Vortioxetine is approved for the treatment of major depressive disorder (MDD). 
This analysis aimed to develop pharmacokinetic (PK) and PK/Efficacy models to 
evaluate the exposure-response relationship for vortioxetine in patients with 
MDD. PK data from 10 MDD and two generalized anxiety disorder studies of 
vortioxetine (3160 patients), and efficacy data [Montgomery-Åsberg Depression 
Rating Scale (MADRS)] from seven MDD studies (2537 patients), were used for the 
development of PK and PK/Efficacy models. One- and two-compartment models were 
evaluated as structural PK models, and linear and nonlinear (Emax) models were 
used to describe the relationship between average vortioxetine concentration at 
steady-state (Cav) and change in MADRS score from baseline (ΔMADRS). The impact 
of selected covariates on the PK and efficacy parameters of vortioxetine was 
also investigated. PK of vortioxetine was best characterized by a 
two-compartment model with first-order absorption and elimination. Mean 
estimates for oral clearance (CL/F) and volume of distribution for the central 
compartment of vortioxetine were 42 L/hr and 2920 L. Creatinine clearance, 
height and geographic region had statistically significant effects on 
vortioxetine CL/F, but the effect of each of these covariates was not considered 
clinically relevant, as they lead to ±26% change in area under the curve or Cmax 
of vortioxetine. An Emax model best described the relationship between ΔMADRS 
and Cav. Half-maximal effective concentration (EC50) and Emax estimates were 
24.9 ng/mL and 7.0. No identified covariates, except region, had clinically 
meaningful effects on vortioxetine efficacy. These PK/Efficacy models adequately 
characterized the vortioxetine exposure-response relationship.