Mirroring everyday clinical practice in clinical trial design: a new concept to improve the external validity of randomized double-blind placebo-controlled trials in the pharmacological treatment of major depression

To improve clinical trial design in major depression so as to reflect clinical practice more closely we propose to present patients with a balanced view of the benefits of study participation irrespective of their assignment to placebo or active treatment. In addition every participant should be given the option to finally receive the active medication. A research agenda is outlined to evaluate the impact of the proposed changes on the efficacy of the drug to be evaluated and on the demographic and clinical characteristics of the enrollment fraction with regard to its representativeness of the eligible population.We propose a list of measures to be taken to improve the external validity of double-blind, placebo-controlled trials in major depression. The recommended changes to clinical trial design may also be relevant for other psychiatric as well as medical disorders in which expectations regarding treatment outcome may affect the outcome itself.The treatment of patients with major depression remains one of the major challenges in psychiatry in the 21st century [1-3]. There is a general consensus that antidepressant medications are an essential component of the treatment plan at any stage of the illness and particularly in severe cases [4,5].In the era of evidence-based medicine, randomized, double-blind, placebo-controlled, trials constitute the gold standard for testing the efficacy of new pharmacological interventions for major depression [6,7]. Their unique strength derives from the fact that they allow comparisons of a psychopharmacologically active medicine to an identical looking 'medicine' which does not contain any active ingredient (placebo). Randomization is thought to ensure unbiased allocation of patients to each treatment arm while blinding both patients and investigators to treatment allocation safeguards against biased reporting of potential benefits or adverse effects [8].During the last few years however it has become increasingly evident that the