Is it time to shift to better characterization of patients in trials assessing novel antidepressants? An example of two relapse prevention studies with agomelatine.

The present paper reports in parallel the findings of the two studies that evaluated the efficacy of agomelatine in preventing relapse of depression. It describes the methodological adjustments made between the first and the second trial, particularly in relation to patient selection and accuracy of diagnosis of depression. Patients with major depressive disorder who responded to an 8/10-week course of agomelatine 25-50 mg treatment were randomly assigned to receive continuation treatment with agomelatine or placebo during a 24-week, randomized, double-blind treatment period with an optional 18- or 20-week double-blind extension period. The cumulative probability of relapse was calculated using the Kaplan-Meier method of survival analysis. Study 1 lacked assay sensitivity because of an unexpectedly low relapse rate in the placebo arm, but was instructive in showing that the agomelatine effect was better than placebo only in those patients with higher symptom levels at baseline. Study 2 showed a robust benefit of agomelatine - a two-fold reduction in the relapse rate - observed at least up to 10 months in both the overall population and the more severely depressed patients. The methodological adjustments introduced in study 2 (e.g. a minimum subscore calculated from eight specific Hamilton Depression Rating Scale items, the use of the self-rating questionnaire Hospital Anxiety Depression Scale and the Sheehan questionnaire) have assured an adequate severity of depression not only on the basis of ratings of symptom severity but also on measures of functional impairment. We did not find increased severity of symptoms in study 2, but we hypothesize that the increased demands on investigators improved the quality of recruitment to represent more real-world patients. Adopting these innovations could contribute towards lower failure rates for future placebo-controlled clinical trials in the field.