Cheap Antidepressant Flops for Severe Breathlessness in Trial

An inexpensive antidepressant proved no better than placebo for alleviating severe, persisting breathlessness from chronic obstructive pulmonary disease (COPD) or interstitial lung disease (ILD), a phase III trial indicated.

After 56 days of treatment, “worst breathlessness” over the past 24 hours — the study’s primary outcome — was no different between patients allocated to receive a daily dose of mirtazapine or placebo, as measured on a 0-10 numeric rating scale (NRS; mean difference 0.105, 95% CI -0.407 to 0.618, P=0.69), reported Irene Higginson, BMBS, PhD, of Kings College London.

“And further, I think our study does show that [mirtazapine] might cause adverse reactions and increase care use and informal care use, so we are not recommending it to alleviate severe breathlessness,” said Higginson at the annual European Respiratory Society congress in Vienna.

Findings from the international randomized trial were published simultaneously in Lancet Respiratory Medicine as well.

Common among COPD and ILD patients, severe breathlessness affects 75 million people worldwide and is a frequent cause of emergency admissions, and medication options are limited, Higginson explained. As a result, physicians often turn to off-label opioids (which have failed in adequately powered trials), benzodiazepines, or antidepressants.

Mirtazapine, an oral tetracyclic antidepressant that can reduce feelings of panic, which often accompanies severe breathlessness, has some biological plausibility in this setting and is backed by case reports and a small feasibility study, said Higginson.

Yet the current study showed no benefit. From baseline to day 56 after treatment, scores on the NRS (a 0-10 scale where higher scores indicate more severe breathlessness) dropped from a mean 6.5 to 6.4 in the mirtazapine group while remaining flat at 6.3 in the placebo group. A between-group difference of 0.55 was the pre-set minimal important difference.

“We should be cautious about using drugs off-label,” Higginson said in her closing remarks. “Using off-label medicines that you can get, because we have the imperative that we want to do something, is probably not advisable,” she added, noting that reductions in symptoms seen in the clinic can be due to other factors.

In an editorial accompanying the study publication, Kris Mooren, MD, PhD, of Spaarne Gasthuis in Haarlem, and Huib Kerstjens, MD, PhD, of University Medical Center Groningen, both in the Netherlands, pointed to the “strong rationale” for the study, dubbed BETTER-B.

“First, tricyclic and tetracyclic antidepressants have an anxiolytic effect,” they noted. “Second, their possible effectiveness is in line with recent studies that underpin the positive role of mood modulation in breathlessness perception. Third, it is not uncommon for healthcare professionals to prescribe antidepressants to patients with intractable breathlessness, aiming to improve both mood and symptoms.”

However, few prior reports have examined the use of antidepressants in this setting, said Mooren and Kerstjens. One randomized controlled trial involving sertraline (Zoloft) showed no benefit with the selective serotonin reuptake inhibitor versus placebo.

“It might be useful to distinguish patients with breathlessness only or mainly triggered on exertion, from emotionally charged breathlessness,” the editorialists wrote. “Based on our own clinical experience, we have the impression that the first group can often handle their breathlessness, provided they receive adequate support. The latter breathlessness evokes feelings of terror, despair, or hopelessness. Perhaps thinking that a one-dimensional therapy such as a pill would be very helpful is too optimistic.”

While awaiting an effective therapy, the duo called for individualized approaches to care that cover the four domains of breathlessness (physical, psychological, social, and spiritual). “These patients need resourceful healthcare professionals, working in a multidisciplinary manner in breathlessness support services or rehabilitation centers.”

BETTER-B was a pragmatic, double-blind trial that randomized 225 patients with severe breathlessness from COPD, ILD, or both to either daily mirtazapine (15 mg, escalating to 45 mg at maximum) or placebo.

Participants were enrolled from February 2021 to March 2023 at 16 sites across seven countries (Australia, Germany, Ireland, Italy, New Zealand, Poland, and the U.K.). For eligibility, patients needed to be considered grade 3 or 4 on the modified Medical Research Council (mMRC) breathlessness scale. Use of antidepressant or other serotonergic active substances were among the exclusion criteria.

Patients had a mean age of 74 years, about two-thirds were men, and 80% had comorbidities. COPD represented the majority of cases (55%), with ILD comprising the rest. More than one-fifth had Hospital Anxiety and Depression Scale (HADS) scores above 10 for anxiety and depression (indicating symptoms that likely correspond with a clinical diagnosis), and 16% were already taking opioids. One-third had grade 4 breathlessness on the mMRC.

Secondary outcomes — including average breathlessness in the past 24 hours on the NRS, healthcare usage during the study period, and changes on the Chronic Respiratory Questionnaire, Integrated Palliative Care Outcome Scale, and HADS, among others — showed no significant differences between groups.

But Higginson pointed out that the mirtazapine group had numerically higher rates of acute hospital visits (mean 0.99 vs 0.48), outpatient visits (mean 1.66 vs 1.32), and hours of family care (mean 73 vs 58) during the study.

Adverse events (AEs) were fairly mild, she said, but higher in the mirtazapine group (64% vs 40% in the placebo group), with dry mouth, somnolence, fatigue, and sedation most commonly observed with the antidepressant. A similar proportion of serious AEs occurred in each group (5% vs 6%, respectively), though one patient in the study arm had a suspected unexpected serious adverse reaction.

Limitations included that the trial was hampered both by the COVID-19 pandemic and Brexit, ultimately enrolling 225 out of a planned 324 participants. As a result, the study was not adequately powered, but sensitivity analyses of the primary endpoint appeared to favor placebo, said Higginson.

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