The need for large multinational studies: from a large clinical cohort initiative to a european platform trial for depression

Randomized controlled trials (RCTs) are the foundation of evidence-based medicine, providing the most reliable means of establishing whether treatments are effective and safe. Yet, traditional RCTs in psychiatry often fail to generate useful evidence for clinical practice. Many are underpowered, evaluate only one intervention against one control, require trial-specific infrastructure that is dismantled after completion, and are slow and costly to initiate.

Platform trials offer a more efficient model of randomized evidence generation. Under a single master protocol and shared infrastructure, multiple interventions can be evaluated concurrently against a shared control group. Ineffective arms can be stopped early, successful arms completed, and new treatments added without establishing a new trial. Sharing controls reduces required sample sizes and participants’ exposure to placebo, while permitting direct treatment comparisons. However, their adaptive complexity requires rigorous planning, simulation, and stakeholder engagement.

The European platform trial PEARLDIVER exemplifies this approach in treatment-resistant depression (TRD). It comprises a 30-site network across six countries and a longitudinal observational cohort and evaluates repurposed oral medication as add-on to standard antidepressants. Co-designed with people with lived experience, PEARLDIVER provides a reusable, collaborative infrastructure for faster, more economical, and clinically relevant randomized evidence generation in TRD.

Gold SM, Mäntylä F-L, Donoghue K, Brasanac J, Freitag MM, König F, Posch M, Ramos-Quiroga T, Benedetti F, Köhler-Forsberg O, Grootendorst N, Hoogendijk W, Pariante CM, Katz ER, Webb S, Lennox B, Furukawa TA, Otte C. Transforming the evidence landscape in mental health with platform trials Nature Mental Health (2025) 3:276-285