Go green or go blue: a protocol proposal for sulforaphane as a therapeutic intervention for young adult major depressive disorder

Background and Rationale

Depression represents one of the most pressing global health challenges of our time, currently affecting over 280 million people worldwide. Between 1990 and 2019, the global prevalence of depression increased 1.6-fold. Despite this alarming trajectory, existing pharmacological approaches frequently fail to address the underlying biological mechanisms of the disorder, underscoring an urgent need for novel, mechanism-based therapeutic strategies, particularly for younger populations experiencing their first depressive episode. Emerging preclinical evidence points to the NRF2-BDNF signaling axis as a key molecular pathway in the pathophysiology of depression(1). NRF2, a master regulator of the cellular antioxidant response, modulates BDNF expression and attenuates neuroinflammation, two processes critically implicated in depressive phenotypes. Disruption of this pathway is associated with depressive behaviors, while its activation, whether through established antidepressants such as fluoxetine and ketamine, or anti-inflammatory agents such as rofecoxib, correlates with restoration of BDNF levels and symptomatic improvement. Preclinical studies have demonstrated that sulforaphane (SFN), a naturally occurring isothiocyanate derived from cruciferous vegetables, activates the Keap1-NRF2 pathway, increases HO-1 and GCL expression, elevates hippocampal BDNF by approximately 45%, and significantly reduces LPS-induced neuroinflammation(2). Furthermore, dietary glucoraphanin, a sulforaphane precursor, administered during juvenile and adolescent developmental windows has been shown to prevent depression-like phenotypes in adulthood(1). This special project is conducted as part of the ECNP educational program in Outcomes Research.

Objectives

To develop a protocol for outcomes definition to be used in the clinical trial based on the 7-steps standard methodology. The outcomes set will be addressed to evaluate the feasibility, safety, and preliminary efficacy of sulforaphane as a therapeutic intervention, in adolescents and young adults experiencing a first episode of major depressive disorder(MDD).

Methods

The target population consists of adolescents and young adults presenting with a first MDD episode. The outcomes research protocol will be developed through a stakeholder co-design process involving patients, patient associates, clinicians, and industry representatives, using a Delphi consensus methodology to establish a Core Outcome Set. Selected outcome domains of depression and the instruments to measure them will be collected and included into the decision panels; for instance legacy instruments like clinician-reported outcomes(HAMD-17/24, MADRS) and patient-reported outcomes(QIDS-SR, PHQ-9), also biological biomarkers (BDNF, IL-6, TNF-α, CRP, HO-1, NQO1), safety and tolerability assessments, treatment adherence, family observation measures, and digital biomarkers. Delphi panels will be conducted to select the best options based on the meaningfulness to patients and the psychometric properties of the instruments.

Expected Impact

It is expected that the outcomes set resulting from the application of this research protocol, will allow to detect benefits of compound sulforaphane, as a biologically plausible, accessible, and potentially well-tolerated candidate for early intervention in depression. By targeting the NRF2-BDNF interplay, a mechanism shared across multiple effective antidepressant treatments, this approach may offer neuroprotective and disease-modifying effects in a high-risk, underserved population. Results from the outcomes research protocol, will draw a roadmap for future research aiming to inform the design of a future randomized controlled trial and contribute to the development of a standardised core outcome set for early-onset depression research in adolescents and adult population.

References

1. Yao W, Lin S, Su J, Cao Q, Chen Y, Chen J, Zhang Z, Hashimoto K, Qi Q, & Zhang J-C. (2021). Activation of BDNF by transcription factor Nrf2 contributes to antidepressant-like actions in rodents. Translational Psychiatry, 11, 140. https://doi.org/10.1038/s41398-021-
2. Yao W, Zhang JC, Ishima T, Dong C, Yang C, Ren Q, Ma M, Han M, Wu J, Suganuma H, Ushida Y, Yamamoto M, & Hashimoto K. (2016). Role of Keap1-Nrf2 signaling in depression and dietary intake of glucoraphanin confers stress resilience in mice. Scientific Reports, 6, 30659. https://doi.org/10.1038/srep30659