The phase III trial of mirtazapine, an inexpensive antidepressant, failed to show any benefit over a placebo in alleviating severe, persisting breathlessness from chronic obstructive pulmonary disease (COPD) or interstitial lung disease (ILD). The study’s primary outcome, “worst breathlessness” over the past 24 hours, as measured on a 0-10 numeric rating scale, showed no significant difference between the mirtazapine and placebo groups after 56 days of treatment. Despite the biological plausibility of mirtazapine in reducing feelings of panic associated with severe breathlessness and previous case reports suggesting its efficacy, the trial results were disappointing.
The international randomized trial, named BETTER-B, enrolled 225 patients with severe breathlessness from COPD, ILD, or both, and randomized them to receive either daily mirtazapine or a placebo. The participants were required to have grade 3 or 4 breathlessness on the modified Medical Research Council (mMRC) breathlessness scale. While the primary outcome and secondary outcomes, including average breathlessness, healthcare usage, and changes in various scales, showed no significant differences between the mirtazapine and placebo groups, the mirtazapine group experienced numerically higher rates of acute hospital visits, outpatient visits, and hours of family care during the study period.
The study results suggest that mirtazapine is not an effective treatment for severe breathlessness in COPD and ILD patients. The lack of benefit, coupled with the potential for adverse reactions and increased care utilization in the mirtazapine group, highlights the importance of caution when using drugs off-label for symptom management. While the editorial accompanying the study acknowledged the rationale behind testing antidepressants for breathlessness, the authors emphasized the need for individualized, multidisciplinary care approaches that address the physical, psychological, social, and spiritual aspects of breathlessness.
Limited Efficacy and Safety Concerns
The lack of efficacy demonstrated by mirtazapine in this trial raises questions about the potential role of antidepressants in managing breathlessness in COPD and ILD patients. The higher rates of adverse events in the mirtazapine group, including dry mouth, somnolence, fatigue, and sedation, further underscore the need for careful consideration of the risks and benefits of using such medications in this population. While serious adverse events were relatively rare, the overall safety profile of mirtazapine in this context appears unfavorable.
Conclusions and Future Directions
The failure of mirtazapine to alleviate severe breathlessness in COPD and ILD patients highlights the challenges of finding effective treatments for this debilitating symptom. The study results call into question the routine use of antidepressants for breathlessness management and emphasize the importance of evidence-based, individualized care approaches. Moving forward, further research is needed to explore alternative therapeutic options and address the complex needs of patients with severe breathlessness in a comprehensive manner.
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