Health inequalities remain resistant to interventions that primarily target individual behaviour. Although systems approaches are increasingly promoted, their application in practice is often not well grounded in real-world settings. In this protocol paper, we present the approach we will take in an overarching project that synthesises the combined insights of four ongoing systems-based research projects on system-based approaches for reducing health inequalities in the Netherlands. By bringing together and comparing findings across diverse contexts, populations and interventions, we aim to generate an empirically grounded understanding of what works, for whom, in what contexts and why, and to derive actionable strategies for systemic change to reduce health inequalities.

We use a realist approach to synthesise insights from the four ongoing projects. The design involves four iterative steps: (1) Identifying cross-cutting themes from project proposals and literature, (2) Developing and refining context–mechanism–outcome (CMO) configurations through literature review and Slow Science meetings, (3) Engaging Critical Friends to co-develop actionable strategies and (4) Assessing and validating these strategies across diverse contexts. Iterative feedback loops ensure continuous refinement, integration of stakeholder perspectives and exploration of emergent challenges. This design enables theory-informed, practice-based strategies to support sustainable system change in reducing health inequalities.

Ethical approval for the four underlying projects has been obtained from the relevant institutional review boards, and the way their data is used for this overarching project falls within their approved scope. Dissemination will be ongoing and co-created with stakeholders, including policy briefs, factsheets, educational tools and academic publications, to support uptake of strategies for systems change.

Major depressive disorder (MDD) is among the most common psychiatric disorders in children and adolescents. While previous meta-analyses have synthesised evidence on the efficacy and acceptability of newer-generation antidepressants in this population, specific adverse events (AEs) remain poorly characterised. This is of high clinical importance, as AEs are burdensome for patients, can reduce treatment adherence and lead to discontinuation. Here, we present a protocol for a network meta-analysis designed to evaluate the specific AE profile and comparative tolerability of newer-generation antidepressants in children and adolescents with MDD.

The planned study will include double-blind randomised controlled trials that compared one active drug with another and/or placebo for the acute treatment of MDD in children and adolescents. The following antidepressants will be considered: agomelatine, alaproclate, bupropion, citalopram, desvenlafaxine, duloxetine, edivoxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, paroxetine, reboxetine, sertraline, venlafaxine, vilazodone and vortioxetine. The primary outcomes will include the number of patients experiencing at least one AE, specific non-serious AEs, serious AEs (eg, suicidal ideation) and AEs leading to treatment discontinuation. Published and unpublished studies will be retrieved through a systematic search in the following databases: PubMed, Embase, Cochrane Library (including the Cochrane Central Register of Controlled Trials), Web of Science Core Collection, PsycInfo and regulatory agencies’ registries. Study selection and data extraction will be performed independently by two reviewers. For each outcome, a network meta-analysis will be performed to synthesise all evidence. Consistency will be assessed through local and global methods, and the confidence in the evidence will be evaluated using the Confidence in Network Meta-Analysis web application. All analyses will be conducted in the R software.

The planned review does not require ethical approval. The findings will be published in a peer-reviewed journal and may be presented at international conferences.

CRD420251011399.