Adverse event profiles of drug-induced liver injury caused by antidepressant drugs: a disproportionality analysis

Abstract

Background:

Antidepressants are widely used to manage depression and other psychiatric diseases. A previous study revealed that hepatotoxicity was the main adverse event related to antidepressants. Therefore, drug-induced liver injury (DILI) caused by antidepressants deserves more attention.

Objectives:

To investigate DILI adverse events reported due to antidepressant use in the United States Food and Drug Administration Adverse Events Reporting System (FAERS) database.

Research design:

A disproportionality analysis of spontaneously reported adverse events was conducted to assess the association between antidepressant drugs and DILI.

Methods:

FAERS data from 1 January 2004 to 31 December 2021 were compiled and analyzed using the reporting odds ratio (ROR) and information component (IC).

Results:

As per the FAERS database, of the 324,588 cases that were administered antidepressants, 10,355 were identified as cases with DILI. Among the identified 42 antidepressants, nefazodone ( n = 47, ROR = 7.79, IC = 2.91), fluvoxamine ( n = 29, ROR = 4.69, IC = 2.20), and clomipramine ( n = 24, ROR = 3.97, IC = 1.96) had the highest ROR for cholestatic injury; mianserin ( n = 3, ROR = 21.46, IC = 3.99), nefazodone ( n = 264, ROR = 18.67, IC = 3.84), and maprotiline ( n = 15, ROR = 5.65, IC = 2.39) for hepatocellular injury; and nefazodone ( n = 187, ROR = 12.71, IC = 0.48), clomipramine ( n = 35, ROR = 2.07, IC = 0.26), and mirtazapine ( n = 483, ROR = 1.96, IC = 0.94) for severe drug-related hepatic disorders. Only nefazodone elicited hepatic failure signals ( n = 48, ROR = 18.64, IC = 4.16). There are limited reports on the adverse reactions of relatively new antidepressant drugs, such as milnacipran, viloxazine, esketamine, and tianeptine, and those not approved by the Food and Drugs Administration, such as reboxetine and agomelatine.

Conclusion:

A significant association was observed between DILI and nefazodone. Duloxetine and clomipramine were associated with three DILI categories, except hepatic failure. The disproportionality analysis cannot conclude on a definite causal link between antidepressants and DILI. Additional research is required to assess new-generation antidepressants for their propensity to cause DILI.

Plain language summary

Adverse events reported on drug-induced liver injury caused by antidepressants

Introduction: Adverse drug events (ADEs) refer to all harmful events related to medications, including adverse drug reactions (ADRs) and other unexpected events. ADEs encompass a wider range and are very important for the post-market surveillance of drugs. This study investigated the voluntary reporting of drug-induced liver injury (DILI) adverse events associated with antidepressant drugs.

Methods: We retrieved data on DILI and related terms submitted between 2004 and 2021 from the United States Food and Drug Administration Adverse Events Reporting System (FAERS) database. We analyzed the data for the detection of DILI signals associated with antidepressants.

Results: We retrieved and analyzed 324,588 reports on antidepressant drugs. A total of 10,355 reports were associated with DILI.

The three drugs with the highest reporting odds ratio (ROR) in each DILI category were as follows:

• cholestatic injury (nefazodone, fluvoxamine, and clomipramine)

• hepatocellular injury (mianserin, nefazodone, and maprotiline)

• hepatic failure (nefazodone)

• drug related hepatic disorders-severe events (nefazodone, clomipramine, and mirtazapine)

The absence of signals from some drugs may be due to:

• non-association with DILI

• novelty of the drug in the market

• non-approval from the Food and Drugs Administration (FDA)

• lack of voluntary reporting of adverse events due to other reasons

Conclusion: Drug safety studies utilizing publicly available large databases allowed the evaluation of the safety profile of widely used antidepressant drugs in clinical practice. Nefazodone, duloxetine, and clomipramine were associated with significant DILI signals. Further research is needed to determine the safety concerns of new-generation antidepressants.