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Among older patients with COPD, new use of serotonergic antidepressants was associated with small, but significant, increases in respiratory-related mortality, hospital admissions, and emergency department visits in a retrospective analysis.

COPD patients newly prescribed either a selective serotonin reuptake inhibitor (SSRI) or serotonin norepinephrine reuptake inhibitor (SNRI) had a 20% increased risk of death over 90 days of follow-up and a 15% increased risk for hospitalization compared to patients who were not taking antidepressants.

The study, published online June 26 in the , is among the first to link antidepressant use to poor respiratory-related outcomes among patients with COPD.

Lead researcher Nicholas Vozoris, MD, of St. Michael's Hospital, Toronto, told 乌鸦传媒 that since depression is a common co-morbidity in COPD, SSRIs and SNRIs are widely prescribed to patients.

"There are several potential ways that antidepressants might contribute to respiratory harm in COPD," he said. "They are associated with sleepiness, which may lead to drops in oxygen levels and increases in carbon dioxide levels."

He noted that serotonergic antidepressants may also predispose patients to respiratory exacerbations by lowering the threshold for infection through its impact on immune cell quantity and function.

In addition, increased concentrations of serotonin produced by SSRIs and SNRIs have been linked to reduced clearance of apoptotic cells, which could lead to inflammation, respiratory tract infection, and exacerbations in COPD, the researchers noted.

Importantly, the study's control group was a broad mix of COPD patients, matched to those receiving antidepressants on multiple factors but not necessarily with a diagnosis of depression. That left open the possibility that the increased mortality stemmed from underlying conditions linked to antidepressant prescription, not from the drugs themselves.

Vozoris and colleagues performed a sensitivity analysis comparing new SSRI/SNRI users with those receiving new prescriptions of tricyclic antidepressants, and it also found significantly increased rates of adverse outcomes with SSRI/SNRI agents, including a 39% higher rate of all-cause mortality (95% CI 22% to 59%). On the other hand, the researchers acknowledged that tricyclics have serotonergic properties, albeit weaker than SSRI/SNRI drugs.

In their newly published study, the researchers examined health administrative data for the province of Ontario, Canada (13.5 million people) collected from April 2008 to March 2014. A total of 118,611 community-dwelling people who were age 66 and older with physician-diagnosed COPD were included in the analysis, including 29,835 (25.2%) who were new users of serotonergic antidepressants.

New SSRI/SNRI users were propensity score matched 1:1 to controls on 40 relevant covariates to minimize potential confounding. The primary outcome was time to hospitalization for COPD or pneumonia, and secondary outcomes included outpatient respiratory exacerbation, emergency department visit for COPD or pneumonia that did not directly result in a hospitalization, admission to an intensive care unit (ICU) during a hospitalization for COPD or pneumonia, COPD or pneumonia-related mortality, and all-cause mortality. All outcomes were evaluated during a 90-day period following the index date.

Compared to non-users, new users of SSRI/SNRI's had the following:

• Higher rates of hospitalization for COPD or pneumonia (absolute risk difference [ARD] 0.5%; HR 1.15, 95% CI 1.05 to 1.25; number needed to harm [NNH] 200), as well as ER visits for COPD or pneumonia (ARD 0.3%; HR 1.13, 95% CI 1.03 to 1.24; NNH 333), COPD or pneumonia-related mortality (ARD 0.1%; HR 1.26, 95% CI 1.03 to 1.55; NNH 1000) and all-cause mortality (ARD 0.8%; HR 1.20, 95% CI 1.11 to 1.29; NNH 125)
• Significantly decreased rate of outpatient exacerbations (HR 0.91; 95% CI 0.86 to 0.96) and there was no significant association with ICU admissions during hospitalizations for COPD or pneumonia (HR 1.07; 95% CI 0.85 to 1.34)
• In the subgroup of individuals with one or more exacerbations requiring hospitalization in the year prior to index, significantly increased rates of hospitalization for COPD or pneumonia (HR 1.23; 95% CI 1.10 to 1.38) and COPD or pneumonia-related mortality (HR 1.45; 95% CI 1.11 to 1.88), but these associations did not extend to other COPD exacerbation frequency subgroups

New antidepressant users showed significantly increased rates of all-cause mortality across all COPD exacerbation frequency subgroups (no exacerbation in the year prior to index: HR 1.13; 95% CI 1.01 to 1.27; one or more outpatient respiratory exacerbation in the year prior to index: HR 1.33; 95% CI 1.07 to 1.66.

"To our knowledge, our large, population-based study is the first to show that, among older adults with COPD, new users of SSRI or SNRI drugs have modest, but statistically significant, increases in rates of respiratory-related morbidity and mortality, as well as all-cause mortality, than controls matched on a wide range of covariates," the researchers wrote. "The fact that similar results were found among subgroups of individuals with less severe COPD strengthens the credibility of our overall findings."

The researchers acknowledged that the observational design of the study and the inability to adjust for certain potential confounders were study limitations.

"Our findings should not be interpreted to indicate that use of SSRI/SNRI drugs should be absolutely avoided in individuals with COPD and comorbid psychiatric disease," they concluded. "Instead, our results should prompt prescribers to consider the potential for increased respiratory-related morbidity and mortality in SSRI/SNRI prescribing decision-making (especially when off-label drug use is being considered), to counsel patients about potential drug respiratory side-effects when prescribing SSRIs/SNRIs and to monitor for potential adverse respiratory effects when SSRI/SNRI drugs are initiated."

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