The RESPOND trial: protocol for a novel phase-based psychotherapy and integrated neurobiological investigation of depression following early life adversity

Exposure to early life adversity (ELA) is one of the most robust predictors of future psychiatric illness. Among individuals assigned female at birth (AFAB), ELA can alter neuroendocrine, epigenetic, and inflammatory processes in ways that increase sensitivity to reproductive hormonal transitions across the lifespan, including the menstrual cycle, postpartum period, and menopause, resulting in cyclical exacerbation of psychiatric symptoms – a clinical profile known as hormonal sensitivity . Despite the high burden of disease, this population is underrepresented in both trauma and mood disorder research due to non-prototypical symptom presentations that often fall outside traditional diagnostic boundaries. There are currently no psychotherapy protocols specifically designed to address the interaction between ELA, hormonal sensitivity, and depression symptoms. The RESPOND trial is a single-arm, open-label, proof-of-concept trial evaluating a novel, phase-based psychotherapy protocol for AFAB individuals with depressive symptoms and a history of ELA. Fourty participants will complete a 12-week intervention, delivered virtually, which integrates components from cognitive behavioural therapy, dialectical behaviour therapy, and cognitive processing therapy. Clinical assessments will be conducted at baseline, mid-treatment, post-treatment, and 3-month follow-up. The primary outcome is change in depressive symptoms measured via the Quick Inventory of Depressive Symptoms (QIDS; [49]). Secondary outcomes include emotional regulation, trauma symptoms, and functioning. Hormonal sensitivity will be measured using daily symptom charting, and biological markers (inflammation, DNA methylation, neurosteroids) will be collected pre- and post-treatment to explore physiological phenomena correlated with symptom change. This trial aims to address the gap in mental health care by targeting the unique clinical needs of AFAB individuals with complex depression related to early life adversity. By combining psychotherapeutic treatment with biomarker analysis, the present study will help characterize biological mechanisms that are common between ELA and mood disturbances and assess whether targeted psychotherapy can alter both clinical symptoms and biological signals of ELA. Results have the potential to inform the development of precision mental health interventions and advance care for a population historically excluded from diagnostic and treatment frameworks. This trial has been registered on ClinicalTrials.gov (ID: NCT07250893). The trial record was first released on 04/08/2025, and is updated as of 13/07/2026.