Use of N-Acetylcysteine for Clozapine-Induced Acute Liver Injury: A Case Report and Literature Review

Abstract

Purpose: To report a case of clozapine-induced hepatotoxicity managed with intravenous (IV) N-acetylcysteine (NAC) and summarize the available literature. Summary: A 46-year-old woman with history of bipolar disorder with psychotic features presented to the intensive care unit with asterixis and elevations in liver enzymes. The patient had been initiated on risperidone, clozapine, and lithium approximately 1 month prior to admission. After ruling out other possible non-drug etiologies, clozapine was suspected as the likeliest cause of the acute liver injury. Her acute liver injury was managed with the discontinuation of all antipsychotics, administration of IV NAC, and other standard of care supportive measures. Conclusion: Although clozapine has been associated with hepatitis and acute liver failure, there are no reports of NAC used in the management of clozapine-induced hepatotoxicity. NAC was used in our patient after considering the potential benefit and limited adverse effects. The role of NAC in non–acetaminophen-induced acute liver failure remains promising, but more research is warranted.

Repurposing N-acetylcysteine for management of non-acetaminophen induced acute liver failure: an evidence scan from a global health perspective

“…We also identified one additional systematic review that included both acetaminophen-induced ALF as well as ALF associated with other drug injury in pediatric patients, comprising 25 articles; the synthesis in this review did not include substantive differentiation between the two types of ALF, and reached the conclusion that this literature is heterogenous and further research is warranted ( 119 ). A 2023 report describing a case of ALI suspected to be related to clozapine noted that acute encephalopathy improved with use of NAC and supportive care, though aminotransferases continued to trend upward ( 89 ). Improvement in liver function tests was observed in a 2021 case of amiodarone-associated ALI ( 90 ) and a 2020 report of two cases of suspected remdesivir-associated ALI ( 91 ).…”

New Insight Into Mechanisms of Hepatic Encephalopathy: An Integrative Analysis Approach to Identify Molecular Markers and Therapeutic Targets

“…Previous studies have reported hepatotoxic effects for clozapine. 106,107 A number of antineoplastic agents such as calphostin C (a potent inhibitor of protein kinase C), cytarabine, doxorubicin, demecolcine (as a microtubule-depolymerizing agent), fluorouracil (as a thymidylate synthase inhibitor), panobinostat (as a non-selective histone deacetylase inhibitor), belinostat (as a histone deacetylase inhibitor), and paclitaxel were also predicted. Furthermore, amiodarone (an antiarrhythmic agent) and isoproterenol (a non-selective β adrenoceptor agonist) were other annotated drugs for cirrhosis-induced HE.…”

Rethinking Clozapine: Lights and Shadows of a Revolutionary Drug

“…Although the mechanism by which Clozapine causes liver toxicity remains unknown [217], the most recognized side effect is the asymptomatic increase in hepatic transaminase aspartate aminotransferase (AST) and alanine aminotransferase (ALT), found in about 30-50% of patients taking Clozapine, which resolves in 6-12 weeks [238]. Moreover, cases of acute pancreatitis in 0.01-0.1% of the patients treated [217] and cases of fulminant hepatitis in 0.001% of the patients treated [216] have been reported. A case report highlighted the history of a 45-year-old woman with schizophrenia admitted to the hospital where she was put to a cross-titration, from Olanzapine, 2.5 mg daily, to Clozapine, 125 mg daily.…”

“…Due to the distressing reappearance of hallucinations, psychiatrists tried unsuccessfully to reintroduce Clozapine at a low dose (100 mg daily). Liver function was altered again, indicating a strong connection between the patient's hepatitis and Clozapine [216].…”