Statistical analysis plan for a parallel group randomized clinical trial comparing schema therapy versus treatment as usual for outpatients with difficult-to-treat depression (DEPRE-ST).

Background: "Difficult-to-treat" depression - here operationalized as either chronic or treatment-resistant depression - encompasses about one third of all patients with depression. Despite its considerable size, the patient group is understudied, and evidence-based psychotherapeutic treatment options are currently limited. The DEPRE-ST trial therefore seeks to investigate beneficial and harmful effects of schema therapy for difficult-to-treat depression.

Methods: This is a randomized multicenter parallel-group superiority clinical trial. A total of 129 patients will be randomized to receive either 30 sessions of individual schema therapy or psychotherapy according to Treatment As Usual, along with psychopharmacological treatment. Participants are assessed before randomization and at 6, 12, and 24 months after randomization. The primary outcome is depression symptoms (6-item Hamilton Rating Scale for Depression), assessed at 12 months. Secondary outcomes include health-related quality of life (European Quality of Life 5 Dimensions 5 Level Version), functional impairment (Work and Social Adjustment Scale), psychological wellbeing (WHO-5 Well-being Index), and negative effects of treatment (Negative Effects Questionnaire), alongside a range of patient-relevant exploratory outcomes. Blinding of treatment allocation is ensured for primary outcome assessors, statisticians, and the data safety and monitoring committee. The primary outcome will be analyzed with multilevel linear regression, with conservative multiple imputation for missing data, and presented as the covariate-adjusted difference between treatments' change scores with its 95% confidence intervals. Further, a health economic analysis will be performed.

Discussion: This statistical analysis plan was developed and submitted before unblinding of data to ensure transparency and diminish bias in selection, analysis, and reporting of results.

Trial registration: ClinicalTrials.gov NCT05833087. Registered on 15th April 2023. https://clinicaltrials.gov/study/NCT05833087?term=depre-st&checkSpell=false&rank=1.