A kinetic-pharmacodynamic model for clinical trial simulation of antidepressant action: application to clomipramine-lithium interaction.

A generic kinetic-pharmacodynamic (K-PD) model to describe the response to treatment assessed by a clinical score for depressed patients treated by antidepressants alone or combined with a drug that shortens the lag-time before effect was developed. The aims of this study were: (1) to verify model's ability to characterize clinical data, (2) to evaluate several statistics to summarize the clinical effect, (3) to compare the analysis based on these statistics to the conventional intent-to-treat analysis and (4) to determine the optimal dates of clinical assessment. The population K-PD model was fitted to the individual data from a randomized clinical trial assessing the efficacies of clomipramine and placebo or clomipramine and lithium to treat major depression in 141 patients. The K-PD model was able to fit the individual data even in the case of oscillating score profiles. The interindividual coefficient of variation of the model parameters ranged from 33 to 161%. The statistical analysis based on the secondary parameters yielded conclusions comparable to those of the conventional intent-to-treat analysis. The population model was then used for a clinical trial simulation. According to the simulation, the most sensitive summary statistics for detecting a difference between lithium and placebo were the fractional reduction of depression and the proportion of responders. The optimal dates to assess these parameters were day 9 and 11 respectively. The K-PD model might serve as a tool for clinical trial planning in the field of research on antidepressants and their facilitators.