Although previous studies have shown that the use of antipsychotics at the time of hospital admission increases the risks of asthma-related death and hospital readmission,[13] the association between the use of antipsychotics and severe asthma exacerbation has not been investigated using a nationwide asthma population. The effects of atypical antipsychotics on severe asthma exacerbation have not been examined. In this case-crossover study, we analyzed 18,657 newly diagnosed asthma patients with severe exacerbation leading to ED visits or hospitalization. Using multivariable conditional logistic regression, we found that use of antipsychotics is associated with increase of the risk of severe asthma exacerbation (adjusted OR: 1.27). This result was not confounded by respiratory infection, schizophrenia, use of NSAIDs or non-selective β-blockers, and different types of inhaled bronchodilator prescription. In the subgroup analysis, use of typical antipsychotics significantly increased the risk of severe asthma exacerbation by 40%. Furthermore, there was a dose-dependent effect of antipsychotics, especially of typical antipsychotics on severe exacerbation of asthma. Analysis for use of atypical antipsychotics did not show an increased risk of severe asthma exacerbation. We thus tentatively conclude that the use of typical antipsychotics is associated with a dose-dependent increased risk of severe asthma exacerbation.
We found that the use of typical antipsychotics led a higher risk of severe asthma exacerbation (adjusted OR: 1.40), whereas the use of atypical antipsychotics did not. This finding is consistent with different adverse events among typical and atypical antipsychotics users. The use of typical antipsychotics is more likely to bring about extrapyramidal symptoms and the use of atypical antipsychotics is often associated with weight gain and metabolic disturbance.[24] A possible explanation for the discordance of side effects between these two groups of drugs is that typical antipsychotics have higher affinity to the dopaminergic receptor and lower affinity to the serotonin receptor compared to those for atypical agents.[10] The higher antipsychotic affinity to specific receptors is associated with a higher risk of different side effects.[25]
We found that simultaneous use of typical and atypical antipsychotics increases risk of severe asthma exacerbation compared to the use of a mono-drug therapy. Combination of two antipsychotics is a widely used strategy for treatment-resistant schizophrenia,[26] and combination of typical and atypical antipsychotics is the most common management in real-world practice.[27] Compare with monotherapy, several studies have reported that combination therapy is associated with increase adverse events and mortality rate.[28–31] Although a recent meta-analysis did not show different risk of serious adverse events between combination antipsychotics and monotherapy, the quality of evidence was very low.[32]
Antipsychotics block the β2 adrenergic, M2 muscarinic, D1 and D2 dopaminergic receptors, which are found in human airway smooth muscle with the function of bronchial relaxation. Blocking these bronchodilation receptors increases airway smooth muscle tone and induces muscle spasms, [20–23] causing severe asthma exacerbation. The results stratified by different receptor functions of antipsychotics in our study showed that there were higher risks of severe asthma exacerbation for antipsychotics that function on the M2 muscarinic and D2 dopaminergic receptors. A plausible explanation is that most antipsychotics have higher affinities on the M2 muscarinic and D2 dopaminergic receptors than the β2 adrenergic receptor (Supplementary Table 4). Blocking the D2 dopaminergic receptor could also induce dystonia of the airway,[33] causing acute exacerbation of an airway disease.
In this study, we found that schizophrenia increased the risk of severe asthma exacerbation. Patients with schizophrenic disorder usually have low adherence to asthma treatment and adopt risky health behaviors such as smoking.[34] Including these patients in the analysis might bias the results. However, the magnitude of the effect was not altered after excluding patients with schizophrenia (Table 3).
Several limitations must be acknowledged in our study. First, the claims data did not include important information such as disease severity and pulmonary function data and we did not take different phenotypes of asthma into consideration. Nevertheless, we adjusted for the use of different inhaled bronchodilators or their combinations, which could be regarded as a surrogate for asthma severity. Consequently, the results were not significantly biased. Second, the diagnoses of asthma and its acute exacerbation should be based on medical history and physical examination instead of ICD codes only. Nevertheless, the accuracy of diagnostic record for asthma in NHIRD had been validated.[16] We further defined newly diagnosed asthma patients as those who had more than one inpatient or two outpatient visits and excluded subjects with the same diagnosis within the prior 2 years. Severe asthma exacerbation was also defined as an acute exacerbation leading to ED visits or hospitalization in combination with the use of short-acting bronchodilators and systemic steroids. Such strict definitions strengthen the validity of our results. Third, adherence to antipsychotics and other medications could not be confirmed using the claims data. Nevertheless, our study used a case-crossover design, in which drug compliance during the case and control period was supposed to be the same. This factor would not significantly affect the results. Forth, we did not include smoking status into the regression model because NHIRD lacks information on smoking status. However, in our case crossover study design, the time interval between the control period and the case period is 60 days, and the smoking status of each enrolled subject may not change in the short period of time. About 70% of enrolled patient in our study cohort were female. The smoking prevalence of women over 18 years old in Taiwan was 3.9–5.5% during the enrolled period of this study.[35] In our study, the impact of smoking on asthma severe exacerbation might be small.