INTENSIFY—a Randomized, Controlled Trial to Investigate the Effect of an Early Intensified Pharmacological Treatment for Major Psychiatric Disorders after Treatment Failure in the Current Episode: a Study Protocol

Schizophrenia, bipolar depression and major depressive disorders collectively affect over 10 million people across the European Union and are associated with annual healthcare and societal costs of more than 600 billion euros. When diagnosed, patients are usually prescribed psychotropic medication. A substantial proportion of patients insufficiently responds to first- and second-line treatments, which is termed as treatment resistance. While third-line treatments are relatively effective in TR conditions, it remains unclear whether providing these treatments in an earlier phase provides benefits. INTENSIFY consists of three international, multicenter, controlled, randomized, open-label trials, with a treatment duration of 6 weeks. After failure of a first-line treatment in the current episode, 1254 participants will be recruited by at least 16 sites and randomized to either a third-line treatment (early intensified pharmacological treatment) or treatment as usual (standard second-line treatment). Adult participants (age ≥ 18yrs) with a diagnosis of schizophrenia, schizoaffective disorder or schizophreniform disorder, major depressive disorder, or bipolar depression are eligible after a treatment failure in the current episode due to lack of efficacy. The primary objective is to compare change in symptom severity after 6 weeks. The secondary objective is to compare the two treatment arms on changes of severity symptoms, cognitive function, quality of life, functional measures, digital mental health markers, side effects and concomitant medication. ANCOVA analyses will be performed. Should the current study show clinical evidence that the use of third-line treatment is efficacious and safe earlier to treat severe mental illness, the results could impact treatment guidelines in due course. In addition, the study will contribute to the identification of clinical, digital and blood-based markers that are associated with treatment response to early and intensified treatments. The trials are registered in www.clinicaltrials.gov under numbers NCT05603104 (merged study protocol; study center in Israel) and under the numbers for the split protocols NCT05958875 (SZ), NCT05973786 (BD) and NCT05973851 (MDD) for the EU and UK sites. The study is registered in the Australian and New Zealand Clinical Trials Registry under Registration number ACTRN12625000327482 (SZ), ACTRN12625000328471 (BD) and ACTRN12625000329460 (MDD). Registered on April 17, 2025.