title: Drug-Induced Liver Injury during Antidepressant Treatment: Results of AMSP, a Drug Surveillance Program.
abstract: BACKGROUND
  Drug-induced liver injury is a common cause of liver damage and the most frequent reason for withdrawal of a drug in the United States. The symptoms of drug-induced liver damage are extremely diverse, with some patients remaining asymptomatic.
  
  
  METHODS
  This observational study is based on data of Arzneimittelsicherheit in der Psychiatrie, a multicenter drug surveillance program in German-speaking countries (Austria, Germany, and Switzerland) recording severe drug reactions in psychiatric inpatients. Of 184234 psychiatric inpatients treated with antidepressants between 1993 and 2011 in 80 psychiatric hospitals, 149 cases of drug-induced liver injury (0.08%) were reported.
  
  
  RESULTS
  The study revealed that incidence rates of drug-induced liver injury were highest during treatment with mianserine (0.36%), agomelatine (0.33%), and clomipramine (0.23%). The lowest probability of drug-induced liver injury occurred during treatment with selective serotonin reuptake inhibitors ([0.03%), especially escitalopram [0.01%], citalopram [0.02%], and fluoxetine [0.02%]). The most common clinical symptoms were nausea, fatigue, loss of appetite, and abdominal pain. In contrast to previous findings, the dosage at the timepoint when DILI occurred was higher in 7 of 9 substances than the median overall dosage. Regarding liver enzymes, duloxetine and clomipramine were associated with increased glutamat-pyruvat-transaminase and glutamat-oxalat-transaminase values, while mirtazapine hardly increased enzyme values. By contrast, duloxetine performed best in terms of gamma-glutamyl-transferase values, and trimipramine, clomipramine, and venlafaxine performed worst.
  
  
  CONCLUSIONS
  Our findings suggest that selective serotonin reuptake inhibitors are less likely than the other antidepressants, examined in this study, to precipitate drug-induced liver injury, especially in patients with preknown liver dysfunction.
authors.affiliation: Department of Psychiatry and Psychotherapy, Division of Biological Psychiatry, Medical University of Vienna, Austria (Drs Friedrich, Akimova, Konstantinidis, Papageorgiou, Winkler, and Kasper); Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany (Dr Toto); Psychiatric Private Hospital, Sanatorium Kilchberg, Switzerland (Dr Greil); Department of Psychiatry and Psychotherapy, Ludwig Maximilian University, Munich, Germany (Drs Greil and Grohmann); Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria (Dr Huf).
authors.forename: Michaela-Elena
authors.initials: ME
authors.lastname: Friedrich
authors.affiliation: Department of Psychiatry and Psychotherapy, Division of Biological Psychiatry, Medical University of Vienna, Austria (Drs Friedrich, Akimova, Konstantinidis, Papageorgiou, Winkler, and Kasper); Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany (Dr Toto); Psychiatric Private Hospital, Sanatorium Kilchberg, Switzerland (Dr Greil); Department of Psychiatry and Psychotherapy, Ludwig Maximilian University, Munich, Germany (Drs Greil and Grohmann); Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria (Dr Huf).
authors.forename: Elena
authors.initials: E
authors.lastname: Akimova
authors.affiliation: Department of Psychiatry and Psychotherapy, Division of Biological Psychiatry, Medical University of Vienna, Austria (Drs Friedrich, Akimova, Konstantinidis, Papageorgiou, Winkler, and Kasper); Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany (Dr Toto); Psychiatric Private Hospital, Sanatorium Kilchberg, Switzerland (Dr Greil); Department of Psychiatry and Psychotherapy, Ludwig Maximilian University, Munich, Germany (Drs Greil and Grohmann); Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria (Dr Huf).
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Huf
authors.affiliation: Department of Psychiatry and Psychotherapy, Division of Biological Psychiatry, Medical University of Vienna, Austria (Drs Friedrich, Akimova, Konstantinidis, Papageorgiou, Winkler, and Kasper); Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany (Dr Toto); Psychiatric Private Hospital, Sanatorium Kilchberg, Switzerland (Dr Greil); Department of Psychiatry and Psychotherapy, Ludwig Maximilian University, Munich, Germany (Drs Greil and Grohmann); Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria (Dr Huf).
authors.forename: Anastasios
authors.initials: A
authors.lastname: Konstantinidis
authors.affiliation: Department of Psychiatry and Psychotherapy, Division of Biological Psychiatry, Medical University of Vienna, Austria (Drs Friedrich, Akimova, Konstantinidis, Papageorgiou, Winkler, and Kasper); Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany (Dr Toto); Psychiatric Private Hospital, Sanatorium Kilchberg, Switzerland (Dr Greil); Department of Psychiatry and Psychotherapy, Ludwig Maximilian University, Munich, Germany (Drs Greil and Grohmann); Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria (Dr Huf).
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Papageorgiou
authors.affiliation: Department of Psychiatry and Psychotherapy, Division of Biological Psychiatry, Medical University of Vienna, Austria (Drs Friedrich, Akimova, Konstantinidis, Papageorgiou, Winkler, and Kasper); Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany (Dr Toto); Psychiatric Private Hospital, Sanatorium Kilchberg, Switzerland (Dr Greil); Department of Psychiatry and Psychotherapy, Ludwig Maximilian University, Munich, Germany (Drs Greil and Grohmann); Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria (Dr Huf).
authors.forename: Dietmar
authors.initials: D
authors.lastname: Winkler
authors.affiliation: Department of Psychiatry and Psychotherapy, Division of Biological Psychiatry, Medical University of Vienna, Austria (Drs Friedrich, Akimova, Konstantinidis, Papageorgiou, Winkler, and Kasper); Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany (Dr Toto); Psychiatric Private Hospital, Sanatorium Kilchberg, Switzerland (Dr Greil); Department of Psychiatry and Psychotherapy, Ludwig Maximilian University, Munich, Germany (Drs Greil and Grohmann); Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria (Dr Huf).
authors.forename: Sermin
authors.initials: S
authors.lastname: Toto
authors.affiliation: Department of Psychiatry and Psychotherapy, Division of Biological Psychiatry, Medical University of Vienna, Austria (Drs Friedrich, Akimova, Konstantinidis, Papageorgiou, Winkler, and Kasper); Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany (Dr Toto); Psychiatric Private Hospital, Sanatorium Kilchberg, Switzerland (Dr Greil); Department of Psychiatry and Psychotherapy, Ludwig Maximilian University, Munich, Germany (Drs Greil and Grohmann); Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria (Dr Huf).
authors.forename: Waldemar
authors.initials: W
authors.lastname: Greil
authors.affiliation: Department of Psychiatry and Psychotherapy, Division of Biological Psychiatry, Medical University of Vienna, Austria (Drs Friedrich, Akimova, Konstantinidis, Papageorgiou, Winkler, and Kasper); Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany (Dr Toto); Psychiatric Private Hospital, Sanatorium Kilchberg, Switzerland (Dr Greil); Department of Psychiatry and Psychotherapy, Ludwig Maximilian University, Munich, Germany (Drs Greil and Grohmann); Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria (Dr Huf).
authors.forename: Renate
authors.initials: R
authors.lastname: Grohmann
authors.affiliation: Department of Psychiatry and Psychotherapy, Division of Biological Psychiatry, Medical University of Vienna, Austria (Drs Friedrich, Akimova, Konstantinidis, Papageorgiou, Winkler, and Kasper); Department of Psychiatry, Social Psychiatry and Psychotherapy, Hannover Medical School, Hannover, Germany (Dr Toto); Psychiatric Private Hospital, Sanatorium Kilchberg, Switzerland (Dr Greil); Department of Psychiatry and Psychotherapy, Ludwig Maximilian University, Munich, Germany (Drs Greil and Grohmann); Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Vienna, Austria (Dr Huf).
authors.forename: Siegfried
authors.initials: S
authors.lastname: Kasper
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems; D000368:Aged; D000928:Antidepressive Agents / Q000009:adverse effects* / Q000627:therapeutic use*; D001317:Austria / Q000453:epidemiology; D056486:Chemical and Drug Induced Liver Injury / Q000201:enzymology / Q000453:epidemiology*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination / Q000706:statistics & numerical data; D005260:Female; D005858:Germany / Q000453:epidemiology; D006778:Hospitals, Psychiatric / Q000706:statistics & numerical data; D006801:Humans; D015994:Incidence; D007297:Inpatients / Q000706:statistics & numerical data; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D001523:Mental Disorders / Q000188:drug therapy / Q000201:enzymology / Q000453:epidemiology; D008875:Middle Aged; D013557:Switzerland / Q000453:epidemiology
chemical_list: D000928:Antidepressive Agents
keywords: Adverse drug reaction; antidepressants; drug surveillance; elevation of liver enzymes