In plain terms

The claim being assessed: Peripheral inflammatory signalling causes major depressive disorder in the subgroup with elevated baseline inflammatory markers.

Where the evidence stands: Γ — Plausible mechanism. There is a believable biological story and partial support, but the causal step has not been demonstrated.

What this mechanism does: This makes the process worse or keeps it going, but something else starts it.

Strongest evidence for it: Overall Γ follows registered SC3. Baseline prediction is Β, and sustained immune-treatment-related syndromes earn a restricted Ε at SC2. Neither narrow immune exposure nor exploratory high-CRP response establishes prospectively identifiable inflammatory MDD causation. Genuine positive clinical pilot findings are retained alongside larger or prospectively stratified nulls. The next clinical subtype boundary remains open rather than being declared refuted.

What decisive evidence would look like

In plain terms, researchers would change the proposed cause, confirm it changed as intended, and measure a meaningful health outcome while checking other explanations. The result should be able to support or count against the claim.

Relative explanatory fit: Alternative ranked ahead

What this review means

Inflammation can alter mood and contribute to defined depressive syndromes; a causal high-inflammation MDD subtype still needs prospective confirmation.

Implications for health and treatment: Overall Γ follows registered SC3. Baseline prediction is Β, and sustained immune-treatment-related syndromes earn a restricted Ε at SC2. Neither narrow immune exposure nor exploratory high-CRP response establishes prospectively identifiable inflammatory MDD causation. Genuine positive clinical pilot findings are retained alongside larger or prospectively stratified nulls. The next clinical subtype boundary remains open rather than being declared refuted.

Limits for individual care: 56 primary reports with 5 selected partial-body examinations; density, heterogeneous controls and incomplete access set the confidence, not correctness. The grade applies to the exact registered claim; stronger findings for narrower subclaims remain separate. No complete-paper audit or blinded calibration is claimed. This educational review does not establish an individual treatment recommendation.

Medical information notice: This review provides general health information, not medical advice. It cannot diagnose a condition or replace an individual discussion with a qualified clinician.

Source checking used bounded original primary abstract passages/status records and selected original partial-body passages. No complete-abstract or complete-paper audit, or independent scientific peer review, is claimed. Detailed access counts and limitations appear in the review.

A low grade is not an accusation. It means the causal work has not been done yet, which is the ordinary state of most actively studied mechanisms in biology.

At a glance

Sub-claims assessed separately

Full assessment

From here the review is written for a technical reader: caps and thresholds, competing models, the independence basis, and the citation ledger.

Sources: 56 primary reports; claims: 60; verified: 60; unverified: 0. Verification is bounded attribution. Access: 5 partial-body and 51 bounded abstract/status examinations. Literature cutoff: 2026-10-09; source examination UTC date: 2026-10-12. No complete-paper audit or blinded calibration claimed.

Adversarial review: Authoring model of record: Sol 6.1 (this package's own review_metadata.reviewer and provenance_header.generated_by fields record "Codex; HSEF v5.3"; recorded, not edited). Adversarially reviewed by Claude Opus 5.5 (Anthropic) on 2026-10-14. 5 corrections applied (see ADVERSARIAL REVIEW AND APPROVAL). Status: Approved as revised.

AT A GLANCE

Inflammation can alter mood and contribute to defined depressive syndromes; a causal high-inflammation MDD subtype still needs prospective confirmation.

Deciding experiment: Prospectively registered marker-stratified MDD trial with a fixed assay/cut-off, powered treatment-by-marker interaction, selective immune-pathway engagement, matched clinical attention and blinded sustained clinical/function outcomes; compare a mechanistically distinct intervention and replicate independently. INSTA-MD addresses part of this design, but drug pleiotropy and target engagement still require examination.

Belief versus evidence: Overall Γ follows registered SC3. Baseline prediction is Β, and sustained immune-treatment-related syndromes earn a restricted Ε at SC2. Neither narrow immune exposure nor exploratory high-CRP response establishes prospectively identifiable inflammatory MDD causation. Genuine positive clinical pilot findings are retained alongside larger or prospectively stratified nulls. The next clinical subtype boundary remains open rather than being declared refuted.

Best-supported rival: Context-specific immune effects. The randomized high-CRP challenge (PMID 40264292) separates genuine immune-triggered acute anhedonia from a purely shared-cause account, but not sustained-MDD primacy. For the clinical subtype boundary, PREDDICT (PMID 37635396) is the strongest prospectively stratified discriminator and is null. These questions and endpoints are deliberately not merged.

COMPETING MECHANISTIC MODELS

Rank 1: Context-specific immune effects (Ε). Defined immune treatments/stimuli alter mood and sometimes sustained depressive trajectories. Interferon clinical chronology and challenge effects establish meaningful restricted contexts. Acute effects and medical drug syndromes do not prove ordinary high-marker MDD primacy.

Rank 2: Shared metabolic/stress causes (Γ). Inflammatory markers and depression share obesity, sleep, smoking, trauma and physical-illness pathways. MR heterogeneity, reverse-direction cohorts and phenotype specificity support this explanation. A flexible shared-cause account cannot explain away all experimentally induced immune symptoms.

Rank 3: Depression-induced inflammation (Β). Depression, treatment and associated behaviour can raise some markers. Prospective reverse direction and antidepressant/CRP associations support part of the chain. Direction is not universal and does not exclude immune-to-mood effects.

Rank 4: Inflammatory MDD subtype (Γ). Peripheral inflammation drives sustained MDD in a baseline-high subgroup. Exploratory treatment interactions, selected pilots and high-CRP acute sensitization support plausibility. Prospective subtype confirmation and selective sustained clinical causality are missing.

The tournament does not alter the nominal level. Compatible pathways and flexible alternatives are not automatically proved by explaining observations.

FULL REVIEW

Registered claim and scope

Peripheral inflammatory signalling causes major depressive disorder in the subgroup with elevated baseline inflammatory markers.

SC3 is the clinical causal claim at the registered scope; narrower molecular, treatment or inherited-syndrome findings cannot replace it. Primary-subclaim aggregation is fixed before grading.

Selection: remaining-priority list position 10 from the editorial list of 2026-10-09. Registered claim assessed against original sources. This is not independent blinded calibration.

Evidence and causal interpretation

Rubric fit: 05-immunology-inflammation governs peripheral immune causal attribution; 07-psychiatry-neuromodulation supplies symptom/expectancy, outcome-hierarchy and mediator controls. A diagnosed or sustained depressive trajectory is distinguished from short-lived mood/anhedonia. Functional recovery is a separate endpoint and is not inferred from rating change. Natural interferon-treatment exposure is a defined therapeutic perturbation, not a randomized ordinary-MDD initiation test.

The most cited subtype signals are exploratory. Infliximab’s primary symptom comparison is null; its threshold was located from the response curve before focused high-CRP exploration, and the response-rate contrast is not significant. MINDEP entered patients at CRP at least 1 mg/L, was overall null, and further CRP-at-least-3 analysis has only six treated participants. Its later sex report is not independent replication. PMID 22945416; PMID 33504955; PMID 36467125.

PREDDICT prospectively fixes inflammatory strata and finds no treatment or interaction effect. A late follow-up difference has substantial attrition and no response/remission separation. MinoTRD is independently null on primary and secondary symptoms. The small positive minocycline pilot is retained rather than dismissed, but is not a confirmed inflammatory-subtype trial. PMID 37635396; PMID 39243988; PMID 36103181; PMID 28857658.

Immune challenge provides actual causal mood evidence. The older-insomnia trial excludes recent MDD and samples depressed mood over hours. The high-CRP MDD challenge measures anhedonia at 1.5 hours: its prespecified primary contrast, the baseline-to-1.5-hour SHAPS change in the high-CRP versus low-CRP endotoxin groups, was significant, while the overall three-way primary interaction was not. It does not measure MADRS at the peak, and the later MADRS group effect reflects improvement. These are susceptibility and symptom-domain findings, not sustained-MDD initiation. PMID 40668551; PMID 40264292.

Prolonged interferon treatment differs from acute sickness: later mood/cognitive depressive syndromes can emerge and clinical course can be modified. Antidepressant/EPA prevention results are heterogeneous, and immune exposure itself is generally not randomized. These studies support a restricted immune-treatment context without transferring its causal role to ordinary baseline-high MDD. PMID 11274622; PMID 11927189; PMID 17292481; PMID 22801672; PMID 24602409.

Natural experiments do not identify all inflammation with CRP. IL6R genotype can raise circulating IL-6 while reducing downstream inflammatory signalling; several CRP genetic analyses are null despite observational associations. Obesity, trauma, smoking, sleep and depression-to-inflammation directions remain viable explanations or modifiers. PMID 29197507; PMID 33631287; PMID 24246360; PMID 36712567; PMID 19416750.

HYPOTHESIS STATE EVALUATION FRAMEWORK (HSEF v5.3)

Subclaim matrix and aggregation

Preregistered aggregation: primary-subclaim. Overall Γ follows registered SC3. Baseline prediction is Β, and sustained immune-treatment-related syndromes earn a restricted Ε at SC2. Neither narrow immune exposure nor exploratory high-CRP response establishes prospectively identifiable inflammatory MDD causation. Genuine positive clinical pilot findings are retained alongside larger or prospectively stratified nulls. The next clinical subtype boundary remains open rather than being declared refuted. Sensitivities: weakest-link Β; primary-subclaim Γ; scope-matched Γ.

Decisive-perturbation inventory and causal tally

[1] Infliximab has no overall HAM-D benefit; baseline-CRP interaction generates an exploratory high-CRP signal. CRP threshold chosen after viewing results, small mixed mood-disorder subgroup and nonsignificant response-rate contrast.

[3] CRP-selected minocycline trial has an overall null with exploratory benefit among six high-CRP treated participants. Entry CRP threshold differs from exploratory threshold; pleiotropic drug, small subgroup and short follow-up.

[6] Prospectively CRP-stratified PREDDICT finds no treatment, stratum or interaction effect on outcome. One drug, modest sample and imperfect marker specificity; null does not exclude every inflammatory pathway.

[31] Randomized endotoxin causes greater acute depressed mood in older adults with insomnia. No recent MDD at entry and hours-long primary mood assessment; not sustained baseline-high MDD initiation.

[32] Baseline-high-CRP MDD participants have greater acute anhedonia under inflammatory challenge. Overall three-way primary interaction nonsignificant; peak MADRS not measured and later MADRS improves rather than worsens.

[40] Multicentre MinoTRD has no primary or secondary symptom benefit versus placebo. Unselected inflammation eligibility and one pleiotropic agent; no universal high-marker subtype exclusion.

[52] Interferon and anti-TNF clinical cohorts show opposite mood/circuit changes across months. Different underlying diseases and nonrandomized therapeutic exposures; circuit mediation remains predictive.

Tally: 4 positive qualifying study units across scoped subclaims; 23 screened discriminating contrast units. These are not independent causal lines or proof of full-claim necessity/sufficiency. Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines. Reports sharing recruitment, instruments or randomization are not automatically independent causal lines. The tally includes discriminating contrasts; positive qualifying source lists alone determine threshold crossings.

Cap audit, precedence and Β/Γ/Δ boundary

Human immune challenges cross within acute mood/sickness scope; this does not cross the registered sustained-MDD SC3 threshold. Prolonged interferon exposure with clinical depressive course supports Ε in its fixed medical-treatment setting. Positive exploratory thresholds and secondary outcomes do not count as a prospectively confirmed marker-defined primary endpoint. No single association cap is reimposed on an independently convergent same-scope causal set; such a sustained high-marker MDD set is not yet established in the examined evidence.

Universal six-cap audit: All six universal caps were considered. Cell-only evidence is bounded by cap 1; unperturbed associations by cap 2; ectopic models by cap 3; biomarker-only trials by cap 4. Cap 5 binds only forced-transfer inference. Cap 6 restricts inherited-syndrome transfer to sporadic scope. Each binds the offered inference, not an independently convergent same-scope causal set.

Gamma hard-rule audit: Abstract association, cellular rescue and biomarker response alone do not demonstrate the registered human clinical claim. Positive narrow perturbations retain their scope; null studies do not earn positive threshold crossings.

SC1 cap: “Pure association evidence — however large, however replicated — cannot exceed Β.” Baseline immune markers predict some depressive trajectories, with symptom, age, metabolic and assay heterogeneity. This registered predictive/existence clause is associational; MR supports some IL6-pathway hypotheses but gives divergent or null CRP effects and does not validate a marker-defined clinical cause.

SC1 field-valid definition: “ - Cell-type-specific conditional knockout or depletion - Pathway-specific blockade (not broad immunosuppression) changing disease course - Human targeted therapy with mechanistic alignment showing disease-modifying effect” Positive full-scope result: no. Baseline immune markers predict some depressive trajectories, with symptom, age, metabolic and assay heterogeneity. This registered predictive/existence clause is associational; MR supports some IL6-pathway hypotheses but gives divergent or null CRP effects and does not validate a marker-defined clinical cause.

SC2 field-valid definition: “ - Cell-type-specific conditional knockout or depletion - Pathway-specific blockade (not broad immunosuppression) changing disease course - Human targeted therapy with mechanistic alignment showing disease-modifying effect” Positive full-scope result: yes. Prolonged interferon exposure can produce a sustained depressive syndrome in defined medical-treatment contexts, with temporally distinct mood and neurovegetative features and modifiable clinical course. This natural therapeutic-perturbation set supports context-specific contribution. Acute endotoxin/vaccine mood effects alone do not establish sustained MDD.

SC3 field-valid definition: “ - Cell-type-specific conditional knockout or depletion - Pathway-specific blockade (not broad immunosuppression) changing disease course - Human targeted therapy with mechanistic alignment showing disease-modifying effect” Positive full-scope result: no. A prospectively identifiable high-inflammation MDD causal subtype remains mechanistically plausible but unconfirmed. Infliximab and the small minocycline study have overall nulls with exploratory threshold/subgroup signals; PREDDICT has a null prospectively stratified interaction. High-CRP EPA clinical differences are nonsignificant. Acute high-CRP challenge susceptibility is not sustained disorder causation.

Upward threshold ladder

SC1 Δ: “Requires pathway- or cell-type-resolved causal perturbation affecting disease or phenotype.” Satisfied: no. A selective immune-pathway intervention prospectively altering incident or persistent depression, with confounding and metabolic alternatives narrowed, would support causal attribution beyond prediction.

SC2 Δ: “Requires pathway- or cell-type-resolved causal perturbation affecting disease or phenotype.” Satisfied: yes.

SC2 Ε: “Requires context-specific causality with explicit scope restriction.” Satisfied: yes.

SC2 Ζ: “Requires multiple convergent causal manipulations and reduced plausibility of downstream-only interpretations.” Satisfied: no. Independent sustained human clinical pathway manipulation with target engagement and credible controls should distinguish immune-specific from illness, drug and psychosocial effects; acute mood and correlated kynurenine changes alone do not cross higher thresholds.

SC3 Δ: “Requires pathway- or cell-type-resolved causal perturbation affecting disease or phenotype.” Satisfied: no. Prospectively fix diagnosis, marker/threshold and interaction analysis; demonstrate target-engaged pathway intervention changes the primary sustained clinical outcome in that subgroup, with appropriate controls and independent replication. Post-hoc cut-offs, positive secondary measures or acute sickness do not replace a positive primary causal test.

Upper ladder: Human therapeutic immune exposures, randomized prevention/modulation, prospective cohorts and genetic instruments were considered as complementary lines. Shared cohorts, immune-marker ambiguity and drug pleiotropy remain. None supplies independent selectively target-engaged primary sustained-MDD effects in the fixed high-marker subgroup. Upper grades remain attainable with prospective subtype trials; the absence of a perfectly clean random immune initiation experiment is not itself a permanent ceiling.

Independence: Infliximab sleep and main reports share one trial. Minocycline sex analysis shares MINDEP recruitment. PREDDICT long-term and primary reports share allocation. Melanoma and HCV symptom/mechanism analyses share parent prevention programs. Acute endotoxin papers may share registered cohorts. UK Biobank and GWAS papers share participants/instruments; repeated papers do not supply independent subtype confirmation.

Prospective and genetic risk [17, 8, 45, 47]: Constrains chronology/reverse-causation under differing assumptions, but shared GWAS, CRP versus signalling and metabolic confounding remain.

Therapeutic cytokine exposure [25, 28, 49, 52]: Tests sustained clinical course in defined exposure settings; immune exposure is usually not randomized and clinical disease/drug coeffects remain.

Randomized acute challenge [31, 32, 50]: Constrains pure biomarker co-occurrence and measures acute effect, but subjective sickness and endpoint duration restrict sustained-MDD inference.

Marker-focused clinical trials [1, 3, 6, 39]: Tests clinically relevant therapeutic modification; threshold exploration, small groups, pleiotropy and null primary results prevent confirmed subtype causality.

Falsification and pitfalls

Target-related biomarker or exploratory response without positive primary clinical result. Infliximab, MINDEP, PREDDICT and EPA studies constrain subtype confirmation; no automatic extra downgrade beyond the uncrossed boundary. Additional downgrade: False.

Baseline marker eligibility confused with post-hoc analytical subgroup. Infliximab and MINDEP cut-off/interaction evidence.

Acute sickness substituted for sustained MDD. Endotoxin and vaccine mood outcomes.

Primary null replaced by secondary/exploratory positive. Late PREDDICT, minocycline functioning and high-CRP challenge analyses.

Adversarial steelman: above, then below

One rung above, Δ: a high-CRP treatment interaction plus experimental immune-to-mood causality could identify a genuine subtype. However, the key positive thresholds are exploratory, the minocycline treated high-CRP group is six people, prospective PREDDICT is null and the 2025 high-CRP challenge measures acute anhedonia rather than sustained new MDD. A positive selective primary clinical result remains missing.

One rung below, Β: much clinical CRP evidence is associational and genetic/trial nulls challenge marker causality. But actual immune exposures, sustained interferon-associated syndromes and randomized acute mood changes provide substantial mechanistic support. Γ preserves that support at the nominal clinical-subtype claim without promoting it to confirmed causation.

Retain Γ for SC3; reject Δ based solely on explored cut-offs or acute symptoms and reject Β as a description of all mechanistic evidence. Nulls constrain the proposed subtype without erasing immune effects in defined contexts.

Final score, causal direction and M/S/D

Overall Γ follows registered SC3. Baseline prediction is Β, and sustained immune-treatment-related syndromes earn a restricted Ε at SC2. Neither narrow immune exposure nor exploratory high-CRP response establishes prospectively identifiable inflammatory MDD causation. Genuine positive clinical pilot findings are retained alongside larger or prospectively stratified nulls. The next clinical subtype boundary remains open rather than being declared refuted.

Inflammatory exposure can precede and change symptoms, so immune effects are not solely consequences or co-occurrence. At the prospectively fixed ordinary-MDD subgroup scope, removal preventing disease, engagement initiating the sustained syndrome and rate limitation are not jointly established, nor is universal requirement. Step 5 assigns a supported context-limited symptom amplifier; high-marker MDD primary-driver attribution remains unconfirmed.

Momentum: Decisive work underway. INSTA-MD (NCT05644301; protocol PMID 39350954, DOI 10.1016/j.bbih.2024.100871) prospectively stratifies MDD by baseline hsCRP and tests immune-targeted augmentation. The official registry read on 11 October 2026 still lists RECRUITING, but its last verification is October 2024 and its September 2026 completion date is estimated. The investigator SINAPS Duffel page actively invites participants and displays a 2026 update. This is an identifiable boundary-testing program; completion or results are not asserted.

Stability: Uncertain. INSTA-MD is a named bidirectional trigger: a positive prespecified high-CRP interaction with verified target engagement could raise the clinical-subtype grade; an adequately engaged, precise null would weaken that attribution. The old registry update prevents a reliable result-date prediction. No positive outcome is presumed.

Divergence: Contested. No manufactured field consensus or arithmetic gap. These dimensions do not change level or confidence.

PROPOSED DECISIVE EXPERIMENTS

Prospectively registered marker-stratified MDD trial with a fixed assay/cut-off, powered treatment-by-marker interaction, selective immune-pathway engagement, matched clinical attention and blinded sustained clinical/function outcomes; compare a mechanistically distinct intervention and replicate independently. INSTA-MD addresses part of this design, but drug pleiotropy and target engagement still require examination.

Readout: Prespecified sustained MDD remission/course and separately measured function, with verified immune target engagement. Controls: Baseline eligibility before outcome, multiplicity plan, expectancy/rater masking, metabolic illness/sleep/medication controls and independent replication. Supporting: Positive primary sustained clinical interaction in the prospectively fixed marker group, with target alignment and replicated mechanism discrimination. Falsifying: Precisely absent or opposite clinical benefit despite adequate selective engagement and powered prespecified interaction, without endpoint or responder redefinition.

KNOWLEDGE GAPS

CRP concentration is neither a specific immune pathway nor a validated causal-subtype definition.

Exploratory threshold effects need prospective independent replication.

Acute anhedonia and sickness require separate assessment from sustained MDD and function.

Immune, metabolic, sleep and medication pathways need selective controls.

Named prospective trials require current registry/result verification; old estimated completion dates are not completed evidence.

REVIEWER NOTES

Bounded original primary abstract/status passages and selected original body sections were examined. Supplements and most complete papers were not audited. Consensus browser synthesis is supplementary and does not count as primary evidence. Scite anchor tallies/outgoing contexts and SciSpace discovery were examined as supplementary inputs. No independent blinded grading is claimed.

Search leads, reviews, protocols and correction notices do not pad the primary count. Downloaded XML does not earn examination credit. Linked notices remain attached; unexamined correction details limit inference. This is a coordinator source/claim consistency assessment, not independent blinded calibration.

Consensus and original-source reconciliation

Original infliximab Methods/Results show an overall null primary outcome and an exploratory CRP threshold identified from the results. A focused responder comparison is nonsignificant; this is not a confirmed prospective subtype. PMID 22945416.

Original MINDEP body uses CRP at least 1 for entry and an overall null. The higher-CRP finding is exploratory and includes only six participants assigned minocycline. PMID 33504955.

Original PREDDICT abstract reports prespecified CRP stratification without a positive treatment-by-stratum result. The later follow-up is the same parent trial and does not supply independent replication. PMID 37635396.

Original challenge body defines an acute anhedonia endpoint over hours, retains a nonsignificant overall three-way interaction and reports later improvement on MADRS. It does not demonstrate sustained new MDD. PMID 40264292.

Original body excludes recent MDD and measures short-lived mood ratings. This cannot establish sustained biomarker-defined major depression. PMID 40668551.

Consensus was used to identify literature and cross-check specific claims about study design, endpoints, scope and research gaps. Those claims were checked against original primary abstracts/status records and, for selected studies, original Methods or Results passages. Consensus output was not treated as original full text. Source-specific access depth and receipts are retained. Scite supplied one five-anchor citation-context/tally query; returned contexts were outgoing references, not an audited incoming contradiction set. SciSpace supplied one discovery pass; it added no primary-count credit.

Research timeline and gap priorities

Selected publication milestones through 9 October 2026. These dates identify source publication years, not priority claims or a comprehensive history.

2001 — Antidepressant prophylaxis during prolonged interferon exposure tests clinically diagnosed depression. PMID 11274622.

2013 — Overall infliximab trial null with exploratory inflammation-related findings. PMID 22945416.

2021 — MINDEP overall null and exploratory higher-CRP subgroup. PMID 33504955.

2022 — Multicentre MinoTRD trial retains a null primary clinical result. PMID 36103181.

2024 — Prospectively stratified PREDDICT report challenges automatic CRP-subtype benefit. PMID 37635396.

2025 — Acute challenge tests anhedonia and time-dependent mood response. PMID 40264292.

2025 — Older-insomnia challenge tests transient mood effects, excluding recent MDD. PMID 40668551.

Research gaps

CRP concentration is neither a specific immune pathway nor a validated causal-subtype definition.

Exploratory threshold effects need prospective independent replication.

Acute anhedonia and sickness require separate assessment from sustained MDD and function.

Immune, metabolic, sleep and medication pathways need selective controls.

Named prospective trials require current registry/result verification; old estimated completion dates are not completed evidence.

Study that would resolve the boundary

Prospectively registered marker-stratified MDD trial with a fixed assay/cut-off, powered treatment-by-marker interaction, selective immune-pathway engagement, matched clinical attention and blinded sustained clinical/function outcomes; compare a mechanistically distinct intervention and replicate independently. INSTA-MD addresses part of this design, but drug pleiotropy and target engagement still require examination.

INSTA-MD: NCT05644301. The retrieved registry still lists recruiting, last verified October 2024, with an estimated September 2026 primary completion date. This is stale administrative status, not an outcome or proof of completion. The investigator recruitment page displays an update of 12-08-2026. The protocol is PMID 39350954, auxiliary and outside the primary-outcome count.

ADVERSARIAL REVIEW AND APPROVAL

Authoring model: Sol 6.1 (the package records its reviewer as "Codex" and generated_by as "Codex; HSEF v5.3"; recorded, not edited). Adversarial reviewer: Claude Opus 5.5 (Anthropic). Date: 2026-10-14. Round: 2 (new-review inventory, group 1).

Scope of checks. All 56 REFERENCES PMIDs verified against PubMed get_article_metadata for title, first author, journal and year: 56/56 resolve correctly, 0 failures. The six PMIDs cited in prose or in the scorecard but correctly kept out of the numbered list were also verified, and each is the kind of record the ledger rule says must not get a row of its own: 32807844 and 34785785 (Published Errata to references 9 and 7), 41152245 (Published Erratum to reference 11), 38699368 and 39149475 (the medRxiv and Research Square preprints of reference 11, superseded by the journal version), and 39350954 (the INSTA-MD trial protocol that the Momentum artifact rests on). No retraction or expression of concern appears in the article-type fields of any of the 62 records checked. Twelve load-bearing claims were spot-checked against PubMed abstracts, concentrating on the trials that set SC3 and the challenge studies that set SC2: the infliximab trial's absence of an overall HAM-D difference, its treatment-by-time-by-log-hsCRP interaction at P=.01, the 5 mg/L crossover point and the nonsignificant 62%-versus-33% response contrast (P=.19); the CRP-selected minocycline trial's CRP>=1 mg/L entry criterion and its null primary comparison; PREDDICT's explicit absence of any treatment, stratum or interaction effect in 119 patients; MinoTRD's null primary (1.46, -1.04 to 3.96, P=.25) and its null secondaries; the Husain minocycline pilot; the older-insomnia endotoxin trial's condition-by-group interaction, its non-depressed entry criterion and its hours-long mood assessment; the high-CRP MDD endotoxin challenge's primary SHAPS contrast, its MADRS timing and the direction of its 24-hour MADRS effect; the IL6R Asp358Ala result (raised serum IL-6, lowered CRP, decreased risk of severe depression or psychosis, OR 0.38, 0.15-0.94); the CRP Mendelian-randomisation null; the high-CRP EPA dose-finding trial's nonsignificant response-rate comparisons; and the interferon prevention trials. Eleven of the twelve matched their source exactly; the twelfth produced finding D-3. Scoring logic was re-derived: the six universal caps, the rubric-05 and rubric-07 routing, the pre-registered primary-subclaim aggregation and both alternatives, the Beta/Gamma/Delta boundary, the causal tally against the ledger flags, the role derivation, and the Momentum/Stability/Divergence artifacts. The validate_review.py v5 validator was re-run.

Findings

No level changed. The headline Γ, Moderate confidence, SC1 Β / SC2 Ε / SC3 Γ, the reinforcing/stabilizing-factor role, the tally of 4 positive qualifying units and the M/S/D values are all unchanged. D-3 does not move a letter: the review already treats the challenge result as acute-susceptibility evidence that cannot establish sustained-MDD initiation, which is the reasoning that holds SC3 at Γ, and it is recorded against SC2 and SC3 in the ledger either way.

Rejected findings (checked, no change)

Lead policy applied — confidence bands and momentum (2026-10-14)

Confidence, two-step test. Step 1: access depth is struck as a determinant. How much of a paper this reviewer could read is neither evidence density nor reproducibility and never justifies a band; the rationale was rewritten accordingly (finding D-5). Step 2: the band was re-derived from what remains. Access depth was not the only thing holding the band down. The surviving determinants are substantive: the association and Mendelian-randomization literature is large but heterogeneous and partly discordant, with IL6R genotype raising circulating IL-6 while lowering downstream CRP and several CRP analyses null against positive observational associations; and the trials bearing on the registered claim are few, use pleiotropic agents (infliximab, minocycline, celecoxib, EPA) rather than selective pathway blockade, and include only one prospectively stratified test. CRP is also a reporter rather than an endogenous tissue readout, which the policy names as a valid determinant. Moderate stands.

Momentum, stricter rule. "Decisive work underway" requires work actually being run that could cross the next threshold; a completed publication or trial never satisfies it, however real the study. Re-checked and the value holds. The artifact is INSTA-MD (NCT05644301), a trial actually being run: the review records that the registry read on 11 October 2026 lists it RECRUITING, that the investigator page actively invites participants, and that completion and results are not asserted — while honestly noting that the registry's last verification predates the read. It is the prospectively stratified marker test that would cross SC3's threshold. The protocol publication (PMID 39350954) is cited to identify the trial, not credited as a completed result.

Residual limitations

• 51 of 56 records are recorded at bounded abstract and status depth, so the figures taken from them were verified against publisher abstracts rather than full Methods. Two numbers that carry real weight could not be reached at abstract depth and rest on the review's own selected-body passages: the "six high-CRP treated participants" in the CRP-selected minocycline trial's exploratory stratum, and the nonsignificant overall three-way interaction in the high-CRP endotoxin challenge. Both are consistent with their abstracts and the review names the body sections it read; neither is flagged as an error.
• SC2's Ε rests on interferon-treatment cohorts in which immune exposure is generally not randomized, which the review states. The letter therefore depends on treating a therapeutic perturbation in a defined medical context as field-valid, which rubric 05 permits but which is weaker than a randomized immune-initiation test.
• The grade turns on a single prospectively stratified null (PREDDICT, one drug, 119 patients). The review says so and declines to call the subtype refuted; a reader should not read Γ as a refutation.

Approval: Following adversarial review and the corrections listed above, the revised document is approved. - Claude Opus 5.5 (Anthropic), 2026-10-14.

REFERENCES

1. Raison CL, Rutherford RE, Woolwine BJ et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA psychiatry. 2013. PMID 22945416. DOI: 10.1001/2013.jamapsychiatry.4. Access: full_text_partial. Study: NCT00463580.

2. Weinberger JF, Raison CL, Rye DB et al. Inhibition of tumor necrosis factor improves sleep continuity in patients with treatment resistant depression and high inflammation. Brain, behavior, and immunity. 2015. PMID 25529904. DOI: 10.1016/j.bbi.2014.12.016. Access: abstract_metadata. Study: NCT00463580.

3. Nettis MA, Lombardo G, Hastings C et al. Augmentation therapy with minocycline in treatment-resistant depression patients with low-grade peripheral inflammation: results from a double-blind randomised clinical trial. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2021. PMID 33504955. DOI: 10.1038/s41386-020-00948-6. Access: full_text_partial. Study: MINDEP.

4. Lombardo G, Nettis MA, Hastings C et al. Sex differences in a double-blind randomized clinical trial with minocycline in treatment-resistant depressed patients: CRP and IL-6 as sex-specific predictors of treatment response. Brain, behavior, & immunity - health. 2022. PMID 36467125. DOI: 10.1016/j.bbih.2022.100561. Access: abstract_metadata. Study: MINDEP.

5. Sampson E, Mills NT, Hori H et al. Long-term characterisation of the relationship between change in depression severity and change in inflammatory markers following inflammation-stratified treatment with vortioxetine augmented with celecoxib or placebo. Brain, behavior, and immunity. 2025. PMID 39243988. DOI: 10.1016/j.bbi.2024.09.003. Access: abstract_metadata. Study: PREDDICT.

6. Kavakbasi E, Sampson E, Mills NT et al. Inflammation-stratified augmentation of vortioxetine with celecoxib: Results from a double-blind, randomized, placebo-controlled trial in major depressive disorder. Journal of neurochemistry. 2024. PMID 37635396. DOI: 10.1111/jnc.15946. Access: abstract_metadata. Study: PREDDICT.

7. Milaneschi Y, Kappelmann N, Ye Z et al. Association of inflammation with depression and anxiety: evidence for symptom-specificity and potential causality from UK Biobank and NESDA cohorts. Molecular psychiatry. 2021. PMID 34135474. DOI: 10.1038/s41380-021-01188-w. Access: abstract_metadata. Study: PMID 34135474.

8. Kelly KM, Smith JA, Mezuk B. Depression and interleukin-6 signaling: A Mendelian Randomization study. Brain, behavior, and immunity. 2021. PMID 33631287. DOI: 10.1016/j.bbi.2021.02.019. Access: abstract_metadata. Study: PMID 33631287.

9. Khandaker GM, Zuber V, Rees JMB et al. Shared mechanisms between coronary heart disease and depression: findings from a large UK general population-based cohort. Molecular psychiatry. 2020. PMID 30886334. DOI: 10.1038/s41380-019-0395-3. Access: abstract_metadata. Study: PMID 30886334.

10. Galan D, Perry BI, Warrier V et al. Applying Mendelian randomization to appraise causality in relationships between smoking, depression and inflammation. Scientific reports. 2022. PMID 36057695. DOI: 10.1038/s41598-022-19214-4. Access: abstract_metadata. Study: PMID 36057695.

11. Mac Giollabhui N, Slaney C, Hemani G et al. Role of inflammation in depressive and anxiety disorders, affect, and cognition: genetic and non-genetic findings in the lifelines cohort study. Translational psychiatry. 2025. PMID 40348744. DOI: 10.1038/s41398-025-03372-w. Access: abstract_metadata. Study: PMID 40348744.

12. Khandaker GM, Zammit S, Burgess S et al. Association between a functional interleukin 6 receptor genetic variant and risk of depression and psychosis in a population-based birth cohort. Brain, behavior, and immunity. 2018. PMID 29197507. DOI: 10.1016/j.bbi.2017.11.020. Access: abstract_metadata. Study: PMID 29197507.

13. Kappelmann N, Arloth J, Georgakis MK et al. Dissecting the Association Between Inflammation, Metabolic Dysregulation, and Specific Depressive Symptoms: A Genetic Correlation and 2-Sample Mendelian Randomization Study. JAMA psychiatry. 2021. PMID 33079133. DOI: 10.1001/jamapsychiatry.2020.3436. Access: abstract_metadata. Study: PMID 33079133.

14. Ye Z, Kappelmann N, Moser S et al. Role of inflammation in depression and anxiety: Tests for disorder specificity, linearity and potential causality of association in the UK Biobank. EClinicalMedicine. 2021. PMID 34505025. DOI: 10.1016/j.eclinm.2021.100992. Access: abstract_metadata. Study: PMID 34505025.

15. Bekkevold OJ, Damås JK, Brumpton BM et al. The causal role of C-reactive protein and interleukin-6 on anxiety and depression symptoms and life satisfaction: Mendelian randomisation analyses in the HUNT study. Psychological medicine. 2023. PMID 37217205. DOI: 10.1017/S0033291723001290. Access: abstract_metadata. Study: PMID 37217205.

16. Zeng Y, Chourpiliadis C, Hammar N et al. Inflammatory Biomarkers and Risk of Psychiatric Disorders. JAMA psychiatry. 2024. PMID 39167384. DOI: 10.1001/jamapsychiatry.2024.2185. Access: abstract_metadata. Study: PMID 39167384.

17. Stewart JC, Rand KL, Muldoon MF et al. A prospective evaluation of the directionality of the depression-inflammation relationship. Brain, behavior, and immunity. 2009. PMID 19416750. DOI: 10.1016/j.bbi.2009.04.011. Access: abstract_metadata. Study: PMID 19416750.

18. Zhong X, Qiang Y, Wang L et al. Peripheral immunity and risk of incident brain disorders: a prospective cohort study of 161,968 participants. Translational psychiatry. 2023. PMID 38071240. DOI: 10.1038/s41398-023-02683-0. Access: abstract_metadata. Study: PMID 38071240.

19. Lucas M, Chocano-Bedoya P, Schulze MB et al. Inflammatory dietary pattern and risk of depression among women. Brain, behavior, and immunity. 2014. PMID 24095894. DOI: 10.1016/j.bbi.2013.09.014. Access: abstract_metadata. Study: PMID 24095894.

20. Sánchez-Villegas A, Ruíz-Canela M, de la Fuente-Arrillaga C et al. Dietary inflammatory index, cardiometabolic conditions and depression in the Seguimiento Universidad de Navarra cohort study. The British journal of nutrition. 2015. PMID 26344165. DOI: 10.1017/S0007114515003074. Access: abstract_metadata. Study: PMID 26344165.

21. Frank P, Kaushal A, Poole L et al. Systemic low-grade inflammation and subsequent depressive symptoms: Is there a mediating role of physical activity? Brain, behavior, and immunity. 2019. PMID 31085217. DOI: 10.1016/j.bbi.2019.05.017. Access: abstract_metadata. Study: PMID 31085217.

22. Haverkamp GLG, Loosman WL, Schouten RW et al. Longitudinal Associations Between Inflammation and Depressive Symptoms in Chronic Dialysis Patients. Psychosomatic medicine. 2019. PMID 30371633. DOI: 10.1097/PSY.0000000000000649. Access: abstract_metadata. Study: PMID 30371633.

23. Vogelzangs N, Comijs HC, Oude Voshaar RC et al. Late-life depression symptom profiles are differentially associated with immunometabolic functioning. Brain, behavior, and immunity. 2014. PMID 24838021. DOI: 10.1016/j.bbi.2014.05.004. Access: abstract_metadata. Study: PMID 24838021.

24. Hamer M, Batty GD, Marmot MG et al. Anti-depressant medication use and C-reactive protein: results from two population-based studies. Brain, behavior, and immunity. 2011. PMID 20863880. DOI: 10.1016/j.bbi.2010.09.013. Access: abstract_metadata. Study: PMID 20863880.

25. Musselman DL, Lawson DH, Gumnick JF et al. Paroxetine for the prevention of depression induced by high-dose interferon alfa. The New England journal of medicine. 2001. PMID 11274622. DOI: 10.1056/NEJM200103293441303. Access: abstract_metadata. Study: MELANOMA_PAROXETINE.

26. Capuron L, Neurauter G, Musselman DL et al. Interferon-alpha-induced changes in tryptophan metabolism. relationship to depression and paroxetine treatment. Biological psychiatry. 2003. PMID 14573318. DOI: 10.1016/s0006-3223(03)00173-2. Access: abstract_metadata. Study: MELANOMA_PAROXETINE.

27. Raison CL, Woolwine BJ, Demetrashvili MF et al. Paroxetine for prevention of depressive symptoms induced by interferon-alpha and ribavirin for hepatitis C. Alimentary pharmacology & therapeutics. 2007. PMID 17451562. DOI: 10.1111/j.1365-2036.2007.03316.x. Access: abstract_metadata. Study: HCV_PAROXETINE.

28. Capuron L, Gumnick JF, Musselman DL et al. Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2002. PMID 11927189. DOI: 10.1016/S0893-133X(01)00407-9. Access: abstract_metadata. Study: MELANOMA_PAROXETINE.

29. Morasco BJ, Rifai MA, Loftis JM et al. A randomized trial of paroxetine to prevent interferon-alpha-induced depression in patients with hepatitis C. Journal of affective disorders. 2007. PMID 17292481. DOI: 10.1016/j.jad.2007.01.007. Access: abstract_metadata. Study: PMID 17292481.

30. McNutt MD, Liu S, Manatunga A et al. Neurobehavioral effects of interferon-α in patients with hepatitis-C: symptom dimensions and responsiveness to paroxetine. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2012. PMID 22353759. DOI: 10.1038/npp.2011.330. Access: abstract_metadata. Study: HCV_PAROXETINE.

31. Irwin MR, Boyle CC, Cho JH et al. Inflammatory Exposure and Depression in Older Adults With Insomnia: A Randomized Clinical Trial. JAMA psychiatry. 2025. PMID 40668551. DOI: 10.1001/jamapsychiatry.2025.1327. Access: full_text_partial. Study: PMID 40668551.

32. Savitz J, Figueroa-Hall LK, Teague TK et al. Systemic Inflammation and Anhedonic Responses to an Inflammatory Challenge in Adults With Major Depressive Disorder: A Randomized Controlled Trial. The American journal of psychiatry. 2025. PMID 40264292. DOI: 10.1176/appi.ajp.20240142. Access: full_text_partial. Study: PMID 40264292.

33. Moieni M, Irwin MR, Jevtic I et al. Sex differences in depressive and socioemotional responses to an inflammatory challenge: implications for sex differences in depression. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2015. PMID 25598426. DOI: 10.1038/npp.2015.17. Access: abstract_metadata. Study: PMID 25598426.

34. Cho JH, Irwin MR, Eisenberger NI et al. Transcriptomic predictors of inflammation-induced depressed mood. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2019. PMID 30643228. DOI: 10.1038/s41386-019-0316-9. Access: abstract_metadata. Study: PMID 30643228.

35. Cho HJ, Eisenberger NI, Olmstead R et al. Preexisting mild sleep disturbance as a vulnerability factor for inflammation-induced depressed mood: a human experimental study. Translational psychiatry. 2016. PMID 26954978. DOI: 10.1038/tp.2016.23. Access: abstract_metadata. Study: PMID 26954978.

36. Boyle CC, Cho JH, Eisenberger NI et al. Inflammation-induced depressed mood and reward responsivity as a function of age in female adults: a randomized controlled trial of endotoxin. Translational psychiatry. 2025. PMID 41298372. DOI: 10.1038/s41398-025-03752-2. Access: abstract_metadata. Study: PMID 41298372.

37. Eisenberger NI, Berkman ET, Inagaki TK et al. Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward. Biological psychiatry. 2010. PMID 20719303. DOI: 10.1016/j.biopsych.2010.06.010. Access: abstract_metadata. Study: PMID 20719303.

38. Kruse JL, Cho JH, Olmstead R et al. Kynurenine metabolism and inflammation-induced depressed mood: A human experimental study. Psychoneuroendocrinology. 2019. PMID 31325802. DOI: 10.1016/j.psyneuen.2019.104371. Access: abstract_metadata. Study: PMID 31325802.

39. Mischoulon D, Dunlop BW, Kinkead B et al. Omega-3 Fatty Acids for Major Depressive Disorder With High Inflammation: A Randomized Dose-Finding Clinical Trial. The Journal of clinical psychiatry. 2022. PMID 36005883. DOI: 10.4088/JCP.21m14074. Access: abstract_metadata. Study: PMID 36005883.

40. Hellmann-Regen J, Clemens V, Grözinger M et al. Effect of Minocycline on Depressive Symptoms in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA network open. 2022. PMID 36103181. DOI: 10.1001/jamanetworkopen.2022.30367. Access: full_text_partial. Study: PMID 36103181.

41. Su KP, Lai HC, Yang HT et al. Omega-3 fatty acids in the prevention of interferon-alpha-induced depression: results from a randomized, controlled trial. Biological psychiatry. 2014. PMID 24602409. DOI: 10.1016/j.biopsych.2014.01.008. Access: abstract_metadata. Study: PMID 24602409.

42. Berk M, Woods RL, Nelson MR et al. Effect of Aspirin vs Placebo on the Prevention of Depression in Older People: A Randomized Clinical Trial. JAMA psychiatry. 2020. PMID 32492080. DOI: 10.1001/jamapsychiatry.2020.1214. Access: abstract_metadata. Study: PMID 32492080.

43. Dean OM, Kanchanatawan B, Ashton M et al. Adjunctive minocycline treatment for major depressive disorder: A proof of concept trial. The Australian and New Zealand journal of psychiatry. 2017. PMID 28578592. DOI: 10.1177/0004867417709357. Access: abstract_metadata. Study: PMID 28578592.

44. Husain MI, Chaudhry IB, Husain N et al. Minocycline as an adjunct for treatment-resistant depressive symptoms: A pilot randomised placebo-controlled trial. Journal of psychopharmacology (Oxford, England). 2017. PMID 28857658. DOI: 10.1177/0269881117724352. Access: abstract_metadata. Study: PMID 28857658.

45. Wium-Andersen MK, Orsted DD, Nordestgaard BG. Elevated C-reactive protein, depression, somatic diseases, and all-cause mortality: a mendelian randomization study. Biological psychiatry. 2014. PMID 24246360. DOI: 10.1016/j.biopsych.2013.10.009. Access: abstract_metadata. Study: PMID 24246360.

46. Perry BI, Upthegrove R, Kappelmann N et al. Associations of immunological proteins/traits with schizophrenia, major depression and bipolar disorder: A bi-directional two-sample mendelian randomization study. Brain, behavior, and immunity. 2021. PMID 34280516. DOI: 10.1016/j.bbi.2021.07.009. Access: abstract_metadata. Study: PMID 34280516.

47. Palmos AB, Hübel C, Lim KX et al. Assessing the Evidence for Causal Associations Between Body Mass Index, C-Reactive Protein, Depression, and Reported Trauma Using Mendelian Randomization. Biological psychiatry global open science. 2023. PMID 36712567. DOI: 10.1016/j.bpsgos.2022.01.003. Access: abstract_metadata. Study: PMID 36712567.

48. Mo X, Wang C, Pu Q et al. Revealing genetic causality between blood-based biomarkers and major depression in east Asian ancestry. Frontiers in psychiatry. 2024. PMID 39323965. DOI: 10.3389/fpsyt.2024.1424958. Access: abstract_metadata. Study: PMID 39323965.

49. Schaefer M, Sarkar R, Knop V et al. Escitalopram for the prevention of peginterferon-α2a-associated depression in hepatitis C virus-infected patients without previous psychiatric disease: a randomized trial. Annals of internal medicine. 2012. PMID 22801672. DOI: 10.7326/0003-4819-157-2-201207170-00006. Access: abstract_metadata. Study: PMID 22801672.

50. Harrison NA, Brydon L, Walker C et al. Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biological psychiatry. 2009. PMID 19423079. DOI: 10.1016/j.biopsych.2009.03.015. Access: abstract_metadata. Study: PMID 19423079.

51. Prather AA, Rabinovitz M, Pollock BG et al. Cytokine-induced depression during IFN-alpha treatment: the role of IL-6 and sleep quality. Brain, behavior, and immunity. 2009. PMID 19615438. DOI: 10.1016/j.bbi.2009.07.001. Access: abstract_metadata. Study: PMID 19615438.

52. Davies KA, Cooper E, Voon V et al. Interferon and anti-TNF therapies differentially modulate amygdala reactivity which predicts associated bidirectional changes in depressive symptoms. Molecular psychiatry. 2021. PMID 32457424. DOI: 10.1038/s41380-020-0790-9. Access: abstract_metadata. Study: PMID 32457424.

53. Grigoleit JS, Kullmann JS, Wolf OT et al. Dose-dependent effects of endotoxin on neurobehavioral functions in humans. PloS one. 2011. PMID 22164271. DOI: 10.1371/journal.pone.0028330. Access: abstract_metadata. Study: PMID 22164271.

54. Eisenberger NI, Inagaki TK, Mashal NM et al. Inflammation and social experience: an inflammatory challenge induces feelings of social disconnection in addition to depressed mood. Brain, behavior, and immunity. 2010. PMID 20043983. DOI: 10.1016/j.bbi.2009.12.009. Access: abstract_metadata. Study: PMID 20043983.

55. Niemegeers P, De Boer P, Dumont GJH et al. Differential Effects of Inflammatory and Psychosocial Stress on Mood, Hypothalamic-Pituitary-Adrenal Axis, and Inflammation in Remitted Depression. Neuropsychobiology. 2016. PMID 28445888. DOI: 10.1159/000466698. Access: abstract_metadata. Study: PMID 28445888.

56. Madison AA, Way B, Ratner KG et al. Typhoid vaccine does not impact feelings of social connection or social behavior in a randomized crossover trial among middle-aged female breast cancer survivors. Brain, behavior, and immunity. 2023. PMID 36208853. DOI: 10.1016/j.bbi.2022.09.021. Access: abstract_metadata. Study: PMID 36208853.

Source-specific evidence cards

[1] A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers.

Shows: Infliximab has no overall HAM-D benefit; baseline-CRP interaction generates an exploratory high-CRP signal.

Does not show: CRP threshold chosen after viewing results, small mixed mood-disorder subgroup and nonsignificant response-rate contrast.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Methods:paragraph3, 2:Results:paragraph1, 2:Results:paragraph2. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

[2] Inhibition of tumor necrosis factor improves sleep continuity in patients with treatment resistant depression and high inflammation.

Shows: Infliximab sleep measures improve in selected high-CRP participants.

Does not show: Same parent trial, secondary small subgroup and sleep rather than sustained-MDD causal attribution.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

[3] Augmentation therapy with minocycline in treatment-resistant depression patients with low-grade peripheral inflammation: results from a double-blind randomised clinical trial.

Shows: CRP-selected minocycline trial has an overall null with exploratory benefit among six high-CRP treated participants.

Does not show: Entry CRP threshold differs from exploratory threshold; pleiotropic drug, small subgroup and short follow-up.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Methods:paragraph0, 1:Methods:paragraph5, 2:Results:paragraph0, 2:Results:paragraph2, 2:Results:paragraph4. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

[4] Sex differences in a double-blind randomized clinical trial with minocycline in treatment-resistant depressed patients: CRP and IL-6 as sex-specific predictors of treatment response.

Shows: Sex-specific exploratory CRP/IL-6 patterns predict minocycline response in the prior small trial.

Does not show: Shared parent recruitment and additional stratification; not independent confirmatory subgroup replication.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

[5] Long-term characterisation of the relationship between change in depression severity and change in inflammatory markers following inflammation-stratified treatment with vortioxetine augmented with celecoxib or placebo.

Shows: PREDDICT follow-up shows a delayed high-CRP celecoxib symptom difference but no response/remission difference.

Does not show: Substantial attrition, late secondary time point and post-hoc TNF grouping; same trial as PMID 37635396.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

[6] Inflammation-stratified augmentation of vortioxetine with celecoxib: Results from a double-blind, randomized, placebo-controlled trial in major depressive disorder.

Shows: Prospectively CRP-stratified PREDDICT finds no treatment, stratum or interaction effect on outcome.

Does not show: One drug, modest sample and imperfect marker specificity; null does not exclude every inflammatory pathway.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

[7] Association of inflammation with depression and anxiety: evidence for symptom-specificity and potential causality from UK Biobank and NESDA cohorts.

Shows: Cohorts and MR associate inflammation particularly with selected somatic/neurovegetative symptoms.

Does not show: Mixed genetic results and phenotype specificity; shared cohorts, linked erratum and no clinical intervention.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. ErratumIn: PMID 34785785. Subclaims: SC1.

[8] Depression and interleukin-6 signaling: A Mendelian Randomization study.

Shows: IL6R MR supports a small potential depression effect with classical/trans-signalling ambiguity.

Does not show: Genetic receptor proxies differ from CRP-defined clinical eligibility and selective therapeutic effects.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[9] Shared mechanisms between coronary heart disease and depression: findings from a large UK general population-based cohort.

Shows: CHD/depression analysis implicates selected inflammatory/metabolic genetic pathways rather than a shared CHD genetic score.

Does not show: Pleiotropy, differing IL-6 signalling interpretation, cohort overlap and linked erratum limit mechanistic specificity.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. ErratumIn: PMID 32807844. Subclaims: SC1.

[10] Applying Mendelian randomization to appraise causality in relationships between smoking, depression and inflammation.

Shows: MR suggests smoking/depression links involving IL-6 but no reciprocal CRP/depression effect.

Does not show: CRP is not interchangeable with upstream signalling; instrument and behavioural confounding assumptions remain.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[11] Role of inflammation in depressive and anxiety disorders, affect, and cognition: genetic and non-genetic findings in the lifelines cohort study.

Shows: Lifelines genetic/non-genetic findings support selected affective associations with inflammation.

Does not show: Multiple phenotypes and modest signals; supersedes earlier versions and has an unexamined linked correction.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. UpdateOf: PMID 38699368; UpdateOf: PMID 39149475; ErratumIn: PMID 41152245. Subclaims: SC1.

[12] Association between a functional interleukin 6 receptor genetic variant and risk of depression and psychosis in a population-based birth cohort.

Shows: Functional IL6R variant associates with less severe depression/psychosis despite higher circulating IL-6.

Does not show: Small case numbers and receptor-pathway effects; circulating concentration does not equal signalling intensity.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[13] Dissecting the Association Between Inflammation, Metabolic Dysregulation, and Specific Depressive Symptoms: A Genetic Correlation and 2-Sample Mendelian Randomization Study.

Shows: Genetic analyses suggest IL-6 involvement in suicidality and metabolic contributions to other symptoms.

Does not show: Symptom-specific and inconsistent CRP effects; multiple testing and shared instruments constrain a broad MDD mechanism.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[14] Role of inflammation in depression and anxiety: Tests for disorder specificity, linearity and potential causality of association in the UK Biobank.

Shows: UK Biobank MR gives differing IL-6 and CRP directions for symptoms.

Does not show: Pathway proxies, outcome definitions and overlap do not define a causal high-CRP clinical subtype.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[15] The causal role of C-reactive protein and interleukin-6 on anxiety and depression symptoms and life satisfaction: Mendelian randomisation analyses in the HUNT study.

Shows: HUNT MR does not support a major CRP contribution to anxiety/depression scores; estimates are imprecise.

Does not show: Symptom scales rather than clinical MDD; weak instruments/precision limit universal exclusion.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[16] Inflammatory Biomarkers and Risk of Psychiatric Disorders.

Shows: Inflammatory markers precede later psychiatric diagnoses in large cohorts with some genetic support.

Does not show: Transdiagnostic associations, surveillance/confounding and shared replication resources; not baseline-high MDD intervention.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[17] A prospective evaluation of the directionality of the depression-inflammation relationship.

Shows: Baseline depressive symptoms predict later IL-6, whereas baseline IL-6 does not predict later depressive change.

Does not show: Older healthy cohort and observational temporal models; supports reverse direction without excluding other contexts.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[18] Peripheral immunity and risk of incident brain disorders: a prospective cohort study of 161,968 participants.

Shows: Elevated innate immune markers associate with later MDD and other brain disorders.

Does not show: UK Biobank recruitment, confounding and nonspecific disease outcomes; not selective peripheral-causal perturbation.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[19] Inflammatory dietary pattern and risk of depression among women.

Shows: An inflammatory dietary pattern associates with incident depression in women.

Does not show: Diet/activity/metabolic confounding and clinical definition; linked correction is an author-name correction.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. ErratumIn: PMIDnot supplied. Subclaims: SC1.

[20] Dietary inflammatory index, cardiometabolic conditions and depression in the Seguimiento Universidad de Navarra cohort study.

Shows: Higher dietary inflammatory index predicts depression in the SUN cohort.

Does not show: Modeled inflammatory diet and residual confounding; no selective pathway engagement or mediator proof.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[21] Systemic low-grade inflammation and subsequent depressive symptoms: Is there a mediating role of physical activity?

Shows: Low physical activity statistically mediates inflammation-to-later-symptom association, with no direct association found.

Does not show: Observational mediation is not manipulated causal pathway separation.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[22] Longitudinal Associations Between Inflammation and Depressive Symptoms in Chronic Dialysis Patients.

Shows: Dialysis cohort has cross-sectional but no longitudinal inflammation/depression association.

Does not show: Physical illness context and finite precision; null is not proof of universal independence.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[23] Late-life depression symptom profiles are differentially associated with immunometabolic functioning.

Shows: Late-life depressed groups show overall immunometabolic downregulation with atypical-profile differences.

Does not show: Cross-sectional symptom-profile and age context challenge uniform high inflammation without defining causation.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[24] Anti-depressant medication use and C-reactive protein: results from two population-based studies.

Shows: Antidepressant use associates with subsequent CRP independently of selected covariates.

Does not show: Confounding by treatment indication and drug effects can generate a downstream marker; no randomization.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[25] Paroxetine for the prevention of depression induced by high-dose interferon alfa.

Shows: Paroxetine reduces diagnosed depression and discontinuation during prolonged high-dose interferon exposure.

Does not show: Antidepressant randomized, interferon exposure not; cancer and regimen context restrict inflammatory-cause attribution.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[26] Interferon-alpha-induced changes in tryptophan metabolism. relationship to depression and paroxetine treatment.

Shows: Interferon changes tryptophan/kynurenine biology; depression-related patterns differ by paroxetine treatment.

Does not show: Correlated mediator and shared clinical program; antidepressant benefit does not selectively block immune signalling.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[27] Paroxetine for prevention of depressive symptoms induced by interferon-alpha and ribavirin for hepatitis C.

Shows: Paroxetine reduces some severity categories during HCV therapy without a significant major-depression incidence difference.

Does not show: Small sample, dropout and symptom subgroup; shared trial with PMID 22353759.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[28] Neurobehavioral effects of interferon-alpha in cancer patients: phenomenology and paroxetine responsiveness of symptom dimensions.

Shows: Interferon neurovegetative effects occur early; mood/cognitive symptoms emerge later and respond differently to paroxetine.

Does not show: Secondary symptom analysis in the same melanoma trial, not independent randomized immune exposure.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[29] A randomized trial of paroxetine to prevent interferon-alpha-induced depression in patients with hepatitis C.

Shows: Prophylactic paroxetine does not reduce interferon-associated depression incidence in a small HCV trial.

Does not show: Changing antiviral regimen, sample and linked erratum; antidepressant-prevention null does not refute cytokine contribution.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. ErratumIn: PMIDnot supplied. Subclaims: SC2.

[30] Neurobehavioral effects of interferon-α in patients with hepatitis-C: symptom dimensions and responsiveness to paroxetine.

Shows: Interferon symptom dimensions differ in paroxetine responsiveness.

Does not show: Secondary analysis and shared HCV trial; not an independent immune-mediator experiment.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[31] Inflammatory Exposure and Depression in Older Adults With Insomnia: A Randomized Clinical Trial.

Shows: Randomized endotoxin causes greater acute depressed mood in older adults with insomnia.

Does not show: No recent MDD at entry and hours-long primary mood assessment; not sustained baseline-high MDD initiation.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Methods:paragraph2, 1:Methods:paragraph6. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[32] Systemic Inflammation and Anhedonic Responses to an Inflammatory Challenge in Adults With Major Depressive Disorder: A Randomized Controlled Trial.

Shows: Baseline-high-CRP MDD participants have greater acute anhedonia under inflammatory challenge.

Does not show: Overall three-way primary interaction nonsignificant; peak MADRS not measured and later MADRS improves rather than worsens.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:METHODS:paragraph0, 1:METHODS:paragraph4, 2:RESULTS:paragraph1, 2:RESULTS:paragraph3. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3.

[33] Sex differences in depressive and socioemotional responses to an inflammatory challenge: implications for sex differences in depression.

Shows: Endotoxin increases cytokines, mood symptoms and social disconnection with sex differences.

Does not show: Acute healthy-volunteer symptoms, subjective unblinding potential and no sustained MDD diagnosis.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[34] Transcriptomic predictors of inflammation-induced depressed mood.

Shows: Baseline transcriptomic patterns predict endotoxin-induced depressed mood.

Does not show: Small exploratory biomarker analysis, shared challenge cohorts and no randomized transcriptomic mediator.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2.

[35] Preexisting mild sleep disturbance as a vulnerability factor for inflammation-induced depressed mood: a human experimental study.

Shows: Sleep disturbance moderates acute inflammatory depressed mood in females.

Does not show: Secondary vulnerability analysis, sex-specific effects and acute time course; no sustained MDD causation.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[36] Inflammation-induced depressed mood and reward responsivity as a function of age in female adults: a randomized controlled trial of endotoxin.

Shows: Endotoxin effects on depressed mood and reward vary with age in female samples.

Does not show: Pooled registered challenge cohorts, acute endpoints and subgroup analysis; not ordinary sustained MDD.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[37] Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward.

Shows: Endotoxin increases acute depressed mood and reduces reward-related ventral-striatal activity.

Does not show: Statistical neural mediation is not selectively manipulated; healthy challenge does not establish sustained MDD.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[38] Kynurenine metabolism and inflammation-induced depressed mood: A human experimental study.

Shows: Endotoxin changes kynurenine metabolites, but they do not mediate cytokine-to-mood association.

Does not show: Nominal correlations fail multiple-testing robustness; acute measures do not establish a sustained clinical mechanism.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[39] Omega-3 Fatty Acids for Major Depressive Disorder With High Inflammation: A Randomized Dose-Finding Clinical Trial.

Shows: High-CRP overweight MDD EPA trial has nonsignificant clinical response differences and limited target effects.

Does not show: Small completer dose-finding sample, prespecified biomarker endpoints and pleiotropic intervention; correlation is not mediation.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

[40] Effect of Minocycline on Depressive Symptoms in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial.

Shows: Multicentre MinoTRD has no primary or secondary symptom benefit versus placebo.

Does not show: Unselected inflammation eligibility and one pleiotropic agent; no universal high-marker subtype exclusion.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Methods:paragraph0, 1:Methods:paragraph4, 2:Results:paragraph5. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

[41] Omega-3 fatty acids in the prevention of interferon-alpha-induced depression: results from a randomized, controlled trial.

Shows: EPA prophylaxis reduces diagnosed interferon-associated depression in HCV treatment, unlike DHA.

Does not show: Specific immune-exposure context and nonspecific fatty-acid effects; not ordinary marker-defined MDD necessity.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[42] Effect of Aspirin vs Placebo on the Prevention of Depression in Older People: A Randomized Clinical Trial.

Shows: Large aspirin prevention trial finds no reduction in new elevated depression scores in older adults.

Does not show: Low-dose aspirin is not selective cytokine blockade and participants were not a high-inflammatory MDD population.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

[43] Adjunctive minocycline treatment for major depressive disorder: A proof of concept trial.

Shows: Minocycline proof-of-concept trial has a null primary depression score with positive secondary functioning/global measures.

Does not show: Outcome hierarchy, multiple measures and no baseline-high eligibility; secondary benefit cannot replace null primary.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

[44] Minocycline as an adjunct for treatment-resistant depressive symptoms: A pilot randomised placebo-controlled trial.

Shows: Small randomized minocycline pilot reports positive symptom improvement.

Does not show: Unselected inflammatory status, small study and pleiotropic mechanism require independent subtype confirmation.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.

[45] Elevated C-reactive protein, depression, somatic diseases, and all-cause mortality: a mendelian randomization study.

Shows: Measured CRP predicts depression, while genetic CRP does not.

Does not show: CRP per se and upstream inflammatory pathways differ; finite instrument power and outcome definitions matter.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[46] Associations of immunological proteins/traits with schizophrenia, major depression and bipolar disorder: A bi-directional two-sample mendelian randomization study.

Shows: Multivariable MR supports potential IL-6 effects on major depression after correction.

Does not show: Shared GWAS, instrument assumptions and some nonrobust tested proteins; no validated baseline-high subtype.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[47] Assessing the Evidence for Causal Associations Between Body Mass Index, C-Reactive Protein, Depression, and Reported Trauma Using Mendelian Randomization.

Shows: MR does not support CRP–MDD causality and implicates BMI/trauma relationships.

Does not show: Reported-trauma measurement and shared cohorts; does not exclude all immune pathways or drug-induced depression.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[48] Revealing genetic causality between blood-based biomarkers and major depression in east Asian ancestry.

Shows: East-Asian genetic analysis implicates selected blood traits and metabolic pathways in depression.

Does not show: Pleiotropic genes and phenotype/instrument specificity; not a selective inflammation intervention.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1.

[49] Escitalopram for the prevention of peginterferon-α2a-associated depression in hepatitis C virus-infected patients without previous psychiatric disease: a randomized trial.

Shows: Escitalopram reduces depression incidence/severity during interferon-based HCV therapy.

Does not show: Antidepressant prevention is not randomized immune initiation; selected no-prior-psychiatric-disease population.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[50] Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity.

Shows: Typhoid challenge causes short-term mood change and circuit associations.

Does not show: Hours-long sickness-linked phenotype and statistical mediation, not sustained MDD or selective brain mediator.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[51] Cytokine-induced depression during IFN-alpha treatment: the role of IL-6 and sleep quality.

Shows: Pretreatment IL-6 predicts depression during interferon therapy with bidirectional symptom/inflammation timing.

Does not show: Selected treatment cohort and sleep/illness confounding; temporal prediction is not selective immune causation.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2.

[52] Interferon and anti-TNF therapies differentially modulate amygdala reactivity which predicts associated bidirectional changes in depressive symptoms.

Shows: Interferon and anti-TNF clinical cohorts show opposite mood/circuit changes across months.

Does not show: Different underlying diseases and nonrandomized therapeutic exposures; circuit mediation remains predictive.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[53] Dose-dependent effects of endotoxin on neurobehavioral functions in humans.

Shows: Endotoxin produces dose-dependent transient mood and physiological changes with mixed cognitive effects.

Does not show: Acute sickness, sympathetic/cortisol changes and no sustained clinical MDD dependency.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[54] Inflammation and social experience: an inflammatory challenge induces feelings of social disconnection in addition to depressed mood.

Shows: Randomized endotoxin increases social disconnection and depressed mood.

Does not show: Correlated social mediation and acute healthy-volunteer response; does not establish a chronic inflammatory subtype.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[55] Differential Effects of Inflammatory and Psychosocial Stress on Mood, Hypothalamic-Pituitary-Adrenal Axis, and Inflammation in Remitted Depression.

Shows: Vaccination lowers mood in remitted MDD patients but psychosocial stress contrasts differ.

Does not show: Short-term mood susceptibility and selected remitted population rather than current sustained MDD initiation.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

[56] Typhoid vaccine does not impact feelings of social connection or social behavior in a randomized crossover trial among middle-aged female breast cancer survivors.

Shows: Typhoid vaccine raises cytokines without social-connection or avoidance changes in cancer survivors.

Does not show: Milder stimulus and selected population constrain generalization; mood/social outcomes are not interchangeable.

Access/status: Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2.

Documentary record

Every grade on this site is reproducible from its record. The files below are the posted edition exactly as assessed.

• ADVERSARIAL_REVIEW.md
• CONSENSUS_CROSSCHECK.html
• CONSENSUS_CROSSCHECK.md
• RESEARCH_TIMELINE.html
• RESEARCH_TIMELINE.md
• SHA256.txt
• adversarial-findings.json
• codex-correction-provenance.json
• consensus-validation.json
• edition-approval-audit.json
• inflammation-depression.review.md
• inflammation-depression.scorecard.json
• reader-summary.json
• research-timeline.json
• validation-report.json
• validation-round2-2026-10-14.json
• validation.txt
• video-insert.md
• web-page.md

Sources: 56 · load-bearing claims: 60 · verified: 60 · unverified: 0 · contradicted: 0 · schema 5.3