{ "$schema_version": "5.3", "review_mode": "fresh", "claim_restatement": { "index_wording": "Inflammatory Depression Hypothesis", "entry_form": "claim", "gradeable_restatement": "Peripheral inflammatory signalling causes major depressive disorder in the subgroup with elevated baseline inflammatory markers.", "restatement_required": true, "split_into": [], "parent_claim": null, "scope_qualifiers": [ { "qualifier": "Genotype, species, tissue, baseline eligibility and treatment timing fixed before outcomes", "determinable_before_outcome": true, "determined_from": "Enrollment and experimental design, before results; no responder-defined scope.", "action": "retained" } ] }, "hypothesis": { "name": "Inflammatory Depression Hypothesis", "central_claim": "Peripheral inflammatory signalling causes major depressive disorder in the subgroup with elevated baseline inflammatory markers.", "proposed_mechanism": "Peripheral inflammatory signalling causes major depressive disorder in the subgroup with elevated baseline inflammatory markers.", "claimed_scope": "MDD with baseline inflammatory eligibility fixed prospectively; acute sickness, immune-drug syndromes and retrospective responders are distinct", "claimed_level": [ "initiation", "progression" ], "is_conjunctive": true, "conjunctive_note": "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." }, "rubric_routing": { "primary_rubric": "05-immunology-inflammation.md", "secondary_rubrics": [ "07-psychiatry-neuromodulation.md" ], "index_notes_applied": [ "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." ], "rubric_fit_note": "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." }, "subclaim_matrix": { "subclaims": [ { "id": "SC1", "statement": "Elevated baseline peripheral inflammatory markers predict depression onset or persistence.", "subclaim_type": "existence", "scope": "Marker assay, threshold and cohort specified before outcomes", "claimed_scope": "Marker assay, threshold and cohort specified before outcomes", "governing_rubric": "05-immunology-inflammation.md", "key_evidence_anchor": "Prospective cohorts and genetic exposure instruments", "hsef_level": "Β", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "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." }, { "id": "SC2", "statement": "Inflammatory pathway activation can cause sustained depressive symptoms through defined mechanisms.", "subclaim_type": "mechanism", "scope": "Sustained human depressive trajectory distinguished from acute sickness behavior", "claimed_scope": "Sustained human depressive trajectory distinguished from acute sickness behavior", "governing_rubric": "05-immunology-inflammation.md", "key_evidence_anchor": "Immune challenge, cytokine therapy and specific pathway manipulation", "hsef_level": "Ε", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "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." }, { "id": "SC3", "statement": "Peripheral inflammation causally drives MDD in a prospectively identifiable high-inflammation subgroup.", "subclaim_type": "primacy", "scope": "MDD plus baseline inflammatory eligibility fixed before outcome; no responder-defined scope", "claimed_scope": "MDD plus baseline inflammatory eligibility fixed before outcome; no responder-defined scope", "governing_rubric": "05-immunology-inflammation.md", "key_evidence_anchor": "Marker-selected randomized pathway inhibition with functional clinical outcomes", "hsef_level": "Γ", "confidence": "Moderate", "governing_cap_or_threshold": "Quoted boundary and upward audit below.", "rationale": "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." } ], "aggregation_rule": "primary-subclaim", "aggregation_preregistered": true, "aggregation_rationale": "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.", "primary_subclaim_id": "SC3", "aggregation_derivation": "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.", "aggregation_alternatives": { "weakest_link_would_return": "Β", "primary_subclaim_would_return": "Γ", "scope_matched_would_return": "Γ", "note": "Separate narrow successes do not replace the preregistered gate." }, "index_rule_deviation": "" }, "competing_models": { "models_evaluated": [ { "rank_in_tournament": 1, "model_id": "M4", "is_nominal": false, "name": "Context-specific immune effects", "core_claim": "Defined immune treatments/stimuli alter mood and sometimes sustained depressive trajectories.", "explains_what_nominal_does_not": "Defined immune treatments/stimuli alter mood and sometimes sustained depressive trajectories.", "strongest_supporting_evidence": [ "Interferon clinical chronology and challenge effects establish meaningful restricted contexts." ], "strongest_contradictory_evidence": [ "Acute effects and medical drug syndromes do not prove ordinary high-marker MDD primacy." ], "hsef_level_for_this_model": "Ε", "rationale": "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_in_tournament": 2, "model_id": "M3", "is_nominal": false, "name": "Shared metabolic/stress causes", "core_claim": "Inflammatory markers and depression share obesity, sleep, smoking, trauma and physical-illness pathways.", "explains_what_nominal_does_not": "Inflammatory markers and depression share obesity, sleep, smoking, trauma and physical-illness pathways.", "strongest_supporting_evidence": [ "MR heterogeneity, reverse-direction cohorts and phenotype specificity support this explanation." ], "strongest_contradictory_evidence": [ "A flexible shared-cause account cannot explain away all experimentally induced immune symptoms." ], "hsef_level_for_this_model": "Γ", "rationale": "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_in_tournament": 3, "model_id": "M2", "is_nominal": false, "name": "Depression-induced inflammation", "core_claim": "Depression, treatment and associated behaviour can raise some markers.", "explains_what_nominal_does_not": "Depression, treatment and associated behaviour can raise some markers.", "strongest_supporting_evidence": [ "Prospective reverse direction and antidepressant/CRP associations support part of the chain." ], "strongest_contradictory_evidence": [ "Direction is not universal and does not exclude immune-to-mood effects." ], "hsef_level_for_this_model": "Β", "rationale": "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_in_tournament": 4, "model_id": "M1", "is_nominal": true, "name": "Inflammatory MDD subtype", "core_claim": "Peripheral inflammation drives sustained MDD in a baseline-high subgroup.", "explains_what_nominal_does_not": "Peripheral inflammation drives sustained MDD in a baseline-high subgroup.", "strongest_supporting_evidence": [ "Exploratory treatment interactions, selected pilots and high-CRP acute sensitization support plausibility." ], "strongest_contradictory_evidence": [ "Prospective subtype confirmation and selective sustained clinical causality are missing." ], "hsef_level_for_this_model": "Γ", "rationale": "Exploratory treatment interactions, selected pilots and high-CRP acute sensitization support plausibility. Prospective subtype confirmation and selective sustained clinical causality are missing." } ], "tournament_summary": "Descriptive comparison; does not modify the nominal score. The randomized high-CRP challenge (PMID40264292) separates genuine immune-triggered acute anhedonia from a purely shared-cause account, but not sustained-MDD primacy. For the clinical subtype boundary, PREDDICT (PMID37635396) is the strongest prospectively stratified discriminator and is null. These questions and endpoints are deliberately not merged.", "study_separating_rank1_from_rank2": "The randomized high-CRP challenge (PMID40264292) separates genuine immune-triggered acute anhedonia from a purely shared-cause account, but not sustained-MDD primacy. For the clinical subtype boundary, PREDDICT (PMID37635396) is the strongest prospectively stratified discriminator and is null. 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No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Sex-specific exploratory CRP/IL-6 patterns predict minocycline response in the prior small trial.", "what_it_does_not_show": "Shared parent recruitment and additional stratification; not independent confirmatory subgroup replication.", "confounders_present": [ "Shared parent recruitment and additional stratification; not independent confirmatory subgroup replication." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 5, "pmid": "39243988", "title": "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.", "citation": "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.", "doi": "10.1016/j.bbi.2024.09.003", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/39243988/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39243988/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PREDDICT", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "PREDDICT follow-up shows a delayed high-CRP celecoxib symptom difference but no response/remission difference.", "what_it_does_not_show": "Substantial attrition, late secondary time point and post-hoc TNF grouping; same trial as PMID37635396.", "confounders_present": [ "Substantial attrition, late secondary time point and post-hoc TNF grouping; same trial as PMID37635396." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 6, "pmid": "37635396", "title": "Inflammation-stratified augmentation of vortioxetine with celecoxib: Results from a double-blind, randomized, placebo-controlled trial in major depressive disorder.", "citation": "Kavakbasi E, Sampson E, Mills NT et al. 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No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "Prospectively CRP-stratified PREDDICT finds no treatment, stratum or interaction effect on outcome.", "what_it_does_not_show": "One drug, modest sample and imperfect marker specificity; null does not exclude every inflammatory pathway.", "confounders_present": [ "One drug, modest sample and imperfect marker specificity; null does not exclude every inflammatory pathway." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 7, "pmid": "34135474", "title": "Association of inflammation with depression and anxiety: evidence for symptom-specificity and potential causality from UK Biobank and NESDA cohorts.", "citation": "Milaneschi Y, Kappelmann N, Ye Z et al. 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No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "natural experiment", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Cohorts and MR associate inflammation particularly with selected somatic/neurovegetative symptoms.", "what_it_does_not_show": "Mixed genetic results and phenotype specificity; shared cohorts, linked erratum and no clinical intervention.", "confounders_present": [ "Mixed genetic results and phenotype specificity; shared cohorts, linked erratum and no clinical intervention." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [ "Shared UK Biobank and/or inflammatory/psychiatric GWAS resources; not automatic independent clinical causal replication." ] }, { "n": 8, "pmid": "33631287", "title": "Depression and interleukin-6 signaling: A Mendelian Randomization study.", "citation": "Kelly KM, Smith JA, Mezuk B. 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No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "natural experiment", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "IL6R MR supports a small potential depression effect with classical/trans-signalling ambiguity.", "what_it_does_not_show": "Genetic receptor proxies differ from CRP-defined clinical eligibility and selective therapeutic effects.", "confounders_present": [ "Genetic receptor proxies differ from CRP-defined clinical eligibility and selective therapeutic effects." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 9, "pmid": "30886334", "title": "Shared mechanisms between coronary heart disease and depression: findings from a large UK general population-based cohort.", "citation": "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.", "doi": "10.1038/s41380-019-0395-3", "pmcid": "PMC7303009", "url": "https://pubmed.ncbi.nlm.nih.gov/30886334/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30886334/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID32807844" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID30886334", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "natural experiment", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "Genetic analyses suggest IL-6 involvement in suicidality and metabolic contributions to other symptoms.", "what_it_does_not_show": "Symptom-specific and inconsistent CRP effects; multiple testing and shared instruments constrain a broad MDD mechanism.", "confounders_present": [ "Symptom-specific and inconsistent CRP effects; multiple testing and shared instruments constrain a broad MDD mechanism." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [ "Shared UK Biobank and/or inflammatory/psychiatric GWAS resources; not automatic independent clinical causal replication." ] }, { "n": 14, "pmid": "34505025", "title": "Role of inflammation in depression and anxiety: Tests for disorder specificity, linearity and potential causality of association in the UK Biobank.", "citation": "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.", "doi": "10.1016/j.eclinm.2021.100992", "pmcid": "PMC8413248", "url": "https://pubmed.ncbi.nlm.nih.gov/34505025/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34505025/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID34505025", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "natural experiment", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "UK Biobank MR gives differing IL-6 and CRP directions for symptoms.", "what_it_does_not_show": "Pathway proxies, outcome definitions and overlap do not define a causal high-CRP clinical subtype.", "confounders_present": [ "Pathway proxies, outcome definitions and overlap do not define a causal high-CRP clinical subtype." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [ "Shared UK Biobank and/or inflammatory/psychiatric GWAS resources; not automatic independent clinical causal replication." ] }, { "n": 15, "pmid": "37217205", "title": "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.", "citation": "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.", "doi": "10.1017/S0033291723001290", "pmcid": "PMC10755231", "url": "https://pubmed.ncbi.nlm.nih.gov/37217205/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/37217205/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID37217205", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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Inflammatory Biomarkers and Risk of Psychiatric Disorders. JAMA psychiatry. 2024.", "doi": "10.1001/jamapsychiatry.2024.2185", "pmcid": "PMC11339698", "url": "https://pubmed.ncbi.nlm.nih.gov/39167384/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39167384/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID39167384", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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A prospective evaluation of the directionality of the depression-inflammation relationship. Brain, behavior, and immunity. 2009.", "doi": "10.1016/j.bbi.2009.04.011", "pmcid": "PMC2749896", "url": "https://pubmed.ncbi.nlm.nih.gov/19416750/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19416750/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID19416750", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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Peripheral immunity and risk of incident brain disorders: a prospective cohort study of 161,968 participants. Translational psychiatry. 2023.", "doi": "10.1038/s41398-023-02683-0", "pmcid": "PMC10710500", "url": "https://pubmed.ncbi.nlm.nih.gov/38071240/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/38071240/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID38071240", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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Inflammatory dietary pattern and risk of depression among women. Brain, behavior, and immunity. 2014.", "doi": "10.1016/j.bbi.2013.09.014", "pmcid": "PMC3947176", "url": "https://pubmed.ncbi.nlm.nih.gov/24095894/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24095894/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "ErratumIn: PMID not supplied" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID24095894", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "An inflammatory dietary pattern associates with incident depression in women.", "what_it_does_not_show": "Diet/activity/metabolic confounding and clinical definition; linked correction is an author-name correction.", "confounders_present": [ "Diet/activity/metabolic confounding and clinical definition; linked correction is an author-name correction." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 20, "pmid": "26344165", "title": "Dietary inflammatory index, cardiometabolic conditions and depression in the Seguimiento Universidad de Navarra cohort study.", "citation": "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.", "doi": "10.1017/S0007114515003074", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/26344165/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/26344165/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID26344165", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Higher dietary inflammatory index predicts depression in the SUN cohort.", "what_it_does_not_show": "Modeled inflammatory diet and residual confounding; no selective pathway engagement or mediator proof.", "confounders_present": [ "Modeled inflammatory diet and residual confounding; no selective pathway engagement or mediator proof." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 21, "pmid": "31085217", "title": "Systemic low-grade inflammation and subsequent depressive symptoms: Is there a mediating role of physical activity?", "citation": "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.", "doi": "10.1016/j.bbi.2019.05.017", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/31085217/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31085217/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID31085217", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "mixed", "what_it_shows": "Low physical activity statistically mediates inflammation-to-later-symptom association, with no direct association found.", "what_it_does_not_show": "Observational mediation is not manipulated causal pathway separation.", "confounders_present": [ "Observational mediation is not manipulated causal pathway separation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 22, "pmid": "30371633", "title": "Longitudinal Associations Between Inflammation and Depressive Symptoms in Chronic Dialysis Patients.", "citation": "Haverkamp GLG, Loosman WL, Schouten RW et al. Longitudinal Associations Between Inflammation and Depressive Symptoms in Chronic Dialysis Patients. Psychosomatic medicine. 2019.", "doi": "10.1097/PSY.0000000000000649", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/30371633/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/30371633/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID30371633", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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Late-life depression symptom profiles are differentially associated with immunometabolic functioning. Brain, behavior, and immunity. 2014.", "doi": "10.1016/j.bbi.2014.05.004", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/24838021/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24838021/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID24838021", "access_depth": "abstract_metadata", "access_note": "Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. 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No complete-paper or supplement audit claimed.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Endotoxin increases acute depressed mood and reduces reward-related ventral-striatal activity.", "what_it_does_not_show": "Statistical neural mediation is not selectively manipulated; healthy challenge does not establish sustained MDD.", "confounders_present": [ "Statistical neural mediation is not selectively manipulated; healthy challenge does not establish sustained MDD." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 38, "pmid": "31325802", "title": "Kynurenine metabolism and inflammation-induced depressed mood: A human experimental study.", "citation": "Kruse JL, Cho JH, Olmstead R et al. Kynurenine metabolism and inflammation-induced depressed mood: A human experimental study. Psychoneuroendocrinology. 2019.", "doi": "10.1016/j.psyneuen.2019.104371", "pmcid": "PMC6842695", "url": "https://pubmed.ncbi.nlm.nih.gov/31325802/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/31325802/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID31325802", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "Endotoxin changes kynurenine metabolites, but they do not mediate cytokine-to-mood association.", "what_it_does_not_show": "Nominal correlations fail multiple-testing robustness; acute measures do not establish a sustained clinical mechanism.", "confounders_present": [ "Nominal correlations fail multiple-testing robustness; acute measures do not establish a sustained clinical mechanism." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 39, "pmid": "36005883", "title": "Omega-3 Fatty Acids for Major Depressive Disorder With High Inflammation: A Randomized Dose-Finding Clinical Trial.", "citation": "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.", "doi": "10.4088/JCP.21m14074", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/36005883/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36005883/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID36005883", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "High-CRP overweight MDD EPA trial has nonsignificant clinical response differences and limited target effects.", "what_it_does_not_show": "Small completer dose-finding sample, prespecified biomarker endpoints and pleiotropic intervention; correlation is not mediation.", "confounders_present": [ "Small completer dose-finding sample, prespecified biomarker endpoints and pleiotropic intervention; correlation is not mediation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 40, "pmid": "36103181", "title": "Effect of Minocycline on Depressive Symptoms in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial.", "citation": "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.", "doi": "10.1001/jamanetworkopen.2022.30367", "pmcid": "PMC9475381", "url": "https://pubmed.ncbi.nlm.nih.gov/36103181/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36103181/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID36103181", "access_depth": "full_text_partial", "access_note": "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.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "null", "what_it_shows": "Multicentre MinoTRD has no primary or secondary symptom benefit versus placebo.", "what_it_does_not_show": "Unselected inflammation eligibility and one pleiotropic agent; no universal high-marker subtype exclusion.", "confounders_present": [ "Unselected inflammation eligibility and one pleiotropic agent; no universal high-marker subtype exclusion." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 41, "pmid": "24602409", "title": "Omega-3 fatty acids in the prevention of interferon-alpha-induced depression: results from a randomized, controlled trial.", "citation": "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.", "doi": "10.1016/j.biopsych.2014.01.008", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/24602409/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24602409/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID24602409", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "EPA prophylaxis reduces diagnosed interferon-associated depression in HCV treatment, unlike DHA.", "what_it_does_not_show": "Specific immune-exposure context and nonspecific fatty-acid effects; not ordinary marker-defined MDD necessity.", "confounders_present": [ "Specific immune-exposure context and nonspecific fatty-acid effects; not ordinary marker-defined MDD necessity." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 42, "pmid": "32492080", "title": "Effect of Aspirin vs Placebo on the Prevention of Depression in Older People: A Randomized Clinical Trial.", "citation": "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.", "doi": "10.1001/jamapsychiatry.2020.1214", "pmcid": "PMC7271558", "url": "https://pubmed.ncbi.nlm.nih.gov/32492080/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32492080/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID32492080", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "Large aspirin prevention trial finds no reduction in new elevated depression scores in older adults.", "what_it_does_not_show": "Low-dose aspirin is not selective cytokine blockade and participants were not a high-inflammatory MDD population.", "confounders_present": [ "Low-dose aspirin is not selective cytokine blockade and participants were not a high-inflammatory MDD population." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 43, "pmid": "28578592", "title": "Adjunctive minocycline treatment for major depressive disorder: A proof of concept trial.", "citation": "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.", "doi": "10.1177/0004867417709357", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/28578592/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28578592/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID28578592", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "Minocycline proof-of-concept trial has a null primary depression score with positive secondary functioning/global measures.", "what_it_does_not_show": "Outcome hierarchy, multiple measures and no baseline-high eligibility; secondary benefit cannot replace null primary.", "confounders_present": [ "Outcome hierarchy, multiple measures and no baseline-high eligibility; secondary benefit cannot replace null primary." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 44, "pmid": "28857658", "title": "Minocycline as an adjunct for treatment-resistant depressive symptoms: A pilot randomised placebo-controlled trial.", "citation": "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.", "doi": "10.1177/0269881117724352", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/28857658/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28857658/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID28857658", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC3" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Small randomized minocycline pilot reports positive symptom improvement.", "what_it_does_not_show": "Unselected inflammatory status, small study and pleiotropic mechanism require independent subtype confirmation.", "confounders_present": [ "Unselected inflammatory status, small study and pleiotropic mechanism require independent subtype confirmation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 45, "pmid": "24246360", "title": "Elevated C-reactive protein, depression, somatic diseases, and all-cause mortality: a mendelian randomization study.", "citation": "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.", "doi": "10.1016/j.biopsych.2013.10.009", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/24246360/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/24246360/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID24246360", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "natural experiment", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "Measured CRP predicts depression, while genetic CRP does not.", "what_it_does_not_show": "CRP per se and upstream inflammatory pathways differ; finite instrument power and outcome definitions matter.", "confounders_present": [ "CRP per se and upstream inflammatory pathways differ; finite instrument power and outcome definitions matter." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 46, "pmid": "34280516", "title": "Associations of immunological proteins/traits with schizophrenia, major depression and bipolar disorder: A bi-directional two-sample mendelian randomization study.", "citation": "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.", "doi": "10.1016/j.bbi.2021.07.009", "pmcid": "PMC7612947", "url": "https://pubmed.ncbi.nlm.nih.gov/34280516/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/34280516/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID34280516", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "natural experiment", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Multivariable MR supports potential IL-6 effects on major depression after correction.", "what_it_does_not_show": "Shared GWAS, instrument assumptions and some nonrobust tested proteins; no validated baseline-high subtype.", "confounders_present": [ "Shared GWAS, instrument assumptions and some nonrobust tested proteins; no validated baseline-high subtype." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 47, "pmid": "36712567", "title": "Assessing the Evidence for Causal Associations Between Body Mass Index, C-Reactive Protein, Depression, and Reported Trauma Using Mendelian Randomization.", "citation": "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.", "doi": "10.1016/j.bpsgos.2022.01.003", "pmcid": "PMC9874165", "url": "https://pubmed.ncbi.nlm.nih.gov/36712567/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36712567/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID36712567", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "natural experiment", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "MR does not support CRP–MDD causality and implicates BMI/trauma relationships.", "what_it_does_not_show": "Reported-trauma measurement and shared cohorts; does not exclude all immune pathways or drug-induced depression.", "confounders_present": [ "Reported-trauma measurement and shared cohorts; does not exclude all immune pathways or drug-induced depression." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [ "Shared UK Biobank and/or inflammatory/psychiatric GWAS resources; not automatic independent clinical causal replication." ] }, { "n": 48, "pmid": "39323965", "title": "Revealing genetic causality between blood-based biomarkers and major depression in east Asian ancestry.", "citation": "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.", "doi": "10.3389/fpsyt.2024.1424958", "pmcid": "PMC11423294", "url": "https://pubmed.ncbi.nlm.nih.gov/39323965/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/39323965/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID39323965", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC1" ], "favors_models": [], "evidence_class": "Moderate", "system": "natural experiment", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "East-Asian genetic analysis implicates selected blood traits and metabolic pathways in depression.", "what_it_does_not_show": "Pleiotropic genes and phenotype/instrument specificity; not a selective inflammation intervention.", "confounders_present": [ "Pleiotropic genes and phenotype/instrument specificity; not a selective inflammation intervention." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 49, "pmid": "22801672", "title": "Escitalopram for the prevention of peginterferon-α2a-associated depression in hepatitis C virus-infected patients without previous psychiatric disease: a randomized trial.", "citation": "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.", "doi": "10.7326/0003-4819-157-2-201207170-00006", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/22801672/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22801672/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID22801672", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Strong", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Escitalopram reduces depression incidence/severity during interferon-based HCV therapy.", "what_it_does_not_show": "Antidepressant prevention is not randomized immune initiation; selected no-prior-psychiatric-disease population.", "confounders_present": [ "Antidepressant prevention is not randomized immune initiation; selected no-prior-psychiatric-disease population." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 50, "pmid": "19423079", "title": "Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity.", "citation": "Harrison NA, Brydon L, Walker C et al. Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biological psychiatry. 2009.", "doi": "10.1016/j.biopsych.2009.03.015", "pmcid": "PMC2885494", "url": "https://pubmed.ncbi.nlm.nih.gov/19423079/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19423079/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID19423079", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Typhoid challenge causes short-term mood change and circuit associations.", "what_it_does_not_show": "Hours-long sickness-linked phenotype and statistical mediation, not sustained MDD or selective brain mediator.", "confounders_present": [ "Hours-long sickness-linked phenotype and statistical mediation, not sustained MDD or selective brain mediator." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 51, "pmid": "19615438", "title": "Cytokine-induced depression during IFN-alpha treatment: the role of IL-6 and sleep quality.", "citation": "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.", "doi": "10.1016/j.bbi.2009.07.001", "pmcid": "PMC2783448", "url": "https://pubmed.ncbi.nlm.nih.gov/19615438/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/19615438/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID19615438", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC1", "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human observational", "decisive_perturbation": false, "endogenous": false, "direction": "supports", "what_it_shows": "Pretreatment IL-6 predicts depression during interferon therapy with bidirectional symptom/inflammation timing.", "what_it_does_not_show": "Selected treatment cohort and sleep/illness confounding; temporal prediction is not selective immune causation.", "confounders_present": [ "Selected treatment cohort and sleep/illness confounding; temporal prediction is not selective immune causation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "", "shared_components": [] }, { "n": 52, "pmid": "32457424", "title": "Interferon and anti-TNF therapies differentially modulate amygdala reactivity which predicts associated bidirectional changes in depressive symptoms.", "citation": "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.", "doi": "10.1038/s41380-020-0790-9", "pmcid": "PMC8589643", "url": "https://pubmed.ncbi.nlm.nih.gov/32457424/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/32457424/", "tier": "A", "source_tier": "A", "kind": "primary", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID32457424", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": true, "endogenous": true, "direction": "supports", "what_it_shows": "Interferon and anti-TNF clinical cohorts show opposite mood/circuit changes across months.", "what_it_does_not_show": "Different underlying diseases and nonrandomized therapeutic exposures; circuit mediation remains predictive.", "confounders_present": [ "Different underlying diseases and nonrandomized therapeutic exposures; circuit mediation remains predictive." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": false, "decisive_test_note": "Pivotal test, including null or negative results and restricted contexts; this flag is not a positive threshold crossing.", "shared_components": [] }, { "n": 53, "pmid": "22164271", "title": "Dose-dependent effects of endotoxin on neurobehavioral functions in humans.", "citation": "Grigoleit JS, Kullmann JS, Wolf OT et al. Dose-dependent effects of endotoxin on neurobehavioral functions in humans. PloS one. 2011.", "doi": "10.1371/journal.pone.0028330", "pmcid": "PMC3229570", "url": "https://pubmed.ncbi.nlm.nih.gov/22164271/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/22164271/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID22164271", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Endotoxin produces dose-dependent transient mood and physiological changes with mixed cognitive effects.", "what_it_does_not_show": "Acute sickness, sympathetic/cortisol changes and no sustained clinical MDD dependency.", "confounders_present": [ "Acute sickness, sympathetic/cortisol changes and no sustained clinical MDD dependency." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 54, "pmid": "20043983", "title": "Inflammation and social experience: an inflammatory challenge induces feelings of social disconnection in addition to depressed mood.", "citation": "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.", "doi": "10.1016/j.bbi.2009.12.009", "pmcid": "PMC2856755", "url": "https://pubmed.ncbi.nlm.nih.gov/20043983/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/20043983/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID20043983", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "supports", "what_it_shows": "Randomized endotoxin increases social disconnection and depressed mood.", "what_it_does_not_show": "Correlated social mediation and acute healthy-volunteer response; does not establish a chronic inflammatory subtype.", "confounders_present": [ "Correlated social mediation and acute healthy-volunteer response; does not establish a chronic inflammatory subtype." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 55, "pmid": "28445888", "title": "Differential Effects of Inflammatory and Psychosocial Stress on Mood, Hypothalamic-Pituitary-Adrenal Axis, and Inflammation in Remitted Depression.", "citation": "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.", "doi": "10.1159/000466698", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/28445888/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/28445888/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID28445888", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "mixed", "what_it_shows": "Vaccination lowers mood in remitted MDD patients but psychosocial stress contrasts differ.", "what_it_does_not_show": "Short-term mood susceptibility and selected remitted population rather than current sustained MDD initiation.", "confounders_present": [ "Short-term mood susceptibility and selected remitted population rather than current sustained MDD initiation." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] }, { "n": 56, "pmid": "36208853", "title": "Typhoid vaccine does not impact feelings of social connection or social behavior in a randomized crossover trial among middle-aged female breast cancer survivors.", "citation": "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.", "doi": "10.1016/j.bbi.2022.09.021", "pmcid": "", "url": "https://pubmed.ncbi.nlm.nih.gov/36208853/", "source_pointer": "https://pubmed.ncbi.nlm.nih.gov/36208853/", "tier": "A", "source_tier": "A", "kind": "rct", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID36208853", "access_depth": "abstract_metadata", "access_note": "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.", "relates_to_subclaims": [ "SC2" ], "favors_models": [], "evidence_class": "Moderate", "system": "human interventional", "decisive_perturbation": false, "endogenous": true, "direction": "null", "what_it_shows": "Typhoid vaccine raises cytokines without social-connection or avoidance changes in cancer survivors.", "what_it_does_not_show": "Milder stimulus and selected population constrain generalization; mood/social outcomes are not interchangeable.", "confounders_present": [ "Milder stimulus and selected population constrain generalization; mood/social outcomes are not interchangeable." ], "verification": "verified", "verification_note": "Bounded source attribution; not proof of the nominal mechanism.", "citation_context": { "retrieved": false, "supporting_count": 0, "mentioning_count": 0, "contrasting_count": 0, "notable_contrasting_statements": [] }, "discriminating_contrast": true, "decisive_test_note": "", "shared_components": [] } ], "verification_summary": { "load_bearing_claims_checked": 60, "verified": 60, "unverified": 0, "contradicted": 0, "note": "Verified attribution is distinct from mechanism truth or complete body access." }, "factual_issues_found": [], "cap_rules_applied": [ { "subclaim_id": "SC1", "cap": "Β", "cap_source": "universal", "triggered": true, "trigger_text_quoted": "Pure association evidence — however large, however replicated — cannot exceed Β.", "specific_trigger": "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.", "resulting_ceiling": "Β" } ], "cap_precedence_resolutions": [ { "collision": "Perturbation in a defined setting versus broader inference", "subclaim_scope_cap_binds_on": "Peripheral inflammatory signalling causes major depressive disorder in the subgroup with elevated baseline inflammatory markers.", "subclaim_scope_threshold_binds_on": "The precise experimentally tested subclaim scope", "resolution": "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.", "note": "Convergent lines are assessed as a set; one weak leg is not re-capped over the assembled case." } ], "boundary_check_BGD": [ { "subclaim_id": "SC1", "field_valid_perturbation_quote": "\n- Cell-type-specific conditional knockout or depletion\n- Pathway-specific blockade (not broad immunosuppression) changing disease course\n- Human targeted therapy with mechanistic alignment showing disease-modifying effect", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "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." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "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.", "ceiling_from_boundary_check": "Γ" }, { "subclaim_id": "SC2", "field_valid_perturbation_quote": "\n- Cell-type-specific conditional knockout or depletion\n- Pathway-specific blockade (not broad immunosuppression) changing disease course\n- Human targeted therapy with mechanistic alignment showing disease-modifying effect", "qualifying_evidence_present": "yes", "qualifying_evidence_citation": "PMID11274622, PMID11927189, PMID24602409, PMID22801672, PMID32457424", "gamma_hard_rules_triggered": [ "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." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "yes", "perturbation_result_note": "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.", "ceiling_from_boundary_check": "Δ or higher" }, { "subclaim_id": "SC3", "field_valid_perturbation_quote": "\n- Cell-type-specific conditional knockout or depletion\n- Pathway-specific blockade (not broad immunosuppression) changing disease course\n- Human targeted therapy with mechanistic alignment showing disease-modifying effect", "qualifying_evidence_present": "no", "qualifying_evidence_citation": "", "gamma_hard_rules_triggered": [ "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." ], "disease_phenotype_relevance": "yes", "perturbation_result_positive": "no", "perturbation_result_note": "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.", "ceiling_from_boundary_check": "Γ" } ], "thresholds_tested": [ { "subclaim_id": "SC1", "threshold": "Δ", "requirement_quoted": "Requires pathway- or cell-type-resolved causal perturbation affecting disease or phenotype.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "A selective immune-pathway intervention prospectively altering incident or persistent depression, with confounding and metabolic alternatives narrowed, would support causal attribution beyond prediction." }, { "subclaim_id": "SC2", "threshold": "Δ", "requirement_quoted": "Requires pathway- or cell-type-resolved causal perturbation affecting disease or phenotype.", "satisfied": "yes", "supporting_evidence": [ "[25] Paroxetine reduces diagnosed depression and discontinuation during prolonged high-dose interferon exposure.", "[28] Interferon neurovegetative effects occur early; mood/cognitive symptoms emerge later and respond differently to paroxetine.", "[41] EPA prophylaxis reduces diagnosed interferon-associated depression in HCV treatment, unlike DHA.", "[49] Escitalopram reduces depression incidence/severity during interferon-based HCV therapy.", "[52] Interferon and anti-TNF clinical cohorts show opposite mood/circuit changes across months." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ε", "requirement_quoted": "Requires context-specific causality with explicit scope restriction.", "satisfied": "yes", "supporting_evidence": [ "[25] Paroxetine reduces diagnosed depression and discontinuation during prolonged high-dose interferon exposure.", "[28] Interferon neurovegetative effects occur early; mood/cognitive symptoms emerge later and respond differently to paroxetine.", "[41] EPA prophylaxis reduces diagnosed interferon-associated depression in HCV treatment, unlike DHA.", "[49] Escitalopram reduces depression incidence/severity during interferon-based HCV therapy.", "[52] Interferon and anti-TNF clinical cohorts show opposite mood/circuit changes across months." ], "what_would_cross_it": "" }, { "subclaim_id": "SC2", "threshold": "Ζ", "requirement_quoted": "Requires multiple convergent causal manipulations and reduced plausibility of downstream-only interpretations.", "satisfied": "no", "supporting_evidence": [ "[25] Paroxetine reduces diagnosed depression and discontinuation during prolonged high-dose interferon exposure.", "[28] Interferon neurovegetative effects occur early; mood/cognitive symptoms emerge later and respond differently to paroxetine.", "[41] EPA prophylaxis reduces diagnosed interferon-associated depression in HCV treatment, unlike DHA.", "[49] Escitalopram reduces depression incidence/severity during interferon-based HCV therapy.", "[52] Interferon and anti-TNF clinical cohorts show opposite mood/circuit changes across months." ], "what_would_cross_it": "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." }, { "subclaim_id": "SC3", "threshold": "Δ", "requirement_quoted": "Requires pathway- or cell-type-resolved causal perturbation affecting disease or phenotype.", "satisfied": "no", "supporting_evidence": [], "what_would_cross_it": "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." } ], "generalization_check": { "generalization_tested": "yes", "context_boundary_mapped": "yes", "internal_negative_controls": [ "PREDDICT prospectively stratified treatment-by-CRP interaction is null.", "MinoTRD primary and secondary symptoms are null despite measurable drug exposure.", "CRP genetic instruments often fail to reproduce observational depression associations.", "Mild typhoid challenge can raise cytokines without tested social changes.", "High-CRP acute challenge has no significant overall three-way anhedonia interaction and later MADRS improvement, not sustained new MDD." ], "note": "Age, sex, insomnia, physical illness, cytokine exposure, symptom domain and baseline assay/threshold were retained. They map context-specific immune effects but do not permit responder-based eligibility or automatic acute-to-sustained transfer." }, "falsification_patterns_met": [ { "pattern": "Target-related biomarker or exploratory response without positive primary clinical result", "evidence": "Infliximab, MINDEP, PREDDICT and EPA studies constrain subtype confirmation; no automatic extra downgrade beyond the uncrossed boundary.", "downgrade_applied": false } ], "pitfalls_flagged": [ { "pitfall": "Baseline marker eligibility confused with post-hoc analytical subgroup", "where": "Infliximab and MINDEP cut-off/interaction evidence." }, { "pitfall": "Acute sickness substituted for sustained MDD", "where": "Endotoxin and vaccine mood outcomes." }, { "pitfall": "Primary null replaced by secondary/exploratory positive", "where": "Late PREDDICT, minocycline functioning and high-CRP challenge analyses." } ], "causal_tally_audit": { "tally_claimed_by_document": 4, "tally_after_audit": 4, "tally_unit": "Positive qualifying study units across scoped subclaims, not independent causal lines or full-claim necessity/sufficiency.", "screened_discriminating_contrasts": 23, "items_rejected": [ "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." ] }, "steelman": { "case_one_rung_higher": "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.", "case_one_rung_lower": "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.", "which_rejected": "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.", "blocking_cap_threshold_or_missing_experiment": "Missing 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." }, "final_score": { "hsef_level": "Γ", "hsef_descriptor": "Mechanistically plausible, partial system support", "confidence": "Moderate", "confidence_rationale": "Moderate reflects evidence density and reproducibility, not correctness and not this reviewer's access depth. The association and Mendelian-randomization literature is large but heterogeneous and partly discordant, while the trials bearing on the registered claim are few, use pleiotropic agents and include only one prospectively stratified test. Access depth is recorded separately in the provenance header and is not a basis for the band.", "rests_on_non_peer_reviewed_work": false, "rationale": "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." }, "role_of_mechanism": { "classification": "reinforcing / stabilizing factor", "derivation_step_matched": 5, "derivation": "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.", "tournament_used_as_tiebreaker": false, "note": "Derived from causal direction, not tournament rank." }, "extended_scoring_MSD": { "momentum": { "value": "Decisive work underway", "artifact": "INSTA-MD (NCT05644301; protocol PMID39350954, DOI10.1016/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.", "justification": "INSTA-MD (NCT05644301; protocol PMID39350954, DOI10.1016/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": { "value": "Uncertain", "trigger": "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.", "justification": "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": { "implied_level": null, "implied_level_basis": "No single field-implied level is defensible from conflicting framings.", "assessed_level": "Γ", "gap_in_rungs": null, "value": "Contested", "justification": "No manufactured field consensus or arithmetic gap." }, "calibration_note": "M/S/D never modify HSEF level or confidence." }, "change_record": { "applies": false, "prior_level": "none assigned", "prior_confidence": null, "prior_source": null, "derived_before_consulting_prior": true, "new_level": "Γ", "direction": "newly assigned", "what_moved_it": "Fresh primary evidence appraisal; not blinded.", "divergence_from_other_reviewers": null }, "proposed_decisive_experiments": [ { "name": "Registered boundary experiment", "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.", "readout": "Prespecified sustained MDD remission/course and separately measured function, with verified immune target engagement", "critical_control": "Baseline eligibility before outcome, multiplicity plan, expectancy/rater masking, metabolic illness/sleep/medication controls and independent replication", "supporting_result": "Positive primary sustained clinical interaction in the prospectively fixed marker group, with target alignment and replicated mechanism discrimination", "falsifying_result": "Precisely absent or opposite clinical benefit despite adequate selective engagement and powered prespecified interaction, without endpoint or responder redefinition" } ], "knowledge_gaps": [ { "name": "Gap 1", "statement": "CRP concentration is neither a specific immune pathway nor a validated causal-subtype definition.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 2", "statement": "Exploratory threshold effects need prospective independent replication.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 3", "statement": "Acute anhedonia and sickness require separate assessment from sustained MDD and function.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 4", "statement": "Immune, metabolic, sleep and medication pathways need selective controls.", "relevance": "Limits mechanism identification or scope." }, { "name": "Gap 5", "statement": "Named prospective trials require current registry/result verification; old estimated completion dates are not completed evidence.", "relevance": "Limits mechanism identification or scope." } ], "review_metadata": { "review_date": "2026-10-11", "reviewer": "Codex", "evidence_base_note": "56 primary reports; literature cutoff 2026-10-09; source examination UTC date 2026-10-12; bounded critical review, not exhaustive systematic review.", "literature_tools_available": true, "literature_tools_note": "Life Sciences Literature PubMed/Entrez, separately logged public original-body retrieval, and Consensus Pro browser searches. Provider output retained as observed browser text with citation-link mappings, or as previously exported connector documents where present. AI synthesis is not primary full-text verification. Consensus retrieved/included counts are not examined-primary counts. One Scite call covered five anchors: provider tallies and outgoing reference contexts, not audited incoming contrasting statements. One SciSpace discovery call returned supplementary leads; none added to the primary count. No independent blinded review.", "skill_version": "5.3", "validator_run": "PASS: exact archived HSEF v5.3 validator, rerun after final sealing.", "validator_warnings_addressed": "No warnings.", "limits": "Bounded critical review; not an exhaustive systematic review, complete-paper audit, independent scientific peer review or blinded calibration. HIV is an existing draft carried forward after a source checkpoint." }, "is_calibration_entry": { "value": false, "entry_role": "not_calibration", "blind_graded": null, "completed_blinded_calibration": false, "expected_band_sealed_at": "", "target_sha256": "", "target_authorship": "not applicable", "target_author_saw_review": null, "future_run_status": "not prepared", "unblinded_reason": "Ranking categorical verdict and index guidance were visible. No completed blinded calibration claimed." }, "upper_ladder_check": { "final_level_below_zeta": true, "equivalents_considered": [ { "kind": "mendelian_randomization", "available": true, "why_not_sufficient": "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." }, { "kind": "natural_experiment", "available": true, "why_not_sufficient": "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." }, { "kind": "dose_response_across_populations", "available": false, "why_not_sufficient": "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." }, { "kind": "withdrawal_rechallenge", "available": false, "why_not_sufficient": "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." }, { "kind": "therapeutic_perturbation_hard_endpoint", "available": false, "why_not_sufficient": "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." } ], "convergence_present": false, "cap_reapplied_to_convergent_set": false }, "provenance_header": { "sources_total": 56, "claims_total": 60, "claims_verified": 60, "claims_unverified": 0, "claims_contradicted": 0, "tier_a_sources": 56, "generated_by": "Codex; HSEF v5.3", "gate_passed": true }, "claims": [ { "id": "C1", "text": "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.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 1 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C2", "text": "Infliximab sleep measures improve in selected high-CRP participants. Same parent trial, secondary small subgroup and sleep rather than sustained-MDD causal attribution.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 2 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C3", "text": "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.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 3 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C4", "text": "Sex-specific exploratory CRP/IL-6 patterns predict minocycline response in the prior small trial. Shared parent recruitment and additional stratification; not independent confirmatory subgroup replication.", "carries_number": true, "load_bearing_for": [ "SC3" ], "source_ns": [ 4 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C5", "text": "PREDDICT follow-up shows a delayed high-CRP celecoxib symptom difference but no response/remission difference. Substantial attrition, late secondary time point and post-hoc TNF grouping; same trial as PMID37635396.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 5 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C6", "text": "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.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 6 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C7", "text": "Cohorts and MR associate inflammation particularly with selected somatic/neurovegetative symptoms. Mixed genetic results and phenotype specificity; shared cohorts, linked erratum and no clinical intervention.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 7 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C8", "text": "IL6R MR supports a small potential depression effect with classical/trans-signalling ambiguity. Genetic receptor proxies differ from CRP-defined clinical eligibility and selective therapeutic effects.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 8 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C9", "text": "CHD/depression analysis implicates selected inflammatory/metabolic genetic pathways rather than a shared CHD genetic score. Pleiotropy, differing IL-6 signalling interpretation, cohort overlap and linked erratum limit mechanistic specificity.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 9 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C10", "text": "MR suggests smoking/depression links involving IL-6 but no reciprocal CRP/depression effect. CRP is not interchangeable with upstream signalling; instrument and behavioural confounding assumptions remain.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 10 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C11", "text": "Lifelines genetic/non-genetic findings support selected affective associations with inflammation. Multiple phenotypes and modest signals; supersedes earlier versions and has an unexamined linked correction.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 11 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C12", "text": "Functional IL6R variant associates with less severe depression/psychosis despite higher circulating IL-6. Small case numbers and receptor-pathway effects; circulating concentration does not equal signalling intensity.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 12 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C13", "text": "Genetic analyses suggest IL-6 involvement in suicidality and metabolic contributions to other symptoms. Symptom-specific and inconsistent CRP effects; multiple testing and shared instruments constrain a broad MDD mechanism.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 13 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C14", "text": "UK Biobank MR gives differing IL-6 and CRP directions for symptoms. Pathway proxies, outcome definitions and overlap do not define a causal high-CRP clinical subtype.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 14 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C15", "text": "HUNT MR does not support a major CRP contribution to anxiety/depression scores; estimates are imprecise. Symptom scales rather than clinical MDD; weak instruments/precision limit universal exclusion.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 15 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C16", "text": "Inflammatory markers precede later psychiatric diagnoses in large cohorts with some genetic support. Transdiagnostic associations, surveillance/confounding and shared replication resources; not baseline-high MDD intervention.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 16 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C17", "text": "Baseline depressive symptoms predict later IL-6, whereas baseline IL-6 does not predict later depressive change. Older healthy cohort and observational temporal models; supports reverse direction without excluding other contexts.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 17 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C18", "text": "Elevated innate immune markers associate with later MDD and other brain disorders. UK Biobank recruitment, confounding and nonspecific disease outcomes; not selective peripheral-causal perturbation.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 18 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C19", "text": "An inflammatory dietary pattern associates with incident depression in women. Diet/activity/metabolic confounding and clinical definition; linked correction is an author-name correction.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 19 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C20", "text": "Higher dietary inflammatory index predicts depression in the SUN cohort. Modeled inflammatory diet and residual confounding; no selective pathway engagement or mediator proof.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 20 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C21", "text": "Low physical activity statistically mediates inflammation-to-later-symptom association, with no direct association found. Observational mediation is not manipulated causal pathway separation.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 21 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C22", "text": "Dialysis cohort has cross-sectional but no longitudinal inflammation/depression association. Physical illness context and finite precision; null is not proof of universal independence.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 22 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C23", "text": "Late-life depressed groups show overall immunometabolic downregulation with atypical-profile differences. Cross-sectional symptom-profile and age context challenge uniform high inflammation without defining causation.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 23 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C24", "text": "Antidepressant use associates with subsequent CRP independently of selected covariates. Confounding by treatment indication and drug effects can generate a downstream marker; no randomization.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 24 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C25", "text": "Paroxetine reduces diagnosed depression and discontinuation during prolonged high-dose interferon exposure. Antidepressant randomized, interferon exposure not; cancer and regimen context restrict inflammatory-cause attribution.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 25 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C26", "text": "Interferon changes tryptophan/kynurenine biology; depression-related patterns differ by paroxetine treatment. Correlated mediator and shared clinical program; antidepressant benefit does not selectively block immune signalling.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 26 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C27", "text": "Paroxetine reduces some severity categories during HCV therapy without a significant major-depression incidence difference. Small sample, dropout and symptom subgroup; shared trial with PMID22353759.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 27 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C28", "text": "Interferon neurovegetative effects occur early; mood/cognitive symptoms emerge later and respond differently to paroxetine. Secondary symptom analysis in the same melanoma trial, not independent randomized immune exposure.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 28 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C29", "text": "Prophylactic paroxetine does not reduce interferon-associated depression incidence in a small HCV trial. Changing antiviral regimen, sample and linked erratum; antidepressant-prevention null does not refute cytokine contribution.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 29 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C30", "text": "Interferon symptom dimensions differ in paroxetine responsiveness. Secondary analysis and shared HCV trial; not an independent immune-mediator experiment.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 30 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C31", "text": "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.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 31 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C32", "text": "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.", "carries_number": false, "load_bearing_for": [ "SC2", "SC3" ], "source_ns": [ 32 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C33", "text": "Endotoxin increases cytokines, mood symptoms and social disconnection with sex differences. Acute healthy-volunteer symptoms, subjective unblinding potential and no sustained MDD diagnosis.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 33 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C34", "text": "Baseline transcriptomic patterns predict endotoxin-induced depressed mood. Small exploratory biomarker analysis, shared challenge cohorts and no randomized transcriptomic mediator.", "carries_number": false, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 34 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C35", "text": "Sleep disturbance moderates acute inflammatory depressed mood in females. Secondary vulnerability analysis, sex-specific effects and acute time course; no sustained MDD causation.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 35 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C36", "text": "Endotoxin effects on depressed mood and reward vary with age in female samples. Pooled registered challenge cohorts, acute endpoints and subgroup analysis; not ordinary sustained MDD.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 36 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C37", "text": "Endotoxin increases acute depressed mood and reduces reward-related ventral-striatal activity. Statistical neural mediation is not selectively manipulated; healthy challenge does not establish sustained MDD.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 37 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C38", "text": "Endotoxin changes kynurenine metabolites, but they do not mediate cytokine-to-mood association. Nominal correlations fail multiple-testing robustness; acute measures do not establish a sustained clinical mechanism.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 38 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C39", "text": "High-CRP overweight MDD EPA trial has nonsignificant clinical response differences and limited target effects. Small completer dose-finding sample, prespecified biomarker endpoints and pleiotropic intervention; correlation is not mediation.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 39 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C40", "text": "Multicentre MinoTRD has no primary or secondary symptom benefit versus placebo. Unselected inflammation eligibility and one pleiotropic agent; no universal high-marker subtype exclusion.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 40 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C41", "text": "EPA prophylaxis reduces diagnosed interferon-associated depression in HCV treatment, unlike DHA. Specific immune-exposure context and nonspecific fatty-acid effects; not ordinary marker-defined MDD necessity.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 41 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C42", "text": "Large aspirin prevention trial finds no reduction in new elevated depression scores in older adults. Low-dose aspirin is not selective cytokine blockade and participants were not a high-inflammatory MDD population.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 42 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C43", "text": "Minocycline proof-of-concept trial has a null primary depression score with positive secondary functioning/global measures. Outcome hierarchy, multiple measures and no baseline-high eligibility; secondary benefit cannot replace null primary.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 43 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C44", "text": "Small randomized minocycline pilot reports positive symptom improvement. Unselected inflammatory status, small study and pleiotropic mechanism require independent subtype confirmation.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 44 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C45", "text": "Measured CRP predicts depression, while genetic CRP does not. CRP per se and upstream inflammatory pathways differ; finite instrument power and outcome definitions matter.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 45 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C46", "text": "Multivariable MR supports potential IL-6 effects on major depression after correction. Shared GWAS, instrument assumptions and some nonrobust tested proteins; no validated baseline-high subtype.", "carries_number": true, "load_bearing_for": [ "SC1" ], "source_ns": [ 46 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C47", "text": "MR does not support CRP–MDD causality and implicates BMI/trauma relationships. Reported-trauma measurement and shared cohorts; does not exclude all immune pathways or drug-induced depression.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 47 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C48", "text": "East-Asian genetic analysis implicates selected blood traits and metabolic pathways in depression. Pleiotropic genes and phenotype/instrument specificity; not a selective inflammation intervention.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 48 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C49", "text": "Escitalopram reduces depression incidence/severity during interferon-based HCV therapy. Antidepressant prevention is not randomized immune initiation; selected no-prior-psychiatric-disease population.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 49 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C50", "text": "Typhoid challenge causes short-term mood change and circuit associations. Hours-long sickness-linked phenotype and statistical mediation, not sustained MDD or selective brain mediator.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 50 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C51", "text": "Pretreatment IL-6 predicts depression during interferon therapy with bidirectional symptom/inflammation timing. Selected treatment cohort and sleep/illness confounding; temporal prediction is not selective immune causation.", "carries_number": true, "load_bearing_for": [ "SC1", "SC2" ], "source_ns": [ 51 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C52", "text": "Interferon and anti-TNF clinical cohorts show opposite mood/circuit changes across months. Different underlying diseases and nonrandomized therapeutic exposures; circuit mediation remains predictive.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 52 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C53", "text": "Endotoxin produces dose-dependent transient mood and physiological changes with mixed cognitive effects. Acute sickness, sympathetic/cortisol changes and no sustained clinical MDD dependency.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 53 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C54", "text": "Randomized endotoxin increases social disconnection and depressed mood. Correlated social mediation and acute healthy-volunteer response; does not establish a chronic inflammatory subtype.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 54 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C55", "text": "Vaccination lowers mood in remitted MDD patients but psychosocial stress contrasts differ. Short-term mood susceptibility and selected remitted population rather than current sustained MDD initiation.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 55 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "C56", "text": "Typhoid vaccine raises cytokines without social-connection or avoidance changes in cancer survivors. Milder stimulus and selected population constrain generalization; mood/social outcomes are not interchangeable.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 56 ], "verification": "verified", "verified_against": "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.", "verified_on": "2026-10-12", "note": "" }, { "id": "CSC1", "text": "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.", "carries_number": false, "load_bearing_for": [ "SC1" ], "source_ns": [ 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 34, 45, 46, 47, 48, 51 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-12", "note": "" }, { "id": "CSC2", "text": "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.", "carries_number": false, "load_bearing_for": [ "SC2" ], "source_ns": [ 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 41, 49, 50, 51, 52, 53, 54, 55, 56 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-12", "note": "" }, { "id": "CSC3", "text": "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.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 1, 2, 3, 4, 5, 6, 31, 32, 39, 40, 42, 43, 44 ], "verification": "verified", "verified_against": "Synthesis of examined primary result/limit cards; framework level is adjudication.", "verified_on": "2026-10-12", "note": "" }, { "id": "CH", "text": "Inflammation can alter mood and contribute to defined depressive syndromes; a causal high-inflammation MDD subtype still needs prospective confirmation.", "carries_number": false, "load_bearing_for": [ "SC3" ], "source_ns": [ 1, 3, 6, 40, 32, 25 ], "verification": "verified", "verified_against": "Bounded synthesis of examined sources; score is adjudication.", "verified_on": "2026-10-12", "note": "" } ], "citation_ledger": [ { "n": 1, "citation": "Raison CL, Rutherford RE, Woolwine BJ et al. 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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.", "tier": "A", "kind": "rct", "pmid": "39243988", "doi": "10.1016/j.bbi.2024.09.003", "url": "https://pubmed.ncbi.nlm.nih.gov/39243988/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PREDDICT", "access_depth": "abstract_metadata", "access_note": "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.", "carries_claims": [ "C5", "CSC3" ] }, { "n": 6, "citation": "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.", "tier": "A", "kind": "rct", "pmid": "37635396", "doi": "10.1111/jnc.15946", "url": "https://pubmed.ncbi.nlm.nih.gov/37635396/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PREDDICT", "access_depth": "abstract_metadata", "access_note": "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.", "carries_claims": [ "C6", "CSC3", "CH" ] }, { "n": 7, "citation": "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. 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EClinicalMedicine. 2021.", "tier": "A", "kind": "primary", "pmid": "34505025", "doi": "10.1016/j.eclinm.2021.100992", "url": "https://pubmed.ncbi.nlm.nih.gov/34505025/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID34505025", "access_depth": "abstract_metadata", "access_note": "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.", "carries_claims": [ "C14", "CSC1" ] }, { "n": 15, "citation": "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.", "tier": "A", "kind": "primary", "pmid": "37217205", "doi": "10.1017/S0033291723001290", "url": "https://pubmed.ncbi.nlm.nih.gov/37217205/", "status_flags": [ "none_found" ], "opened": true, "opened_on": "2026-10-12", "status_checked_on": "2026-10-12", "study_id": "PMID37217205", "access_depth": "abstract_metadata", "access_note": "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.", "carries_claims": [ "C15", "CSC1" ] }, { "n": 16, "citation": "Zeng Y, Chourpiliadis C, Hammar N et al. Inflammatory Biomarkers and Risk of Psychiatric Disorders. 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