000078943 001__ 78943 000078943 005__ 20200716101455.0 000078943 0247_ $$2doi$$a10.1007/s40263-019-00611-9 000078943 0248_ $$2sideral$$a111313 000078943 037__ $$aART-2019-111313 000078943 041__ $$aeng 000078943 100__ $$aPladevall-Vila, M. 000078943 245__ $$aRisk 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 000078943 260__ $$c2019 000078943 5060_ $$aAccess copy available to the general public$$fUnrestricted 000078943 5203_ $$aBackground: Agomelatine is a melatonin receptor agonist and serotonin 5-HT 2C 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. 000078943 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc$$uhttp://creativecommons.org/licenses/by-nc/3.0/es/ 000078943 590__ $$a4.786$$b2019 000078943 591__ $$aCLINICAL NEUROLOGY$$b34 / 204 = 0.167$$c2019$$dQ1$$eT1 000078943 591__ $$aPSYCHIATRY$$b23 / 154 = 0.149$$c2019$$dQ1$$eT1 000078943 591__ $$aPHARMACOLOGY & PHARMACY$$b34 / 270 = 0.126$$c2019$$dQ1$$eT1 000078943 592__ $$a1.522$$b2019 000078943 593__ $$aNeurology (clinical)$$c2019$$dQ1 000078943 593__ $$aPsychiatry and Mental Health$$c2019$$dQ1 000078943 593__ $$aPharmacology (medical)$$c2019$$dQ1 000078943 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion 000078943 700__ $$aPottegård, A. 000078943 700__ $$aSchink, T. 000078943 700__ $$aReutfors, J. 000078943 700__ $$aMorros, R. 000078943 700__ $$aPoblador-Plou, B. 000078943 700__ $$aTimmer, A. 000078943 700__ $$aForns, J. 000078943 700__ $$aHellfritzsch, M. 000078943 700__ $$aReinders, T. 000078943 700__ $$aHägg, D. 000078943 700__ $$aGiner-Soriano, M. 000078943 700__ $$0(orcid)0000-0002-5704-6056$$aPrados-Torres, A. 000078943 700__ $$aCainzos-Achirica, M. 000078943 700__ $$aHallas, J. 000078943 700__ $$aBrandt, L. 000078943 700__ $$aCortés, J. 000078943 700__ $$aAguado, J. 000078943 700__ $$aPerlemuter, G. 000078943 700__ $$aFalissard, B. 000078943 700__ $$aCastellsagué, J. 000078943 700__ $$aJacquot, E. 000078943 700__ $$aDeltour, N. 000078943 700__ $$aPerez-Gutthann, S. 000078943 773__ $$g33, 4 (2019), 383-395$$pCNS drugs$$tCNS DRUGS$$x1172-7047 000078943 8564_ $$s196897$$uhttps://zaguan.unizar.es/record/78943/files/texto_completo.pdf$$yVersión publicada 000078943 8564_ $$s105492$$uhttps://zaguan.unizar.es/record/78943/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada 000078943 909CO $$ooai:zaguan.unizar.es:78943$$particulos$$pdriver 000078943 951__ $$a2020-07-16-09:08:59 000078943 980__ $$aARTICLE