{
  "cutoff": "2026-10-09",
  "note": "Selected publication milestones, not an exhaustive history or priority-of-discovery determination.",
  "milestones": [
    {
      "year": "2001",
      "pmid": "11274622",
      "doi": "10.1056/NEJM200103293441303",
      "title": "Paroxetine for the prevention of depression induced by high-dose interferon alfa.",
      "interpretation": "Antidepressant prophylaxis during prolonged interferon exposure tests clinically diagnosed depression.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/11274622/"
    },
    {
      "year": "2013",
      "pmid": "22945416",
      "doi": "10.1001/2013.jamapsychiatry.4",
      "title": "A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers.",
      "interpretation": "Overall infliximab trial null with exploratory inflammation-related findings.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/22945416/"
    },
    {
      "year": "2021",
      "pmid": "33504955",
      "doi": "10.1038/s41386-020-00948-6",
      "title": "Augmentation therapy with minocycline in treatment-resistant depression patients with low-grade peripheral inflammation: results from a double-blind randomised clinical trial.",
      "interpretation": "MINDEP overall null and exploratory higher-CRP subgroup.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/33504955/"
    },
    {
      "year": "2022",
      "pmid": "36103181",
      "doi": "10.1001/jamanetworkopen.2022.30367",
      "title": "Effect of Minocycline on Depressive Symptoms in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial.",
      "interpretation": "Multicentre MinoTRD trial retains a null primary clinical result.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/36103181/"
    },
    {
      "year": "2024",
      "pmid": "37635396",
      "doi": "10.1111/jnc.15946",
      "title": "Inflammation-stratified augmentation of vortioxetine with celecoxib: Results from a double-blind, randomized, placebo-controlled trial in major depressive disorder.",
      "interpretation": "Prospectively stratified PREDDICT report challenges automatic CRP-subtype benefit.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/37635396/"
    },
    {
      "year": "2025",
      "pmid": "40264292",
      "doi": "10.1176/appi.ajp.20240142",
      "title": "Systemic Inflammation and Anhedonic Responses to an Inflammatory Challenge in Adults With Major Depressive Disorder: A Randomized Controlled Trial.",
      "interpretation": "Acute challenge tests anhedonia and time-dependent mood response.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/40264292/"
    },
    {
      "year": "2025",
      "pmid": "40668551",
      "doi": "10.1001/jamapsychiatry.2025.1327",
      "title": "Inflammatory Exposure and Depression in Older Adults With Insomnia: A Randomized Clinical Trial.",
      "interpretation": "Older-insomnia challenge tests transient mood effects, excluding recent MDD.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/40668551/"
    }
  ],
  "gaps": [
    "CRP concentration is neither a specific immune pathway nor a validated causal-subtype definition.",
    "Exploratory threshold effects need prospective independent replication.",
    "Acute anhedonia and sickness require separate assessment from sustained MDD and function.",
    "Immune, metabolic, sleep and medication pathways need selective controls.",
    "Named prospective trials require current registry/result verification; old estimated completion dates are not completed evidence."
  ],
  "decisive_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."
}