Recent advances in understanding the role of antidepressants to manage breathlessness in supportive and palliative care.

Purpose of review: Breathlessness is a prevalent and distressing symptom in palliative and supportive care, with limited licensed pharmacological options once disease-directed therapies are no longer effective. Antidepressants have been proposed as a potential treatment, even in the absence of comorbid mood disorders, due to their modulation of neural circuits and serotonin pathways involved in breathlessness perception. Despite their off-label use in clinical practice for managing refractory or chronic breathlessness, robust evidence supporting their efficacy is needed. This review critically evaluates the latest evidence on their potential benefits and safety in breathlessness management.

Recent findings: Breathlessness is influenced by at least three interrelated axes: lung-brain, behavioural-functional, and psycho-social-spiritual. These mechanisms operate across diseases, making them relevant in palliative and supportive care. Despite promise from early case reports and small trials, two recent large, randomised studies of mirtazapine and sertraline found no benefit in alleviating breathlessness or improving other outcomes. The mirtazapine trial also reported more adverse events than placebo. Earlier trials were small with design limitations, reducing reliability. A 2016 trial of sertraline found benefits for depression in stable COPD. Recent concerns over increased morbidity associated with antidepressant use in respiratory disease highlight the need for early detection of people at risk of worsening breathlessness or depression and a holistic, individualised approach.

Summary: Current evidence does not support antidepressants for breathlessness in respiratory disease. Non-pharmacological approaches should be first line, given their proven benefits and low risk. Off-label medicine use requires caution and should ideally be offered within a trial or evaluation. Given the complex nature of breathlessness, future research should focus on innovating and then testing treatments and therapies in well-designed trials with appropriate outcome measures and reporting of adverse events, health care use and informal carer effects.