Typical Antipsychotics Is Associated With Increased Risk of Severe Exacerbation in Asthma Patients

A Nationwide Population-Based Cohort Study

Chin-Wei Kuo; Szu-Chun Yang; Yu-Fen Shih; Xin-Min Liao; Sheng-Hsiang Lin

BMC Pulm Med. 2022;22(85)

Abstract and Introduction

Abstract

Background: Severe asthma exacerbation reduces patients' quality of life, results in visits to the emergency department (ED) and hospitalization, and incurs additional medical costs. Antipsychotics block receptors with bronchodilation function; however, the association between antipsychotic use and severe asthma exacerbation is unknown. This study aimed to investigate the effects of antipsychotics on asthma-related ED visits and hospitalizations.

Methods: A case-crossover design was used in this study. Using the 2003–2017 Taiwan National Health Insurance Reimbursement Database, we established a cohort of 18,657 adults with asthma exacerbation leading to ED visits or hospitalization. Univariate and multivariate conditional logistic regressions were conducted to explore the association between antipsychotic use and severe asthma exacerbation. Subgroup analyses of different classes, doses, receptor functions of antipsychotics, different psychiatric disease, and sensitivity analyses of excluding patients with schizophrenia were also performed.

Results: Antipsychotic use was associated with a higher risk of severe asthma exacerbation (adjusted odds ratio [OR]: 1.27; 95% confidence interval [CI] 1.05–1.54; P = 0.013) compared with no use of antipsychotics. The use of typical antipsychotics increased the risk of severe asthma exacerbation (adjusted OR: 1.40, 95% CI 1.10–1.79, P = 0.007), whereas the use of atypical antipsychotics did not. These results did not change after the exclusion of patients with schizophrenia. There was a dose-dependent effect of antipsychotics (trend test, P = 0.025). Antipsychotics that block the M2 muscarinic or D2 dopaminergic receptors were associated with an increased risk of severe asthma exacerbation (adjusted OR: 1.39, 95% CI 1.10–1.76, P = 0.007 and adjusted OR: 1.33, 95% CI 1.08–1.63, P = 0.008, respectively). However, use of antipsychotics did not increase risk of severe asthma exacerbation in patients with psychiatric disorder.

Conclusions: The use of typical antipsychotics is associated with a dose-dependent increased risk of severe asthma exacerbation, especially for patients without psychiatric disorders. Further research on the impact of typical antipsychotics on asthma exacerbation is warranted.

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Abstract and Introduction
Background
Methods
Results
Discussion
Conclusions
References

Table 1. Characteristics of patients in the case and control periods
Characteristics	Number (%)		Conditional logistic regression
Characteristics	Case period (n = 18,657)	Control period (n = 18,657)	Crude OR (95% CI)	P value
Male	5577 (29.9)	5577 (29.9)	–	–
Age, mean (SD)	47.7 (17.9)	47.5 (17.7)
Comorbidities
Heart failure	395 (2.1)	349 (1.9)	2.18 (1.49–3.18)	< 0.001
Ischemic heart disease	931 (5.0)	873 (4.7)	1.62 (1.25–2.10)	< 0.001
Stroke	530 (2.8)	498 (2.7)	1.62 (1.14–2.28)	0.007
GERD	762 (4.1)	671 (3.6)	1.65 (1.34–2.04)	< 0.001
Obesity	77 (0.4)	49 (0.3)	4.11 (1.98–8.52)	< 0.001
Rhinosinusitis	3393 (18.2)	3125 (16.8)	1.44 (1.30–1.60)	< 0.001
Obstructive sleep apnea	51 (0.3)	44 (0.2)	1.64 (0.77–3.46)	0.198
Psychiatric disorder
Anxiety	166 (0.9)	159 (0.9)	1.21 (0.76–1.92)	0.415
Bipolar disorder	154 (0.8)	146 (0.8)	1.62 (0.81–3.23)	0.174
Depression	747 (4.0)	741 (4.0)	1.08 (0.79–1.47)	0.633
Schizophrenia	148 (0.8)	136 (0.7)	5.00 (1.45–17.27)	0.011
Respiratory infection
Pneumonia	726 (3.9)	533 (2.9)	2.44 (2.00–2.98)	< 0.001
Acute upper airway infection	8308 (44.5)	7140 (38.3)	2.00 (1.86–2.14)	< 0.001
Medications
Cardiovascular drugs
Antiplatelet	1184 (6.4)	1019 (5.5)	1.52 (1.32–1.75)	< 0.001
Cardioselective β-blockers	716 (3.8)	660 (3.5)	1.24 (1.04–1.47)	0.015
Non-selective β-blockers	676 (3.6)	553 (3.0)	1.52 (1.29–1.78)	< 0.001
Statins	909 (4.9)	883 (4.7)	1.08 (0.93–1.25)	0.324
Anti-inflammation
Colchicine	138 (0.7)	147 (0.8)	0.90 (0.67–1.22)	0.492
NSAIDs	5175 (27.7)	3098 (16.6)	2.32 (2.19–2.47)	< 0.001
Metformin	753 (4.0)	721 (3.9)	1.15 (0.96–1.39)	0.133
Psychoactive drugs
Antidepressants	957 (5.1)	857 (4.6)	1.39 (1.19–1.64)	< 0.001
Lithium	16 (0.1)	13 (0.1)	2.00 (0.50–8.00)	0.327
Antipsychotics	713 (3.8)	601 (3.2)	1.48 (1.25–1.74)	< 0.001
Anticholinergic agents
Bladder	116 (0.6)	93 (0.5)	1.43 (1.01–2.04)	0.044
Gastrointestinal tract	1442 (7.7)	888 (4.8)	1.86 (1.69–2.05)	< 0.001
Parkinsonism	107 (0.6)	100 (0.5)	1.28 (0.76–2.16)	0.358
Antihistamine
First generation	3234 (17.3)	1817 (9.7)	2.26 (2.11–2.43)	< 0.001
Second/third generation	4372 (23.4)	2615 (14.0)	2.27 (2.13–2.42)	< 0.001
Inhaled bronchodilators
SABA	2615 (14.0)	1087 (5.8)	3.25 (2.98–3.54)	< 0.001
SAMA	305 (1.6)	60 (0.3)	6.56 (4.78–9.01)	< 0.001
SABA + SAMA	154 (0.8)	79 (0.4)	2.50 (1.80–3.47)	< 0.001
LABA	3 (0.02)	0 (0.0)	–	–
LAMA	37 (0.2)	30 (0.2)	1.44 (0.76–2.72)	0.265
LABA + ICS	1575 (8.4)	1217 (6.5)	1.55 (1.41–1.72)	< 0.001
LABA + LAMA + ICS	0 (0.0)	0 (0.0)	–	–
ICS	381 (2.0)	283 (1.5)	1.50 (1.25–1.80)	< 0.001
Oral bronchodilators
Xanthium	3844 (20.6)	1771 (9.5)	3.40 (3.15–3.66)	< 0.001
Leukotriene receptor antagonists	550 (3.0)	404 (2.2)	1.78 (1.49–2.12)	< 0.001

GERD: gastroesophageal reflux disease; ICS: inhaled corticosteroid, LABA: long-acting β-agonist; LAMA: long-acting muscarinic antagonist; NSAID: non-steroidal anti-inflammatory drug; OR: odds ratio; SABA: short-acting β-agonist; SAMA: short-acting muscarinic antagonist

Table 2. Risk of severe asthma exacerbation by different classes of antipsychotics and doses
Characteristics	No. (%)		Conditional logistic regression				P for trend
Characteristics	Case period (n = 18,657)	Control period (n = 18,657)	Crude OR (95% CI)	P value	Adjusted OR^a (95% CI)	P value	P for trend
No use of anti-psychotics	17,944 (96.18)	18,056 (96.78)	Ref		Ref
Any use of anti-psychotics	713 (3.82)	601 (3.22)	1.48 (1.25–1.74)	< 0.001	1.27 (1.05–1.53)	0.015
Antipsychotics class^b
Typical only	269 (1.44)	193 (1.03)	1.63 (1.31–2.04)	< 0.001	1.42 (1.10–1.82)	0.006
Atypical only	411 (2.20)	390 (2.09)	1.25 (0.98–1.59)	0.072	1.05 (0.80–1.38)	0.704
Both	33 (0.18)	18 (0.10)	3.03 (1.40–6.57)	0.005	2.34 (1.02–5.35)	0.045
Dose
Low (≤ 0.25 DDD)	604 (3.24)	504 (2.70)	1.47 (1.24–1.74)	< 0.001	1.25 (1.03–1.50)	0.023	0.038
Medium to high (> 0.25 DDD)	109 (3.24)	97 (0.52)	1.57 (1.11–2.21)	0.011	1.47 (1.00–2.15)	0.049
Dose (for typical only)
Low (≤ 0.25 DDD)	255 (1.37)	184 (0.99)	1.61 (1.28–2.02)	< 0.001	1.37 (1.06–1.75)	0.015	0.006
Medium to high (> 0.25 DDD)	14 (0.08)	9 (0.05)	2.85 (0.96–8.50)	0.060	4.58 (1.36–15.40)	0.014
Dose (for atypical only)
Low (≤ 0.25 DDD)	326 (1.75)	311 (1.67)	1.27 (0.99–1.63)	0.066	1.06 (0.80–1.41)	0.682	0.767
Medium to high (> 0.25 DDD)	85 (0.46)	79 (0.42)	1.36 (0.91–2.03)	0.134	1.18 (0.76–1.83)	0.468

DDD: defined daily dose; OR: odds ratio
^aAdjusted for heart failure, ischemic heart disease, stroke, gastroesophageal reflux disease, obesity disorder, rhinosinusitis, schizophrenia, depression, bipolar disorder, pneumonia, acute upper airway infection, antiplatelet agents, cardioselective β-blocker, non-selective β-blocker, NSAID, anti-psychotics, anti-depressants, bladder anticholinergic agents, gastrointestinal tract anticholinergic agents, first generation anti-histamine, second/third generation anti-histamine, short-acting beta-agonist, short-acting muscarinic antagonist, short-acting beta-agonist plus short-acting muscarinic antagonist, long-acting beta-agonist plus long-acting beta-agonist, long-acting beta-agonist, xanthine inhibitor, leukotriene receptor antagonist
^bSee Additional file 1: Table S1

Table 3. Risk of severe asthma exacerbation by different classes of antipsychotics and doses after excluding schizophrenia patients
Characteristics	No. (%)		Conditional logistic regression				P for trend
Characteristics	Case period	Control period	Crude OR (95% CI)	P value	Adjusted OR^a (95% CI)	P value	P for trend
No use of antipsychotics	17,900 (96.73)	18,008 (97.31)	Ref		Ref
Any use of antipsychotics	606 (3.3)	498 (2.7)	1.49 (1.26–1.77)	< 0.001	1.28 (1.06–1.57)	0.011
Antipsychotics class^b
Typical only	260 (1.40)	186 (1.01)	1.62 (1.29–2.03)	< 0.001	1.37 (1.07–1.76)	0.012
Atypical only	326 (1.76)	298 (1.61)	1.32 (1.01–1.71)	0.039	1.15 (0.86–1.54)	0.344
Both	20 (0.11)	14 (0.08)	1.87 (0.81–4.30)	0.142	1.60 (0.66–3.92)	0.300
Dose
Low (≤ 0.25 DDD)	535 (2.89)	441 (2.38)	1.48 (1.25–1.76)	< 0.001	1.27 (1.05–1.54)	0.016	0.005
Medium to high (> 0.25 DDD)	71 (0.38)	57 (0.31)	1.81 (1.17–2.78)	0.007	1.65 (1.03–2.62)	0.036
Dose (typical only)
Low (≤ 0.25 DDD)	249 (1.35)	181 (0.98)	1.60 (1.27–2.01)	< 0.001	1.37 (1.06–1.76)	0.015	0.004
Medium to high (> 0.25 DDD)	11 (0.06)	5 (0.03)	4.30 (1.15–16.15)	0.031	5.74 (1.33–24.67)	0.019
Dose (atypical only)
Low (≤ 0.25 DDD)	271 (1.46)	252 (1.36)	1.30 (0.99–1.70)	0.057	1.12 (0.83–1.52)	0.451	0.282
Medium to high (> 0.25 DDD)	55 (0.30)	46 (0.25)	1.51 (0.92–2.47)	0.107	1.33 (0.78–2.27)	0.301

DDD: defined daily dose, OR: odds ratio
^aAdjusted for heart failure, ischemic heart disease, stroke, gastroesophageal reflux disease, obesity disorder, rhinosinusitis, schizophrenia, depression, bipolar disorder, pneumonia, acute upper airway infection, antiplatelet agents, cardioselective β-blocker, non-selective β-blocker, NSAID, anti-psychotics, anti-depressants, bladder anticholinergic agents, gastrointestinal tract anticholinergic agents, first generation anti-histamine, second/third generation anti-histamine, short-acting beta-agonist, short-acting muscarinic antagonist, short-acting beta-agonist plus short-acting muscarinic antagonist, long-acting beta-agonist plus long-acting beta-agonist, long-acting beta-agonist, xanthine inhibitor, leukotriene receptor antagonist
^bSee Additional file 1: Table S1

Table 4. Risk of severe asthma exacerbation of antipsychotics with high blocking affinity of receptor
Characteristics	Number (%)		Conditional logistic regression			P value
Characteristics	Case period	Control period	Crude OR (95% CI)	P value	Adjusted OR^a (95% CI)	P value
No antipsychotics use	17,927	18,037	Ref		Ref
Antipsychotics with high blocking affinity^b,c
β2 adrenergic receptor	302 (1.7)	276 (1.5)	1.37 (0.98–1.92)	0.064	1.25 (0.87–1.81)	0.227
M2 muscarinic receptor	442 (2.4)	356 (1.9)	1.60 (1.29–1.99)	< 0.001	1.39 (1.10–1.76)	0.007
D1 dopaminergic receptor	391 (2.1)	357 (1.9)	1.34 (1.04–1.73)	0.025	1.17 (0.88–1.55)	0.283
D2 dopaminergic receptor	535 (2.9)	440 (2.4)	1.52 (1.26–1.84)	< 0.001	1.33 (1.08–1.63)	0.008

^aAdjusted for heart failure, ischemic heart disease, stroke, gastroesophageal reflux disease, obesity disorder, rhinosinusitis, schizophrenia, pneumonia, acute upper airway infection, antiplatelet agents, cardioselective β-blocker, non-selective β-blocker, NSAID, anti-psychotics, anti-depressants, bladder anticholinergic agents, gastrointestinal tract anticholinergic agents, first generation anti-histamine, second/third generation anti-histamine, short-acting beta-agonist, short-acting muscarinic antagonist, short-acting beta-agonist plus short-acting muscarinic antagonist, long-acting beta-agonist plus long-acting beta-agonist, long-acting beta-agonist, xanthine inhibitor, leukotriene receptor antagonist
^bHigh blocking affinity is defined as Ki value < 100 (see Additional file 1: Table S4)
^cAntipsychotics without Ki (inhibitory constant) value were excluded from analysis