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CNS Drugs
Published in: CNS Drugs 4/2019

Open Access 01-04-2019 | Antidepressant Drugs | Original Research Article

Risk of Acute Liver Injury in Agomelatine and Other Antidepressant Users in Four European Countries: A Cohort and Nested Case–Control Study Using Automated Health Data Sources

Authors: Manel Pladevall-Vila, Anton Pottegård, Tania Schink, Johan Reutfors, Rosa Morros, Beatriz Poblador-Plou, Antje Timmer, Joan Forns, Maja Hellfritzsch, Tammo Reinders, David Hägg, Maria Giner-Soriano, Alexandra Prados-Torres, Miguel Cainzos-Achirica, Jesper Hallas, Lena Brandt, Jordi Cortés, Jaume Aguado, Gabriel Perlemuter, Bruno Falissard, Jordi Castellsagué, Emmanuelle Jacquot, Nicolas Deltour, Susana Perez-Gutthann

Published in: CNS Drugs | Issue 4/2019

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Abstract

Background

Agomelatine is a melatonin receptor agonist and serotonin 5-HT2C receptor antagonist indicated for depression in adults. Hepatotoxic reactions like acute liver injury (ALI) are an identified risk in the European risk management plan for agomelatine. Hepatotoxic reactions have been reported for other antidepressants, but population studies quantifying these risks are scarce. Antidepressants are widely prescribed, and users often have risk factors for ALI (e.g. metabolic syndrome).

Objective

The goal was to estimate the risk of ALI associated with agomelatine and other antidepressants (fluoxetine, paroxetine, sertraline, escitalopram, mirtazapine, venlafaxine, duloxetine, and amitriptyline) when compared with citalopram in routine clinical practice.

Method

A nested case–control study was conducted using data sources in Denmark, Germany, Spain, and Sweden (study period 2009–2014). Three ALI endpoints were defined using International Classification of Diseases (ICD) codes: primary (specific codes) and secondary (all codes) endpoints used only hospital discharge codes; the tertiary endpoint included both inpatient and outpatient settings (all codes). Validation of endpoints was implemented. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for current use were estimated for each data source and combined.

Results

We evaluated 3,238,495 new antidepressant and 74,440 agomelatine users. For the primary endpoint, the OR for agomelatine versus citalopram was 0.48 (CI 0.13–1.71). Results were also < 1 when no exclusion criteria were applied (OR 0.37; CI 0.19–0.74), when all exclusion criteria except alcohol and drug abuse were applied (OR 0.47; CI 0.20–1.07), and for the secondary (OR 0.40; CI 0.05–3.11) and tertiary (OR 0.79; CI 0.50–1.25) endpoints. Regarding other antidepressants versus citalopram, most OR point estimates were also below one, although with varying widths of the 95% CIs. The result of the tertiary endpoint and the sensitivity analyses of the primary endpoint were the most precise.

Conclusion

In this study, using citalopram as a comparator, agomelatine was not associated with an increased risk of ALI hospitalisation. The results for agomelatine should be interpreted in the context of the European risk minimisation measures in place. Those measures may have induced selective prescribing and could explain the lower risk of ALI for agomelatine when compared with citalopram. Most other antidepressants evaluated had ORs suggesting a lower risk than citalopram, but additional studies are required to confirm or refute these results.
Appendix
Available only for authorised users
Footnotes
1
The terms “specific” and “nonspecific” are used here to indicate groups of codes that have in previous studies showed more (specific) or less (nonspecific) positive predictive values for ALI.
 
Literature
1.
2.
3.
Voican CS, Corruble E, Naveau S, Perlemuter G. Antidepressant-induced liver injury: a review for clinicians. Am J Psychiatry. 2014;171(4):404–15.CrossRefPubMed
4.
Park SH, Ishino R. Liver injury associated with antidepressants. Curr Drug Saf. 2013;8(3):207–23.CrossRefPubMed
5.
Aithal GP, Watkins PB, Andrade RJ, Larrey D, Molokhia M, Takikawa H, et al. Case definition and phenotype standardization in drug-induced liver injury. Clin Pharmacol Ther. 2011;89(6):806–15.CrossRefPubMed
6.
Hussaini SH, Farrington EA. Idiosyncratic drug-induced liver injury: an update on the 2007 overview. Expert Opin Drug Saf. 2014;13(1):67–81.CrossRefPubMed
7.
Katz AJ, Ryan PB, Racoosin JA, Stang PE. Assessment of case definitions for identifying acute liver injury in large observational databases. Drug Saf. 2013;36(8):651–61.CrossRefPubMed
8.
Lewer D, O’Reilly C, Mojtabai R, Evans-Lacko S. Antidepressant use in 27 European countries: associations with sociodemographic, cultural and economic factors. Br J Psychiatry. 2015;207(3):221–6.CrossRefPubMed
9.
Pratt LA, Brody DJ, Gu Q. Antidepressant use among persons aged 12 and over: United States, 2011–2014. NCHS Data Brief. 2017;283:1–8.
10.
Breslow RA, Dong C, White A. Prevalence of alcohol-interactive prescription medication use among current drinkers: United States, 1999 to 2010. Alcohol Clin Exp Res. 2015;39(2):371–9.CrossRefPubMedPubMedCentral
11.
Du Y, Wolf IK, Knopf H. Psychotropic drug use and alcohol consumption among older adults in Germany: results of the German Health Interview and Examination Survey for Adults 2008–2011. BMJ Open. 2016;6(10):e012182.CrossRefPubMedPubMedCentral
12.
Rethorst CD, Bernstein I, Trivedi MH. Inflammation, obesity, and metabolic syndrome in depression: analysis of the 2009–2010 National Health and Nutrition Examination Survey (NHANES). J Clin Psychiatry. 2014;75(12):e1428–32.CrossRefPubMedPubMedCentral
13.
Chen M, Suzuki A, Borlak J, Andrade RJ, Isabel Lucena M. Drug-induced liver injury: interactions between drug properties and host factors. J Hepatol. 2015;63(2):503–14.CrossRefPubMed
14.
Leise MD, Poterucha JJ, Talwalkar JA. Drug-induced liver injury. Mayo Clin Proc. 2014;89(1):95–106.CrossRefPubMed
15.
Lin ND, Norman H, Regev A, Perahia DG, Li H, Chang CL, et al. Hepatic outcomes among adults taking duloxetine: a retrospective cohort study in a US health care claims database. BMC Gastroenterol. 2015;15:134.CrossRefPubMedPubMedCentral
16.
Xue F, Strombom I, Turnbull B, Zhu S, Seeger JD. Duloxetine for depression and the incidence of hepatic events in adults. J Clin Psychopharmacol. 2011;31(4):517–22.CrossRefPubMed
17.
18.
19.
20.
Prados-Torres A, Poblador-Plou B, Gimeno-Miguel A, Calderon-Larranaga A, Poncel-Falco A, Gimeno-Feliu LA, et al. Cohort profile: the epidemiology of chronic diseases and multimorbidity. The EpiChron Cohort Study. Int J Epidemiol. 2018;47(2):382–4.CrossRefPubMedPubMedCentral
21.
Jobski K, Schmedt N, Kollhorst B, Krappweis J, Schink T, Garbe E. Characteristics and drug use patterns of older antidepressant initiators in Germany. Eur J Clin Pharmacol. 2017;73(1):105–13.CrossRefPubMed
22.
Jobski K, Kollhorst B, Garbe E, Schink T. The risk of ischemic cardio- and cerebrovascular events associated with oxycodone-naloxone and other extended-release high-potency opioids: a nested case-control study. Drug Saf. 2017;40(6):505–15.CrossRefPubMed
23.
Pigeot I, Ahrens W. Establishment of a pharmacoepidemiological database in Germany: methodological potential, scientific value and practical limitations. Pharmacoepidemiol Drug Saf. 2008;17(3):215–23.CrossRefPubMed
24.
Schmidt M, Pedersen L, Sorensen HT. The Danish Civil Registration System as a tool in epidemiology. Eur J Epidemiol. 2014;29(8):541–9.CrossRefPubMed
25.
Lynge E, Sandegaard JL, Rebolj M. The Danish National Patient Register. Scand J Public Health. 2011;39(7 Suppl):30–3.CrossRefPubMed
26.
Schmidt M, Schmidt SA, Sandegaard JL, Ehrenstein V, Pedersen L, Sorensen HT. The Danish National Patient Registry: a review of content, data quality, and research potential. Clin Epidemiol. 2015;7:449–90.CrossRefPubMedPubMedCentral
27.
Pottegard A, Schmidt SA, Wallach-Kildemoes H, Sorensen HT, Hallas J, Schmidt M. Data resource profile: the Danish National Prescription Registry. Int J Epidemiol. 2017;46(3):798-f.
28.
Johannesdottir SA, Horváth-Puhó E, Ehrenstein V, Schmidt M, Pedersen L, Sørensen HT. Existing data sources for clinical epidemiology: the Danish National Database of Reimbursed Prescriptions. Clin Epidemiol. 2012;4:303–13.CrossRefPubMedPubMedCentral
29.
Furu K, Wettermark B, Andersen M, Martikainen JE, Almarsdottir AB, Sørensen HT. The Nordic countries as a cohort for pharmacoepidemiological research. Basic Clin Pharmacol Toxicol. 2010;106(2):86–94.CrossRefPubMed
30.
Ludvigsson JF, Andersson E, Ekbom A, Feychting M, Kim JL, Reuterwall C, et al. External review and validation of the Swedish national inpatient register. BMC Public Health. 2011;11:450.CrossRefPubMedPubMedCentral
31.
Wettermark B, Hammar N, Fored CM, Leimanis A, Otterblad Olausson P, Bergman U, et al. The new Swedish Prescribed Drug Register—opportunities for pharmacoepidemiological research and experience from the first six months. Pharmacoepidemiol Drug Saf. 2007;16(7):726–35.CrossRefPubMed
32.
Danan G, Benichou C. Causality assessment of adverse reactions to drugs—I. A novel method based on the conclusions of international consensus meetings: application to drug-induced liver injuries. J Clin Epidemiol. 1993;46(11):1323–30.CrossRefPubMed
33.
Forns J, Cainzos-Achirica M, Hellfritzsch M, Giner-Soriano M, Poblador-Plou B, Hallas J, et al. How valid are the codes used to identify acute liver injury (ALI)? A study in 3 European data sources. Pharmacoepidemiol Drug Saf. 2018;27(Suppl 2):371 (abstract # 811).
34.
Sikka R, Xia F, Aubert RE. Estimating medication persistency using administrative claims data. Am J Manag Care. 2005;11(7):449–57.PubMed
35.
Kaye JA, Castellsague J, Bui CL, Calingaert B, McQuay LJ, Riera-Guardia N, et al. Risk of acute liver injury associated with the use of moxifloxacin and other oral antimicrobials: a retrospective, population-based cohort study. Pharmacotherapy. 2014;34(4):336–49.CrossRefPubMed
36.
Weng HY, Hsueh YH, Messam LL, Hertz-Picciotto I. Methods of covariate selection: directed acyclic graphs and the change-in-estimate procedure. Am J Epidemiol. 2009;169(10):1182–90.CrossRefPubMed
37.
38.
Ruigomez A, Brauer R, Rodriguez LA, Huerta C, Requena G, Gil M, et al. Ascertainment of acute liver injury in two European primary care databases. Eur J Clin Pharmacol. 2014;70(10):1227–35.CrossRefPubMed
39.
Billioti de Gage S, Collin C, Le-Tri T, Pariente A, Begaud B, Verdoux H, et al. Antidepressants and hepatotoxicity: a cohort study among 5 million individuals registered in the French National Health Insurance Database. CNS Drugs. 2018;32(7):673–84.CrossRefPubMedPubMedCentral
40.
Montastruc F, Scotto S, Vaz IR, Guerra LN, Escudero A, Sainz M, et al. Hepatotoxicity related to agomelatine and other new antidepressants: a case/noncase approach with information from the Portuguese, French, Spanish, and Italian pharmacovigilance systems. J Clin Psychopharmacol. 2014;34(3):327–30.CrossRefPubMed
41.
Gahr M, Zeiss R, Lang D, Connemann BJ, Hiemke C, Schonfeldt-Lecuona C. Drug-induced liver injury associated with antidepressive psychopharmacotherapy: an explorative assessment based on quantitative signal detection using different MedDRA terms. J Clin Pharmacol. 2016;56(6):769–78.CrossRefPubMed
42.
Douros A, Bronder E, Andersohn F, Klimpel A, Thomae M, Sarganas G, et al. Drug-induced liver injury: results from the hospital-based Berlin Case-Control Surveillance Study. Br J Clin Pharmacol. 2015;79(6):988–99.CrossRefPubMedPubMedCentral
43.
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(1):95–102.CrossRefPubMed
44.
Jurek AM, Greenland S, Maldonado G. How far from non-differential does exposure or disease misclassification have to be to bias measures of association away from the null? Int J Epidemiol. 2008;37(2):382–5.CrossRefPubMed
45.
Lo Re V 3rd, Haynes K, Goldberg D, Forde KA, Carbonari DM, Leidl KB, et al. Validity of diagnostic codes to identify cases of severe acute liver injury in the US Food and Drug Administration’s Mini-Sentinel Distributed Database. Pharmacoepidemiol Drug Saf. 2013;22(8):861–72.CrossRefPubMedPubMedCentral
46.
Maggini M, Raschetti R, Agostinis L, Cattaruzzi C, Troncon MG, Simon G. Use of amoxicillin and amoxicillin-clavulanic acid and hospitalization for acute liver injury. Ann Ist Super Sanita. 1999;35(3):429–33.PubMed
47.
Traversa G, Bianchi C, Da Cas R, Abraha I, Menniti-Ippolito F, Venegoni M. Cohort study of hepatotoxicity associated with nimesulide and other non-steroidal anti-inflammatory drugs. BMJ. 2003;327(7405):18–22.CrossRefPubMedPubMedCentral
48.
Shin J, Hunt CM, Suzuki A, Papay JI, Beach KJ, Cheetham TC. Characterizing phenotypes and outcomes of drug-associated liver injury using electronic medical record data. Pharmacoepidemiol Drug Saf. 2013;22(2):190–8.CrossRefPubMed
49.
Bui CL, Kaye JA, Castellsague J, Calingaert B, McQuay LJ, Riera-Guardia N, et al. Validation of acute liver injury cases in a population-based cohort study of oral antimicrobial users. Curr Drug Saf. 2014;9(1):23–8.CrossRefPubMed
50.
Lo Re V 3rd, Carbonari DM, Forde KA, Goldberg D, Lewis JD, Haynes K, et al. Validity of diagnostic codes and laboratory tests of liver dysfunction to identify acute liver failure events. Pharmacoepidemiol Drug Saf. 2015;24(7):676–83.CrossRefPubMed
51.
Udo R, Maitland-van der Zee AH, Egberts TC, den Breeijen JH, Leufkens HG, van Solinge WW, et al. Validity of diagnostic codes and laboratory measurements to identify patients with idiopathic acute liver injury in a hospital database. Pharmacoepidemiol Drug Saf. 2016;25(Suppl 1):21–8.CrossRefPubMed
52.
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(11):2437–43.CrossRefPubMed
Metadata
Title
Risk of Acute Liver Injury in Agomelatine and Other Antidepressant Users in Four European Countries: A Cohort and Nested Case–Control Study Using Automated Health Data Sources
Authors
Manel Pladevall-Vila
Anton Pottegård
Tania Schink
Johan Reutfors
Rosa Morros
Beatriz Poblador-Plou
Antje Timmer
Joan Forns
Maja Hellfritzsch
Tammo Reinders
David Hägg
Maria Giner-Soriano
Alexandra Prados-Torres
Miguel Cainzos-Achirica
Jesper Hallas
Lena Brandt
Jordi Cortés
Jaume Aguado
Gabriel Perlemuter
Bruno Falissard
Jordi Castellsagué
Emmanuelle Jacquot
Nicolas Deltour
Susana Perez-Gutthann
Publication date
01-04-2019
Publisher
Springer International Publishing
Published in
CNS Drugs / Issue 4/2019
Print ISSN: 1172-7047
Electronic ISSN: 1179-1934
DOI
https://doi.org/10.1007/s40263-019-00611-9

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