
==== Front
Drugs Real World Outcomes
Drugs Real World Outcomes
Drugs - Real World Outcomes
2199-1154
2198-9788
Springer International Publishing Cham

38837010
419
10.1007/s40801-024-00419-0
Original Research Article
The Association Between Antidepressant Use and Drug-Induced Liver Injury: A Nationwide, Population-Based Case–Control Study in Taiwan
Huang Ching-Ya 12
http://orcid.org/0009-0001-7802-6097
You Ying-Shu 34
Lai Jian-Ming 3
Lin Cheng-Li 5
http://orcid.org/0000-0003-4424-9476
Hsu Hsing-Yu 3
http://orcid.org/0000-0002-0523-3482
Hsieh Yow-Wen yowenhsieh@gmail.com

23
1 https://ror.org/038a1tp19 grid.252470.6 0000 0000 9263 9645 Department of Pharmacy, Asia University Hospital, Taichung, Taiwan
2 https://ror.org/032d4f246 grid.412449.e 0000 0000 9678 1884 School of Pharmacy, China Medical University, Taichung, Taiwan
3 https://ror.org/0368s4g32 grid.411508.9 0000 0004 0572 9415 Department of Pharmacy, China Medical University Hospital, 2 Yuh-Der Road, Taichung, 404327 Taiwan
4 https://ror.org/05bqach95 grid.19188.39 0000 0004 0546 0241 Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
5 https://ror.org/0368s4g32 grid.411508.9 0000 0004 0572 9415 Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
5 6 2024
5 6 2024
9 2024
11 3 513520
25 2 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by-nc/4.0/ Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
Background and Objective

The complex risk factors of liver injury have prevented the establishment of causal relationships. This study aimed to explore the effects of antidepressant class, cumulative days of medication exposure, presence of comorbidities, and the use of confounding drugs on the risk of antidepressant-induced liver injury.

Methods

The population-based case–control study sample included individuals registered on the Taiwan National Health Insurance Database between 2000 and 2018. Hospitalized patients with suspected drug-induced liver injury were considered as cases, while control subjects were matched 1:1 by age, gender, and index date (the first observed diagnosis of liver injury). Multivariable regression models were performed to evaluate the association between antidepressants and liver injury.

Results

The findings showed that antidepressant users exhibited a higher risk of liver injury (adjusted odds ratio [aOR] 1.16, 95% confidence interval [CI] 1.12–1.20), particularly those prescribed non-selective serotonin reuptake inhibitors (NSRIs; aOR 1.05; 95% CI 1.01–1.10), selective serotonin reuptake inhibitors (SSRIs; aOR 1.22; 95% CI 1.16–1.29), serotonin-norepinephrine reuptake inhibitors (SNRIs; aOR 1.18; 95% CI 1.13–1.24), and others (aOR 1.27; 95% CI 1.14–1.42). Moreover, cases exhibited a more significant proportion of antidepressant usage and longer durations of treatment compared with controls. The risk of liver injury was higher in the first 30 days of use across all classes of antidepressants (aOR 1.24; 95% CI 1.18–1.29).

Conclusion

SSRIs or SNRIs are commonly used to treat depression and other psychological disorders, and consideration of their potential effects on the liver is essential.

Taiwan Ministry of Health and Welfare Clinical Trial CenterMOHW110-TDU-B-212-124004 issue-copyright-statement© Springer Nature Switzerland AG 2024
==== Body
pmcKey Points

This population-based study revealed an increased risk of liver injury among individuals using antidepressants, notably selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and other non-selective serotonin reuptake inhibitors (NSRIs).	
A 1.24-fold higher risk of liver injury was linked to early stages of antidepressant use, emphasizing the need for cautious monitoring during the initial 30 days.	
Understanding the heightened risk of liver injury associated with commonly prescribed antidepressants like SSRIs and SNRIs underscores the importance of considering potential hepatic effects in patient care strategies.	

Introduction

Drug-induced liver injury (DILI) is a relatively rare occurrence, with an incidence rate ranging from 1 per 10,000 to 100,000 individuals [1]. A recent study in France reported that DILI had an incidence rate of approximately 14 per 100,000 person-years, of whom 12% required hospitalization and 6% died [2]. Despite this, there is limited evidence extrapolating the overall incidence of DILI to Taiwan. Prospective studies conducted in Taiwan reported an incidence of 768 cases per 100,000 person-years for statin-induced DILI [3], as well as an incidence of 31.6 cases per 10,000 persons for antifungal agent-induced DILI, exemplified by fluconazole [4]. Given the high prevalence of hepatitis in Taiwan and the clinical presentation similarities with DILI, accurate diagnosis is often complicated, suggesting that reported incidence rates might underestimate the true prevalence.

The risk factors for DILI include age, gender, presence of comorbidities, drug interactions, and drug dosage [5]. Evidence suggests that age can increase sensitivity to and limit the metabolism of hepatotoxic drugs in humans [6], with drug efficacy and metabolism rates significantly differing in children and elderly individuals compared with adults [7]. One study found that females exhibited a higher risk of adverse drug reactions, potentially due to differences in metabolism rates and medication dosage between genders [6], although this was contradicted by another study that reported observing the opposite results [8]. Drug interactions and the presence of comorbidities can also increase the risk of DILI, with Bell and Chalasani demonstrating that patients diagnosed with hepatitis types B and C and human immunodeficiency virus (HIV) exhibited an increased risk of being diagnosed with DILI [9]. Concurrent use of other hepatotoxic drugs was also identified as a risk factor for DILI [10].

In Japan, 60% of DILI occurs within 30 days of commencing medication usage, while 80% occurs within 90 days of commencing usage [11]. Several other studies have also shown that acute DILI may develop within 1–3 months of commencing medication usage [12–14]. Some studies have shown that approximately 1.28–4 patients per 100,000 patient-years require hospitalization for antidepressant-induced liver injury (AILI). In particular, the incidence rates of AILI associated with nefazodone and tricyclic/tetracyclic antidepressant usage are approximately 28.96 and 4 patients per 100,000 patient-years, respectively [15–18]. Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) have also been shown to lead to asymptomatic mildly abnormal liver function in approximately 0.5–1% of patients, while monoamine oxidase inhibitors (MAOIs) usage resulted in AILI in approximately 3% of patients [17]. However, diagnosis of AILI is challenging as it is primarily based on exclusion, suggesting that the incidence rates may be underestimated [18].

DILI primarily has two pathophysiological types, as follows: (1) idiosyncratic: dose-independent, unpredictable, occurs as a consequence of either immune-mediated liver damage (immuno-allergic idiosyncratic DILI) or direct cellular injury (metabolic idiosyncratic DILI); and (2) intrinsic: dose-dependent, predictable, occurs as a consequence of drug accumulation [17]. Most pathophysiological types of AILI are either immune-allergic or metabolic idiosyncratic DILI, with the majority being of the hepatocellular type and fewer being the cholestatic or mixed types. Moreover, acute hepatocellular injury and jaundice have a mortality rate of approximately 10% [17]. Although there are reports of hepatotoxicity linked to adverse reactions from antidepressants, extensive studies conducted in Taiwan exclusively centered around the occurrence of liver cancer, reporting a low incidence and mortality rate [19, 20]. This contrasts with other research exploring the mechanisms of liver injury, revealing a notable research gap concerning the impact of diverse antidepressant drug treatments and their dose–response relationships on the risk of hepatotoxicity.

Therefore, this nationwide population-based study aims to assess the risk of AILI associated with different pharmacological classifications and the duration of antidepressant use. The investigation relies on data from the Taiwan National Health Insurance Database from 2000 to 2018.

Methods

Data Sources

This population-based, case–control study used the Taiwan National Health Insurance (NHI) database, which was established in 1995 and covers more than 99.6% of the Taiwanese population. The National Health Insurance Research Database (NHIRD) contains claims data (e.g., registry of beneficiaries, clinical and hospital care records, drug prescriptions, and other medical service records) from the NHI database and is reviewed annually. Additionally, data from the Longitudinal Generation Tracking Database (LGTD 2005), which contains approximately two million individuals randomly selected from the NHIRD, was also used. The clinics and hospitals recorded diagnoses using the International Classification of Diseases, Ninth and Tenth Revision, and Clinical Modification (ICD-9-CM and ICD-10-CM). Patient confidentiality was protected through data pseudonymization (wherein all original identification numbers were replaced with encoded serial numbers to enable linkage to claims data) implemented by the Taiwanese government prior to the release of data for research.

Study Population

The study population included individuals aged 20 years or over who did not have any history of relevant code from ICD-9-CM [21] of malignant neoplasms (140–239); viral hepatitis A, B, or C infections, other viral hepatitis infections (070.0–070.9), or carriers of the hepatitis virus (V026.1–V026.9); infectious mononucleosis and cytomegalovirus and coxsackie virus infections (573.1–573.2); cholelithiasis (574.0–574.9); chronic liver disease; cirrhosis; alcoholic liver disease; liver abscess; portal pyemia; hepatic coma; portal hypertension; hepatorenal syndrome; chronic passive congestion of the liver (571.0–573.0); and liver disorders during pregnancy (646.7) between January 1, 2000 and December 31, 2018.

Cases were patients hospitalized with the diagnosis code of suspected DILI during the study period based on the ICD-9-CM, ICD-10-CM, and the previous study, including disorders of bilirubin excretion, acute and subacute necrosis of liver, liver cirrhosis, chronic liver disease (nonalcoholic), hepatic coma, hepatitis (non-viral), other disorders of the liver, and other specified disorders of the biliary tract [3, 4, 21]. A control individual free from liver injury was randomly selected for each case, matching (1:1) on age, gender, and the index date (the first observed diagnosis of liver injury in the case).

Exposure to Antidepressants

The antidepressants included in this study were monoamine oxidase A inhibitors (MAO-AIs), non-selective serotonin reuptake inhibitors (NSRIs), SSRIs, and SNRIs. Medications not included in the aforementioned classes were classified as other antidepressants (i.e., trazodone hydrochloride, oxitriptan, mirtazapine, and agomelatine, etc.). The cumulative exposure to antidepressants was defined as the total number of days before the index date that the patient was prescribed antidepressants. Patients were categorized into groups (i.e., 1–30 days, 31–90 days, and 91+ days) based on their cumulative exposure to antidepressants to allow examination of the association with the risk of liver injury. Non-users were those who had never used antidepressants before the index date.

Covariates

Factors such as the use of other medications and a history of comorbidities have been shown to be related to liver injury and, therefore, were considered confounders in the current analysis (Table 1). Medications causing liver damage were prescribed for >90 days a year before the index date, including anti-tuberculosis agents, statins (or fibrates), antibiotics, antifungals, anti-epileptics, non-steroidal anti-inflammatory drugs (NSAIDs), and other potential hepatotoxic agents (i.e., acetaminophen, amiodarone, and methotrexate) [22]. Comorbidities were defined as the presence of chronic renal failure, hyperthyroidism, diabetes mellitus, malnutrition, hyperlipidemia, heart failure, hypertension, ischemic heart disease, arrhythmia, chronic kidney disease, and renal failure.Table 1 Demographics of the study population after matching

	Overall
(n = 119,978)	Cases
(n = 59,989)	Controls
(n = 59,989)	p-Value	
Age, mean (SD)	49.5 (17.1)	49.5 (17.1)	49.5 (17.1)	0.55	
Gender, n (%)				1.00	
 Female	66,994 (55.8)	33,497 (55.8)	33,497 (55.8)		
 Male	52,984 (44.2)	26,492 (44.2)	26,492 (44.2)		
Ever use of antidepressants, n (%)	20,479 (17.1)	12,145 (20.3)	8334 (13.9)	<0.001	
Cumulative duration of antidepressant uses in days, median/IQR (Q1–Q3)	31 (9–147)	33 (9–154)	30 (5–133)	<0.001	
History of comorbidities before index date, n (%)					
 Hypertension	34,519 (28.8)	19,886 (33.2)	14,633 (24.4)	<0.001	
 Diabetes mellitus	16,654 (13.9)	10,599 (17.7)	6055 (10.1)	<0.001	
 Ischemic heart disease	17,126 (14.3)	10,184 (17.0)	6942 (11.6)	<0.001	
 Arrhythmia	6947 (5.8)	4180 (7.0)	1767 (4.6)	<0.001	
 Heart failure	4535 (3.8)	2882 (4.8)	1653 (2.8)	<0.001	
 Hyperlipidemia	27,007 (22.5)	17,672 (29.5)	9335 (15.6)	<0.001	
 CKD and renal failure	5102 (4.3)	3465 (5.8)	1637 (2.7)	<0.001	
 Hyperthyroidism	2414 (2.0)	1548 (2.6)	866 (1.4)	<0.001	
 Fasting, malnutrition	4669 (0.4)	328 (0.6)	138 (0.2)	<0.001	
Medications for >90 days, n (%)					
 Statins and fibrates	14,367 (11.97)	8640 (14.40)	5727 (9.55)	<0.001	
 Antifungals	782 (0.65)	473 (0.79)	309 (0.52)	<0.001	
 Anti-tuberculosis agents	1380 (1.15)	1044 (1.74)	336 (0.56)	<0.001	
 Antibiotics	44,851 (37.38)	26,602 (44.34)	18,249 (30.42)	<0.001	
 Anti-epileptics	6901 (5.75)	4376 (7.29)	2525 (4.21)	<0.001	
 NSAIDs	44,720 (37.27)	26,586 (44.32)	18,134 (30.23)	<0.001	
 Other potential hepatotoxic agents (i.e., acetaminophen, amiodarone, and methotrexate)	67,761 (56.48)	38,474 (64.14)	29,287 (48.82)	<0.001	
Cases were patients hospitalized with a primary diagnosis of liver injury, and controls consisted of individuals matched by age, gender, and index date (the first observed diagnosis of liver injury) in a 1:1 ratio

CKD chronic kidney disease, IQR interquartile range, NASIDs non-steroidal anti-inflammatory drugs, SD standard deviation

Statistical Analyses

Descriptive statistics were compared between the cases and controls using the Student’s t-test or Mann–Whitney U test for continuous variables and the Chi-square test for categorical variables, respectively. Crude and multivariate logistic regressions were used to compare the risk of liver injury between antidepressant users and non-users, and the findings were reported as odds ratios (ORs) and 95% confidence intervals (CIs). The multivariate models adjusted for age, gender, history of comorbidities, and use of liver damage-related drugs prior to the index date of 1 year. All data analyses were carried out using SAS 9.4 (SAS Institute, Cary, NC, USA), and a two-tailed p value of <0.05 was considered statistically significant.

Results

The study sample included 59,989 cases hospitalized with a primary diagnosis of liver injury and 59,989 controls matched by age, gender, and index date. Approximately half of the cases exhibited hepatitis (49%), and were statistically significantly more likely than controls to have a higher prevalence of antidepressant usage (20.3% vs 13.9%), longer durations of antidepressant exposure (33 days vs 30 days), and use of other liver damage-related medications for >90 days (i.e., statins, antifungals, anti-tuberculosis agents, antibiotics, anti-epileptics, NSAIDs, acetaminophen, amiodarone, and methotrexate). Moreover, a greater proportion of cases were likely to have a history of comorbidities, including hypertension (33.2% vs 24.4%), diabetes mellitus (17.7% vs 10.1%), ischemic heart disease (17.0% vs 11.6%), arrhythmia (7.0% vs 4.6%), heart failure (4.8% vs 2.8%), hyperlipidemia (29.5% vs 15.6%), chronic kidney disease and renal failure (5.8% vs 2.7%), hyperthyroidism (2.6% vs 1.4%), and fasting or malnutrition (0.6% vs 0.2%) than controls (Table 1).

Table 2 presents the distribution and odds of antidepressant users among the study population. Compared with the controls, cases had a significantly higher proportion of patients using any classes of antidepressants, which was associated with an increased risk of liver injury across all durations of use (the range of crude ORs was 1.44–2.35). After adjusting for covariates, antidepressant users exhibited a significantly higher risk of liver injury (adjusted OR [aOR] 1.16, 95% CI 1.12–1.20). This risk was particularly elevated when individuals were prescribed NSRIs (aOR 1.05; 95% CI 1.01–1.10), SSRIs (aOR 1.22; 95% CI 1.16–1.29), SNRIs (aOR 1.18; 95% CI 1.13–1.24), or other types of antidepressants including trazodone hydrochloride, oxitriptan, mirtazapine, and agomelatine (aOR 1.27; 95% CI 1.14–1.42). However, all MAO-AIs users had no significant result compared with non-users.Table 2 The crude and adjusted odds ratios for liver injury by antidepressant usage

Antidepressants	Cases
(n = 59,989)	Controls
(n = 59,989)	Crude OR	Adjusted OR*	
n (%)	n (%)	OR (95% CI)	OR (95% CI)	
Non-users	47,844 (79.7)	51,647 (86.1)	Ref.	Ref.	
Users	12,145 (20.3)	8342 (13.9)	1.57 (1.52–1.62)	1.16 (1.12–1.20)	
 1–30 d	5819 (9.70)	4065 (6.78)	1.55 (1.48–1.61)	1.24 (1.18–1.29)	
 31–90 d	2367 (3.95)	1698 (2.83)	1.51 (1.41–1.60)	1.09 (1.02–1.17)	
 91+ d	3959 (6.60)	2579 (4.30)	1.66 (1.58–1.74)	1.07 (1.01–1.13)	
MAO-AIs usage					
 Non-users	59,453 (99.11)	59,653 (99.44)	Ref.	Ref.	
 Users	536 (0.89)	336 (0.56)	1.60 (0.40–1.84)	1.15 (0.99–1.32)	
  1–30 d	285 (0.48)	164 (0.27)	1.74 (1.44–2.11)	1.26 (1.03–1.54)	
  31–90 d	122 (0.20)	82 (0.14)	1.49 (1.13–1.98)	1.08 (0.81–1.45)	
  91+ d	129 (0.22)	90 (0.15)	1.44 (1.10–1.88)	1.00 (0.75–1.32)	
NSRIs usage					
 Non-users	53,226 (88.73)	55,258 (92.11)	Ref.	Ref.	
 Users	6763 (11.27)	4731 (7.89)	1.48 (1.43–1.54)	1.05 (1.01–1.10)	
  1–30 d	4177 (6.96)	2884 (4.81)	1.50 (1.43–1.58)	1.14 (1.08–1.20)	
  31–90 d	1285 (2.14)	920 (1.53)	1.45 (1.33–1.58)	0.95 (0.86–1.04)	
  91+ d	1301 (2.17)	927 (1.55)	1.46 (1.34–1.59)	0.86 (0.79–0.94)	
SSRIs usage					
 Non-users	55,698 (92.85)	57,322 (95.55)	Ref.	Ref.	
 Users	4291 (7.15)	2667 (4.45)	1.66 (1.58–1.74)	1.22 (1.16–1.29)	
  1–30 d	1693 (2.82)	1046 (1.74)	1.67 (1.54–1.80)	1.34 (1.24–1.45)	
  31–90 d	873 (1.46)	553 (0.92)	1.63 (1.46–1.81)	1.20 (1.07–1.34)	
  91+ d	1725 (2.88)	1068 (1.78)	1.66 (1.54–1.80)	1.12 (1.03–1.21)	
SNRIs usage					
 Non-users	54,768 (91.3)	56,696 (94.5)	Ref.	Ref.	
 Users	5221 (8.70)	3293 (5.49)	1.64 (1.57–1.72)	1.18 (1.13–1.24)	
  1–30 d	2629 (4.38)	1709 (2.85)	1.59 (1.50–1.69)	1.21 (1.14–1.30)	
  31–90 d	1038 (1.73)	666 (1.11)	1.61 (1.46–1.78)	1.13 (1.02–1.26)	
  91+ d	1554 (2.59)	918 (1.53)	1.75 (1.61–1.90)	1.16 (1.06–1.26)	
Other antidepressants usage					
 Non-users	59,005 (98.4)	59,451 (99.1)	Ref.	Ref.	
 Users	984 (1.64)	538 (0.90)	1.84 (1.66–2.05)	1.27 (1.14–1.42)	
  1–30 d	412 (0.69)	230 (0.38)	1.81 (1.54–2.12)	1.37 (1.15–1.62)	
  31–90 d	226 (0.38)	97 (0.16)	2.35 (1.85–2.98)	1.57 (1.23–2.01)	
  91+ d	346 (0.58)	211 (0.35)	1.65 (1.39–1.96)	1.04 (0.87–1.25)	
Cases were patients hospitalized with a primary diagnosis of liver injury, and controls consisted of individuals matched by sex, age, and index date (the first observed diagnosis of liver injury) in a 1:1 ratio

Values in bold were statistically significant

CI confidence interval, MAO-AIs monoamine oxidase A inhibitors, NSRIs nonselective monoamine reuptake inhibitors, OR odds ratio, Ref reference, SNRIs serotonin-norepinephrine reuptake inhibitors, SSRIs selective serotonin reuptake inhibitors

*The multivariate models adjusted for age, gender, history of comorbidities, and medication of liver damage-related drugs during the same period as antidepressants exposure

Subgroup analyses presented in Table 2, stratified based on days of drug usage, revealed that individuals using any class of antidepressants faced a higher risk of developing liver injury within the initial 1–30 days compared with non-users (aOR 1.24; 95% CI 1.03–1.54). Furthermore, these findings remained consistent across all classes, including MAO-AI (aOR 1.26; 95% CI 1.03–1.54), NSRI (aOR 1.14; 95% CI 1.08–1.20), SSRI (aOR 1.34; 95% CI 1.24–1.45), and SNRI (aOR 1.21; 95% CI 1.14–1.30) users. Notably, there was a discernible declining trend in risk with longer durations of usage, especially among patients using NSRIs for >90 days, who exhibited a significantly reduced risk when compared with individuals who had not utilized any form of NSRI (aOR 0.86; 95% CI 0.79–0.94).

Discussion

To the best of our knowledge, this is the first Asian population-based study to illustrate the association between antidepressant use and the risk of DILI in the general population. The current study first demonstrates the nationwide risk of AILI in Taiwan over 18 years. Systematically, the study collected data encompassing the risk of liver injury linked to all classes of antidepressants, analyzing the cumulative days of exposure. The findings of the current study showed an association between antidepressant usage and risk of liver injury, with a significantly larger proportion of patients with liver injury using antidepressants compared with those without liver injury. Additionally, the median duration of antidepressant use was significantly longer in patients with liver injury compared with those without liver injury. Noteworthy is the observation that nearly 50% of suspected AILI patients presented with non-viral hepatitis. Furthermore, a higher prevalence of AILI was observed in patients with comorbidities, including cardiovascular disease, diabetes, renal disease, and others.

The risk of AILI in this study is lower than in the previous research, which may be due to differences in drug category distribution and other demographics [23]. Further analysis showed that certain pharmaceutical classes of antidepressants (e.g., SSRIs and other classes of antidepressants) were associated with an overall higher risk of liver injury compared with other classes, except for MAOIs. In addition, certain antidepressants may carry an increased risk of liver injury, particularly in the first 30 days of use, as suggested by research findings [23]. Patients using these medications should exercise caution, and healthcare providers should monitor for potential liver-related adverse effects during the initial month of treatment.

The prevalence of liver injury was also relatively high among those who had used anti-tuberculosis agents, statins (or fibrates), antibiotics, antifungals, anti-epileptics, NSAIDs, and other potential hepatotoxic agents (i.e., acetaminophen, amiodarone, and methotrexate) [22] for >90 days compared with those who had not, consistent with previous studies [12]. This could be attributed to the independent association of these drugs with the risk of liver injury. When combined with antidepressants, they may collectively contribute to an increased burden on the liver, potentially leading to damage.

The mechanism for AILI is not yet fully understood. Studies suggest that DILI may be related to allergic reactions, oxidative stress, lipid peroxidation, cytochrome-P450 enzyme (CYP450) metabolites, or immune-mediated reactions [17, 24]. SSRIs and SNRIs are metabolized in the liver, especially through the CYP450 enzyme pathway, which includes CYP2C19, CYP2C9, and CYP2D6 [25]. In elderly patients or CYP2C19 poor metabolizers, the oral clearance rate is diminished, leading to a higher likelihood of adverse reactions and hepatotoxicity due to dose accumulation [26]. In clinical management, the dosage or medication regimen may be altered when an elevation in the patient’s liver indices is detected. This could explain the slight reduction in the observed risk of liver injury after a treatment duration exceeding 30 days.

MAO-AIs inhibit monoamine oxidase in the liver, reducing the breakdown of neurotransmitters and increasing their concentration in the synaptic cleft. In this study, the overall risk of DILI in users of MAO-AIs was not significantly higher than that in non-users, perhaps due to the known liver toxicity of these drugs, leading clinicians to avoid prescribing them to high-risk patients. However, MAO-AIs demonstrate multiple interactions with other medications, food, or overdose, leading to an elevated risk of hepatotoxicity [27]. A significantly higher risk observed within the first 30 days with MAO-AI use in this study may be attributed to the potential omission of these interaction factors during the initial administration period.

On the other hand, using NSRIs involves liver metabolism, either through a direct toxic effect or a hypersensitivity reaction, and is influenced by other drugs that induce or inhibit microsomal enzymes [24]. Long-term NSRI users typically administer low doses. Hence, the risk of hepatotoxicity is less obvious. In particular, our findings revealed that patients using NSRIs (e.g., tricyclic antidepressants [TCAs] like imipramine or amitriptyline) for more than 90 days had a significantly reduced risk compared with non-users. This can be explained by the fact that most prescriptions for NSRIs with a low dose and long duration are given to nocturia sufferers. Nocturia is often managed by addressing underlying causes or conditions that contribute to increased nighttime urination, such as age, diabetes, and cardiovascular-related conditions [28, 29]. NSRIs, with their anticholinergic effects that can affect bladder function, have been used off-label for managing nocturia. Overall, it is important to note that there may be residual confounding from long-term antidepressant usage in mitigating the risk of certain adverse outcomes.

Antidepressants, particularly SSRIs and SNRIs, are commonly used to treat depression and other psychological disorders, and awareness of their potential effects on the liver is essential. Clinicians should evaluate the patient’s condition when considering the risks and benefits of prescribing antidepressants and take appropriate measures where necessary.

Strengths and Limitations

The current study had several strengths, including a large sample size and longitudinal follow-up, which facilitated robust investigation of rare events such as liver injury. The effects of the duration of and cumulative exposure to antidepressant use were also examined to supplement existing evidence on the association between long-term antidepressant use and liver injury. Strict statistical analysis, including subgroup comparisons, was carried out to reduce the risk of bias.

This study also had several limitations. Firstly, this nationwide case–control study lacked detailed laboratory information such as hepatic fibrosis stage, baseline liver biochemical tests (e.g., alanine aminotransferase [ALT], alkaline phosphatase [ALP], total bilirubin [TB]), and lipid profile (e.g., triglycerides, low density lipoprotein cholesterol). Secondly, lack of access to medical records prevented use of a standardized definition for liver damage (e.g., Roussel Uclaf Causality Assessment Method [RUCAM]). Therefore, the lack of a validation study specifically conducted for the diagnosis code of liver injury in the NHIRD and the inclusion of only patients hospitalized with a primary diagnosis of liver injury (defined using ICD codes) may have led to selection bias. Thirdly, the NHIRD did not include information on the patients’ body index (e.g., height and weight), behavioral factors (e.g., alcohol consumption and smoking), and use of alternative medications (e.g., over-the-counter products and herbal products). These limitations were addressed by imposing strict criteria to exclude non-DILI patients.

Conclusion

This population-based study adds to existing evidence by exploring the association between antidepressant use and the risk of liver injury. Overall, the findings showed that antidepressant usage was consistently associated with an increased risk of liver injury, and this was particularly applicable to SSRI and SNRI users as well as those using antidepressants for 1–30 days.

Declarations

Conflict of Interest

None of the authors have any conflicts of interest to disclose.

Funding

This study was partly supported by the Taiwan Ministry of Health and Welfare Clinical Trial Center (MOHW112-TDU-B-212-144004), China Medical University Hospital (DMR-111-105; DMR-112-087;DMR-113-009). We express our gratitude to the Health Data Science Center, China Medical University Hospital for providing administrative, technical, and funding support.

Ethics Approval

This study involving human participants was reviewed and approved by Institutional Review Board of China Medical University Hospital Research Ethics Committee [CMUH109-REC2-031(CR-4)] on February 04, 2024. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Data Availability

The original contributions presented in the study are included in the article materials. The dataset used in this study is held by the Taiwan Ministry of Health and Welfare (MOHW). The Ministry of Health and Welfare must approve our application to access this data. Any researcher interested in accessing this dataset can submit an application form to the Ministry of Health and Welfare requesting access. Please contact the staff of MOHW (Email: wt.vog.whom@uwloracts) for further assistance. Taiwan Ministry of Health and Welfare Address: No.488, Sec. 6, Zhongxiao E. Rd., Nangang Dist., Taipei City 115, Taiwan (R.O.C.). Phone: +886-2-8590-6848.

Code Availability

Not applicable.

Author Contributions

CYH and YWH contributed to the conception of the study and design. YSY took responsibility for the material preparation and methodology. YSY, CML, CLL, and HYH conducted the data collection, analysis, and interpretation. All authors drafted the manuscript, and CYH and YWH critically reviewed the article’s intellectual content. All authors read and approved the final version.
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References

1. Navarro VJ Senior JR Drug-related hepatotoxicity N Engl J Med 2006 354 731 739 10.1056/NEJMra052270 16481640
Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med. 2006;354:731–9.16481640 10.1056/NEJMra052270
2. Sgro C Clinard F Ouazir K Chanay H Allard C Guilleminet C Incidence of drug-induced hepatic injuries: a French population-based study Hepatology (Baltimore, MD) 2002 36 451 455 10.1053/jhep.2002.34857 12143055
Sgro C, Clinard F, Ouazir K, Chanay H, Allard C, Guilleminet C, et al. Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology (Baltimore, MD). 2002;36:451–5.12143055 10.1053/jhep.2002.34857
3. Chang CH Chang YC Lee YC Liu YC Chuang LM Lin JW Severe hepatic injury associated with different statins in patients with chronic liver disease: a nationwide population-based cohort study J Gastroenterol Hepatol 2015 30 155 162 10.1111/jgh.12657 25041076
Chang CH, Chang YC, Lee YC, Liu YC, Chuang LM, Lin JW. Severe hepatic injury associated with different statins in patients with chronic liver disease: a nationwide population-based cohort study. J Gastroenterol Hepatol. 2015;30:155–62.25041076 10.1111/jgh.12657
4. Kao WY Su CW Huang YS Chou YC Chen YC Chung WH Risk of oral antifungal agent-induced liver injury in Taiwanese Br J Clin Pharmacol 2014 77 180 189 10.1111/bcp.12178 23750489
Kao WY, Su CW, Huang YS, Chou YC, Chen YC, Chung WH, et al. Risk of oral antifungal agent-induced liver injury in Taiwanese. Br J Clin Pharmacol. 2014;77:180–9.23750489 10.1111/bcp.12178
5. Lee WM Drug-induced hepatotoxicity N Engl J Med 2003 349 474 485 10.1056/NEJMra021844 12890847
Lee WM. Drug-induced hepatotoxicity. N Engl J Med. 2003;349:474–85.12890847 10.1056/NEJMra021844
6. Lucena MI Andrade RJ Kaplowitz N García-Cortes M Fernández MC Romero-Gomez M Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex Hepatology (Baltimore, MD) 2009 49 2001 2009 10.1002/hep.22895 19475693
Lucena MI, Andrade RJ, Kaplowitz N, García-Cortes M, Fernández MC, Romero-Gomez M, et al. Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and sex. Hepatology (Baltimore, MD). 2009;49:2001–9.19475693 10.1002/hep.22895
7. Kato Y Nakata K Omagari K Kusumoto Y Mori I Furukawa R Clinical features of fulminant hepatitis in Nagasaki Prefecture, Japan Intern Med Tokyo Jpn 2001 40 5 8 10.2169/internalmedicine.40.5
Kato Y, Nakata K, Omagari K, Kusumoto Y, Mori I, Furukawa R, et al. Clinical features of fulminant hepatitis in Nagasaki Prefecture, Japan. Intern Med Tokyo Jpn. 2001;40:5–8.10.2169/internalmedicine.40.5
8. Stirnimann G Kessebohm K Lauterburg B Liver injury caused by drugs: an update Swiss Med Wkly 2010 140 w13080 20927685
Stirnimann G, Kessebohm K, Lauterburg B. Liver injury caused by drugs: an update. Swiss Med Wkly. 2010;140: w13080.20927685
9. Bell LN Chalasani N Epidemiology of idiosyncratic drug-induced liver injury Semin Liver Dis 2009 29 337 347 10.1055/s-0029-1240002 19826967
Bell LN, Chalasani N. Epidemiology of idiosyncratic drug-induced liver injury. Semin Liver Dis. 2009;29:337–47.19826967 10.1055/s-0029-1240002
10. Tajiri K Shimizu Y Practical guidelines for diagnosis and early management of drug-induced liver injury World J Gastroenterol 2008 14 6774 6785 10.3748/wjg.14.6774 19058303
Tajiri K, Shimizu Y. Practical guidelines for diagnosis and early management of drug-induced liver injury. World J Gastroenterol. 2008;14:6774–85.19058303 10.3748/wjg.14.6774
11. Takikawa H Murata Y Horiike N Fukui H Onji M Drug-induced liver injury in Japan: an analysis of 1676 cases between 1997 and 2006 Hepatol Res Off J Jpn Soc Hepatol 2009 39 427 431 10.1111/j.1872-034X.2008.00486.x
Takikawa H, Murata Y, Horiike N, Fukui H, Onji M. Drug-induced liver injury in Japan: an analysis of 1676 cases between 1997 and 2006. Hepatol Res Off J Jpn Soc Hepatol. 2009;39:427–31.10.1111/j.1872-034X.2008.00486.x
12. Hussaini SH Farrington EA Idiosyncratic drug-induced liver injury: an overview Expert Opin Drug Saf 2007 6 673 684 10.1517/14740338.6.6.673 17967156
Hussaini SH, Farrington EA. Idiosyncratic drug-induced liver injury: an overview. Expert Opin Drug Saf. 2007;6:673–84.17967156 10.1517/14740338.6.6.673
13. Norris W Paredes AH Lewis JH Drug-induced liver injury in 2007 Curr Opin Gastroenterol 2008 24 287 297 10.1097/MOG.0b013e3282f9764b 18408456
Norris W, Paredes AH, Lewis JH. Drug-induced liver injury in 2007. Curr Opin Gastroenterol. 2008;24:287–97.18408456 10.1097/MOG.0b013e3282f9764b
14. Carey EJ Vargas HE Douglas DD Balan V Byrne TJ Harrison ME Inpatient admissions for drug-induced liver injury: results from a single center Dig Dis Sci 2008 53 1977 1982 10.1007/s10620-008-0250-x 18392678
Carey EJ, Vargas HE, Douglas DD, Balan V, Byrne TJ, Harrison ME, et al. Inpatient admissions for drug-induced liver injury: results from a single center. Dig Dis Sci. 2008;53:1977–82.18392678 10.1007/s10620-008-0250-x
15. DeSanty KP Amabile CM Antidepressant-induced liver injury Ann Pharmacother 2007 41 1201 1211 10.1345/aph.1K114 17609231
DeSanty KP, Amabile CM. Antidepressant-induced liver injury. Ann Pharmacother. 2007;41:1201–11.17609231 10.1345/aph.1K114
16. Carvajal García-Pando A García del Pozo J Sánchez AS Velasco MA Rueda de Castro AM Lucena MI Hepatotoxicity associated with the new antidepressants J Clin Psychiatry 2002 63 135 137 10.4088/JCP.v63n0208 11874214
Carvajal García-Pando A, García del Pozo J, Sánchez AS, Velasco MA, Rueda de Castro AM, Lucena MI. Hepatotoxicity associated with the new antidepressants. J Clin Psychiatry. 2002;63:135–7.11874214 10.4088/JCP.v63n0208
17. Voican CS Corruble E Naveau S Perlemuter G Antidepressant-induced liver injury: a review for clinicians Am J Psychiatry 2014 171 404 415 10.1176/appi.ajp.2013.13050709 24362450
Voican CS, Corruble E, Naveau S, Perlemuter G. Antidepressant-induced liver injury: a review for clinicians. Am J Psychiatry. 2014;171:404–15.24362450 10.1176/appi.ajp.2013.13050709
18. Ferrajolo C Scavone C Donati M Bortolami O Stoppa G Motola D Antidepressant-Induced acute liver injury: a case–control study in an Italian inpatient population Drug Saf 2018 41 95 102 10.1007/s40264-017-0583-5 28770534
Ferrajolo C, Scavone C, Donati M, Bortolami O, Stoppa G, Motola D, et al. Antidepressant-Induced acute liver injury: a case–control study in an Italian inpatient population. Drug Saf. 2018;41:95–102.28770534 10.1007/s40264-017-0583-5
19. Chen VCH Lin CF Hsieh YH Liang HY Huang KY Chiu WC Hepatocellular carcinoma and antidepressants: a nationwide population-based study Oncotarget 2016 8 30464 30470 10.18632/oncotarget.12826
Chen VCH, Lin CF, Hsieh YH, Liang HY, Huang KY, Chiu WC, et al. Hepatocellular carcinoma and antidepressants: a nationwide population-based study. Oncotarget. 2016;8:30464–70.10.18632/oncotarget.12826
20. Huang KL Chen YL Stewart R Chen VCH Antidepressant use and mortality among patients with hepatocellular carcinoma JAMA Netw Open 2023 6 e2332579 10.1001/jamanetworkopen.2023.32579 37672269
Huang KL, Chen YL, Stewart R, Chen VCH. Antidepressant use and mortality among patients with hepatocellular carcinoma. JAMA Netw Open. 2023;6: e2332579.37672269 10.1001/jamanetworkopen.2023.32579
21. Jinjuvadia K Kwan W Fontana RJ Searching for a needle in a haystack: use of ICD-9-CM codes in drug-induced liver injury Am J Gastroenterol 2007 102 2437 2443 10.1111/j.1572-0241.2007.01456.x 17662100
Jinjuvadia K, Kwan W, Fontana RJ. Searching for a needle in a haystack: use of ICD-9-CM codes in drug-induced liver injury. Am J Gastroenterol. 2007;102:2437–43.17662100 10.1111/j.1572-0241.2007.01456.x
22. Chen M Suzuki A Thakkar S Yu K Hu C Tong W DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans Drug Discov Today 2016 21 648 653 10.1016/j.drudis.2016.02.015 26948801
Chen M, Suzuki A, Thakkar S, Yu K, Hu C, Tong W. DILIrank: the largest reference drug list ranked by the risk for developing drug-induced liver injury in humans. Drug Discov Today. 2016;21:648–53.26948801 10.1016/j.drudis.2016.02.015
23. Licata A Minissale MG Calvaruso V Craxì A A focus on epidemiology of drug-induced liver injury: analysis of a prospective cohort Eur Rev Med Pharmacol Sci 2017 21 112 121 28379588
Licata A, Minissale MG, Calvaruso V, Craxì A. A focus on epidemiology of drug-induced liver injury: analysis of a prospective cohort. Eur Rev Med Pharmacol Sci. 2017;21:112–21.28379588
24. Todorović Vukotić N Đorđević J Pejić S Đorđević N Pajović SB Antidepressants- and antipsychotics-induced hepatotoxicity Arch Toxicol 2021 95 767 789 10.1007/s00204-020-02963-4 33398419
Todorović Vukotić N, Đorđević J, Pejić S, Đorđević N, Pajović SB. Antidepressants- and antipsychotics-induced hepatotoxicity. Arch Toxicol. 2021;95:767–89.33398419 10.1007/s00204-020-02963-4
25. Tracy TS Chaudhry AS Prasad B Thummel KE Schuetz EG Zhong X-B Interindividual variability in cytochrome P450-mediated drug metabolism Drug Metab Dispos Biol Fate Chem. 2016 44 343 351 10.1124/dmd.115.067900 26681736
Tracy TS, Chaudhry AS, Prasad B, Thummel KE, Schuetz EG, Zhong X-B, et al. Interindividual variability in cytochrome P450-mediated drug metabolism. Drug Metab Dispos Biol Fate Chem. 2016;44:343–51.26681736 10.1124/dmd.115.067900
26. Hicks J Bishop J Sangkuhl K Müller D Ji Y Leckband S Clinical pharmacogenetics implementation consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors Clin Pharmacol Ther 2015 98 127 134 10.1002/cpt.147 25974703
Hicks J, Bishop J, Sangkuhl K, Müller D, Ji Y, Leckband S, et al. Clinical pharmacogenetics implementation consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clin Pharmacol Ther. 2015;98:127–34.25974703 10.1002/cpt.147
27. Fiedorowicz JG Swartz KL The role of monoamine oxidase inhibitors in current psychiatric practice J Psychiatr Pract 2004 10 239 248 10.1097/00131746-200407000-00005 15552546
Fiedorowicz JG, Swartz KL. The role of monoamine oxidase inhibitors in current psychiatric practice. J Psychiatr Pract. 2004;10:239–48.15552546 10.1097/00131746-200407000-00005
28. FitzGerald MP Litman HJ Link CL McKinlay JB The association of nocturia with cardiac disease, diabetes, body mass index, age and diuretic use: results from the BACH survey J Urol 2007 177 1385 1389 10.1016/j.juro.2006.11.057 17382738
FitzGerald MP, Litman HJ, Link CL, McKinlay JB. The association of nocturia with cardiac disease, diabetes, body mass index, age and diuretic use: results from the BACH survey. J Urol. 2007;177:1385–9.17382738 10.1016/j.juro.2006.11.057
29. Lightner DJ Krambeck AE Jacobson DJ McGree ME Jacobsen SJ Lieber MM Nocturia is associated with an increased risk of coronary heart disease and death BJU Int 2012 110 848 853 10.1111/j.1464-410X.2011.10806.x 22233166
Lightner DJ, Krambeck AE, Jacobson DJ, McGree ME, Jacobsen SJ, Lieber MM, et al. Nocturia is associated with an increased risk of coronary heart disease and death. BJU Int. 2012;110:848–53.22233166 10.1111/j.1464-410X.2011.10806.x
