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. Author manuscript; available in PMC: 2022 Aug 1.
Published in final edited form as: Clin Pharmacol Ther. 2021 Mar 14;110(2):409–423. doi: 10.1002/cpt.2195

Table 2.

Antidepressant drug interaction signals, given statistically significantly increased rates of unintentional traumatic injury, by pharmacologic class of antidepressant, by therapeutic category of precipitant drug, by magnitude of association

Object drug (ASO rating) Precipitant drug Precipitant drug therapeutic category RR, semi-Bayes shrunk Lower bound of 95% CI Upper bound of 95% CI
5-hydroxytryptamine2 receptor antagonist
Nefazodone (4) meperidine*,**,*** CNS 2.94 1.41 6.12
quetiapine, 2.26 1.06 4.83
levonorgestrel Endocrine and metabolic 3.06 1.42 6.60
finasteride Renal and genitourinary 1.86 1.03 3.38
cetirizine Respiratory 1.55 1.07 2.25
Trazodone (3) cefaclor*** Anti-infective 1.96 1.01 3.81
hydroxychloroquine* Biologic and immunologic 1.38 1.06 1.80
hydralazine CV 1.40 1.06 1.85
indomethacin,*** CNS 1.45 1.05 2.00
nabumetone,*** 1.34 1.03 1.75
donepezil* 1.18 1.01 1.38
lorazepam* 1.15 1.03 1.29
desogestrel Endocrine and metabolic 1.75 1.16 2.64
liothyronine 1.53 1.06 2.21
risedronate 1.28 1.07 1.54
levothyroxine 1.15 1.06 1.26
sodium biphosphate* GI 1.78 1.04 3.06
metoclopramide 1.34 1.09 1.65
multivitamin with iron Nutrients and nutritional 2.02 1.12 3.64
spironolactone Renal and genitourinary 1.21 1.01 1.45
homatropine Respiratory 1.60 1.05 2.44
Dopamine reuptake blocking compound
Bupropion (1) nebivolol, CV 1.41 1.03 1.92
valsartan 1.23 1.05 1.43
atorvastatin 1.10 1.01 1.19
rizatriptan CNS 1.26 1.03 1.54
buspirone 1.23 1.04 1.45
pregabalin 1.23 1.01 1.49
cyclobenzaprine*** 1.21 1.10 1.32
glimepiride Endocrine and metabolic 1.37 1.05 1.79
glipizide 1.31 1.02 1.69
allopurinol 1.27 1.00 1.60
lubiprostone GI 1.70 1.24 2.34
metolazone Renal and genitourinary 1.76 1.08 2.89
silodosin 1.70 1.05 2.74
furosemide 1.21 1.07 1.36
sildenafil 1.17 1.00 1.36
cetirizine Respiratory 1.15 1.01 1.32
Noradrenergic antagonist
Mirtazapine (3) clarithromycin*** Anti-infective 1.94 1.21 3.09
trimethoprim*** 1.76 1.50 2.06
sulfamethoxazole*** 1.74 1.48 2.05
metronidazole 1.37 1.02 1.86
levofloxacin*** 1.34 1.13 1.60
rosuvastatin CV 1.57 1.13 2.16
amiodarone 1.32 1.00 1.74
caffeine CNS 1.89 1.27 2.80
butalbital*** 1.76 1.19 2.61
primidone 1.62 1.02 2.57
lamotrigine 1.60 1.19 2.14
pregabalin 1.60 1.20 2.12
alprazolam* 1.32 1.14 1.54
tramadol*,**,*** 1.23 1.10 1.38
lorazepam* 1.22 1.07 1.40
megestrol Endocrine and metabolic 1.24 1.04 1.49
rabeprazole GI 1.74 1.05 2.89
clopidogrel Hematological 1.37 1.16 1.60
tadalafil Renal and genitourinary 2.38 1.25 4.53
alfuzosin 2.06 1.12 3.77
solifenacin 1.43 1.01 2.03
spironolactone 1.35 1.04 1.76
hydrochlorothiazide 1.21 1.07 1.38
furosemide 1.12 1.01 1.23
Serotonin-norepinephrine reuptake inhibitors
Desvenlafaxine (0) erythromycin*** Anti-infective 2.08 1.04 4.14
fenofibrate CV 1.48 1.01 2.17
lisinopril 1.23 1.00 1.50
metaxalone*,*** CNS 1.53 1.07 2.18
methylprednisolone Endocrine and metabolic 1.44 1.02 2.03
Duloxetine (0) famciclovir Anti-infective 1.75 1.16 2.65
trimethoprim*** 1.25 1.09 1.43
sulfamethoxazole*** 1.24 1.07 1.43
levofloxacin*** 1.19 1.03 1.37
methotrexate Antineoplastic 1.35 1.09 1.68
hydroxychloroquine Biologic and immunologic 1.34 1.12 1.61
flurazepam CNS 2.54 1.35 4.79
valproic acid 1.82 1.10 3.03
tapentadol*,*** 1.64 1.06 2.54
metaxalone*,,*** 1.25 1.04 1.51
gabapentin 1.07 1.00 1.15
liothyronine Endocrine and metabolic 1.58 1.18 2.12
apixaban Hematological 2.62 1.62 4.26
multivitamin with minerals Nutrients and nutritional 1.91 1.14 3.19
multivitamin prenatal 1.59 1.06 2.39
levocetirizine Respiratory 1.38 1.07 1.79
Venlafaxine (0) proguanil Anti-infective 1.81 1.11 2.95
atovaquone 1.69 1.03 2.79
isosorbide dinitrate CV 1.58 1.02 2.44
ramipril 1.34 1.11 1.62
atorvastatin 1.09 1.01 1.17
oxymorphone*,*** CNS 1.67 1.04 2.66
valdecoxib,*** 1.55 1.18 2.06
chlordiazepoxide 1.41 1.02 1.93
etodolac,,*** 1.36 1.08 1.71
tizanidine*** 1.25 1.10 1.43
rizatriptan*,** 1.23 1.00 1.50
metaxalone*,**,*** 1.22 1.01 1.46
tramadol*,**,*** 1.11 1.02 1.22
ethynodiol Endocrine and metabolic 1.76 1.12 2.77
liothyronine 1.33 1.04 1.70
methylprednisolone 1.18 1.00 1.38
clidinium GI 1.51 1.04 2.19
methscopolamine 1.36 1.00 1.85
cholecalciferol Nutrients and nutritional 1.71 1.21 2.41
bumetanide Renal and genitourinary 1.59 1.14 2.22
metolazone 1.44 1.03 2.02
Selective serotonin reuptake inhibitors
Citalopram (0) mebendazole Anti-infective 2.45 1.15 5.20
ampicillin*** 1.61 1.06 2.43
amantadine 1.55 1.12 2.15
sulfamethoxazole*** 1.45 1.33 1.57
trimethoprim*** 1.43 1.32 1.55
losartan CV 1.09 1.00 1.18
valproic acid CNS 1.51 1.01 2.25
pramipexole 1.37 1.15 1.63
haloperidol*,** 1.34 1.06 1.69
modafinil 1.33 1.02 1.73
metaxalone*,,*** 1.25 1.04 1.49
lamotrigine 1.20 1.04 1.38
sumatriptan*,** 1.16 1.01 1.33
tramadol*,**,*** 1.11 1.05 1.18
codeine*,*** 1.11 1.01 1.23
cyclobenzaprine*,,*** 1.08 1.01 1.15
clonazepam 1.08 1.01 1.16
lorazepam 1.08 1.01 1.15
gabapentin 1.06 1.00 1.12
norgestrel Endocrine and metabolic 1.52 1.16 2.00
mesalamine GI 1.29 1.02 1.62
ticagrelor Hematological 2.25 1.35 3.74
prasugrel 1.50 1.02 2.20
multivitamin Nutrients and nutritional 1.36 1.02 1.80
omega-3 polyunsaturated fatty acid 1.25 1.01 1.54
metolazone Renal and genitourinary 1.45 1.21 1.74
bumetanide 1.36 1.11 1.68
Escitalopram (0) amantadine Anti-infective 1.70 1.22 2.37
sulfamethoxazole*** 1.21 1.09 1.34
trimethoprim*** 1.21 1.09 1.34
cyclosporine Biologic and immunologic 1.88 1.02 3.49
aliskiren CV 1.46 1.02 2.09
ranolazine* 1.41 1.00 1.99
terazosin 1.33 1.00 1.77
losartan 1.15 1.03 1.27
pramipexole CNS 1.30 1.07 1.58
aripiprazole* 1.24 1.07 1.43
carisoprodol*** 1.20 1.05 1.38
clonazepam 1.15 1.07 1.24
thyroid desiccated Endocrine and metabolic 1.20 1.01 1.43
glimepiride 1.19 1.01 1.40
rabeprazole GI 1.16 1.02 1.32
omeprazole*,** 1.07 1.01 1.14
dabigatran Hematological 1.56 1.01 2.39
fesoterodine Renal and genitourinary 1.46 1.02 2.09
tolterodine* 1.20 1.03 1.40
theophylline Respiratory 1.49 1.03 2.16
Fluoxetine (1) ampicillin*** Anti-infective 1.69 1.05 2.72
sulfamethoxazole*,*** 1.32 1.18 1.48
trimethoprim*,*** 1.32 1.18 1.47
nitrofurantoin 1.22 1.06 1.41
azilsartan CV 2.28 1.07 4.83
carvedilol 1.13 1.00 1.29
nabumetone,,*** CNS 1.25 1.05 1.50
divalproex sodium 1.24 1.06 1.45
carisoprodol*** 1.16 1.02 1.32
cyclobenzaprine*,**,*** 1.10 1.03 1.19
budesonide Endocrine and metabolic 1.73 1.04 2.89
desogestrel 1.25 1.02 1.53
levothyroxine 1.10 1.04 1.16
esomeprazole GI 1.14 1.04 1.25
cilostazol, Hematological 1.70 1.09 2.65
clopidogrel, 1.17 1.05 1.31
acetazolamide Renal and genitourinary 1.74 1.16 2.62
solifenacin* 1.20 1.00 1.44
Furosemide 1.08 1.01 1.16
Pseudoephedrine Respiratory 1.11 1.00 1.23
Fluvoxamine (1) Lisinopril CV 1.71 1.04 2.81
Ezetimibe 1.62 1.06 2.48
Benztropine CNS 2.26 1.09 4.67
buspirone** 1.52 1.08 2.14
esomeprazole GI 1.79 1.26 2.54
Paroxetine (3) quinine* Anti-infective 1.47 1.02 2.11
terbinafine** 1.33 1.04 1.69
sulfamethoxazole*** 1.22 1.07 1.38
trimethoprim*** 1.22 1.08 1.38
ciprofloxacin*** 1.16 1.03 1.30
Methotrexate Antineoplastic 1.33 1.02 1.72
propafenone* CV 1.98 1.15 3.40
Primidone CNS 1.41 1.05 1.88
prochlorperazine 1.38 1.02 1.87
Eszopiclone 1.24 1.00 1.53
Lorazepam 1.14 1.05 1.25
tramadol*,**,*** 1.09 1.00 1.19
Gabapentin 1.09 1.00 1.18
Hydrocortisone Endocrine and metabolic 1.73 1.13 2.64
Sitagliptin 1.25 1.01 1.54
Omeprazole GI 1.11 1.04 1.19
multivitamin with iron Nutrients and nutritional 1.61 1.01 2.58
Sertraline (0) Valganciclovir Anti-infective 2.44 1.20 4.98
sulfamethoxazole*** 1.50 1.38 1.63
trimethoprim*** 1.46 1.35 1.59
levofloxacin*,*** 1.12 1.02 1.23
Erlotinib Antineoplastic 2.37 1.19 4.74
mycophenolate mofetil Biologic and immunologic 1.50 1.06 2.12
nebivolol CV 1.39 1.14 1.68
Midodrine 1.33 1.02 1.74
dexmethylphenidate CNS 2.07 1.24 3.44
pyridostigmine 1.98 1.13 3.47
triazolam 1.51 1.09 2.11
chlordiazepoxide 1.32 1.00 1.74
haloperidol, 1.29 1.02 1.63
butalbital*** 1.23 1.06 1.43
Caffeine 1.22 1.05 1.42
Diazepam 1.13 1.01 1.26
Temazepam 1.13 1.00 1.28
tramadol,**,*** 1.10 1.03 1.16
alprazolam* 1.08 1.02 1.14
thyroid desiccated Endocrine and metabolic 1.21 1.03 1.41
Progesterone 1.20 1.03 1.40
Megestrol 1.18 1.01 1.39
dipyridamole Hematological 1.33 1.03 1.70
clopidogrel 1.13 1.05 1.22
omega-3 polyunsaturated fatty acid Nutrients and nutritional 1.40 1.16 1.68
Indapamide Renal and genitourinary 1.54 1.03 2.29
Mirabegron 1.48 1.12 1.97
Metolazone 1.39 1.15 1.69
Tricyclic and related antidepressants
Amitriptyline (9) sulfamethoxazole*,**,*** Anti-infective 1.28 1.11 1.47
trimethoprim*,**,*** 1.27 1.10 1.45
amiodarone** CV 1.76 1.36 2.27
Ramipril 1.52 1.13 2.03
isosorbide mononitrate 1.30 1.05 1.62
risperidone* CNS 1.52 1.07 2.16
Lamotrigine 1.49 1.11 2.00
Lorazepam 1.17 1.01 1.34
Pregabalin 1.17 1.03 1.34
Prednisone Endocrine and metabolic 1.13 1.02 1.26
levothyroxine** 1.09 1.00 1.18
Esomeprazole GI 1.12 1.00 1.26
Clopidogrel Hematological 1.15 1.02 1.31
potassium chloride Nutrients and nutritional 1.14 1.04 1.26
Darifenacin Renal and genitourinary 1.68 1.13 2.48
Metolazone 1.48 1.08 2.04
Desipramine (4) Atorvastatin CV 1.50 1.00 2.25
Methylprednisolone Endocrine and metabolic 1.93 1.04 3.60
Doxepin (9) sulfamethoxazole*,**,*** Anti-infective 1.43 1.04 1.96
trimethoprim*,**,*** 1.38 1.01 1.88
Memantine CNS 2.05 1.20 3.49
Diazepam 1.56 1.09 2.21
Pantoprazole GI 1.41 1.09 1.84
Imipramine (6) ondansetron*,** CNS 2.15 1.22 3.80
Omeprazole GI 1.39 1.05 1.85
Triamterene Renal and genitourinary 2.02 1.19 3.43
Nortriptyline (3) sulfamethoxazole*,**,*** Anti-infective 1.33 1.03 1.73
trimethoprim*,**,*** 1.33 1.03 1.73
ketoprofen,*** CNS 2.96 1.48 5.91
oxaprozin,*** 1.67 1.02 2.74
Glipizide Endocrine and metabolic 1.65 1.05 2.60
pioglitazone 1.65 1.07 2.53
estradiol*,** 1.50 1.08 2.07
omeprazole GI 1.19 1.03 1.39
multivitamin with iron Nutrients and nutritional 2.55 1.14 5.67
silodosin Renal and genitourinary 2.28 1.16 4.51

ASO = anticholinergic activity, sedation, and orthostasis; CV = cardiovascular; CNS = central nervous system; GI = gastrointestinal; RR = rate ratio

Rate ratios > 2.00 are bolded to highlight N = 22 potential signals that may warrant particular attention in future etiologic work.

Categorization of object drugs by severity of anticholinergic activity, sedation, and orthostasis: Within the Facts & Comparisons eAnswers central nervous system agents therapeutic category, we used the antidepressants monograph to categorize object drugs by severity of anticholinergic activity, sedation, and orthostasis. Our rationale for focusing on these adverse effects was their potential relationships with the unintentional traumatic injury outcomes being examined. For each antidepressant, we calculated a composite score by summing numeric severity ratings (0 = none or very low, 1 = low, 2 = moderate, 3 = high) for each of the three adverse effects. Therefore, each antidepressant was assigned a score of zero through nine, with a nine indicating a drug with high severity for anticholinergic activity, sedation, and orthostasis.

*

drug interaction with impact on object documented in Micromedex

**

drug interaction with impact on object documented in Facts & Comparisons eAnswers

***

finding may be particularly affected by protopathic bias

drug interaction with impact on precipitant documented in Micromedex

drug interaction with impact on precipitant documented in Facts & Comparisons eAnswers