{ "schema_version": "chamgap-public-evidence-check-1.0", "public_id": "v3109-main", "verdict_number": "3109", "title": "Folic acid × Reduction of BDI-II depression severity as an antidepressant adjunct", "view_version": "1.0", "view_created_date": "2026-11-05", "criteria_version": "NGM-v3109-FOLATED-BDI-II-AUC-1.0", "criteria_date": "2026-10-05", "review_date": "2026-10-05", "legacy_evidence_date": "2026-09-15", "review_scope": { "materials_read": "Stored Korean and English manuscripts and case-specific criteria and application records", "clinical_papers_directly_read": false, "new_clinical_search": false, "limitation": "No new external clinical abstracts, full texts, registrations or analysis plans were read. Reading stored summaries is distinguished from not reading external source materials; the original verdict, numerical values and unverified information are preserved. No new searches, calculations or reassessment were performed.", "date_meaning": "This is the date the stored materials were checked, not the date of an up-to-date clinical literature search." }, "claim_context": { "population": "Adults with clinician-diagnosed moderate-to-severe unipolar MDD; screened for folate/B12 deficiency; pregnancy/planned pregnancy excluded. Page applicability is restricted to nonlactating adults, but trial lactation status is unverified.", "intervention": "5 mg folic acid tablets overencapsulated in opaque hard gelatin capsules with lactose BP filler; salt, original tablet manufacturer, lot and purity unverified", "dose": "Folic acid 5 mg, 1 dose daily; common optimized antidepressant treatment", "comparator": "Matching lactose placebo under the same antidepressant optimization and usual-care policy; individual antidepressant drugs and doses were not identical across all participants", "endpoint": "Time-weighted AUC average of the BDI-II total score over 0–25 weeks: between-group difference adjusted for baseline and stratification variables; lower scores indicate improvement", "duration": "12 weeks of trial treatment; observation through 25 weeks from randomization", "excluded_extensions": [ "L-methylfolate/folinic acid/B-vitamin combinations, or improvement in blood folate alone", "Extrapolating the initial single time point at 25 weeks or trials with other doses, durations, scales, subgroups or pediatric populations to the primary AUC outcome", "Effect of 0/equivalence/ineffectiveness of all folic acid in all MDD", "Pregnancy/lactation, long-term/rare harms, or individual dosing recommendations", "Substituting biomarkers/remission/mortality for BDI-II AUC" ] }, "requirements": [ { "item_id": "N01", "question_type": "Distinct claim", "question": "Which folic acid adjunct regimen and BDI-II outcome are being asked about?", "needed": "Current original claim, actual population, 5 mg/day for 12 weeks, common antidepressant policy, placebo, and the 0–25-week time-weighted mean BDI-II", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid extending the conclusion to all folic acid and all depression.", "application_exception": "L-methylfolate, combination products, biomarkers and the single 25-week endpoint are not framed as the same question.", "criterion": "Link the original claim to the boundaries of the actual regimen, comparison and time-weighted endpoint.", "basis": "M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed; M03 §3.2.1; detailed population criteria are internally designed; M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Review direct results within these boundaries separately from materials addressing other questions.", "current_reports": [ "S02", "S06", "S07" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "The selected question is whether oral folic acid 5 mg/day added for 12 weeks to common optimized antidepressant treatment in adults with unipolar MDD results in a lower 0–25-week time-weighted mean BDI-II than placebo. The subclaims list is empty.", "condition_status": "Met", "status_reason": "Confirms preservation of the boundaries; it is neither efficacy certification nor a verdict that all folic acid is ineffective.", "missingness": "Confirms preservation of the boundaries; it is neither efficacy certification nor a verdict that all folic acid is ineffective.", "uncertainty": "Confirms preservation of the boundaries; it is neither efficacy certification nor a verdict that all folic acid is ineffective.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Current original claim, actual population, 5 mg/day for 12 weeks, common antidepressant policy, placebo, and the 0–25-week time-weighted mean BDI-II" }, { "item_id": "N02", "question_type": "Ingredient and product", "question": "Are the actual folic acid product and unverified manufacturing details distinguished?", "needed": "Active ingredient, 5 mg tablet, overencapsulation, filler, Bilcare supply, and documentation of salt/manufacturer/lot/purity", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid equating the supplier with the manufacturing source or with other folate products.", "application_exception": "The authorized Flamingo product does not establish the identity of the FolATED product.", "criterion": "Record the reported active ingredient and overencapsulation separately from unverified manufacturing details.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Compare trial product, batch and ingredient records with the original medication section.", "current_reports": [ "S02", "S11" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "Folic acid tablets were overencapsulated in opaque hard gelatin capsules with lactose BP filler. Bilcare supply was reported, but the exact salt, manufacturing source, original tablet manufacturer, batch and purity remain unverified.", "condition_status": "Partly verified", "status_reason": "Product form and supply are preserved, but manufacturing details and current comparison with the original source remain unverified.", "missingness": "Product form and supply are preserved, but manufacturing details and current comparison with the original source remain unverified.", "uncertainty": "Product form and supply are preserved, but manufacturing details and current comparison with the original source remain unverified.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Active ingredient, 5 mg tablet, overencapsulation, filler, Bilcare supply, and documentation of salt/manufacturer/lot/purity" }, { "item_id": "N03", "question_type": "Route and nominal dose", "question": "Is 5 mg as 1 daily dose the same as actual total exposure?", "needed": "Oral route, nominal amount for 1 dose and dosing frequency, dosing records and total exposure", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid turning the trial dose into an individual recommendation or a claim of actual complete adherence.", "application_exception": "Do not calculate new cumulative doses, conversions or recommended doses.", "criterion": "Distinguish the planned oral 5 mg as 1 daily dose from unverified actual exposure.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application; M08 §8.2.2, M15 §15.3.1; internal application", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Link arm-specific dosing, missed doses and adherence records to the effect of interest.", "current_reports": [ "S02" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "The plan for oral folic acid 5 mg as 1 daily dose is verified. The current stored materials were not taken to verify every participant's actual total exposure and adherence, and no new cumulative dose was calculated.", "condition_status": "Partly verified", "status_reason": "A nominal dose is available, but actual individual exposure has not been fully verified.", "missingness": "A nominal dose is available, but actual individual exposure has not been fully verified.", "uncertainty": "A nominal dose is available, but actual individual exposure has not been fully verified.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Oral route, nominal amount for 1 dose and dosing frequency, dosing records and total exposure" }, { "item_id": "N04", "question_type": "Treatment and observation", "question": "Are 12 weeks of treatment distinguished from 25 weeks of observation?", "needed": "End of trial treatment, observation measured from randomization, and visit times", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid turning 25 weeks of observation into 25 weeks of treatment or a lasting long-term effect.", "application_exception": "Do not impose all long-term follow-up as a requirement for this narrow question.", "criterion": "Show 12 weeks of treatment separately from observation through 25 weeks.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "If persistence after treatment discontinuation is the question, review direct estimates and exposure at that time.", "current_reports": [ "S02", "S07" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "Trial treatment lasted 12 weeks; observation extended through 25 weeks from randomization. The 0–25-week mean was not recast as 25 weeks of continuous treatment or a confirmed persistent effect after discontinuation.", "condition_status": "Met", "status_reason": "Confirms the time boundaries; it does not verify long-term efficacy or safety.", "missingness": "Confirms the time boundaries; it does not verify long-term efficacy or safety.", "uncertainty": "Confirms the time boundaries; it does not verify long-term efficacy or safety.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "End of trial treatment, observation measured from randomization, and visit times" }, { "item_id": "N05", "question_type": "Placebo and background treatment", "question": "What were the matching placebo and common antidepressant policy?", "needed": "Lactose placebo, visual matching for blinding, optimization/usual-care policy, and individual drug names/doses", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid describing a shared policy as identical drugs and doses for all participants.", "application_exception": "Do not automatically exclude comparative results because concomitant treatment was used.", "criterion": "Distinguish the actual added-ingredient contrast from the common policy and unverified individual exposure.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application; M08 §8.2.2, M15 §15.3.1; internal application", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Link arm-specific antidepressants and medication changes to the selected BDI-II analysis.", "current_reports": [ "S02" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "The comparison used a visually matched lactose placebo, and both arms followed a common optimized-antidepressant and usual-care policy. This does not mean all participants received an identical drug and fixed dose.", "condition_status": "Partly verified", "status_reason": "The actual placebo and policy are preserved, but individual concomitant-treatment histories have not been fully verified.", "missingness": "The actual placebo and policy are preserved, but individual concomitant-treatment histories have not been fully verified.", "uncertainty": "The actual placebo and policy are preserved, but individual concomitant-treatment histories have not been fully verified.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Lactose placebo, visual matching for blinding, optimization/usual-care policy, and individual drug names/doses" }, { "item_id": "N06", "question_type": "Changes and concurrent exposure", "question": "Were medication changes, psychotherapy and dietary/supplement exposure verified?", "needed": "Arm-specific antidepressant changes, rescue treatment, psychotherapy, dietary/fortified-food/supplement exposure and their handling", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid describing permitted changes as absent or attributing the result solely to folic acid.", "application_exception": "Do not impose a new condition that all changes must be identical.", "criterion": "Separate the permitted clinical context from unverified actual treatment and exposure histories.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M03 §3.2.3, M08 §8.2.2–8.2.3; internal application; M08 §8.2.2, M15 §15.3.1; internal application; M19 §19.2.2–19.2.4 considerations for study design; detailed recording of confounding is internally designed", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Compare arm-specific changes and concurrent-exposure records with how the effect of assignment was handled.", "current_reports": [ "S02" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "The context allowing medication changes and psychotherapy is preserved. Complete individual antidepressant-change and rescue-treatment histories, and dietary, fortified-food and concurrent-supplement exposure remain unverified.", "condition_status": "Partly verified", "status_reason": "The policy permitting changes is verified, but a complete comparison of actual concurrent-exposure balance and its analytical impact remains outstanding.", "missingness": "The policy permitting changes is verified, but a complete comparison of actual concurrent-exposure balance and its analytical impact remains outstanding.", "uncertainty": "The policy permitting changes is verified, but a complete comparison of actual concurrent-exposure balance and its analytical impact remains outstanding.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Arm-specific antidepressant changes, rescue treatment, psychotherapy, dietary/fortified-food/supplement exposure and their handling" }, { "item_id": "N07", "question_type": "Diagnosis and baseline status", "question": "Which adult MDD population and screening criteria were used?", "needed": "Clinician diagnosis under ICD10, moderate/severe depression, BDI-II screening/randomization criteria, and new/existing antidepressant use", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid recasting the population as entirely treatment-resistant depression or as general low mood.", "application_exception": "Do not generalize trial screening cutpoints into diagnostic criteria for all clinical care.", "criterion": "Preserve BDI-II screening ≥19 and randomization ≥17, clinician diagnosis and the actual population boundaries.", "basis": "M03 §3.2.1; detailed population criteria are internally designed; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application; M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Link original inclusion/exclusion criteria, recruitment and baseline status to the actual denominators.", "current_reports": [ "S02", "S04", "S18" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "Participants were adults with clinician-diagnosed moderate-to-severe unipolar MDD under ICD10. BDI-II thresholds were ≥19 at screening and ≥17 at randomization, with a mixture of new and existing antidepressant users. Bipolar and psychotic depression were excluded; participants were not described as uniformly treatment-resistant.", "condition_status": "Met", "status_reason": "Confirms the retained diagnostic and eligibility boundaries; it does not establish an effect applicable to all adults or depression subtypes.", "missingness": "Confirms the retained diagnostic and eligibility boundaries; it does not establish an effect applicable to all adults or depression subtypes.", "uncertainty": "Confirms the retained diagnostic and eligibility boundaries; it does not establish an effect applicable to all adults or depression subtypes.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Clinician diagnosis under ICD10, moderate/severe depression, BDI-II screening/randomization criteria, and new/existing antidepressant use" }, { "item_id": "N08", "question_type": "Nutritional status", "question": "Does deficiency screening establish normal nutritional status in everyone?", "needed": "Folate/B12 deficiency screening, baseline values/units and subgroups with low values", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid turning a screening policy into a claim that every participant had normal status.", "application_exception": "Do not repurpose results from a small low-value subgroup as the overall primary effect or an effect in confirmed deficiency.", "criterion": "Preserve screening records, small low-value subgroups and unverified units separately.", "basis": "M03 §3.2.1; detailed population criteria are internally designed; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application; M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Compare baseline tests/units and eligibility with the prospective plan for stratified analyses.", "current_reports": [ "S02", "S03", "S10" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "Folate and B12 deficiency were screened, but small subgroups with low values were also reported later. Normal nutritional status was not assumed for everyone, and some baseline biochemical units remain unverified.", "condition_status": "Partly verified", "status_reason": "Screening and subgroups are preserved, but verification of every individual's nutritional status and comparison of units remain incomplete.", "missingness": "Screening and subgroups are preserved, but verification of every individual's nutritional status and comparison of units remain incomplete.", "uncertainty": "Screening and subgroups are preserved, but verification of every individual's nutritional status and comparison of units remain incomplete.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Folate/B12 deficiency screening, baseline values/units and subgroups with low values" }, { "item_id": "N09", "question_type": "Pregnancy and lactation", "question": "Is restricting the page to nonlactating adults the same as verifying actual lactation status?", "needed": "Exclusion of pregnancy/planned pregnancy, lactation inclusion/exclusion criteria and actual status", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid turning a page restriction into a record that lactating participants were actually excluded from the trial.", "application_exception": "Do not turn unverified lactation status into confirmed harm, efficacy or exclusion during lactation.", "criterion": "Separate exclusion of pregnancy/planned pregnancy from unverified lactation status.", "basis": "M03 §3.2.1; detailed population criteria are internally designed; M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed; M19 §19.1.2–19.2.4; internal application", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Compare actual eligibility criteria, lactation status and evidence for special populations separately.", "current_reports": [ "S02", "S04", "S18" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "The trial excluded pregnancy and planned pregnancy. Page applicability is restricted to nonlactating adults, but actual trial lactation status could not be explicitly verified.", "condition_status": "Partly verified", "status_reason": "Pregnancy exclusion is preserved, and lactation status remains unverified.", "missingness": "Pregnancy exclusion is preserved, and lactation status remains unverified.", "uncertainty": "Pregnancy exclusion is preserved, and lactation status remains unverified.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Exclusion of pregnancy/planned pregnancy, lactation inclusion/exclusion criteria and actual status" }, { "item_id": "N10", "question_type": "BDI-II measurement", "question": "Are the subjective scale's direction and collection distinguished from blinding?", "needed": "BDI-II total score, lower-is-better direction, collection at visits, matching placebo/blinding, and limitations in implementation", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid asserting absence of all measurement bias solely from the scale name or double blinding.", "application_exception": "Do not treat a subjective scale as an automatic failure or recast it as a biomarker.", "criterion": "Explain the patient-reported depression total score, reported blinding and the extent of implementation not cross-checked.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M08 §8.1–8.2.3; internal application; M08 Table 8.2.a, M03 §3.2.4; internal application", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Link scale collection and blinding implementation at each visit to the selected analysis.", "current_reports": [ "S02", "S07" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "BDI-II is a patient-reported total score for depressive symptoms; lower is better. Stored records describe a multicenter randomized, blinded design with a matching placebo, but original measurement and blinding implementation were not newly verified in this review.", "condition_status": "Partly verified", "status_reason": "The scale, direction and design are preserved, but current comparison of implementation details with the original source remains outstanding.", "missingness": "The scale, direction and design are preserved, but current comparison of implementation details with the original source remains outstanding.", "uncertainty": "The scale, direction and design are preserved, but current comparison of implementation details with the original source remains outstanding.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "BDI-II total score, lower-is-better direction, collection at visits, matching placebo/blinding, and limitations in implementation" }, { "item_id": "N11", "question_type": "AUC definition and units", "question": "How should the time-weighted mean be interpreted?", "needed": "Area across baseline and weeks 4/12/25, divided by the actual observation period; mean expressed in BDI-II points", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid recasting it as point-weeks, within-group change or a single endpoint.", "application_exception": "Do not perform new AUC calculations or conversions in this review.", "criterion": "Link the final plan's time-weighted AUC average, units and adjusted between-group estimand.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M08 §8.2.2, M15 §15.3.1; internal application", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Compare definitions of the estimand and units in the original SAP and results tables.", "current_reports": [ "S02", "S06", "S07" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "This is the time-weighted mean obtained by dividing the area between baseline and week 4, 12 and 25 scores by the actual observation period. Its unit is BDI-II points, not point-weeks, change from baseline or the week-25 endpoint.", "condition_status": "Met", "status_reason": "Confirms the retained definition; it is not a newly calculated AUC from individual-level data.", "missingness": "Confirms the retained definition; it is not a newly calculated AUC from individual-level data.", "uncertainty": "Confirms the retained definition; it is not a newly calculated AUC from individual-level data.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Area across baseline and weeks 4/12/25, divided by the actual observation period; mean expressed in BDI-II points" }, { "item_id": "N12", "question_type": "Plan changes", "question": "Were the initial 25-week endpoint and the final AUC the same from the outset?", "needed": "Original protocol, erratum, final SAP, unblinding/amendment approval dates and registration history", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid concealing the endpoint change and unverified details.", "application_exception": "Do not turn an unavailable plan into confirmed selective reporting or a claim of an identical prospective plan from the outset.", "criterion": "Show separately the initial single time point, final AUC, reportedly pre-unblinding SAP and unverified approval date.", "basis": "M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design; M08 Table 8.2.a, M04 §4.6.3; internal application", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Compare protocol, erratum and SAP versions, registration changes and approval timing.", "current_reports": [ "S04", "S07", "S08", "S09", "S18" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "The initial single time point at 25 weeks differs from the final AUC average. The final report describes a SAP before unblinding, and S07 identifies the passage about the unblinding meeting dated 2011-10-10; the exact amendment approval date and complete registration history remain unverified.", "condition_status": "Partly verified", "status_reason": "The change and its reported location are preserved, but direct comparison of the full chronology remains incomplete.", "missingness": "The change and its reported location are preserved, but direct comparison of the full chronology remains incomplete.", "uncertainty": "The change and its reported location are preserved, but direct comparison of the full chronology remains incomplete.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Original protocol, erratum, final SAP, unblinding/amendment approval dates and registration history" }, { "item_id": "N13", "question_type": "Design and allocation", "question": "To what extent are the actual comparative design and allocation process verified?", "needed": "Multicenter individually randomized parallel groups, matching placebo, allocation/concealment and baseline balance", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid extending the design label into complete verification of concealment and baseline balance.", "application_exception": "Do not turn unverified details into a nonrandomized classification or automatic failure.", "criterion": "Distinguish the recorded actual design from details not cross-checked in this review.", "basis": "M03 §3.2.1; detailed population criteria are internally designed; M08 §8.1–8.2.3; internal application", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Link original randomization/concealment information and baseline tables to the selected outcome.", "current_reports": [ "S02", "S04" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "FolATED was a multicenter individually randomized, matched-placebo parallel-group trial under a common antidepressant optimization policy. During this summary conversion, the complete original text on allocation, concealment and baseline balance was not newly cross-checked.", "condition_status": "Partly verified", "status_reason": "The design is preserved, but verification of detailed implementation does not extend beyond the current local records.", "missingness": "The design is preserved, but verification of detailed implementation does not extend beyond the current local records.", "uncertainty": "The design is preserved, but verification of detailed implementation does not extend beyond the current local records.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Multicenter individually randomized parallel groups, matching placebo, allocation/concealment and baseline balance" }, { "item_id": "N14", "question_type": "Allocation and analysis denominators", "question": "What do the denominators of 475 and 440 represent?", "needed": "Valid allocation 237/238, total 475; 35 with no follow-up BDI-II; mITT 223/217, total 440", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid substituting the allocation denominator for analysis or completion denominators.", "application_exception": "Do not create dropout rates, new denominators or new calculations in this review.", "criterion": "Preserve allocation, reasons for exclusion and primary-analysis denominators together with their arms.", "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M08 §8.2.2, M15 §15.3.1; internal application", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Compare the original flowchart, analysis definitions and loss to follow-up by arm.", "current_reports": [ "S03", "S06" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "There were 475 valid randomized participants (237 folic acid, 238 placebo). The primary analysis included 440 (223 and 217) after excluding 35 with no postrandomization BDI-II at all. The 440 were not described as completers of every visit or as ITT including all 475.", "condition_status": "Met", "status_reason": "Confirms preservation of the denominator distinctions; it does not mean the impact of loss to follow-up has been resolved.", "missingness": "Confirms preservation of the denominator distinctions; it does not mean the impact of loss to follow-up has been resolved.", "uncertainty": "Confirms preservation of the denominator distinctions; it does not mean the impact of loss to follow-up has been resolved.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Valid allocation 237/238, total 475; 35 with no follow-up BDI-II; mITT 223/217, total 440" }, { "item_id": "N15", "question_type": "mITT and missing data", "question": "Does regression imputation include the 35 excluded participants?", "needed": "Assigned groups retained; inclusion requires at least 1 follow-up; imputation within the 440; sensitivity analysis of all randomized participants", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid calling imputation full ITT or removing the B1 defect.", "application_exception": "Do not infer that imputation within the included group brought excluded participants into the primary analysis.", "criterion": "Separate the inclusion criteria for modified ITT from the scope of imputation and exclusions.", "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M08 §8.2.2, M15 §15.3.1; internal application", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Compare original missing-data reasons, imputation and sensitivity methods with the effect of interest.", "current_reports": [ "S02", "S03", "S07" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "The primary analysis retained assigned groups but was mITT, including only participants with at least 1 follow-up value. Regression imputation was used for missing data within the included 440. The 35 with no follow-up BDI-II were excluded from the primary analysis; this was not recast as ITT including all 475.", "condition_status": "Partly verified", "status_reason": "The retained analysis and missing-data scope are available, but the impact of exclusions was neither fully resolved nor reanalyzed.", "missingness": "The retained analysis and missing-data scope are available, but the impact of exclusions was neither fully resolved nor reanalyzed.", "uncertainty": "The retained analysis and missing-data scope are available, but the impact of exclusions was neither fully resolved nor reanalyzed.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Assigned groups retained; inclusion requires at least 1 follow-up; imputation within the 440; sensitivity analysis of all randomized participants" }, { "item_id": "N16", "question_type": "Sensitivity analyses and completion denominators", "question": "Are alternative analyses of the same trial counted as new replications?", "needed": "Complete-case, repeated mixed-model and reweighted-allocation analyses; denominators for completing visits and for complete BDI data", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid turning analysis counts into trial counts or collapsing different completion denominators into one.", "application_exception": "Do not infer exact completion denominators absent from the current summary.", "criterion": "Preserve sensitivity analyses within the same family and the differences in denominators.", "basis": "M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M08 §8.2.2, M15 §15.3.1; internal application", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Compare original Tables 18–20 and participant flow with each analysis denominator and result.", "current_reports": [ "S02", "S03", "S07" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "Complete-case, repeated mixed-model and sensitivity analyses reweighting all randomized participants are analyses of the same FolATED trial. The record that completers of all visits and complete BDI cases have different denominators is preserved; exact counts absent from the current summary were not filled in.", "condition_status": "Partly verified", "status_reason": "Sensitivity-analysis types and denominator differences are available, but comparison of all values and denominators in the original tables remains outstanding.", "missingness": "Sensitivity-analysis types and denominator differences are available, but comparison of all values and denominators in the original tables remains outstanding.", "uncertainty": "Sensitivity-analysis types and denominator differences are available, but comparison of all values and denominators in the original tables remains outstanding.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Complete-case, repeated mixed-model and reweighted-allocation analyses; denominators for completing visits and for complete BDI data" }, { "item_id": "N17", "question_type": "Primary effect and direction", "question": "What exact comparison and interval does +1.09 points refer to?", "needed": "Table 13 adjusted folic acid minus placebo, 0–25-week AUC average, CI/P, 223/217 and lower-is-better direction", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid presenting a positive value as improvement or recasting it as a within-group or endpoint difference.", "application_exception": "Do not calculate new effects, CIs, P values or standardized estimates.", "criterion": "Preserve +1.09, CI −0.48 to 2.66 and P=0.173 together with the original estimand.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M08 §8.2.2, M15 §15.3.1; internal application; M15 §15.3.1–15.3.3; internal application", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Compare original Table 13, narrative text, analysis definitions and printed values.", "current_reports": [ "S03", "S06", "S07" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "The adjusted primary-analysis folic-acid-minus-placebo difference was +1.09 BDI-II points, 95% CI −0.48 to 2.66, P=0.173, with 223/217 participants. Additional improvement was not demonstrated on a lower-is-better scale. The result was not recast as within-group change or a difference at the 25-week endpoint.", "condition_status": "Met", "status_reason": "Confirms preservation of the reported effect and direction; the original table's SE conflict remains separately recorded.", "missingness": "Confirms preservation of the reported effect and direction; the original table's SE conflict remains separately recorded.", "uncertainty": "Confirms preservation of the reported effect and direction; the original table's SE conflict remains separately recorded.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Table 13 adjusted folic acid minus placebo, 0–25-week AUC average, CI/P, 223/217 and lower-is-better direction" }, { "item_id": "N18", "question_type": "SE conflict", "question": "Do the printed SE and CI/P in Table 13 agree?", "needed": "Printed SE 0.86, CI/P, and records of numerical conflicts in tables and narrative text", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid deleting problematic printed values or silently replacing them with recalculated values.", "application_exception": "Preserve the historical conflict record; do not conduct a new normal-approximation check or generate new values.", "criterion": "Preserve both the printed values and the explanation of the conflict.", "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed; M15 §15.3.1–15.3.3; internal application", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "During an authorized correction, compare the original table, analysis output and errata, and retain before-and-after values.", "current_reports": [ "S03", "S06" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "The original review records that the SE=0.86 printed in Table 13 does not agree with CI/P under the usual normal approximation. +1.09, CI −0.48 to 2.66, P=0.173 and SE 0.86 are all preserved; no new SE/CI/P was generated.", "condition_status": "Conflicting printed values", "status_reason": "The conflict between original printed values remains unresolved; no new calculation or correction was made in this review.", "missingness": "The conflict between original printed values remains unresolved; no new calculation or correction was made in this review.", "uncertainty": "The conflict between original printed values remains unresolved; no new calculation or correction was made in this review.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Printed SE 0.86, CI/P, and records of numerical conflicts in tables and narrative text" }, { "item_id": "N19", "question_type": "Unadjusted sign conflict", "question": "Were +0.06 and −0.06 overwritten with the same sign?", "needed": "Unadjusted AUC difference in Tables 12/18, the sign printed in each table, and distinction from the adjusted primary effect", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid erasing the sign conflict or transferring it to the adjusted primary effect.", "application_exception": "Differences between analyses are not automatically treated as conflicts, but the actual conflict recorded here is preserved.", "criterion": "Retain the original conflict between +0.06 in Table 12 and −0.06 in Table 18 unchanged.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed; M08 §8.2.2, M15 §15.3.1; internal application", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Compare original tables/directions, errata and analysis outputs as a separate correction event.", "current_reports": [ "S03", "S06" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "The original record that the unadjusted AUC difference differs between Table 12 (+0.06) and Table 18 (−0.06) is preserved. Neither value was used as an alternative or correction to the adjusted primary effect of +1.09.", "condition_status": "Conflicting printed values", "status_reason": "Resolution of the unadjusted sign conflict remains unverified; no correction or recalculation was made in this review.", "missingness": "Resolution of the unadjusted sign conflict remains unverified; no correction or recalculation was made in this review.", "uncertainty": "Resolution of the unadjusted sign conflict remains unverified; no correction or recalculation was made in this review.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Unadjusted AUC difference in Tables 12/18, the sign printed in each table, and distinction from the adjusted primary effect" }, { "item_id": "N20", "question_type": "Interpreting nonsignificance", "question": "Does failure to demonstrate benefit mean an effect of 0, equivalence or ineffectiveness in all MDD?", "needed": "Direction of the primary effect, CI, fixed question and original meaning of E0", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid turning nonsignificance into established absence of effect or equivalence.", "application_exception": "Do not remove positive results for other doses, populations or scales.", "criterion": "Distinguish failure to demonstrate improvement in this narrow comparison from the range allowed by the interval.", "basis": "M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed; M15 §15.3.1–15.3.3; internal application; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Review direct results for the same estimand and relevant clinical thresholds alongside additional evidence.", "current_reports": [ "S06", "S13", "S15" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "The CI for +1.09 includes 0, and improvement was not demonstrated in this comparison. This does not mean an exact effect of 0, equivalence or ineffectiveness of every dose in all MDD. Positive adjacent results are also preserved.", "condition_status": "Met", "status_reason": "Confirms preservation of interpretive boundaries; it is not a new conclusion of equivalence or ineffectiveness.", "missingness": "Confirms preservation of interpretive boundaries; it is not a new conclusion of equivalence or ineffectiveness.", "uncertainty": "Confirms preservation of interpretive boundaries; it is not a new conclusion of equivalence or ineffectiveness.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Direction of the primary effect, CI, fixed question and original meaning of E0" }, { "item_id": "N21", "question_type": "MCID and precision", "question": "Is the initial 3-point power target the MCID for AUC?", "needed": "Reported CI, a validated between-group threshold for clinical importance of the AUC average, and the initial 3-point target at 25 weeks", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid using a power target as an MCID or as evidence excluding clinically important benefit.", "application_exception": "Do not create a universal minimum sample size, duration or study count, or a new MCID.", "criterion": "Separate the unverified applicable AUC MCID from the role of the initial design target.", "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M15 §15.3.1–15.3.3; internal application", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Compare a justified threshold for the same endpoint and estimand with the CI.", "current_reports": [ "S02", "S06" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "A validated between-group MCID applicable to the AUC average was not obtained. The initial 3-point power target for the single 25-week time point was not repurposed as an AUC MCID. The original C0 is preserved unchanged.", "condition_status": "Unverified", "status_reason": "Because an applicable importance threshold is unverified, exclusion of clinically important benefit is not established.", "missingness": "Because an applicable importance threshold is unverified, exclusion of clinically important benefit is not established.", "uncertainty": "Because an applicable importance threshold is unverified, exclusion of clinically important benefit is not established.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Reported CI, a validated between-group threshold for clinical importance of the AUC average, and the initial 3-point target at 25 weeks" }, { "item_id": "N22", "question_type": "Single 25-week result", "question": "Are endpoint means, adjusted endpoint differences and the primary AUC separated?", "needed": "Adjusted 25-week difference +1.27/CI/P, arm-specific unadjusted means and SDs, and distinct estimands", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid combining different results into one primary effect.", "application_exception": "Do not calculate new endpoint differences, standardized estimates or change scores.", "criterion": "Preserve the three types of values, the 25-week time point and units separately.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed; M08 §8.2.2, M15 §15.3.1; internal application", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Compare Table 14 and Appendix 10/Table 42 with the original analysis definitions.", "current_reports": [ "S10", "S12" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "The adjusted 25-week difference was +1.27 points (CI −0.99 to 3.54; P=0.270); unadjusted means (SDs) were 22.61 (13.53) for folic acid and 22.33 (14.09) for placebo. These were not interchanged with the primary AUC difference of +1.09 or with within-group change.", "condition_status": "Met", "status_reason": "Confirms preservation of time-point, dispersion and analysis distinctions; the original tables were not newly verified in this review.", "missingness": "Confirms preservation of time-point, dispersion and analysis distinctions; the original tables were not newly verified in this review.", "uncertainty": "Confirms preservation of time-point, dispersion and analysis distinctions; the original tables were not newly verified in this review.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Adjusted 25-week difference +1.27/CI/P, arm-specific unadjusted means and SDs, and distinct estimands" }, { "item_id": "N23", "question_type": "Reports and trial families", "question": "Are FolATED reports and appendices counted as independent trials?", "needed": "FOLATED links among the report, Methods/Results, protocol/erratum, SAP, registration and appendices", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid inflating independent replication or participant counts from the number of documents.", "application_exception": "Keep verified document identities separate from the unverified complete registration history.", "criterion": "Preserve the 11 linked reports S01/02/03/04/06/07/08/09/10/12/18 as one FOLATED family.", "basis": "M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Verify the unique recruitment/allocation identity and distinctions from other families at the original locations.", "current_reports": [ "S01", "S02", "S03", "S04", "S06", "S07", "S08", "S09", "S10", "S12", "S18" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "The current evidence links S01, S02, S03, S04, S06, S07, S08, S09, S10, S12 and S18 to one FOLATED trial family. Economic, genetic, biochemical and sensitivity analyses are also not new independent replications.", "condition_status": "Met", "status_reason": "Confirms preservation of family links; it does not mean 19 bibliographic records represent 19 trials.", "missingness": "Confirms preservation of family links; it does not mean 19 bibliographic records represent 19 trials.", "uncertainty": "Confirms preservation of family links; it does not mean 19 bibliographic records represent 19 trials.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "FOLATED links among the report, Methods/Results, protocol/erratum, SAP, registration and appendices" }, { "item_id": "N24", "question_type": "Coppen positive result", "question": "Why is the positive female-subgroup HDRS-17 result not counted as direct replication?", "needed": "127 participants, 500 µg/day, 10 weeks, fluoxetine 20 mg, female-subgroup HDRS17, and subgroup denominators/plans", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid deleting favorable adjacent results or transferring them to FolATED's overall AUC.", "application_exception": "Do not infer the exact female denominator or prospective interaction testing.", "criterion": "Preserve 6.8 (SD 4.1) versus 11.7 (SD 6.7), P<0.001, and the different population stratum, dose, scale and duration.", "basis": "M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application; M03 §3.2.1; detailed population criteria are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application; M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Compare the abstract's scope with subgroup plans/denominators and the direct comparison in the original full text.", "current_reports": [ "S13" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "The positive Coppen result is preserved: 127 participants in total; folic acid 500 µg/day added to fluoxetine 20 mg/day; 10-week female-subgroup HDRS17 endpoints of 6.8 (SD 4.1) versus 11.7 (SD 6.7), P<0.001. The exact female denominator and prospective interaction testing remain unverified; this is not replication of FolATED's overall AUC.", "condition_status": "Partly verified", "status_reason": "A positive abstract result is available, but subgroup plans/denominators, the full text and direct applicability to the identical question remain unverified.", "missingness": "A positive abstract result is available, but subgroup plans/denominators, the full text and direct applicability to the identical question remain unverified.", "uncertainty": "A positive abstract result is available, but subgroup plans/denominators, the full text and direct applicability to the identical question remain unverified.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "127 participants, 500 µg/day, 10 weeks, fluoxetine 20 mg, female-subgroup HDRS17, and subgroup denominators/plans" }, { "item_id": "N25", "question_type": "Another positive BDI-II result", "question": "What role does the uncorrected author proof for 2.5 mg over 8 weeks have?", "needed": "Sepehrmanesh 45/45, citalopram 20 mg, 2.5 mg/day for 8 weeks, BDI-II, and version/registration", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid calling it replication of the 5 mg, 25-week AUC solely because it uses the same scale name.", "application_exception": "Do not upgrade an uncorrected author proof to complete verification of the final published version.", "criterion": "Preserve the positive result of 13.31 (SD 6.57) versus 19.11 (SD 8.59), P<0.001, together with version limitations.", "basis": "M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application; M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed; M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Compare the final publication version, registration history, denominators and plans with the different exposures and estimands.", "current_reports": [ "S15" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "The Sepehrmanesh uncorrected author proof reports 45 versus 45 participants, folic acid 2.5 mg/day for 8 weeks added to citalopram 20 mg/day, and endpoint BDI-II of 13.31 (SD 6.57) versus 19.11 (SD 8.59), P<0.001. The positive result is preserved without counting it as replication of the FolATED AUC; final-version and registration limitations are retained.", "condition_status": "Partly verified", "status_reason": "Results are available from the accessed version, but the final version and registration, and direct replication of the selected question, remain unverified.", "missingness": "Results are available from the accessed version, but the final version and registration, and direct replication of the selected question, remain unverified.", "uncertainty": "Results are available from the accessed version, but the final version and registration, and direct replication of the selected question, remain unverified.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Sepehrmanesh 45/45, citalopram 20 mg, 2.5 mg/day for 8 weeks, BDI-II, and version/registration" }, { "item_id": "N26", "question_type": "Candidate with results not obtained", "question": "Was Resler metadata promoted to verified results?", "needed": "PMID18716414/DOI, the scope of access failure, and actual dose/denominators/effect", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid promoting a literature candidate to verified efficacy or a replication count.", "application_exception": "Access failure does not mean absence of a study or an effect of 0.", "criterion": "Separate candidate identity from unverified full-text results.", "basis": "M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application; M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "If separately obtaining the source is authorized, link the original results, design, exposure and denominators.", "current_reports": [ "S14" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "Resler2008 is a candidate human trial of folic acid plus fluoxetine, but access to the full results failed. The exact dose, denominators and effect estimate remain unverified; it was retained only as a metadata candidate and excluded from replication counts and scoring.", "condition_status": "Unverified", "status_reason": "A bibliographic candidate exists, but no full-text verification is available to satisfy the result criteria.", "missingness": "A bibliographic candidate exists, but no full-text verification is available to satisfy the result criteria.", "uncertainty": "A bibliographic candidate exists, but no full-text verification is available to satisfy the result criteria.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "PMID18716414/DOI, the scope of access failure, and actual dose/denominators/effect" }, { "item_id": "N27", "question_type": "Reviews and pediatric exclusion", "question": "Were reviews and trials in people younger than 18 combined with direct adult results?", "needed": "Discovery role of reviews S16/19, population boundary for pediatric S17, and original families", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid counting reviews and material outside the adult population as independent adult replications.", "application_exception": "Preserve the roles of reviews and excluded material without deleting them.", "criterion": "Distinguish evidence mapping and exclusion from the adult population from unverified direct results.", "basis": "M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application; M03 §3.2.1; detailed population criteria are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed; M04 §4.6.1–4.6.2, M15 §15.3.1; internal application", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "If needed, separately compare underlying trial identities, adult-population boundaries and actual results.", "current_reports": [ "S16", "S17", "S19" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "Reviews S16/19 provide clues for literature discovery and mapping contrary results. S17 is a fluoxetine adjunct trial in people younger than 18, outside the adult MDD population boundary; it was not added to adult denominators or funding assessments for the direct trial.", "condition_status": "Met", "status_reason": "Confirms roles and exclusion boundaries; not all underlying trials in the reviews were verified in this review.", "missingness": "Confirms roles and exclusion boundaries; not all underlying trials in the reviews were verified in this review.", "uncertainty": "Confirms roles and exclusion boundaries; not all underlying trials in the reviews were verified in this review.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Discovery role of reviews S16/19, population boundary for pediatric S17, and original families" }, { "item_id": "N28", "question_type": "Unfavorable SF-12 result", "question": "Was the secondary SF-12 result merged into BDI-II worsening or confirmed harm?", "needed": "SF12 mental-health AUC −1.97/CI/P, favoring placebo, and nominal secondary comparison", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid concealing an unfavorable result or repurposing it as a different endpoint.", "application_exception": "Do not turn nominal secondary significance into established clinical harm.", "criterion": "Preserve −1.97, CI −3.49 to −0.44, P=0.012 and the endpoint's role and multiplicity context.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed; M08 Table 8.2.a, M04 §4.6.3; internal application; M03 §3.2.4; internally defined boundaries for extending the claim; M19 §19.1.2–19.2.4; internal application", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Compare original Table 13, the plan, multiplicity and clinical meaning for that scale.", "current_reports": [ "S03", "S06", "S10" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "The difference in the time-weighted SF-12 mental-health mean was −1.97 points for folic acid minus placebo (CI −3.49 to −0.44; P=0.012), a nominal secondary comparison favoring placebo. It was not merged into BDI-II worsening or established clinical harm.", "condition_status": "Met", "status_reason": "Confirms preservation of the unfavorable result and its role; it does not certify a causal harm relationship.", "missingness": "Confirms preservation of the unfavorable result and its role; it does not certify a causal harm relationship.", "uncertainty": "Confirms preservation of the unfavorable result and its role; it does not certify a causal harm relationship.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "SF12 mental-health AUC −1.97/CI/P, favoring placebo, and nominal secondary comparison" }, { "item_id": "N29", "question_type": "Subgroups and biochemistry", "question": "Do small subgroups, response/remission or blood results replace the primary effect?", "needed": "Plans, denominators and individual results for low-folate/genotype/sex subgroups, response/remission and biochemistry", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid using favorable selected results as the overall BDI-II primary effect.", "application_exception": "Do not fill in new quantitative effects or interactions absent from the current summary.", "criterion": "Preserve the existence and roles of other results and the boundaries of the primary effect.", "basis": "M04 §4.6.1–4.6.2 distinction between studies and reports; cohort/outcome linkage is an internal application; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed; M08 Table 8.2.a, M04 §4.6.3; internal application; M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed; M03 §3.2.4; internally defined boundaries for extending the claim", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Separately compare prospective subgroup/interaction plans, denominators, multiplicity and original results.", "current_reports": [ "S03", "S10" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "Small low-folate, genotype and sex subgroups, response, remission and biochemical results were reported, but they do not replace the overall primary outcome. Biochemical/response analyses in the appendices belong to the same FolATED family; effects absent from the current summary were not created.", "condition_status": "Partly verified", "status_reason": "The roles of other analyses are available, but verification of complete plans, quantitative results and denominators is limited.", "missingness": "The roles of other analyses are available, but verification of complete plans, quantitative results and denominators is limited.", "uncertainty": "The roles of other analyses are available, but verification of complete plans, quantitative results and denominators is limited.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Plans, denominators and individual results for low-folate/genotype/sex subgroups, response/remission and biochemistry" }, { "item_id": "N30", "question_type": "Funding and conflicts of interest", "question": "Does public funding mean there are no competing interests?", "needed": "NIHR HTA04/35/08, COBALZ advisory/shareholder roles, Bilcare supply and funding for adjacent studies", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid extending public funding into a guarantee of no conflicts or bias.", "application_exception": "Do not automatically exclude results because a competing interest exists.", "criterion": "Preserve verified public funding together with disclosed author and supplier relationships.", "basis": "Chamgap's own criteria for independence and attribution. The official methods sections used in this pilot do not endorse all of these detailed items", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Compare the original funding/COI/supply information and the scope of adjacent-study disclosures.", "current_reports": [ "S01", "S02", "S13", "S15", "S18" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "Funding for the decisive FolATED trial was NIHR HTA04/35/08; Andrew McCaddon's scientific-advisor/shareholder relationship with COBALZ Ltd and Bilcare supply are also preserved. Public funding does not mean absence of conflicts. Coppen funding was unverified in the accessed abstract.", "condition_status": "Partly verified", "status_reason": "Public funding and disclosed relationships are available, but not all competing interests or funding for adjacent studies have been fully verified.", "missingness": "Public funding and disclosed relationships are available, but not all competing interests or funding for adjacent studies have been fully verified.", "uncertainty": "Public funding and disclosed relationships are available, but not all competing interests or funding for adjacent studies have been fully verified.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "NIHR HTA04/35/08, COBALZ advisory/shareholder roles, Bilcare supply and funding for adjacent studies" }, { "item_id": "N31", "question_type": "Adverse events and counts", "question": "Are 33/45 and 6/14 counts of events or people?", "needed": "25-week AE 33/45, SAE 6/14, possible drug reactions 4/3, and unique-person denominators/collection", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid turning event counts into unique patient counts, incidence or NNH.", "application_exception": "Do not calculate new harm rates, comparative risks or NNH.", "criterion": "Distinguish reported event counts and observation duration from unverified person denominators.", "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed differentiation is internally designed; M19 §19.2 questions about harms by study design; details of temporal relationships are internally designed; M19 §19.2.2–19.2.4, M03 §3.2.3; internal application; M19 §19.2.2–19.2.4 considerations for study design; detailed recording of confounding is internally designed; M19 §19.1.2–19.2.4, M04 §4.6.3; internal application; Chamgap's own interpretive boundaries. M19 principles are referenced; no official causality assessment tool was applied", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Compare event definitions and collection, exposure, unique people and missingness in original Tables 15–17.", "current_reports": [ "S03" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "Over 25 weeks, AE counts were 33 for folic acid and 45 for placebo; SAE counts were 6 and 14; possible drug reactions were 4 and 3. These are event counts and were not assumed to equal unique patient counts. Incidence, NNH and new risk differences were not generated.", "condition_status": "Partly verified", "status_reason": "Reported event counts are available, but verification of unique-person denominators, complete collection, causality and comparative risk remains incomplete.", "missingness": "Reported event counts are available, but verification of unique-person denominators, complete collection, causality and comparative risk remains incomplete.", "uncertainty": "Reported event counts are available, but verification of unique-person denominators, complete collection, causality and comparative risk remains incomplete.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "25-week AE 33/45, SAE 6/14, possible drug reactions 4/3, and unique-person denominators/collection" }, { "item_id": "N32", "question_type": "0 events within a reaction category", "question": "Are 0 serious/unexpected reactions being read as 0 events overall?", "needed": "Scope of 0 serious or unexpected reactions among the 4/3 possible drug reactions", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid extending 0 in one subcategory to all AE/SAE or to long-term absence of risk.", "application_exception": "Do not turn failure to verify a significant difference into equivalence or an assurance of safety.", "criterion": "State both the category to which 0 refers and the overall event counts.", "basis": "M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed differentiation is internally designed; Chamgap's own interpretive boundaries. M19 principles are referenced; no official causality assessment tool was applied", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Compare original reaction classifications, seriousness/expectedness and collection scope.", "current_reports": [ "S03" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "Among the 4 and 3 possible drug reactions, 0 were serious or unexpected. This does not mean that all AE/SAE counts were 0, and it does not establish long-term absence of risk or equivalence.", "condition_status": "Met", "status_reason": "Confirms preservation of the scope of 0 events; it does not verify absence of all harms.", "missingness": "Confirms preservation of the scope of 0 events; it does not verify absence of all harms.", "uncertainty": "Confirms preservation of the scope of 0 events; it does not verify absence of all harms.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Scope of 0 serious or unexpected reactions among the 4/3 possible drug reactions" }, { "item_id": "N33", "question_type": "MINI risk classification", "question": "Do 25/223 and 28/217 represent suicide attempts or deaths?", "needed": "25-week MINI high-risk category, imputed analysis with 223/217, and actual suicidal-behavior/death events", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid turning a scale classification into counts of actual behavior or deaths.", "application_exception": "Do not fill unverified behavior or death counts with 0.", "criterion": "Separate risk-category counts of 25/223 and 28/217 from unverified separately counted events.", "basis": "M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M08 Table 8.2.a, M15 §15.3, M19 §19.1.2–19.2.4; adaptations for each study design are internally designed; M03 §3.2.4; internally defined boundaries for extending the claim; M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed differentiation is internally designed; M19 §19.1.2–19.2.4, M04 §4.6.3; internal application; Chamgap's own interpretive boundaries. M19 principles are referenced; no official causality assessment tool was applied", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Compare original MINI definitions, imputation, collection and actual event records with their respective denominators.", "current_reports": [ "S03" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "In the 25-week imputed MINI analysis, the high-risk category included 25/223 participants receiving folic acid and 28/217 receiving placebo. These are not counts of actual suicide attempts or deaths by suicide. Separately counted arm-specific behavioral and death events remain unverified.", "condition_status": "Partly verified", "status_reason": "Risk classification is preserved, but event data for comparisons of actual behavior and deaths remain unverified.", "missingness": "Risk classification is preserved, but event data for comparisons of actual behavior and deaths remain unverified.", "uncertainty": "Risk classification is preserved, but event data for comparisons of actual behavior and deaths remain unverified.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "25-week MINI high-risk category, imputed analysis with 223/217, and actual suicidal-behavior/death events" }, { "item_id": "N34", "question_type": "Official safety materials", "question": "What is the scope of documents on B12 masking and interactions?", "needed": "Masking of hematological signs of B12 deficiency, neurological problems, antiepileptics/methotrexate, and partial NIH material/SmPC", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid using general context from official documents as FolATED incidence or independent events.", "application_exception": "Citing an official document again does not constitute a new independent event or evidence of authorization for depression.", "criterion": "Record general safety context, the scope of material access, and boundaries between other products and trial data.", "basis": "M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed; M19 §19.1.2–19.2.4; internal application; M19 §19.1.2–19.2.4; detailed differentiation is internally designed; M19 §19.2 questions about harms by study design; details of temporal relationships are internally designed; M19 §19.2.2–19.2.4 considerations for study design; detailed recording of confounding is internally designed; M04 §4.6.1–4.6.2; adaptations for harms data are internally designed; Chamgap's own interpretive boundaries. M19 principles are referenced; no official causality assessment tool was applied", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Separately compare original safety documents, case/study families, exposure, timing and alternative explanations.", "current_reports": [ "S05", "S11" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "The original safety explanation that folic acid can improve hematological signs of B12 deficiency while delaying recognition of neurological problems, and the antiepileptic/methotrexate context, are preserved. For NIH, access failed after partial search extracts; the Flamingo SmPC entry records historical access to an official label. These do not establish FolATED incidence, product identity or a depression indication.", "condition_status": "Partly verified", "status_reason": "Safety context is available, but confirmation of the same events, causality and frequency in the direct trial, and current verification of original full texts, are separate matters.", "missingness": "Safety context is available, but confirmation of the same events, causality and frequency in the direct trial, and current verification of original full texts, are separate matters.", "uncertainty": "Safety context is available, but confirmation of the same events, causality and frequency in the direct trial, and current verification of original full texts, are separate matters.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Masking of hematological signs of B12 deficiency, neurological problems, antiepileptics/methotrexate, and partial NIH material/SmPC" }, { "item_id": "N35", "question_type": "Long-term use and vulnerable populations", "question": "Does 25-week observation answer every long-term or special-population safety question?", "needed": "Direct exposure and events for high-dose/long-term use, pregnancy/lactation/children, hepatic/renal disease and cancer history", "role": "Required for extended harm questions", "role_reason": "Needed to avoid expanding narrow observation into assurances for all vulnerable populations or rare harms.", "application_exception": "Do not impose studies in all special populations as requirements for this narrow efficacy question.", "criterion": "Distinguish trial scope from each unverified extended harm question.", "basis": "M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed; M19 §19.1.2–19.2.4; internal application; Chamgap's own interpretive boundaries. M19 principles are referenced; no official causality assessment tool was applied", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "Separately design or review material suited to the relevant exposure, population and long-term/rare events.", "current_reports": [ "S02", "S05", "S11" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "The scope of verification for long-term and high-dose use, pregnancy, lactation, children, severe hepatic/renal disease and cancer history is separate. 12 weeks of treatment, 25 weeks of observation and official safety materials alone were not described as verifying all special populations or rare harms.", "condition_status": "Unverified", "status_reason": "Extended harm information remains unverified within the selected materials.", "missingness": "Extended harm information remains unverified within the selected materials.", "uncertainty": "Extended harm information remains unverified within the selected materials.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Direct exposure and events for high-dose/long-term use, pregnancy/lactation/children, hepatic/renal disease and cancer history" }, { "item_id": "N36", "question_type": "Reading and dates", "question": "Is reading summaries distinguished from past reading of external sources?", "needed": "Exact locations/values/SHA of current stored summaries, access levels of 19 bibliographic entries, report-specific access dates and evidence cutoff date", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid upgrading a summary link to current full-text verification or using the review date as an access date.", "application_exception": "Do not label external access not attempted as access failure.", "criterion": "Link the local summaries actually read in this review separately from past access levels and unread external sources.", "basis": "M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed; M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "When original materials are actually obtained, separately preserve material types, dates, locations read and original bytes.", "current_reports": [ "S01", "S05", "S09", "S13", "S14", "S15" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "The relevant locations and values in the current stored summaries were actually read in this review. The 19 bibliographic entries' full_text, abstract, metadata, partial-access/failure and uncorrected-author-proof levels are historical records. Actual report-specific access-date fields are absent and therefore blank; 2026-09-15 is kept separately as the evidence cutoff. Current external full texts have not been read.", "condition_status": "Partly verified", "status_reason": "The current summaries are verified, but current reading of external full texts, their original bytes and report-specific access dates remain unverified.", "missingness": "The current summaries are verified, but current reading of external full texts, their original bytes and report-specific access dates remain unverified.", "uncertainty": "The current summaries are verified, but current reading of external full texts, their original bytes and report-specific access dates remain unverified.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Exact locations/values/SHA of current stored summaries, access levels of 19 bibliographic entries, report-specific access dates and evidence cutoff date" }, { "item_id": "N37", "question_type": "Searches, registration and corrections", "question": "Does the prior search scope represent a current exhaustive search or retraction check?", "needed": "2026-09-15 search scope, partial/failed registration access, protocol correction, and the scope of checking retractions/new evidence", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid turning 0 new searches in this review into 0 studies, proof of absence, or a claim that no recent corrections exist.", "application_exception": "Do not merge a protocol erratum and a correction to original results into the same event.", "criterion": "Link existing search/correction records to the scope of work currently not performed and information remaining unverified.", "basis": "M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed; M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design; M08 Table 8.2.a, M04 §4.6.3; internal application", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "During a separately authorized search or correction, preserve complete original texts, events, before-and-after values and versions.", "current_reports": [ "S04", "S09", "S18" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "The evidence scope is ChatGPT_search_through_2026-09-15 and absence_proven=false. The ISRCTN identifier was cross-checked against the report and protocol, but access to the complete registration history failed. The 2009 protocol erratum is preserved; new clinical searches and external retraction/correction checks in this review total 0.", "condition_status": "Partly verified", "status_reason": "Historical searches, partial registration information and a protocol correction are available, but there is no current exhaustive search or verification that no recent retractions exist.", "missingness": "Historical searches, partial registration information and a protocol correction are available, but there is no current exhaustive search or verification that no recent retractions exist.", "uncertainty": "Historical searches, partial registration information and a protocol correction are available, but there is no current exhaustive search or verification that no recent retractions exist.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "2026-09-15 search scope, partial/failed registration access, protocol correction, and the scope of checking retractions/new evidence" }, { "item_id": "N38", "question_type": "Original grade and certification", "question": "Are D30 and B/P/R1/I2/E0/B1/C0 being presented as a new verdict?", "needed": "Original grade/score/axes, 1 strength, document quality A, self-review and clinical certification=false", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid turning table-criterion counts, colors or structural checks into a new efficacy score or clinical certification.", "application_exception": "External content QA is inspection of the current table conversion; it is not retroactively treated as independent review of the original clinical assessment.", "criterion": "Preserve the original D30/Caution, 7 axes, meaning of E0, document quality and review level unchanged.", "basis": "M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed; M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design; Chamgap's own criteria for independence and attribution. The official methods sections used in this pilot do not endorse all of these detailed items; M15 §15.3.1–15.3.3; internal application", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "If a correction is separately authorized, record the original evidence, verdict, reasons and before-and-after values as an event.", "current_reports": [ "S01", "S02", "S06" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "The original D/30 points/Caution and B/P/R1/I2/E0/B1/C0 are preserved. This is the original fixed anchor with I2 as 1 strength; no new score was calculated. E0 denotes a narrow failure to demonstrate benefit and was not changed to F/RX. Document quality A and single-assistant self-review are not independent clinical or journal certification.", "condition_status": "Met", "status_reason": "Confirms preservation of original values and review boundaries; no new clinical grade or certification was assigned.", "missingness": "Confirms preservation of original values and review boundaries; no new clinical grade or certification was assigned.", "uncertainty": "Confirms preservation of original values and review boundaries; no new clinical grade or certification was assigned.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Original grade/score/axes, 1 strength, document quality A, self-review and clinical certification=false" }, { "item_id": "N39", "question_type": "Boundaries for extending efficacy claims", "question": "Are optimal dose, biomarkers, remission and mortality combined into the same answer?", "needed": "The selected AUC question and direct questions about other doses/durations, L-methylfolate, B-vitamin combinations and clinical events", "role": "Required for extended efficacy questions", "role_reason": "Needed to avoid requiring all extension studies for the selected numerical outcome or extrapolating automatically.", "application_exception": "Do not use inapplicability of an extension as a substitute for actual unverified product, plan or MCID information.", "criterion": "Keep efficacy questions outside the selected question within separate boundaries.", "basis": "M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed; M03 §3.2.4, M15 §15.3.1–15.3.3; outcome adaptations for each question are internally designed; M03 §3.2.1–3.2.4; details on dose, duration and effect modification are internally designed; M03 §3.2.4; internally defined boundaries for extending the claim", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "If an extension is asked about, separately compare direct dose, follow-up and event data.", "current_reports": [ "S02", "S10", "S13", "S15" ], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "Optimal dose, other folate chemical forms/B-vitamin combinations, blood-level increases, mortality and all clinical events were not automatically combined into the answer to the selected 5 mg/12-week BDI-II AUC question. Material suited to each extension is needed.", "condition_status": "Not applicable", "status_reason": "Indicates that an extension outside the selected question is not applicable; it does not erase unverified information about the actual trial.", "missingness": "Indicates that an extension outside the selected question is not applicable; it does not erase unverified information about the actual trial.", "uncertainty": "Indicates that an extension outside the selected question is not applicable; it does not erase unverified information about the actual trial.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "The selected AUC question and direct questions about other doses/durations, L-methylfolate, B-vitamin combinations and clinical events" }, { "item_id": "N40", "question_type": "ID, publication and updates", "question": "Do historical deployment flags mean that this table has now been publicly published?", "needed": "Original 3109/assigned code/URL, server_deployed true/write false, dates, update policy and before-and-after original text", "role": "Required for the selected FolATED BDI-II comparison", "role_reason": "Needed to avoid presenting historical identity/deployment wording as completed public publication of the current local sheet.", "application_exception": "Do not arbitrarily correct differences in original metadata wording or extend deployment authorization.", "criterion": "Preserve original identity and wording, and distinguish local unpublished status and versions of criteria, observations and events.", "basis": "M03 §3.1, §3.2.1–3.2.4 principles for clarifying the question; detailed separation rules are internally designed; M04 §4.5–4.6 principles for collecting/selecting material; the separation of access from reading and the hyperlink contract are internally designed; M04 §4.6.3, M15 §15.3.1–15.3.3; the separation of statuses is internally designed; M04 §4.5, §4.6.3; limits on the present conversion of material reflect the user-defined scope and internal design", "condition_origin": "Known development criteria designed after actually reading the current 3109 source materials; not blinded, clinically preregistered or independently clinically certified", "proposed_research": "During an authorized update, retain complete originals, original values/contrary results, reasons for changes and versions.", "current_reports": [], "existence": "Current stored bibliographic, structural-evidence and historical records exist; this does not verify current external availability or corrections", "acquired_read": "The exact locations and values in the preserved stored summaries were actually read; external sources and older separate original documents were not read in this review", "observation": "Original ID3109, assigned code, original URL, server_deployed=true, server_write_performed=false and deployed_at 2026-09-16 are all preserved, along with the Korean statement that actual server implementation was not performed. This table is prepared locally, with 0 public deployments. Updates for new evidence, full texts, corrections or errors accumulate a history at the same ID/URL.", "condition_status": "Partly verified", "status_reason": "Original metadata and update provisions are preserved, but authoritative correction of publication wording and actual site implementation were not performed in this review.", "missingness": "Original metadata and update provisions are preserved, but authoritative correction of publication wording and actual site implementation were not performed in this review.", "uncertainty": "Original metadata and update provisions are preserved, but authoritative correction of publication wording and actual site implementation were not performed in this review.", "review_date": "2026-10-05", "reading_status": "Original source not read · Stored summary read", "additional_material": "Original 3109/assigned code/URL, server_deployed true/write false, dates, update policy and before-and-after original text" } ], "reports": [ { "report_id": "S01", "title": "FolATED: randomized trial and economic evaluation, HTA 18(48), 2014", "url": "https://www.ncbi.nlm.nih.gov/books/NBK262306/", "report_type": "Direct trial report", "existence": "Stored bibliography/historical access records; 0 current external lookups in this review", "acquired_read": "Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review", "study_family": "FOLATED", "independent_replication": "19 bibliographic records ≠ 19 trials; the 11 FolATED reports belong to one family, with other families, reviews and labels assigned distinct roles; no new trials or participants were summed", "observed_result": "Report of the primary trial, public funding and COI; one family", "result_level": "Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts", "materials": [ { "material_type": "Preserved stored-summary bibliographic information, linked summaries and historical access", "public_status": "Preserved locally", "access_status": "Acquired", "acquired": true, "actually_read": "Summary read", "as_of": "2026-10-05", "qualification": "Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text", "material_id": "S01-M1", "url": null, "parent_url": "https://www.ncbi.nlm.nih.gov/books/NBK262306/" }, { "material_type": "Full text of the published report", "public_status": "Unverified (0 external lookups in this review)", "access_status": "Access not attempted", "acquired": false, "actually_read": "Not read", "as_of": "2026-10-05", "qualification": "Distinguish historical access levels from access not attempted and sources not read in this review; the existence of a link does not mean the original source was verified in this review", "material_id": "S01-M2", "url": "https://www.ncbi.nlm.nih.gov/books/NBK262306/", "parent_url": "https://www.ncbi.nlm.nih.gov/books/NBK262306/" } ], "links": [ { "label": "Source", "url": "https://www.ncbi.nlm.nih.gov/books/NBK262306/" } ] }, { "report_id": "S02", "title": "FolATED Chapter 2: Methods", "url": "https://www.ncbi.nlm.nih.gov/books/NBK262311/", "report_type": "Methods from the same trial", "existence": "Stored bibliography/historical access records; 0 current external lookups in this review", "acquired_read": "Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review", "study_family": "FOLATED", "independent_replication": "19 bibliographic records ≠ 19 trials; the 11 FolATED reports belong to one family, with other families, reviews and labels assigned distinct roles; no new trials or participants were summed", "observed_result": "Medication, eligibility and analysis policies; manufacturing and lactation unverified", "result_level": "Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts", "materials": [ { "material_type": "Preserved stored-summary bibliographic information, linked summaries and historical access", "public_status": "Preserved locally", "access_status": "Acquired", "acquired": true, "actually_read": "Summary read", "as_of": "2026-10-05", "qualification": "Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text", "material_id": "S02-M1", "url": null, "parent_url": "https://www.ncbi.nlm.nih.gov/books/NBK262311/" }, { "material_type": "Full text of the report's Methods", "public_status": "Unverified (0 external lookups in this review)", "access_status": "Access not attempted", "acquired": false, "actually_read": "Not read", "as_of": "2026-10-05", "qualification": "Distinguish historical access levels from access not attempted and sources not read in this review; the existence of a link does not mean the original source was verified in this review", "material_id": "S02-M2", "url": "https://www.ncbi.nlm.nih.gov/books/NBK262311/", "parent_url": "https://www.ncbi.nlm.nih.gov/books/NBK262311/" } ], "links": [ { "label": "Source", "url": "https://www.ncbi.nlm.nih.gov/books/NBK262311/" } ] }, { "report_id": "S03", "title": "FolATED Chapter 3: Results", "url": "https://www.ncbi.nlm.nih.gov/books/NBK262313/", "report_type": "Results from the same trial", "existence": "Stored bibliography/historical access records; 0 current external lookups in this review", "acquired_read": "Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review", "study_family": "FOLATED", "independent_replication": "19 bibliographic records ≠ 19 trials; the 11 FolATED reports belong to one family, with other families, reviews and labels assigned distinct roles; no new trials or participants were summed", "observed_result": "Denominators, effects, numerical conflicts, harms and sensitivity analyses", "result_level": "Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts", "materials": [ { "material_type": "Preserved stored-summary bibliographic information, linked summaries and historical access", "public_status": "Preserved locally", "access_status": "Acquired", "acquired": true, "actually_read": "Summary read", "as_of": "2026-10-05", "qualification": "Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text", "material_id": "S03-M1", "url": null, "parent_url": "https://www.ncbi.nlm.nih.gov/books/NBK262313/" }, { "material_type": "Full text of the report's Results", "public_status": "Unverified (0 external lookups in this review)", "access_status": "Access not attempted", "acquired": false, "actually_read": "Not read", "as_of": "2026-10-05", "qualification": "Distinguish historical access levels from access not attempted and sources not read in this review; the existence of a link does not mean the original source was verified in this review", "material_id": "S03-M2", "url": "https://www.ncbi.nlm.nih.gov/books/NBK262313/", "parent_url": "https://www.ncbi.nlm.nih.gov/books/NBK262313/" } ], "links": [ { "label": "Source", "url": "https://www.ncbi.nlm.nih.gov/books/NBK262313/" } ] }, { "report_id": "S04", "title": "Roberts et al. 2007 FolATED protocol", "url": "https://link.springer.com/article/10.1186/1471-244X-7-65", "report_type": "Protocol of the same trial", "existence": "Stored bibliography/historical access records; 0 current external lookups in this review", "acquired_read": "Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review", "study_family": "FOLATED", "independent_replication": "19 bibliographic records ≠ 19 trials; the 11 FolATED reports belong to one family, with other families, reviews and labels assigned distinct roles; no new trials or participants were summed", "observed_result": "Initial plan for a single time point at 25 weeks; distinguished from the final AUC", "result_level": "Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts", "materials": [ { "material_type": "Preserved stored-summary bibliographic information, linked summaries and historical access", "public_status": "Preserved locally", "access_status": "Acquired", "acquired": true, "actually_read": "Summary read", "as_of": "2026-10-05", "qualification": "Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text", "material_id": "S04-M1", "url": null, "parent_url": "https://link.springer.com/article/10.1186/1471-244X-7-65" }, { "material_type": "Full protocol text", "public_status": "Unverified (0 external lookups in this review)", "access_status": "Access not attempted", "acquired": false, "actually_read": "Not read", "as_of": "2026-10-05", "qualification": "Distinguish historical access levels from access not attempted and sources not read in this review; the existence of a link does not mean the original source was verified in this review", "material_id": "S04-M2", "url": "https://link.springer.com/article/10.1186/1471-244X-7-65", "parent_url": "https://link.springer.com/article/10.1186/1471-244X-7-65" } ], "links": [ { "label": "Source", "url": "https://link.springer.com/article/10.1186/1471-244X-7-65" } ] }, { "report_id": "S05", "title": "NIH ODS Folate health-professional fact sheet", "url": "https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/", "report_type": "Partially accessed safety material", "existence": "Stored bibliography/historical access records; 0 current external lookups in this review", "acquired_read": "Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review", "study_family": "Official safety commentary", "independent_replication": "19 bibliographic records ≠ 19 trials; the 11 FolATED reports belong to one family, with other families, reviews and labels assigned distinct roles; no new trials or participants were summed", "observed_result": "Access failed after partial search extracts; not a direct trial or incidence estimate", "result_level": "Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts", "materials": [ { "material_type": "Preserved stored-summary bibliographic information, linked summaries and historical access", "public_status": "Preserved locally", "access_status": "Acquired", "acquired": true, "actually_read": "Summary read", "as_of": "2026-10-05", "qualification": "Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text", "material_id": "S05-M1", "url": null, "parent_url": "https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/" }, { "material_type": "Official NIH ODS web document", "public_status": "Unverified (0 external lookups in this review)", "access_status": "Access not attempted", "acquired": false, "actually_read": "Not read", "as_of": "2026-10-05", "qualification": "Distinguish historical access levels from access not attempted and sources not read in this review; the existence of a link does not mean the original source was verified in this review", "material_id": "S05-M2", "url": "https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/", "parent_url": "https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/" } ], "links": [ { "label": "Source", "url": "https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/" } ] }, { "report_id": "S06", "title": "FolATED Table 13: adjusted primary AUC-average estimates", "url": "https://www.ncbi.nlm.nih.gov/books/NBK262313/table/table13/?report=objectonly", "report_type": "Table 13 from the same trial", "existence": "Stored bibliography/historical access records; 0 current external lookups in this review", "acquired_read": "Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review", "study_family": "FOLATED", "independent_replication": "19 bibliographic records ≠ 19 trials; the 11 FolATED reports belong to one family, with other families, reviews and labels assigned distinct roles; no new trials or participants were summed", "observed_result": "Primary effect +1.09/CI/P, SE conflict and secondary SF12", "result_level": "Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts", "materials": [ { "material_type": "Preserved stored-summary bibliographic information, linked summaries and historical access", "public_status": "Preserved locally", "access_status": "Acquired", "acquired": true, "actually_read": "Summary read", "as_of": "2026-10-05", "qualification": "Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text", "material_id": "S06-M1", "url": null, "parent_url": "https://www.ncbi.nlm.nih.gov/books/NBK262313/table/table13/?report=objectonly" }, { "material_type": "Original report table", "public_status": "Unverified (0 external lookups in this review)", "access_status": "Access not attempted", "acquired": false, "actually_read": "Not read", "as_of": "2026-10-05", "qualification": "Distinguish historical access levels from access not attempted and sources not read in this review; the existence of a link does not mean the original source was verified in this review", "material_id": "S06-M2", "url": "https://www.ncbi.nlm.nih.gov/books/NBK262313/table/table13/?report=objectonly", "parent_url": "https://www.ncbi.nlm.nih.gov/books/NBK262313/table/table13/?report=objectonly" } ], "links": [ { "label": "Source", "url": "https://www.ncbi.nlm.nih.gov/books/NBK262313/table/table13/?report=objectonly" } ] }, { "report_id": "S07", "title": "FolATED Appendix 5: final analysis plan", "url": "https://www.ncbi.nlm.nih.gov/books/NBK262296/", "report_type": "Final SAP of the same trial", "existence": "Stored bibliography/historical access records; 0 current external lookups in this review", "acquired_read": "Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review", "study_family": "FOLATED", "independent_replication": "19 bibliographic records ≠ 19 trials; the 11 FolATED reports belong to one family, with other families, reviews and labels assigned distinct roles; no new trials or participants were summed", "observed_result": "AUC, mITT/missing-data definitions and the source location for the record of the unblinding meeting; approval date unverified", "result_level": "Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts", "materials": [ { "material_type": "Preserved stored-summary bibliographic information, linked summaries and historical access", "public_status": "Preserved locally", "access_status": "Acquired", "acquired": true, "actually_read": "Summary read", "as_of": "2026-10-05", "qualification": "Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text", "material_id": "S07-M1", "url": null, "parent_url": "https://www.ncbi.nlm.nih.gov/books/NBK262296/" }, { "material_type": "Full analysis plan text", "public_status": "Unverified (0 external lookups in this review)", "access_status": "Access not attempted", "acquired": false, "actually_read": "Not read", "as_of": "2026-10-05", "qualification": "Distinguish historical access levels from access not attempted and sources not read in this review; the existence of a link does not mean the original source was verified in this review", "material_id": "S07-M2", "url": "https://www.ncbi.nlm.nih.gov/books/NBK262296/", "parent_url": "https://www.ncbi.nlm.nih.gov/books/NBK262296/" } ], "links": [ { "label": "Source", "url": "https://www.ncbi.nlm.nih.gov/books/NBK262296/" } ] }, { "report_id": "S08", "title": "FolATED protocol amendment history", "url": "https://www.ncbi.nlm.nih.gov/books/NBK262312/", "report_type": "Amendment history of the same trial", "existence": "Stored bibliography/historical access records; 0 current external lookups in this review", "acquired_read": "Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review", "study_family": "FOLATED", "independent_replication": "19 bibliographic records ≠ 19 trials; the 11 FolATED reports belong to one family, with other families, reviews and labels assigned distinct roles; no new trials or participants were summed", "observed_result": "Protocol amendment chronology; not a substitute for the complete registration history", "result_level": "Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts", "materials": [ { "material_type": "Preserved stored-summary bibliographic information, linked summaries and historical access", "public_status": "Preserved locally", "access_status": "Acquired", "acquired": true, "actually_read": "Summary read", "as_of": "2026-10-05", "qualification": "Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text", "material_id": "S08-M1", "url": null, "parent_url": "https://www.ncbi.nlm.nih.gov/books/NBK262312/" }, { "material_type": "Full report appendix text", "public_status": "Unverified (0 external lookups in this review)", "access_status": "Access not attempted", "acquired": false, "actually_read": "Not read", "as_of": "2026-10-05", "qualification": "Distinguish historical access levels from access not attempted and sources not read in this review; the existence of a link does not mean the original source was verified in this review", "material_id": "S08-M2", "url": "https://www.ncbi.nlm.nih.gov/books/NBK262312/", "parent_url": "https://www.ncbi.nlm.nih.gov/books/NBK262312/" } ], "links": [ { "label": "Source", "url": "https://www.ncbi.nlm.nih.gov/books/NBK262312/" } ] }, { "report_id": "S09", "title": "ISRCTN37558856 FolATED registration", "url": "https://www.isrctn.com/ISRCTN37558856", "report_type": "Candidate registration record for the same trial", "existence": "Stored bibliography/historical access records; 0 current external lookups in this review", "acquired_read": "Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review", "study_family": "FOLATED", "independent_replication": "19 bibliographic records ≠ 19 trials; the 11 FolATED reports belong to one family, with other families, reviews and labels assigned distinct roles; no new trials or participants were summed", "observed_result": "Identifier cross-check and access failure after metadata; complete versions unverified", "result_level": "Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts", "materials": [ { "material_type": "Preserved stored-summary bibliographic information, linked summaries and historical access", "public_status": "Preserved locally", "access_status": "Acquired", "acquired": true, "actually_read": "Summary read", "as_of": "2026-10-05", "qualification": "Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text", "material_id": "S09-M1", "url": null, "parent_url": "https://www.isrctn.com/ISRCTN37558856" }, { "material_type": "ISRCTN metadata", "public_status": "Unverified (0 external lookups in this review)", "access_status": "Access not attempted", "acquired": false, "actually_read": "Not read", "as_of": "2026-10-05", "qualification": "Distinguish historical access levels from access not attempted and sources not read in this review; the existence of a link does not mean the original source was verified in this review", "material_id": "S09-M2", "url": "https://www.isrctn.com/ISRCTN37558856", "parent_url": "https://www.isrctn.com/ISRCTN37558856" } ], "links": [ { "label": "Source", "url": "https://www.isrctn.com/ISRCTN37558856" } ] }, { "report_id": "S10", "title": "FolATED Appendix 10: detailed clinical results", "url": "https://www.ncbi.nlm.nih.gov/books/NBK262303/", "report_type": "Detailed appendix from the same trial", "existence": "Stored bibliography/historical access records; 0 current external lookups in this review", "acquired_read": "Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review", "study_family": "FOLATED", "independent_replication": "19 bibliographic records ≠ 19 trials; the 11 FolATED reports belong to one family, with other families, reviews and labels assigned distinct roles; no new trials or participants were summed", "observed_result": "25-week means/SDs, response/remission/biochemistry; not a new trial", "result_level": "Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts", "materials": [ { "material_type": "Preserved stored-summary bibliographic information, linked summaries and historical access", "public_status": "Preserved locally", "access_status": "Acquired", "acquired": true, "actually_read": "Summary read", "as_of": "2026-10-05", "qualification": "Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text", "material_id": "S10-M1", "url": null, "parent_url": "https://www.ncbi.nlm.nih.gov/books/NBK262303/" }, { "material_type": "Full text of the detailed results appendix", "public_status": "Unverified (0 external lookups in this review)", "access_status": "Access not attempted", "acquired": false, "actually_read": "Not read", "as_of": "2026-10-05", "qualification": "Distinguish historical access levels from access not attempted and sources not read in this review; the existence of a link does not mean the original source was verified in this review", "material_id": "S10-M2", "url": "https://www.ncbi.nlm.nih.gov/books/NBK262303/", "parent_url": "https://www.ncbi.nlm.nih.gov/books/NBK262303/" } ], "links": [ { "label": "Source", "url": "https://www.ncbi.nlm.nih.gov/books/NBK262303/" } ] }, { "report_id": "S11", "title": "Flamingo Pharma folic acid 5 mg tablet SmPC, text revised 20 May 2026", "url": "https://www.medicines.org.uk/emc/product/14604/smpc", "report_type": "Official SmPC for a different product", "existence": "Stored bibliography/historical access records; 0 current external lookups in this review", "acquired_read": "Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review", "study_family": "Official product label", "independent_replication": "19 bibliographic records ≠ 19 trials; the 11 FolATED reports belong to one family, with other families, reviews and labels assigned distinct roles; no new trials or participants were summed", "observed_result": "Flamingo 5 mg label, revised 2026-05-20; not the FolATED product or authorization for MDD", "result_level": "Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts", "materials": [ { "material_type": "Preserved stored-summary bibliographic information, linked summaries and historical access", "public_status": "Preserved locally", "access_status": "Acquired", "acquired": true, "actually_read": "Summary read", "as_of": "2026-10-05", "qualification": "Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text", "material_id": "S11-M1", "url": null, "parent_url": "https://www.medicines.org.uk/emc/product/14604/smpc" }, { "material_type": "Official manufacturer label", "public_status": "Unverified (0 external lookups in this review)", "access_status": "Access not attempted", "acquired": false, "actually_read": "Not read", "as_of": "2026-10-05", "qualification": "Distinguish historical access levels from access not attempted and sources not read in this review; the existence of a link does not mean the original source was verified in this review", "material_id": "S11-M2", "url": "https://www.medicines.org.uk/emc/product/14604/smpc", "parent_url": "https://www.medicines.org.uk/emc/product/14604/smpc" } ], "links": [ { "label": "Source", "url": "https://www.medicines.org.uk/emc/product/14604/smpc" } ] }, { "report_id": "S12", "title": "FolATED Table 14: adjusted individual follow-up scores", "url": "https://www.ncbi.nlm.nih.gov/books/NBK262313/table/table14/?report=objectonly", "report_type": "Table 14 from the same trial", "existence": "Stored bibliography/historical access records; 0 current external lookups in this review", "acquired_read": "Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review", "study_family": "FOLATED", "independent_replication": "19 bibliographic records ≠ 19 trials; the 11 FolATED reports belong to one family, with other families, reviews and labels assigned distinct roles; no new trials or participants were summed", "observed_result": "Adjusted single 25-week result +1.27; separate from the AUC", "result_level": "Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts", "materials": [ { "material_type": "Preserved stored-summary bibliographic information, linked summaries and historical access", "public_status": "Preserved locally", "access_status": "Acquired", "acquired": true, "actually_read": "Summary read", "as_of": "2026-10-05", "qualification": "Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text", "material_id": "S12-M1", "url": null, "parent_url": "https://www.ncbi.nlm.nih.gov/books/NBK262313/table/table14/?report=objectonly" }, { "material_type": "Original report table", "public_status": "Unverified (0 external lookups in this review)", "access_status": "Access not attempted", "acquired": false, "actually_read": "Not read", "as_of": "2026-10-05", "qualification": "Distinguish historical access levels from access not attempted and sources not read in this review; the existence of a link does not mean the original source was verified in this review", "material_id": "S12-M2", "url": "https://www.ncbi.nlm.nih.gov/books/NBK262313/table/table14/?report=objectonly", "parent_url": "https://www.ncbi.nlm.nih.gov/books/NBK262313/table/table14/?report=objectonly" } ], "links": [ { "label": "Source", "url": "https://www.ncbi.nlm.nih.gov/books/NBK262313/table/table14/?report=objectonly" } ] }, { "report_id": "S13", "title": "Coppen and Bailey 2000: folic acid added to fluoxetine", "url": "https://pubmed.ncbi.nlm.nih.gov/10967371/", "report_type": "Original study providing positive adjacent evidence", "existence": "Stored bibliography/historical access records; 0 current external lookups in this review", "acquired_read": "Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review", "study_family": "COPPEN2000", "independent_replication": "19 bibliographic records ≠ 19 trials; the 11 FolATED reports belong to one family, with other families, reviews and labels assigned distinct roles; no new trials or participants were summed", "observed_result": "Positive female-subgroup HDRS17 result with 500 µg over 10 weeks; female denominator/interaction unverified", "result_level": "Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts", "materials": [ { "material_type": "Preserved stored-summary bibliographic information, linked summaries and historical access", "public_status": "Preserved locally", "access_status": "Acquired", "acquired": true, "actually_read": "Summary read", "as_of": "2026-10-05", "qualification": "Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text", "material_id": "S13-M1", "url": null, "parent_url": "https://pubmed.ncbi.nlm.nih.gov/10967371/" }, { "material_type": "Abstract/official index", "public_status": "Unverified (0 external lookups in this review)", "access_status": "Access not attempted", "acquired": false, "actually_read": "Not read", "as_of": "2026-10-05", "qualification": "Distinguish historical access levels from access not attempted and sources not read in this review; the existence of a link does not mean the original source was verified in this review", "material_id": "S13-M2", "url": "https://pubmed.ncbi.nlm.nih.gov/10967371/", "parent_url": "https://pubmed.ncbi.nlm.nih.gov/10967371/" } ], "links": [ { "label": "Source", "url": "https://pubmed.ncbi.nlm.nih.gov/10967371/" } ] }, { "report_id": "S14", "title": "Resler et al. 2008: folic acid plus fluoxetine", "url": "https://pubmed.ncbi.nlm.nih.gov/18716414/", "report_type": "Candidate whose results were not obtained", "existence": "Stored bibliography/historical access records; 0 current external lookups in this review", "acquired_read": "Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review", "study_family": "RESLER2008", "independent_replication": "19 bibliographic records ≠ 19 trials; the 11 FolATED reports belong to one family, with other families, reviews and labels assigned distinct roles; no new trials or participants were summed", "observed_result": "Metadata/partial-access failure; denominator/effect unverified", "result_level": "Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts", "materials": [ { "material_type": "Preserved stored-summary bibliographic information, linked summaries and historical access", "public_status": "Preserved locally", "access_status": "Acquired", "acquired": true, "actually_read": "Summary read", "as_of": "2026-10-05", "qualification": "Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text", "material_id": "S14-M1", "url": null, "parent_url": "https://pubmed.ncbi.nlm.nih.gov/18716414/" }, { "material_type": "Metadata candidate", "public_status": "Unverified (0 external lookups in this review)", "access_status": "Access not attempted", "acquired": false, "actually_read": "Not read", "as_of": "2026-10-05", "qualification": "Distinguish historical access levels from access not attempted and sources not read in this review; the existence of a link does not mean the original source was verified in this review", "material_id": "S14-M2", "url": "https://pubmed.ncbi.nlm.nih.gov/18716414/", "parent_url": "https://pubmed.ncbi.nlm.nih.gov/18716414/" } ], "links": [ { "label": "Source", "url": "https://pubmed.ncbi.nlm.nih.gov/18716414/" } ] }, { "report_id": "S15", "title": "Sepehrmanesh et al.: Acid Folic Supplementation in MDD Treatment", "url": "https://www.researchgate.net/publication/306347545_Acid_Folic_Supplementation_in_Major_Depressive_Disorder_Treatment_A_Double-Blind_Randomized_Clinical_Trial", "report_type": "Author copy providing positive adjacent evidence", "existence": "Stored bibliography/historical access records; 0 current external lookups in this review", "acquired_read": "Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review", "study_family": "SEPEHRMANESH", "independent_replication": "19 bibliographic records ≠ 19 trials; the 11 FolATED reports belong to one family, with other families, reviews and labels assigned distinct roles; no new trials or participants were summed", "observed_result": "Positive BDI-II result with 2.5 mg over 8 weeks; uncorrected proof, with final version/registration unverified", "result_level": "Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts", "materials": [ { "material_type": "Preserved stored-summary bibliographic information, linked summaries and historical access", "public_status": "Preserved locally", "access_status": "Acquired", "acquired": true, "actually_read": "Summary read", "as_of": "2026-10-05", "qualification": "Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text", "material_id": "S15-M1", "url": null, "parent_url": "https://www.researchgate.net/publication/306347545_Acid_Folic_Supplementation_in_Major_Depressive_Disorder_Treatment_A_Double-Blind_Randomized_Clinical_Trial" }, { "material_type": "Uncorrected author proof of the original article", "public_status": "Unverified (0 external lookups in this review)", "access_status": "Access not attempted", "acquired": false, "actually_read": "Not read", "as_of": "2026-10-05", "qualification": "Distinguish historical access levels from access not attempted and sources not read in this review; the existence of a link does not mean the original source was verified in this review", "material_id": "S15-M2", "url": "https://www.researchgate.net/publication/306347545_Acid_Folic_Supplementation_in_Major_Depressive_Disorder_Treatment_A_Double-Blind_Randomized_Clinical_Trial", "parent_url": "https://www.researchgate.net/publication/306347545_Acid_Folic_Supplementation_in_Major_Depressive_Disorder_Treatment_A_Double-Blind_Randomized_Clinical_Trial" } ], "links": [ { "label": "Source", "url": "https://www.researchgate.net/publication/306347545_Acid_Folic_Supplementation_in_Major_Depressive_Disorder_Treatment_A_Double-Blind_Randomized_Clinical_Trial" } ] }, { "report_id": "S16", "title": "Khalili et al. 2022/2023 folic acid depression systematic review", "url": "https://www.emerald.com/nfs/article/53/3/521/453862/The-effects-of-folic-acid-supplementation-on", "report_type": "Systematic review used for evidence mapping", "existence": "Stored bibliography/historical access records; 0 current external lookups in this review", "acquired_read": "Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review", "study_family": "Review", "independent_replication": "19 bibliographic records ≠ 19 trials; the 11 FolATED reports belong to one family, with other families, reviews and labels assigned distinct roles; no new trials or participants were summed", "observed_result": "Discovery/contrary-evidence map; not itself direct replication of a primary trial", "result_level": "Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts", "materials": [ { "material_type": "Preserved stored-summary bibliographic information, linked summaries and historical access", "public_status": "Preserved locally", "access_status": "Acquired", "acquired": true, "actually_read": "Summary read", "as_of": "2026-10-05", "qualification": "Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text", "material_id": "S16-M1", "url": null, "parent_url": "https://www.emerald.com/nfs/article/53/3/521/453862/The-effects-of-folic-acid-supplementation-on" }, { "material_type": "Review abstract", "public_status": "Unverified (0 external lookups in this review)", "access_status": "Access not attempted", "acquired": false, "actually_read": "Not read", "as_of": "2026-10-05", "qualification": "Distinguish historical access levels from access not attempted and sources not read in this review; the existence of a link does not mean the original source was verified in this review", "material_id": "S16-M2", "url": "https://www.emerald.com/nfs/article/53/3/521/453862/The-effects-of-folic-acid-supplementation-on", "parent_url": "https://www.emerald.com/nfs/article/53/3/521/453862/The-effects-of-folic-acid-supplementation-on" } ], "links": [ { "label": "Source", "url": "https://www.emerald.com/nfs/article/53/3/521/453862/The-effects-of-folic-acid-supplementation-on" } ] }, { "report_id": "S17", "title": "Karbasi Amel and Haghshenas 2025: folic acid with fluoxetine below age18", "url": "https://brieflands.com/journals/jcp/articles/162489", "report_type": "Original study excluded by population", "existence": "Stored bibliography/historical access records; 0 current external lookups in this review", "acquired_read": "Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review", "study_family": "PEDIATRIC2025", "independent_replication": "19 bibliographic records ≠ 19 trials; the 11 FolATED reports belong to one family, with other families, reviews and labels assigned distinct roles; no new trials or participants were summed", "observed_result": "Fluoxetine adjunct in people younger than 18; excluded from the direct adult denominator", "result_level": "Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts", "materials": [ { "material_type": "Preserved stored-summary bibliographic information, linked summaries and historical access", "public_status": "Preserved locally", "access_status": "Acquired", "acquired": true, "actually_read": "Summary read", "as_of": "2026-10-05", "qualification": "Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text", "material_id": "S17-M1", "url": null, "parent_url": "https://brieflands.com/journals/jcp/articles/162489" }, { "material_type": "Full text of the pediatric original study", "public_status": "Unverified (0 external lookups in this review)", "access_status": "Access not attempted", "acquired": false, "actually_read": "Not read", "as_of": "2026-10-05", "qualification": "Distinguish historical access levels from access not attempted and sources not read in this review; the existence of a link does not mean the original source was verified in this review", "material_id": "S17-M2", "url": "https://brieflands.com/journals/jcp/articles/162489", "parent_url": "https://brieflands.com/journals/jcp/articles/162489" } ], "links": [ { "label": "Source", "url": "https://brieflands.com/journals/jcp/articles/162489" } ] }, { "report_id": "S18", "title": "Roberts et al. 2009 FolATED protocol erratum", "url": "https://link.springer.com/article/10.1186/1471-244X-9-14", "report_type": "Protocol correction for the same trial", "existence": "Stored bibliography/historical access records; 0 current external lookups in this review", "acquired_read": "Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review", "study_family": "FOLATED", "independent_replication": "19 bibliographic records ≠ 19 trials; the 11 FolATED reports belong to one family, with other families, reviews and labels assigned distinct roles; no new trials or participants were summed", "observed_result": "2009-04-07 protocol erratum; separate from a correction of results", "result_level": "Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts", "materials": [ { "material_type": "Preserved stored-summary bibliographic information, linked summaries and historical access", "public_status": "Preserved locally", "access_status": "Acquired", "acquired": true, "actually_read": "Summary read", "as_of": "2026-10-05", "qualification": "Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text", "material_id": "S18-M1", "url": null, "parent_url": "https://link.springer.com/article/10.1186/1471-244X-9-14" }, { "material_type": "Full protocol correction text", "public_status": "Unverified (0 external lookups in this review)", "access_status": "Access not attempted", "acquired": false, "actually_read": "Not read", "as_of": "2026-10-05", "qualification": "Distinguish historical access levels from access not attempted and sources not read in this review; the existence of a link does not mean the original source was verified in this review", "material_id": "S18-M2", "url": "https://link.springer.com/article/10.1186/1471-244X-9-14", "parent_url": "https://link.springer.com/article/10.1186/1471-244X-9-14" } ], "links": [ { "label": "Source", "url": "https://link.springer.com/article/10.1186/1471-244X-9-14" } ] }, { "report_id": "S19", "title": "Altaf et al. 2021 folate adjunct SSRI/SNRI systematic review", "url": "https://www.sciencedirect.com/science/article/pii/S0965229921001114", "report_type": "Systematic review used for evidence mapping", "existence": "Stored bibliography/historical access records; 0 current external lookups in this review", "acquired_read": "Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review", "study_family": "Review", "independent_replication": "19 bibliographic records ≠ 19 trials; the 11 FolATED reports belong to one family, with other families, reviews and labels assigned distinct roles; no new trials or participants were summed", "observed_result": "Discovery of literature on folate adjuncts to SSRI/SNRI; not counted as an independent trial", "result_level": "Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts", "materials": [ { "material_type": "Preserved stored-summary bibliographic information, linked summaries and historical access", "public_status": "Preserved locally", "access_status": "Acquired", "acquired": true, "actually_read": "Summary read", "as_of": "2026-10-05", "qualification": "Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text", "material_id": "S19-M1", "url": null, "parent_url": "https://www.sciencedirect.com/science/article/pii/S0965229921001114" }, { "material_type": "Review abstract/search metadata", "public_status": "Unverified (0 external lookups in this review)", "access_status": "Access not attempted", "acquired": false, "actually_read": "Not read", "as_of": "2026-10-05", "qualification": "Distinguish historical access levels from access not attempted and sources not read in this review; the existence of a link does not mean the original source was verified in this review", "material_id": "S19-M2", "url": "https://www.sciencedirect.com/science/article/pii/S0965229921001114", "parent_url": "https://www.sciencedirect.com/science/article/pii/S0965229921001114" } ], "links": [ { "label": "Source", "url": "https://www.sciencedirect.com/science/article/pii/S0965229921001114" } ] } ], "method_sources": [ { "id": "M03", "version": "Cochrane Handbook 6.5 (2024), chapter updated 2023-08", "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-03", "section": "§3.1, §3.2.1–3.2.3, MECIR C5/C7/C13", "official_principle": "Clearly record the question, eligibility criteria and reasons for changes, and distinguish variations in the intervention.", "review_level": "Reuse of case 1585 methodological principles/versions and byte-for-byte copies of 5 HTML files; no new reading of complete methods texts or application of an official tool in this review" }, { "id": "M04", "version": "Cochrane Handbook 6.5.1 (2025), chapter updated 2025-03", "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-04", "section": "§4.5, §4.6.1–4.6.3, MECIR C42", "official_principle": "Distinguish and link studies and reports, and do not omit a study solely because its outcomes are not reported.", "review_level": "Reuse of case 1585 methodological principles/versions and byte-for-byte copies of 5 HTML files; no new reading of complete methods texts or application of an official tool in this review" }, { "id": "M08", "version": "Cochrane Handbook 6.5 (2024), chapter updated 2019-10", "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-08", "section": "§8.1–8.2.3, Table 8.2.a", "official_principle": "Hold the outcome and effect of interest fixed, then assess randomization, deviations, missing data, measurement and selective reporting.", "review_level": "Reuse of case 1585 methodological principles/versions and byte-for-byte copies of 5 HTML files; no new reading of complete methods texts or application of an official tool in this review" }, { "id": "M15", "version": "Cochrane Handbook 6.5 (2024), chapter updated 2023-08", "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-15", "section": "§15.2.4, §15.3.1–15.3.3", "official_principle": "Distinguish effect estimates, intervals, importance and applicability. Sample size alone does not determine precision.", "review_level": "Reuse of case 1585 methodological principles/versions and byte-for-byte copies of 5 HTML files; no new reading of complete methods texts or application of an official tool in this review" }, { "id": "M19", "version": "Cochrane Handbook 6.5 (2024), chapter updated 2019-10", "url": "https://www.cochrane.org/authors/handbooks-and-manuals/handbook/current/chapter-19", "section": "§19.1.2, §19.2.1–19.2.4", "official_principle": "Questions about harms may require designs, populations and follow-up different from efficacy questions. Case reports do not establish incidence.", "review_level": "Reuse of case 1585 methodological principles/versions and byte-for-byte copies of 5 HTML files; no new reading of complete methods texts or application of an official tool in this review" } ], "status_dictionary": { "Partly verified": "Some preserved information is available, but gaps remain in manufacturing, exposure, plans, denominators, harms and original sources", "Unverified": "Necessary information or conditions cannot be established within this review's scope", "Review incomplete": "Original-source comparisons or searches were not performed within the permitted scope", "Not reported": "A scope-limited status indicating that the item was not stated in the particular material or section read", "Inaccessible": "Used only for material for which access was actually attempted and failed. Not assigned to clinical materials in this review.", "Insufficient eligible evidence": "Used only when, after reviewing relevant studies within a defined scope, evidence is insufficient to answer the condition. Not applied universally in this review.", "Not applicable": "An extension beyond the selected AUC comparison is not applicable; this does not substitute for actual unverified information", "Conflicting information": "Used when comparison reveals information that is difficult to reconcile for the same question, time point and analysis. Not assigned solely because review estimates differ.", "Met": "The stated preservation, boundary, distinction or linkage condition is verified; this does not mean new clinical efficacy verification, full-text reading or safety certification", "Conflicting printed values": "The conflict between printed values in the original record is preserved; no new calculation or correction" }, "study_overlap": { "state": "These are links among reports in the stored manuscript. FOLATED: one decisive directly applicable trial family (S01, S02, S03, S04, S06, S07, S08, S09, S10, S12, S18) / COPPEN2000: positive adjacent evidence; not direct replication (S13) / RESLER2008: evidence-map candidate (S14) / SEPEHRMANESH: positive adjacent evidence; not direct replication (S15) / PEDIATRIC2025: evidence excluded by population (S17) / Official safety commentary, a different product's label and reviews used for evidence mapping; not counted as independent clinical trials (S05, S11, S16, S19). Current conversion of preserved materials into a table; external original articles, registrations, official documents and older separate ZIP/PDF/log files were not read in this review; new clinical searches, calculations, reassessment, Laya, API/private access and deployment: 0. Report and family labels are not summed as independent trial counts or participant counts.", "unique_trial_count": 1, "unique_participant_count": null, "reason": "These are links among reports in the stored manuscript. FOLATED: one decisive directly applicable trial family (S01, S02, S03, S04, S06, S07, S08, S09, S10, S12, S18) / COPPEN2000: positive adjacent evidence; not direct replication (S13) / RESLER2008: evidence-map candidate (S14) / SEPEHRMANESH: positive adjacent evidence; not direct replication (S15) / PEDIATRIC2025: evidence excluded by population (S17) / Official safety commentary, a different product's label and reviews used for evidence mapping; not counted as independent clinical trials (S05, S11, S16, S19). Current conversion of stored materials into a table; external original articles, registrations, official documents and older separate ZIP/PDF/log files were not read in this review; new clinical searches, calculations, reassessment, Laya, API/private access and deployment: 0. Report and family labels are not summed as independent trial counts or participant counts." }, "history": [ { "date": "2026-11-05", "kind": "Separation of public-facing display and data", "view_version": "1.0", "change": "A public-facing display and data were prepared from the existing 40 items. No new clinical search, change in verification status or scoring was performed." } ], "language": "en", "translation_date": "2026-11-05" }