High Use of Antidepressant Medication in Both Mild-to-Modelate and Possible Severe Asthma – A Nationwide Cohort Study

Figures & data

Table 1 Demographics, Prevalence of Antidepressant Use and Comorbidities in 60,534 Patients with Actively Treated Asthma and an Age- and Sex Matched Control Group in a Nationwide Cohort

Demographics & Comorbidities	Overall, N = 121,068	Controls, N = 60,534^1	Mild-to-Moderate Asthma, N = 57,059^1	Possible Severe Asthma, N = 3475^1	p-value^2
Age	38 (29, 43)	38 (29, 43)^3	37 (29, 43)	41 (34, 45)	<0.001
Female	66,112 (55%)	33,056 (55%)	31,144 (55%)	1912 (55%)	0.9
Secondary Care Asthma Management	10,694 (18%)^4	NA	9338 (16%)	1356 (39%)	<0.001
Antidepressant Use	15,854 (13%)	6190 (10%)	8887 (16%)	777 (22%)	<0.001
Charlson Score >1	752 (0.6%)	284 (0.5%)	411 (0.7%)	57 (1.6%)	<0.001
Any Malignancy	1362 (1.1%)	670 (1.1%)	645 (1.1%)	47 (1.1%)	0.4
Cerebrovascular Disease	715 (0.6%)	300 (0.5%)	377 (0.7%)	38 (1.1%)	<0.001
Dementia	7 (<0.1%)	3 (<0.1%)	4 (<0.1%)	0 (0%)	NA
Diabetes with Complications	317 (0.3%)	114 (0.2%)	175 (0.3%)	28 (0.8%)	<0.001
Diabetes without Complications	1240 (1.0%)	475 (0.8%)	688 (1.2%)	77 (2.2%)	<0.001
Heart Failure	187 (0.2%)	53 (<0.1%)	111 (0.2%)	23 (0.7%)	<0.001
Hemi/Tetraplegia	180 (0.1%)	72 (0.1%)	97 (0.2%)	11 (0.3%)	0.003
Leukaemia	32 (<0.1%)	13 (<0.1%)	18 (<0.1%)	1 (<0.1%)	NA
Lymphoma	103 (<0.1%)	49 (<0.1%)	50 (<0.1%)	4 (0.1%)	NA
Liver Disease, Mild	657 (0.5%)	257 (0.4%)	356 (0.6%)	44 (1.3%)	<0.001
Liver Disease, Severe	59 (<0.1%)	27 (<0.1%)	26 (<0.1%)	6 (0.2%)	NA
Myocardial Infarction	341 (0.3%)	135 (0.2%)	179 (0.3%)	27 (0.8%)	<0.001
Peptic Ulcer Disease	322 (0.3%)	120 (0.2%)	184 (0.3%)	18 (0.5%)	<0.001
Peripheral Vascular Disease	200 (0.2%)	89 (0.1%)	99 (0.2%)	12 (0.3%)	0.016
Renal Disease	245 (0.2%)	104 (0.2%)	125 (0.2%)	16 (0.5%)	<0.001
Rheumatic Disease	820 (0.7%)	313 (0.5%)	459 (0.8%)	48 (1.4%)	<0.001

Notes: ¹Statistics presented: n (%); median (IQR). ²Statistical tests performed: Kruskal–Wallis rank sum test; Pearson’s Chi-squared test. P-values correspond to tests across all three subpopulations Controls, Mild-to-Moderate Asthma and Possible Severe Asthma. ³P-value for Age < 0.9 between Controls and Asthma patients when not stratified by disease severity. ⁴Of patients with asthma only. ³Prevalence based on the asthma subpopulation (n=60,534).

Table 2 Pharmacologic Asthma Treatment and Disease Control Measurements in 60,534 Patients with Actively Treated Asthma in a Nationwide Cohort, Stratified by Antidepressant Use

	Overall, N = 60,534	No Antidepressant Use, N = 50,870^1	Antidepressant Users, N = 9664^1	p-value^2
Population				<0.001
Mild-to-moderate Asthma	57,059 (94%)	48,172 (95%)	8887 (92%)
Possible Severe Asthma	3475 (5.7%)	2698 (5.3%)	777 (8.0%)
GINA 2020 Step				<0.001
Step 1	25,497 (42%)	21,476 (42%)	4021 (42%)
Step 2	13,092 (22%)	11,089 (22%)	2003 (21%)
Step 3	13,411 (22%)	11,381 (22%)	2030 (21%)
Step 4	6005 (9.9%)	4939 (9.7%)	1066 (11%)
Step 5	2529 (4.2%)	1985 (3.9%)	544 (5.6%)
ICS Dose^3				<0.001
Below Low	25,497 (42%)	21,476 (42%)	4021 (42%)
Low	21,911 (36%)	18,590 (37%)	3321 (34%)
Moderate	9380 (15%)	7833 (15%)	1547 (16%)
High	3746 (6.2%)	2971 (5.8%)	775 (8.0%)
Add-on Therapies
Long-acting Beta-2-agonists (LABA)	23,302 (38%)	19,677 (39%)	3625 (38%)	0.030
Long-acting Antimuscarinics (LAMA)	1574 (2.6%)	1128 (2.2%)	446 (4.6%)	<0.001
Dual Long-acting Bronchodilators (LABA+LAMA)	1031 (1.7%)	760 (1.5%)	271 (2.8%)	<0.001
Leukotriene Receptor Antagonists	3530 (5.8%)	2950 (5.8%)	580 (6.0%)	0.4
Decongestants and Anti-allergic Drugs	6928 (11%)	5807 (11%)	1121 (12%)	0.6
Proton-pump Inhibitors	10,152 (17%)	6903 (14%)	3249 (34%)	<0.001
Annual SABA Doses	195 (60, 280)	175 (60, 267)	200 (100, 350)	<0.001
>600 Annual Doses	5762 (9.5%)	4503 (8.9%)	1259 (13%)	<0.001
Moderate Exacerbation(s)	4380 (7.2%)	3342 (6.6%)	1038 (11%)	<0.001
1 Exacerbation^4	2276 (52%)	1756 (53%)	520 (50%)	0.3
2 Exacerbations^4	956 (22%)	729 (22%)	227 (22%)
3 Exacerbations^4	519 (12%)	396 (12%)	123 (12%)
4+ Exacerbations^4	629 (14%)	461 (14%)	168 (16%)
Severe Exacerbation(s)	5819 (9.6%)	4455 (8.8%)	1364 (14%)	<0.001
1 Exacerbation^4	4076 (70%)	3173 (71%)	903 (66%)	<0.001
2 Exacerbations^4	1057 (18%)	805 (18%)	252 (18%)
3 Exacerbations^4	328 (5.6%)	236 (5.3%)	92 (6.7%)
4+ Exacerbations^4	358 (6.2%)	241 (5.4%)	117 (8.6%)

Notes: ¹Statistics presented: n (%); median (IQR). ²Statistical tests performed: chi-square test of independence; Wilcoxon rank sum test. ³Based on daily beclomethasone eq. exposure during the study period; below low < 200 daily mcg, low 200–599 daily mcg, moderate 600–1200 daily mcg, high >1200 mcg daily. ⁴During the study period.

Table 3 Multivariable Logistic Regression of Antidepressant Treatment in 60,534 Patients with Actively Treated Asthma and 60,534 Age- and Sex-Matched Controls

Logistic Regression	Bivariable			Multivariable
	OR^1	95% CI	p-value	OR^1	95% CI	p-value
Population
Background Population	1	—		1	—
Mild-to-Moderate Asthma	1.62	1.56, 1.68	<0.001	1.40	1.35, 1.46	<0.001
Possible Severe Asthma	2.53	2.32, 2.75	<0.001	1.55	1.41, 1.70	<0.001
Female				1.53	1.47, 1.59	<0.001
Age				1.03	1.03, 1.04	<0.001
Workforce Status
Employed				1	—
Transfer Income Recipient				3.96	3.76, 4.16	<0.001
Currently Under Education				1.34	1.23, 1.45	<0.001
Level of Education
Primary and Basic Education				1	—
Vocational Training				1.01	0.96, 1.06	0.8
Higher Education				0.84	0.80, 0.88	<0.001
Taxable Income Level
Low (1st Quartile)				1	—
Middle (2nd + 3rd Quartile)				1.01	0.96, 1.06	0.8
High (4th Quartile)				0.61	0.56, 0.65	<0.001
Civil Status
Married				1	—
Separated				1.61	1.52, 1.71	<0.001
Never Married				1.31	1.25, 1.37	<0.001
Metropolitan Residence
Use of decongestants and antiallergics				1.10	1.03, 1.17	0.007
PPI use				2.26	2.16, 2.36	<0.001
Charlson Score ≥2				1.26	1.06, 1.50	0.008

Abbreviations: ¹CI, confidence interval; OR, odds ratio; PPI, proton-pump inhibitor.

Table 4 Multivariable Logistic Regression for Odds of Antidepressant Treatment in 60,534 Patients with Actively Treated Asthma, Stratified by Asthma Severity and Adjusted for Specialist Asthma Care and Common Risk Factors

Logistic Regression
	OR^1	95% CI	p-value
Population
Mild-to-Moderate Asthma	1
Possible Severe Asthma	1.15	1.05, 1.26	0.004
Specialist Asthma Care	0.90	0.84, 0.96	<0.001
Female	1.52	1.44, 1.60	<0.001
Age	1.03	1.03, 1.04	<0.001
Workforce Status
Employed	1
Transfer Income Recipient	4.02	3.76, 4.30	<0.001
Currently Under Education	1.32	1.19, 1.47	<0.001
Level of Education
Primary and Basic Education	1
Vocational Training	1.04	0.97, 1.11	0.3
Higher Education	0.87	0.82, 0.93	<0.001
Taxable Income Level
Low (1st Quartile)	1
Middle (2nd + 3rd Quartile)	0.97	0.91, 1.04	0.5
High (4th Quartile)	0.58	0.53, 0.64	<0.001
Civil Status
Married	1
Separated	1.63	1.51, 1.76	<0.001
Never Married	1.34	1.26, 1.42	<0.001
Metropolitan Residence	0.87	0.82, 0.92	<0.001
Use of decongestants and antiallergics	1.03	0.96, 1.11	0.4
PPI use	2.12	2.00, 2.23	<0.001
Charlson Score ≥2	1.33	1.07, 1.64	0.008

Abbreviations: ¹CI, confidence interval; OR, odds ratio; PPI, proton-pump inhibitor.

Table 5 Multivariable Logistic Regression for Odds of Antidepressant Treatment in 60,534 Patients with Actively Treated Asthma, Using Three Different Measures of Asthma Control

	>600 Annual SABA Doses			≥2 Moderate Exacerbations^1			≥1 Severe Exacerbation(s)^2
	OR^3	95% CI	p-value	OR^1	95% CI	p-value	OR^1	95% CI	p-value
Asthma Control Measure^4	1.04	0.96, 1.12	0.3	1.11	0.99, 1.24	0.071	1.11	1.04, 1.20	0.004
Female	1.51	1.44, 1.59	<0.001	1.51	1.43, 1.59	<0.001	1.51	1.43, 1.58	<0.001
Age	1.03	1.03, 1.04	<0.001	1.03	1.03, 1.04	<0.001	1.03	1.03, 1.04	<0.001
Workforce Status
Employed	1			1			1
Transfer Income Recipient	4.01	3.76, 4.29	<0.001	4.01	3.75, 4.29	<0.001	4.00	3.74, 4.28	<0.001
Currently Under Education	1.32	1.19, 1.47	<0.001	1.32	1.19, 1.47	<0.001	1.32	1.19, 1.47	<0.001
Level of Education
Primary and Basic Education	1			1			1
Vocational Training	1.04	0.97, 1.11	0.3	1.04	0.97, 1.11	0.3	1.04	0.97, 1.11	0.2
Higher Education	0.87	0.82, 0.93	<0.001	0.87	0.82, 0.93	<0.001	0.87	0.82, 0.93	<0.001
Taxable Income Level
Low (1st Quartile)	1			1			1
Middle (2nd + 3rd Quartile)	0.97	0.91, 1.04	0.4	0.97	0.91, 1.04	0.4	0.97	0.91, 1.04	0.5
High (4th Quartile)	0.58	0.53, 0.64	<0.001	0.58	0.52, 0.64	<0.001	0.58	0.53, 0.64	<0.001
Civil Status
Married	1			1			1
Separated	1.63	1.51, 1.76	<0.001	1.63	1.51, 1.76	<0.001	1.63	1.51, 1.76	<0.001
Never Married	1.34	1.27, 1.42	<0.001	1.34	1.27, 1.43	<0.001	1.34	1.27, 1.43	<0.001
Metropolitan Residence	0.87	0.82, 0.92	<0.001	0.87	0.82, 0.92	<0.001	0.87	0.82, 0.92	<0.001
Use of decongestants and antiallergics	1.03	0.96, 1.11	0.4	1.03	0.96, 1.11	0.4	1.04	0.96, 1.12	0.4
PPI use	2.11	2.00, 2.23	<0.001	2.11	1.99, 2.23	<0.001	2.10	1.99, 2.22	<0.001
Charlson Score ≥2	1.32	1.07, 1.64	0.010	1.32	1.07, 1.63	0.010	1.30	1.05, 1.61	0.015

Notes: ¹Defined as at least two redeemed prescriptions for oral corticosteroids. ²Defined as at least one asthma-related hospitalization. ⁴As defined in table header.

Abbreviations: ³CI, confidence interval; OR, odds ratio; PPI, proton-pump inhibitor.