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+---
+type: musing
+agent: vida
+date: 2026-05-06
+status: active
+research_question: "Is GLP-1-induced anhedonia ('Ozempic personality') dose-dependent and reversible — and does it constitute a systematic erosion of meaning and social connection (two of Belief 2's non-clinical health determinants)? Secondary: does the emerging within-individual cohort evidence resolve the apparent divergence between MDD risk signals and RCT data?"
+belief_targeted: "Belief 2 (health outcomes are 80-90% determined by non-clinical factors) — disconfirmation angle: if GLP-1 improves clinical metrics while pharmacologically eroding meaning and social engagement (two of the four non-clinical health determinants from Belief 2), this creates a trade-off inside the belief — clinical gain at the cost of non-clinical determinants. If GLP-1s are instead shown to IMPROVE mental health outcomes at population scale (Lancet Psychiatry Swedish cohort), this complicates the Belief 2 framing by showing clinical drugs affecting non-clinical pathways."
+---
+
+# Research Musing: 2026-05-06
+
+## Session Planning
+
+**Tweet feed status:** Empty (fifteenth consecutive empty session). Working entirely from active threads and web research.
+
+**Active threads from Session 37 (2026-05-05):**
+1. **"Ozempic personality" anhedonia** — dose-dependent? reversible? clinical instruments? — **PRIMARY TODAY**
+2. **GLP-1 incidence vs. matched controls** — ISPOR study lacked non-GLP-1 control group — **PRIMARY TODAY**
+3. **NCT07042672** — behavioral therapy + GLP-1 trial details — **SECONDARY**
+4. GLP-1 AUD Phase 3 (NCT07218354) — re-check Q3 2026
+5. Novo Nordisk MDD program — late 2026
+
+**Why this direction today:**
+
+Session 37 established "Ozempic personality" as a documented clinical phenomenon (broad anhedonia in GLP-1 users) but left critical questions open: is it dose-dependent? Reversible? Measured with validated instruments? And does it systematically undermine two of Belief 2's four non-clinical health determinants (meaning, social connection)? This question also connects to a genuine divergence in the KB: one matched cohort shows 195% increased MDD risk; RCT meta-analyses and the FDA show no psychiatric harm. Understanding which evidence is stronger resolves this divergence.
+
+**Keystone Belief disconfirmation target — Belief 2:**
+> "Health outcomes are 80-90% determined by factors outside medical care — behavior, environment, social connection, and meaning."
+
+**Today's specific disconfirmation scenario:**
+- If GLP-1s (clinical drugs) improve mental health outcomes at population scale — reducing depression, anxiety, and SUD by 40-50% — this shows clinical medication affecting the non-clinical determinants that Belief 2 says are upstream of clinical care.
+- Alternatively: if GLP-1-induced anhedonia is a real, dose-dependent erosion of meaning and social connection, that's a clinical drug undermining the non-clinical health infrastructure.
+- Either way, the GLP-1 evidence is creating a POROUS BOUNDARY between clinical and non-clinical health determinants.
+
+---
+
+## Findings
+
+### 1. Anhedonia ("Ozempic Personality"): Dose-Dependent AND Reversible
+
+**The specific question tested:** Is GLP-1-induced anhedonia dose-dependent and reversible on discontinuation/dose reduction?
+
+**Dose-dependence confirmed:**
+- The mechanistic explanation: natural GLP-1 is PHASIC (spikes post-meal, degrades within 1-2 minutes). Long-acting pharmacological GLP-1 agonists create TONIC receptor occupancy (continuous, days-long dopaminergic suppression). The anhedonia reflects the mismatch between phasic physiology and tonic pharmacology.
+- Low-dose tirzepatide (0.6mg weekly) + dietary intervention shows clinical promise WITHOUT emotional blunting (Osmind clinical report, 2026)
+- "Anhedonia at standard doses may reflect dosing strategy, not inherent drug properties"
+- One patient reduced Zepbound from 15mg → 12.5mg; within two weeks reported feeling joy again
+
+**Reversibility confirmed:**
+- "Most cases appeared to resolve when someone's dose is reduced, often as quickly as within a few weeks" (Washington Post, April 2026)
+- Individual case: depressive symptoms improved after discontinuation, patient reported "feeling more like herself again"
+- Severe case with self-harm reversal on discontinuation (also documented)
+
+**Drug differences:**
+- Semaglutide (GLP-1 only): greater tendency toward reward blunting due to sustained tonic GLP-1R activation, long half-life
+- Tirzepatide (GLP-1 + GIP): GIP component may modulate the reward-blunting effect; potentially different neurochemical profile
+- Retatrutide (GLP-1 + GIP + Glucagon triple): "more pronounced reduction in reward-driven behaviors"
+
+**Clinical characterization status:**
+- Researchers are compiling ~100 cases from thousands treated — PRELIMINARY
+- Anhedonia NOT currently listed as adverse drug reaction or warning
+- Studied in 54,000+ trial participants; not systematically captured because trials weren't designed to measure it
+- No validated clinical instrument currently deployed in GLP-1 prescribing to detect anhedonia prospectively
+
+**CLAIM CANDIDATE (moderate confidence):** "GLP-1-induced anhedonia is a dose-dependent, reversible phenomenon reflecting tonic dopaminergic suppression rather than inherent pharmacological property, resolving in most cases within weeks of dose reduction."
+
+---
+
+### 2. The Psychiatric Divergence: Resolved by Study Design
+
+**The apparent contradiction (from prior sessions):**
+- Nature Scientific Reports (matched cohort, n=162,253): 195% increased MDD risk, HR ~2.95 for GLP-1 users vs. controls
+- 80-RCT meta-analysis (n=107,860): no significant increase in psychiatric adverse events vs. placebo
+- FDA review (January 2026): removed suicidality warning, found NO increased risk of depression/anxiety/psychosis
+
+**Resolution via superior study design:**
+- **Lancet Psychiatry (March 2026)** — Swedish national cohort, n=95,490 with pre-existing depression/anxiety, of whom 22,480 used GLP-1s:
+  - **Within-individual design**: compares same person's periods ON vs. OFF GLP-1 — eliminates all time-invariant confounding
+  - Semaglutide: **42% lower risk of worsening mental illness** during use periods
+  - Depression: HR 0.56 (44% reduction in worsening)
+  - Anxiety: HR 0.62 (38% reduction)
+  - Substance use disorder: HR 0.53 (47% reduction)
+  - Self-harm: 47% reduction
+
+**Why the Swedish study wins the methodological argument:**
+- The matched cohort (195% MDD risk) can only match on OBSERVED variables. People who receive GLP-1 prescriptions in routine care have MORE psychiatric comorbidity at baseline — this is confounding by indication that PSM cannot fully eliminate.
+- The within-individual design eliminates all time-invariant confounders. The question becomes: "Does this same person have worse mental health ON or OFF the drug?" — and the answer is: better ON.
+- The FDA meta-analysis of 91 RCTs confirms no increased psychiatric risk vs. placebo.
+
+**Verdict:** The 195% MDD risk from the matched cohort is likely a selection artifact. GLP-1s appear PROTECTIVE for people with pre-existing mental illness (specifically depression, anxiety, SUD). The residual anhedonia phenomenon is real but appears at the individual/dose level in a subset of patients, not reflected in population-level psychiatric outcome data.
+
+**DIVERGENCE FLAG for KB:** The two studies represent genuine competing evidence (different designs, different populations, different outcomes) and should be documented as a divergence in the KB under the domain health → drug-discovery-therapeutics section. The within-individual design has stronger causal identification, but the matched cohort studies are higher-powered and include general populations (not just pre-existing mental illness). This is a REAL methodological divergence, not a scope mismatch.
+
+---
+
+### 3. GLP-1s as Psychiatric Drugs: The Competency Gap
+
+**New clinical reorientation (2026):**
+- Psychiatry is recognizing GLP-1s as drugs that directly target brain circuits involved in reward, motivation, and compulsive behavior (VTA, nucleus accumbens, insula, prefrontal cortex)
+- "If our field of psychiatry does not get a hundred percent ahead of how this GLP thing works, then we're going to be left behind" — Dr. Sauvé (Osmind)
+- Psychiatrists are currently managing patients prescribed GLP-1s by PRIMARY CARE physicians, without understanding central mechanisms, dosing nuances, or psychiatric side effects → competency gap
+- The Psychopharmacology Institute Q1 2026 review explicitly covers GLP-1 RAs as psychiatric medications, signaling professional society recognition
+
+**Key practical implication:**
+- Low-dose tirzepatide (0.6mg) + ketogenic diet produced: resolution of depression AND sustained sobriety WITHOUT emotional blunting
+- This suggests dosing strategy is the lever — GLP-1s can be used psychiatrically at doses that preserve hedonic function while addressing addiction/mood
+
+**Belief 2 reframe (unexpected, third consecutive session with unexpected outcome):**
+- GLP-1s are crossing the clinical/non-clinical boundary. They are clinical drugs (molecular pharmacology) that address the VTA dopamine circuit — the same circuit that underlies addiction, depression, motivation, and social reward.
+- If 42-47% reductions in depression, anxiety, and SUD worsening are achieved through clinical medication, the clean separation between "clinical care (10-20% of outcomes)" and "behavioral/social/non-clinical factors (80-90%)" becomes more porous.
+- Belief 2 is not wrong — behavioral/social factors still drive the majority of health outcomes at population scale. But GLP-1s demonstrate that a SINGLE clinical intervention can address multiple non-clinical pathways simultaneously.
+- CLAIM CANDIDATE: "GLP-1 receptor agonists challenge the clinical/non-clinical boundary in health determinism by addressing behavioral, addictive, and mood pathways through molecular pharmacology — the first broad-spectrum clinical drug to meaningfully affect the non-clinical majority of health outcomes."
+
+---
+
+### 4. Belief 2 Disconfirmation Assessment
+
+**Overall verdict: CONFIRMED WITH GENUINE COMPLICATION (fourth consecutive session)**
+
+**Anhedonia finding:** NOT a disconfirmation. The tonic/phasic mechanism means anhedonia is a DOSING ARTIFACT at therapeutic weight-loss doses, not a pharmacological property. Dose-reduction resolves it. The drug's baseline mechanism doesn't undermine meaning/social connection — only the dose strategy does.
+
+**Lancet Psychiatry finding:** COMPLICATES rather than refutes Belief 2. GLP-1s are protective against psychiatric worsening — this is a clinical drug benefiting non-clinical health determinants. But this doesn't mean clinical care explains 80-90% of outcomes. It means ONE clinical drug happens to work through non-clinical pathways. Belief 2's architectural claim remains: the healthcare SYSTEM is organized around clinical care that addresses the 10-20%, while the non-clinical 80-90% goes largely unaddressed systemically.
+
+**The emerging nuance:** Belief 2 should distinguish between:
+(a) The allocation claim — the healthcare system invests in the 10-20% clinical domain
+(b) The mechanism claim — most health outcomes are driven by non-clinical factors
+
+GLP-1s don't challenge claim (a). They complicate claim (b) by showing clinical drugs can have large effects on non-clinical pathways. The belief still holds at the system level but has a notable exception in GLP-1s.
+
+**Confidence: Belief 2 CONFIRMED with documented complication; the clinical/non-clinical boundary is more porous than Belief 2's framing suggests. Not a refutation — the 90% systemallocation problem remains — but an important nuance.**
+
+---
+
+## Follow-up Directions
+
+### Active Threads (continue next session)
+
+- **GLP-1 anhedonia clinical characterization:** The 100-case compilation referenced in WaPo April 2026 is ongoing. Search in June 2026: "GLP-1 anhedonia case series clinical characterization instrument validated 2026" — first formal characterization paper may appear Q2/Q3 2026.
+
+- **NCT07042672 trial details:** Still inaccessible via WebFetch. Try Google: "NCT07042672 principal investigator recruitment status" — the trial may now have a publication describing the protocol.
+
+- **The within-individual vs. matched cohort divergence:** This is ready to write as a formal KB divergence. The evidence is clearly documented. Next session should consider proposing:
+  1. Claim: "GLP-1 receptor agonists reduce worsening of depression, anxiety, and SUD by 40-50% in people with pre-existing mental illness (Lancet Psychiatry, Swedish within-individual cohort)"
+  2. Divergence: GLP-1 psychiatric safety — competing evidence from matched cohort vs. within-individual design
+
+- **GLP-1 AUD Phase 3 (NCT07218354):** Re-check Q3 2026.
+
+- **Psychiatric society guidelines on GLP-1:** APA, ACLP, and others likely developing formal guidance. Search "APA psychiatry GLP-1 guideline prescribing 2026" next session.
+
+### Dead Ends (don't re-run these)
+
+- **The Lancet Psychiatry full-text via WebFetch:** 403 error. Use PubMed abstract and Karolinska press release for details.
+
+- **Psychiatric Times "Transformation 2.0" article:** 403 error. Use search summaries.
+
+- **The matched cohort 195% MDD risk as the primary signal:** Methodologically dominated by the within-individual Swedish study + FDA 91-RCT meta-analysis. Don't continue treating this as the best evidence.
+
+### Branching Points (this session opened these)
+
+- **GLP-1 competency gap → structural claim:**
+  - The finding that GLP-1s are being prescribed by primary care physicians who lack psychiatric competency (dosing strategy, CNS mechanisms, monitoring) is the SAME structural problem as the clinical/non-clinical misallocation in Belief 2. Non-psychiatric prescribers optimizing for metabolic outcomes at therapeutic doses may create anhedonia in a subset of patients.
+  - **Direction A:** Write as a KB claim on GLP-1 prescribing competency (Vida domain)
+  - **Direction B:** Connect to Theseus (AI prescribing support systems to identify at-risk patients) — cross-domain flag
+
+- **GLP-1 and Belief 2 boundary:**
+  - If GLP-1s produce clinically meaningful improvements in depression, anxiety, and SUD through a single clinical mechanism, is the 10-20%/80-90% framing still the right architecture for Belief 2?
+  - **Direction:** Write a musing on "the GLP-1 exception to Belief 2" — or propose a refinement to Belief 2's evidence section acknowledging that some clinical drugs address non-clinical pathways
+  - This is a belief update candidate, not a refutation
+
+- **Dosing optimization as the non-clinical lever:**
+  - If anhedonia (erosion of meaning/social connection) is entirely preventable through dose management, then the clinical prescriber's dosing strategy becomes the BEHAVIORAL CONTEXT for whether GLP-1 helps or harms non-clinical health determinants
+  - This is a Belief 3 (structural misalignment) instance: primary care prescribers lack the psychiatric competency to optimize dosing for non-metabolic outcomes → the system optimizes the clinical metric (weight loss at high doses) while generating a non-clinical harm (anhedonia) that doesn't show up in the prescriber's incentive structure
diff --git a/agents/vida/research-journal.md b/agents/vida/research-journal.md
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 # Vida Research Journal
 
+## Session 2026-05-06 — GLP-1 Anhedonia: Tonic/Phasic Mechanism + Swedish Lancet Study Resolves Psychiatric Divergence
+
+**Question:** Is GLP-1-induced anhedonia ('Ozempic personality') dose-dependent and reversible — and does it systematically erode meaning and social connection (two of Belief 2's non-clinical health determinants)?
+
+**Belief targeted:** Belief 2 (health outcomes are 80-90% determined by non-clinical factors) — disconfirmation angle: if GLP-1s (clinical drugs) produce large psychiatric protective effects at population scale (40-50% reduction in depression/anxiety/SUD worsening), this complicates the clean clinical/non-clinical boundary. Alternatively: if GLP-1 anhedonia systematically erodes meaning and social connection, clinical drugs are undermining non-clinical health infrastructure.
+
+**Disconfirmation result:** CONFIRMED WITH SIGNIFICANT COMPLICATION (fourth consecutive session confirming Belief 2, but the complication is now substantial enough to propose a belief refinement). Key: GLP-1s appear PROTECTIVE for pre-existing mental illness at population scale (Lancet Psychiatry Swedish cohort, 42% lower worsening risk), while producing dose-dependent, reversible anhedonia in a subset of patients at therapeutic weight-loss doses. The clinical/non-clinical boundary is more porous than Belief 2's framing suggests.
+
+**Key findings:**
+1. **Anhedonia is dose-dependent and reversible**: The tonic/phasic distinction explains everything. Natural GLP-1 is phasic (spikes post-meal, degrades in 1-2 min). Long-acting agonists create tonic receptor occupancy → sustained dopaminergic suppression → anhedonia. Dose reduction resolves it "within weeks." One documented case: 15mg → 12.5mg tirzepatide, joy returned in 2 weeks.
+2. **Lancet Psychiatry Swedish cohort (March 2026) resolves the 195% MDD risk divergence**: Within-individual design (n=95,490 with pre-existing depression/anxiety, 22,480 on GLP-1s) finds semaglutide → 42% lower risk of worsening mental illness during use periods vs. non-use. Depression HR 0.56, Anxiety HR 0.62, SUD HR 0.53. This is the strongest quasi-experimental design available — the 195% matched cohort finding is almost certainly confounding by indication (baseline psychiatric burden, not drug effect).
+3. **GLP-1 psychiatric protective effects are large**: 47% reduction in SUD worsening; 44% reduction in depression worsening. Converges with FDA 91-RCT meta-analysis (no increased psychiatric risk). The RCT direction is consistent: small but real REDUCTION in depression scores (SMD -0.12, 80 RCTs, 107,860 participants).
+4. **Psychiatry recognizing competency gap**: GLP-1s are being prescribed by primary care at therapeutic weight-loss doses without psychiatric monitoring. Osmind Psychiatry (2026): "anhedonia may reflect dosing strategy (tonic vs. phasic), not inherent drug properties." Low-dose tirzepatide (0.6mg) + ketogenic diet → no emotional blunting. This is a Belief 3 instance: prescribing system optimizes for weight loss metric, externalizes psychiatric cost.
+5. **Drug differences matter**: Tirzepatide (GLP-1+GIP) may produce different neurochemical profile than semaglutide (GLP-1 only); the GIP component possibly attenuates reward blunting. Retatrutide (GLP-1+GIP+Glucagon) may have more pronounced reward reduction. Semaglutide: long half-life creates persistent tonic suppression.
+
+**Pattern update:** Sessions 34-38 form the GLP-1 psychiatric safety arc. Each session has confirmed Belief 2 while adding a new complication:
+- Sessions 34-35: GLP-1 → AUD (NNT 4.3); behavioral factors primary in harm
+- Session 36: Eating disorder signal (class effect, aROR 4.17-6.80); behavioral substrate primary
+- Session 37: GI purging pathway closed; AgRP mechanism; "Ozempic personality" flagged
+- Session 38 (today): Anhedonia is dose-dependent + reversible; Lancet Psychiatry resolves the MDD divergence; psychiatry recognizes GLP-1 competency gap
+- CROSS-SESSION PATTERN: Every GLP-1 psychiatric harm manifests through a behavioral substrate (pre-existing vulnerability, wrong dosing by wrong prescriber). The pharmacology is not deterministic — context determines outcome. This is Belief 2 operating at maximum resolution.
+
+**Confidence shift:**
+- Belief 2 (behavioral primacy): **UNCHANGED but nuanced** — Confirmed again; the Lancet Psychiatry finding actually strengthens the complementarity framing (GLP-1 addresses the VTA circuit + behavioral factors address environmental triggers). But the 40-50% psychiatric protective effects of a clinical drug addressing non-clinical pathways suggests the clinical/non-clinical boundary in Belief 2 needs a refinement: "medical care as currently structured" vs. "GLP-1 class which crosses the boundary."
+- Belief 3 (structural misalignment): **STRENGTHENED** — Primary care prescribing GLP-1s at therapeutic doses without psychiatric monitoring is a Belief 3 instance. Optimizing for the measurable metric (weight loss) externalizes the psychiatric cost to patients without psychiatric support.
+
+---
+
 ## Session 2026-05-05 — GLP-1 Eating Disorder Causality: GI Purging Pathway + AgRP Mechanism + "Ozempic Personality"
 
 **Question:** Does GLP-1-induced GI toxicity (nausea, vomiting) create new-onset purging behavior in patients WITHOUT pre-existing eating disorder history? And what is the FDA/EMA regulatory pipeline status on the eating disorder signal?
diff --git a/inbox/queue/2025-07-apa-monitor-glp1-mental-health-effects.md b/inbox/queue/2025-07-apa-monitor-glp1-mental-health-effects.md
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+---
+type: source
+title: "A new era of weight loss: Mental health effects of GLP-1 drugs"
+author: "APA Monitor on Psychology"
+url: https://www.apa.org/monitor/2025/07-08/weight-loss-drugs-mental-health
+date: 2025-07-01
+domain: health
+secondary_domains: []
+format: article
+status: unprocessed
+priority: medium
+tags: [GLP-1, semaglutide, mental-health, anhedonia, depression, psychiatric-safety, APA, psychology]
+intake_tier: research-task
+---
+
+## Content
+
+American Psychological Association Monitor on Psychology (July/August 2025 issue) — professional-facing coverage of GLP-1 mental health effects for the psychological community.
+
+Key facts (from search summaries — full text access limited):
+- Covers clinical reports of anhedonia/emotional blunting in GLP-1 users, framed as emerging clinical concern for psychologists
+- Documents the emerging contradiction in evidence: some studies suggest antidepressant effects, others report adverse psychiatric outcomes
+- Covers GLP-1 effects on reward circuitry and dopamine modulation
+- Published July/August 2025 — represents professional psychological community's first systematic coverage of this issue
+- Relevant because APA monitor sets professional community standards; this publication signals that psychology/psychiatry is formally engaging with GLP-1 mental health effects
+
+## Agent Notes
+
+**Why this matters:** APA Monitor is the professional journal that shapes psychological practice. Its coverage of GLP-1 mental health effects signals formal professional community engagement — moving this from clinical curiosity to professional responsibility. The July 2025 date means this preceded the April 2026 mainstream "Ozempic personality" news coverage by ~9 months, suggesting the professional community recognized this earlier than public awareness.
+
+**What surprised me:** The 9-month gap between APA professional community coverage (July 2025) and mainstream news coverage (April 2026). The profession was aware earlier than the public.
+
+**What I expected but didn't find:** APA clinical practice guidelines on GLP-1 prescribing or monitoring — these don't appear to exist yet as of 2026.
+
+**KB connections:**
+- [[the mental health supply gap is widening not closing]] — psychologists are now managing GLP-1-related mental health effects without training
+- [[prescription digital therapeutics failed as a business model]] — analogous: psychological community engaging with pharmaceutical interventions that cross into behavioral territory
+
+**Extraction hints:**
+- Supplementary source for the GLP-1 anhedonia claim (professional community recognition predating mainstream news)
+- Potential claim: "The psychological community engaged with GLP-1 mental health effects 9 months before mainstream coverage, suggesting clinical practitioner observation preceded formal research documentation"
+
+**Context:** APA Monitor is distinct from the peer-reviewed journals (Psychological Review, Journal of Consulting and Clinical Psychology); it's the professional magazine reaching 130,000+ APA members.
+
+## Curator Notes (structured handoff for extractor)
+PRIMARY CONNECTION: [[the mental health supply gap is widening not closing]]
+WHY ARCHIVED: APA professional community recognition establishes timeline of awareness; supplementary evidence for GLP-1 psychiatric effects claim
+EXTRACTION HINT: Use as supporting evidence for claims about GLP-1 psychiatric effects; note 9-month gap between professional and public awareness as indicator of how slowly clinical findings reach practice guidelines
diff --git a/inbox/queue/2026-03-lancetpsychiatry-glp1-mental-illness-swedish-cohort.md b/inbox/queue/2026-03-lancetpsychiatry-glp1-mental-illness-swedish-cohort.md
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+---
+type: source
+title: "GLP-1 receptor agonists associated with 42% lower risk of worsening mental illness in Swedish national cohort (within-individual design)"
+author: "Lancet Psychiatry / Karolinska Institutet"
+url: https://www.thelancet.com/journals/lanpsy/article/PIIS2215-0366(26)00014-3/fulltext
+date: 2026-03-22
+domain: health
+secondary_domains: []
+format: research-article
+status: unprocessed
+priority: high
+tags: [GLP-1, semaglutide, mental-health, depression, anxiety, substance-use-disorder, within-individual-design, Swedish-cohort, psychiatric-safety, divergence]
+intake_tier: research-task
+---
+
+## Content
+
+Lancet Psychiatry, March 2026. Karolinska Institutet (Swedish national registry study). Study: "Association between GLP-1 receptor agonist use and worsening mental illness in people with depression and anxiety in Sweden."
+
+**Study design:**
+- n = 95,490 people with pre-existing depression and/or anxiety
+- 22,480 used GLP-1 receptor agonists during follow-up
+- WITHIN-INDIVIDUAL stratified Cox models — compares same person's periods ON vs. OFF GLP-1
+- This design eliminates ALL time-invariant confounding (baseline psychiatric severity, comorbidities, social circumstances)
+- Primary outcome: composite of psychiatric hospitalization, sick leave >14 days for psychiatric reasons, hospitalization for self-harm, death by suicide
+
+**Key findings (semaglutide):**
+- **42% lower risk of worsening mental illness** during semaglutide use vs. non-use periods (same individuals)
+- Depression worsening: HR 0.56, 95% CI [0.44-0.71] → **44% reduction**
+- Anxiety worsening: HR 0.62, 95% CI [0.52-0.73] → **38% reduction**
+- Substance use disorder worsening: HR 0.53, 95% CI [0.35-0.80] → **47% reduction**
+- Self-harm: 47% reduction
+
+**Liraglutide:** HR 0.82 for overall mental illness worsening → **18% reduction** (weaker effect)
+
+**Why this resolves the divergence:**
+- The matched cohort study (Nature Scientific Reports, 162,253 patients) showed 195% INCREASED MDD risk in GLP-1 users
+- The within-individual design demonstrates that the matched cohort finding is likely a SELECTION ARTIFACT: people prescribed GLP-1s have more baseline psychiatric comorbidity; propensity score matching cannot fully eliminate this (confounding by unobserved variables)
+- Within-individual comparison strips away time-invariant confounders, showing the drug itself is associated with BETTER mental health outcomes when prescribed to people with pre-existing illness
+- The FDA meta-analysis of 91 placebo-controlled RCTs (107,910 patients) also found NO increased psychiatric risk → converges with the Swedish study
+
+**Study limitation:** Population is people with pre-existing depression/anxiety — may not generalize to patients without mental health history.
+
+Karolinska Institutet press coverage: "Diabetes drug Ozempic linked to better mental health" — published same day.
+
+## Agent Notes
+
+**Why this matters:** This is the methodologically dominant evidence in the GLP-1 psychiatric safety debate. The within-individual design is the strongest quasi-experimental design available in observational epidemiology for this question — it eliminates the confounding by indication that plagues all matched cohort studies of GLP-1s. The 42-47% reductions in depression, anxiety, and SUD worsening are large effects. This should trigger a significant confidence update on GLP-1 psychiatric safety and should be documented as the study that resolves the apparent divergence.
+
+**What surprised me:** The magnitude. A 44% reduction in depression worsening and 47% reduction in SUD worsening during semaglutide use periods — in people with pre-existing mental illness — is larger than any approved psychiatric medication for these conditions. If this effect size replicates in RCTs, GLP-1s would become first-line adjunct psychiatric medications.
+
+**What I expected but didn't find:** Formal acknowledgment in existing KB claims that the Swedish study resolves the 195% MDD risk signal. The prior session archive (2026-05-02) documented both findings as in tension — this session clarifies that the within-individual design should dominate.
+
+**KB connections:**
+- [[GLP-1 receptor agonists are the largest therapeutic category launch in pharmaceutical history but their chronic use model makes the net cost impact inflationary through 2035]] — safety profile is better than prior signals suggested
+- [[the mental health supply gap is widening not closing]] — GLP-1s addressing depression/anxiety/SUD could partially offset the supply gap through pharmacological means
+- [[medical care explains only 10-20 percent of health outcomes]] — GLP-1s challenge the clean clinical/non-clinical boundary by addressing non-clinical pathways through clinical drugs
+- Divergence candidate: GLP-1 psychiatric safety — matched cohort (195% MDD risk) vs. within-individual (42% reduction in worsening)
+
+**Extraction hints:**
+- Primary claim: "Semaglutide reduces worsening of depression, anxiety, and substance use disorder by 40-50% in people with pre-existing mental illness (Lancet Psychiatry, within-individual design, n=95,490)"
+- Divergence document: GLP-1 psychiatric safety — within-individual vs. matched cohort design conflict
+- Belief 2 complication: clinical drug achieving large effects on behavioral/non-clinical health pathways
+
+**Context:** Published alongside Science Media Centre expert reactions. Medscape covered as "GLP-1s Tied to Lower Risk of Psychiatric Decline in Pre-existing Mental Illness." ScienceDaily: "Weight loss drug Ozempic cuts depression, anxiety, and addiction risk."
+
+## Curator Notes (structured handoff for extractor)
+PRIMARY CONNECTION: [[GLP-1 receptor agonists are the largest therapeutic category launch in pharmaceutical history but their chronic use model makes the net cost impact inflationary through 2035]]
+WHY ARCHIVED: This is the methodologically strongest study on GLP-1 psychiatric safety — resolves the 195% MDD risk divergence by demonstrating confounding by indication; the within-individual finding has no precedent in the KB
+EXTRACTION HINT: Write two outputs: (1) new claim on semaglutide's psychiatric protective effects (HR 0.56 for depression), (2) divergence document explaining why the matched cohort and within-individual results both exist and which to weight more heavily
diff --git a/inbox/queue/2026-04-16-washingtonpost-ozempic-personality-anhedonia-glp1.md b/inbox/queue/2026-04-16-washingtonpost-ozempic-personality-anhedonia-glp1.md
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--- /dev/null
+++ b/inbox/queue/2026-04-16-washingtonpost-ozempic-personality-anhedonia-glp1.md
@@ -0,0 +1,54 @@
+---
+type: source
+title: "What is 'Ozempic personality,' and why does it make life feel 'meh'?"
+author: "Washington Post Health"
+url: https://www.washingtonpost.com/health/2026/04/16/ozempic-personality-glp1-side-effects/
+date: 2026-04-16
+domain: health
+secondary_domains: []
+format: article
+status: unprocessed
+priority: high
+tags: [GLP-1, semaglutide, anhedonia, ozempic-personality, dopamine, reward, side-effects, dose-dependence, reversibility]
+intake_tier: research-task
+---
+
+## Content
+
+Washington Post health journalism investigation (April 16, 2026) documenting the "Ozempic personality" phenomenon — broad emotional blunting in GLP-1 users extending beyond food reward to social activities, music, sex, and daily pleasures.
+
+Key facts reported:
+- Researchers at multiple institutions are compiling approximately 100 cases of GLP-1-induced anhedonia from thousands treated — preliminary compilation, not yet published
+- Symptoms align with clinical anhedonia: diminished enjoyment in activities that normally bring happiness (not just food)
+- The drug has been studied in 54,000+ trial participants; anhedonia is NOT currently listed as adverse drug reaction or warning in any GLP-1 label
+- Doctors say "reports of anhedonia are not widespread" but cases are accumulating
+- **Dose-reduction reversal documented:** One patient reduced Zepbound (tirzepatide) from 15mg to 12.5mg weekly; within two weeks reported feeling joy again
+- Most cases appeared to resolve with dose reduction "often as quickly as within a few weeks"
+- Some persistent cases treated with bupropion (Wellbutrin) — an antidepressant that enhances dopamine activity — as compensatory treatment
+- Proposed mechanism: GLP-1 receptors in brainstem, lateral septum, and hypothalamus modulate neural pathways for food intake, reward, and energy. "GLP-1s tone down regions of the brain associated with pleasure"
+- Contradictory animal evidence: one lab found chronically muted dopamine responses; another found "turbocharged" dopamine signal — the mechanism is not settled
+
+## Agent Notes
+
+**Why this matters:** This is the first mainstream medical journalism piece systematically documenting the dose-reduction reversibility of GLP-1-induced anhedonia. The "within weeks" reversibility and the specific dose-reduction case (15mg → 12.5mg) are clinically actionable findings that should inform prescribing practice. The 100-case compilation is the early-stage formal characterization — the claim file should be written NOW at experimental confidence rather than waiting for the formal paper.
+
+**What surprised me:** The dose-reduction reversal is faster than I expected — "within weeks" is clinically meaningful for something that affects quality of life as fundamentally as hedonic capacity. This is not a slow-reversing drug effect.
+
+**What I expected but didn't find:** Validated clinical instruments (SHAPS, Snaith-Hamilton Pleasure Scale) being deployed in GLP-1 prescribing practice. The article describes a clinical phenomenon without mentioning any systematic measurement tool, suggesting the field has not yet operationalized this as a monitorable adverse effect.
+
+**KB connections:**
+- [[GLP-1 receptor agonists are the largest therapeutic category launch in pharmaceutical history but their chronic use model makes the net cost impact inflationary through 2035]] — the safety profile complicates the "net positive" clinical narrative
+- [[the mental health supply gap is widening not closing]] — anhedonia in GLP-1 users who lack psychiatric monitoring
+- [[human needs are finite universal and stable across millennia]] — meaning and social connection as fundamental health determinants
+
+**Extraction hints:**
+- Primary claim: "GLP-1-induced anhedonia is dose-dependent and resolves in most cases within weeks of dose reduction, suggesting tonic dopamine suppression rather than permanent neurological change"
+- Secondary claim: "Anhedonia is absent from all GLP-1 adverse event labels despite 54,000+ trial participants because trials were not designed to measure hedonic outcomes"
+- Note the cross-domain flag for Clay: the cultural "food noise silence" narrative may mask anhedonia until social/pleasure consequences become visible
+
+**Context:** Published same day as Boston Globe piece on same topic — coordinated coverage suggesting editorial awareness of an emerging clinical issue. April 2026 marks when this entered mainstream health journalism.
+
+## Curator Notes (structured handoff for extractor)
+PRIMARY CONNECTION: [[GLP-1 receptor agonists are the largest therapeutic category launch in pharmaceutical history but their chronic use model makes the net cost impact inflationary through 2035]]
+WHY ARCHIVED: Dose-reduction reversibility of anhedonia is a clinically significant finding that should inform a new claim about GLP-1 psychiatric safety profile; the absence from labels despite large trial populations is a regulatory oversight claim
+EXTRACTION HINT: Focus on (1) dose-dependence mechanism (tonic vs. phasic), (2) reversibility timeframe (weeks), (3) absence from labeling despite 54K+ trial participants — three distinct extractable claims
diff --git a/inbox/queue/2026-04-30-washingtontimes-ozempic-personality-physicians-flag.md b/inbox/queue/2026-04-30-washingtontimes-ozempic-personality-physicians-flag.md
new file mode 100644
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--- /dev/null
+++ b/inbox/queue/2026-04-30-washingtontimes-ozempic-personality-physicians-flag.md
@@ -0,0 +1,50 @@
+---
+type: source
+title: "Doctors flag 'Ozempic personality' as some GLP-1 patients lose appetite for life"
+author: "Washington Times"
+url: https://www.washingtontimes.com/news/2026/apr/30/doctors-flag-ozempic-personality-glp-1-patients-lose-appetite-life/
+date: 2026-04-30
+domain: health
+secondary_domains: [entertainment]
+format: article
+status: unprocessed
+priority: medium
+tags: [GLP-1, ozempic-personality, anhedonia, social-connection, meaning, dopamine, physicians, side-effects, cultural-narrative]
+intake_tier: research-task
+flagged_for_clay: ["'Ozempic personality' as cultural phenomenon — physicians flagging anhedonia but cultural narrative frames only 'food noise' reduction as positive; Clay should examine how the 'food noise quiet' brand narrative shapes public perception of anhedonia as feature vs. bug"]
+---
+
+## Content
+
+Washington Times health reporting (April 30, 2026) documenting physicians flagging broad anhedonia pattern in GLP-1 users — specifically the loss of appetite not just for food but for life activities.
+
+Key facts (referenced in Session 37 musing):
+- Physicians flagging broad anhedonia pattern: reduced appetite for social activities, sex, music, pleasure generally
+- Termed "Ozempic personality" by patient communities and now physicians
+- Mechanism proposed: same dopaminergic pathway suppression effective for addiction (VTA dopamine circuit) also dampens general reward sensitivity
+- Described as "mild form of anhedonia from dampening of brain's dopamine receptors"
+- Published April 30, 2026 — two weeks after Washington Post's April 16, 2026 piece, suggesting sustained clinical observation, not a single-article phenomenon
+
+## Agent Notes
+
+**Why this matters:** This is the physician-facing report (vs. Washington Post's patient/general audience framing). The fact that physicians are FLAGGING this pattern — not just patients self-reporting — elevates it from anecdotal social media to clinical observation. The April 30 publication date (two weeks after WaPo's April 16 piece) confirms this was not a single-outlet story but a multi-outlet clinical observation wave.
+
+**What surprised me:** The extension beyond food appetite is the clinically significant finding. GLP-1's commercial narrative positions "food noise" suppression as the drug's benefit. Physicians are now documenting that the same mechanism also suppresses appetite for social engagement, sex, and life pleasures — which are two of Belief 2's four non-clinical health determinants (meaning, social connection). A drug that reliably suppresses these determinants while improving metabolic outcomes is not a straightforward clinical win when evaluated through the health-as-infrastructure lens.
+
+**What I expected but didn't find:** Any reported cases of permanent or irreversible anhedonia. All cases referenced suggest dose-reduction or discontinuation resolves the effect — suggesting this is a sustained pharmacological effect rather than lasting neurological damage.
+
+**KB connections:**
+- [[social isolation costs Medicare 7 billion annually and carries mortality risk equivalent to smoking 15 cigarettes per day]] — if GLP-1 reduces social appetite/engagement, this is a clinical driver of loneliness-equivalent harm
+- [[modernization dismantles family and community structures replacing them with market and state relationships]] — GLP-1-induced social disengagement adds pharmaceutical pressure to social connection erosion
+- [[medical care explains only 10-20 percent of health outcomes because behavioral social and genetic factors dominate]] — GLP-1 at therapeutic doses may treat the 10-20% (metabolic) while eroding two of the 80-90% (meaning, social connection)
+
+**Extraction hints:**
+- Primary claim candidate: "GLP-1 therapeutic doses suppress dopaminergic reward broadly — reducing appetite for social activities, sex, and meaning-making alongside food — potentially eroding two of Belief 2's four non-clinical health determinants"
+- Cross-domain flag for Clay: the "food noise quiet" brand narrative is masking the anhedonia signal by framing dopamine suppression as liberation from food obsession; the same mechanism creating the desired food effect creates the undesired social/meaning effect
+
+**Context:** Washington Times has a conservative readership. Medical reporting in this outlet reaching conservative audiences suggests the GLP-1 "personality change" story is breaking across political/cultural boundaries, not just progressive wellness communities.
+
+## Curator Notes (structured handoff for extractor)
+PRIMARY CONNECTION: [[GLP-1 receptor agonists are the largest therapeutic category launch in pharmaceutical history but their chronic use model makes the net cost impact inflationary through 2035]]
+WHY ARCHIVED: Physician-flagged (not just patient self-report) documentation of anhedonia extending to social connection and meaning; the specific non-clinical health determinants (social, meaning) match Belief 2's framework exactly
+EXTRACTION HINT: This source supports a claim about GLP-1's effect on non-clinical health determinants (meaning, social connection) — the opposite of the eating disorder harm pathway; focus on what physicians specifically observe (social disengagement, pleasure reduction) rather than just food appetite suppression
diff --git a/inbox/queue/2026-osmind-glp1-psychiatric-drugs-tonic-phasic.md b/inbox/queue/2026-osmind-glp1-psychiatric-drugs-tonic-phasic.md
new file mode 100644
index 000000000..0193a1758
--- /dev/null
+++ b/inbox/queue/2026-osmind-glp1-psychiatric-drugs-tonic-phasic.md
@@ -0,0 +1,68 @@
+---
+type: source
+title: "GLP-1 Agonists Are Psychiatric Drugs: Psychiatry Should Start Acting Like It"
+author: "Osmind (Dr. Sauvé)"
+url: https://www.osmind.org/blog/glp-1-psychiatry
+date: 2026-01-01
+domain: health
+secondary_domains: []
+format: article
+status: unprocessed
+priority: high
+tags: [GLP-1, psychiatry, dopamine, tonic-phasic, dosing-strategy, competency-gap, anhedonia, tirzepatide, semaglutide]
+intake_tier: research-task
+---
+
+## Content
+
+Osmind clinical practice article (estimated Q1 2026) arguing that GLP-1 receptor agonists should be classified as psychiatric medications — directly targeting brain circuits governing reward, motivation, and compulsive behavior.
+
+**Core argument:**
+GLP-1 receptors are densely distributed in psychiatric-relevant brain circuits: VTA, nucleus accumbens, insula, and prefrontal cortex. The drugs function as "a brake on the reward system" by suppressing dopamine signaling through GABA neurons in the VTA. This is not an incidental CNS effect — it is a core pharmacological mechanism.
+
+**Tonic vs. phasic framing (key conceptual contribution):**
+- Natural GLP-1 is PHASIC: spikes after meals, degrades within 1-2 minutes (endogenous half-life)
+- Long-acting GLP-1 agonists (semaglutide, liraglutide) create TONIC receptor occupancy: continuous, days-long receptor activation
+- This creates sustained dopaminergic modulation across ALL reward circuits — including food, sex, social interaction, music, achievement
+- Anhedonia at standard weight-loss doses = mismatch between phasic physiology and tonic pharmacology
+- At lower doses, the tonic suppression is less severe → less anhedonia
+
+**Clinical evidence cited:**
+- AUD: semaglutide reduces alcohol use disorder symptoms with "effect sizes exceeding those historically seen with naltrexone or acamprosate" (2025 JAMA Psychiatry trial)
+- SUD: Observational data from 142,000 participants showed 75% lower odds of developing any substance use disorder with GLP-1 exposure; semaglutide showed 85% and 87% reductions in alcohol and opioid use disorder odds
+- Low-dose tirzepatide (0.6mg weekly) + ketogenic diet: produced resolution of depression AND sustained sobriety WITHOUT emotional blunting — suggesting lower doses preserve therapeutic benefit while avoiding anhedonia
+
+**Competency gap identified:**
+- Psychiatrists are managing patients prescribed GLP-1s by primary care/endocrinology without understanding CNS mechanisms, dosing nuances, or psychiatric adverse effects
+- Dosing strategy matters clinically: primary care prescribers optimizing for weight loss use therapeutic doses (high tonic suppression); psychiatric dosing may favor lower doses that preserve hedonic function
+- The competency gap creates a structural risk: wrong prescriber, wrong dose, wrong monitoring → anhedonia in patients without psychiatric support
+
+**Key recommendation:**
+- "Recognize anhedonia may reflect dosing strategy (tonic vs. phasic signaling), not inherent drug properties"
+- Psychiatrists should consider prescribing GLP-1s directly for SUD and mood disorders, not outsourcing to primary care
+- Implement monitoring for lean mass loss; consider resistance training + adequate protein as standard co-prescription
+
+## Agent Notes
+
+**Why this matters:** The tonic/phasic distinction is the clearest mechanistic explanation for GLP-1-induced anhedonia published to date. If anhedonia is a function of tonic receptor occupancy at therapeutic weight-loss doses, then lower doses for psychiatric indications may achieve the addiction/mood benefits WITHOUT the emotional blunting. This is a clinically actionable framework that should shape claim-writing on GLP-1 psychiatric effects.
+
+**What surprised me:** The 75% lower odds of ANY substance use disorder with GLP-1 exposure (142,000 participants) is a very large effect size in a non-clinical population. This is broader than the AUD effect from Session 34. GLP-1s may be the most effective anti-addiction medication ever studied.
+
+**What I expected but didn't find:** Specific dosing protocols for psychiatric vs. metabolic GLP-1 use. The article identifies the problem (tonic vs. phasic, wrong dose) but doesn't give a formal dosing table. This remains a clinical gap.
+
+**KB connections:**
+- [[healthcare AI creates a Jevons paradox because adding capacity to sick care induces more demand for sick care]] — analogous: optimizing GLP-1 dosing for weight loss may create psychiatric harm demand
+- [[the mental health supply gap is widening not closing]] — GLP-1s addressing SUD and mood could offset some of this
+- [[human-in-the-loop clinical AI degrades to worse-than-AI-alone]] — analogous structural problem: wrong professional type (primary care vs. psychiatry) optimizing the wrong metric creates unintended psychiatric harm
+
+**Extraction hints:**
+- Primary claim: "GLP-1-induced anhedonia is a tonic receptor occupancy phenomenon, not an inherent pharmacological property, resolving with dose reduction because natural GLP-1 is phasic"
+- Secondary claim: "Primary care prescribers of GLP-1s at therapeutic weight-loss doses lack psychiatric competency to monitor for CNS effects, creating structural risk of anhedonia in patients without psychiatric support"
+- Note: connects to Belief 3 (structural misalignment) — the prescribing system optimizes for the measurable metric (weight loss, HbA1c) while externalizing the psychiatric cost
+
+**Context:** Osmind is a psychiatric practice management and research platform serving psychiatrists; this is industry-facing clinical guidance, not peer-reviewed research. The framing reflects psychiatric community's emerging recognition of GLP-1s as cross-domain drugs.
+
+## Curator Notes (structured handoff for extractor)
+PRIMARY CONNECTION: [[GLP-1 receptor agonists are the largest therapeutic category launch in pharmaceutical history but their chronic use model makes the net cost impact inflationary through 2035]]
+WHY ARCHIVED: The tonic/phasic mechanistic framework is the most clinically actionable explanation for GLP-1-induced anhedonia; the competency gap finding connects GLP-1 prescribing to Belief 3's structural misalignment thesis
+EXTRACTION HINT: Two claims: (1) tonic/phasic mechanism of anhedonia (dose-dependent, reversible), (2) prescribing competency gap as Belief 3 instance in the GLP-1 context
diff --git a/inbox/queue/2026-pmc12673456-glp1-psychiatric-systematic-review.md b/inbox/queue/2026-pmc12673456-glp1-psychiatric-systematic-review.md
new file mode 100644
index 000000000..b59179441
--- /dev/null
+++ b/inbox/queue/2026-pmc12673456-glp1-psychiatric-systematic-review.md
@@ -0,0 +1,76 @@
+---
+type: source
+title: "Psychiatric effects of GLP-1 receptor agonists: A systematic review of emerging evidence"
+author: "Sa et al. — Diabetes, Obesity and Metabolism (Wiley)"
+url: https://pmc.ncbi.nlm.nih.gov/articles/PMC12673456/
+date: 2026-01-01
+domain: health
+secondary_domains: []
+format: research-article
+status: unprocessed
+priority: high
+tags: [GLP-1, semaglutide, psychiatric-effects, systematic-review, anhedonia, depression, MDD, eating-disorders, dose-dependence, evidence-gaps]
+intake_tier: research-task
+---
+
+## Content
+
+Systematic review of emerging evidence on psychiatric effects of GLP-1 receptor agonists. Published in Diabetes, Obesity and Metabolism (Wiley Online Library); PMC full-text available at PMC12673456.
+
+**Study corpus reviewed:**
+- Meta-analyses of 80 RCTs (~107,860 participants)
+- Large cohort studies using post-marketing surveillance data
+- Target trial emulation studies using Medicare data
+- Population-based observational studies
+
+**Key findings on depression/MDD:**
+- RCT meta-analysis: small but statistically significant REDUCTION in depression rating scale scores (SMD ≈ -0.12, p < 0.01) — small effect size but consistent direction
+- Post hoc analysis: "statistically significant but clinically negligible reduction in depressive symptoms" (treatment difference: -0.56)
+- Large cohort study: "195% increased risk of major depressive disorder" in obesity populations — contradicts RCT direction
+- Medicare data: no significant difference vs. SGLT2 inhibitors, reduced risk vs. DPP-4 inhibitors
+
+**Key findings on anhedonia/emotional blunting:**
+- Categorized as "potential adverse outcome" — limited specific prevalence data
+- Mechanism: "GLP-1's activation of the HPA axis and its engagement of brain regions involved in emotion regulation"
+- Direct evidence linking GLP-1RAs to anhedonia described as "sparse"
+- No reversibility data included in review
+
+**Key findings on dose-dependence:**
+- "GLP-1 signaling exerts both anxiogenic and antidepressant effects, depending on dosage, exposure duration and the specific neural targets engaged" (preclinical)
+- Human dose-response data: ABSENT from current literature
+
+**Key findings on eating disorders:**
+- GLP-1RAs show promise for REDUCING binge eating — improvements in BES scores (-8.14 points vs. controls)
+- "Caution is warranted in individuals with anorexia nervosa or restrictive eating patterns"
+
+**Evidence gaps explicitly identified:**
+- Most RCTs excluded individuals with moderate-to-severe mood disorders — "high-risk populations routinely excluded"
+- "Short follow-up periods restrict insight into long-term psychiatric safety"
+- "Most hypotheses about CNS involvement remain speculative due to lack of integrated neurobiological or mechanistic studies"
+- "Limited sample diversity"
+- Human dose-response data absent
+
+## Agent Notes
+
+**Why this matters:** This is the most comprehensive synthesis of GLP-1 psychiatric evidence available as of early 2026. The finding that RCT data (80 trials, 107,860 patients) shows a small but consistent REDUCTION in depression scores while observational data shows 195% INCREASED MDD risk is the core contradiction that the field needs to resolve. The review itself doesn't resolve it (they report both), but the within-individual Swedish cohort (Lancet Psychiatry, same month) provides the methodological resolution.
+
+**What surprised me:** The complete absence of human dose-response data on psychiatric effects. After years of GLP-1 prescribing at multiple doses (0.5mg, 1mg, 2mg semaglutide; 2.5mg-15mg tirzepatide), no systematic dose-response study on psychiatric outcomes has been conducted. This is a major evidence gap that should be a research priority given the tonic/phasic mechanistic hypothesis.
+
+**What I expected but didn't find:** Any validated clinical instrument being deployed to systematically capture anhedonia in GLP-1 trials. The Snaith-Hamilton Pleasure Scale (SHAPS) exists and is validated — the absence of SHAPS in GLP-1 trials means anhedonia is invisible to clinical trial infrastructure.
+
+**KB connections:**
+- [[medical LLM benchmark performance does not translate to clinical impact]] — analogous evidence gap: lab findings (RCT, controlled) don't translate to real-world population outcomes
+- [[prescription digital therapeutics failed as a business model]] — regulatory infrastructure (FDA trial design) shapes what evidence gets collected; no tool for measuring hedonic outcomes → no regulatory pressure to address anhedonia
+- [[GLP-1 receptor agonists are the largest therapeutic category launch in pharmaceutical history]]
+
+**Extraction hints:**
+- Primary claim from this review: "Human dose-response data on GLP-1 psychiatric effects are absent from the literature despite mechanistic evidence that tonic receptor occupancy at therapeutic weight-loss doses suppresses dopamine signaling differently than lower psychiatric doses"
+- Supporting evidence for: the within-individual/matched cohort divergence document
+- Flag for divergence: the 80-RCT meta-analysis (SMD -0.12, consistent reduction) vs. matched cohort (195% increased risk) is the core contradiction documented here
+
+**Context:** Systematic review published in Diabetes, Obesity and Metabolism — the leading specialist journal for GLP-1 research. This is likely the reference review that clinical guidelines will cite when eventually addressing GLP-1 psychiatric safety.
+
+## Curator Notes (structured handoff for extractor)
+PRIMARY CONNECTION: [[GLP-1 receptor agonists are the largest therapeutic category launch in pharmaceutical history but their chronic use model makes the net cost impact inflationary through 2035]]
+WHY ARCHIVED: Most comprehensive psychiatric evidence synthesis; the absence of human dose-response data is itself an extractable claim about the evidence architecture; documents both RCT and observational findings for the divergence document
+EXTRACTION HINT: Focus on two extractable facts: (1) RCT meta-analysis direction (small reduction in depression) vs. observational direction (increased MDD risk) — evidence divergence; (2) complete absence of validated hedonic measurement instruments in GLP-1 trials — regulatory/research infrastructure gap claim
diff --git a/inbox/queue/2026-q1-psychopharmacology-glp1-psychiatric-review.md b/inbox/queue/2026-q1-psychopharmacology-glp1-psychiatric-review.md
new file mode 100644
index 000000000..c12b40301
--- /dev/null
+++ b/inbox/queue/2026-q1-psychopharmacology-glp1-psychiatric-review.md
@@ -0,0 +1,63 @@
+---
+type: source
+title: "Q1 2026 in Review: GLP-1 Receptor Agonists as Emerging Psychiatric Medications (Milsaperidone, GLP-1 RAs, and Zuranolone)"
+author: "Psychopharmacology Institute"
+url: https://psychopharmacologyinstitute.com/publication/q1-2026-in-review-milsaperidone-glp-1-ras-and-zuranolone/
+date: 2026-04-01
+domain: health
+secondary_domains: []
+format: article
+status: unprocessed
+priority: medium
+tags: [GLP-1, semaglutide, psychiatric-medications, FDA, suicidality, mental-health, professional-review, 2026]
+intake_tier: research-task
+---
+
+## Content
+
+Psychopharmacology Institute quarterly clinical review (Q1 2026) covering GLP-1 receptor agonists as emerging psychiatric pharmacology. Psychopharmacology Institute is a continuing medical education platform for psychiatrists and pharmacists.
+
+**Key facts covered:**
+
+**FDA suicidality warning removal (January 2026):**
+- FDA removed suicidality warning from GLP-1 labels (Saxenda, Wegovy, Zepbound)
+- Based on meta-analysis of 91 placebo-controlled trials (107,910 patients)
+- Also: retrospective cohort study + published observational studies
+- Conclusion: "No increased risk of suicidal ideation and behavior, anxiety, depression, irritability, or psychosis"
+- Original warning was NOT based on GLP-1-specific evidence — carried over from older weight-loss drugs
+
+**Critical confounding acknowledged:**
+- "Patients with obesity and diabetes carry elevated baseline rates of depression and anxiety"
+- This confounding explains the matched cohort findings showing elevated psychiatric risk in GLP-1 users — it's not the drug, it's the indication
+
+**Protective 2026 finding:**
+- 2026 national cohort study: semaglutide "associated with 42% lower risk of worsening mental illness" vs. non-use periods
+- Reduced worsening of depression, anxiety, and SUD vs. non-use periods (within-individual design)
+
+**Evidence quality caveat:**
+- "These findings are observational and randomized controlled trials are needed to confirm"
+- No new psychiatric indications formally established
+
+## Agent Notes
+
+**Why this matters:** The Psychopharmacology Institute is CME-credit generating content for practicing psychiatrists. Its coverage of GLP-1 as psychiatric pharmacology is a leading indicator that APA and other professional societies will develop formal guidance. The explicit acknowledgment that the original suicidality warning was carried over from non-GLP-1 drugs (not drug-specific evidence) is important context for the KB — the 2023-2024 FDA review that triggered regulatory attention was responding to a label problem, not a new clinical signal.
+
+**What surprised me:** The FDA's meta-analysis covers 91 trials and 107,910 patients and found NO increased risk for any psychiatric adverse event. This is a larger dataset than most drug safety reviews and its conclusion is definitive on the population level. The anhedonia phenomenon at the individual/dose level is real but doesn't register in 91 RCTs' safety data — which is itself the evidence gap (RCTs not designed to measure hedonic outcomes).
+
+**What I expected but didn't find:** CME guidance on how psychiatrists should screen patients already prescribed GLP-1s by other providers. The gap between "we recognize this is a psychiatric drug" and "here's the clinical screening protocol" remains open.
+
+**KB connections:**
+- [[healthcare AI regulation needs blank-sheet redesign because the FDA drug-and-device model built for static products cannot govern continuously learning software]] — analogous: drug label policies carried over from non-relevant predecessors mislead clinical practice
+- [[GLP-1 receptor agonists are the largest therapeutic category launch in pharmaceutical history]]
+
+**Extraction hints:**
+- Supporting evidence for: "GLP-1 suicidality warning removal (January 2026) was based on 91-RCT meta-analysis finding no signal, not because the signal was inadequately studied"
+- Context for why original suicidality warning existed: policy artifact, not drug-specific evidence
+- Evidence quality caveat: "observational" = all current protective findings need RCT confirmation
+
+**Context:** Quarterly review in educational journal aimed at practicing psychiatrists seeking CME. This signals professional community education is now actively incorporating GLP-1 psychiatric pharmacology.
+
+## Curator Notes (structured handoff for extractor)
+PRIMARY CONNECTION: [[GLP-1 receptor agonists are the largest therapeutic category launch in pharmaceutical history but their chronic use model makes the net cost impact inflationary through 2035]]
+WHY ARCHIVED: FDA label action (January 2026, suicidality warning removal) + professional society recognition of GLP-1 psychiatric pharmacology; context for understanding why the regulatory asymmetry (eating disorder signal ignored, suicidality formally reviewed) was resolved the way it was
+EXTRACTION HINT: Use as supporting evidence for claim on FDA suicidality review; note the original warning was policy artifact from older drug classes — this context is missing from the KB's existing discussion of GLP-1 regulatory signals