Mirtazapine Fails to Ease Breathlessness in New Study Despite Previous Hopes

Irene Higginson
Credit: 2014 World Cancer Congress

Mirtazapine may have previously shown promise in the modulation of respiratory sensation, but a new phase 3 study revealed this antidepressant does not improve breathlessness in patients with respiratory disease.¹

“Despite being a widespread issue, we still don’t have effective treatments available,” said first author Irene Higginson, FFPHM, from King’s College London, in a statement.² “As such, many doctors turn to off-label prescribing, trying to help their patients.”

It has been suggested antidepressants may modulate respiratory sensation even in the absence of a mood disorder by increasing serotonin levels in respiratory control and other centers such as the amygdala. After all, mirtazapine reduces panic, and it is known panic often comes with episodes of severe breathlessness.

Although an earlier trial found sertraline did not affect chronic breathlessness, Higginson and colleagues conducted a study to evaluate whether another antidepressant—mirtazapine—was effective at reducing breathlessness.¹ Findings of BETTER B, an international, multicenter, phase 3, parallel-group, double-blind, randomized, placebo-controlled pragmatic trial, were presented at the ERS Congress in Vienna. The BETTER B trial was conducted in 16 centers in Australia, Germany, Ireland, Italy, New Zealand, Poland, and the UK and was informed by a feasibility trial published in 2020.

The primary outcome was the reduction of self-reported worst breathlessness over the past 24 hours, measured at day 56, compared with placebo. Secondary outcomes included the worst breathlessness at various times, average breathlessness, number and duration of breathlessness episodes, and physical and emotional aspects of breathlessness such as dyspnea, fatigue, emotional function, and quality life. Another secondary outcome was symptoms and concerns evaluated by the integrated palliative care outcome scale.

The sample, screened between February 4, 2021, and March 28, 2024, were aged ≥ 18 years (mean age: 74 years); had either COPD, interstitial lung diseases, or both; and were grade 3 or 4 of the modified Medical Research Council breathlessness scale. All participants were stable for the previous 2 weeks before baseline and on optimal treatment for reversible causes of breathlessness, determined by the referring clinician and best clinical guidance. People were excluded from the study if they had existing use of antidepressants or serotonergic active substances, had known contraindications to mirtazapine, or received an Australia-modified Karnofsky Performance Scale score of ≤ 40 which indicates they are in bed ≥ 50% of the time.

Participants (n = 225) were randomized 1:1 to receive either mirtazapine or placebo daily for 56 days. They had a dose of 15 mg orally for the first 14 days. After that, there were 2 assessments for dose escalations, at days 14 and 28. Participants had their dose increased to 30 mg at day 14 and to 45 mg at day 28 if they did not show improvement in their breathlessness, measured using the Numerical Rating Scale over the previous 24 hours. At the end of day 56, the dose was tapered and discontinued.

Investigators assessed participants at baseline and at days 7, 14, 28, 56, and 7 days after completing the trial to assess for safety and toxicity of the treatment. Participants were called 180 days from baseline by phone, video call, or mail to complete the last self-reported questionnaire. Caregivers completed questionnaires at days 28, 56, and 180.

At day 14, nearly half (48%) of participants on mirtazapine had escalation, compared with 53% on placebo. At day 28, 35% participants on mirtazapine had escalation, which was slightly less than those on placebo (36%).

At day 56, 3 participants on mirtazapine and 2 on placebo died. At day 180, the number of people who died was 6% in the mirtazapine arm and 10% in the placebo arm. In total, 5 participants were lost to follow-up, with 3% in the mirtazapine arm and 2% in the placebo am.

Investigators did not observe a difference in worst breathlessness score day 56 between mirtazapine and placebo (difference in adjusted mean score [mirtazapine minus placebo], 0.105; 95% confidence interval [CI], -0.407 to 0.618; P = .69). The sensitivity analysis, to account for missing data, also found no evidence of a difference between treatment arms (difference in adjusted mean score; 0.232; 95% CI, -9.308 to 0.773; P = .40). Secondary outcomes also demonstrated no differences between the arms in terms of measures of breathlessness, overall palliative symptoms, average breathlessness score, chronic respiratory questionnaire subscales, anxiety and depression, number and duration of breathlessness, Australia-modified Karnofsky performance scale, and generalized-efficacy scale.

The study reported 215 adverse events in 64% participants on mirtazapine and 40% on placebo

The study reported 215 adverse events in 64% participants on mirtazapine and 40% on placebo, with the most common ones in the mirtazapine arm being dry mouth, somnolence, fatigue, and sedation. Serious adverse events occurred in 5% of participants on mirtazapine and 6% on placebo.

“This new trial concludes that mirtazapine is not recommended for the treatment of breathlessness, that the use of unlicensed medicines should be approached with caution and that it’s crucial to subject medicines in palliative care to rigorous trials,” Higginson said.²

References

1. ^{Higginson, I, Brown, S, Oluyase, A, et al. Mirtazapine to alleviate severe breathlessness in patients with COPD or interstitial lung diseases (BETTER-B): an international, multicentre, double-blind, randomised, placebo-controlled, phase 3 mixed-method trial. The Lancet Respiratory Medicine. 2024. https://www.thelancet.com/journals/lanres/article/PIIS2213-2600(24)00187-5/fulltext. Accessed September 10, 2024.}
2. ^{Drugs prescribed off-label may do more harm than good. EurekAlert! September 9, 2024. https://www.eurekalert.org/news-releases/1056889. Accessed September 10, 2024.}