Effective Vortioxetine Dose Varies with Extent of Antidepressant Use Across Countries.

Objective: One of the possible explanations for the antidepressant resistance is tolerance to the effect of increasing synaptic serotonin. Vortioxetine is thought to work through a combination of two pharmacological modes of action: serotonin reuptake inhibition and modification of serotonin receptor activity, in a dose-dependent manner. This mechanism of action allows for examination of the hypothesis that antidepressant non-response may be due to exposure to persistently elevated synaptic amine levels.
Methods: We hypothesized that lower doses of vortioxetine, which exclusively inhibit serotonin reuptake, would not be effective in the setting of prolonged exposure to antidepressants, but higher doses, which interact in various ways to multiple post-synaptic serotonin receptors, would be relatively more effective in the setting of prolonged, prestudy antidepressant exposure. We examined the relationship between Defined Daily Dose (DDD), which is a measure of the extent of antidepressant use in each country, and the minimal effective dose of vortioxetine. Principal Observation: There is a significant relationship between the DDD and effective vortioxetine dose (P = 0.035). Conclusions: In countries with high antidepressant utilization, higher doses of vortioxetine were required, and obverse was true in countries with lower antidepressant utilization. These data support the hypothesis that tolerance to serotonin reuptake inhibition drives poor antidepressant response.