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Original Investigation
March 2017

Association Between Antipsychotic Agents and Risk of Acute Respiratory Failure in Patients With Chronic Obstructive Pulmonary Disease

Author Affiliations
  • 1School of Pharmacy, National Defense Medical Center, Taipei, Taiwan, Republic of China
  • 2Division of Pulmonary and Critical Care, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China
  • 3Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China
  • 4Division of Pulmonary and Critical Care Medicine, Mackay Memorial Hospital, New Taipei City, Taiwan, Republic of China
JAMA Psychiatry. 2017;74(3):252-260. doi:10.1001/jamapsychiatry.2016.3793
Key Points

Question  Is the use of antipsychotic drugs associated with the risk of acute respiratory failure (ARF) in a population of patients with chronic obstructive pulmonary disease?

Findings  In this population-based case-crossover study of 5032 patients with newly diagnosed ARF identified from 61 620 patients with chronic obstructive pulmonary disease, after accounting for cardiogenic, traumatic, and septic ARF as well as proxies of the severity of chronic obstructive pulmonary disease, the use of antipsychotic drugs was associated with a 1.66-fold increased risk of ARF within 14 days of therapy initiation.

Meaning  These findings suggest an acute risk of ARF from antipsychotic use in patients with chronic obstructive pulmonary disease, and future studies are required to confirm the observed association.


Importance  Acute respiratory failure (ARF) is a life-threatening event that has been linked in case reports to antipsychotic use, but this association lacks population-based evidence. Particular attention should be focused on patients with chronic obstructive pulmonary disease (COPD) regarding this drug safety concern because these patients are prone to ARF and are commonly treated with antipsychotics.

Objective  To determine whether the use of antipsychotics is associated with an increased risk of ARF in patients with COPD.

Design, Setting, and Participants  A population-based case-crossover study analyzing the Taiwan National Health Insurance Research Database was conducted of all patients with COPD, who were newly diagnosed with ARF in hospital or emergency care settings necessitating intubation or mechanical ventilation from January 1, 2000, to December 31, 2011. Patients with prior ARF, lung cancer, and cardiogenic, traumatic, or septic ARF were excluded to analyze idiopathic ARF. The pilot study was conducted from November 1 to December 31, 2013, and full data analysis was performed from October 15, 2015, to November 8, 2016.

Exposures  The use of antipsychotics was self-compared during days 1 to 14 (the risk period according to previous case reports) and days 75 to 88 (control period) preceding the ARF event or index date. The antipsychotic class, route of administration, and dose were also examined.

Main Outcomes and Measures  Risk of ARF.

Results  There were 5032 patients with ARF (mean [SD] age, 74.4 [9.9] years; 3533 males [70.2%]) among the 61 620 patients with COPD. Five hundred ninety patients with ARF (11.7%) filled at least 1 antipsychotic prescription during the case period compared with 443 (8.8%) during the control period, corresponding to a 1.66-fold (95% CI, 1.34-2.05; P < .001) adjusted increased risk of ARF regardless of antipsychotic class and administration route. A dose-dependent risk of ARF associated with antipsychotics was identified (test for trend, adjusted odds ratio, 1.35; 95% CI, 1.19-1.52; P < .001), which increased from a 1.52-fold risk for a low daily dose (95% CI, 1.20-1.92; P < .001) to a 3.74-fold risk for a high dose (95% CI, 1.68-8.36; P = .001). The increased risk persisted under a case-time-control analysis (adjusted odds ratio, 1.62; 95% CI, 1.16-2.27; P = .005) and nested case-control study (adjusted odds ratio, 2.16; 95% CI, 1.91-2.15; P < .001).

Conclusions and Relevance  Antipsychotic use is associated with an acute and dose-dependent increased risk of ARF in patients with COPD. Clinicians should exercise caution when prescribing antipsychotics to patients with COPD and avoid high doses if possible.