Table 5.
Global assessment through adapted Bradford Hill Criteria about Semaglutide.
| Criteria | Assessment | Description | Source/method |
|---|---|---|---|
| Strength of the association | Weak | Although ROR and ICs show a modest positive signal in pharmacovigilance databases, this contradicts clinical study evidence showing protective effects of GLP-1RAs against depression. | Disproportionality analysis, Clinical literature |
| Consistency | Inconsistent | While pharmacovigilance results are consistent across FAERS and VigiAccess databases, they are fundamentally inconsistent with systematic reviews and meta-analyses demonstrating antidepressant effects of GLP-1RAs in clinical studies. | Disproportionality analysis, Literature review |
| Analogy | Contradicted | While isolated case reports exist, the majority of evidence for other GLP-1RAs (liraglutide, exenatide, dulaglutide) demonstrates neuroprotective and antidepressant effects. Our study found no depressive signals for liraglutide or tirzepatide, contradicting a class effect. | Literature, Current study findings |
| Biological plausibility/empirical evidence | Contradicted | Established biological mechanisms contradict our observed association. GLP-1RAs demonstrate neuroprotective effects through: (1) anti-neuroinflammatory pathways, (2) beneficial modulation of neurotransmitter systems (serotonin, dopamine, GABA), (3) enhanced neuroplasticity and neurogenesis, (4) improved brain insulin signaling. These mechanisms theoretically support mood improvement rather than depression. | Preclinical and mechanistic studies |
| Exclusion of biases/confounders | Not Met | Multiple potential confounders cannot be excluded: (1) indication bias (patients with obesity have higher baseline depression risk), (2) detection bias (increased media attention leading to enhanced reporting), (3) rapid weight loss psychological effects, (4) gastrointestinal side effects impacting mood. Pharmacovigilance databases cannot adequately control for these factors. | Disproportionality analysis, Methodological limitations |
| Specificity | Inconsistent | While only semaglutide showed signals in our pharmacovigilance analysis, this contradicts clinical literature where multiple GLP-1RAs demonstrate protective effects. The apparent specificity may reflect differential reporting patterns rather than true drug-specific effects. | Literature, Disproportionality analysis |
| Temporal relationship | Partially Met | Temporal relationship exists in pharmacovigilance data, but this alone is insufficient given the contradictory evidence from controlled clinical studies showing mood improvement with GLP-1RAs. | Time-to-onset analysis, Literature |
| Reversibility | Not Applicable | This criterion is of limited value here as there is no data on discontinuation and de-challenge in the FAERS and Vigiaccess database. | Not applicable |
| Coherence | Not Met | Our findings lack coherence with established scientific knowledge. The observed association conflicts with: (1) systematic reviews showing antidepressant effects, (2) established neuroprotective mechanisms, (3) clinical trial evidence of mood improvement, creating fundamental incoherence in the causal assessment. | Literature, Systematic reviews |