Folic acid × Reduction of BDI-II depression severity as an antidepressant adjunct

Required evidence, verification status and materials actually read
Item	AVerification status	BReading scope	CReview item	DCurrent findings	EWhy unverified	FRequired materials and conditions	GFurther research
1	Met	Full text not readStored summary read	N01 · Distinct claimWhich folic acid adjunct regimen and BDI-II outcome are being asked about?Required for the selected FolATED BDI-II comparison	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. S02 S06 S07	Confirms preservation of the boundaries; it is neither efficacy certification nor a verdict that all folic acid is ineffective.	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	Review direct results within these boundaries separately from materials addressing other questions.
2	Partly verified	Full text not readStored summary read	N02 · Ingredient and productAre the actual folic acid product and unverified manufacturing details distinguished?Required for the selected FolATED BDI-II comparison	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. S02 S11	Product form and supply are preserved, but manufacturing details and current comparison with the original source remain unverified.	Active ingredient, 5 mg tablet, overencapsulation, filler, Bilcare supply, and documentation of salt/manufacturer/lot/purity	Compare trial product, batch and ingredient records with the original medication section.
3	Partly verified	Full text not readStored summary read	N03 · Route and nominal doseIs 5 mg as 1 daily dose the same as actual total exposure?Required for the selected FolATED BDI-II comparison	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. S02	A nominal dose is available, but actual individual exposure has not been fully verified.	Oral route, nominal amount for 1 dose and dosing frequency, dosing records and total exposure	Link arm-specific dosing, missed doses and adherence records to the effect of interest.
4	Met	Full text not readStored summary read	N04 · Treatment and observationAre 12 weeks of treatment distinguished from 25 weeks of observation?Required for the selected FolATED BDI-II comparison	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. S02 S07	Confirms the time boundaries; it does not verify long-term efficacy or safety.	End of trial treatment, observation measured from randomization, and visit times	If persistence after treatment discontinuation is the question, review direct estimates and exposure at that time.
5	Partly verified	Full text not readStored summary read	N05 · Placebo and background treatmentWhat were the matching placebo and common antidepressant policy?Required for the selected FolATED BDI-II comparison	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. S02	The actual placebo and policy are preserved, but individual concomitant-treatment histories have not been fully verified.	Lactose placebo, visual matching for blinding, optimization/usual-care policy, and individual drug names/doses	Link arm-specific antidepressants and medication changes to the selected BDI-II analysis.
6	Partly verified	Full text not readStored summary read	N06 · Changes and concurrent exposureWere medication changes, psychotherapy and dietary/supplement exposure verified?Required for the selected FolATED BDI-II comparison	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. S02	The policy permitting changes is verified, but a complete comparison of actual concurrent-exposure balance and its analytical impact remains outstanding.	Arm-specific antidepressant changes, rescue treatment, psychotherapy, dietary/fortified-food/supplement exposure and their handling	Compare arm-specific changes and concurrent-exposure records with how the effect of assignment was handled.
7	Met	Full text not readStored summary read	N07 · Diagnosis and baseline statusWhich adult MDD population and screening criteria were used?Required for the selected FolATED BDI-II comparison	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. S02 S04 S18	Confirms the retained diagnostic and eligibility boundaries; it does not establish an effect applicable to all adults or depression subtypes.	Clinician diagnosis under ICD10, moderate/severe depression, BDI-II screening/randomization criteria, and new/existing antidepressant use	Link original inclusion/exclusion criteria, recruitment and baseline status to the actual denominators.
8	Partly verified	Full text not readStored summary read	N08 · Nutritional statusDoes deficiency screening establish normal nutritional status in everyone?Required for the selected FolATED BDI-II comparison	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. S02 S03 S10	Screening and subgroups are preserved, but verification of every individual's nutritional status and comparison of units remain incomplete.	Folate/B12 deficiency screening, baseline values/units and subgroups with low values	Compare baseline tests/units and eligibility with the prospective plan for stratified analyses.
9	Partly verified	Full text not readStored summary read	N09 · Pregnancy and lactationIs restricting the page to nonlactating adults the same as verifying actual lactation status?Required for the selected FolATED BDI-II comparison	The trial excluded pregnancy and planned pregnancy. Page applicability is restricted to nonlactating adults, but actual trial lactation status could not be explicitly verified. S02 S04 S18	Pregnancy exclusion is preserved, and lactation status remains unverified.	Exclusion of pregnancy/planned pregnancy, lactation inclusion/exclusion criteria and actual status	Compare actual eligibility criteria, lactation status and evidence for special populations separately.
10	Partly verified	Full text not readStored summary read	N10 · BDI-II measurementAre the subjective scale's direction and collection distinguished from blinding?Required for the selected FolATED BDI-II comparison	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. S02 S07	The scale, direction and design are preserved, but current comparison of implementation details with the original source remains outstanding.	BDI-II total score, lower-is-better direction, collection at visits, matching placebo/blinding, and limitations in implementation	Link scale collection and blinding implementation at each visit to the selected analysis.
11	Met	Full text not readStored summary read	N11 · AUC definition and unitsHow should the time-weighted mean be interpreted?Required for the selected FolATED BDI-II comparison	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. S02 S06 S07	Confirms the retained definition; it is not a newly calculated AUC from individual-level data.	Area across baseline and weeks 4/12/25, divided by the actual observation period; mean expressed in BDI-II points	Compare definitions of the estimand and units in the original SAP and results tables.
12	Partly verified	Full text not readStored summary read	N12 · Plan changesWere the initial 25-week endpoint and the final AUC the same from the outset?Required for the selected FolATED BDI-II comparison	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. S04 S07 S08 S09 S18	The change and its reported location are preserved, but direct comparison of the full chronology remains incomplete.	Original protocol, erratum, final SAP, unblinding/amendment approval dates and registration history	Compare protocol, erratum and SAP versions, registration changes and approval timing.
13	Partly verified	Full text not readStored summary read	N13 · Design and allocationTo what extent are the actual comparative design and allocation process verified?Required for the selected FolATED BDI-II comparison	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. S02 S04	The design is preserved, but verification of detailed implementation does not extend beyond the current local records.	Multicenter individually randomized parallel groups, matching placebo, allocation/concealment and baseline balance	Link original randomization/concealment information and baseline tables to the selected outcome.
14	Met	Full text not readStored summary read	N14 · Allocation and analysis denominatorsWhat do the denominators of 475 and 440 represent?Required for the selected FolATED BDI-II comparison	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. S03 S06	Confirms preservation of the denominator distinctions; it does not mean the impact of loss to follow-up has been resolved.	Valid allocation 237/238, total 475; 35 with no follow-up BDI-II; mITT 223/217, total 440	Compare the original flowchart, analysis definitions and loss to follow-up by arm.
15	Partly verified	Full text not readStored summary read	N15 · mITT and missing dataDoes regression imputation include the 35 excluded participants?Required for the selected FolATED BDI-II comparison	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. S02 S03 S07	The retained analysis and missing-data scope are available, but the impact of exclusions was neither fully resolved nor reanalyzed.	Assigned groups retained; inclusion requires at least 1 follow-up; imputation within the 440; sensitivity analysis of all randomized participants	Compare original missing-data reasons, imputation and sensitivity methods with the effect of interest.
16	Partly verified	Full text not readStored summary read	N16 · Sensitivity analyses and completion denominatorsAre alternative analyses of the same trial counted as new replications?Required for the selected FolATED BDI-II comparison	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. S02 S03 S07	Sensitivity-analysis types and denominator differences are available, but comparison of all values and denominators in the original tables remains outstanding.	Complete-case, repeated mixed-model and reweighted-allocation analyses; denominators for completing visits and for complete BDI data	Compare original Tables 18–20 and participant flow with each analysis denominator and result.
17	Met	Full text not readStored summary read	N17 · Primary effect and directionWhat exact comparison and interval does +1.09 points refer to?Required for the selected FolATED BDI-II comparison	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. S03 S06 S07	Confirms preservation of the reported effect and direction; the original table's SE conflict remains separately recorded.	Table 13 adjusted folic acid minus placebo, 0–25-week AUC average, CI/P, 223/217 and lower-is-better direction	Compare original Table 13, narrative text, analysis definitions and printed values.
18	Conflicting printed values	Full text not readStored summary read	N18 · SE conflictDo the printed SE and CI/P in Table 13 agree?Required for the selected FolATED BDI-II comparison	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. S03 S06	The conflict between original printed values remains unresolved; no new calculation or correction was made in this review.	Printed SE 0.86, CI/P, and records of numerical conflicts in tables and narrative text	During an authorized correction, compare the original table, analysis output and errata, and retain before-and-after values.
19	Conflicting printed values	Full text not readStored summary read	N19 · Unadjusted sign conflictWere +0.06 and −0.06 overwritten with the same sign?Required for the selected FolATED BDI-II comparison	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. S03 S06	Resolution of the unadjusted sign conflict remains unverified; no correction or recalculation was made in this review.	Unadjusted AUC difference in Tables 12/18, the sign printed in each table, and distinction from the adjusted primary effect	Compare original tables/directions, errata and analysis outputs as a separate correction event.
20	Met	Full text not readStored summary read	N20 · Interpreting nonsignificanceDoes failure to demonstrate benefit mean an effect of 0, equivalence or ineffectiveness in all MDD?Required for the selected FolATED BDI-II comparison	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. S06 S13 S15	Confirms preservation of interpretive boundaries; it is not a new conclusion of equivalence or ineffectiveness.	Direction of the primary effect, CI, fixed question and original meaning of E0	Review direct results for the same estimand and relevant clinical thresholds alongside additional evidence.
21	Unverified	Full text not readStored summary read	N21 · MCID and precisionIs the initial 3-point power target the MCID for AUC?Required for the selected FolATED BDI-II comparison	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. S02 S06	Because an applicable importance threshold is unverified, exclusion of clinically important benefit is not established.	Reported CI, a validated between-group threshold for clinical importance of the AUC average, and the initial 3-point target at 25 weeks	Compare a justified threshold for the same endpoint and estimand with the CI.
22	Met	Full text not readStored summary read	N22 · Single 25-week resultAre endpoint means, adjusted endpoint differences and the primary AUC separated?Required for the selected FolATED BDI-II comparison	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. S10 S12	Confirms preservation of time-point, dispersion and analysis distinctions; the original tables were not newly verified in this review.	Adjusted 25-week difference +1.27/CI/P, arm-specific unadjusted means and SDs, and distinct estimands	Compare Table 14 and Appendix 10/Table 42 with the original analysis definitions.
23	Met	Full text not readStored summary read	N23 · Reports and trial familiesAre FolATED reports and appendices counted as independent trials?Required for the selected FolATED BDI-II comparison	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. S01 S02 S03 S04 S06 S07 S08 S09 S10 S12 S18	Confirms preservation of family links; it does not mean 19 bibliographic records represent 19 trials.	FOLATED links among the report, Methods/Results, protocol/erratum, SAP, registration and appendices	Verify the unique recruitment/allocation identity and distinctions from other families at the original locations.
24	Partly verified	Full text not readStored summary read	N24 · Coppen positive resultWhy is the positive female-subgroup HDRS-17 result not counted as direct replication?Required for the selected FolATED BDI-II comparison	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. S13	A positive abstract result is available, but subgroup plans/denominators, the full text and direct applicability to the identical question remain unverified.	127 participants, 500 µg/day, 10 weeks, fluoxetine 20 mg, female-subgroup HDRS17, and subgroup denominators/plans	Compare the abstract's scope with subgroup plans/denominators and the direct comparison in the original full text.
25	Partly verified	Full text not readStored summary read	N25 · Another positive BDI-II resultWhat role does the uncorrected author proof for 2.5 mg over 8 weeks have?Required for the selected FolATED BDI-II comparison	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. S15	Results are available from the accessed version, but the final version and registration, and direct replication of the selected question, remain unverified.	Sepehrmanesh 45/45, citalopram 20 mg, 2.5 mg/day for 8 weeks, BDI-II, and version/registration	Compare the final publication version, registration history, denominators and plans with the different exposures and estimands.
26	Unverified	Full text not readStored summary read	N26 · Candidate with results not obtainedWas Resler metadata promoted to verified results?Required for the selected FolATED BDI-II comparison	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. S14	A bibliographic candidate exists, but no full-text verification is available to satisfy the result criteria.	PMID18716414/DOI, the scope of access failure, and actual dose/denominators/effect	If separately obtaining the source is authorized, link the original results, design, exposure and denominators.
27	Met	Full text not readStored summary read	N27 · Reviews and pediatric exclusionWere reviews and trials in people younger than 18 combined with direct adult results?Required for the selected FolATED BDI-II comparison	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. S16 S17 S19	Confirms roles and exclusion boundaries; not all underlying trials in the reviews were verified in this review.	Discovery role of reviews S16/19, population boundary for pediatric S17, and original families	If needed, separately compare underlying trial identities, adult-population boundaries and actual results.
28	Met	Full text not readStored summary read	N28 · Unfavorable SF-12 resultWas the secondary SF-12 result merged into BDI-II worsening or confirmed harm?Required for the selected FolATED BDI-II comparison	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. S03 S06 S10	Confirms preservation of the unfavorable result and its role; it does not certify a causal harm relationship.	SF12 mental-health AUC −1.97/CI/P, favoring placebo, and nominal secondary comparison	Compare original Table 13, the plan, multiplicity and clinical meaning for that scale.
29	Partly verified	Full text not readStored summary read	N29 · Subgroups and biochemistryDo small subgroups, response/remission or blood results replace the primary effect?Required for the selected FolATED BDI-II comparison	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. S03 S10	The roles of other analyses are available, but verification of complete plans, quantitative results and denominators is limited.	Plans, denominators and individual results for low-folate/genotype/sex subgroups, response/remission and biochemistry	Separately compare prospective subgroup/interaction plans, denominators, multiplicity and original results.
30	Partly verified	Full text not readStored summary read	N30 · Funding and conflicts of interestDoes public funding mean there are no competing interests?Required for the selected FolATED BDI-II comparison	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. S01 S02 S13 S15 S18	Public funding and disclosed relationships are available, but not all competing interests or funding for adjacent studies have been fully verified.	NIHR HTA04/35/08, COBALZ advisory/shareholder roles, Bilcare supply and funding for adjacent studies	Compare the original funding/COI/supply information and the scope of adjacent-study disclosures.
31	Partly verified	Full text not readStored summary read	N31 · Adverse events and countsAre 33/45 and 6/14 counts of events or people?Required for the selected FolATED BDI-II comparison	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. S03	Reported event counts are available, but verification of unique-person denominators, complete collection, causality and comparative risk remains incomplete.	25-week AE 33/45, SAE 6/14, possible drug reactions 4/3, and unique-person denominators/collection	Compare event definitions and collection, exposure, unique people and missingness in original Tables 15–17.
32	Met	Full text not readStored summary read	N32 · 0 events within a reaction categoryAre 0 serious/unexpected reactions being read as 0 events overall?Required for the selected FolATED BDI-II comparison	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. S03	Confirms preservation of the scope of 0 events; it does not verify absence of all harms.	Scope of 0 serious or unexpected reactions among the 4/3 possible drug reactions	Compare original reaction classifications, seriousness/expectedness and collection scope.
33	Partly verified	Full text not readStored summary read	N33 · MINI risk classificationDo 25/223 and 28/217 represent suicide attempts or deaths?Required for the selected FolATED BDI-II comparison	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. S03	Risk classification is preserved, but event data for comparisons of actual behavior and deaths remain unverified.	25-week MINI high-risk category, imputed analysis with 223/217, and actual suicidal-behavior/death events	Compare original MINI definitions, imputation, collection and actual event records with their respective denominators.
34	Partly verified	Full text not readStored summary read	N34 · Official safety materialsWhat is the scope of documents on B12 masking and interactions?Required for the selected FolATED BDI-II comparison	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. S05 S11	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.	Masking of hematological signs of B12 deficiency, neurological problems, antiepileptics/methotrexate, and partial NIH material/SmPC	Separately compare original safety documents, case/study families, exposure, timing and alternative explanations.
35	Unverified	Full text not readStored summary read	N35 · Long-term use and vulnerable populationsDoes 25-week observation answer every long-term or special-population safety question?Required for extended harm questions	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. S02 S05 S11	Extended harm information remains unverified within the selected materials.	Direct exposure and events for high-dose/long-term use, pregnancy/lactation/children, hepatic/renal disease and cancer history	Separately design or review material suited to the relevant exposure, population and long-term/rare events.
36	Partly verified	Full text not readStored summary read	N36 · Reading and datesIs reading summaries distinguished from past reading of external sources?Required for the selected FolATED BDI-II comparison	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. S01 S05 S09 S13 S14 S15	The current summaries are verified, but current reading of external full texts, their original bytes and report-specific access dates remain unverified.	Exact locations/values/SHA of current stored summaries, access levels of 19 bibliographic entries, report-specific access dates and evidence cutoff date	When original materials are actually obtained, separately preserve material types, dates, locations read and original bytes.
37	Partly verified	Full text not readStored summary read	N37 · Searches, registration and correctionsDoes the prior search scope represent a current exhaustive search or retraction check?Required for the selected FolATED BDI-II comparison	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. S04 S09 S18	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.	2026-09-15 search scope, partial/failed registration access, protocol correction, and the scope of checking retractions/new evidence	During a separately authorized search or correction, preserve complete original texts, events, before-and-after values and versions.
38	Met	Full text not readStored summary read	N38 · Original grade and certificationAre D30 and B/P/R1/I2/E0/B1/C0 being presented as a new verdict?Required for the selected FolATED BDI-II comparison	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. S01 S02 S06	Confirms preservation of original values and review boundaries; no new clinical grade or certification was assigned.	Original grade/score/axes, 1 strength, document quality A, self-review and clinical certification=false	If a correction is separately authorized, record the original evidence, verdict, reasons and before-and-after values as an event.
39	Not applicable	Full text not readStored summary read	N39 · Boundaries for extending efficacy claimsAre optimal dose, biomarkers, remission and mortality combined into the same answer?Required for extended efficacy questions	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. S02 S10 S13 S15	Indicates that an extension outside the selected question is not applicable; it does not erase unverified information about the actual trial.	The selected AUC question and direct questions about other doses/durations, L-methylfolate, B-vitamin combinations and clinical events	If an extension is asked about, separately compare direct dose, follow-up and event data.
40	Partly verified	Full text not readStored summary read	N40 · ID, publication and updatesDo historical deployment flags mean that this table has now been publicly published?Required for the selected FolATED BDI-II comparison	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.	Original metadata and update provisions are preserved, but authoritative correction of publication wording and actual site implementation were not performed in this review.	Original 3109/assigned code/URL, server_deployed true/write false, dates, update policy and before-and-after original text	During an authorized update, retain complete originals, original values/contrary results, reasons for changes and versions.

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40 itemsWhat the statuses mean

Assessment scope

Stored-material review date: 2026-10-05
Original evidence cut-off: 2026-09-15
Scope actually checked: Stored Korean and English manuscripts and case-specific criteria and application records. Full papers, supplements, registrations, plans and original data were not read.
What the dates mean: This is the date the stored materials were checked, not the date of an up-to-date clinical literature search.
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.
Ingredient, formulation and route: 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
Measured outcome: 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
Questions outside this scope: 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

Evidence and sources

The links below lead to the sources. A link alone does not mean the original source was read or its latest publication status verified.

S01 · FolATED: randomized trial and economic evaluation, HTA 18(48), 2014

Source

Material type: Direct trial report
Materials actually read: Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review
Findings recorded in the stored summary: Report of the primary trial, public funding and COI; one family
Record level: Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts
Study overlap and 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

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Preserved stored-summary bibliographic information, linked summaries and historical access No external link · retained summary	Preserved locally	Acquired	Summary read	Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text
Full text of the published report Open material ↗	Unverified (0 external lookups in this review)	Access not attempted	Not read	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

S02 · FolATED Chapter 2: Methods

Source

Material type: Methods from the same trial
Materials actually read: Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review
Findings recorded in the stored summary: Medication, eligibility and analysis policies; manufacturing and lactation unverified
Record level: Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts
Study overlap and 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

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Preserved stored-summary bibliographic information, linked summaries and historical access No external link · retained summary	Preserved locally	Acquired	Summary read	Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text
Full text of the report's Methods Open material ↗	Unverified (0 external lookups in this review)	Access not attempted	Not read	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

S03 · FolATED Chapter 3: Results

Source

Material type: Results from the same trial
Materials actually read: Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review
Findings recorded in the stored summary: Denominators, effects, numerical conflicts, harms and sensitivity analyses
Record level: Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts
Study overlap and 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

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Preserved stored-summary bibliographic information, linked summaries and historical access No external link · retained summary	Preserved locally	Acquired	Summary read	Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text
Full text of the report's Results Open material ↗	Unverified (0 external lookups in this review)	Access not attempted	Not read	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

S04 · Roberts et al. 2007 FolATED protocol

Source

Material type: Protocol of the same trial
Materials actually read: Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review
Findings recorded in the stored summary: Initial plan for a single time point at 25 weeks; distinguished from the final AUC
Record level: Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts
Study overlap and 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

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Preserved stored-summary bibliographic information, linked summaries and historical access No external link · retained summary	Preserved locally	Acquired	Summary read	Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text
Full protocol text Open material ↗	Unverified (0 external lookups in this review)	Access not attempted	Not read	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

S05 · NIH ODS Folate health-professional fact sheet

Source

Material type: Partially accessed safety material
Materials actually read: Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review
Findings recorded in the stored summary: Access failed after partial search extracts; not a direct trial or incidence estimate
Record level: Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts
Study overlap and 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

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Preserved stored-summary bibliographic information, linked summaries and historical access No external link · retained summary	Preserved locally	Acquired	Summary read	Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text
Official NIH ODS web document Open material ↗	Unverified (0 external lookups in this review)	Access not attempted	Not read	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

S06 · FolATED Table 13: adjusted primary AUC-average estimates

Source

Material type: Table 13 from the same trial
Materials actually read: Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review
Findings recorded in the stored summary: Primary effect +1.09/CI/P, SE conflict and secondary SF12
Record level: Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts
Study overlap and 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

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Preserved stored-summary bibliographic information, linked summaries and historical access No external link · retained summary	Preserved locally	Acquired	Summary read	Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text
Original report table Open material ↗	Unverified (0 external lookups in this review)	Access not attempted	Not read	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

S07 · FolATED Appendix 5: final analysis plan

Source

Material type: Final SAP of the same trial
Materials actually read: Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review
Findings recorded in the stored summary: AUC, mITT/missing-data definitions and the source location for the record of the unblinding meeting; approval date unverified
Record level: Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts
Study overlap and 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

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Preserved stored-summary bibliographic information, linked summaries and historical access No external link · retained summary	Preserved locally	Acquired	Summary read	Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text
Full analysis plan text Open material ↗	Unverified (0 external lookups in this review)	Access not attempted	Not read	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

S08 · FolATED protocol amendment history

Source

Material type: Amendment history of the same trial
Materials actually read: Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review
Findings recorded in the stored summary: Protocol amendment chronology; not a substitute for the complete registration history
Record level: Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts
Study overlap and 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

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Preserved stored-summary bibliographic information, linked summaries and historical access No external link · retained summary	Preserved locally	Acquired	Summary read	Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text
Full report appendix text Open material ↗	Unverified (0 external lookups in this review)	Access not attempted	Not read	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

S09 · ISRCTN37558856 FolATED registration

Source

Material type: Candidate registration record for the same trial
Materials actually read: Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review
Findings recorded in the stored summary: Identifier cross-check and access failure after metadata; complete versions unverified
Record level: Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts
Study overlap and 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

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Preserved stored-summary bibliographic information, linked summaries and historical access No external link · retained summary	Preserved locally	Acquired	Summary read	Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text
ISRCTN metadata Open material ↗	Unverified (0 external lookups in this review)	Access not attempted	Not read	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

S10 · FolATED Appendix 10: detailed clinical results

Source

Material type: Detailed appendix from the same trial
Materials actually read: Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review
Findings recorded in the stored summary: 25-week means/SDs, response/remission/biochemistry; not a new trial
Record level: Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts
Study overlap and 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

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Preserved stored-summary bibliographic information, linked summaries and historical access No external link · retained summary	Preserved locally	Acquired	Summary read	Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text
Full text of the detailed results appendix Open material ↗	Unverified (0 external lookups in this review)	Access not attempted	Not read	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

S11 · Flamingo Pharma folic acid 5 mg tablet SmPC, text revised 20 May 2026

Source

Material type: Official SmPC for a different product
Materials actually read: Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review
Findings recorded in the stored summary: Flamingo 5 mg label, revised 2026-05-20; not the FolATED product or authorization for MDD
Record level: Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts
Study overlap and 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

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Preserved stored-summary bibliographic information, linked summaries and historical access No external link · retained summary	Preserved locally	Acquired	Summary read	Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text
Official manufacturer label Open material ↗	Unverified (0 external lookups in this review)	Access not attempted	Not read	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

S12 · FolATED Table 14: adjusted individual follow-up scores

Source

Material type: Table 14 from the same trial
Materials actually read: Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review
Findings recorded in the stored summary: Adjusted single 25-week result +1.27; separate from the AUC
Record level: Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts
Study overlap and 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

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Preserved stored-summary bibliographic information, linked summaries and historical access No external link · retained summary	Preserved locally	Acquired	Summary read	Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text
Original report table Open material ↗	Unverified (0 external lookups in this review)	Access not attempted	Not read	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

S13 · Coppen and Bailey 2000: folic acid added to fluoxetine

Source

Material type: Original study providing positive adjacent evidence
Materials actually read: Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review
Findings recorded in the stored summary: Positive female-subgroup HDRS17 result with 500 µg over 10 weeks; female denominator/interaction unverified
Record level: Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts
Study overlap and 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

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Preserved stored-summary bibliographic information, linked summaries and historical access No external link · retained summary	Preserved locally	Acquired	Summary read	Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text
Abstract/official index Open material ↗	Unverified (0 external lookups in this review)	Access not attempted	Not read	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

S14 · Resler et al. 2008: folic acid plus fluoxetine

Source

Material type: Candidate whose results were not obtained
Materials actually read: Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review
Findings recorded in the stored summary: Metadata/partial-access failure; denominator/effect unverified
Record level: Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts
Study overlap and 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

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Preserved stored-summary bibliographic information, linked summaries and historical access No external link · retained summary	Preserved locally	Acquired	Summary read	Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text
Metadata candidate Open material ↗	Unverified (0 external lookups in this review)	Access not attempted	Not read	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

S15 · Sepehrmanesh et al.: Acid Folic Supplementation in MDD Treatment

Source

Material type: Author copy providing positive adjacent evidence
Materials actually read: Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review
Findings recorded in the stored summary: Positive BDI-II result with 2.5 mg over 8 weeks; uncorrected proof, with final version/registration unverified
Record level: Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts
Study overlap and 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

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Preserved stored-summary bibliographic information, linked summaries and historical access No external link · retained summary	Preserved locally	Acquired	Summary read	Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text
Uncorrected author proof of the original article Open material ↗	Unverified (0 external lookups in this review)	Access not attempted	Not read	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

S16 · Khalili et al. 2022/2023 folic acid depression systematic review

Source

Material type: Systematic review used for evidence mapping
Materials actually read: Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review
Findings recorded in the stored summary: Discovery/contrary-evidence map; not itself direct replication of a primary trial
Record level: Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts
Study overlap and 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

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Preserved stored-summary bibliographic information, linked summaries and historical access No external link · retained summary	Preserved locally	Acquired	Summary read	Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text
Review abstract Open material ↗	Unverified (0 external lookups in this review)	Access not attempted	Not read	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

S17 · Karbasi Amel and Haghshenas 2025: folic acid with fluoxetine below age18

Source

Material type: Original study excluded by population
Materials actually read: Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review
Findings recorded in the stored summary: Fluoxetine adjunct in people younger than 18; excluded from the direct adult denominator
Record level: Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts
Study overlap and 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

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Preserved stored-summary bibliographic information, linked summaries and historical access No external link · retained summary	Preserved locally	Acquired	Summary read	Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text
Full text of the pediatric original study Open material ↗	Unverified (0 external lookups in this review)	Access not attempted	Not read	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

S18 · Roberts et al. 2009 FolATED protocol erratum

Source

Material type: Protocol correction for the same trial
Materials actually read: Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review
Findings recorded in the stored summary: 2009-04-07 protocol erratum; separate from a correction of results
Record level: Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts
Study overlap and 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

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Preserved stored-summary bibliographic information, linked summaries and historical access No external link · retained summary	Preserved locally	Acquired	Summary read	Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text
Full protocol correction text Open material ↗	Unverified (0 external lookups in this review)	Access not attempted	Not read	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

S19 · Altaf et al. 2021 folate adjunct SSRI/SNRI systematic review

Source

Material type: Systematic review used for evidence mapping
Materials actually read: Exact stored bibliographic information and linked summaries were actually read; external sources and older separate original documents were not read in this review
Findings recorded in the stored summary: Discovery of literature on folate adjuncts to SSRI/SNRI; not counted as an independent trial
Record level: Limited to the explicitly stated scope of historical stored bibliographic information/summaries; not new verification of clinical full texts
Study overlap and 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

Public availability, access and reading status by material
Material	Public availability	Access status	Actually read	Notes
Preserved stored-summary bibliographic information, linked summaries and historical access No external link · retained summary	Preserved locally	Acquired	Summary read	Exact stored-summary pointers, values and SHA; not the original bytes of the original clinical full text
Review abstract/search metadata Open material ↗	Unverified (0 external lookups in this review)	Access not attempted	Not read	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

Report counts versus independent study counts

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.

Review criteria

Version NGM-v3109-FOLATED-BDI-II-AUC-1.0 · Criteria record date 2026-10-05. These are Chamgap's own application conditions, informed by the referenced methods. They do not constitute official assessment-tool certification or a new efficacy score.

N01 · Which folic acid adjunct regimen and BDI-II outcome are being asked about?

Required materials and conditions: 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
Conditions for verification: Link the original claim to the boundaries of the actual regimen, comparison and time-weighted endpoint.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: L-methylfolate, combination products, biomarkers and the single 25-week endpoint are not framed as the same question.
Why this condition is needed: Needed to avoid extending the conclusion to all folic acid and all depression.
Referenced methods: 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

N02 · Are the actual folic acid product and unverified manufacturing details distinguished?

Required materials and conditions: Active ingredient, 5 mg tablet, overencapsulation, filler, Bilcare supply, and documentation of salt/manufacturer/lot/purity
Conditions for verification: Record the reported active ingredient and overencapsulation separately from unverified manufacturing details.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: The authorized Flamingo product does not establish the identity of the FolATED product.
Why this condition is needed: Needed to avoid equating the supplier with the manufacturing source or with other folate products.
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed

N03 · Is 5 mg as 1 daily dose the same as actual total exposure?

Required materials and conditions: Oral route, nominal amount for 1 dose and dosing frequency, dosing records and total exposure
Conditions for verification: Distinguish the planned oral 5 mg as 1 daily dose from unverified actual exposure.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not calculate new cumulative doses, conversions or recommended doses.
Why this condition is needed: Needed to avoid turning the trial dose into an individual recommendation or a claim of actual complete adherence.
Referenced methods: 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

N04 · Are 12 weeks of treatment distinguished from 25 weeks of observation?

Required materials and conditions: End of trial treatment, observation measured from randomization, and visit times
Conditions for verification: Show 12 weeks of treatment separately from observation through 25 weeks.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not impose all long-term follow-up as a requirement for this narrow question.
Why this condition is needed: Needed to avoid turning 25 weeks of observation into 25 weeks of treatment or a lasting long-term effect.
Referenced methods: 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

N05 · What were the matching placebo and common antidepressant policy?

Required materials and conditions: Lactose placebo, visual matching for blinding, optimization/usual-care policy, and individual drug names/doses
Conditions for verification: Distinguish the actual added-ingredient contrast from the common policy and unverified individual exposure.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not automatically exclude comparative results because concomitant treatment was used.
Why this condition is needed: Needed to avoid describing a shared policy as identical drugs and doses for all participants.
Referenced methods: 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

N06 · Were medication changes, psychotherapy and dietary/supplement exposure verified?

Required materials and conditions: Arm-specific antidepressant changes, rescue treatment, psychotherapy, dietary/fortified-food/supplement exposure and their handling
Conditions for verification: Separate the permitted clinical context from unverified actual treatment and exposure histories.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not impose a new condition that all changes must be identical.
Why this condition is needed: Needed to avoid describing permitted changes as absent or attributing the result solely to folic acid.
Referenced methods: 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

N07 · Which adult MDD population and screening criteria were used?

Required materials and conditions: Clinician diagnosis under ICD10, moderate/severe depression, BDI-II screening/randomization criteria, and new/existing antidepressant use
Conditions for verification: Preserve BDI-II screening ≥19 and randomization ≥17, clinician diagnosis and the actual population boundaries.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not generalize trial screening cutpoints into diagnostic criteria for all clinical care.
Why this condition is needed: Needed to avoid recasting the population as entirely treatment-resistant depression or as general low mood.
Referenced methods: 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

N08 · Does deficiency screening establish normal nutritional status in everyone?

Required materials and conditions: Folate/B12 deficiency screening, baseline values/units and subgroups with low values
Conditions for verification: Preserve screening records, small low-value subgroups and unverified units separately.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not repurpose results from a small low-value subgroup as the overall primary effect or an effect in confirmed deficiency.
Why this condition is needed: Needed to avoid turning a screening policy into a claim that every participant had normal status.
Referenced methods: 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

N09 · Is restricting the page to nonlactating adults the same as verifying actual lactation status?

Required materials and conditions: Exclusion of pregnancy/planned pregnancy, lactation inclusion/exclusion criteria and actual status
Conditions for verification: Separate exclusion of pregnancy/planned pregnancy from unverified lactation status.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not turn unverified lactation status into confirmed harm, efficacy or exclusion during lactation.
Why this condition is needed: Needed to avoid turning a page restriction into a record that lactating participants were actually excluded from the trial.
Referenced methods: 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

N10 · Are the subjective scale's direction and collection distinguished from blinding?

Required materials and conditions: BDI-II total score, lower-is-better direction, collection at visits, matching placebo/blinding, and limitations in implementation
Conditions for verification: Explain the patient-reported depression total score, reported blinding and the extent of implementation not cross-checked.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not treat a subjective scale as an automatic failure or recast it as a biomarker.
Why this condition is needed: Needed to avoid asserting absence of all measurement bias solely from the scale name or double blinding.
Referenced methods: 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

N11 · How should the time-weighted mean be interpreted?

Required materials and conditions: Area across baseline and weeks 4/12/25, divided by the actual observation period; mean expressed in BDI-II points
Conditions for verification: Link the final plan's time-weighted AUC average, units and adjusted between-group estimand.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not perform new AUC calculations or conversions in this review.
Why this condition is needed: Needed to avoid recasting it as point-weeks, within-group change or a single endpoint.
Referenced methods: 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

N12 · Were the initial 25-week endpoint and the final AUC the same from the outset?

Required materials and conditions: Original protocol, erratum, final SAP, unblinding/amendment approval dates and registration history
Conditions for verification: Show separately the initial single time point, final AUC, reportedly pre-unblinding SAP and unverified approval date.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not turn an unavailable plan into confirmed selective reporting or a claim of an identical prospective plan from the outset.
Why this condition is needed: Needed to avoid concealing the endpoint change and unverified details.
Referenced methods: 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

N13 · To what extent are the actual comparative design and allocation process verified?

Required materials and conditions: Multicenter individually randomized parallel groups, matching placebo, allocation/concealment and baseline balance
Conditions for verification: Distinguish the recorded actual design from details not cross-checked in this review.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not turn unverified details into a nonrandomized classification or automatic failure.
Why this condition is needed: Needed to avoid extending the design label into complete verification of concealment and baseline balance.
Referenced methods: M03 §3.2.1; detailed population criteria are internally designed; M08 §8.1–8.2.3; internal application

N14 · What do the denominators of 475 and 440 represent?

Required materials and conditions: Valid allocation 237/238, total 475; 35 with no follow-up BDI-II; mITT 223/217, total 440
Conditions for verification: Preserve allocation, reasons for exclusion and primary-analysis denominators together with their arms.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not create dropout rates, new denominators or new calculations in this review.
Why this condition is needed: Needed to avoid substituting the allocation denominator for analysis or completion denominators.
Referenced methods: 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

N15 · Does regression imputation include the 35 excluded participants?

Required materials and conditions: Assigned groups retained; inclusion requires at least 1 follow-up; imputation within the 440; sensitivity analysis of all randomized participants
Conditions for verification: Separate the inclusion criteria for modified ITT from the scope of imputation and exclusions.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not infer that imputation within the included group brought excluded participants into the primary analysis.
Why this condition is needed: Needed to avoid calling imputation full ITT or removing the B1 defect.
Referenced methods: 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

N16 · Are alternative analyses of the same trial counted as new replications?

Required materials and conditions: Complete-case, repeated mixed-model and reweighted-allocation analyses; denominators for completing visits and for complete BDI data
Conditions for verification: Preserve sensitivity analyses within the same family and the differences in denominators.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not infer exact completion denominators absent from the current summary.
Why this condition is needed: Needed to avoid turning analysis counts into trial counts or collapsing different completion denominators into one.
Referenced methods: 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

N17 · What exact comparison and interval does +1.09 points refer to?

Required materials and conditions: Table 13 adjusted folic acid minus placebo, 0–25-week AUC average, CI/P, 223/217 and lower-is-better direction
Conditions for verification: Preserve +1.09, CI −0.48 to 2.66 and P=0.173 together with the original estimand.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not calculate new effects, CIs, P values or standardized estimates.
Why this condition is needed: Needed to avoid presenting a positive value as improvement or recasting it as a within-group or endpoint difference.
Referenced methods: 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

N18 · Do the printed SE and CI/P in Table 13 agree?

Required materials and conditions: Printed SE 0.86, CI/P, and records of numerical conflicts in tables and narrative text
Conditions for verification: Preserve both the printed values and the explanation of the conflict.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Preserve the historical conflict record; do not conduct a new normal-approximation check or generate new values.
Why this condition is needed: Needed to avoid deleting problematic printed values or silently replacing them with recalculated values.
Referenced methods: 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

N19 · Were +0.06 and −0.06 overwritten with the same sign?

Required materials and conditions: Unadjusted AUC difference in Tables 12/18, the sign printed in each table, and distinction from the adjusted primary effect
Conditions for verification: Retain the original conflict between +0.06 in Table 12 and −0.06 in Table 18 unchanged.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Differences between analyses are not automatically treated as conflicts, but the actual conflict recorded here is preserved.
Why this condition is needed: Needed to avoid erasing the sign conflict or transferring it to the adjusted primary effect.
Referenced methods: 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

N20 · Does failure to demonstrate benefit mean an effect of 0, equivalence or ineffectiveness in all MDD?

Required materials and conditions: Direction of the primary effect, CI, fixed question and original meaning of E0
Conditions for verification: Distinguish failure to demonstrate improvement in this narrow comparison from the range allowed by the interval.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not remove positive results for other doses, populations or scales.
Why this condition is needed: Needed to avoid turning nonsignificance into established absence of effect or equivalence.
Referenced methods: 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

N21 · Is the initial 3-point power target the MCID for AUC?

Required materials and conditions: Reported CI, a validated between-group threshold for clinical importance of the AUC average, and the initial 3-point target at 25 weeks
Conditions for verification: Separate the unverified applicable AUC MCID from the role of the initial design target.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not create a universal minimum sample size, duration or study count, or a new MCID.
Why this condition is needed: Needed to avoid using a power target as an MCID or as evidence excluding clinically important benefit.
Referenced methods: 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

N22 · Are endpoint means, adjusted endpoint differences and the primary AUC separated?

Required materials and conditions: Adjusted 25-week difference +1.27/CI/P, arm-specific unadjusted means and SDs, and distinct estimands
Conditions for verification: Preserve the three types of values, the 25-week time point and units separately.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not calculate new endpoint differences, standardized estimates or change scores.
Why this condition is needed: Needed to avoid combining different results into one primary effect.
Referenced methods: 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

N23 · Are FolATED reports and appendices counted as independent trials?

Required materials and conditions: FOLATED links among the report, Methods/Results, protocol/erratum, SAP, registration and appendices
Conditions for verification: Preserve the 11 linked reports S01/02/03/04/06/07/08/09/10/12/18 as one FOLATED family.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Keep verified document identities separate from the unverified complete registration history.
Why this condition is needed: Needed to avoid inflating independent replication or participant counts from the number of documents.
Referenced methods: 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

N24 · Why is the positive female-subgroup HDRS-17 result not counted as direct replication?

Required materials and conditions: 127 participants, 500 µg/day, 10 weeks, fluoxetine 20 mg, female-subgroup HDRS17, and subgroup denominators/plans
Conditions for verification: Preserve 6.8 (SD 4.1) versus 11.7 (SD 6.7), P<0.001, and the different population stratum, dose, scale and duration.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not infer the exact female denominator or prospective interaction testing.
Why this condition is needed: Needed to avoid deleting favorable adjacent results or transferring them to FolATED's overall AUC.
Referenced methods: 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

N25 · What role does the uncorrected author proof for 2.5 mg over 8 weeks have?

Required materials and conditions: Sepehrmanesh 45/45, citalopram 20 mg, 2.5 mg/day for 8 weeks, BDI-II, and version/registration
Conditions for verification: Preserve the positive result of 13.31 (SD 6.57) versus 19.11 (SD 8.59), P<0.001, together with version limitations.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not upgrade an uncorrected author proof to complete verification of the final published version.
Why this condition is needed: Needed to avoid calling it replication of the 5 mg, 25-week AUC solely because it uses the same scale name.
Referenced methods: 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

N26 · Was Resler metadata promoted to verified results?

Required materials and conditions: PMID18716414/DOI, the scope of access failure, and actual dose/denominators/effect
Conditions for verification: Separate candidate identity from unverified full-text results.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Access failure does not mean absence of a study or an effect of 0.
Why this condition is needed: Needed to avoid promoting a literature candidate to verified efficacy or a replication count.
Referenced methods: 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

N27 · Were reviews and trials in people younger than 18 combined with direct adult results?

Required materials and conditions: Discovery role of reviews S16/19, population boundary for pediatric S17, and original families
Conditions for verification: Distinguish evidence mapping and exclusion from the adult population from unverified direct results.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Preserve the roles of reviews and excluded material without deleting them.
Why this condition is needed: Needed to avoid counting reviews and material outside the adult population as independent adult replications.
Referenced methods: 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

N28 · Was the secondary SF-12 result merged into BDI-II worsening or confirmed harm?

Required materials and conditions: SF12 mental-health AUC −1.97/CI/P, favoring placebo, and nominal secondary comparison
Conditions for verification: Preserve −1.97, CI −3.49 to −0.44, P=0.012 and the endpoint's role and multiplicity context.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not turn nominal secondary significance into established clinical harm.
Why this condition is needed: Needed to avoid concealing an unfavorable result or repurposing it as a different endpoint.
Referenced methods: 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

N29 · Do small subgroups, response/remission or blood results replace the primary effect?

Required materials and conditions: Plans, denominators and individual results for low-folate/genotype/sex subgroups, response/remission and biochemistry
Conditions for verification: Preserve the existence and roles of other results and the boundaries of the primary effect.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not fill in new quantitative effects or interactions absent from the current summary.
Why this condition is needed: Needed to avoid using favorable selected results as the overall BDI-II primary effect.
Referenced methods: 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

N30 · Does public funding mean there are no competing interests?

Required materials and conditions: NIHR HTA04/35/08, COBALZ advisory/shareholder roles, Bilcare supply and funding for adjacent studies
Conditions for verification: Preserve verified public funding together with disclosed author and supplier relationships.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not automatically exclude results because a competing interest exists.
Why this condition is needed: Needed to avoid extending public funding into a guarantee of no conflicts or bias.
Referenced methods: Chamgap's own criteria for independence and attribution. The official methods sections used in this pilot do not endorse all of these detailed items

N31 · Are 33/45 and 6/14 counts of events or people?

Required materials and conditions: 25-week AE 33/45, SAE 6/14, possible drug reactions 4/3, and unique-person denominators/collection
Conditions for verification: Distinguish reported event counts and observation duration from unverified person denominators.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not calculate new harm rates, comparative risks or NNH.
Why this condition is needed: Needed to avoid turning event counts into unique patient counts, incidence or NNH.
Referenced methods: 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

N32 · Are 0 serious/unexpected reactions being read as 0 events overall?

Required materials and conditions: Scope of 0 serious or unexpected reactions among the 4/3 possible drug reactions
Conditions for verification: State both the category to which 0 refers and the overall event counts.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not turn failure to verify a significant difference into equivalence or an assurance of safety.
Why this condition is needed: Needed to avoid extending 0 in one subcategory to all AE/SAE or to long-term absence of risk.
Referenced methods: 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

N33 · Do 25/223 and 28/217 represent suicide attempts or deaths?

Required materials and conditions: 25-week MINI high-risk category, imputed analysis with 223/217, and actual suicidal-behavior/death events
Conditions for verification: Separate risk-category counts of 25/223 and 28/217 from unverified separately counted events.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not fill unverified behavior or death counts with 0.
Why this condition is needed: Needed to avoid turning a scale classification into counts of actual behavior or deaths.
Referenced methods: 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

N34 · What is the scope of documents on B12 masking and interactions?

Required materials and conditions: Masking of hematological signs of B12 deficiency, neurological problems, antiepileptics/methotrexate, and partial NIH material/SmPC
Conditions for verification: Record general safety context, the scope of material access, and boundaries between other products and trial data.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Citing an official document again does not constitute a new independent event or evidence of authorization for depression.
Why this condition is needed: Needed to avoid using general context from official documents as FolATED incidence or independent events.
Referenced methods: 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

N35 · Does 25-week observation answer every long-term or special-population safety question?

Required materials and conditions: Direct exposure and events for high-dose/long-term use, pregnancy/lactation/children, hepatic/renal disease and cancer history
Conditions for verification: Distinguish trial scope from each unverified extended harm question.
Requirement and applicability: Required for extended harm questions
Application exceptions: Do not impose studies in all special populations as requirements for this narrow efficacy question.
Why this condition is needed: Needed to avoid expanding narrow observation into assurances for all vulnerable populations or rare harms.
Referenced methods: 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

N36 · Is reading summaries distinguished from past reading of external sources?

Required materials and conditions: Exact locations/values/SHA of current stored summaries, access levels of 19 bibliographic entries, report-specific access dates and evidence cutoff date
Conditions for verification: Link the local summaries actually read in this review separately from past access levels and unread external sources.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not label external access not attempted as access failure.
Why this condition is needed: Needed to avoid upgrading a summary link to current full-text verification or using the review date as an access date.
Referenced methods: 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

N37 · Does the prior search scope represent a current exhaustive search or retraction check?

Required materials and conditions: 2026-09-15 search scope, partial/failed registration access, protocol correction, and the scope of checking retractions/new evidence
Conditions for verification: Link existing search/correction records to the scope of work currently not performed and information remaining unverified.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not merge a protocol erratum and a correction to original results into the same event.
Why this condition is needed: Needed to avoid turning 0 new searches in this review into 0 studies, proof of absence, or a claim that no recent corrections exist.
Referenced methods: 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

N38 · Are D30 and B/P/R1/I2/E0/B1/C0 being presented as a new verdict?

Required materials and conditions: Original grade/score/axes, 1 strength, document quality A, self-review and clinical certification=false
Conditions for verification: Preserve the original D30/Caution, 7 axes, meaning of E0, document quality and review level unchanged.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: External content QA is inspection of the current table conversion; it is not retroactively treated as independent review of the original clinical assessment.
Why this condition is needed: Needed to avoid turning table-criterion counts, colors or structural checks into a new efficacy score or clinical certification.
Referenced methods: 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

N39 · Are optimal dose, biomarkers, remission and mortality combined into the same answer?

Required materials and conditions: The selected AUC question and direct questions about other doses/durations, L-methylfolate, B-vitamin combinations and clinical events
Conditions for verification: Keep efficacy questions outside the selected question within separate boundaries.
Requirement and applicability: Required for extended efficacy questions
Application exceptions: Do not use inapplicability of an extension as a substitute for actual unverified product, plan or MCID information.
Why this condition is needed: Needed to avoid requiring all extension studies for the selected numerical outcome or extrapolating automatically.
Referenced methods: 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

N40 · Do historical deployment flags mean that this table has now been publicly published?

Required materials and conditions: Original 3109/assigned code/URL, server_deployed true/write false, dates, update policy and before-and-after original text
Conditions for verification: Preserve original identity and wording, and distinguish local unpublished status and versions of criteria, observations and events.
Requirement and applicability: Required for the selected FolATED BDI-II comparison
Application exceptions: Do not arbitrarily correct differences in original metadata wording or extend deployment authorization.
Why this condition is needed: Needed to avoid presenting historical identity/deployment wording as completed public publication of the current local sheet.
Referenced methods: 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

Referenced methods and the sections actually reviewed

M03 · Cochrane Handbook 6.5 (2024), chapter updated 2023-08

Official methodology · §3.1, §3.2.1–3.2.3, MECIR C5/C7/C13

Referenced principle: Clearly record the question, eligibility criteria and reasons for changes, and distinguish variations in the intervention.
Extent of review: 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

M04 · Cochrane Handbook 6.5.1 (2025), chapter updated 2025-03

Official methodology · §4.5, §4.6.1–4.6.3, MECIR C42

Referenced principle: Distinguish and link studies and reports, and do not omit a study solely because its outcomes are not reported.
Extent of review: 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

M08 · Cochrane Handbook 6.5 (2024), chapter updated 2019-10

Official methodology · §8.1–8.2.3, Table 8.2.a

Referenced principle: Hold the outcome and effect of interest fixed, then assess randomization, deviations, missing data, measurement and selective reporting.
Extent of review: 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

M15 · Cochrane Handbook 6.5 (2024), chapter updated 2023-08

Official methodology · §15.2.4, §15.3.1–15.3.3

Referenced principle: Distinguish effect estimates, intervals, importance and applicability. Sample size alone does not determine precision.
Extent of review: 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

M19 · Cochrane Handbook 6.5 (2024), chapter updated 2019-10

Official methodology · §19.1.2, §19.2.1–19.2.4

Referenced principle: Questions about harms may require designs, populations and follow-up different from efficacy questions. Case reports do not establish incidence.
Extent of review: 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

What the statuses mean

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

Change history

2026-11-05 · Public page/material version 1.0

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.

The stored-material review date (2026-10-05) and original evidence cut-off (2026-09-15) were retained unchanged.

Researcher downloads

These materials provide the same evidence, scope and verification status as this page.

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N01 · Which folic acid adjunct regimen and BDI-II outcome are being asked about?

Current findings: 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.
Verification status: Met
Materials actually 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
Why unverified: Confirms preservation of the boundaries; it is neither efficacy certification nor a verdict that all folic acid is ineffective.
Reason for missing information: Confirms preservation of the boundaries; it is neither efficacy certification nor a verdict that all folic acid is ineffective.
Required materials and conditions: 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
Materials to obtain first: 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
Further research: Review direct results within these boundaries separately from materials addressing other questions.
Remaining uncertainty: Confirms preservation of the boundaries; it is neither efficacy certification nor a verdict that all folic acid is ineffective.
Conditions for verification: Link the original claim to the boundaries of the actual regimen, comparison and time-weighted endpoint.
Why this condition is needed: Needed to avoid extending the conclusion to all folic acid and all depression.
Application exceptions: L-methylfolate, combination products, biomarkers and the single 25-week endpoint are not framed as the same question.
Referenced methods: 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

Related sources S02 S06 S07

N02 · Are the actual folic acid product and unverified manufacturing details distinguished?

Current findings: 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.
Verification status: Partly verified
Materials actually 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
Why unverified: Product form and supply are preserved, but manufacturing details and current comparison with the original source remain unverified.
Reason for missing information: Product form and supply are preserved, but manufacturing details and current comparison with the original source remain unverified.
Required materials and conditions: Active ingredient, 5 mg tablet, overencapsulation, filler, Bilcare supply, and documentation of salt/manufacturer/lot/purity
Materials to obtain first: Active ingredient, 5 mg tablet, overencapsulation, filler, Bilcare supply, and documentation of salt/manufacturer/lot/purity
Further research: Compare trial product, batch and ingredient records with the original medication section.
Remaining uncertainty: Product form and supply are preserved, but manufacturing details and current comparison with the original source remain unverified.
Conditions for verification: Record the reported active ingredient and overencapsulation separately from unverified manufacturing details.
Why this condition is needed: Needed to avoid equating the supplier with the manufacturing source or with other folate products.
Application exceptions: The authorized Flamingo product does not establish the identity of the FolATED product.
Referenced methods: M03 §3.2.2–3.2.3; reverse-direction labeling and adaptations for testing are internally designed

Related sources S02 S11

N03 · Is 5 mg as 1 daily dose the same as actual total exposure?

Current findings: 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.
Verification status: Partly verified
Materials actually 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
Why unverified: A nominal dose is available, but actual individual exposure has not been fully verified.
Reason for missing information: A nominal dose is available, but actual individual exposure has not been fully verified.
Required materials and conditions: Oral route, nominal amount for 1 dose and dosing frequency, dosing records and total exposure
Materials to obtain first: Oral route, nominal amount for 1 dose and dosing frequency, dosing records and total exposure
Further research: Link arm-specific dosing, missed doses and adherence records to the effect of interest.
Remaining uncertainty: A nominal dose is available, but actual individual exposure has not been fully verified.
Conditions for verification: Distinguish the planned oral 5 mg as 1 daily dose from unverified actual exposure.
Why this condition is needed: Needed to avoid turning the trial dose into an individual recommendation or a claim of actual complete adherence.
Application exceptions: Do not calculate new cumulative doses, conversions or recommended doses.
Referenced methods: 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

Related sources S02

N04 · Are 12 weeks of treatment distinguished from 25 weeks of observation?

Current findings: 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.
Verification status: Met
Materials actually 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
Why unverified: Confirms the time boundaries; it does not verify long-term efficacy or safety.
Reason for missing information: Confirms the time boundaries; it does not verify long-term efficacy or safety.
Required materials and conditions: End of trial treatment, observation measured from randomization, and visit times
Materials to obtain first: End of trial treatment, observation measured from randomization, and visit times
Further research: If persistence after treatment discontinuation is the question, review direct estimates and exposure at that time.
Remaining uncertainty: Confirms the time boundaries; it does not verify long-term efficacy or safety.
Conditions for verification: Show 12 weeks of treatment separately from observation through 25 weeks.
Why this condition is needed: Needed to avoid turning 25 weeks of observation into 25 weeks of treatment or a lasting long-term effect.
Application exceptions: Do not impose all long-term follow-up as a requirement for this narrow question.
Referenced methods: 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

Related sources S02 S07

N05 · What were the matching placebo and common antidepressant policy?

Current findings: 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.
Verification status: Partly verified
Materials actually 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
Why unverified: The actual placebo and policy are preserved, but individual concomitant-treatment histories have not been fully verified.
Reason for missing information: The actual placebo and policy are preserved, but individual concomitant-treatment histories have not been fully verified.
Required materials and conditions: Lactose placebo, visual matching for blinding, optimization/usual-care policy, and individual drug names/doses
Materials to obtain first: Lactose placebo, visual matching for blinding, optimization/usual-care policy, and individual drug names/doses
Further research: Link arm-specific antidepressants and medication changes to the selected BDI-II analysis.
Remaining uncertainty: The actual placebo and policy are preserved, but individual concomitant-treatment histories have not been fully verified.
Conditions for verification: Distinguish the actual added-ingredient contrast from the common policy and unverified individual exposure.
Why this condition is needed: Needed to avoid describing a shared policy as identical drugs and doses for all participants.
Application exceptions: Do not automatically exclude comparative results because concomitant treatment was used.
Referenced methods: 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

Related sources S02

N06 · Were medication changes, psychotherapy and dietary/supplement exposure verified?

Current findings: 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.
Verification status: Partly verified
Materials actually 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
Why unverified: The policy permitting changes is verified, but a complete comparison of actual concurrent-exposure balance and its analytical impact remains outstanding.
Reason for missing information: The policy permitting changes is verified, but a complete comparison of actual concurrent-exposure balance and its analytical impact remains outstanding.
Required materials and conditions: Arm-specific antidepressant changes, rescue treatment, psychotherapy, dietary/fortified-food/supplement exposure and their handling
Materials to obtain first: Arm-specific antidepressant changes, rescue treatment, psychotherapy, dietary/fortified-food/supplement exposure and their handling
Further research: Compare arm-specific changes and concurrent-exposure records with how the effect of assignment was handled.
Remaining uncertainty: The policy permitting changes is verified, but a complete comparison of actual concurrent-exposure balance and its analytical impact remains outstanding.
Conditions for verification: Separate the permitted clinical context from unverified actual treatment and exposure histories.
Why this condition is needed: Needed to avoid describing permitted changes as absent or attributing the result solely to folic acid.
Application exceptions: Do not impose a new condition that all changes must be identical.
Referenced methods: 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

Related sources S02

N07 · Which adult MDD population and screening criteria were used?

Current findings: 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.
Verification status: Met
Materials actually 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
Why unverified: Confirms the retained diagnostic and eligibility boundaries; it does not establish an effect applicable to all adults or depression subtypes.
Reason for missing information: Confirms the retained diagnostic and eligibility boundaries; it does not establish an effect applicable to all adults or depression subtypes.
Required materials and conditions: Clinician diagnosis under ICD10, moderate/severe depression, BDI-II screening/randomization criteria, and new/existing antidepressant use
Materials to obtain first: Clinician diagnosis under ICD10, moderate/severe depression, BDI-II screening/randomization criteria, and new/existing antidepressant use
Further research: Link original inclusion/exclusion criteria, recruitment and baseline status to the actual denominators.
Remaining uncertainty: Confirms the retained diagnostic and eligibility boundaries; it does not establish an effect applicable to all adults or depression subtypes.
Conditions for verification: Preserve BDI-II screening ≥19 and randomization ≥17, clinician diagnosis and the actual population boundaries.
Why this condition is needed: Needed to avoid recasting the population as entirely treatment-resistant depression or as general low mood.
Application exceptions: Do not generalize trial screening cutpoints into diagnostic criteria for all clinical care.
Referenced methods: 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

Related sources S02 S04 S18

N08 · Does deficiency screening establish normal nutritional status in everyone?

Current findings: 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.
Verification status: Partly verified
Materials actually 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
Why unverified: Screening and subgroups are preserved, but verification of every individual's nutritional status and comparison of units remain incomplete.
Reason for missing information: Screening and subgroups are preserved, but verification of every individual's nutritional status and comparison of units remain incomplete.
Required materials and conditions: Folate/B12 deficiency screening, baseline values/units and subgroups with low values
Materials to obtain first: Folate/B12 deficiency screening, baseline values/units and subgroups with low values
Further research: Compare baseline tests/units and eligibility with the prospective plan for stratified analyses.
Remaining uncertainty: Screening and subgroups are preserved, but verification of every individual's nutritional status and comparison of units remain incomplete.
Conditions for verification: Preserve screening records, small low-value subgroups and unverified units separately.
Why this condition is needed: Needed to avoid turning a screening policy into a claim that every participant had normal status.
Application exceptions: Do not repurpose results from a small low-value subgroup as the overall primary effect or an effect in confirmed deficiency.
Referenced methods: 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

Related sources S02 S03 S10

N09 · Is restricting the page to nonlactating adults the same as verifying actual lactation status?

Current findings: The trial excluded pregnancy and planned pregnancy. Page applicability is restricted to nonlactating adults, but actual trial lactation status could not be explicitly verified.
Verification status: Partly verified
Materials actually 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
Why unverified: Pregnancy exclusion is preserved, and lactation status remains unverified.
Reason for missing information: Pregnancy exclusion is preserved, and lactation status remains unverified.
Required materials and conditions: Exclusion of pregnancy/planned pregnancy, lactation inclusion/exclusion criteria and actual status
Materials to obtain first: Exclusion of pregnancy/planned pregnancy, lactation inclusion/exclusion criteria and actual status
Further research: Compare actual eligibility criteria, lactation status and evidence for special populations separately.
Remaining uncertainty: Pregnancy exclusion is preserved, and lactation status remains unverified.
Conditions for verification: Separate exclusion of pregnancy/planned pregnancy from unverified lactation status.
Why this condition is needed: Needed to avoid turning a page restriction into a record that lactating participants were actually excluded from the trial.
Application exceptions: Do not turn unverified lactation status into confirmed harm, efficacy or exclusion during lactation.
Referenced methods: 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

Related sources S02 S04 S18

N10 · Are the subjective scale's direction and collection distinguished from blinding?

Current findings: 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.
Verification status: Partly verified
Materials actually 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
Why unverified: The scale, direction and design are preserved, but current comparison of implementation details with the original source remains outstanding.
Reason for missing information: The scale, direction and design are preserved, but current comparison of implementation details with the original source remains outstanding.
Required materials and conditions: BDI-II total score, lower-is-better direction, collection at visits, matching placebo/blinding, and limitations in implementation
Materials to obtain first: BDI-II total score, lower-is-better direction, collection at visits, matching placebo/blinding, and limitations in implementation
Further research: Link scale collection and blinding implementation at each visit to the selected analysis.
Remaining uncertainty: The scale, direction and design are preserved, but current comparison of implementation details with the original source remains outstanding.
Conditions for verification: Explain the patient-reported depression total score, reported blinding and the extent of implementation not cross-checked.
Why this condition is needed: Needed to avoid asserting absence of all measurement bias solely from the scale name or double blinding.
Application exceptions: Do not treat a subjective scale as an automatic failure or recast it as a biomarker.
Referenced methods: 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

Related sources S02 S07

N11 · How should the time-weighted mean be interpreted?

Current findings: 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.
Verification status: Met
Materials actually 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
Why unverified: Confirms the retained definition; it is not a newly calculated AUC from individual-level data.
Reason for missing information: Confirms the retained definition; it is not a newly calculated AUC from individual-level data.
Required materials and conditions: Area across baseline and weeks 4/12/25, divided by the actual observation period; mean expressed in BDI-II points
Materials to obtain first: Area across baseline and weeks 4/12/25, divided by the actual observation period; mean expressed in BDI-II points
Further research: Compare definitions of the estimand and units in the original SAP and results tables.
Remaining uncertainty: Confirms the retained definition; it is not a newly calculated AUC from individual-level data.
Conditions for verification: Link the final plan's time-weighted AUC average, units and adjusted between-group estimand.
Why this condition is needed: Needed to avoid recasting it as point-weeks, within-group change or a single endpoint.
Application exceptions: Do not perform new AUC calculations or conversions in this review.
Referenced methods: 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

Related sources S02 S06 S07

N12 · Were the initial 25-week endpoint and the final AUC the same from the outset?

Current findings: 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.
Verification status: Partly verified
Materials actually 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
Why unverified: The change and its reported location are preserved, but direct comparison of the full chronology remains incomplete.
Reason for missing information: The change and its reported location are preserved, but direct comparison of the full chronology remains incomplete.
Required materials and conditions: Original protocol, erratum, final SAP, unblinding/amendment approval dates and registration history
Materials to obtain first: Original protocol, erratum, final SAP, unblinding/amendment approval dates and registration history
Further research: Compare protocol, erratum and SAP versions, registration changes and approval timing.
Remaining uncertainty: The change and its reported location are preserved, but direct comparison of the full chronology remains incomplete.
Conditions for verification: Show separately the initial single time point, final AUC, reportedly pre-unblinding SAP and unverified approval date.
Why this condition is needed: Needed to avoid concealing the endpoint change and unverified details.
Application exceptions: Do not turn an unavailable plan into confirmed selective reporting or a claim of an identical prospective plan from the outset.
Referenced methods: 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

Related sources S04 S07 S08 S09 S18

N13 · To what extent are the actual comparative design and allocation process verified?

Current findings: 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.
Verification status: Partly verified
Materials actually 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
Why unverified: The design is preserved, but verification of detailed implementation does not extend beyond the current local records.
Reason for missing information: The design is preserved, but verification of detailed implementation does not extend beyond the current local records.
Required materials and conditions: Multicenter individually randomized parallel groups, matching placebo, allocation/concealment and baseline balance
Materials to obtain first: Multicenter individually randomized parallel groups, matching placebo, allocation/concealment and baseline balance
Further research: Link original randomization/concealment information and baseline tables to the selected outcome.
Remaining uncertainty: The design is preserved, but verification of detailed implementation does not extend beyond the current local records.
Conditions for verification: Distinguish the recorded actual design from details not cross-checked in this review.
Why this condition is needed: Needed to avoid extending the design label into complete verification of concealment and baseline balance.
Application exceptions: Do not turn unverified details into a nonrandomized classification or automatic failure.
Referenced methods: M03 §3.2.1; detailed population criteria are internally designed; M08 §8.1–8.2.3; internal application

Related sources S02 S04

N14 · What do the denominators of 475 and 440 represent?

Current findings: 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.
Verification status: Met
Materials actually 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
Why unverified: Confirms preservation of the denominator distinctions; it does not mean the impact of loss to follow-up has been resolved.
Reason for missing information: Confirms preservation of the denominator distinctions; it does not mean the impact of loss to follow-up has been resolved.
Required materials and conditions: Valid allocation 237/238, total 475; 35 with no follow-up BDI-II; mITT 223/217, total 440
Materials to obtain first: Valid allocation 237/238, total 475; 35 with no follow-up BDI-II; mITT 223/217, total 440
Further research: Compare the original flowchart, analysis definitions and loss to follow-up by arm.
Remaining uncertainty: Confirms preservation of the denominator distinctions; it does not mean the impact of loss to follow-up has been resolved.
Conditions for verification: Preserve allocation, reasons for exclusion and primary-analysis denominators together with their arms.
Why this condition is needed: Needed to avoid substituting the allocation denominator for analysis or completion denominators.
Application exceptions: Do not create dropout rates, new denominators or new calculations in this review.
Referenced methods: 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

Related sources S03 S06

N15 · Does regression imputation include the 35 excluded participants?

Current findings: 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.
Verification status: Partly verified
Materials actually 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
Why unverified: The retained analysis and missing-data scope are available, but the impact of exclusions was neither fully resolved nor reanalyzed.
Reason for missing information: The retained analysis and missing-data scope are available, but the impact of exclusions was neither fully resolved nor reanalyzed.
Required materials and conditions: Assigned groups retained; inclusion requires at least 1 follow-up; imputation within the 440; sensitivity analysis of all randomized participants
Materials to obtain first: Assigned groups retained; inclusion requires at least 1 follow-up; imputation within the 440; sensitivity analysis of all randomized participants
Further research: Compare original missing-data reasons, imputation and sensitivity methods with the effect of interest.
Remaining uncertainty: The retained analysis and missing-data scope are available, but the impact of exclusions was neither fully resolved nor reanalyzed.
Conditions for verification: Separate the inclusion criteria for modified ITT from the scope of imputation and exclusions.
Why this condition is needed: Needed to avoid calling imputation full ITT or removing the B1 defect.
Application exceptions: Do not infer that imputation within the included group brought excluded participants into the primary analysis.
Referenced methods: 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

Related sources S02 S03 S07

N16 · Are alternative analyses of the same trial counted as new replications?

Current findings: 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.
Verification status: Partly verified
Materials actually 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
Why unverified: Sensitivity-analysis types and denominator differences are available, but comparison of all values and denominators in the original tables remains outstanding.
Reason for missing information: Sensitivity-analysis types and denominator differences are available, but comparison of all values and denominators in the original tables remains outstanding.
Required materials and conditions: Complete-case, repeated mixed-model and reweighted-allocation analyses; denominators for completing visits and for complete BDI data
Materials to obtain first: Complete-case, repeated mixed-model and reweighted-allocation analyses; denominators for completing visits and for complete BDI data
Further research: Compare original Tables 18–20 and participant flow with each analysis denominator and result.
Remaining uncertainty: Sensitivity-analysis types and denominator differences are available, but comparison of all values and denominators in the original tables remains outstanding.
Conditions for verification: Preserve sensitivity analyses within the same family and the differences in denominators.
Why this condition is needed: Needed to avoid turning analysis counts into trial counts or collapsing different completion denominators into one.
Application exceptions: Do not infer exact completion denominators absent from the current summary.
Referenced methods: 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

Related sources S02 S03 S07

N17 · What exact comparison and interval does +1.09 points refer to?

Current findings: 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.
Verification status: Met
Materials actually 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
Why unverified: Confirms preservation of the reported effect and direction; the original table's SE conflict remains separately recorded.
Reason for missing information: Confirms preservation of the reported effect and direction; the original table's SE conflict remains separately recorded.
Required materials and conditions: Table 13 adjusted folic acid minus placebo, 0–25-week AUC average, CI/P, 223/217 and lower-is-better direction
Materials to obtain first: Table 13 adjusted folic acid minus placebo, 0–25-week AUC average, CI/P, 223/217 and lower-is-better direction
Further research: Compare original Table 13, narrative text, analysis definitions and printed values.
Remaining uncertainty: Confirms preservation of the reported effect and direction; the original table's SE conflict remains separately recorded.
Conditions for verification: Preserve +1.09, CI −0.48 to 2.66 and P=0.173 together with the original estimand.
Why this condition is needed: Needed to avoid presenting a positive value as improvement or recasting it as a within-group or endpoint difference.
Application exceptions: Do not calculate new effects, CIs, P values or standardized estimates.
Referenced methods: 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

Related sources S03 S06 S07

N18 · Do the printed SE and CI/P in Table 13 agree?

Current findings: 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.
Verification status: Conflicting printed values
Materials actually 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
Why unverified: The conflict between original printed values remains unresolved; no new calculation or correction was made in this review.
Reason for missing information: The conflict between original printed values remains unresolved; no new calculation or correction was made in this review.
Required materials and conditions: Printed SE 0.86, CI/P, and records of numerical conflicts in tables and narrative text
Materials to obtain first: Printed SE 0.86, CI/P, and records of numerical conflicts in tables and narrative text
Further research: During an authorized correction, compare the original table, analysis output and errata, and retain before-and-after values.
Remaining uncertainty: The conflict between original printed values remains unresolved; no new calculation or correction was made in this review.
Conditions for verification: Preserve both the printed values and the explanation of the conflict.
Why this condition is needed: Needed to avoid deleting problematic printed values or silently replacing them with recalculated values.
Application exceptions: Preserve the historical conflict record; do not conduct a new normal-approximation check or generate new values.
Referenced methods: 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

Related sources S03 S06

N19 · Were +0.06 and −0.06 overwritten with the same sign?

Current findings: 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.
Verification status: Conflicting printed values
Materials actually 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
Why unverified: Resolution of the unadjusted sign conflict remains unverified; no correction or recalculation was made in this review.
Reason for missing information: Resolution of the unadjusted sign conflict remains unverified; no correction or recalculation was made in this review.
Required materials and conditions: Unadjusted AUC difference in Tables 12/18, the sign printed in each table, and distinction from the adjusted primary effect
Materials to obtain first: Unadjusted AUC difference in Tables 12/18, the sign printed in each table, and distinction from the adjusted primary effect
Further research: Compare original tables/directions, errata and analysis outputs as a separate correction event.
Remaining uncertainty: Resolution of the unadjusted sign conflict remains unverified; no correction or recalculation was made in this review.
Conditions for verification: Retain the original conflict between +0.06 in Table 12 and −0.06 in Table 18 unchanged.
Why this condition is needed: Needed to avoid erasing the sign conflict or transferring it to the adjusted primary effect.
Application exceptions: Differences between analyses are not automatically treated as conflicts, but the actual conflict recorded here is preserved.
Referenced methods: 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

Related sources S03 S06

N20 · Does failure to demonstrate benefit mean an effect of 0, equivalence or ineffectiveness in all MDD?

Current findings: 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.
Verification status: Met
Materials actually 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
Why unverified: Confirms preservation of interpretive boundaries; it is not a new conclusion of equivalence or ineffectiveness.
Reason for missing information: Confirms preservation of interpretive boundaries; it is not a new conclusion of equivalence or ineffectiveness.
Required materials and conditions: Direction of the primary effect, CI, fixed question and original meaning of E0
Materials to obtain first: Direction of the primary effect, CI, fixed question and original meaning of E0
Further research: Review direct results for the same estimand and relevant clinical thresholds alongside additional evidence.
Remaining uncertainty: Confirms preservation of interpretive boundaries; it is not a new conclusion of equivalence or ineffectiveness.
Conditions for verification: Distinguish failure to demonstrate improvement in this narrow comparison from the range allowed by the interval.
Why this condition is needed: Needed to avoid turning nonsignificance into established absence of effect or equivalence.
Application exceptions: Do not remove positive results for other doses, populations or scales.
Referenced methods: 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

Related sources S06 S13 S15

N21 · Is the initial 3-point power target the MCID for AUC?

Current findings: 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.
Verification status: Unverified
Materials actually 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
Why unverified: Because an applicable importance threshold is unverified, exclusion of clinically important benefit is not established.
Reason for missing information: Because an applicable importance threshold is unverified, exclusion of clinically important benefit is not established.
Required materials and conditions: Reported CI, a validated between-group threshold for clinical importance of the AUC average, and the initial 3-point target at 25 weeks
Materials to obtain first: Reported CI, a validated between-group threshold for clinical importance of the AUC average, and the initial 3-point target at 25 weeks
Further research: Compare a justified threshold for the same endpoint and estimand with the CI.
Remaining uncertainty: Because an applicable importance threshold is unverified, exclusion of clinically important benefit is not established.
Conditions for verification: Separate the unverified applicable AUC MCID from the role of the initial design target.
Why this condition is needed: Needed to avoid using a power target as an MCID or as evidence excluding clinically important benefit.
Application exceptions: Do not create a universal minimum sample size, duration or study count, or a new MCID.
Referenced methods: 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

Related sources S02 S06

N22 · Are endpoint means, adjusted endpoint differences and the primary AUC separated?

Current findings: 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.
Verification status: Met
Materials actually 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
Why unverified: Confirms preservation of time-point, dispersion and analysis distinctions; the original tables were not newly verified in this review.
Reason for missing information: Confirms preservation of time-point, dispersion and analysis distinctions; the original tables were not newly verified in this review.
Required materials and conditions: Adjusted 25-week difference +1.27/CI/P, arm-specific unadjusted means and SDs, and distinct estimands
Materials to obtain first: Adjusted 25-week difference +1.27/CI/P, arm-specific unadjusted means and SDs, and distinct estimands
Further research: Compare Table 14 and Appendix 10/Table 42 with the original analysis definitions.
Remaining uncertainty: Confirms preservation of time-point, dispersion and analysis distinctions; the original tables were not newly verified in this review.
Conditions for verification: Preserve the three types of values, the 25-week time point and units separately.
Why this condition is needed: Needed to avoid combining different results into one primary effect.
Application exceptions: Do not calculate new endpoint differences, standardized estimates or change scores.
Referenced methods: 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

Related sources S10 S12

N23 · Are FolATED reports and appendices counted as independent trials?

Current findings: 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.
Verification status: Met
Materials actually 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
Why unverified: Confirms preservation of family links; it does not mean 19 bibliographic records represent 19 trials.
Reason for missing information: Confirms preservation of family links; it does not mean 19 bibliographic records represent 19 trials.
Required materials and conditions: FOLATED links among the report, Methods/Results, protocol/erratum, SAP, registration and appendices
Materials to obtain first: FOLATED links among the report, Methods/Results, protocol/erratum, SAP, registration and appendices
Further research: Verify the unique recruitment/allocation identity and distinctions from other families at the original locations.
Remaining uncertainty: Confirms preservation of family links; it does not mean 19 bibliographic records represent 19 trials.
Conditions for verification: Preserve the 11 linked reports S01/02/03/04/06/07/08/09/10/12/18 as one FOLATED family.
Why this condition is needed: Needed to avoid inflating independent replication or participant counts from the number of documents.
Application exceptions: Keep verified document identities separate from the unverified complete registration history.
Referenced methods: 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

Related sources S01 S02 S03 S04 S06 S07 S08 S09 S10 S12 S18

N24 · Why is the positive female-subgroup HDRS-17 result not counted as direct replication?

Current findings: 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.
Verification status: Partly verified
Materials actually 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
Why unverified: A positive abstract result is available, but subgroup plans/denominators, the full text and direct applicability to the identical question remain unverified.
Reason for missing information: A positive abstract result is available, but subgroup plans/denominators, the full text and direct applicability to the identical question remain unverified.
Required materials and conditions: 127 participants, 500 µg/day, 10 weeks, fluoxetine 20 mg, female-subgroup HDRS17, and subgroup denominators/plans
Materials to obtain first: 127 participants, 500 µg/day, 10 weeks, fluoxetine 20 mg, female-subgroup HDRS17, and subgroup denominators/plans
Further research: Compare the abstract's scope with subgroup plans/denominators and the direct comparison in the original full text.
Remaining uncertainty: A positive abstract result is available, but subgroup plans/denominators, the full text and direct applicability to the identical question remain unverified.
Conditions for verification: Preserve 6.8 (SD 4.1) versus 11.7 (SD 6.7), P<0.001, and the different population stratum, dose, scale and duration.
Why this condition is needed: Needed to avoid deleting favorable adjacent results or transferring them to FolATED's overall AUC.
Application exceptions: Do not infer the exact female denominator or prospective interaction testing.
Referenced methods: 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

Related sources S13

N25 · What role does the uncorrected author proof for 2.5 mg over 8 weeks have?

Current findings: 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.
Verification status: Partly verified
Materials actually 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
Why unverified: Results are available from the accessed version, but the final version and registration, and direct replication of the selected question, remain unverified.
Reason for missing information: Results are available from the accessed version, but the final version and registration, and direct replication of the selected question, remain unverified.
Required materials and conditions: Sepehrmanesh 45/45, citalopram 20 mg, 2.5 mg/day for 8 weeks, BDI-II, and version/registration
Materials to obtain first: Sepehrmanesh 45/45, citalopram 20 mg, 2.5 mg/day for 8 weeks, BDI-II, and version/registration
Further research: Compare the final publication version, registration history, denominators and plans with the different exposures and estimands.
Remaining uncertainty: Results are available from the accessed version, but the final version and registration, and direct replication of the selected question, remain unverified.
Conditions for verification: Preserve the positive result of 13.31 (SD 6.57) versus 19.11 (SD 8.59), P<0.001, together with version limitations.
Why this condition is needed: Needed to avoid calling it replication of the 5 mg, 25-week AUC solely because it uses the same scale name.
Application exceptions: Do not upgrade an uncorrected author proof to complete verification of the final published version.
Referenced methods: 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

Related sources S15

N26 · Was Resler metadata promoted to verified results?

Current findings: 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.
Verification status: Unverified
Materials actually 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
Why unverified: A bibliographic candidate exists, but no full-text verification is available to satisfy the result criteria.
Reason for missing information: A bibliographic candidate exists, but no full-text verification is available to satisfy the result criteria.
Required materials and conditions: PMID18716414/DOI, the scope of access failure, and actual dose/denominators/effect
Materials to obtain first: PMID18716414/DOI, the scope of access failure, and actual dose/denominators/effect
Further research: If separately obtaining the source is authorized, link the original results, design, exposure and denominators.
Remaining uncertainty: A bibliographic candidate exists, but no full-text verification is available to satisfy the result criteria.
Conditions for verification: Separate candidate identity from unverified full-text results.
Why this condition is needed: Needed to avoid promoting a literature candidate to verified efficacy or a replication count.
Application exceptions: Access failure does not mean absence of a study or an effect of 0.
Referenced methods: 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

Related sources S14

N27 · Were reviews and trials in people younger than 18 combined with direct adult results?

Current findings: 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.
Verification status: Met
Materials actually 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
Why unverified: Confirms roles and exclusion boundaries; not all underlying trials in the reviews were verified in this review.
Reason for missing information: Confirms roles and exclusion boundaries; not all underlying trials in the reviews were verified in this review.
Required materials and conditions: Discovery role of reviews S16/19, population boundary for pediatric S17, and original families
Materials to obtain first: Discovery role of reviews S16/19, population boundary for pediatric S17, and original families
Further research: If needed, separately compare underlying trial identities, adult-population boundaries and actual results.
Remaining uncertainty: Confirms roles and exclusion boundaries; not all underlying trials in the reviews were verified in this review.
Conditions for verification: Distinguish evidence mapping and exclusion from the adult population from unverified direct results.
Why this condition is needed: Needed to avoid counting reviews and material outside the adult population as independent adult replications.
Application exceptions: Preserve the roles of reviews and excluded material without deleting them.
Referenced methods: 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

Related sources S16 S17 S19

N28 · Was the secondary SF-12 result merged into BDI-II worsening or confirmed harm?

Current findings: 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.
Verification status: Met
Materials actually 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
Why unverified: Confirms preservation of the unfavorable result and its role; it does not certify a causal harm relationship.
Reason for missing information: Confirms preservation of the unfavorable result and its role; it does not certify a causal harm relationship.
Required materials and conditions: SF12 mental-health AUC −1.97/CI/P, favoring placebo, and nominal secondary comparison
Materials to obtain first: SF12 mental-health AUC −1.97/CI/P, favoring placebo, and nominal secondary comparison
Further research: Compare original Table 13, the plan, multiplicity and clinical meaning for that scale.
Remaining uncertainty: Confirms preservation of the unfavorable result and its role; it does not certify a causal harm relationship.
Conditions for verification: Preserve −1.97, CI −3.49 to −0.44, P=0.012 and the endpoint's role and multiplicity context.
Why this condition is needed: Needed to avoid concealing an unfavorable result or repurposing it as a different endpoint.
Application exceptions: Do not turn nominal secondary significance into established clinical harm.
Referenced methods: 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

Related sources S03 S06 S10

N29 · Do small subgroups, response/remission or blood results replace the primary effect?

Current findings: 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.
Verification status: Partly verified
Materials actually 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
Why unverified: The roles of other analyses are available, but verification of complete plans, quantitative results and denominators is limited.
Reason for missing information: The roles of other analyses are available, but verification of complete plans, quantitative results and denominators is limited.
Required materials and conditions: Plans, denominators and individual results for low-folate/genotype/sex subgroups, response/remission and biochemistry
Materials to obtain first: Plans, denominators and individual results for low-folate/genotype/sex subgroups, response/remission and biochemistry
Further research: Separately compare prospective subgroup/interaction plans, denominators, multiplicity and original results.
Remaining uncertainty: The roles of other analyses are available, but verification of complete plans, quantitative results and denominators is limited.
Conditions for verification: Preserve the existence and roles of other results and the boundaries of the primary effect.
Why this condition is needed: Needed to avoid using favorable selected results as the overall BDI-II primary effect.
Application exceptions: Do not fill in new quantitative effects or interactions absent from the current summary.
Referenced methods: 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

Related sources S03 S10

N30 · Does public funding mean there are no competing interests?

Current findings: 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.
Verification status: Partly verified
Materials actually 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
Why unverified: Public funding and disclosed relationships are available, but not all competing interests or funding for adjacent studies have been fully verified.
Reason for missing information: Public funding and disclosed relationships are available, but not all competing interests or funding for adjacent studies have been fully verified.
Required materials and conditions: NIHR HTA04/35/08, COBALZ advisory/shareholder roles, Bilcare supply and funding for adjacent studies
Materials to obtain first: NIHR HTA04/35/08, COBALZ advisory/shareholder roles, Bilcare supply and funding for adjacent studies
Further research: Compare the original funding/COI/supply information and the scope of adjacent-study disclosures.
Remaining uncertainty: Public funding and disclosed relationships are available, but not all competing interests or funding for adjacent studies have been fully verified.
Conditions for verification: Preserve verified public funding together with disclosed author and supplier relationships.
Why this condition is needed: Needed to avoid extending public funding into a guarantee of no conflicts or bias.
Application exceptions: Do not automatically exclude results because a competing interest exists.
Referenced methods: Chamgap's own criteria for independence and attribution. The official methods sections used in this pilot do not endorse all of these detailed items

Related sources S01 S02 S13 S15 S18

N31 · Are 33/45 and 6/14 counts of events or people?

Current findings: 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.
Verification status: Partly verified
Materials actually 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
Why unverified: Reported event counts are available, but verification of unique-person denominators, complete collection, causality and comparative risk remains incomplete.
Reason for missing information: Reported event counts are available, but verification of unique-person denominators, complete collection, causality and comparative risk remains incomplete.
Required materials and conditions: 25-week AE 33/45, SAE 6/14, possible drug reactions 4/3, and unique-person denominators/collection
Materials to obtain first: 25-week AE 33/45, SAE 6/14, possible drug reactions 4/3, and unique-person denominators/collection
Further research: Compare event definitions and collection, exposure, unique people and missingness in original Tables 15–17.
Remaining uncertainty: Reported event counts are available, but verification of unique-person denominators, complete collection, causality and comparative risk remains incomplete.
Conditions for verification: Distinguish reported event counts and observation duration from unverified person denominators.
Why this condition is needed: Needed to avoid turning event counts into unique patient counts, incidence or NNH.
Application exceptions: Do not calculate new harm rates, comparative risks or NNH.
Referenced methods: 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

Related sources S03

N32 · Are 0 serious/unexpected reactions being read as 0 events overall?

Current findings: 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.
Verification status: Met
Materials actually 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
Why unverified: Confirms preservation of the scope of 0 events; it does not verify absence of all harms.
Reason for missing information: Confirms preservation of the scope of 0 events; it does not verify absence of all harms.
Required materials and conditions: Scope of 0 serious or unexpected reactions among the 4/3 possible drug reactions
Materials to obtain first: Scope of 0 serious or unexpected reactions among the 4/3 possible drug reactions
Further research: Compare original reaction classifications, seriousness/expectedness and collection scope.
Remaining uncertainty: Confirms preservation of the scope of 0 events; it does not verify absence of all harms.
Conditions for verification: State both the category to which 0 refers and the overall event counts.
Why this condition is needed: Needed to avoid extending 0 in one subcategory to all AE/SAE or to long-term absence of risk.
Application exceptions: Do not turn failure to verify a significant difference into equivalence or an assurance of safety.
Referenced methods: 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

Related sources S03

N33 · Do 25/223 and 28/217 represent suicide attempts or deaths?

Current findings: 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.
Verification status: Partly verified
Materials actually 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
Why unverified: Risk classification is preserved, but event data for comparisons of actual behavior and deaths remain unverified.
Reason for missing information: Risk classification is preserved, but event data for comparisons of actual behavior and deaths remain unverified.
Required materials and conditions: 25-week MINI high-risk category, imputed analysis with 223/217, and actual suicidal-behavior/death events
Materials to obtain first: 25-week MINI high-risk category, imputed analysis with 223/217, and actual suicidal-behavior/death events
Further research: Compare original MINI definitions, imputation, collection and actual event records with their respective denominators.
Remaining uncertainty: Risk classification is preserved, but event data for comparisons of actual behavior and deaths remain unverified.
Conditions for verification: Separate risk-category counts of 25/223 and 28/217 from unverified separately counted events.
Why this condition is needed: Needed to avoid turning a scale classification into counts of actual behavior or deaths.
Application exceptions: Do not fill unverified behavior or death counts with 0.
Referenced methods: 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

Related sources S03

N34 · What is the scope of documents on B12 masking and interactions?

Current findings: 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.
Verification status: Partly verified
Materials actually 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
Why unverified: 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.
Reason for missing information: 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.
Required materials and conditions: Masking of hematological signs of B12 deficiency, neurological problems, antiepileptics/methotrexate, and partial NIH material/SmPC
Materials to obtain first: Masking of hematological signs of B12 deficiency, neurological problems, antiepileptics/methotrexate, and partial NIH material/SmPC
Further research: Separately compare original safety documents, case/study families, exposure, timing and alternative explanations.
Remaining 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.
Conditions for verification: Record general safety context, the scope of material access, and boundaries between other products and trial data.
Why this condition is needed: Needed to avoid using general context from official documents as FolATED incidence or independent events.
Application exceptions: Citing an official document again does not constitute a new independent event or evidence of authorization for depression.
Referenced methods: 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

Related sources S05 S11

N35 · Does 25-week observation answer every long-term or special-population safety question?

Current findings: 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.
Verification status: Unverified
Materials actually 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
Why unverified: Extended harm information remains unverified within the selected materials.
Reason for missing information: Extended harm information remains unverified within the selected materials.
Required materials and conditions: Direct exposure and events for high-dose/long-term use, pregnancy/lactation/children, hepatic/renal disease and cancer history
Materials to obtain first: Direct exposure and events for high-dose/long-term use, pregnancy/lactation/children, hepatic/renal disease and cancer history
Further research: Separately design or review material suited to the relevant exposure, population and long-term/rare events.
Remaining uncertainty: Extended harm information remains unverified within the selected materials.
Conditions for verification: Distinguish trial scope from each unverified extended harm question.
Why this condition is needed: Needed to avoid expanding narrow observation into assurances for all vulnerable populations or rare harms.
Application exceptions: Do not impose studies in all special populations as requirements for this narrow efficacy question.
Referenced methods: 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

Related sources S02 S05 S11

N36 · Is reading summaries distinguished from past reading of external sources?

Current findings: 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.
Verification status: Partly verified
Materials actually 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
Why unverified: The current summaries are verified, but current reading of external full texts, their original bytes and report-specific access dates remain unverified.
Reason for missing information: The current summaries are verified, but current reading of external full texts, their original bytes and report-specific access dates remain unverified.
Required materials and conditions: Exact locations/values/SHA of current stored summaries, access levels of 19 bibliographic entries, report-specific access dates and evidence cutoff date
Materials to obtain first: Exact locations/values/SHA of current stored summaries, access levels of 19 bibliographic entries, report-specific access dates and evidence cutoff date
Further research: When original materials are actually obtained, separately preserve material types, dates, locations read and original bytes.
Remaining uncertainty: The current summaries are verified, but current reading of external full texts, their original bytes and report-specific access dates remain unverified.
Conditions for verification: Link the local summaries actually read in this review separately from past access levels and unread external sources.
Why this condition is needed: Needed to avoid upgrading a summary link to current full-text verification or using the review date as an access date.
Application exceptions: Do not label external access not attempted as access failure.
Referenced methods: 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

Related sources S01 S05 S09 S13 S14 S15

N37 · Does the prior search scope represent a current exhaustive search or retraction check?

Current findings: 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.
Verification status: Partly verified
Materials actually 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
Why unverified: 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.
Reason for missing information: 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.
Required materials and conditions: 2026-09-15 search scope, partial/failed registration access, protocol correction, and the scope of checking retractions/new evidence
Materials to obtain first: 2026-09-15 search scope, partial/failed registration access, protocol correction, and the scope of checking retractions/new evidence
Further research: During a separately authorized search or correction, preserve complete original texts, events, before-and-after values and versions.
Remaining 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.
Conditions for verification: Link existing search/correction records to the scope of work currently not performed and information remaining unverified.
Why this condition is needed: 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 exceptions: Do not merge a protocol erratum and a correction to original results into the same event.
Referenced methods: 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

Related sources S04 S09 S18

N38 · Are D30 and B/P/R1/I2/E0/B1/C0 being presented as a new verdict?

Current findings: 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.
Verification status: Met
Materials actually 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
Why unverified: Confirms preservation of original values and review boundaries; no new clinical grade or certification was assigned.
Reason for missing information: Confirms preservation of original values and review boundaries; no new clinical grade or certification was assigned.
Required materials and conditions: Original grade/score/axes, 1 strength, document quality A, self-review and clinical certification=false
Materials to obtain first: Original grade/score/axes, 1 strength, document quality A, self-review and clinical certification=false
Further research: If a correction is separately authorized, record the original evidence, verdict, reasons and before-and-after values as an event.
Remaining uncertainty: Confirms preservation of original values and review boundaries; no new clinical grade or certification was assigned.
Conditions for verification: Preserve the original D30/Caution, 7 axes, meaning of E0, document quality and review level unchanged.
Why this condition is needed: Needed to avoid turning table-criterion counts, colors or structural checks into a new efficacy score or clinical certification.
Application exceptions: External content QA is inspection of the current table conversion; it is not retroactively treated as independent review of the original clinical assessment.
Referenced methods: 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

Related sources S01 S02 S06

N39 · Are optimal dose, biomarkers, remission and mortality combined into the same answer?

Current findings: 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.
Verification status: Not applicable
Materials actually 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
Why unverified: Indicates that an extension outside the selected question is not applicable; it does not erase unverified information about the actual trial.
Reason for missing information: Indicates that an extension outside the selected question is not applicable; it does not erase unverified information about the actual trial.
Required materials and conditions: The selected AUC question and direct questions about other doses/durations, L-methylfolate, B-vitamin combinations and clinical events
Materials to obtain first: The selected AUC question and direct questions about other doses/durations, L-methylfolate, B-vitamin combinations and clinical events
Further research: If an extension is asked about, separately compare direct dose, follow-up and event data.
Remaining uncertainty: Indicates that an extension outside the selected question is not applicable; it does not erase unverified information about the actual trial.
Conditions for verification: Keep efficacy questions outside the selected question within separate boundaries.
Why this condition is needed: Needed to avoid requiring all extension studies for the selected numerical outcome or extrapolating automatically.
Application exceptions: Do not use inapplicability of an extension as a substitute for actual unverified product, plan or MCID information.
Referenced methods: 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

Related sources S02 S10 S13 S15

N40 · Do historical deployment flags mean that this table has now been publicly published?

Current findings: 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.
Verification status: Partly verified
Materials actually 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
Why unverified: Original metadata and update provisions are preserved, but authoritative correction of publication wording and actual site implementation were not performed in this review.
Reason for missing information: Original metadata and update provisions are preserved, but authoritative correction of publication wording and actual site implementation were not performed in this review.
Required materials and conditions: Original 3109/assigned code/URL, server_deployed true/write false, dates, update policy and before-and-after original text
Materials to obtain first: Original 3109/assigned code/URL, server_deployed true/write false, dates, update policy and before-and-after original text
Further research: During an authorized update, retain complete originals, original values/contrary results, reasons for changes and versions.
Remaining uncertainty: Original metadata and update provisions are preserved, but authoritative correction of publication wording and actual site implementation were not performed in this review.
Conditions for verification: Preserve original identity and wording, and distinguish local unpublished status and versions of criteria, observations and events.
Why this condition is needed: Needed to avoid presenting historical identity/deployment wording as completed public publication of the current local sheet.
Application exceptions: Do not arbitrarily correct differences in original metadata wording or extend deployment authorization.
Referenced methods: 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

Related sources