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Hepatitis, Interstitial Nephritis, and Pancreatitis in Association With Clozapine Treatment

A Systematic Review of Case Series and Reports

Lally, John, MB, MSc, MRCPsych*†‡; al Kalbani, Hana; Krivoy, Amir, MD; Murphy, Kieran C., MMedSci, PhD, FRCPI, FRCPsych; Gaughran, Fiona, MD, FRCPI, FRCP, FRCPsych*∥; MacCabe, James H., BSc, MBBS, FRCPsych, MSc, PhD*∥

Journal of Clinical Psychopharmacology: October 2018 - Volume 38 - Issue 5 - p 520–527
doi: 10.1097/JCP.0000000000000922
Review Articles
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Purpose/Background Clozapine is the criterion standard in treatment-resistant schizophrenia. We sought to review data on several inflammatory effects associated with clozapine, specifically interstitial nephritis, hepatitis, and pancreatitis.

Methods/Procedures We conducted a systematic review to identify studies, published up until December 2017, describing clozapine-induced hepatitis, nephritis, and pancreatitis. The primary objective was to characterize the clinical characteristics associated with each of the specific inflammatory reactions to clozapine.

Findings/Results We identified 42 cases of inflammatory reactions associated with clozapine treatment- 20 :cases of clozapine-induced hepatitis, 11 cases of nephritis, and 11 of pancreatitis. The mean (SD) age was 38.8 (11.9) years. The mean (SD) dose of clozapine used was 252.4 (133.7) mg. Time to onset of pancreatitis (17.9 [11.2] days; range 4–35 days) was shorter than that for hepatitis (34.2 [20.1] days; range, 12–90 days) and nephritis (27.9 [27.0]; range, 8–90 days) but was not statistically significant (F = 2.267, P = 0.117). The mean (SD) time to recovery was shorter for cases of pancreatitis (15.7 [18.4] days) compared with cases of hepatitis (25.9 [16.5] days) and nephritis (24.5 [18.9] days). Three cases with hepatitis died. Seven of the cases had a clozapine rechallenge (hepatitis [n = 3], nephritis [n = 1], pancreatitis [n = 3]), with 5 having a recurrence at a mean (SD) onset of 3.5 (2.5) days (range, 1–7 days); 2 hepatitis cases were successfully rechallenged.

Implications/Conclusions Clozapine-induced hepatitis, nephritis, and pancreatitis are uncommon adverse events, reflected in the paucity of case studies in the literature. Early recognition of the signs and symptoms of clozapine-associated hepatitis, nephritis, and pancreatitis is important, as when identified, clozapine should be urgently discontinued. Clozapine is associated with evidence of benign inflammatory processes; the extent to which hepatitis, and other inflammatory reactions, may be on a continuum with these more benign and self-limiting reactions is unclear, and this can only be resolved by prospectively following cohorts of clozapine-treated patients.

From the *Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom;

Department of Psychiatry, Beaumont Hospital, Royal College of Surgeons in Ireland;

Department of Psychiatry, St Vincent's University Hospital, School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland;

§Sackler Faculty of Medicine, Tel-Aviv University, Ramat-Aviv, Israel; and

National Psychosis Service, South London and Maudsley NHS Foundation Trust, London, United Kingdom.

Received January 26, 2018; accepted after revision June 7, 2018.

Reprints: John Lally, MB, MSc, MRCPsych, Department of Psychosis Studies Institute of Psychiatry, Psychology and Neuroscience, King's College London, PO63, De Crespigny Park, London SE5 8AF, United Kingdom (e-mail: john.lally@kcl.ac.uk).

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