A review of liver function tests during treatment with atypical antipsychotic drugs: A chart review study

Progress in Neuro-Psychopharmacology & Biological Psychiatry 31 (2007) 1255 – 1260 www.elsevier.com/locate/pnpbp

A review of liver function tests during treatment with atypical antipsychotic drugs: A chart review study Nuray Atasoy a,⁎, Ayten Erdogan b , Irem Yalug c , Ulkem Ozturk a , Numan Konuk a , Levent Atik a , Yucel Ustundag d a Department of Psychiatry, Zonguldak Karaelmas University, Faculty of Medicine, Zonguldak, Turkey Department of Child and Adolescent Psychiatry, Zonguldak Karaelmas University, Faculty of Medicine, Zonguldak, Turkey c Department of Psychiatry, Kocaeli University, Faculty of Medicine, Kocaeli, Turkey Department of Internal Medicine, Division of Gastroenterology, Zonguldak Karaelmas University, Faculty of Medicine, Zonguldak, Turkey b

d

Received 22 March 2007; received in revised form 14 May 2007; accepted 14 May 2007 Available online 25 May 2007

Abstract Objective: 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. Method: 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). Results: 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%). Conclusion: 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. © 2007 Elsevier Inc. All rights reserved. Keywords: Atypical antipsychotic; Hepatotoxicity; Liver enzymes; Olanzapine; Quetiapine; Risperidone

1. Introduction Recent studies showed that liver enzyme abnormalities were not only seen with typical antipsychotics drugs but also with atypical

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; GGT, gamma glutamyl transpeptidase; IDB, Indirect biluribin; DB, direct biluribin. ⁎ Corresponding author. Zonguldak Karaelmas Üniversitesi, Tıp Fakültesi Psikiyatri Anabilim Dalı, 67600, Kozlu, Zonguldak, Turkey. Tel./fax: +90 372 261 02 43. E-mail address: [email protected] (N. Atasoy). 0278-5846/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2007.05.005

antipsychotics (Gaertner et al., 2001; Mouradian-Stamatiadis et al., 2002; Garcia-Unzueta et al., 2003; Erdogan et al., 2004). Asymptomatic elevation of liver enzymes has been observed in approximately 50% of patients treated with atypical antipsychotics (Hummer et al., 1997; Kumra et al., 1997; Szigethy et al., 1999). However, serious hepatotoxicity with these agents has been rarely reported (Dumotier et al., 2002; Ozcanli et al., 2006). The clozapine related hepatotoxicity has been well documented. To date one case of clozapine associated fatal fulminant hepatitis (Macfarlane et al., 1997) and seven cases of cholestatic or mixed hepatitis have been reported (Schmidt et al., 1987; Dorta et al., 1989; Kellner et al., 1993; Hovens et al., 1994; Thatcher

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et al., 1995; Worrall et al., 1995; Lammert and Matern, 1997). Serious hepatotoxicity induced by olanzapine has also been published in the current literature (Raz et al., 2001; Llinares Tello et al., 2005; Esposito et al., 2005). Immunoallergic hepatitis, acute hepatocellular-cholestatic liver injury and hepatocellular hepatitis have been reported to be associated with olanzapine (Raz et al., 2001; Jadallah et al., 2003; Tchernichovsky and Sirota, 2004). Several cases of risperidone induced hepatotoxicity; cholestatic hepatitis and immunoallergic hepatitis have been reported (Fuller et al., 1996; Kumra et al., 1997; Krebs et al., 2001; Esposito et al., 2005; Radzik et al., 2005). There is only one case report of subfulminant liver failure associated with quetiapine (El Hajj et al., 2004). Up to date there has not been any reports of serious hepatotoxicity associated with other atypical antipsychotics; ziprasidone, aripipirazole, and amisulpiride. Fifty-three percent of patients treated with clozapine alone showed an increase in the ALT levels and 39% showed an increase in AST levels (Hummer et al., 1997). Olanzapine and risperidone also commonly cause asymptomatic increase in liver enzyme levels (Tollefson et al., 1997; Gomez et al., 2000). It has been reported transient, nondose-dependent, asymptomatic liver enzyme elevations in olanzapine-treated patients (Conley and Meltzer, 2000; Gonzalez-Heydrich et al., 2003) and this elevation was more marked with divalproex combination (Gonzalez-Heydrich et al., 2003). Similar results were found in risperidone treated patients (Kumra et al., 1997; Szigethy et al., 1999). Garver (2000) reviewed side effects of quetiapine and reported that a small percentage (1%) of quetiapine-treated patients exhibit transient and asymptomatic increases in liver enzymes. Although other atypical antipsychotics were relatively new compared to clozapine, recent studies began to reveal several cases of hepatotoxicity with olanzapine, risperidone and quetiapine as well. It can take a long period to reveal their unknown adverse effects on liver. To date there is no study in the literature comparing these three atypical antipsychotics with regard to hepatotoxicity potentials. Moreover, there is no consensus on the necessity for testing these patients using these drugs for the liver enzyme elevations. A study comparing their hepatobiliary side effect profiles for a period of time may highlight on these issues. Therefore in the present study we aimed to evaluate retrospectively the clinical relevance of liver enzyme abnormalities associated with atypical antipsychotics treatment.

therapies from June 2005 to March 2006. Baseline patient demographics including patient age, gender, comorbid medical conditions and past medical history were compiled. Laboratory data were analyzed to determine if there is any change in liver function tests including ALT, AST, GGT, ALP and serum bilirubin. These tests had been obtained before and after the atypical antipsychotics treatment. Patients were grouped by the type of antipsychotic they received such as olanzapine, risperidone or quetiapine. Ziprasidone, sertindole and aripiprazole were not included in the atypical antipsychotic group as because they are newer atypical medications and the timeframe used for this study did not allow for creation of sufficiently sized samples of patients receiving these medications. The criteria for inclusion were patients under 65 years of age receiving olanzapine, risperidone or quetiapine with any of the psychiatric diagnosis. In order to enroll in the study, all patients were required to have a minimum of one month of follow-up and had normal liver enzymes at baseline. The criteria for exclusion were lacking follow-up information, prescriptions for more than one antipsychotic on the same date, use of antipsychotics less than 15 days, a history of past or present alcohol dependence and other substance abuse and evidence or history of hepatic disease or other medical diseases. Monotherapy was defined as the absence of simultaneously administered medication. 3. Laboratory data I. Baseline liver enzymes information was defined as the measured liver function tests (ALT, AST, GGT, ALP and serum biluribins) before the initiation of atypical antipsychotics treatment. Follow-up liver enzymes information was defined as any liver enzymes measured within the first month and after the six months of treatment. II. For purposes of this chart review study, abnormal liver function was defined by serum ALT, AST, GGT, ALP or serum bilirubin values falling outside the normal laboratory ranges. The following limits were defined as elevations of liver enzymes values: ALT (7–35 U/L for women, 10– 40 U/L for men), AST (7–35 U/L for women, 10–40 U/L for men), GGT (5–39 U/L for women, 10–66 U/L for men), and ALP (N 240 U/L for women, N270 U/L for men). III. Clinically relevant increases of liver enzymes was defined established reference range of 3-fold elevations of ALT, AST, GGT and 2-fold elevations of ALP and greater than normal values of DB (N0.4 mg/dl) and IDB (N0.8 mg/dl).

2. Methods This study was conducted at the Department of Psychiatry, Faculty of Medicine, Karaelmas University in Zonguldak, Turkey. It was designed as a retrospective review through the available computerized medical records of patients treated with atypical antipsychotics namely olanzapine, risperidone and quetiapine for any psychiatric disturbances. The database includes information of subjects from psychiatric inpatient unit. All the patient's prescription charts and medical records were reviewed in order to identify those who were prescribed antipsychotic medication and dosages or combination

In our clinic, if there is an elevation in hepatic parameters upon treatment with medication, patients are examined and followed-up with regular laboratory monitoring with collaboration of department of internal medicine. When ALT, AST, GGT reached to three times of the upper normal limits and ALP reached to two times of the upper normal limits, we preferred to reduce the dose initially, if enzymes elevation persisted we withdraw the drugs. Exclusion of other causes such as chronic viral hepatitis B and C, alcoholic liver disease, hemochromatosis, and nonalcoholic fatty liver disease is done as well.

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4. Statistical analyses Data collected from medical, laboratory and pharmacy records was noted and entered into a database. Relations between two or more variables were described by [chi]2 test, t-test. Analysis of variance or the Mann–Whitney U-test was applied to compare continuous variables where appropriate. Due to the distribution of the frequencies of liver enzymes and bilirubin above normal range were in small numbers, the difference between groups were analysed with Fisher exact [chi]2 test adjusted by Bonferroni correction. Adjusted type 1 error was accepted as 0.017 (0.05/3). The association between antipsychotic use and liver enzyme changes with time was measured by analysis of covariance (ANCOVA). p b 0.05 (two-tailed) was considered statistically significant. Further data analysis was descriptive. 5. Results The charts of 312 inpatients were reviewed and 194 patients treated with atypical antipsychotic drugs were scrutinized. Five patients excluded because of using antipsychotics less than 15 days. Seventy-six patients treated with atypical antipsychotic drugs were excluded due to absence of follow-up of liver enzymes and serum biluribin levels. Three of patients having a hepatic enzyme increase before the antipsychotic therapy were excluded. Of these, and according to inclusion and exclusion criteria, 110 patients with either olanzapine (n = 33), risperidone (n = 29) or quetiapine (n = 48) alone were finally included in the study (age range, 12–63) (mean age: 35.8 years), (48 male, 62 female), (no pregnant patient was available). Ziprasidone and aripiprazole were not included in the atypical antipsychotic group, as the timeframe used for this study did not allow for creation of sufficiently sized samples of patients receiving these medications (n = 4, n = 1 respectively). Diagnosis of patients were psychotic disorders (n = 62), bipolar disorders (n = 27), anxiety disorders (n = 19) and dementia (n = 3). Table 1 shows the clinical parameters of each study group. Liver enzyme elevation greater than 3 fold of the normal ranges was observed in 1.8% of the patients. Two of the 110 patients (1.8%) presented with increased AST levels of up to 4 fold and ALT levels of up 3 fold of the basal level and needed to Table 1 Clinical parameters of study groups Variables

Olanzapine (n = 33)

Quetiapine (n = 48)

Risperidone (n = 29)

Age (year) ± SD Gender (M/F) Daily dose (mg/day) Psychotic disorders (n: %) Bipolar disorders (n: %) Anxiety disorders (n: %) Dementia (n: %)

33.73 ± 9.48 17/16 15 ± 8.48

39.04 ± 11.28 20/28 244.2 ± 309.5

33.14 ± 15.22 11/18 2.93 ± 1.72

22 (66.7%)

20 (41.7%)

20 (69.0%)

7 (21.2%)

11 (22.9%)

8 (27.6%)

4 (12.1%)

14 (29.2%)

1 (3.4%)

–

3 (6.3%)

–

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stop treatment (AST increase in one female with olanzapine 20 mg/day; ALT increase in one male with olanzapine 30 mg/ day). When the drugs were discontinued, the liver enzyme levels returned to normal in both cases. Thirty one of the 110 patients (28.1%) showed an asymptomatic increase in one or more of the liver enzymes in the first month of this study. An increase in one or more of ALT, AST, GGT, ALP or serum bilirubin levels to greater than the normal ranges was distributed as follows: 30.3% with olanzapine, 27.6% with risperidone, and 27.1% with quetiapine treatments. After 6 months of the treatment with these agents, increased enzyme levels were observed in 27 patients (24.5%). An increase in one or more of these liver emzymes to greater than the normal ranges was distributed as follows: 18.2% with olanzapine, 27.6% with risperidone and 27.1% with quetiapine. Table 2 shows the detailed frequencies of hepatic enzyme elevations in three antipsychotic treated groups. Group comparisons showed no significant differences with regard to the frequencies of increase in any of ALT, AST, GGT, ALP or serum bilirubin levels in the first month and after the 6 months of the treatment with different drugs (p N 0.05). The association between antipsychotic use and liver enzyme changes with time was measured by analysis of covariance (ANCOVA). Baseline liver enzymes and biluribin were evaluated as covariate variable. Adjusted levels of first and sixth month levels of liver enzymes and biluribin are presented in Table 3. A significant correlation between baseline levels of ALT, AST, GGT, IDB, ALP and first and sixth month levels was found (p b 0.0001; p = 0.015; p b 0.0001; p b 0.0001; p b 0.0001 respectively), however no significant correlation was found between baseline levels of DB and first and sixth month levels of DB (p = 0.241). There was no significant interaction between groups and first and sixth month levels of ALT, AST, GGT, IDB, DB, and ALP (p = 0.166; p = 0.234; p = 0.211; p = 0.565; p = 0.378; p = 0.05 respectively). These results show that difference between groups is not related to time; also difference between first and sixth month measurements is not related to groups. There was no significant difference between periods in each group in ALT, AST, GGT, IDB except DB and ALP (p = 0.245; p = 0.139; p = 0.092; p = 0.092 respectively). There was a significant difference between first and sixth month levels of DB in each group and sixth month levels of DB was significantly higher than first month levels of DB (p = 0.019). There were no significant difference in ALT, AST, GGT, IDB and DB between groups in each period (p = 0.674; p = 0.120; p = 0.617; p = 0.816; p = 0.361 respectively). Frequencies of liver enzyme and serum bilirubin elevations greater than the conventional upper limits in first month were 20 of 62 (32.2%) in female group and 11 of 48 (22.9%) in male group. In the sixth month were as follows 19 of 62 (30.6%) in female group and eight of 48 in male group (16.6%). There was no gender difference regarding the frequency of liver enzyme elevation during the first and sixth months of treatment (respectively p = 0.19 and p = 0.07). Frequencies of liver enzyme and serum bilirubin elevations greater than the conventional upper limits in all patients treated with monotherapy were as follows: eight patients in olanzapine group (24.4%); seven

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patients in quetiapine group (14.5%); six patients in risperidone group (27.5%). In combined therapy group elevations were as follows: two patients in olanzapine group (6.0%); six patients in quetiapine group (12.5%); two patients in risperidone group (6.8%). Age was not found as an independent risk factor for liver enzyme elevation during treatment with these drugs (p N 0.05). 5.1. Olanzapine Olanzapine-treated group consisted of 33 patients (mean age: 33.6 years, age range, 18–56), (17 male, 16 female). Mean treatment dose was 14.8 mg/day (5 to 30). Two (8 mg daily dosage) patients presented with increased AST and ALT of thrice the basal level and needed to stop treatment. Ten of the 33 patients (30.3%) showed asymptomatic increases in one or more of liver enzymes in the first month of the study. Olanzapine led to the defined increase of one enzyme above the normal range in 9%, of two enzymes in 3%, of three enzymes in 3%, and of four enzymes in 4% of the patients. Increase in bilirubin levels above the normal range was seen 6% of treated patients. After the 6 months with olanzapine treatment, the increased enzyme levels were observed only in 6 patients (18.8%). Olanzapine led to the defined increase of one enzyme above the normal range in 15.1%, of two enzymes in 3% of the patients.

Table 3 Adjusted means of first and sixth month levels of liver enzymes and biluribines

ALT1 ALT2 AST1 AST2 GGT1 GGT2 ALP1 ALP2 IDB1 IDB2 DB1 DB2

Olanzapine means ± SD

Quetiapine means ± SD

Risperidone means ± SD

27.8 ± 14.4 24.5 ± 14.3 30.4 ± 16.9 28.6 ± 13.4 33.4 ± 25.8 26.3 ± 23.9 130.7 ± 72.7 111.9 ± 71.1 0.50 ± 0.45 0.38 ± 0.21 0.10 ± 0.05 0.16 ± 0.11

23.2 ± 14.0 26.7 ± 14.0 24.1 ± 16.8 25.1 ± 13.4 28.7 ± 25.4 32.7 ± 23.5 95.2 ± 72.6 106.9 ± 71.3 0.47 ± 0.41 0.43 ± 0.20 0.14 ± 0.06 0.18 ± 0.12

20.6 ± 13.9 26.1 ± 13.9 20.5 ± 17.1 24.1 ± 13.6 24.6 ± 25.8 27.5 ± 23.6 141.5 ± 71.0 112.1 ± 70.8 0.41 ± 0.43 0.40 ± 0.21 0.11 ± 0.05 0.20 ± 0.10

ALT; alanine aminotransferase, AST; aspartate aminotransferase, ALP; alkaline phosphatase, GGT; gamma glutamyl transpeptidase, IDB; Indirect biluribines, DB; Direct biluribines, 1; within the first month, 2; within the sixth month.

Increased serum bilirubin above the normal range was seen 6.8% of these patients. Nine of 29 patients (31%) presented with increased liver enzymes at the sixth month of treatment. The defined increase of one enzyme above the normal range in 24.1%, of two enzymes 3.4% in risperidone group. At that time, the increase in serum bilirubin levels above the normal range was seen in 6.8% of the patients on risperidone treatment.

5.2. Risperidone

5.3. Quetiapine

There were 29 patients (mean age: 33.1 years, age range, 12– 63) on risperidone treatment (11 male, 18 female).The mean treatment dose was 2.9 mg (range; 1 to 8). Liver enzyme elevation with risperidone treatment was modest and none of them had AST and ALT 3 times higher than the basal level. Eight of 29 patients presented with increased AST, ALT, GGT or serum bilirubin values falling outside the normal laboratory ranges within the treatment period of one month (27.5%). Risperidone led to the defined increase of one enzyme above the normal range in 20.6%, of two enzymes in 6.8% of patients.

Forty-eight patients (mean age: 42.4 years, age range, 17– 67 years) were on the quetiapine (20 male, 28 female). Mean treatment dose was 244 mg/day (25 to 1200 mg). None of the quetiapine-treated patients in our study presented increased AST or ALT of thrice the basal level. Thirteen of the 48 patients showed asymptomatic increases in liver enzymes in the first month of the study (27.0%). The defined increase of one enzyme above the normal range in 22.9%, of two enzymes 8.3%, of three enzymes 4.1% patients in quetiapine group. At end of the first month, the increase of serum bilirubin levels was seen at 8.3% of patients in quetiapine group. After 6 months, the increase in serum enzyme levels was observed in 11 patients (22.9%). The defined increase of one enzyme above the normal range was seen in 12.5%, of two enzymes 6.2%, of three enzymes 2%, of four enzymes 2% of patients in quetiapine group. Increase of bilirubin levels above the normal range was seen only in 2% of patients in quetiapine group.

Table 2 The frequency of liver enzyme and serum bilirubin elevation in the first and sixth months of the treatment with the antipsychotics are documented Variable

Olanzapine (n = 33)

Quetiapine (n = 48)

Risperidone (n = 29)

χ2; p

ALT 1 ALT2 AST1 AST2 GGT1 GGT2 IDB1 IDB2 DB1 DB2 ALP1 ALP2

4 (12.1%) 3 (9.4%) 6(18.2%) 2 (6.7%) 2 (6.1%) 1 (3.3%) 3 (9.1%) 2 (6.3%) – – 1 (3%) 1 (3.1%)

4 (8.3%) 5 (10.4%) 3 (6.3%) 6 (13.3%) 6 (12.5%) 6 (12.8%) 3 (6.3%) 2 (4.2%) – – 1 (2.1%) 1 (2.1%)

3 (10.3%) 4 (13.8%) 0 3 (12%) 1 (3.4%) 1 (3.7%) 2 (6.9%) 2 (6.9%) – 1 (3.4%) 3 (10.3%) 1 (3.4%)

χ2 = 0.31; p = 0.5 χ2 = 0.38; p = 0.3 χ2 = 0.31; p = 0.5 χ2 = 0.85; p = 0.6 χ2 = 2.25; p = 0.3 χ2 = 3.11; p = 0.2 χ2 = 0.24; p = 0.8 χ2 = 0.30; p = 0.8 – χ2 = 3.09; p = 0.2 χ2 = 0.14; p = 0.9

ALT: alanine aminotransferase; AST: aspartate aminotransferase; ALP: alkaline phosphatase; GGT: gamma glutamyl transpeptidase; IDB: Indirect biluribines; DB: Direct biluribines; 1; within the first month, 2; within the sixth month.

6. Discussion In this retrospective study, we evaluated the abnormalities of liver enzymes and serum biluribin levels induced by three atypical antipsychotics; olanzapine, risperidone and quetiapine. Mild asymptomatic increase of liver enzymes was observed in 28.1% of the cases within the first month of treatment and 24.5% of the cases after the six months of treatment with these agents. According to our findings, atypical antipsychotic druginduced serious hepatotoxicity is a rare event since only in two cases (1.8%) we found serious liver enzymes abnormalities.

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Most of the literature cases with clozapine (Thompson et al., 1998; Panagiotis, 1999; Gaertner et al., 2001; Larsen et al., 2001), olanzapine (Cadario, 2000; Raz et al., 2001; GonzalezHeydrich et al., 2003), and risperidone (Werapongset et al., 1998; Whitworth et al., 1999; Krebs et al., 2001) reported liver enzymes abnormalities similar to our observations. In accordance with our findings, Pae et al. (2005) found hepatic enzyme elevation in 26.9% of patients in the olanzapine group and in 14.2% of patients in the risperidone group. The frequencies found in the present study were somewhat higher than other frequencies reported previously, whereas transient liver enzyme elevation was noted in 9.4% of olanzapine-treated patients in phase II and III clinical trials and in 0.1–1% of risperidonetreated patients (Mesotten et al., 1989; Beasley et al., 1996). These discrepancies might be due to the differences between the designs and sample characteristics of studies. There are only a few researches that compare the different atypical antipsychotic drugs with regard to potential hepatotoxicity in the literature. Clinical consequences such as cholestatic jaundice, chronic ductopenic syndrome and even cirrhosis have been described in several cases treated with atypical antipsychotics, mainly with clozapine and olanzapine (0.1–1%) (Gaertner et al., 2001; Mouradian-Stamatiadis et al., 2002). Although other atypical antipsychotics were relatively new compared to clozapine, recent studies began to reveal several cases of hepatotoxicity with olanzapine and risperidone as well (Krebs et al., 2001; Esposito et al., 2005; Llinares Tello et al., 2005; Rettenbacher et al., 2006). Similar to our findings, Mouradian-Stamatiadis et al. (2002) studied the hepatic enzyme levels of 23 patients treated by risperidone, amisulpiride, olanzapine, or clozapine. They observed serious liver enzyme elevation in six cases; three of them were related to the olanzapine, however olanzapine-treated patients were also using other drugs or consuming alcohol. Similarly Gaertner et al. (2001) retrospectively reviewed liver enzymes abnormalities in 7263 patients treated with typical and atypical antipsychotics; clozapine, haloperidol, perazine, and perphenazine. Serious liver enzymes abnormalities with clozapine were reported to be around 1% in that study. Recently Pae et al. (2005) reviewed charts of 667 patients treated with risperidone (n = 289) or olanzapine (n = 145) and they found liver enzyme elevations were higher in the olanzapine-treated group than in the risperidone-treated group. In a study of Bender et al. (2004) including 86,439 patients, increased liver enzymes were mostly reported in clozapine, olanzapine and perazine patients. Accordingly, an increase in liver enzymes was most frequent with olanzapine. However, in about half of these cases, olanzapine was not imputed alone. In contrast with their findings, in our study, the frequencies of liver enzyme elevations above the normal range within the different treatment regimens did not show significant differences with regard to the medication they used. Precise mechanisms of the hepatotoxicity remain unclear. Hypersensitivity syndrome or eosinophilia has been reported, suggesting a possible immuno-allergic mechanism. Presence of risk factors have been retrieved, in some observations, like high daily dosage, high plasmatic concentration, age, alcoholism,

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obesity or antecedent of hepatic disorders like Gilbert syndrome (Lewis, 2000). Special care has been advised for these patients. Hepatic injuries generally occurred within the first weeks of treatment but this delay highly varied in the literature from 1 to 8 weeks, 12 days to 5 months, 1 day to 17 months for clozapine, olanzapine and risperidone, respectively (Dumotier et al., 2002). In concordant with the previous findings, in our study, liver enzyme elevation of thrice the basal level occurred only in two patients within the first months of treatment. Nevertheless, we could not show statistically significant differences in the frequency of asymptomatic liver enzyme elevations between the first and sixth months of treatment. Liver injury of the hepatitic AST, ALT, or GGT or the cholestatic AP and bilirubin elevations type have both been described (Selim and Kaplowitz, 1999). In the present study, the asymptomatic enzyme elevation patterns of olanzapine, risperidone and quetiapine had almost identical patterns of elevated liver enzymes. Co-medication with hepatotoxic drugs might increase the risk as it has been suggested previously. Prescription of antidepressive, mood stabilizing or hypnotic drugs may increase the susceptibility to hepatic trouble (Chitturi and George, 2002; Gonzalez-Heydrich et al., 2003). A notable drug is valproic acid, which has been associated with asymptomatic rises in serum transaminase levels and with rare cases of fatal hepatic reactions (Sherlock and Dooley, 1993). However, we found that the subpopulation having the above-defined liver pathology showed no difference with regard to combined treatment with the population having the normal values of all liver enzymes and serum bilirubin levels. In contrast GonzalezHeydrich et al. (2003) reported that combined treatment with olanzapine and divalproex was associated with higher elevations in hepatic enzymes (42%) than treatment with either agent alone. The present study has some limitations. The present study has a retrospective nature, and some selection biases cannot be excluded. Although the data obtained from 110 patients were used in this study, the small number of subgroups limited the opportunity to investigate the stratification of hepatic enzymes with adequate statistical power. Further research needed with larger samples to allow more reliable conclusions. Another limitation of the present study was that we cannot absolutely determine what factors might increase the risk of hepatotoxicity in atypical antipsychotics treated patients, since in most of the cases the patients were taking other medications. Also other factors that might affect the level of hepatic enzymes, such as weight gain, changes of other metabolic parameters like glucose and serum lipids were not evaluated in present study. The potential correlations need to be explored. 7. Conclusion In summary, these cases highlight the need for obtaining baseline liver function tests before starting atypical antipsychotic therapy and regular monitoring of serum aminotransferase values that had any of the risk factors for liver damage during maintenance therapy. Precautions should be taken when using atypical antipsychotic agents in patients with pre-existing hepatic disorders, in patients using potentially hepatotoxic drugs or if signs or symptoms of hepatic impairment appear. Because little

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