# HSEF v5.3 review: Dopamine Hypothesis of Schizophrenia > Sources: 50 primary reports; claims: 54; verified: 54; unverified: 0. Verification is bounded attribution. Access: 3 partial-body and 47 bounded abstract/status examinations. Literature cutoff: 2026-10-09; source examination UTC date: 2026-10-12. No complete-paper audit or blinded calibration claimed. > **Adversarial review:** Generated by Sol 6.1; adversarially reviewed by Claude Opus 5.5 (Anthropic) on 2026-10-14. 1 correction applied and 1 calibration finding recorded without a level change (see ADVERSARIAL REVIEW AND APPROVAL). Status: **Approved as revised.** ## AT A GLANCE **Dopamine dysregulation is relevant to psychosis and symptom modulation; unselected mesolimbic D2 primacy is not established.** | Level | Confidence | Causal role | Momentum | Stability | Divergence | |---|---|---|---|---|---| | Γ — Mechanistically plausible, partial system support | Moderate | reinforcing / stabilizing factor | Mechanistic only | Stable | Contested | **Deciding 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. **Belief versus evidence:** Overall Γ follows registered SC3, with association SC1 at Β and a conservative Γ for the strictly audited SC2 mechanism gate. The nominal claim fixes mesolimbic anatomy and unselected primacy, whereas strong human findings often concern associative striatum or symptom-responsive contexts. Clinical symptom modulation remains supported; the unresolved exact causal-primacy claim cannot be rescued by changing the anatomical label or retrospectively selecting responders. **Best-supported rival:** Heterogeneous psychosis pathways. Demjaha treatment-response comparison (PMID23034655) favors heterogeneity over a uniform pathway; STRATA (PMID32910150) fails to reproduce a clear dopamine responder separator and prevents turning a small-study result into a settled subtype classifier. The strongest rank-1/rank-2 distinction remains imperfect because heterogeneous pathways can include downstream dopamine mediation. ## COMPETING MECHANISTIC MODELS **Rank 1: Heterogeneous psychosis pathways (Γ).** Different states/subgroups combine dopamine and other circuit mechanisms. TRS, remission, compartment and STRATA findings reveal nonuniform neurochemistry. Heterogeneity does not itself establish every proposed subtype mechanism. **Rank 2: Downstream dopamine mediator (Γ).** Upstream circuit/developmental changes converge partly on dopamine-mediated positive symptoms. Prospective synthesis, challenge response and upstream rodent perturbations support this account. Not all human upstream-to-dopamine pathways or symptom dependency are selectively established. **Rank 3: Glutamate/neurodevelopmental upstream mechanisms (Γ).** Cortical/hippocampal dysfunction can generate downstream dopamine changes. DISC1/parvalbumin/Cyclin-D2 models and modest ACC glutamate differences support plausibility. Rodent proxies and clinical correlations do not prove a universal human alternative. **Rank 4: Mesolimbic D2 primacy (Γ).** Excess mesolimbic D2 signalling primarily causes schizophrenia psychotic symptoms. D2 treatment-response relations and dopamine challenge give a substantial steelman. Anatomical, clinical-state and resistance boundaries block unselected primacy. The tournament does not alter the nominal level. Compatible pathways and flexible alternatives are not automatically proved by explaining observations. ## FULL REVIEW ### Registered claim and scope Excess dopamine transmission at D2 receptors in mesolimbic pathways is the primary cause of psychotic symptoms in schizophrenia. SC3 is the clinical causal claim at the registered scope; narrower molecular, treatment or inherited-syndrome findings cannot replace it. Primary-subclaim aggregation is fixed before grading. Selection: remaining-priority list position 9 from the editorial list of 2026-10-09. Registered claim assessed against original sources. This is not independent blinded calibration. ### Evidence and causal interpretation Rubric fit: 07-psychiatry-neuromodulation governs clinical psychotic-symptom mechanism claims. Positive-symptom ratings are relevant because the nominal claim is symptomatic, not functional recovery. Registration and expectancy/mediator-control requirements are retained. The strict SC2 audit remains bounded by access/provenance and should not be generalized into a negative claim about established clinical drug efficacy. The human association is substantial but anatomically specific. The prospective transition study used outcome assessment blinded to imaging and found the strongest difference in associative striatum, with no significant limbic difference. Baseline-depletion and regional PET findings support altered dopamine stimulation, but binding displacement is not direct proof of primary symptom causation. PMID21768612; PMID20194823; PMID10884434. Response heterogeneity deserves symmetrical treatment. Demjaha and clozapine-treated comparisons support lower synthesis in resistant groups, but medication and small samples limit trait attribution. STRATA does not find the predicted dopamine response-group difference; its glutamate discrimination is weak. Consensus’s simple normal-dopamine TRS category is therefore too settled. PMID23034655; PMID27857125; PMID32910150. Occupancy is relevant to response and adverse effects, but neither continuous threshold necessity nor equivalent pharmacology is universal. Stable patients, dose reductions and transient quetiapine occupancy qualify acute-phase thresholds; aripiprazole partial agonism differs from antagonism. Historical challenge and clinical occupancy studies support modulation, while incomplete registration/expectancy verification limits this strict mechanism audit. PMID10739409; PMID23899638; PMID25099201; PMID10839333; PMID17728427. Muscarinic trials supply a meaningful competing intervention. EMERGENT-3 has registered prespecified symptom endpoints and clinical benefit, but excludes treatment resistance and does not measure selective dopamine mediation. It is not evidence that dopamine is irrelevant, universally essential or that KarXT treats resistant illness. Shared sponsor/protocol and adverse-effect differences limit independent mechanism attribution. PMID38691387; PMID38104575. Upstream developmental/circuit manipulations can create dopamine alterations and behaviour in rodents. Their timing, genotype and surrogate behaviour do not establish ordinary human disease primacy. The Syt11 study strengthens the nominal steelman within an adolescent mouse context without resolving unselected human mesolimbic causation. PMID20188653; PMID24888524; PMID30301879; PMID39632880. ## HYPOTHESIS STATE EVALUATION FRAMEWORK (HSEF v5.3) ### Subclaim matrix and aggregation | Subclaim | Scope | Level | Decision | |---|---|---|---| | SC1 Schizophrenia psychosis is associated with altered striatal dopamine synthesis or release. | Anatomical compartment and treatment status defined before outcome | Β | Imaging, depletion-derived binding and prospective risk studies reproducibly associate striatal dopamine differences with clinical state, with substantial compartment/treatment heterogeneity. The registered SC1 is an association/existence clause; its rating does not claim a causal disease dependency. | | SC2 Dopamine/D2 pathway manipulation causally changes psychotic symptom trajectories. | Diagnosed psychosis with objective trajectory, target engagement and credible comparator | Γ | Clinical challenge, drug-dose and occupancy studies support symptom modulation, but this bounded audit has not verified the psychiatry rubric combination of prespecified/registered primary symptom outcomes, credible expectancy controls and selective human D2 mediator manipulation. Occupancy-response correlation alone is insufficient. Γ here records an incompletely crossed strict mechanistic audit gate, not absence of antipsychotic efficacy or evidence that dopamine manipulation has no effects. | | SC3 Excess mesolimbic D2 signaling is the primary cause of schizophrenia psychotic symptoms. | Unselected schizophrenia psychosis, not retrospectively defined treatment responders | Γ | Human mesolimbic primacy in unselected schizophrenia remains unestablished. Associative-striatal findings, response/state heterogeneity and upstream rodent manipulations constrain the claim. Treatment benefit and premorbid synthesis elevation neither identify a universally primary mesolimbic cause nor prove dopamine is irrelevant. | Preregistered aggregation: primary-subclaim. Overall Γ follows registered SC3, with association SC1 at Β and a conservative Γ for the strictly audited SC2 mechanism gate. The nominal claim fixes mesolimbic anatomy and unselected primacy, whereas strong human findings often concern associative striatum or symptom-responsive contexts. Clinical symptom modulation remains supported; the unresolved exact causal-primacy claim cannot be rescued by changing the anatomical label or retrospectively selecting responders. Sensitivities: weakest-link Β; primary-subclaim Γ; scope-matched Γ. ### Decisive-perturbation inventory and causal tally [10] Double-blind haloperidol PET study links D2 occupancy with response and adverse effects. Small historical study; measured mediator correlation, registration and expectancy controls are incompletely verified. [13] Multicentre STRATA does not find a responder/nonresponder dopamine-synthesis difference; ACC glutamate difference is modest. Clinical group definitions and site heterogeneity constrain sensitivity; does not prove all resistance is nondopaminergic. [14] EMERGENT-3 xanomeline-trospium improves prespecified symptom scores versus placebo. Treatment-resistant history excluded; no dopamine mediator measurement, short follow-up and adverse-effect differences. Erratum retained. [40] Responders have elevated synthesis relative to TRS patients and controls, with no TRS/control difference. Small chronically treated groups and response-defined sampling; medication effects and heterogeneity limit generalization. [43] Depletion-derived excess synaptic dopamine appears in associative striatum, not limbic/sensorimotor regions. Primary endpoint is receptor-binding inference; no selective symptom trajectory experiment. [48] Depletion reveals higher dopamine occupancy in untreated patients and predicts later treatment response. Occupancy and treatment-response correlation are not independent randomized symptom-mediator manipulation. Tally: 0 positive qualifying study units across scoped subclaims; 18 screened discriminating contrast units. These are not independent causal lines or proof of full-claim necessity/sufficiency. Null and negative contrasts are discriminators, not positive threshold crossings. Reports and replications are not independent causal lines. Reports sharing recruitment, instruments or randomization are not automatically independent causal lines. The tally includes discriminating contrasts; positive qualifying source lists alone determine threshold crossings. No positive field-valid crossing was verified for the registered causal scope in this bounded audit. The proposed registered experiment makes that scope testable. Pivotal symptom studies remain informative; missing registration or mediator verification is an audit limitation, not evidence that dopamine has no effects or that antipsychotics lack efficacy. ### Cap audit, precedence and Β/Γ/Δ boundary Positive symptom ratings can be a clinical phenotype here, but acute occupancy, synthesis and statistical mediation alone cannot cross the mechanistic gate. Blinded drug-dose studies and challenges are not downgraded simply because they are human; their preregistration, acute-effect controls and precise mediator attribution are the unresolved verification boundary. Mouse behavioural results cross within model biology, while psychiatry rodent-proxy and universal scope rules limit the inference to human SC3. Universal six-cap audit: All six universal caps were considered. Cell-only evidence is bounded by cap 1; unperturbed associations by cap 2; ectopic models by cap 3; biomarker-only trials by cap 4. Cap 5 binds only forced-transfer inference. Cap 6 restricts inherited-syndrome transfer to sporadic scope. Each binds the offered inference, not an independently convergent same-scope causal set. Gamma hard-rule audit: SC1 is primarily imaging, binding and symptom association. Historical challenges have acute subjective effects and incompletely verified outcome-registration/expectancy safeguards; occupancy correlations do not independently manipulate the proposed clinical mediator. Rodent developmental and behavioural results do not satisfy unselected human primacy. KarXT clinical efficacy does not demonstrate dopamine dispensability or direct D2 mediator engagement. SC1 cap: “Pure association evidence — however large, however replicated — cannot exceed Β.” Imaging, depletion-derived binding and prospective risk studies reproducibly associate striatal dopamine differences with clinical state, with substantial compartment/treatment heterogeneity. The registered SC1 is an association/existence clause; its rating does not claim a causal disease dependency. SC3 cap: “Mechanistic plausibility with in vitro, rodent, or unblinded human support caps at Γ.” Human mesolimbic primacy in unselected schizophrenia remains unestablished. Associative-striatal findings, response/state heterogeneity and upstream rodent manipulations constrain the claim. Treatment benefit and premorbid synthesis elevation neither identify a universally primary mesolimbic cause nor prove dopamine is irrelevant. SC1 field-valid definition: “at least one of: - Active comparator matched for acute subjective effect, blinding integrity measured and reported - Blinded on/off, staggered-onset, or randomized-withdrawal neuromodulation, reversible and within-subject - Mediator manipulation with the intervention intact: antagonist blockade of the acute experience with the drug still given, or dosing under general anaesthesia - Depletion or challenge experiment in humans whose outcome is symptom trajectory, not a biomarker - Psychotherapy component dismantling, or scaffold removal from a drug arm, with blinded assessors Rating-scale or biomarker change alone does NOT satisfy this threshold when the claim is functional, and statistical mediation alone never satisfies it.” Positive full-scope result: no. Imaging, depletion-derived binding and prospective risk studies reproducibly associate striatal dopamine differences with clinical state, with substantial compartment/treatment heterogeneity. The registered SC1 is an association/existence clause; its rating does not claim a causal disease dependency. SC2 field-valid definition: “at least one of: - Active comparator matched for acute subjective effect, blinding integrity measured and reported - Blinded on/off, staggered-onset, or randomized-withdrawal neuromodulation, reversible and within-subject - Mediator manipulation with the intervention intact: antagonist blockade of the acute experience with the drug still given, or dosing under general anaesthesia - Depletion or challenge experiment in humans whose outcome is symptom trajectory, not a biomarker - Psychotherapy component dismantling, or scaffold removal from a drug arm, with blinded assessors Rating-scale or biomarker change alone does NOT satisfy this threshold when the claim is functional, and statistical mediation alone never satisfies it.” Positive full-scope result: no. Clinical challenge, drug-dose and occupancy studies support symptom modulation, but this bounded audit has not verified the psychiatry rubric combination of prespecified/registered primary symptom outcomes, credible expectancy controls and selective human D2 mediator manipulation. Occupancy-response correlation alone is insufficient. Γ here records an incompletely crossed strict mechanistic audit gate, not absence of antipsychotic efficacy or evidence that dopamine manipulation has no effects. SC3 field-valid definition: “at least one of: - Active comparator matched for acute subjective effect, blinding integrity measured and reported - Blinded on/off, staggered-onset, or randomized-withdrawal neuromodulation, reversible and within-subject - Mediator manipulation with the intervention intact: antagonist blockade of the acute experience with the drug still given, or dosing under general anaesthesia - Depletion or challenge experiment in humans whose outcome is symptom trajectory, not a biomarker - Psychotherapy component dismantling, or scaffold removal from a drug arm, with blinded assessors Rating-scale or biomarker change alone does NOT satisfy this threshold when the claim is functional, and statistical mediation alone never satisfies it.” Positive full-scope result: no. Human mesolimbic primacy in unselected schizophrenia remains unestablished. Associative-striatal findings, response/state heterogeneity and upstream rodent manipulations constrain the claim. Treatment benefit and premorbid synthesis elevation neither identify a universally primary mesolimbic cause nor prove dopamine is irrelevant. ### Upward threshold ladder SC1 Δ: “Requires a controlled human interventional study with a credible active comparator, or a mediator manipulation in humans, with a pre-registered primary outcome.” Satisfied: no. Selective prospective mediator perturbation tied to clinical psychotic trajectory would be required for a causal claim beyond this registered association clause. SC2 Δ: “Requires a controlled human interventional study with a credible active comparator, or a mediator manipulation in humans, with a pre-registered primary outcome.” Satisfied: no. Verify a prospectively registered primary symptom trajectory under selective D2/dopamine manipulation with credible acute-effect/expectancy controls and blinded assessors; recover protocol/registration evidence for historical challenges rather than assume it exists. SC3 Δ: “Requires a controlled human interventional study with a credible active comparator, or a mediator manipulation in humans, with a pre-registered primary outcome.” Satisfied: no. Predefine anatomy and eligibility in unselected psychosis, measure selective target engagement, compare competing pathway interventions and test necessity, initiating precedence and rate limitation without redefining scope from responders. Upper ladder: Blinded dose comparisons, withdrawal/medication-placebo periods, prospective imaging and genetic associations were considered. They constrain different errors, but registration/expectancy separation and selective unselected mesolimbic clinical mediation remain incomplete in this source audit. This is an access/evidence-identification limit as well as a mechanistic scope limit; it does not prove that no stronger clinical study exists. Upper grades remain reachable with the required source verification. Independence: FDOPA studies share tracer/model assumptions and sometimes recruitment or research teams. EMERGENT trials are distinct randomizations within one sponsor program; they are not independent mechanism-identification experiments. STRATA is a genuine multicentre contradictory classifier result. Orthogonality does not repair missing exact-scope mediator controls. Prospective timing [47, 27]: Constrains dopamine elevation being measured only after frank psychosis, but shared recruitment/research program and prodromal upstream processes remain. Human challenge/occupancy [48, 42, 10, 45]: Constrains pure static imaging association, but acute subjective effects, receptor specificity and outcome registration require verification. Response/state boundaries [40, 49, 13, 37]: Constrains universal excess and response assumptions; selected groups, medication and overlapping cohorts remain. Muscarinic symptom interventions [15, 14]: Tests clinical efficacy without direct D2 antagonism, but no selective dopamine mediation/dispensability readout and shared sponsor/program. ### Falsification and pitfalls Persistence or clinical heterogeneity despite the proposed uniform mechanism. TRS, remitted-state and occupancy exceptions constrain uniform primacy; STRATA also prevents overclaiming a simple rival subtype classification. Additional downgrade: False. Therapeutic mediator equated with initiating primary cause. Occupancy and symptom response do not establish unselected primacy. Anatomical relabeling. Associative/dorsal findings cannot silently substitute for mesolimbic SC3. Response-defined scope rescue. Retrospective responders and TRS contrasts do not replace unselected eligibility. ### Adversarial steelman: above, then below One rung above, Δ: acute dopamine challenge worsens positive symptoms and D2 drug exposure predicts improvement, making a causal contribution very plausible. Yet SC3 asks specifically for unselected mesolimbic primacy, not some striatal contribution. Anatomical localization and selective initiating/rate-limiting evidence are missing; the strict SC2 registration/expectancy audit is also incomplete. One rung below, Β: the strongest premorbid and treatment-stratification findings are observational. However, receptor pharmacology, human challenges and developmental-model perturbations provide substantial partial-system mechanistic support. Γ preserves that support while rejecting clinical primacy transfer. Retain Γ for exact SC3. Do not relabel associative striatum as mesolimbic, equate therapeutic mediation with etiology, or conclude that a conservative mechanism audit invalidates demonstrated symptom benefit. ### Final score, causal direction and M/S/D Overall Γ follows registered SC3, with association SC1 at Β and a conservative Γ for the strictly audited SC2 mechanism gate. The nominal claim fixes mesolimbic anatomy and unselected primacy, whereas strong human findings often concern associative striatum or symptom-responsive contexts. Clinical symptom modulation remains supported; the unresolved exact causal-primacy claim cannot be rescued by changing the anatomical label or retrospectively selecting responders. Dopamine differences can precede frank psychosis, so they are not established as solely a consequence of that phenotype. Challenge and treatment evidence supports a modifiable pathway in selected contexts, beyond co-occurrence alone. Unselected mesolimbic initiation, prevention and rate limitation are not jointly shown, and universal necessity is contradicted or unresolved. Step 5 assigns a context-limited symptom amplifier/mediator; it does not establish a universal upstream root cause. Momentum: Mechanistic only. Syt11 conditional developmental perturbation (PMID39632880, 2024) tests initiation and D2 intervention in mice, while EMERGENT-3 (NCT04738123) tests symptom therapy. The first has rodent proxy/scope limits and the latter excludes TRS and lacks dopamine mediator measurement; neither crosses unselected human SC3. Stability: Stable. No verified named pending result that would change the registered full-scope grade was identified. This does not mean that no relevant trial exists. Divergence: Contested. No manufactured field consensus or arithmetic gap. These dimensions do not change level or confidence. ## PROPOSED DECISIVE EXPERIMENTS 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. Readout: Prespecified positive-psychotic symptom course and anatomy-specific engagement, with functional outcome as a separate endpoint. Controls: Expectancy, acute subjective effects, rater blinding, medication history, adherence and competing-pathway engagement. Supporting: Selective pathway perturbation predicts and changes symptoms across the fixed unselected scope, with initiating precedence and rate-limiting evidence. Falsifying: Symptoms persist despite adequate selective engagement, anatomy fails prospective prediction, or independent competing-pathway effects explain trajectory without required dopamine change. ## KNOWLEDGE 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. ## REVIEWER NOTES Bounded original primary abstract/status passages and selected original body sections were examined. Supplements and most complete papers were not audited. Consensus browser synthesis is supplementary and does not count as primary evidence. Scite anchor tallies/outgoing contexts and SciSpace discovery were examined as supplementary inputs. No independent blinded grading is claimed. Search leads, reviews, protocols and correction notices do not pad the primary count. Downloaded XML does not earn examination credit. Linked notices remain attached; unexamined correction details limit inference. This is a coordinator source/claim consistency assessment, not independent blinded calibration. ## Consensus and original-source reconciliation Original prospective study body supports a striatal association in a small converter group. The limbic comparison is nonsignificant; a prospective association is not a selective mesolimbic necessity test. [PMID 21768612](https://pubmed.ncbi.nlm.nih.gov/21768612/). Original multicentre STRATA body finds no responder/nonresponder dopamine difference. A settled diagnostic classifier cannot be inferred from earlier small studies. [PMID 32910150](https://pubmed.ncbi.nlm.nih.gov/32910150/). Original EMERGENT-3 body verifies registration and a positive PANSS endpoint, but excludes treatment-resistant history and does not measure a selective dopamine mediator. It does not establish efficacy in TRS or dopamine dispensability. [PMID 38691387](https://pubmed.ncbi.nlm.nih.gov/38691387/). Original primary abstract links occupancy to clinical response and adverse effects. This bounded audit does not verify a preregistered selective mesolimbic mediator/trajectory experiment; failure to verify that provenance is not failure of antipsychotic efficacy. [PMID 10739409](https://pubmed.ncbi.nlm.nih.gov/10739409/). Consensus was used to identify literature and cross-check specific claims about study design, endpoints, scope and research gaps. Those claims were checked against original primary abstracts/status records and, for selected studies, original Methods or Results passages. Consensus output was not treated as original full text. Source-specific access depth and receipts are retained. Scite supplied one five-anchor citation-context/tally query; returned contexts were outgoing references, not an audited incoming contradiction set. SciSpace supplied one discovery pass; it added no primary-count credit. ## Research timeline and gap priorities Selected publication milestones through 9 October 2026. These dates identify source publication years, not priority claims or a comprehensive history. **2000 — Double-blind PET/treatment study relates D2 occupancy to response and adverse effects.** [PMID 10739409](https://pubmed.ncbi.nlm.nih.gov/10739409/). **2000 — Depletion imaging tests endogenous baseline occupancy differences.** [PMID 10884434](https://pubmed.ncbi.nlm.nih.gov/10884434/). **2010 — Regional depletion study localizes a stronger associative than limbic signal.** [PMID 20194823](https://pubmed.ncbi.nlm.nih.gov/20194823/). **2011 — Prospective high-risk PET study tests temporal association with transition.** [PMID 21768612](https://pubmed.ncbi.nlm.nih.gov/21768612/). **2012 — Small responder/TRS comparison suggests heterogeneity.** [PMID 23034655](https://pubmed.ncbi.nlm.nih.gov/23034655/). **2021 — Multicentre STRATA challenges a settled dopamine response classifier.** [PMID 32910150](https://pubmed.ncbi.nlm.nih.gov/32910150/). **2024 — Registered muscarinic trial improves symptoms without resolving dopamine mediation.** [PMID 38691387](https://pubmed.ncbi.nlm.nih.gov/38691387/). ## Research 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. ## Study that would resolve the boundary 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. ## ADVERSARIAL REVIEW AND APPROVAL Authoring model: **Sol 6.1**. Adversarial reviewer: **Claude Opus 5.5 (Anthropic)**. Date: **2026-10-14**. Scope of checks: all 50 REFERENCES PMIDs verified against PubMed metadata (50/50 resolved to the stated title, first author, journal and year; no retraction or expression-of-concern notices); 11 load-bearing claims spot-checked against the cited abstracts; scoring logic re-derived against `references/hsef-framework.md`, `references/evidence-rubrics/07-psychiatry-neuromodulation.md` and SKILL.md Steps 2-3, 11 and 12 (six universal caps, primary-subclaim aggregation, the rubric's field-valid list and its named equivalents, `upper_ladder_check` record, Momentum/Stability/Divergence artifacts). | ID | Severity | Location | Original -> corrected | Evidence | |---|---|---|---|---| | DS-1 | Major (recorded; no level changed) | SC2 subclaim level and the causal tally | "Γ" and "0 positive qualifying study units" — **retained**, with this calibration limitation recorded | Rubric 07 names "blinding-integrity-reported randomized trials, discontinuation and rechallenge designs, and genetic instruments" as field-valid equivalents and states that they "do not lower the bar here — they are listed so that a genuinely convergent case is not capped by the absence of a clean blind." The examined body contains a single-blind model-guided dose-reduction pilot (PMID 31188232) and an AMPT depletion study whose outcome is subjective experience correlated with occupancy (PMID 11682247), but no registered, blinded randomized-withdrawal or discontinuation trial, although that design class exists in the literature. The SC2 Γ and the zero tally therefore rest in part on an evidence-identification gap, which the review states explicitly ("This is an access/evidence-identification limit as well as a mechanistic scope limit"). The letter was not changed, because raising it would require adding and examining sources rather than re-reading the present ones, and the headline is set by SC3 under the preregistered primary-subclaim rule and would remain Γ in either case. Recommended action for the editorial lead: commission a targeted retrieval of registered discontinuation / randomized-withdrawal antipsychotic trials and re-score SC2 before publication. | | DS-2 | Minor | "Registered claim and scope", Selection line | "; existing HIV draft consulted after a source-based checkpoint" removed | No HIV draft belongs to this case's provenance; the clause is batch boilerplate present in all five cases of this batch, accurate only for `hiv-aids`. | Rejected findings (checked, no change): - Headline Γ for SC3. The registered claim fixes **mesolimbic** anatomy and **unselected** primacy. The strongest human findings localise to the associative striatum (PMID 21768612, PMID 20194823), the response-stratification results are small and medication-confounded, and the multicentre STRATA study finds no striatal dopamine difference between responders and non-responders, so neither Δ for the registered scope nor Β is forced. The review also states plainly that this is not a claim that antipsychotics lack efficacy, which is the error most available here. - Confidence "Moderate" is defensible: compartment, treatment-status and response heterogeneity are exactly the "methodological heterogeneity" the Moderate band describes. The access-based wording of the rationale recurs across this batch and is noted for the lead. - Momentum "Mechanistic only" carries its required artifact and names the work: Syt11 conditional developmental perturbation (PMID 39632880) and EMERGENT-3 (NCT04738123). - Divergence "Contested" is appropriate for a field split between textbook dopamine framing and a heterogeneity literature. - Primary-subclaim aggregation on SC3 returns Γ; alternatives reported (weakest-link Β, scope-matched Γ). - `upper_ladder_check` records which field-valid equivalents were considered and why none carried the claim further, as rubric 07 requires for a level below Ζ. - Numeric and design claims verified: prospective ultra-high-risk transition group elevated in striatum and its associative subdivision (PMID 21768612); increased synaptic dopamine in associative rather than limbic or sensorimotor striatum (PMID 20194823); responders higher than treatment-resistant patients and controls with no resistant-versus-control difference (PMID 23034655); STRATA no striatal dopamine group difference with a modest anterior cingulate glutamate difference and area under the curve 0.59 (PMID 32910150); EMERGENT-3 prespecified symptom endpoint with treatment-resistant history excluded and an erratum retained (PMID 38691387); single-blind model-guided dose reduction with no PANSS difference but a Clinical Global Impression positive-subscale difference (PMID 31188232); Syt11 deficiency in adolescent but not adult mice (PMID 39632880). Residual limitations: access depth is unchanged at 3 partial-body and 47 abstract/status examinations; registration and expectancy provenance for the historical challenge and occupancy studies was not recovered, which is the stated basis of the conservative SC2 gate and the subject of finding DS-1. **Approval:** Following adversarial review and the correction listed above, the revised document is approved, with finding DS-1 recorded for the editorial lead. — Claude Opus 5.5 (Anthropic), 2026-10-14. ## REFERENCES 1. Ozawa C, Bies RR, Pillai N et al. Model-Guided Antipsychotic Dose Reduction in Schizophrenia: A Pilot, Single-Blind Randomized Controlled Trial. Journal of clinical psychopharmacology. 2019. [PMID 31188232](https://pubmed.ncbi.nlm.nih.gov/31188232/). DOI: 10.1097/JCP.0000000000001046. Access: abstract_metadata. Study: PMID31188232. 2. Potkin SG, Keator DB, Kesler-West ML et al. 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Dopamine D2 receptor occupancy with risperidone or olanzapine during maintenance treatment of schizophrenia: a cross-sectional study. Progress in neuro-psychopharmacology & biological psychiatry. 2012. [PMID 22230651](https://pubmed.ncbi.nlm.nih.gov/22230651/). DOI: 10.1016/j.pnpbp.2011.12.013. Access: abstract_metadata. Study: PMID22230651. 6. Agid O, Mamo D, Ginovart N et al. Striatal vs extrastriatal dopamine D2 receptors in antipsychotic response--a double-blind PET study in schizophrenia. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2007. [PMID 17077809](https://pubmed.ncbi.nlm.nih.gov/17077809/). DOI: 10.1038/sj.npp.1301242. Access: abstract_metadata. Study: PMID17077809. 7. Zipursky RB, Christensen BK, Daskalakis Z et al. Treatment response to olanzapine and haloperidol and its association with dopamine D receptor occupancy in first-episode psychosis. Canadian journal of psychiatry. Revue canadienne de psychiatrie. 2005. [PMID 16127964](https://pubmed.ncbi.nlm.nih.gov/16127964/). DOI: 10.1177/070674370505000806. Access: abstract_metadata. Study: PMID16127964. 8. Takeuchi H, Suzuki T, Bies RR et al. Dose reduction of risperidone and olanzapine and estimated dopamine D₂ receptor occupancy in stable patients with schizophrenia: findings from an open-label, randomized, controlled study. The Journal of clinical psychiatry. 2014. [PMID 25099201](https://pubmed.ncbi.nlm.nih.gov/25099201/). DOI: 10.4088/JCP.13m08841. Access: abstract_metadata. Study: PMID25099201. 9. de Haan L, van Bruggen M, Lavalaye J et al. Subjective experience and D2 receptor occupancy in patients with recent-onset schizophrenia treated with low-dose olanzapine or haloperidol: a randomized, double-blind study. The American journal of psychiatry. 2003. [PMID 12562577](https://pubmed.ncbi.nlm.nih.gov/12562577/). DOI: 10.1176/appi.ajp.160.2.303. Access: abstract_metadata. Study: PMID12562577. 10. Kapur S, Zipursky R, Jones C et al. Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. The American journal of psychiatry. 2000. [PMID 10739409](https://pubmed.ncbi.nlm.nih.gov/10739409/). DOI: 10.1176/appi.ajp.157.4.514. Access: abstract_metadata. Study: PMID10739409. 11. Mamo D, Graff A, Mizrahi R et al. Differential effects of aripiprazole on D(2), 5-HT(2), and 5-HT(1A) receptor occupancy in patients with schizophrenia: a triple tracer PET study. The American journal of psychiatry. 2007. [PMID 17728427](https://pubmed.ncbi.nlm.nih.gov/17728427/). DOI: 10.1176/appi.ajp.2007.06091479. Access: abstract_metadata. Study: PMID17728427. 12. Kapur S, Zipursky R, Jones C et al. A positron emission tomography study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy. Archives of general psychiatry. 2000. [PMID 10839333](https://pubmed.ncbi.nlm.nih.gov/10839333/). DOI: 10.1001/archpsyc.57.6.553. Access: abstract_metadata. Study: PMID10839333. 13. Egerton A, Murphy A, Donocik J et al. Dopamine and Glutamate in Antipsychotic-Responsive Compared With Antipsychotic-Nonresponsive Psychosis: A Multicenter Positron Emission Tomography and Magnetic Resonance Spectroscopy Study (STRATA). Schizophrenia bulletin. 2021. [PMID 32910150](https://pubmed.ncbi.nlm.nih.gov/32910150/). DOI: 10.1093/schbul/sbaa128. Access: full_text_partial. Study: PMID32910150. 14. Kaul I, Sawchak S, Walling DP et al. Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia: A Randomized Clinical Trial. JAMA psychiatry. 2024. [PMID 38691387](https://pubmed.ncbi.nlm.nih.gov/38691387/). DOI: 10.1001/jamapsychiatry.2024.0785. Access: full_text_partial. Study: PMID38691387. 15. Kaul I, Sawchak S, Correll CU et al. Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial. Lancet (London, England). 2024. [PMID 38104575](https://pubmed.ncbi.nlm.nih.gov/38104575/). DOI: 10.1016/S0140-6736(23)02190-6. Access: abstract_metadata. Study: PMID38104575. 16. Krystal JH, Kane JM, Correll CU et al. Emraclidine, a novel positive allosteric modulator of cholinergic M4 receptors, for the treatment of schizophrenia: a two-part, randomised, double-blind, placebo-controlled, phase 1b trial. Lancet (London, England). 2022. [PMID 36528376](https://pubmed.ncbi.nlm.nih.gov/36528376/). DOI: 10.1016/S0140-6736(22)01990-0. Access: abstract_metadata. Study: PMID36528376. 17. Prata DP, Mechelli A, Fu CH et al. Opposite effects of catechol-O-methyltransferase Val158Met on cortical function in healthy subjects and patients with schizophrenia. Biological psychiatry. 2009. [PMID 19054502](https://pubmed.ncbi.nlm.nih.gov/19054502/). DOI: 10.1016/j.biopsych.2008.09.027. Access: abstract_metadata. Study: PMID19054502. 18. Niwa M, Kamiya A, Murai R et al. Knockdown of DISC1 by in utero gene transfer disturbs postnatal dopaminergic maturation in the frontal cortex and leads to adult behavioral deficits. Neuron. 2010. [PMID 20188653](https://pubmed.ncbi.nlm.nih.gov/20188653/). DOI: 10.1016/j.neuron.2010.01.019. Access: abstract_metadata. Study: PMID20188653. 19. Blasi G, Napolitano F, Ursini G et al. DRD2/AKT1 interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia. Proceedings of the National Academy of Sciences of the United States of America. 2011. [PMID 21187413](https://pubmed.ncbi.nlm.nih.gov/21187413/). DOI: 10.1073/pnas.1013535108. Access: abstract_metadata. Study: PMID21187413. 20. Stenkrona P, Matheson GJ, Halldin C et al. D1-Dopamine Receptor Availability in First-Episode Neuroleptic Naive Psychosis Patients. The international journal of neuropsychopharmacology. 2019. [PMID 30958880](https://pubmed.ncbi.nlm.nih.gov/30958880/). DOI: 10.1093/ijnp/pyz017. Access: abstract_metadata. Study: PMID30958880. 21. Taylor SF, Koeppe RA, Tandon R et al. In vivo measurement of the vesicular monoamine transporter in schizophrenia. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2000. [PMID 11063922](https://pubmed.ncbi.nlm.nih.gov/11063922/). DOI: 10.1016/S0893-133X(00)00165-2. Access: abstract_metadata. Study: PMID11063922. 22. De Koning MB, Bloemen OJ, Van Duin ED et al. Pre-pulse inhibition and striatal dopamine in subjects at an ultra-high risk for psychosis. Journal of psychopharmacology (Oxford, England). 2014. [PMID 24526133](https://pubmed.ncbi.nlm.nih.gov/24526133/). DOI: 10.1177/0269881113519507. Access: abstract_metadata. Study: PMID24526133. 23. Veselinović T, Vernaleken I, Janouschek H et al. The role of striatal dopamine D2/3 receptors in cognitive performance in drug-free patients with schizophrenia. Psychopharmacology. 2018. [PMID 29717334](https://pubmed.ncbi.nlm.nih.gov/29717334/). DOI: 10.1007/s00213-018-4916-6. Access: abstract_metadata. Study: PMID29717334. 24. Dahoun T, Nour MM, Adams RA et al. Disrupted-in-schizophrenia 1 functional polymorphisms and D2 /D3 receptor availability: A [11 C]-(+)-PHNO imaging study. Genes, brain, and behavior. 2019. [PMID 31264367](https://pubmed.ncbi.nlm.nih.gov/31264367/). DOI: 10.1111/gbb.12596. Access: abstract_metadata. Study: PMID31264367. 25. Kubota M, Nagashima T, Takano H et al. Affinity States of Striatal Dopamine D2 Receptors in Antipsychotic-Free Patients with Schizophrenia. The international journal of neuropsychopharmacology. 2017. [PMID 29016872](https://pubmed.ncbi.nlm.nih.gov/29016872/). DOI: 10.1093/ijnp/pyx063. Access: abstract_metadata. Study: PMID29016872. 26. Kumakura Y, Cumming P, Vernaleken I et al. Elevated [18F]fluorodopamine turnover in brain of patients with schizophrenia: an [18F]fluorodopa/positron emission tomography study. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2007. [PMID 17652599](https://pubmed.ncbi.nlm.nih.gov/17652599/). DOI: 10.1523/JNEUROSCI.0805-07.2007. Access: abstract_metadata. Study: PMID17652599. 27. Howes OD, Montgomery AJ, Asselin MC et al. Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Archives of general psychiatry. 2009. [PMID 19124684](https://pubmed.ncbi.nlm.nih.gov/19124684/). DOI: 10.1001/archgenpsychiatry.2008.514. Access: abstract_metadata. Study: PMID19124684. 28. Zhang JP, Robinson DG, Gallego JA et al. Association of a Schizophrenia Risk Variant at the DRD2 Locus With Antipsychotic Treatment Response in First-Episode Psychosis. Schizophrenia bulletin. 2015. [PMID 26320194](https://pubmed.ncbi.nlm.nih.gov/26320194/). DOI: 10.1093/schbul/sbv116. Access: abstract_metadata. Study: PMID26320194. 29. Cassidy CM, Zucca FA, Girgis RR et al. Neuromelanin-sensitive MRI as a noninvasive proxy measure of dopamine function in the human brain. Proceedings of the National Academy of Sciences of the United States of America. 2019. [PMID 30796187](https://pubmed.ncbi.nlm.nih.gov/30796187/). DOI: 10.1073/pnas.1807983116. Access: abstract_metadata. Study: PMID30796187. 30. Lenk HÇ, Koch E, O'Connell KS et al. Genome-wide association analysis of treatment resistant schizophrenia for variant discovery and polygenic assessment. Human genomics. 2024. [PMID 39334510](https://pubmed.ncbi.nlm.nih.gov/39334510/). DOI: 10.1186/s40246-024-00673-x. Access: abstract_metadata. Study: PMID39334510. 31. Veronese M, Santangelo B, Jauhar S et al. A potential biomarker for treatment stratification in psychosis: evaluation of an [18F] FDOPA PET imaging approach. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2021. [PMID 32961543](https://pubmed.ncbi.nlm.nih.gov/32961543/). DOI: 10.1038/s41386-020-00866-7. Access: abstract_metadata. Study: PMID32961543. 32. Frankle WG, Himes M, Mason NS et al. Prefrontal and Striatal Dopamine Release Are Inversely Correlated in Schizophrenia. Biological psychiatry. 2022. [PMID 35791965](https://pubmed.ncbi.nlm.nih.gov/35791965/). DOI: 10.1016/j.biopsych.2022.05.009. Access: abstract_metadata. Study: PMID35791965. 33. Boley AM, Perez SM, Lodge DJ. A fundamental role for hippocampal parvalbumin in the dopamine hyperfunction associated with schizophrenia. Schizophrenia research. 2014. [PMID 24888524](https://pubmed.ncbi.nlm.nih.gov/24888524/). DOI: 10.1016/j.schres.2014.05.005. Access: abstract_metadata. Study: PMID24888524. 34. Lipina TV, Niwa M, Jaaro-Peled H et al. Enhanced dopamine function in DISC1-L100P mutant mice: implications for schizophrenia. Genes, brain, and behavior. 2010. [PMID 20618446](https://pubmed.ncbi.nlm.nih.gov/20618446/). DOI: 10.1111/j.1601-183X.2010.00615.x. Access: abstract_metadata. Study: PMID20618446. 35. Grimm CM, Aksamaz S, Schulz S et al. Schizophrenia-related cognitive dysfunction in the Cyclin-D2 knockout mouse model of ventral hippocampal hyperactivity. Translational psychiatry. 2018. [PMID 30301879](https://pubmed.ncbi.nlm.nih.gov/30301879/). DOI: 10.1038/s41398-018-0268-6. Access: abstract_metadata. Study: PMID30301879. 36. Servonnet A, Allain F, Gravel-Chouinard A et al. Dopaminergic mechanisms underlying the expression of antipsychotic-induced dopamine supersensitivity in rats. Neuropharmacology. 2021. [PMID 34364897](https://pubmed.ncbi.nlm.nih.gov/34364897/). DOI: 10.1016/j.neuropharm.2021.108747. Access: abstract_metadata. Study: PMID34364897. 37. Avram M, Brandl F, Cabello J et al. Reduced striatal dopamine synthesis capacity in patients with schizophrenia during remission of positive symptoms. Brain : a journal of neurology. 2019. [PMID 31135051](https://pubmed.ncbi.nlm.nih.gov/31135051/). DOI: 10.1093/brain/awz093. Access: abstract_metadata. Study: PMID31135051. 38. Huttunen J, Heinimaa M, Svirskis T et al. Striatal dopamine synthesis in first-degree relatives of patients with schizophrenia. Biological psychiatry. 2008. [PMID 17655830](https://pubmed.ncbi.nlm.nih.gov/17655830/). DOI: 10.1016/j.biopsych.2007.04.017. Access: abstract_metadata. Study: PMID17655830. 39. Nozaki S, Kato M, Takano H et al. Regional dopamine synthesis in patients with schizophrenia using L-[beta-11C]DOPA PET. Schizophrenia research. 2009. [PMID 19056247](https://pubmed.ncbi.nlm.nih.gov/19056247/). DOI: 10.1016/j.schres.2008.11.006. Access: abstract_metadata. Study: PMID19056247. 40. Demjaha A, Murray RM, McGuire PK et al. Dopamine synthesis capacity in patients with treatment-resistant schizophrenia. The American journal of psychiatry. 2012. [PMID 23034655](https://pubmed.ncbi.nlm.nih.gov/23034655/). DOI: 10.1176/appi.ajp.2012.12010144. Access: abstract_metadata. Study: PMID23034655. 41. Voruganti L, Slomka P, Zabel P et al. Subjective effects of AMPT-induced dopamine depletion in schizophrenia: correlation between dysphoric responses and striatal D(2) binding ratios on SPECT imaging. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2001. [PMID 11682247](https://pubmed.ncbi.nlm.nih.gov/11682247/). DOI: 10.1016/S0893-133X(01)00263-9. Access: abstract_metadata. Study: PMID11682247. 42. Abi-Dargham A, Gil R, Krystal J et al. Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. The American journal of psychiatry. 1998. [PMID 9619147](https://pubmed.ncbi.nlm.nih.gov/9619147/). DOI: 10.1176/ajp.155.6.761. Access: abstract_metadata. Study: PMID9619147. 43. Kegeles LS, Abi-Dargham A, Frankle WG et al. Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. Archives of general psychiatry. 2010. [PMID 20194823](https://pubmed.ncbi.nlm.nih.gov/20194823/). DOI: 10.1001/archgenpsychiatry.2010.10. Access: abstract_metadata. Study: PMID20194823. 44. Shotbolt P, Stokes PR, Owens SF et al. Striatal dopamine synthesis capacity in twins discordant for schizophrenia. Psychological medicine. 2011. [PMID 21426628](https://pubmed.ncbi.nlm.nih.gov/21426628/). DOI: 10.1017/S0033291711000341. Access: abstract_metadata. Study: PMID21426628. 45. Eisenberg DP, Yankowitz L, Ianni AM et al. Presynaptic Dopamine Synthesis Capacity in Schizophrenia and Striatal Blood Flow Change During Antipsychotic Treatment and Medication-Free Conditions. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2017. [PMID 28387222](https://pubmed.ncbi.nlm.nih.gov/28387222/). DOI: 10.1038/npp.2017.67. Access: abstract_metadata. Study: PMID28387222. 46. Breier A, Su TP, Saunders R et al. Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proceedings of the National Academy of Sciences of the United States of America. 1997. [PMID 9122236](https://pubmed.ncbi.nlm.nih.gov/9122236/). DOI: 10.1073/pnas.94.6.2569. Access: abstract_metadata. Study: PMID9122236. 47. Howes OD, Bose SK, Turkheimer F et al. Dopamine synthesis capacity before onset of psychosis: a prospective [18F]-DOPA PET imaging study. The American journal of psychiatry. 2011. [PMID 21768612](https://pubmed.ncbi.nlm.nih.gov/21768612/). DOI: 10.1176/appi.ajp.2011.11010160. Access: full_text_partial. Study: PMID21768612. 48. Abi-Dargham A, Rodenhiser J, Printz D et al. Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proceedings of the National Academy of Sciences of the United States of America. 2000. [PMID 10884434](https://pubmed.ncbi.nlm.nih.gov/10884434/). DOI: 10.1073/pnas.97.14.8104. Access: abstract_metadata. Study: PMID10884434. 49. Kim E, Howes OD, Veronese M et al. Presynaptic Dopamine Capacity in Patients with Treatment-Resistant Schizophrenia Taking Clozapine: An [18F]DOPA PET Study. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2017. [PMID 27857125](https://pubmed.ncbi.nlm.nih.gov/27857125/). DOI: 10.1038/npp.2016.258. Access: abstract_metadata. Study: PMID27857125. 50. Chen Y, Gu Y, Wang B et al. Synaptotagmin-11 deficiency mediates schizophrenia-like behaviors in mice via dopamine over-transmission. Nature communications. 2024. [PMID 39632880](https://pubmed.ncbi.nlm.nih.gov/39632880/). DOI: 10.1038/s41467-024-54604-4. Access: abstract_metadata. Study: PMID39632880. ## Source-specific evidence cards ### [1] Model-Guided Antipsychotic Dose Reduction in Schizophrenia: A Pilot, Single-Blind Randomized Controlled Trial. **Shows:** Randomized model-guided dose reduction maintains several outcomes but increases selected worsening signals. **Does not show:** Small single-blind pilot, modeled occupancy and endpoint differences; no mesolimbic primacy test. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2. ### [2] D2 receptor occupancy following lurasidone treatment in patients with schizophrenia or schizoaffective disorder. **Shows:** Lurasidone exposure and D2 occupancy associate with positive-symptom improvement. **Does not show:** Occupancy-outcome correlation and variable concentrations do not manipulate a selective symptom mediator independently. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2. ### [3] Estimated dopamine D₂ receptor occupancy and remission in schizophrenia: analysis of the CATIE data. **Shows:** Selected CATIE remitters often lack continuous estimated occupancy above the proposed threshold. **Does not show:** Modeled occupancy and remission selection; linked erratum retained, no universal numerical threshold asserted. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. ErratumIn: PMID25719960. Subclaims: SC2. ### [4] 5-HT2 and D2 receptor occupancy of olanzapine in schizophrenia: a PET investigation. **Shows:** Olanzapine occupies both serotonin and D2 receptors with dose-dependent D2 binding. **Does not show:** Multireceptor exposure and imaging alone do not isolate the clinical mediator. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2. ### [5] Dopamine D2 receptor occupancy with risperidone or olanzapine during maintenance treatment of schizophrenia: a cross-sectional study. **Shows:** Stable patients often have estimated D2 occupancy below a continuously maintained conventional threshold. **Does not show:** Cross-sectional survivor selection and estimated concentrations; does not establish zero D2 contribution. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2. ### [6] Striatal vs extrastriatal dopamine D2 receptors in antipsychotic response--a double-blind PET study in schizophrenia. **Shows:** Double-blind PET treatment study links striatal rather than extrastriatal occupancy with positive-symptom response. **Does not show:** Regional occupancies correlate and mediator is not independently randomized; no proof of specifically mesolimbic primacy. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3. ### [7] Treatment response to olanzapine and haloperidol and its association with dopamine D receptor occupancy in first-episode psychosis. **Shows:** Olanzapine/haloperidol first-episode treatment shows response with similar adjusted D2 occupancy. **Does not show:** Active drugs differ in other receptors; small sample and mediator correlation do not identify universal disease cause. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2. ### [8] Dose reduction of risperidone and olanzapine and estimated dopamine D₂ receptor occupancy in stable patients with schizophrenia: findings from an open-label, randomized, controlled study. **Shows:** Randomized dose reduction lowers estimated occupancy with few short-term relapses. **Does not show:** Open-label small maintenance sample and model estimates; acute-onset efficacy and long-term necessity differ. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2. ### [9] Subjective experience and D2 receptor occupancy in patients with recent-onset schizophrenia treated with low-dose olanzapine or haloperidol: a randomized, double-blind study. **Shows:** Double-blind active-drug comparison links D2 occupancy range with subjective experience. **Does not show:** Subjective experience is not psychotic-symptom primacy; drug pleiotropy and unverified blinding integrity remain. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2. ### [10] Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. **Shows:** Double-blind haloperidol PET study links D2 occupancy with response and adverse effects. **Does not show:** Small historical study; measured mediator correlation, registration and expectancy controls are incompletely verified. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2. ### [11] Differential effects of aripiprazole on D(2), 5-HT(2), and 5-HT(1A) receptor occupancy in patients with schizophrenia: a triple tracer PET study. **Shows:** Aripiprazole shows high D2 occupancy with a different adverse-effect profile from antagonists. **Does not show:** Partial agonism means occupancy is not equivalent to blockade; no universal threshold or initiating mechanism. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2. ### [12] A positron emission tomography study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy. **Shows:** Quetiapine response occurs with transiently high rather than sustained D2 occupancy. **Does not show:** Preliminary open treatment and other-receptor/nonpharmacological effects require controls. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2. ### [13] Dopamine and Glutamate in Antipsychotic-Responsive Compared With Antipsychotic-Nonresponsive Psychosis: A Multicenter Positron Emission Tomography and Magnetic Resonance Spectroscopy Study (STRATA). **Shows:** Multicentre STRATA does not find a responder/nonresponder dopamine-synthesis difference; ACC glutamate difference is modest. **Does not show:** Clinical group definitions and site heterogeneity constrain sensitivity; does not prove all resistance is nondopaminergic. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Methods:paragraph3, 1:Methods:paragraph4, 2:Results:paragraph11. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3. ### [14] Efficacy and Safety of Xanomeline-Trospium Chloride in Schizophrenia: A Randomized Clinical Trial. **Shows:** EMERGENT-3 xanomeline-trospium improves prespecified symptom scores versus placebo. **Does not show:** Treatment-resistant history excluded; no dopamine mediator measurement, short follow-up and adverse-effect differences. Erratum retained. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:Methods:paragraph0, 1:Methods:paragraph1, 1:Methods:paragraph4, 1:Methods:paragraph5, 2:Results:paragraph7. No complete-paper or supplement audit claimed. ErratumIn: PMID38958995. Subclaims: SC2, SC3. ### [15] Efficacy and safety of the muscarinic receptor agonist KarXT (xanomeline-trospium) in schizophrenia (EMERGENT-2) in the USA: results from a randomised, double-blind, placebo-controlled, flexible-dose phase 3 trial. **Shows:** EMERGENT-2 meets primary symptom endpoint with muscarinic treatment versus placebo. **Does not show:** Same sponsor/program and short duration; not proof that dopamine is dispensable. Linked erratum not examined. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. ErratumIn: PMID38823993. Subclaims: SC2, SC3. ### [16] Emraclidine, a novel positive allosteric modulator of cholinergic M4 receptors, for the treatment of schizophrenia: a two-part, randomised, double-blind, placebo-controlled, phase 1b trial. **Shows:** Early emraclidine trial tests M4 modulation with comparable overall adverse-event rates and preliminary efficacy signals. **Does not show:** Small phase-1b sample and exploratory efficacy; cannot establish later confirmatory success or unselected mechanism primacy. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3. ### [17] Opposite effects of catechol-O-methyltransferase Val158Met on cortical function in healthy subjects and patients with schizophrenia. **Shows:** COMT genotype has opposite cortical activation associations in controls and patients. **Does not show:** Genotype/fMRI association, task and medication effects are not selective D2 psychosis causation. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1. ### [18] Knockdown of DISC1 by in utero gene transfer disturbs postnatal dopaminergic maturation in the frontal cortex and leads to adult behavioral deficits. **Shows:** Early cortical DISC1 knockdown alters later mesocortical dopamine maturation and behaviour. **Does not show:** Developmental gene-transfer model and rodent behavioural proxies do not establish the registered human primary mechanism. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3. ### [19] DRD2/AKT1 interaction on D2 c-AMP independent signaling, attentional processing, and response to olanzapine treatment in schizophrenia. **Shows:** DRD2/AKT1 interaction associates with molecular, attentional and olanzapine-response phenotypes. **Does not show:** Candidate genetic interaction and correlated outcomes require independent validation; no selective mediator perturbation. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2. ### [20] D1-Dopamine Receptor Availability in First-Episode Neuroleptic Naive Psychosis Patients. **Shows:** Drug-naive first-episode patients show lower prefrontal D1 availability without a striatal difference. **Does not show:** D1 cortical biology differs from the claimed mesolimbic D2 pathway; group imaging is associational. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1. ### [21] In vivo measurement of the vesicular monoamine transporter in schizophrenia. **Shows:** VMAT2 imaging does not support increased striatal terminal density in schizophrenia. **Does not show:** Terminal density and dopamine release are different measurements; small sample cannot exclude functional dysregulation. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1. ### [22] Pre-pulse inhibition and striatal dopamine in subjects at an ultra-high risk for psychosis. **Shows:** UHR PPI impairment does not correlate with measured depletion-derived synaptic dopamine. **Does not show:** Distinct proxy measures and small groups; no direct clinical primacy or therapeutic test. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1. ### [23] The role of striatal dopamine D2/3 receptors in cognitive performance in drug-free patients with schizophrenia. **Shows:** D2/3 availability relates to selected cognitive performance without a significant overall group increase. **Does not show:** Cognition differs from positive psychosis; receptor availability mixes occupancy and density. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1. ### [24] Disrupted-in-schizophrenia 1 functional polymorphisms and D2 /D3 receptor availability: A [11 C]-(+)-PHNO imaging study. **Shows:** Common DISC1 functional variants do not associate with striatal D2/3 availability in healthy volunteers. **Does not show:** Small selected genetic sample; null receptor binding does not exclude other DISC1 pathways. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1. ### [25] Affinity States of Striatal Dopamine D2 Receptors in Antipsychotic-Free Patients with Schizophrenia. **Shows:** Ligand-binding ratios suggest altered D2 affinity states despite nonsignificant individual binding differences. **Does not show:** Indirect ratio and post-hoc regional tests; no selective causal symptom manipulation. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1. ### [26] Elevated [18F]fluorodopamine turnover in brain of patients with schizophrenia: an [18F]fluorodopa/positron emission tomography study. **Shows:** FDOPA modeling suggests elevated turnover with reduced steady-state storage in untreated patients. **Does not show:** Tracer kinetics and reference assumptions matter; synthesis, storage and receptor stimulation are not interchangeable. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1. ### [27] Elevated striatal dopamine function linked to prodromal signs of schizophrenia. **Shows:** Prodromal dopamine synthesis elevation localizes mainly to associative striatum and correlates with symptoms. **Does not show:** Case-control prodromal association is not proof of mesolimbic primacy or universal conversion. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3. ### [28] Association of a Schizophrenia Risk Variant at the DRD2 Locus With Antipsychotic Treatment Response in First-Episode Psychosis. **Shows:** DRD2-locus variant associates with positive-symptom response during first-episode drug treatment. **Does not show:** Treatment randomized, genotype not; linked variants, multiple phenotypes and side effects restrict interpretation. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2. ### [29] Neuromelanin-sensitive MRI as a noninvasive proxy measure of dopamine function in the human brain. **Shows:** Neuromelanin MRI associates with striatal dopamine release and psychosis severity. **Does not show:** Proxy validity does not confer causal direction or establish a D2-specific mechanism. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1. ### [30] Genome-wide association analysis of treatment resistant schizophrenia for variant discovery and polygenic assessment. **Shows:** TRS GWAS finds polygenic association and a suggestive locus below genome-wide significance. **Does not show:** Suggestive genetic evidence is not a validated causal locus or selective dopamine mechanism. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3. ### [31] A potential biomarker for treatment stratification in psychosis: evaluation of an [18F] FDOPA PET imaging approach. **Shows:** FDOPA imaging discriminates treatment-response groups in limited datasets. **Does not show:** Small setting-dependent samples, potential recruitment overlap and retrospective group definitions; not a prospective treatment-selection trial. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1. ### [32] Prefrontal and Striatal Dopamine Release Are Inversely Correlated in Schizophrenia. **Shows:** Cortical dopamine-release deficits correlate inversely with dorsal caudate release in patients. **Does not show:** Compartment heterogeneity and association do not prove direction, universal dopamine excess or primary mesolimbic pathology. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3. ### [33] A fundamental role for hippocampal parvalbumin in the dopamine hyperfunction associated with schizophrenia. **Shows:** Reducing hippocampal parvalbumin causes downstream dopamine activity and amphetamine-response changes. **Does not show:** Gene knockdown and locomotor proxy show an upstream route in rodents, not the complete human symptom mechanism. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3. ### [34] Enhanced dopamine function in DISC1-L100P mutant mice: implications for schizophrenia. **Shows:** DISC1 mutant mice show dopamine-related behavioural abnormalities modifiable by haloperidol. **Does not show:** Genetic model and PPI/hyperactivity are translational proxies; endogenous human rate limitation remains unshown. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3. ### [35] Schizophrenia-related cognitive dysfunction in the Cyclin-D2 knockout mouse model of ventral hippocampal hyperactivity. **Shows:** Cyclin-D2 knockout hyperactivity resists D1/D2 antagonism but responds to a glutamate-pathway agonist. **Does not show:** Rodent proxy and developmental deletion are not treatment-resistant human schizophrenia. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3. ### [36] Dopaminergic mechanisms underlying the expression of antipsychotic-induced dopamine supersensitivity in rats. **Shows:** Drug-withdrawal rat supersensitivity has distinct D1/D2 dependence; central dopamine increase alone is insufficient. **Does not show:** Treatment-induced adaptation differs from spontaneous human disease initiation and unselected psychotic symptoms. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2, SC3. ### [37] Reduced striatal dopamine synthesis capacity in patients with schizophrenia during remission of positive symptoms. **Shows:** Patients in positive-symptom remission show lower striatal synthesis and cognitive associations. **Does not show:** Treated/remitted cross-sectional state and statistical mediation do not establish initiating cause. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1. ### [38] Striatal dopamine synthesis in first-degree relatives of patients with schizophrenia. **Shows:** First-degree relatives show higher striatal FDOPA uptake in a selected study. **Does not show:** Familial association and possible confounding; not a sufficient prediction of future psychosis. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1. ### [39] Regional dopamine synthesis in patients with schizophrenia using L-[beta-11C]DOPA PET. **Shows:** Drug-naive/free patients show regional synthesis elevation, mainly left caudate, with selected symptom correlations. **Does not show:** Small sample and multiple regions; not uniform excess or selective mesolimbic causality. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1. ### [40] Dopamine synthesis capacity in patients with treatment-resistant schizophrenia. **Shows:** Responders have elevated synthesis relative to TRS patients and controls, with no TRS/control difference. **Does not show:** Small chronically treated groups and response-defined sampling; medication effects and heterogeneity limit generalization. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3. ### [41] Subjective effects of AMPT-induced dopamine depletion in schizophrenia: correlation between dysphoric responses and striatal D(2) binding ratios on SPECT imaging. **Shows:** AMPT depletion induces variable dysphoria correlated with dopamine-binding changes. **Does not show:** Dysphoria rather than psychotic trajectory is the main endpoint; obvious subjective effects complicate blind comparisons. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC2. ### [42] Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. **Shows:** Amphetamine challenge replicates excess release and transient positive-symptom worsening in a second cohort. **Does not show:** Acute subjective challenge, limited registration/expectancy verification and catecholamine specificity; not mesolimbic primacy. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2. ### [43] Increased synaptic dopamine function in associative regions of the striatum in schizophrenia. **Shows:** Depletion-derived excess synaptic dopamine appears in associative striatum, not limbic/sensorimotor regions. **Does not show:** Primary endpoint is receptor-binding inference; no selective symptom trajectory experiment. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3. ### [44] Striatal dopamine synthesis capacity in twins discordant for schizophrenia. **Shows:** Discordant twins and stable patients do not show elevated synthesis versus controls. **Does not show:** Low symptom levels, treatment and small sample restrict interpretation as an absolute vulnerability null. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1. ### [45] Presynaptic Dopamine Synthesis Capacity in Schizophrenia and Striatal Blood Flow Change During Antipsychotic Treatment and Medication-Free Conditions. **Shows:** Medication versus placebo periods alter striatal blood flow with symptom and synthesis associations. **Does not show:** Physiological and mediator associations do not selectively isolate D2 necessity or premorbid cause. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2. ### [46] Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. **Shows:** PET challenge shows greater amphetamine-associated binding displacement, with primate calibration support. **Does not show:** Binding inference and acute drug response differ from spontaneous human disease dependency. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1. ### [47] Dopamine synthesis capacity before onset of psychosis: a prospective [18F]-DOPA PET imaging study. **Shows:** Prospective converters have elevated dopamine synthesis before psychosis, strongest in associative striatum. **Does not show:** Small transition cohort, transdiagnostic outcomes and no mediator intervention; not proved initiating primacy. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. Selected body sections: 1:METHOD:paragraph2, 1:METHOD:paragraph5, 2:RESULTS:paragraph3, 2:RESULTS:paragraph4. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3. ### [48] Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. **Shows:** Depletion reveals higher dopamine occupancy in untreated patients and predicts later treatment response. **Does not show:** Occupancy and treatment-response correlation are not independent randomized symptom-mediator manipulation. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC2. ### [49] Presynaptic Dopamine Capacity in Patients with Treatment-Resistant Schizophrenia Taking Clozapine: An [18F]DOPA PET Study. **Shows:** Symptom-matched clozapine-treated TRS patients show lower synthesis than first-line responders. **Does not show:** Small groups and differential medications cannot fully separate disease traits from treatment effects. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC1, SC3. ### [50] Synaptotagmin-11 deficiency mediates schizophrenia-like behaviors in mice via dopamine over-transmission. **Shows:** Adolescent Syt11 deficiency or dopamine over-excitation produces persistent behavioural deficits with D2-intervention effects. **Does not show:** Age-defined engineered mouse model and social/behavioural proxies cannot establish unselected human mesolimbic primacy. **Access/status:** Bounded original primary abstract Results/Findings/conclusion passages and linked-status metadata examined; no complete-abstract audit asserted. No complete-paper or supplement audit claimed. none_found. Subclaims: SC3.