At doses of 25-50 mg, trazodone's metabolite mCPP exhibits partial agonist activity at melatonin MT1 receptors, phase-advancing the circadian clock and reducing circadian misalignment associated with accelerated neurodegeneration. Circadian entrainment increases nighttime melatonin secretion, enhancing antioxidant defenses. However, the direct connection between trazodone metabolites and MT1 receptors in human brain is not well-characterized, and the specific contribution to disease modification beyond sleep effects is speculative.
Curated pathway from expert analysis
flowchart TD
A["MTNR1A MT1, MTNR1B MT2, PER1/PER2 clock genes, SOD2<br/>Hypothesis Target"]
B["Pathway Dysregulation<br/>Cited Mechanism"]
C["Cellular Response<br/>Stress or Clearance Change"]
D["Neural Circuit Effect<br/>Synapse/Glia Vulnerability"]
E["AD<br/>Disease-Relevant Outcome"]
A --> B
B --> C
C --> D
D --> E
style A fill:#1a237e,stroke:#4fc3f7,color:#4fc3f7
style B fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style E fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9aNo linked papers recorded for this hypothesis yet.
No curated PDB or AlphaFold mapping for MTNR1A yet. Search RCSB →
Median TPM across 13 brain regions for MTNR1A (MT1), MTNR1B (MT2), PER1/PER2 clock genes, SOD2 from GTEx v10.
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for MTNR1A (MT1), MTNR1B (MT2), PER1.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.
No resource usage or linked notebooks recorded for this hypothesis yet.
| Prediction | Predicted | Observed | Status | Conf |
|---|---|---|---|---|
| IF individuals with early-stage Parkinson's disease (Hoehn-Yahr 1-2) without current melatoninergic medication receive low-dose trazodone (25-50 mg) nightly for 48 weeks, THEN their annualized rate of | Reduced annualized sNfL increase (≤2 pg/mL/year) and slower MDS-UPDRS Part III progression (≤3 points/year) in trazodone-treated vs control group. | — no observation — | pending | 0.28 |
| IF community-dwelling adults aged 60-80 with documented circadian misalignment (DELTA > 30 min between habitual sleep onset and dim-light melatonin onset) receive low-dose trazodone (25-50 mg) nightly | Mean advancement of DLMO by ≥20 min and IV improvement ≥15% in active treatment arm vs placebo after 12 weeks. | — no observation — | pending | 0.35 |