Severe drug-induced liver injury in patients under treatment with antipsychotic drugs: Data from the AMSP study

Abstract

Objectives

Drug-induced liver injury (DILI) has been associated with various antipsychotic drugs (APDs). Comparative studies between individual APDs are largely not available.

Methods

Antipsychotic drug utilisation data and reports of severe antipsychotic DILI were assessed by using data from an observational pharmacovigilance programme—Arzneimittelsicherheit in der Psychiatrie (AMSP)—during the period 1993–2016.

Results

Of the 333,175 patients treated with APDs, a total of 246 (0.07%) events of severe DILI were identified. Phenothiazines were associated with significantly higher rates of severe DILI (0.03%, 95% CI = 0.02–0.04) than thioxanthenes (0.01%, 95% CI = 0.00–0.02) or butyrophenones (0.01%, 95% CI = 0.00–0.01). Among individual drugs, olanzapine (0.12%, 95% CI = 0.10–0.16), perazine (0.09%, 95% CI = 0.05–0.15) and clozapine (0.09%, 95% CI = 0.10–0.12 ranked highest. In 78 cases (31.7%), combination therapies with antipsychotic and antidepressant drugs or with two or more APDs were considered responsible. Male sex and a diagnosis of mania were associated with significantly higher rates of severe DILI while older patients (≥65 years old) were significantly less often affected.

Conclusions

In the present analysis of a representative psychiatric inpatient cohort, olanzapine, perazine, and clozapine were the most common individual APDs associated with severe DILI.

Keywords:

• AMSP programme
• severe drug-induced liver injury
• antipsychotic drugs
• adverse drug reactions
• psychiatric inpatients

Acknowledgements

The authors are grateful to all participating hospitals and drug monitors for their voluntary and careful collection of data.

Disclosure statement

The AMSP drug safety programme is facilitated by non-profit associations in Germany, Austria and Switzerland. The AMSP programme has been supported with unrestricted educational and research grants since 1993 by the following companies:

Austrian companies: Astra Zeneca Österreich GmbH, Boehringer Ingelheim Austria, Bristol-Myers Squibb GmbH, CSC Pharmaceuticals GmbH, Eli Lilly GmbH, Germania Pharma GmbH, GlaxoSmithKline Pharma GmbH, Janssen-Cilag Pharma GmbH, Lundbeck GmbH, Novartis Pharma GmbH, Pfizer Med Inform, and Wyeth Lederle Pharma GmbH.

German companies: Abbott GmbH & Co. KG, AstraZeneca GmbH, Aventis Pharma Deutschland GmbH GE–O/R/N, Bayer Vital GmbH, Boehringer Mannheim GmbH, Bristol-Myers-Squibb, Ciba Geigy GmbH, Desitin Arzneimittel GmbH, Duphar Pharma GmbH & Co. KG, Eisai GmbH, Esparma GmbH Arzneimittel, GlaxoSmithKline Pharma GmbH & Co. KG, Hoffmann-La Roche AG Medical Affairs, Janssen-Cilag GmbH, Janssen Research Foundation, Knoll Deutschland GmbH, Lilly Deutschland GmbH Niederlassung Bad Homburg, Lundbeck GmbH & Co. KG, Novartis Pharma GmbH, Nordmark Arzneimittel GmbH, Organon GmbH, Otsuka-Pharma Frankfurt, Pfizer GmbH, Pharmacia & Upjohn GmbH, Promonta Lundbeck Arzneimittel, Rhone-Poulenc Rohrer, Sanofi-Synthelabo GmbH, Sanofi-Aventis Deutschland, Schering AG, SmithKlineBeecham Pharma GmbH, Solvay Arzneimittel GmbH, Synthelabo Arzneimittel GmbH, Dr. Wilmar Schwabe GmbH & Co., Thiemann Arzneimittel GmbH, Troponwerke GmbH & Co. KG, Upjohn GmbH, Wander Pharma GmbH, and Wyeth-Pharma GmbH.

Swiss companies: AHP (Schweiz) AG, AstraZeneca AG, Bristol-Myers Squibb AG, Desitin Pharma GmbH, Eli Lilly (Suisse) S.A., Essex Chemie AG, GlaxoSmithKline AG, Janssen-Cilag AG, Lundbeck (Suisse) AG, Organon AG, Pfizer AG, Pharmacia, Sanofi-Aventis (Suisse) S.A., Sanofi-Synthelabo SA, Servier SA, SmithKlineBeecham AG, Solvay Pharma AG, Wyeth AHP (Suisse) AG, and Wyeth Pharmaceuticals AG.

Disclaimer statements: K. Druschky, S. Bleich, R. R. Engel, J. Seifert, H. B. Maier, A. Neyazi, J. Baumgärtner, S. Stübner, Y. J. Rudolph, H. Schwörer, E. Rüther, D. Degner: no conflicts of interest to be declared; S. Toto, and R. Grohmann are project managers of the AMSP programme; S. Toto has been a member of the advisory board for Otsuka and Janssen-Cliag and has received speaker’s honoraria from Janssen-Cilag, Lundbeck, Otsuka and Servier. J. Seifert has taken part in an educational event sponsored by Otsuka and Lundbeck.