Association Between Venlafaxine Exposure And Treatment Outcomes In Older Adults With Depression: Association entre l’exposition à la venlafaxine et les résultats du traitement chez les personnes âgées atteintes de dépression

Background Venlafaxine is commonly prescribed for older adults with depression, yet the relationship between venlafaxine-related exposure and treatment outcomes remains unclear. We aimed to assess the association of exposure to venlafaxine, its active metabolite O-desmethylvenlafaxine (ODV) and its active moiety (i.e., venlafaxine + ODV) with treatment response and adverse effects in late-life depression. Method We analyzed data from 325 participants from the Incomplete Response in Late-Life Depression: Getting to Remission (IRL-GRey) study. Participants were ≥ 60 years old, treated openly with venlafaxine (up to 300 mg/day) for 12 weeks. Treatment response was assessed with the Montgomery–Asberg Depression Rating Scale and adverse effects were evaluated with the Udvalg for Kliniske Undersøgelser (UKU) rating scale. Venlafaxine-related exposures were derived from a published population pharmacokinetic model based on the IRL-GRey study, and their associations with treatment outcomes were assessed using regression analyses. Result At week 4, the primary endpoint, higher venlafaxine-related exposures were not associated with greater symptom improvement. While at the end of treatment (week 12), we did not observe additional antidepressant benefit with increased venlafaxine-related exposures, higher ODV and active moiety exposures were associated with the occurrence of at least one adverse effect (odds ratio [OR] = 1.6 [1.1, 2.3], p = 0.02 and 1.8 [1.2, 2.6], p = 0.003, respectively). Also, higher venlafaxine and active moiety exposures were associated with nausea/vomiting (OR = 1.1 [1.0, 1.2], p = 0.02 and 2.3 [1.3, 4.0], p = 0.006); while higher active moiety exposure was associated with orthostatic dizziness (OR = 1.9 [1.1, 3.2], p = 0.02). Conclusion Our findings suggest a potential threshold effect, where venlafaxine-related exposure past a certain level did not enhance antidepressant response but increased adverse-effect burden. These results support incorporating exposure measures from therapeutic drug monitoring in antidepressant studies to address the heterogeneity of safety and tolerability outcomes.