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Antidepressant-Induced Acute Liver Injury: A Case–Control Study in an Italian Inpatient Population

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Abstract

Introduction

Pre-marketing clinical trials show that antidepressant-induced liver injury seems to be a rare adverse event. Because of short follow-up trial duration, the incidence of liver injury due to antidepressant use could be underestimated.

Objectives

We aimed to quantify the risk of acute liver injury associated with antidepressant use through a case–control analysis among an inpatient population.

Methods

A multicenter study was carried out in nine Italian hospitals from October 2010 to January 2014, within the DILI-IT (Drug-Induced Liver Injury in Italy) study project. After exclusion of all patients with a clear competing cause of liver injury, cases were defined as adults admitted to the hospital with a diagnosis of acute liver injury, while controls had any other acute clinical condition not related to the liver. Antidepressant exposure was evaluated within 90 days prior to the date of the first sign/symptom of liver injury. Odds ratio (OR) with 95% confidence interval (95% CI) was calculated as a measure of risk estimates for liver injury.

Results

We included 17 cases exposed to antidepressants matched to 99 controls. According to the features of liver injury, all cases showed symptomatic liver function test abnormalities at hospital admission, with the main signs/symptoms represented by fatigue, nausea, asthenia, or dark urine. Citalopram was the antidepressant mostly involved in the increase of liver enzymes, mainly alanine aminotransferase. Compared with non-use, current use of antidepressants was associated with a significantly increased risk of liver injury (adjusted OR, ORADJ, 1.84; 95% CI 1.02–3.32). Specifically, an increased, but not significant, risk of developing liver injury was observed for citalopram, a selective serotonin-reuptake inhibitor (ORADJ 1.82; 95% CI 0.60–5.53).

Conclusion

The use of antidepressants is not as safe in terms of liver injury as expected; instead, the risk of antidepressant-induced liver injury is likely underestimated. The lack of significance does not reflect the absence of risk, but rather suggests the need to evaluate it in a wider setting of antidepressant users.

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Acknowledgements

We are grateful for the help and support of the DILI-IT Study Group, which includes the following clinical investigators: Franco Capra, Angelo Tonon, University Hospital of Verona; Marco Zoli, University Hospital S. Orsola-Malpighi of Bologna and the Head of each Internal Medicine, Geriatric, and other participating units; Enrica Cecchi, Stefano Grifoni, Careggi Hospital of Florence; Fulvio Calise, Cardarelli Hospital of Naples; Pietro Amoroso, Cotugno Hospital of Naples; Evangelista Sagnelli, San Sebastiano Hospital of Caserta; Annamaria Frola, Umberto I Hospital Unit of Salerno. Study monitors: Elena Arzenton, Giovanna Stoppa, Verona; Maria Carmela Lenti, Roberto Bonaiuti, Florence; Carolina Tiani, Bologna; Carla Migliaccio, Andrea Vitale, Nancy Acampa, Naples. Steering Committee: Nicola Montanaro, University of Bologna; Francesco Lapi and Alessandro Mugelli, University of Florence; Francesco Rossi, University of Naples. Data manager: Giulia Bisoffi, University Hospital of Verona. We thank the members of the External Advisory Board: Maria Grazia Franzosi, Nicola Magrini, Luigi Pagliaro, Giuseppe Traversa, and Mauro Venegoni.

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Authors and Affiliations

  1. Unit of Clinical Pharmacology, Department of Experimental Medicine, Campania Regional Center of Pharmacovigilance and Pharmacoepidemiology, University of Campania “Luigi Vanvitelli”, via de Crecchio 7, 80138, Naples, Italy

    Carmen Ferrajolo, Cristina Scavone & Annalisa Capuano

  2. Department of Medical Informatics, Erasmus MC University, Rotterdam, The Netherlands

    Carmen Ferrajolo

  3. Unit of Pharmacology, Department of Medical and Surgical Sciences, University of Bologna, via Irnerio 48, 40126, Bologna, Italy

    Monia Donati & Domenico Motola

  4. School of Health and Related Research, University of Sheffield, Regent Street, S1 4DA, Sheffield, UK

    Oscar Bortolami

  5. Pharmacology Unit, Department of Diagnostics and Public Health, University of Verona, p.le L.A. Scuro 10, 37134, Verona, Italy

    Giovanna Stoppa & Roberto Leone

  6. Unit of Adverse Drug Reactions Monitoring and Pharmacoepidemiology, Department of Neurosciences, Psychology, Drug Research and Child Health (NeuroFarBa), Tuscan Regional Centre of Pharmacovigilance, University of Florence, Florence, Italy

    Alfredo Vannacci & Alessandro Mugelli

Authors
  1. Carmen Ferrajolo
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  2. Cristina Scavone
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  3. Monia Donati
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  4. Oscar Bortolami
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  6. Domenico Motola
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  7. Alfredo Vannacci
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  8. Alessandro Mugelli
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  9. Roberto Leone
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  10. Annalisa Capuano
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Consortia

on behalf of DILI-IT Study Group

  • Franco Capra
  • , Angelo Tonon
  • , Marco Zoli
  • , Enrica Cecchi
  • , Stefano Grifoni
  • , Fulvio Calise
  • , Pietro Amoroso
  • , Evangelista Sagnelli
  • , Annamaria Frola
  • , Elena Arzenton
  • , Giovanna Stoppa
  • , Maria Carmela Lenti
  • , Roberto Bonaiuti
  • , Carolina Tiani
  • , Carla Migliaccio
  • , Andrea Vitale
  • , Nancy Acampa
  • , Nicola Montanaro
  • , Francesco Lapi
  • , Alessandro Mugelli
  • , Francesco Rossi
  • , Giulia Bisoffi
  • , Maria Grazia Franzosi
  • , Nicola Magrini
  • , Luigi Pagliaro
  • , Giuseppe Traversa
  •  & Mauro Venegoni

Corresponding author

Correspondence to Carmen Ferrajolo.

Ethics declarations

Funding

This study was funded by the Italian Medicines Agency (AIFA), through a call for independent research (ID Study FARM8B2TY7). All institutions received financial support from AIFA for the research study; there are no financial relationships with any organizations that might have an interest in the submitted work in the previous three years.

Conflict of interests

Carmen Ferrajolo, Cristina Scavone, Monia Donati, Oscar Bortolami, Giovanna Stoppa, Domenico Motola, Alfredo Vannacci, Alessandro Mugelli, Roberto Leone, and Annalisa Capuano have no conflicts of interest that are directly relevant to the content of this study.

Ethical approval

The study protocol was independently approved by ethics committees for each participant hospital.

Patient consent

Each patient was informed about the aim of the study and written informed consent was signed before the interview.

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Ferrajolo, C., Scavone, C., Donati, M. et al. Antidepressant-Induced Acute Liver Injury: A Case–Control Study in an Italian Inpatient Population. Drug Saf 41, 95–102 (2018). https://doi.org/10.1007/s40264-017-0583-5

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  • DOI: https://doi.org/10.1007/s40264-017-0583-5

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