baye 2026, PMID 42168153). A 9-year NESDA analysis (n=928) found no association of CYP2D6 or CYP2C19 status with switching, discontinuation, or the number of perceived side effects (Brouwer 2024, PMID 38797832). A case report describes protracted escitalopram withdrawal in a CYP2C19 poor metabolizer, but cannot estimate predictive utility (Tran 2026, PMID 41646208). No comparative cohort or trial testing whether CYP phenotype predicts DESS or taper-symptom burden was found in a scoped PubMed search on 2026-10-07 (0 records); query in LOG.md. The older depression-restricted search also returned 0 but missed this case report. | OQ-5, OQ-16 |
| D-6 | Five genomic factors explain about 66% of genetic variance on average across 14 psychiatric disorders (1,056,201 cases) and 238 pleiotropic loci. The schizophrenia-bipolar factor and the internalizing factor (major depression, PTSD, anxiety) have high polygenic overlap and very few disorder-specific loci (Grotzinger 2026, PMID 41372416). | In NESARC-III (n=36,309), lifetime DSM-5 MDD prevalence was 20.6% and the mixed-features specifier characterized 15.5% of MDD cases. Adjusted for severity, the specifier was associated with early onset, poor course, and suicidality in a cross-sectional survey (Hasin 2018, PMID 29450462). | The cited cross-sectional survey cannot establish subsequent bipolar conversion. The question is whether DSM-5 mixed features and the genomic factors add calibrated prospective prediction beyond known conversion risks; a scoped PubMed search on 2026-10-07 did not identify that joint test. BRIDGE-II-Mix (n=2,347 with MDD) stated that its cross-sectional design could not assess conversion from MDD to bipolar disorder (Mazzarini 2018, PMID 29310066). On 2026-10-07 PubMed returned 7 records for mixed features plus bipolar plus conversion or prospective course in depression, and 1 record for mixed features plus a polygenic score: a bipolar sample (n=402) in which mixed features showed no polygenic-score-by-maltreatment interaction (Aas 2020, PMID 31628696). Queries in LOG.md. | OQ-13, OQ-18 |
| D-7 | In modern continuation-pharmacotherapy studies, 51.1% (95% CI 44.7-57.4%) of ECT responders relapsed by 12 months and 37.7% (30.7-45.2%) by 6 months (Jelovac 2013, PMID 23774532). | Post-ECT sleep measures have already been linked to recurrence: in 20 ECT responders, shorter polysomnographic REM latency was associated with symptoms returning by 6 months (55% were symptomatic) (Grunhaus 1994, PMID 7986885). In a separate late-life ECT cohort, residual reduced sleep predicted 6-month relapse (OR 2.03, 95% CI 1.11-3.69; 80 responders) (Lambrichts 2022, PMID 35933854). Wrist actigraphy measured activity changes in 15 ECT patients but did not test relapse prediction (Winkler 2014, PMID 24998016). | The junction is externally validated passive sleep/activity monitoring after ECT that predicts relapse beyond clinician-rated residual sleep. A scoped PubMed search for post-ECT relapse plus actigraphy, wearables, or passive sensing returned 0 records on 2026-10-07; query in LOG.md. | OQ-6 |
| D-8 | In a mixed-methods study (survey n=148, interviews n=26), 19% of health-related quality-of-life qualitative codes mapped to the EQ-5D-5L (Kerr 2023, PMID 37734244). | In a phase 3 trial, 227 adults were randomized and 197 completed day 28. Esketamine plus a new oral antidepressant differed from a new oral antidepressant plus placebo by -4.0 MADRS points (SE 1.69, 95% CI -7.31 to -0.64) (Popova 2019, PMID 31109201). | The content patients described and the scale a phase 3 primary endpoint used are different instruments. On 2026-10-07 PubMed returned 0 records for a phase 3 or pivotal major-depression trial with a co-primary endpoint in function, quality of life, recovery, or a patient-reported outcome alongside MADRS, an antidepressant, or esketamine. Query string in LOG.md. | OQ-19 |
| D-9 | In 21 countries (51,547 respondents), 4.6% met 12-month DSM-IV MDD criteria and 16.5% of those individuals received minimally adequate treatment: 1 in 5 in high-income countries and 1 in 27 in low- and lower-middle-income countries (Thornicroft 2017, PMID 27908899). | Measurement-based care versus clinicians' choice produced response of 86.9% versus 62.7% and remission of 73.8% versus 28.8% (n=61 versus n=59) (Guo 2015, PMID 26315978). In 7 cities in Pakistan (n=154), measurement-based care shortened median time to response from 4 weeks (IQR 2-12) to 2 weeks (IQR 2-4) and median time to remission from 8 weeks to 4 weeks (IQR 4-8); week-24 response and remission rates did not differ, and the HDRS-17 reduction was -18.1 (95% CI 16.4-19.6) versus -17.0 (95% CI 15.6-18.5) (Husain 2025, PMID 40892412). | Pakistan has a measurement-based-care trial in a low-resource health system, and its primary outcomes were time to response and time to remission. On 2026-10-07 PubMed returned 18 records for measurement-based care, depression, and equity, disparity, low-income, or middle-income settings. Husain 2025 is in that set. None of the 18 is a randomized trial with equity as the primary outcome. Query string in LOG.md. | OQ-12 |
| D-11 | A meta-analysis of 70 studies and 240,704 participants found higher HOMA-IR in acute depression than in controls, no elevation during remission, and no change in insulin resistance with antidepressant treatment; heterogeneity was high (Fernandes 2022, PMID 35777578). | Versus active control, walking or jogging reduced depressive symptoms by Hedges g -0.62 (95% CrI -0.80 to -0.45; n=1,210, 51 arms) in a network of 218 studies and 14,170 participants. Effects were proportional to prescribed intensity (Noetel 2024, PMID 38355154). A correction clarified standardization and reported no material change in the findings (PMID 38806193). | A review pooling exercise with dietary and supplement adjuncts reported follow-up symptom SMD -0.88 (95% CI -1.19 to -0.57) and remission OR 2.28 (1.42-3.66), but did not test baseline insulin resistance as a moderator (Jeremiah 2020, PMID 32995594). In a partially randomized depression/anxiety sample, baseline immunometabolic features did not moderate the depression benefit of running versus antidepressants (Vreijling 2025, PMID 39477079). A narrower HOMA-IR-by-exercise interaction remains untested in the scoped PubMed searches on 2026-10-07; queries in LOG.md. | OQ-10 |
| D-12 | In chronic DSM-IV MDD (N=681), baseline sexual dysfunction was present in 65% of men and 48% of women. Over 12 weeks, sexual interest/satisfaction improved in the nefazodone, CBASP, and combination arms (p<0.001). Controlling for depressive symptoms and gender, combination improved total sexual interest/satisfaction more than CBASP alone (p=0.007) and did not differ from nefazodone alone (Zajecka 2002, PMID 12197452). | Across 101 studies and 11,910 patients, combination treatment produced a higher response rate than psychotherapy alone (RR 1.27, 95% CI 1.14-1.39) and pharmacotherapy alone (RR 1.25, 95% CI 1.14-1.37) (Cuijpers 2020, PMID 31922679). | Zajecka 2002 already compared sexual interest across combination, psychotherapy, and pharmacotherapy, in a nefazodone trial. The remaining junction is whether a preference-weighted net-benefit model for current antidepressants changes treatment rankings when patients value sexual functioning alongside response. On 2026-10-07 PubMed returned 4 records for psychotherapy, an antidepressant or pharmacotherapy, combination treatment, depression, and sexual function; Zajecka 2002 is the only trial in the set. Query string in LOG.md. | OQ-4, OQ-19 |
| D-13 | In an individual-participant meta-analysis drawing on 100 studies and 44,503 participants, the subset using semistructured interviews yielded pooled PHQ-9 sensitivity 0.85 (95% CI 0.79-0.89) and specificity 0.85 (0.82-0.87) at a cutoff of 10 or higher (Negeri 2021, PMID 34610915). | In 21 countries, 16.5% of people with 12-month DSM-IV MDD received minimally adequate treatment, and 1 in 27 did so in low- and lower-middle-income countries (Thornicroft 2017, PMID 27908899). | Where screening or feedback was randomized in resourced settings, symptom and quality-of-life outcomes did not improve: DISCOVER 6-month PHQ-9 fell 3.4, 3.5, and 3.7 points across no feedback, non-tailored feedback, and tailored feedback (p=0.72; 1,178 screen-positive of those screened) (Kohlmann 2024, PMID 38906611); GET.FEEDBACK.GP fell 4.15, 4.19, and 4.91 points (global p=0.13) (Löwe 2024, PMID 38432236); CODIACS-QoL changed quality-adjusted life-years by -0.06 in the screen-notify-and-treat, screen-and-notify, and no-screen arms (P=0.98; n=1,500) (Kronish 2020, PMID 31633746). A Spanish primary-care cluster trial found recognition of 58.0% versus 48.1% (OR 1.40, 95% CI 0.73-2.68) (Romera 2013, PMID 23497463). In Malawi, supervising follow-up inside a programme that already included screening raised remission from 36% to 55% (difference 19 percentage points, 95% CI 3-34) while screening fidelity stayed 58% versus 53% (Pence 2024, PMID 38408462). On 2026-10-07 a PubMed title search for randomized depression-screening outcomes returned 48 records. The 48-title PubMed search did not identify a screening-versus-no-screening trial in a low-resource setting that measured both treatment access and clinical benefit; the Malawi trial randomized follow-up supervision after screening, and the 1-in-27 estimate is a country-income aggregate rather than a measured access rate at any trial site. Query string in LOG.md. | OQ-12, OQ-21 |
| D-14 | A Swedish register cohort estimated 13-year conversion from major depression to bipolar disorder at 5.84% (95% CI 5.72-5.96); family bipolar risk, inpatient care, and psychotic depression were the strongest predictors (Rhee 2023, PMID 37427550). | A Taiwan register-biobank analysis of 772 antidepressant-treated patients with depression reported 145 early antidepressant-induced mania events within 28 days of use or discontinuation; its bipolar polygenic-score association did not reach statistical significance (Huang 2026, PMID 41274093). This early event is distinct from later diagnostic conversion. | Does treatment-emergent activation add prospective bipolar-conversion prediction beyond register risk factors, without misclassifying transient drug effects as bipolar disorder? A scoped PubMed query combining antidepressant-induced mania with later bipolar conversion returned 0 records on 2026-10-07; query in LOG.md. | OQ-22 |
| D-15 | In a rural Indian task-sharing implementation, 458 trained community health workers delivered 13,008 Healthy Activity Program sessions; 2,160 of 2,208 patients completed treatment (97.82%), with large pre/post symptom change (Cohen d 2.52, 95% CI 2.44-2.61), an uncontrolled effectiveness estimate (Agrawal 2025, PMID 40866825). | Interviews with 45 recipients of a task-shifted depression intervention in Vietnam identified daily responsibilities, health conditions, and stigma as barriers to participation; interpersonal support was a valued facilitator (Chau 2024, PMID 39695579). | High completion and average symptom change can coexist with patient burdens. The junction is a prospectively measured, patient-defined burden outcome alongside symptoms and completion when task-shared care scales, distinct from the supervision-intensity question in OQ-24. | OQ-20, OQ-24 |
| D-16 | Across 268 studies (10,842,094 people with depression and 2,837,933,536 controls), all-cause mortality RR was 2.10 (95% CI 1.87-2.35, I-squared 99.9%), suicide RR 9.89 (7.59-12.88), and natural-cause RR 1.63 (1.51-1.75) (Chan 2025, PMID 40948054). GBD 2019 calculated deaths and years of life lost only for anorexia nervosa and bulimia nervosa, and stated that the estimated years of life lost for mental disorders do not reflect premature mortality (GBD 2019, PMID 35026139). | The same Chan synthesis associated antidepressant use versus none with all-cause mortality RR 0.79 (95% CI 0.68-0.93, I-squared 99.2%) and ECT versus none with all-cause RR 0.73 (0.66-0.82, I-squared 0%), natural-cause RR 0.76 (0.59-0.97), and suicide RR 0.67 (0.53-0.85). | Those treatment figures are observational associations. Target-trial emulations of other contrasts have been published. In CKD stages G3-G5 with incident depression, initiation versus non-initiation of an antidepressant was not associated with all-cause mortality; the abstract does not print the mortality hazard ratio (Zhu 2024, PMID 38032000). In treatment-resistant depression (39,949 patients per arm), antipsychotic augmentation versus a third-line antidepressant had a naive suicide-attempt subdistribution HR of 0.77 (95% CI 0.72-0.83); after clone-censor-weighting the suicide-attempt HR was 1.06 (0.89-1.29), the suicide-death HR was 1.22 (0.91-1.71), and the all-cause mortality HR was 1.21 (1.07-1.33) (Tsai 2026, PMID 40197402). In cancer-related depression, esketamine versus oral antidepressant monotherapy had a 2-year all-cause mortality HR of 0.737 (95% CI 0.614-0.886) in 1,751 propensity-matched patients per group (Chen 2026, PMID 42235877). On 2026-10-07 PubMed returned 6 records for a target-trial emulation of an antidepressant and mortality in depression. The set also includes an SSRI comparison for osteoporosis (PMID 40062740) and a STAR*D sequencing emulation whose primary outcome is remission (9-month probabilities 43.5% sequential monotherapy, 47.6% sequential dual therapy, 53.2% guidelines-based; PMID 36639294). None of the six emulates antidepressant initiation versus no antidepressant for all-cause or cause-specific survival in major depression outside a defined medical comorbidity. Query string in LOG.md. | OQ-17 |