Open questions — post-traumatic stress disorder¶
Last curated: 2026-09-02 (build), revised 2026-09-02 by the independent audit. All cited PMIDs and NCT IDs were retrieved live from PubMed E-utilities and the ClinicalTrials.gov v2 API in the sessions that wrote them.
17 questions (10 Tier 1 + 2 added by audit, 5 Tier 2) and 20 unconnected-dot junctions. Tier 1 questions could change practice and are designable now. Tier 2 questions require measurement, methods or a preceding answer. Stable IDs are preserved.
Tier 1 — practice-changing and designable now¶
OQ-1. Which therapy maximizes retention-adjusted benefit?¶
Adult networks rank symptom efficacy, while PTSD CBT dropout can exceed controls and routine-care rates of 38–51% motivated a 916-person direct analysis (Mavranezouli 2020, PMID 32063234; Carpenter 2018, PMID 29451967; Harper 2026, PMID 41926191). An IPD network meta-analysis can jointly model assignment, dose, dropout, post-dropout outcome and function.
OQ-2. Do effects transport across DSM-5 PTSD, ICD-11 PTSD and ICD-11 CPTSD?¶
The systems select non-identical populations, and ITQ-defined CPTSD is rarely stratified in treatment trials (Cloitre 2018, PMID 30178492; Brewin 2017, PMID 29029837). Existing item-level trial data could reconstruct strata.
OQ-3. Does CPTSD require phase-based treatment before trauma-focused work?¶
Complex-event component evidence supports benefit but does not settle fixed sequencing (Coventry 2020, PMID 32813696). A pragmatic non-inferiority/superiority trial should compare immediate trauma focus with criterion-triggered stabilisation.
OQ-4. Which prospectively defined phenotype predicts prazosin benefit?¶
Three positive trials conflict with the 304-person PACT null result (Raskind 2003, PMID 12562588; Raskind 2007, PMID 17069768; Raskind 2013, PMID 23846759; Raskind 2018, PMID 29414272), and two meta-analyses still rate prazosin effective for trauma-related nightmares (Yücel 2020, PMID 31855732; Zhang 2022, PMID 35661755). The leading candidate marker is pretreatment standing systolic blood pressure, where each 10 mm Hg predicted an additional 14-point CAPS reduction under prazosin but not placebo in a secondary analysis (Raskind 2016, PMID 27320368), contested in a comorbid alcohol-use-disorder sample (Manhapra 2019, PMID 30143236). Status as of the audit's live registry check on 2026-09-02: a phase 3 prazosin-versus-placebo trial designed around noradrenergic biomarkers (NCT03539614, n=87) records an actual primary completion date of 1 January 2026 and is active-not-recruiting, with no results publication indexed in PubMed. The question is therefore no longer "is anyone testing this" but "what did that trial find" — the first item to check at the next sweep.
OQ-5. Can independent MDMA replication address expectancy and therapist effects?¶
Phase 3 effects were d=.91 and d=.70, but the FDA declined approval in August 2024 and required another phase 3 trial (Mitchell 2021, PMID 33972795; Mitchell 2023, PMID 37709999; Wolfgang 2025, PMID 39741438; Morland 2026, PMID 41820235). A 2026 meta-analysis of eight randomized trials estimates SMD −1.19 (95% CI −1.95 to −0.42) with most studies at high risk of bias in outcome measurement (Fares-Otero 2026, PMID 41825162), and the 2026 state-of-the-science review names blinding, absent active comparators, absent head-to-head therapy-model comparisons, inadequate safety monitoring and narrow generalizability as the specific design debts. Independent funding, expectancy measurement and safety adjudication are designable now.
OQ-6. Which early intervention prevents PTSD without over-treating recovery?¶
Single-session debriefing is ineffective and potentially harmful, while targeted early CBT has supportive evidence (Rose 2002, PMID 12076399; Bryant 2007, PMID 21352105). A risk-stratified stepped-care trial can estimate absolute benefit and overtreatment.
OQ-7. Do military/civilian differences represent true effect modification?¶
Exposure meta-regression found larger effects in civilian/refugee than military studies, but study-level confounding is substantial (McLean 2022, PMID 34954460). Harmonized IPD can test within-trial interactions.
OQ-8. Does preference matching improve completion and function?¶
Preference matters to uptake, but assignment-by-preference can confound treatment effects (PMID 32074319; Harper 2026, PMID 41926191). A doubly randomized preference design is feasible.
OQ-9. Which pediatric TF-CBT components are necessary?¶
TF-CBT has the largest evidence base—52 of 70 pediatric RCTs—and g=1.06 versus passive control (Hoppen 2025, PMID 39630422). Component or sequential multiple-assignment designs could reduce burden while preserving benefit.
OQ-10. What adverse-event standard should PTSD psychotherapy trials use?¶
Adverse-event data were absent from most trials in a major review (Cusack 2016, PMID 26574151). A consensus taxonomy and mandatory arm-level reporting are achievable now.
OQ-16. Does psilocybin do anything for PTSD under a control condition?¶
The 2022 statement that no psilocybin PTSD trial existed (Khan 2022, PMID 35711024) is no longer current: two uncontrolled trials have since been published — an open-label phase 2 study in 22 participants reporting CAPS-5 change of −29.9 at week 4 (McGowan 2026, PMID 40883964) and an open-label veteran pilot in 12 participants reporting −27.5 points (95% CI 19.9–35.1) at one month (Armstrong 2026, PMID 42533157, NCT05554094). The dated gap as of 2026-09-02 is precise: 34 participants total, no control condition, and no randomized psilocybin PTSD trial published. Given that open-label PTSD trials routinely produce large within-group change, a randomized comparison is the only design that can distinguish drug effect from expectancy and regression.
OQ-17. Can a rapid-acting drug effect be separated from the therapy package it is delivered inside?¶
The MDMA phase 3 programme deliberately bundled drug with a manualized therapy (Mitchell 2021, PMID 33972795; Mitchell 2023, PMID 37709999), which is exactly why attribution has been contested. A phase 2 trial of the neuroplastogen TSND-201 with no psychotherapy component found a CAPS-5 advantage over placebo (LS mean difference 9.64; 90% CI −16.48 to −2.80) in 65 participants (Jones 2026, PMID 41706459, NCT05741710), and ketamine trials without a therapy package disagree with each other (Feder 2021, PMID 33397139; Abdallah 2022, PMID 35046508). A factorial drug × therapy design in one population would answer directly what the current literature only permits inferring across incomparable trials.
Tier 2 — depends on methods or prior answers¶
OQ-11. Is moral injury separable enough to warrant a distinct treatment pathway?¶
The 116-study review found no consensus definition or gold-standard measure (Griffin 2019, PMID 30688367). Measurement must separate exposure, appraisal and impairment before comparative treatment testing.
OQ-12. Can biological measures predict individual treatment response?¶
HPA, autonomic and imaging differences are heterogeneous group associations, not clinical predictors (Pitman 2012, PMID 23047775; Campbell 2019, PMID 30779926). Reliable assays and external validation are prerequisites.
OQ-13. Are categorical CPTSD and dimensional DSO equally prognostic?¶
Latent-profile studies recover classes across populations but model fit does not establish clinical thresholds (Karatzias 2017, PMID 27723542; Vang 2019, PMID 31984942).
OQ-14. Which outcomes define recovery beyond symptom loss?¶
Function, sleep, relationships, work, parenting and meaning are inconsistently co-primary. Trials and patient-priority studies need a core outcome set (PMID 39514500; PMID 37722204).
OQ-15. Can PTSD–pain treatment target shared avoidance without conflating outcomes?¶
Only 13 studies met criteria in a childhood-trauma/PTSD/CPTSD/chronic-pain review, and four explicitly tested the linkage (Karimov-Zwienenberg 2024, PMID 39213321).
Dots not yet connected¶
| # | Dot A | Dot B | Missing junction | Powers |
|---|---|---|---|---|
| D1 | Adult therapy NMA ranks symptoms (PMID 32063234) | Direct dropout evidence exists (PMID 41926191) | Retention-adjusted comparative benefit | OQ-1 |
| D2 | ITQ identifies CPTSD (PMID 30178492) | Most trials used DSM definitions | Reconstructed diagnostic-stratum effects | OQ-2, OQ-3 |
| D3 | Complex-trauma interventions can help (PMID 32813696) | Phase-based care is widely proposed | Randomized sequencing by measured need | OQ-3 |
| D4 | Prazosin meta-analyses positive (PMIDs: 31855732, 35661755) | PACT null (PMID 29414272) | Published result of the completed biomarker trial NCT03539614 | OQ-4 |
| D5 | MDMA phase 3 effects positive (PMIDs: 33972795, 37709999) | FDA required another trial (PMID 39741438) | Independent design resolving expectancy/safety | OQ-5 |
| D6 | Debriefing can harm (PMID 12076399) | Targeted early CBT can help (PMID 21352105) | Calibrated triage threshold | OQ-6 |
| D7 | Military studies dominate | Civilian/refugee effects appear larger (PMID 34954460) | Patient-level transport model | OQ-7 |
| D8 | Preferences shape uptake (PMID 32074319) | Treatments have similar active-comparator effects | Randomized preference-sensitive pathway | OQ-8 |
| D9 | Pediatric TF-CBT evidence is strongest (PMID 39630422) | Caregiver availability/safety varies | Component-by-caregiver configuration | OQ-9 |
| D10 | Psychotherapy benefit is established (PMID 26574151) | Adverse-event reporting is sparse | Core harm taxonomy | OQ-10 |
| D11 | Moral injury correlates with PTSD (PMID 33475402) | No gold-standard moral-injury outcome (PMID 30688367) | Discriminant measurement before treatment | OQ-11 |
| D12 | Autonomic group difference exists (PMID 30779926) | Therapy selection remains preference/availability-led | Prospective validated treatment predictor | OQ-12 |
| D13 | CPTSD profiles replicate (PMID 27723542) | Prognosis is continuous | Category-versus-dimension prediction | OQ-13 |
| D14 | Symptom endpoints dominate | Patient sources prioritize function and relationships | Co-designed core outcome set | OQ-14 |
| D15 | PTSD and chronic pain co-occur (PMID 39213321) | Avoidance is targeted in both fields | Factorial integrated intervention | OQ-15 |
| D16 | Psilocybin produces large uncontrolled PTSD change (PMIDs: 40883964, 42533157) | No randomized psilocybin PTSD trial exists | A controlled comparison at all | OQ-16 |
| D17 | A drug-only trial shows a PTSD effect (PMID 41706459) | MDMA effects are measured only inside a therapy package (PMIDs: 33972795, 37709999) | Factorial drug × therapy design in one population | OQ-17 |
| D18 | Pre-trauma cohorts identify predisposing neural and fear-learning markers (PMIDs: 40024495, 41103636) | Treatment selection uses none of them | Prospective marker-stratified treatment assignment | OQ-12 |
| D19 | Sequencing CBT-I before CPT helps (PMID 34265777) | Integrating CBT-I with PE does not (PMID 40488726) | Head-to-head test of sequence vs integration | OQ-3 |
| D20 | Massed and telehealth delivery are non-inferior (PMIDs: 29362795, 26243685) | Routine care still delivers weekly in-person courses with 38–51% dropout (PMID 41926191) | Implementation trial of the non-inferior format as default | OQ-1 |
Pooling control¶
GAD and PTSD are neighbours, not subsets. A mixed-anxiety trial or pooled anxiety-disorder effect does not answer a PTSD question unless a PTSD stratum is reported. Comorbid depression is cross-linked to the depression condition and measured separately.