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.

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.

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.

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.

The liver is the organ by which the majority of substances are metabolized, including psychotropic drugs. There are several pharmacokinetic changes in end-stage liver disease that can interfere with the metabolization of psychotropic drugs. This fact is particularly true in drugs with extensive first-pass metabolism, highly protein bound drugs and drugs depending on phase I hepatic metabolic reactions. Psychopharmacological agents are also associated with a risk of hepatotoxicity. The evidence is insufficient for definite conclusions regarding the prevalence and severity of psychiatric drug-induced liver injury. High-risk psychotropics are not advised when there is pre-existing liver disease, and after starting a psychotropic agent in a patient with hepatic impairment, frequent liver function/lesion monitoring is advised. The authors carefully review the pharmacokinetic disturbances induced by end-stage liver disease and the potential of psychopharmacological agents for liver toxicity.

Clozapine is an effective antipsychotic drug but is associated with serious side effects. Most treatment guidelines give no clear recommendations on regular monitoring of liver function tests, even though up to 60% of patients experience elevations in hepatic transaminases, with 15% to 30% experiencing an elevation two to three times greater than normal. Though elevations in liver function tests are often transient and asymptomatic, there are many reported cases of clozapine-induced hepatotoxicity, with damage to the liver, involvement of multiple organs, and even fulminant liver failure arising with moderate clozapine doses. This case report describes a Chinese woman who developed hepatotoxicity on a low dose of clozapine, and reviews the relevant literature.

Systematic assessment of the prevalence and pattern of liver function test (LFT) abnormalities associated with regular antipsychotics in adult humans and consideration of management of such abnormalities.

Systematic search identifying cohort, cross-sectional or case studies/series, reporting LFT abnormalities in patients receiving regular antipsychotics. EMBASE, PsychINFO, and MEDLINE were searched for studies in English from record onset.

Abstracts were independently screened for eligibility by 2 researchers. Ineligible studies included those that did not report LFT reference ranges, those that studied fewer than 10 patients on a given antipsychotic, and those studying children.

Key variables in group studies were extracted. Case studies/series were examined for patient outcome.

Ten group studies and 91 case studies/series were eligible, although quality was poor. All groups receiving regular antipsychotics had a prevalence of LFT abnormalities greater than chance. The median percentage of patients with any abnormal LFT on any antipsychotic was 32%, with a range of 5% to 78%. The median percentage of patients with clinically significant elevations was 4%, with a range of 0% to 15%. Transaminases were most commonly elevated. Abnormalities were generally asymptomatic, arose within 6 weeks, and were either stably persistent or resolved with continued treatment. Case reports suggested that antipsychotics can be associated with severe hepatitis, fatal in a small minority of cases. Chlorpromazine is most commonly associated with acute liver injury.

The LFT abnormalities in patients receiving regular antipsychotics are common but generally mild and transient. Very rarely, a severe or fatal hepatic injury can emerge.

Fulminant hepatic failure (FHF) refers to the rapid development of severe acute liver injury with impaired synthetic function and encephalopathy in a person who previously had a normal liver or had wellcompensated liver disease. The potential causes of FHF are numerous, but viral or toxin-induced hepatitis are the most common. Clozapineinduced hepatotoxicity has rarely been reported in the literature, occurs via an unknown mechanism and results in liver biochemical abnormalities that are usually of no clinical significance. In approximately 30% to 50% of patients treated with clozapine, there is an asymptomatic rise in serum aminotransaminase levels; however, there are no current guidelines for routine monitoring of liver function tests and liver enzymes during its use. Fatal fulminant hepatitis has only been reported in three patients receiving clozapine. A case of fatal FHF that occurred in a schizophrenic woman who began clozapine therapy shortly before her illness developed is described.

Atypical antipsychotic drugs commonly cause asymptomatic increase in the liver enzymes and serum bilirubin levels. However they rarely may induce a serious hepatic toxicity. In this article we aimed to evaluate the effect of atypical antipsychotic drugs namely olanzapine, risperidone and quetiapine on the hepatic enzymes and serum bilirubin levels in psychiatric patients.

Chart reviews of 312 patient followed-up at Psychiatry Department of Zonguldak Karaelmas University Hospital were examined in detail. The patients whose baseline and follow-up liver function tests including alanine aminotransfeaminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), alkaline phosphotase (ALP) and serum bilirubin that were measured before and within the treatment period of first and sixth months were enrolled. Forty eight males and 62 females whose ages ranging from 12 to 65 years were eligible for this study (no pregnant case was present).

The repartition according to treatment is as follows: olanzapine (n=33), risperidone (n=29), and quetiapine (n=48). Two of the 110 patients (1.8%) presented with increased AST levels of up to 4 fold and ALT of thrice the basal level and needed to stop treatment (AST increase in one female with olanzapine 20 mg/day; ALT increase in one male with olanzapine 30 mg/day). Thirty of the 110 patients (27.2%) showed asymptomatic increases in ALT, AST, GGT and serum bilirubin levels in the first month of the study. After 6 months of the treatment, abnormalities in the liver function tests were observed in 25 patients (22.7%).

These results were in accordance with previous studies that asymptomatic increase of liver enzymes are common but significant liver enzyme elevations are rare during atypical antipsychotic treatment. We suggest that obtaining baseline liver enzyme tests before atypical antipsychotic therapy and monitoring regularly specifically in patients with risk factors for liver damage during therapy.

Clozapine-induced hepatotoxicity is not infrequent and usually transient. It mostly causes asymptomatic elevation of liver transaminases. "Elevation in liver enzymes to what extent should preclude further treatment?" or "Is only a dose-reduction sufficient?" are questions yet to be answered. The present article uses a case report to discuss the treatment alternatives when liver enzymes reach three times the upper normal limits during the clozapine therapy.

In the following case report, the authors describe a 27-year-old male patient diagnosed with schizophrenia, resistant to different atypical and typical antipsychotics. Based on the pathological findings of our patient and a review of the literature, the author summarizes the reasons for the liver enzymes increase and treatment alternatives during clozapine treatment.

Substantial improvement was achieved with clozapine therapy. Increase in liver enzymes at the beginning of the clozapine treatment was successfully managed with a multidisciplinary approach: the treatment was initially withdrawn, afterwards restarted, and carefully continued.

The authors demonstrate that clozapine may be cautiously continued in selected patients who showed marked psychiatric improvement with clozapine in the face of liver enzyme elevation.

Platelet dysfunction and thrombocytopenia rarely occur during clozapine therapy, but constitute an important source of morbidity and mortality if they are not detected and therapy is discontinued. The manufacturer recommends discontinuing clozapine when the platelet count falls below 100,000/muL and resuming therapy when the count returns to within normal range (150,000-450,000/muL). If thrombocytopenia recurs, clozapine should be permanently discontinued. The authors report a rare case of long-term thrombocytopenia persisting 40 months postclozapine treatment. In addition, increased in vitro platelet [14C]serotonin release was observed in the presence of the drug, suggesting an immune-related cause for the thrombocytopenia.