Background Chronic breathlessness is a prevalent and debilitating symptom in people with advanced life-limiting disease and significantly impacts on function and quality of life. Despite this affecting at least half of our patients in the advanced stages of malignant or non-malignant disease, management options remain limited and inadequate. Current medication options, including opioids and benzodiazepines, lack robust evidence of efficacy and can cause significant adverse effects (Holland 2024, Feliciano 2021). Exploration of alternative pharmacotherapies, such as antidepressants, has the potential to improve symptoms and enhance outcomes for patients living with breathlessness due to advanced disease.

Objective To describe the protocol for a systematic review evaluating the efficacy and safety of antidepressants for the management of breathlessness in patients with advanced life-limiting disease.

Methods A comprehensive literature search will be undertaken of electronic databases including Medline, Embase, CINAHL, Cochrane and Emcare. The search strategy will include medical subject headings and text words related to ‘antidepressants’, ‘breathlessness/dyspnoea’, ‘palliative care’ and ‘advanced disease’, incorporating multiple conditions affecting respiratory function. Reference lists of included studies, grey literature and relevant reviews and guidelines will be hand-searched. Published peer-reviewed studies with no date or language restriction, covering adults with both malignant and non-malignant advanced diseases who receive antidepressants for the management of breathlessness will be included. Studies with mood, depression or anxiety as the primary outcome will be excluded. All retrieved titles and abstracts, as well as full text articles, will be independently dual screened. Disagreements will be resolved through consultation with a third reviewer if necessary. The primary aim of this review is to clarify the efficacy and safety of antidepressants in alleviating breathlessness in patients with advanced disease. Reporting of results will be in accordance with the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines. If sufficient quantitative data can be analysed together, a meta-analysis approach will be employed. If this is not possible, a narrative synthesis will be used to report findings.

Discussion The results of this review, which are to follow, will evaluate whether antidepressants are beneficial in the symptomatic treatment of breathlessness in patients with advanced disease, thereby informing clinical practice. This review will also identify evidence limitations and gaps in this space that will guide research priorities in evaluating effective pharmacotherapies for managing breathlessness to optimise outcomes in this population.

Ethics and Dissemination As this is a planned review of published literature, ethics approval is not required. The findings of this systematic review will be of broad interest to clinicians and educators in palliative care, and results will be presented at conferences and published in a peer-reviewed journal. The systematic review has been registered on PROSPERO (CRD42024519856).

References

1. Holland AE, Spathis A, Marsaa K, et al. European respiratory society clinical practice guideline on symptom management for adults with serious respiratory illness. Eur Respir J 2024.

2. Feliciano JL, Waldfogel JM, Sharma R, et al. Pharmacologic interventions for breathlessness in patients with advanced cancer: a systematic review and meta-analysis. JAMA Netw Open 2021;4(2): e2037632.