Antidepressants and the risk of traumatic brain injury in the elderly: differences between individual agents

Figures & data

Table 1 Characteristics of cases of traumatic brain injury and matched controls

Demographics	Cases (n=16,750)		Controls (n=1,673,320)
	n	%	n	%	aORa	95% CIb
Sex
Women					–	–
Men					–	–
Age (years)
65–74	4,492	26.8	449,145	26.8	–	–
75–84	7,394	44.1	739,385	44.2	–	–
≥85	4,864	29.0	484,790	29.0	–	–
Median (25°; 75° percentile)	80	(74; 85)	80	(74; 85)	–	–
Comorbidities
Depressionc	8,929	53.3	795,843	47.6	1.01	(0.98–1.04)
Anxiety disordersc	1,964	11.7	194,354	11.6	0.90	(0.85–0.94)
Dementiac	5,562	33.2	305,519	18.3	1.75	(1.68–1.82)
Bipolar disordersc	213	1.3	11,447	0.7	1.26	(1.09–1.44)
Schizophreniac	223	1.3	12,158	0.7	1.14	(0.99–1.30)
Obsessive compulsive disordersc	49	0.3	4,425	0.3	0.97	(0.73–1.28)
Parkinson’s disease and movement disordersc	6,942	41.4	563,184	33.7	1.14	(1.10–1.18)
Deliriumc	488	2.9	14,732	0.9	1.51	(1.37–1.66)
Paind	15,616	93.2	1,557,928	93.1	0.97	(0.91–1.03)
Myocardial infarctiond	2,167	12.9	181,721	10.9	1.02	(0.97–1.08)
Other coronary heart diseased	8,679	51.8	805,955	48.2	1.00	(0.96–1.03)
Atrial fibrillationd	4,411	26.3	320,139	19.1	1.21	(1.16–1.26)
Other arrhythmias and conduction disordersd	8,312	49.6	770,645	46.1	1.00	(0.97–1.04)
Valvular disorders and endocarditisd	4,680	27.9	414,867	24.8	1.05	(1.01–1.09)
Pericardial disordersd	217	1.3	16,858	1.0	1.12	(0.98–1.28)
Myocarditisd	79	0.5	8,710	0.5	0.81	(0.65–1.01)
Peripheral vascular diseased	6,470	38.6	584,318	34.9	1.04	(1.00–1.07)
Hypertensiond	14,822	88.5	1,450,023	86.7	1.01	(0.95–1.06)
Chronic pulmonary diseased	8,326	49.7	830,544	49.6	0.92	(0.89–0.96)
Pulmonary circulation disordersd	1,294	7.7	97,524	5.8	1.11	(1.04–1.18)
Rheumatoid arthritis, other arthropathies and connective tissue disordersd	4,037	24.1	401,908	24.0	0.98	(0.95–1.02)
Liver insufficiencyd	4,574	27.3	415,310	24.8	1.01	(0.97–1.04)
Renal insufficiencyd	3,997	23.9	330,646	19.8	1.02	(0.98–1.06)
Cancerd,e	5,193	31.0	500,400	29.9	1.00	(0.97–1.04)
Diabetesd,f	6,580	39.3	592,384	35.4	1.00	(0.96–1.04)
Osteoporosis and other diseases of bone density and structured	6,681	39.9	642,462	38.4	0.97	(0.94–1.01)
Syncope and dizzinessd	9,622	57.4	786,652	47.0	1.38	(1.34–1.43)
Vision disordersd	13,729	82.0	1,361,833	81.4	1.04	(1.00–1.09)
Dyslipidemiad	10,845	64.7	1,085,092	64.8	0.94	(0.91–0.97)
Hip or pelvis fractured	2,944	17.6	217,973	13.0	0.95	(0.91–1.00)
Other fracturesd	5,907	35.3	425,188	25.4	1.38	(1.33–1.43)
Infectious diseasesg	6,642	39.7	622,183	37.2	0.97	(0.94–1.00)
Comedications
Insulind	1,570	9.4	118,763	7.1	0.98	(0.92–1.04)
Antidiabetic medicationsd	3,103	18.5	263,683	15.8	1.02	(0.97–1.07)
Antithrombotic medicationsd	10,913	65.2	917,133	54.8	1.14	(1.10–1.19)
Cardiac glycosidesd	2,774	16.6	203,054	12.1	1.09	(1.03–1.14)
Antiarrhythmic medicationsd	895	5.3	67,071	4.0	1.02	(0.95–1.10)
Other antihypertensive medicationsd	1,637	9.8	158,416	9.5	0.93	(0.88–0.98)
Diureticsd	10,424	62.2	921,438	55.1	1.02	(0.98–1.06)
Vasodilatorsd	5,964	35.6	572,529	34.2	0.94	(0.91–0.98)
β-Adrenergic agonistsd	10,895	65.0	1,031,895	61.7	0.96	(0.93–1.00)
Calcium antagonistsd	7,680	45.9	731,923	43.7	0.97	(0.93–1.00)
ACE inhibitorsd	10,932	65.3	1,015,792	60.7	1.03	(0.99–1.07)
Angiotensin II antagonistsd	5,017	30.0	500,072	29.9	0.99	(0.95–1.02)
Lipid-lowering medicationsd	7,741	46.2	719,184	43.0	1.02	(0.99–1.06)
Hormone therapyd	4,429	26.4	456,466	27.3	0.98	(0.94–1.02)
Glucocorticoidsd	6,189	36.9	619,758	37.0	0.97	(0.94–1.00)
Antiparkinson medicationsd	2,740	16.4	211,964	12.7	1.03	(0.99–1.08)
Respiratory medicationsd	5,033	30.0	505,948	30.2	0.94	(0.90–0.98)
Nonsteroidal anti-inflammatory medicationsd	14,232	85.0	1,409,458	84.2	1.04	(0.99–1.09)
Antipsychoticsg	5,880	35.1	422,562	25.3	1.06	(1.02–1.10)
Antiepilepticsg	1,954	11.7	143,021	8.5	1.07	(1.01–1.12)
Anxiolyticsg	2,059	12.3	171,987	10.3	1.03	(0.98–1.08)
Hypnotics and sedativesg	1,980	11.8	155,927	9.3	1.07	(1.02–1.13)
Muscle relaxantsg	466	2.8	51,331	3.1	0.81	(0.74–0.89)
Indicators of lifestyle habits
Alcohol abuse	1,179	7.0	55,294	3.3	1.78	(1.67–1.90)
Illicit drug use	625	3.7	50,116	3.0	0.96	(0.89–1.04)
Obesity	3,886	23.2	376,683	22.5	0.93	(0.90–0.97)
Smoking	792	4.7	69,861	4.2	0.95	(0.88–1.02)
Indicators of health status, frailty and use of health care
Charlson Comorbidity Index >2d,h	11,920	71.2	1,045,988	62.5	1.12	(1.07–1.17)
Number of medicationsh,i
1–4	5,296	31.6	697,888	41.7	1.10	(0.98–1.23)
5–8	7,229	43.2	666,923	39.9	1.25	(1.11–1.41)
9 and more	3,888	23.2	248,109	14.8	1.46	(1.28–1.66)
Nursing home residencec,h	1,390	8.3	67,039	4.0	1.12	(1.05–1.19)
Hospitalized time >5%c,h	4,544	27.1	224,770	13.4	1.72	(1.65–1.79)

Notes:

a Model adjusted for myocardial infarction, other coronary heart disease, atrial fibrillation, other cardiac arrhythmias and conduction disorders, valvular disorders and endocarditis, pericardial disorders, myocarditis, peripheral vascular disease, hypertension, dementia, chronic pulmonary disease, pulmonary circulation disorders, rheumatic arthritis/collagen vascular disease, liver disease, Parkinson’s disease, other extrapyramidal and movement disorders, depression, diabetes, renal failure, cancer (except malignant neoplasm of the skin), obesity, alcohol abuse, drug abuse, osteoporosis and other disorders of bone density and structure, syncope, dizziness and tendency to fall, vision disorders, dyslipidemia, bipolar disorders, schizophrenia, smoking, anxiety disorders, obsessive compulsive disorders, other movement disorders, pain, infectious diseases, delirium, use of insulin, antidiabetic medications, antithrombotic medications, cardiac glycosides, antiarrhythmic medications, other antihypertensive medications, diuretics, vasodilators, β-adrenergic agonists, calcium antagonists, ACE inhibitors, angiotensin II antagonists, lipid-lowering medications, hormone therapy, glucocorticoids, antiparkinson medications, respiratory medications, nonsteroidal anti-inflammatory medications, antipsychotics, antiepileptic medications, anxiolytics, hypnotics and sedatives, muscle relaxants, number of medications (1–4, 5–8, 9 and more), hospitalized time (≤5%, >5%), Charlson Comorbidity Index (≤2, >2) and nursing home residence.

b 95% CI.

c Assessed within 365 days before the index date and at the index date.

d Assessed any time before the index date.

e Except malignant neoplasm of the skin.

f Includes both type 1 and type 2 diabetes.

g Assessed within 181 days before and at the index date.

h Cutoffs were defined as follows: for Charlson Comorbidity Index the first tertile among controls, for number of medications prior studies, for hospitalized time the first decile among controls.

i Medication of different therapeutic classes.

Abbreviations: ACE, angiotensin converting enzyme; aOR, adjusted OR.

Table 2 OR with 95% CI of traumatic brain injury in current, recent and past users of ADs compared with remote users of any AD

	Cases (n=16,750)		Controls (n=1,673,320)		Matched ORa (95% CI)	Adjusted ORb (95% CI)
	n	%	n	%
Remote use of any ADc	8,432	50.3	1,004,327	60.0	1.00 (–)	1.00 (–)
TCA
Current use	1,620	9.7	172,230	10.3	1.30 (1.23–1.38)	1.22 (1.15–1.29)
Recent use	394	2.4	48,554	2.9	1.14 (1.03–1.26)	1.11 (1.00–1.23)
Past use	422	2.5	60,234	3.6	0.97 (0.88–1.08)	0.98 (0.88–1.08)
SSRI
Current use	3,735	22.3	205,603	12.3	2.52 (2.41–2.62)	1.86 (1.78–1.94)
Recent use	104	0.6	9,101	0.5	1.59 (1.31–1.94)	1.27 (1.05–1.55)
Past use	158	0.9	14,429	0.9	1.51 (1.29–1.77)	1.23 (1.04–1.44)
NASSA
Current use	1,273	7.6	115,607	6.9	1.53 (1.44–1.63)	1.12 (1.05–1.20)
Recent use	104	0.6	9,875	0.6	1.48 (1.22–1.80)	1.22 (1.01–1.49)
Past use	131	0.8	13,266	0.8	1.37 (1.15–1.63)	1.15 (0.96–1.37)
SSNRI
Current use	575	3.4	31,335	1.9	2.48 (2.27–2.70)	1.84 (1.68–2.01)
Recent use	24	0.1	2,110	0.1	1.58 (1.06–2.37)	1.27 (0.85–1.90)
Past use	26	0.2	2,956	0.2	1.21 (0.82–1.78)	0.97 (0.66–1.43)
MAO
Current use	13	0.1	1,734	0.1	1.04 (0.60–1.79)	0.80 (0.46–1.38)
Recent use	3	<0.1	107	<0.1	3.95 (1.26–12.37)	3.27 (1.03–10.37)
Past use	2	<0.1	167	<0.1	1.66 (0.41–6.70)	1.35 (0.33–5.46)
NARI
Current use	19	0.1	1,207	0.1	2.20 (1.40–3.47)	1.55 (0.98–2.45)
Recent use	2	<0.1	138	<0.1	2.04 (0.50–8.22)	1.31 (0.32–5.32)
Past use	1	<0.1	188	<0.1	0.74 (0.10–5.29)	0.55 (0.08–3.96)
Other Ads
Current use	77	0.5	5,153	0.3	2.05 (1.63–2.57)	1.45 (1.15–1.82)
Recent use	8	<0.1	716	<0.1	1.57 (0.78–3.14)	1.07 (0.53–2.16)
Past use	13	0.1	918	0.1	1.94 (1.12–3.36)	1.4 (0.81–2.42)
Multiple AD
Current use	1,005	6.0	52,313	3.1	2.58 (2.42–2.76)	1.69 (1.56–1.83)
Recent use	7	<0.1	603	<0.1	1.59 (0.75–3.35)	1.17 (0.55–2.47)
Past use	16	0.1	1,462	0.1	1.49 (0.91–2.43)	1.19 (0.73–1.96)
Current switchersd	556	3.3	28,675	1.7	1.97 (1.81–2.15)	1.08 (0.98–1.19)

Notes:

a Adjusted for age, sex and length of follow-up by matching.

b Model adjusted for myocardial infarction, other coronary heart disease, atrial fibrillation, other cardiac arrhythmias and conduction disorders, valvular disorders and endocarditis, pericardial disorders, myocarditis, peripheral vascular disease, hypertension, dementia, chronic pulmonary disease, pulmonary circulation disorders, rheumatic arthritis/collagen vascular disease, liver disease, Parkinson’s disease, other extrapyramidal and movement disorders, depression, diabetes, renal failure, cancer (except malignant neoplasm of the skin), obesity, alcohol abuse, drug abuse, osteoporosis and other disorders of bone density and structure, syncope, dizziness and tendency to fall, vision disorders, dyslipidemia, bipolar disorders, schizophrenia, smoking, anxiety disorders, obsessive compulsive disorders, other movement disorders, pain, infectious diseases, delirium, use of insulin, antidiabetic medications, antithrombotic medications, cardiac glycosides, antiarrhythmic medications, other antihypertensive medications, diuretics, vasodilators, β-adrenergic agonists, calcium antagonists, ACE inhibitors, angiotensin II antagonists, lipid-lowering medications, hormone therapy, glucocorticoids, antiparkinson medications, respiratory medications, nonsteroidal anti-inflammatory medications, antipsychotics, antiepileptic medications, anxiolytics, hypnotics and sedatives, muscle relaxants, number of medications (1–4, 5–8, 9 and more), hospitalized time (≤5%, >5%), Charlson Comorbidity Index (≤2, >2), nursing home residence.

c Reference category.

d Current switching: current use of one AD class with recent use of a different AD class.

Abbreviations: ACE, angiotensin converting enzyme; AD, antidepressant; MAO, monoamine oxidase inhibitor; NARI, noradrenaline reuptake inhibitor; NASSA, noradrenergic and specific serotonergic antidepressant; SSNRI, selective serotonin–noradrenaline reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic.

Table 3 OR with 95% CI of traumatic brain injury in current, recent and past users of individual AD compared with remote users of the same individual AD or with remote users of any AD

		Cases (n=16,750)		Controls (n=1,673,320)		Reference category: remote users
						Of the same individual AD		Of any AD
						Matched ORa (95% CI)	Adjusted ORb (95% CI)	Adjusted ORb (95% CI)
		n	%	n	%
Remote use of any ADc		8,432	50.3	1,004,327	60.0	–	–	1.00 (–)
TCA
	Doxepin
	Current use	213	1.3	26,413	1.6	1.10 (0.95–1.27)	1.05 (0.90–1.23)	0.71 (0.58–0.86)
	Recent use	80	0.5	9,925	0.6	1.11 (0.89–1.38)	1.11 (0.88–1.40)	0.84 (0.56–1.26)
	Past use	96	0.6	11,495	0.7	1.2 (0.90–1.36)	1.18 (0.95–1.46)	0.89 (0.61–1.31)
	Remote used	892	5.3	119,746	7.2	1.00 (−)	1.00 (−)	–
	Amitriptyline
	Current use	754	4.5	69,046	4.1	1.55 (1.43–1.69)	1.45 (1.32–1.58)	1.34 (1.24–1.44)
	Recent use	163	1.0	16,743	1.0	1.39 (1.18–1.63)	1.38 (1.17–1.62)	1.27 (1.09–1.49)
	Past use	157	0.9	20,452	1.2	1.09 (0.93–1.29)	1.09 (0.92–1.29)	1.01 (0.86–1.19)
	Remote used	1,792	10.7	251,065	15.0	1.00 (−)	1.00 (−)	–
	Opipramol
	Current use	371	2.2	49,797	3.0	1.09 (0.97–1.23)	1.11 (0.99–1.25)	1.03 (0.93–1.15)
	Recent use	73	0.4	11,178	0.7	0.96 (0.76–1.21)	1.02 (0.81–1.30)	0.95 (0.75–1.20)
	Past use	80	0.5	14,716	0.9	0.8 (0.63–1.00)	0.85 (0.68–1.07)	0.79 (0.64–0.99)
	Remote used	1,461	8.7	212,541	12.7	1.00 (−)	1.00 (−)	–
	Trimipramine
	Current use	172	1.0	19,928	1.2	1.16 (0.98–1.37)	1.17 (0.99–1.38)	1.14 (0.98–1.33)
	Recent use	58	0.3	8,836	0.5	0.88 (0.67–1.15)	0.92 (0.70–1.21)	0.91 (0.70–1.18)
	Past use	73	0.4	11,585	0.7	0.85 (0.66–1.08)	0.90 (0.70–1.14)	0.88 (0.70–1.11)
	Remote used	803	4.8	107,497	6.4	1.00 (−)	1.00 (−)	–
SSRI
	Sertraline
	Current use	422	2.5	23,195	1.4	1.88 (1.59–2.22)	1.66 (1.40–1.97)	1.80 (1.63–2.00)
	Recent use	4	<0.1	816	<0.1	0.51 (0.19–1.37)	0.51 (0.19–1.37)	0.55 (0.21–1.48)
	Past use	13	0.1	1,323	0.1	1.01 (0.58–1.78)	1.00 (0.57–1.75)	1.08 (0.63–1.88)
	Remote used	217	1.3	22,339	1.3	1.00 (−)	1.00 (−)	–
	Citalopram
	Current use	2,807	16.8	150,836	9	2.0 (1.87–2.14)	1.70 (1.58–1.83)	1.87 (1.78–1.96)
	Recent use	83	0.5	6,730	0.4	1.33 (1.06–1.66)	1.21 (0.96–1.52)	1.33 (1.07–1.66)
	Past use	123	0.7	10,719	0.6	1.23 (1.02–1.48)	1.14 (0.95–1.38)	1.26 (1.05–1.51)
	Remote used	1,352	8.1	141,697	8.5	1.00 (−)	1.00 (−)	–
	Paroxetine
	Current use	116	0.7	8,836	0.5	1.61 (1.23–2.10)	1.57 (1.20–2.06)	1.56 (1.30–1.88)
	Recent use	4	<0.1	484	<0.1	1.01 (0.37–2.77)	1.07 (0.39–2.93)	1.07 (0.40–2.87)
	Past use	6	<0.1	661	<0.1	1.11 (0.49–2.55)	1.13 (0.49–2.59)	1.13 (0.50–2.52)
	Remote used	104	0.6	12,751	0.8	1.00 (−)	1.00 (−)	–
	Fluoxetine
	Current use	98	0.6	7,145	0.4	1.70 (1.29–2.23)	1.64 (1.24–2.15)	1.59 (1.30–1.94)
	Recent use	7	<0.1	414	<0.1	2.10 (0.97–4.53)	2.18 (1.01–4.73)	2.12 (1.00–4.49)
	Past use	6	<0.1	686	<0.1	1.08 (0.47–2.47)	1.11 (0.49–2.55)	1.09 (0.49–2.43)
	Remote used	114	0.7	14,100	0.8	1.00 (−)	1.00 (−)	–
	Escitalopram
	Current use	213	1.3	12,071	0.7	1.92 (1.57–2.36)	1.74 (1.41–2.15)	1.76 (1.53–2.03)
	Recent use	6	<0.1	609	<0.1	1.07 (0.47–2.44)	1.07 (0.47–2.44)	1.09 (0.48–2.43)
	Past use	9	0.1	950	0.1	1.03 (0.53–2.02)	1.01 (0.51–1.99)	1.03 (0.53–1.99)
	Remote used	168	1.0	18,234	1.1	1.00 (−)	1.00 (−)	–
NASSA
	Mirtazapine
	Current use	1,262	7.5	114,605	6.8	1.22 (1.13–1.32)	1.03 (0.94–1.12)	1.11 (1.04–1.18)
	Recent use	102	0.6	9,606	0.6	1.18 (0.96–1.45)	1.12 (0.91–1.38)	1.22 (1.00–1.48)
	Past use	128	0.8	12,944	0.8	1.10 (0.91–1.32)	1.05 (0.87–1.26)	1.13 (0.95–1.35)
	Remote used	1,351	8.1	149,402	8.9	1.00 (−)	1.00 (−)
SSNRI
	Duloxetine
	Current use	267	1.6	14,857	0.9	2.14 (1.79–2.55)	1.87 (1.56–2.24)	1.81 (1.59–2.05)
	Recent use	11	0.1	1,170	0.1	1.12 (0.61–2.06)	1.12 (0.61–2.06)	1.08 (0.60–1.97)
	Past use	17	0.1	1,726	0.1	1.17 (0.71–1.92)	1.12 (0.68–1.85)	1.09 (0.67–1.76)
	Remote used	237	1.4	28,123	1.7	1.00 (–)	1.00 (–)	–
	Venlafaxine
	Current use	302	1.8	16,335	1.0	2.01 (1.66–2.42)	1.76 (1.45–2.15)	1.81 (1.61–2.04)
	Recent use	13	0.1	939	0.1	1.5 (0.85–2.65)	1.41 (0.80–2.50)	1.45 (0.84–2.51)
	Past use	9	0.1	1,222	0.1	0.8 (0.41–1.57)	0.76 (0.39–1.50)	0.78 (0.41–1.51)
	Remote used	171	1.0	18,576	1.1	1.00 (−)	1.00 (−)	–

Notes:

a Adjusted for age, sex and length of follow-up by matching.

b Model adjusted for myocardial infarction, other coronary heart disease, atrial fibrillation, other cardiac arrhythmias and conduction disorders, valvular disorders and endocarditis, pericardial disorders, myocarditis, peripheral vascular disease, hypertension, dementia, chronic pulmonary disease, pulmonary circulation disorders, rheumatic arthritis/collagen vascular disease, liver disease, Parkinson’s disease, other extrapyramidal and movement disorders, depression, diabetes, renal failure, cancer (except malignant neoplasm of the skin), obesity, alcohol abuse, drug abuse, osteoporosis and other disorders of bone density and structure, syncope, dizziness and tendency to fall, vision disorders, dyslipidemia, bipolar disorders, schizophrenia, smoking, anxiety disorders, obsessive compulsive disorders, other movement disorders, pain, infectious diseases, delirium, use of insulin, antidiabetic medications, antithrombotic medications, cardiac glycosides, antiarrhythmic medications, other antihypertensive medications, diuretics, vasodilators, β-adrenergic agonists, calcium antagonists, ACE inhibitors, angiotensin II antagonists, lipid-lowering medications, hormone therapy, glucocorticoids, antiparkinson medications, respiratory medications, nonsteroidal anti-inflammatory medications, antipsychotics, antiepileptic medications, anxiolytics, hypnotics and sedatives, muscle relaxants, number of medications (1–4, 5–8, 9 and more), hospitalized time (≤5%, >5%), Charlson Comorbidity Index (≤2, >2), nursing home residence.

c Reference category remote users of any AD.

d Reference category remote users of the same AD.

Abbreviations: ACE, angiotensin converting enzyme; AD, antidepressant; MAO, monoamine oxidase inhibitor; NARI, noradrenaline reuptake inhibitor; NASSA, noradrenergic and specific serotonergic antidepressant; SSNRI, selective serotonin–noradrenaline reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic.

Figure 1 aOR with 95% CI of traumatic brain injury in users of antidepressants compared with remote users of any AD, by diagnosed dementia.

Abbreviations: AD, antidepressant; aOR, adjusted OR; NASSA, noradrenergic and specific serotonergic antidepressant; SSNRI, selective serotonin–noradrenaline reuptake inhibitor; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic.