{
  "cutoff": "2026-10-09",
  "note": "Selected publication milestones, not an exhaustive history or priority-of-discovery determination.",
  "milestones": [
    {
      "year": "2000",
      "pmid": "10739409",
      "doi": "10.1176/appi.ajp.157.4.514",
      "title": "Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia.",
      "interpretation": "Double-blind PET/treatment study relates D2 occupancy to response and adverse effects.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/10739409/"
    },
    {
      "year": "2000",
      "pmid": "10884434",
      "doi": "10.1073/pnas.97.14.8104",
      "title": "Increased baseline occupancy of D2 receptors by dopamine in schizophrenia.",
      "interpretation": "Depletion imaging tests endogenous baseline occupancy differences.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/10884434/"
    },
    {
      "year": "2010",
      "pmid": "20194823",
      "doi": "10.1001/archgenpsychiatry.2010.10",
      "title": "Increased synaptic dopamine function in associative regions of the striatum in schizophrenia.",
      "interpretation": "Regional depletion study localizes a stronger associative than limbic signal.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/20194823/"
    },
    {
      "year": "2011",
      "pmid": "21768612",
      "doi": "10.1176/appi.ajp.2011.11010160",
      "title": "Dopamine synthesis capacity before onset of psychosis: a prospective [18F]-DOPA PET imaging study.",
      "interpretation": "Prospective high-risk PET study tests temporal association with transition.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/21768612/"
    },
    {
      "year": "2012",
      "pmid": "23034655",
      "doi": "10.1176/appi.ajp.2012.12010144",
      "title": "Dopamine synthesis capacity in patients with treatment-resistant schizophrenia.",
      "interpretation": "Small responder/TRS comparison suggests heterogeneity.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/23034655/"
    },
    {
      "year": "2021",
      "pmid": "32910150",
      "doi": "10.1093/schbul/sbaa128",
      "title": "Dopamine and Glutamate in Antipsychotic-Responsive Compared With Antipsychotic-Nonresponsive Psychosis: A Multicenter Positron Emission Tomography and Magnetic Resonance Spectroscopy Study (STRATA).",
      "interpretation": "Multicentre STRATA challenges a settled dopamine response classifier.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/32910150/"
    },
    {
      "year": "2024",
      "pmid": "38691387",
      "doi": "10.1001/jamapsychiatry.2024.0785",
      "title": "Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia: A Randomized Clinical Trial.",
      "interpretation": "Registered muscarinic trial improves symptoms without resolving dopamine mediation.",
      "url": "https://pubmed.ncbi.nlm.nih.gov/38691387/"
    }
  ],
  "gaps": [
    "Associative and limbic striatum are distinct anatomical hypotheses.",
    "Historical challenge registration, expectancy controls and selective mediator evidence need fuller source recovery.",
    "Treatment resistance and symptomatic remission complicate uniform excess.",
    "Muscarinic efficacy does not demonstrate dopamine dispensability; EMERGENT-3 excluded TRS.",
    "Prospective mechanistic stratification needs independent validation rather than retrospective response-group discrimination."
  ],
  "decisive_experiment": "Prospectively register a selective human dopamine/D2 mediator comparison in anatomically and clinically predefined psychosis strata, measure target engagement and acute-effect expectancy/blinding, use blinded symptom trajectories and an orthogonal nondopaminergic comparator, and prospectively test responses without selecting eligibility from observed treatment outcome."
}