A Women-Centered Internet-Based Cognitive Behavioral Therapy for Depressive Symptoms (the 3D Program): Protocol for a Randomized Controlled Trial

Abstract

Abstract Background Depressive disorders are a leading cause of disability among women worldwide, yet existing interventions often fail to account for the biological and sociocultural factors shaping women’s risk and symptom presentation. Objective In response, this randomized, single-blind, controlled trial will evaluate the efficacy of the 3D Program—a gender-sensitive, guided internet-based cognitive behavioral therapy (iCBT) intervention for women with moderate depressive symptoms. Methods A total of 120 women presenting with moderate depressive symptoms (17-item Hamilton Depression Rating Scale score 17‐23), aged 18 to 45 years, will be randomized to receive either the 10-week 3D Program or informational video content, with both groups continuing treatment as usual. The 3D Program will integrate personalized therapist support, self-guided digital modules, and a moderated online group, with content cocreated alongside women with lived experience of depressive symptoms. The primary outcome will be the change in depressive symptom severity, measured by the 17-item Hamilton Depression Rating Scale at 12- and 26-week postbaseline assessments. Secondary outcomes will include functioning, quality of life, perceived stress, and menstrual-related distress. Additionally, the study will explore potential biological predictors of treatment response, analyzing metabolic markers related to tryptophan metabolism and adrenal steroid pathways across multiple biological matrices. Data analyses will use linear mixed-effects models and multivariate techniques to examine treatment effects and possible biomarker associations. Results The trial was funded in October 2023 (grant PI23/00257, Spanish Ministry of Economy and Competitiveness), and ethical approval was obtained in February 2024. The trial was registered in July 2025 (ClinicalTrials.gov NCT07060690). Data collection began in March 2026 and is projected to conclude in August 2027. As of April 2026, a total of 8 participants have been enrolled. Data analysis has not yet commenced. The results are expected to be published in the summer of 2028. Conclusions This trial aims to address critical gaps in accessible, personalized, and gender-sensitive mental health care. If effective, the 3D Program may serve as a scalable, cost-efficient adjunct to routine care for women with depressive symptoms in public health systems, while biomarker findings may lay the groundwork for future trials examining predictors of response.