Clozapine was the first atypical antipsychotic approved for treatment of schizophrenia. Because it is associated with severe and potentially fatal side effects (agranulocytosis), its use is restricted to refractory schizophrenia, and monitoring during therapy is required. Clozapine therapy is associated with serum aminotransferase elevations and in rare instances has been linked to clinically apparent acute liver injury.


Clozapine (kloe" za peen) is an atypical antipsychotic medication that appears to act both as a dopamine (D) and serotonin (5-HT2) receptor antagonist. Clozapine was introduced into clinical practice in 1971, but subsequently withdrawn in 1975 after reports of fatal agranulocytosis with its use. Nevertheless, because of its potent activity, clozapine was approved for restricted use in refractory schizophrenia in the United States in 1989 and only with surveillance using close monitoring of complete blood counts. As a result, use of clozapine has been limited. Clozapine was also approved to prevent suicide in patients with schizophrenia or schizoaffective disorder. Clozapine is available as scored tablets of 25 and 100 mg in generic forms and under the brand names of Clozaril. The dosage of clozapine varies greatly. The starting dose is 12.5 mg once or twice daily, which can be cautiously increased to target doses of 300 to 450 mg daily clinical response and tolerability. Common side effects include sedation, tremors, drooling, dizziness, headache, hypotension and syncope, dry mouth, constipation, and weight gain. Uncommon, but potential severe side effects include severe neutropenia, agranulocytosis, orthostatic hypotension and syncope, falls, seizures, cardiomyopathy, prolongation of the QTc interval, diabetes, dyslipidemia, weight gain and neuroleptic malignant syndrome. Clozapine has a boxed warning of severe neutropenia orthostatic hypotension, bradycardia and syncope, seizure, myocarditis and cardiomyopathy and increased mortality in elderly patients with dementia-related psychosis. It is available only as a part of a Risk Evaluation and Mitigation Strategy (REMS) program that includes certification of healthcare providers and pharmacies, patient consent, and scheduled regular monitoring and reporting of neutrophil counts.


Serum enzyme elevations arise in up to two-thirds of patients on clozapine but are usually modest and resolve spontaneously after 6 to 12 weeks, often not requiring dose modification or discontinuation. ALT elevations above 3 times ULN arise in 10% to 20% of patients but are usually transient. Occasionally, serum enzyme elevations are associated with symptoms of nausea, weakness and abdominal discomfort, and therapy should be discontinued or managed with careful dose reduction.

Acute, clinically apparent episodes of liver injury with marked liver enzyme elevations and jaundice have been reported in more than fifty patients receiving clozapine and is estimated to occur in ~1:2000 treated patients. The onset of injury is usually within a few days to several weeks after starting, and the pattern of serum enzyme elevations is typically mixed but can be hepatocellular or cholestatic. Severe instances of acute liver injury with progressive hepatic failure and death or need for emergency transplantation have been described usually occurring after a delay in stopping clozapine after onset of evidence of liver injury. Eosinophilia or leukocytosis occur in a proportion of patients, and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome with fever and rash have been reported, although generally mild-to-moderate in severity and self-limited in course. Autoimmune markers are rare. Almost all cases resolve once therapy is stopped, vanishing bile duct syndrome and chronic injury have not been reported.

Likelihood score: A (a rare, but well-known cause of clinically apparent liver injury).

Mechanism of Injury

The mechanism by which clozapine causes liver injury is not known. Cases with features of hypersensitivity suggest that the injury is immunologically mediated. Clozapine is extensively metabolized by the liver, partially via the cytochrome P450 system (CYP 1A2 and others), and production of a toxic or immunogenic intermediate of metabolism may underlie the acute liver injury that can occur on clozapine therapy. Serum enzyme elevations during clozapine therapy can occasionally be managed with dose reduction, suggesting an element of direct hepatotoxicity.

Outcome and Management

The serum aminotransferase elevations that occur on clozapine therapy are often self-limited and usually do not require dose modification or discontinuation of therapy. Most instances of clinically apparent liver injury due to clozapine have been mild-to-moderate in severity and rapidly resolve. Several cases of acute liver failure due to clozapine have been reported, but there have been no instances of chronic liver disease or vanishing bile duct syndrome. Re-exposure is usually followed by reoccurrence of injury with a more rapid time to onset. However, in several instances very cautious reintroduction with a slow escalation of dose has been tolerated without recurrence of liver injury. Persons with intolerance to clozapine can usually tolerate other atypical antipsychotic agents, such as haloperidol, risperidone, quetiapine and olanzapine.

Drug Class: Antipsychotic Agents, Atypicals



Clozapine – Generic, Clozaril®


Antipsychotic Agents


Product labeling at DailyMed, National Library of Medicine, NIH



References updated: 06 June 2023

Abbreviations: DRESS, drug reaction with eosinophilia and systemic symptoms.

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    (47 year old woman with schizophrenia developed eosinophilia at 4 weeks, fever and myalgias at 5 weeks, and jaundice at 8 weeks after starting clozapine [bilirubin 6.0 mg/dL, ALT 254 U/L, GGT 573 U/L, eosinophils 12.9%], resolving rapidly on stopping and not recurring with olanzapine and haloperidol therapy).
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    (Systematic review of 81 studies of clozapine suggests that discontinuation of clozapine is warranted for ALT or AST elevations beyond 3 times ULN, but that dose lowering and rechallenge is sometimes possible).
  • Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology. 2013;144:1419–25. [PubMed: 23419359]
    (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, but none were attributed to clozapine or olanzapine).
  • Kane JP, O'Neill FA. Clozapine-induced liver injury and pleural effusion. Ment Illn. 2014;6:5403. [PMC free article: PMC4274456] [PubMed: 25553232]
    (48 year old woman with schizophrenia developed fatigue and fever [bilirubin 1.4 mg/dL, ALT 894 U/L, Alk P 220 U/L, eosinophils 2390], with worsening of abnormalities until clozapine was stopped, whereupon all tests returned to normal within 6 weeks).
  • Douros A, Bronder E, Andersohn F, Klimpel A, Thomae M, Sarganas G, Kreutz R, et al. Drug-induced liver injury: results from the hospital-based Berlin Case-Control Surveillance Study. Br J Clin Pharmacol. 2015;79:988–99. [PMC free article: PMC4456131] [PubMed: 25444550]
    (Among 76 cases of suspected drug induced liver injury and 377 controls enrolled in a German, prospective hospital-based registry, 5 cases but only 1 control were receiving clozapine [odds ratio=34.6]).
  • Wu Chou AI, Lu ML, Shen WW. Hepatotoxicity induced by clozapine: a case report and review of literature. Neuropsychiatr Dis Treat. 2014;10:1585–7. [PMC free article: PMC4155895] [PubMed: 25210451]
    (45 year old woman with schizophrenia develop fatigue 12 days after switching from olanzapine to clozapine [bilirubin normal, ALT 181 U/L, Alk P not given], resolving within 2 weeks of stopping and recurring [fever and ALT 69 U/L] at a dose of 100 mg daily).
  • Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A, Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol. 2014;13:231–9. [PubMed: 24552865]
    (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, but none were attributed to clozapine or olanzapine).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al. United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology. 2015;148:1340–52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 5 [0.7%] were attributed to antipsychotic medications, including 3 to quetiapine and 2 to olanzapine, but none to clozapine).
  • Drugs for psychotic disorders. Med Lett Drugs Ther. 2016;58(1510):160–4. [PubMed: 27960194]
    (Concise review of medications available in the US for therapy of psychotic disorders; mentions that olanzapine can cause aminotransferase elevations, and that olanzapine and ziprasidone can cause DRESS syndrome, but does not mention ALT elevations or hepatotoxicity for any of agents discussed, including aripiprazole, brexpiprazole, cariprazine, clozapine, quetiapine, risperidone, asenapine, iloperidone, paliperidone and lurasidone).
  • Lally J, Al Kalbani H, Krivoy A, Murphy KC, Gaughran F, MacCabe JH. Hepatitis, interstitial nephritis, and pancreatitis in association with clozapine treatment: a systematic review of case series and reports. J Clin Psychopharmacol. 2018;38:520–527. [PubMed: 30059436]
    (A systematic review of the literature identified 42 cases of inflammatory reactions to clozapine, including 20 cases of hepatitis which arose within 8 weeks of starting therapy, half with jaundice, 3 fatal and 2 recurred when “successfully rechallenged”).
  • Takács A, Sollychin M, Thomas N, Connally F, Pantelis C. Clozapine rechallenge in a patient with clozapine-induced hepatitis. Australas Psychiatry. 2019;27:535. [PubMed: 31545088]
    (35 year old woman with long standing schizophrenia developed weakness and liver injury within a few months of starting clozapine at age 20, and was tried again on clozapine at age 28 developing abnormal liver tests within 3 days [ALT 136 U/L, Alk P 372 U/L]; was started on a slow titration of clozapine [5 mg daily and increase by 5 mg every 3 days to a final dose of 400 mg daily] at age 31, during which her liver tests remained normal during follow up of 4 years).
  • de Filippis R, Soldevila-Matías P, De Fazio P, Guinart D, Fuentes-Durá I, Rubio JM, Kane JM, et al. Clozapine-related drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: a systematic review. Expert Rev Clin Pharmacol. 2020;13:875–883. [PubMed: 32576056]
    (Systematic review identified publication of 6 cases of DRESS syndrome associated with clozapine hepatotoxicity, including 3 women, 3 men; ages 27 to 73; latency 8-36 days and one 300 days; all with either fever, rash or both; 2 with lymphadenopathy, 4 with eosinophilia, 4 treated with corticosteroids, all recovered, no deaths, 2 who were rechallenged both had recurrence).
  • Zarghami M, Hoseini SD, Kazemi A, Elyasi F. Concurrent hepatotoxicity and neutropenia induced by clozapine. Arch Iran Med. 2020;23:141–143. [PubMed: 32061077]
    (58 year old man with schizophrenia developed fever and weakness within 7 weeks of starting clozapine [150 mg daily] with neutropenia and hepatitis [bilirubin 11.5 mg/dL, ALT 214 U/L, Alk P 215 U/L, neutrophils 352/µL], resolving within one week of stopping therapy).
  • Dias CL, Fonseca L, Gadelha A, Noto C. Clozapine-induced hepatotoxicity: A life threatening situation. Schizophr Res. 2021;235:3–4. [PubMed: 34274796]
    (Two patients: 33 year old man developed nausea and confusion 12 days after starting clozapine [150 mg] with total bilirubin 1.6 mg/dL and ALT 242 U/L, which fell to normal within a month of stopping and clozapine was later re-introduced without recurrence. 48 year old woman developed nausea and dark urine 20 days after adding clozapine to olanzapine with normal bilirubin, ALT 77 U/L, and Alk P 161 U/L, which returned to normal after stopping clozapine and reintroducing olanzapine).
  • de Filippis R, Soldevila-Matías P, Guinart D, De Fazio P, Rubio JM, Kane JM, Schoretsanitis G. Unravelling cases of clozapine-related drug reaction with eosinophilia and systemic symptoms (DRESS) in patients reported otherwise: A systematic review. J Psychopharmacol. 2021;35:1062–1073. [PubMed: 34044659]
    (Systematic review identified publication of 27 cases of DRESS syndrome due to clozapine, most commonly with organ involvement of the lung [12 cases: 44%], liver [11 cases: 41%], heart [9 cases: 33%], kidney [9 cases: 33%], gastrointestinal tract, thyroid and bone marrow; 25 with fever, 11 with rash, 13 atypical lymphocytes, 18 eosinophils, 3 fatal, 4 with recurrence upon reexposure, but only 5 identified as DRESS in the original report).
  • Sernoskie SC, Jee A, Uetrecht JP. The emerging role of the innate immune response in idiosyncratic drug reactions. Pharmacol Rev. 2021;73:861–896. [PubMed: 34016669]
    (Review of the role of the innate immune response in drug induced liver disease, uses clozapine as an example).
  • Revilla-Zúñiga J, Cornejo-Del Carpio J, Cruzado L. Hepatoxicity induced by clozapine: case report and brief review. Rev Colomb Psiquiatr (Engl Ed). 2021:S0034-7450(21)00087-1. English, Spanish. [PubMed: 34167791]
    (39 year old woman with schizophrenia developed jaundice 4 weeks after starting clozapine [200 mg daily] [bilirubin 3.5 mg/dL, ALT 268 U/L, eosinophils 40/µL], with persistence of injury and progressive hepatic failure resulting in multiorgan failure and death 6 weeks after presentation).
  • Druschky K, Toto S, Bleich S, Baumgärtner J, Engel RR, Grohmann R, Maier HB, et al. Severe drug-induced liver injury in patients under treatment with antipsychotic drugs: data from the AMSP study. World J Biol Psychiatry. 2021;22:373–386. [PubMed: 32892689]
    (Among 246 cases of severe liver injury due to antipsychotic medications identified in a prospective registry of German psychiatric hospitals between 1993 and 2016, 46 arose in 38,349 patients [0.12%] who received clozapine [34 as a single antipsychotic agent]; other commonly implicated agents being olanzapine [n=90 of 54,822: 0.16%], quetiapine [34 of 66,209: 0.05%] and risperidone [27 of 51,683: 0.05%]; two fatal cases occurred in olanzapine-treated patients).
  • Ou H, Huang SY. Corticosteroid therapy for clozapine-induced hepatitis and eosinophilia. Am J Ther. 2022;29:e720–e721. [PubMed: 33395053]
    (72 year old woman with schizophrenia developed fever and weakness 4 weeks after starting escalating doses of clozapine [ALT 309 rising to 731 U/L, eosinophils 882 rising to 1907/µL], which improved with stopping clozapine and a short course of corticosteroids, all values being normal 2 months later).
  • Zeiss R, Hafner S, Schönfeldt-Lecuona C, Connemann BJ, Gahr M. Drug-associated liver injury related to antipsychotics: exploratory analysis of pharmacovigilance data. J Clin Psychopharmacol. 2022;42:440–444. [PubMed: 35730552]
    (Review of the VigiBase data base of individual case safety reports on antipsychotics and liver injury found positive hepatic safety signals for olanzapine and clozapine, but none for risperidone, quetiapine, ziprasidone, asenapine, aripiprazole, brexpiprazole, and cariprazine).
  • Shah J, Muir J, Furfaro D, Beitler JR, Dzierba AL. Use of N-acetylcysteine for clozapine-induced acute liver injury: a case report and literature review. J Pharm Pract. 2023;36:463–467. [PubMed: 34284670]
    (46 year old woman with bipolar disorder and psychosis developed fever and lethargy 1 month after switching from risperidone to clozapine [bilirubin 0.3 rising to 0.7 mg/dL, ALT 364 to 1313 U/L, Alk P 75 to 299 U/L, INR 1.2 to 1.3], who upon worsening was treated with intravenous N-acetylcysteine with subsequent improvement).
  • Gunther M, Dopheide JA. Antipsychotic safety in liver disease: a narrative review and practical guide for the clinician. J Acad Consult Liaison Psychiatry. 2023;64:73–82. [PubMed: 36180017]
    (Review of the literature on hepatotoxicity of antipsychotic medications and guidance on their use in patients with liver disease characterizes chlorpromazine, clozapine, and olanzapine as having the greatest risk for causing liver injury; quetiapine and risperidone as having moderate risk, haloperidol as having low risk, and paliperidone, aripiprazole, lurasidone, and loxapine as having low risk).