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Background and Objectives: Depression is one of the most common and treatable of mental illness. In any six-month period, 340 million people in the world suffer from this disease.  Eighty to 90 percent of those who suffer from depression can be effectively treated, and nearly all people who receive treatment derive some benefit.  Placebo effect is an important component of the efficiency of antidepressant drug that has to be taken into account when predicting the time course and the variability of the drug effect.  The objective is to develop a placebo response longitudinal model in depression as measured with the Hamilton depression scale accounting for dropout.

Method: Placebo data from a 6-week double blind, placebo-controlled study were used. Hamilton depression scale measurements were obtained before the start of the treatment and at week 1, 2, 3, 4, and 6 during the treatment period. Modelling was performed using NONMEM V. Since the problem of missing data is almost ever-present in clinical trials, alternative methods for analysing longitudinal data in presence of dropout were explored.

Results: Indirect-response model was used to describe the time course of the Hamilton depression scale. The time course of HAMD is determined as the net resultant of an onset (kin) and a loss rate (kout) process. Placebo produces indirect action on the inhibition of the onset response rate.

Placebo effect can be characterised by the administration of a “virtual” drug with unknown PK using a K-PD model strategy. This approach enables placebo effect to be linked to a dose regimen. Alternative mechanisms of dropping out were also investigated by exploring the Missing Completely At Random, the Missing At Random and the Informative Dropout possible mechanism. The most informative dropping out model was selected based on the log-likelihood ratio test.

Conclusion: This PKPD model allows the description of placebo related change in Hamilton depression scale with a mechanistic approach rather than a descriptive approach.

References:
[1] Pillai G et al. Br J Clin Pharmacol. (58:6) 2004, 618-631
[2] Gabrielsson J et al. Biopharm Drug Dispos. (21) 2000, 41-52