INTRODUCTION

Attention Deficit Hyperactivity Disorder (ADHD) is the most common psychiatric disorder among children and adolescents. Atomoxetine is the first non stimulant medication that has been FDA approved for the treatment of ADHD. Several placebo-controlled trials showed good efficacy and tolerability of atomoxetine. One or two daily doses are required to reach optimal benefit (1,2).

Atomoxetine was associated with relatively few adverse drug reactions: dyspepsia, nausea, vomiting, fatigue, rash, decreased appetite and weight loss (3). Rare but more severe adverse effects of both stimulants and atomoxetine are possible cardiovascular effects. Both drug classes can increase blood pressure and pulse rate, though mostly on a clinically insignificant level (4,5). Furthermore, atomoxetine has been associated with an increased rate of suicidal ideation among children (6) and recently received a black box warning for increased suicidality in children and adolescents. Because atomoxetine is a relatively new treatment option, it is even more important for children and adolescents treated with this drug that are well-monitored and do receive regular physical check-ups. Studies of safety and effectiveness of atomoxetine conducted on large samples have found no clinically significant abnormalities of liver function tests with treatment. However the labeling of atomoxetine was recently modified in 2004 to include severe liver injury among adverse events, based on recent case reports of hepatotoxicity with atomoxetine (7,8). Atomoxetine may cause clinically significant hepatotoxicity either by metabolic idiosyncrasy or by inducing autoimmune hepatitis (7,8).

Although to date there has been no recommendation for clinicians to do routine monitoring of liver function tests during atomoxetine treatment, it has been recommended that parents and clinicians should be informed of the evidence of liver problems during the treatment with this agent (9). Recently, Erdoğan et al. (10) reported an acute liver failure that is probably associated with atomoxetine. Therefore, it may be argued that the effects of atomoxetine on liver functions of children and adolescents are currently unclear.

In this study we aimed to investigate the changes in the liver enzyme levels associated with one month of atomoxetine treatment in children and adolescents.

METHODS

All patients who were referred in Bakırköy Prof. Dr. Mazhar Osman Research and Training Hospital for Psychiatry and Neurological Disease Child and Adolescent Clinic outpatient unit between September 2010 and December 2010, and diagnosed as ADHD according to DSM-IV and started on atomoxetine were included in the study.

In our clinic, we usually measure baseline and follow-up liver function tests if a pharmacotherapeutic agent which is metabolized by liver has been started. Patients were included in this study if patients’ hepatobiliary function tests including ALT and AST, GGT, ALP and serum bilirubin levels were measured at baseline and one month follow-up.

Patients using vitamin/mineral supplements and/or herbal remedies, having a history of hepatic disease, having any other active and chronic illness, having a comorbid alcohol or drug abuse, having comorbid psychiatric illness, using other medications beside atomoxetine or who used any drug in the last two weeks before atomoxetine has been started and lacking follow-up information were excluded.

Retrospective chart review was done for 216 patients with a diagnosis of ADHD according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV) criteria (12). The numbers of patients treated with atomoxetine were 84. Patients’ age at initial evaluation, gender, weight, medical history were recorded from the charts. Atomoxetine dosage information, symptomatic and/or adverse events reported during the treatment, baseline and one month follow-up liver function tests results were recorded. Twenty-two patients, who used other medications besides atomoxetine, having another chronic illness and lacking baseline and follow-up information were excluded. Finally, 62 patients between 6 and 15 years of age were eligible for the study.

For this study the following limits were defined as elevations of liver enzymes: for ALT: >35 U/L for females, >40 U/L for males; for AST: >35 U/L for females, >40 U/L for males; for GGT: >39 U/L for females, >66 U/L for males; for ALP: between 1 to 9 years of age, >420 U/L for females and males; between 10 to 11 years of age, >560 U/L for females and males; between 12 to 13 years of age, >420 U/L for females, >495 U/L for males; between 14 to 15 years of age; >230 U/L for females, >515 U/L for males; between 16 to 19 years of age, >130 U/L for females, >260 U/L for males. The following limits were defined as elevations of total bilirubin values: >1.2 mg/dl. Elevations in liver enzymes and bilirubin were accepted as clinically relevant if ALT, AST, GGT and ALP levels increased to two-folds of established reference ranges and if total bilirubin values were greater than normal.

Statistical Analysis

Statistical Package for the Social Sciences for Windows, Version 15.0 (Chicago, IL., USA) was used for statistical comparisons. To evaluate the changes in liver enzymes and total bilirubin levels between baseline and first month, paired samples t-test applied. Covariance analysis used to evaluate the effects of age, gender and dosage on liver enzymes changes. The significance level was accepted as 0.05.

RESULTS

Eighty-four patients treated with atomoxetine were identified. Twenty-two patients who used any other drug in addition to atomoxetine or whose hepatobiliary function tests data were missing were excluded from the study. Sixty two child and adolescent patients treated with atomoxetine were included in the study. The study included 51 (82.3%) male, 11 (17.7%) female, ages between 6 and 15 (mean age 10.07±2.52). The dose of atomoxetine ranged from 10 to 60 mg/day or 0.5 to 1.32 mg/kg/day. Atomoxetine was routinely started with a dose of 0.5 mg per kilogram body weight, with a target dose of 1.2 mg per kilogram body weight after one week.

Liver Function Tests

No case of jaundice or hepatic failure was seen in the treatment period of one month. ALT levels were significantly lower than baseline at first month. The mean levels of other liver enzymes and bilirubin levels of the patients at the first month were not significantly different than baseline. Mean levels of total bilirubin was 0.58 mg/dl at baseline and 0.60 mg/dl at first month. Comparison of liver enzymes at the baseline and first month were presented in Table 1. Clinically nonsignificant elevation of liver enzymes and bilirubin from the defined normal levels was observed in 8 different patients. The elevation of AST above the normal range was seen in 1 (0.62%), increase of GGT in 3 (1.86%), increase of total bilirubin was seen in 4 (2.48%) patients. No variables (age, gender, dosage) predicted change between those two end-points (Table 2 and Graphic 1).

DISCUSSION

In this study, we retrospectively evaluated the changes of liver enzymes and serum bilirubin levels with one month of atomoxetine treatment in sixty-two children and adolescents with ADHD. In 8 patients elevation of liver enzymes and bilirubin levels was observed, but this was found as clinically nonsignificant. Interestingly ALT levels were significantly lower than baseline at first month. The variables that might have caused this change were not investigated because of the retrospective design of the study. But it was considered to be a possible feature specific to this study group.

Our results are consistent with previous studies that reported no significant changes of liver enzymes and bilirubin levels with atomoxetine treatment on children and adolescents (13-15). Takahashi et al. (13) assessed efficacy and safety of atomoxetine in 245 Japanese children and adolescents over 8 weeks. They did not find clinically meaningful treatment differences in laboratory values including liver enzymes between atomoxetine and placebo used patients. Similarly Svanborg et al. (14) studied the safety of atomoxetine in Swedish children and adolescents, over 10 weeks and did not find clinically meaningful treatment differences in laboratory values. Wilens et al. (15) evaluated the efficacy and tolerability of atomoxetine in 617 children and adolescents with ADHD. They did not find clinically meaningful treatment differences in adverse event rates, vital signs, laboratory values including liver enzymes between atomoxetine and placebo used patients. In a meta-analysis (13-study; seven double-blind/placebo-controlled, six open-label), Kratochvil et al. (16) evaluated the effectiveness and tolerability of long-term atomoxetine treatment among young children with ADHD. They concluded that no changes were deemed both statistically significant and clinically meaningful among any vital signs, electrocardiographic measures, or laboratory tests including liver enzymes.

However in literature, there have been reports of hepatic abnormalities with atomoxetine. In an investigation of case reports identified by a computerized search that contained potential hepatic events, of the 7962 pediatric and adult patients treated with atomoxetine in clinical trials, 41 were identified as requiring further analysis. Of those 41 cases, none progressed to liver failure, and most of these events were mild increases in ALT and AST levels (17). During the 4 years after the market launch of atomoxetine, 351 cases of liver injury were related to the drug treatment for ADHD. Of those 351 cases, 69 had explanations unrelated to the use of the drug, 146 presented insufficient information to assess the cause, 133 contained confounding factors and were labeled as possibly related to drug use, and the remaining 3 cases reported liver injury probably related to atomoxetine use (17). Lim et al. (7) reported two children presented with acute hepatitis in the first month of treatment with atomoxetine. Later Stojanovski et al. (8) reported hepatotoxicity in a child treated with atomoxetine. According to these case reports atomoxetine may have a considerable potential to cause liver function abnormalities. In accordance with these cases the labeling of atomoxetine was recently modified (late 2004) to include severe liver injury among adverse events, based on mentioned case reports of hepatotoxicity with atomoxetine (7,8).

In reported cases, reasons showed for significant hepatotoxicity with atomoxetine were metabolic idiosyncrasy or autoimmune hepatitis induction (7,8). Idiosyncratic drug-induced liver injury (DILI) is unpredictable and does not depend directly on dose. Although some drugs cause DILI through direct damage to hepatocytes or interference with bile secretion, others cause delayed, often idiosyncratic DILI with clinical features, such as mild lymphocytic infiltrate, that are reminiscent of allergic reactions involving activation of the adaptive immune system. Idiosyncratic DILI is rare even among individuals who are exposed to drugs that are known to be hepatotoxic. It occurs in 1 in 5000 to 1 in 100,000 individuals who take medication; the risk is lower for some drugs (18). Pharmacovigilance and pharmacoepidemiology studies in children are infrequent for all drugs. Although in the present study no variables (age, gender, dosage) predicted change between baseline and follow-up values, susceptibility to drug toxicity changes with age and can differ largely between newborns, toddlers, adolescents and adults, because of age-dependent maturation of pharmacokinetic processes. This is particularly so for the liver which is the main organism for drug metabolism. Most drugs are metabolized through the cytochrome P450 (CYP 450) isoenzymes. The change in maturation and activity of CYP 450 occurring with age may have a strong influence on the capacity to eliminate drugs (19).

This study has a number of limitations. Firstly this study was limited in power by the number of patients and retrospective design. Another limitation of this study is that we did not collect information about patients’ prior exposure to atomoxetine or other medications before the washout period. However, to ameliorate this limitation, we included only patients who have normal baseline liver function tests in the study. Further studies are needed with larger randomized samples in prospective design to allow more reliable conclusions.

CONCLUSION

In conclusion, it appears that atomoxetine treatment in the short term commonly does not lead to clinically significant liver function changes at therapeutic doses in children and adolescents. However based on the reported hepatotoxicity cases, further studies are needed to assess the liver function tests abnormalities and role of variables over these abnormalities in youth population.

REFERENCES

1. Michelson D, Allen AJ, Busner J, Casat C, Dunn D, Kratochvil C, Newcorn J, Sallee FR, Sangal RB, Saylor K, West S, Kelsey D, Wernicke J, Trap NJ, Harder D. Once-daily atomoxetine treatment for children and adolescents with attention-deficit hyperactivity disorder: a randomized, placebo-controlled study. Am J Psychiatry 2002; 159:1896-1901.

2. Spencer T, Heiligenstein JH, Biederman J, Faries DE, Kratochvil CJ, Conners CK, Potter WZ. Results from two proof-of-concept, placebo-controlled studies of atomoxetine in children with attention-deficit/hyperactivity disorder. J Clin Psychiatry 2002; 63:1140-1147.

3. Caballero J, Nahata MC. Atomoxetine hydrochloride for the treatment of attention deficit/hyperactivity disorder. Clin Ther 2003; 25:3065-3083.

4. Rapport MD, Moffitt C. Attention deficit/hyperactivity disorder and methylphenidate. A review of height/weight, cardiovascular, and somatic complaint side effects. Clin Psychol Rev 2002; 22:1107-1131.

5. Wernicke JF, Faries D, Girod D, Brown J, Gao, H, Kelsey D, Quintana H, Lipetz R, Michelson D, Heiligenstein J. Cardiovascular effects of atomoxetine in children, adolescents, and adults. Drug Saf 2003; 26:729-740.

6. Wooltorton E. Suicidal ideation among children taking atomoxetine (Strattera). CMAJ 2005; 173:1447.

7. Lim JR, Faught PR, Chalasani NP, Molleston JP. Severe liver injury after initiating therapy with atomoxetine in two children. J Pediatr 2006; 148:831-834.

8. Stojanovski SD, Casavant MJ, Mousa HM, Baker P, Nahata MC. Atomoxetine-induced hepatitis in a child. Clin Toxicol 2007; 45:51-55.

9. Graham J, Banaschewski T, Buitelaar J, Coghill D, Danckaerts M, Dittmann RW, Döpfner M, Hamilton R, Hollis C, Holtmann M, Hulpke-Wette M, Lecendreux M, Rosenthal E, Rothenberger A, Santosh P, Sergeant J, Simonoff E, Sonuga-Barke E, Wong IC, Zuddas A, Steinhausen HC, Taylor E, European guidelines group. European guidelines on managing adverse effects of medication for ADHD. Eur Child Adolesc Psychiatry 2011; 20:17-37.

10. Erdogan A, Ozcay F, Piskin E, Karaman MG, Bilezikci B, Calik M, Tekin I, Haberal M. Idiosyncratic liver failure probably associated with atomoxetine: a case report. J Child Adolesc Psychopharmacol 2011; 21:295-297.

11. DuPaul GJ, Power TJ, Anastopoulos AD, Reid R. ADHD rating scale-iv: Checklists, norms, and clinical interpretation. New York: Guilford Press, 1998.

12. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders DSM-IV-TR. American Psychiatric Association, 2000.

13. Takahashi M, Takita Y, Yamazaki K, Hayashi T, Ichikawa H, Kambayashi Y, Koeda T, Oki J, Saito K, Takeshita K, Allen AJ. A randomized, double-blind, placebo-controlled study of atomoxetine in Japanese children and adolescents with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 2009; 19:341-350.

14. Svanborg P, Thernlund G, Gustafsson PA, Hägglöf B, Poole L, Kadesjö B. Efficacy and safety of atomoxetine as add-on to psychoeducation in the treatment of attention deficit/hyperactivity disorder: A randomized, double-blind, placebo-controlled study in stimulant-naïve Swedish children and adolescents. Eur Child Adolesc Psychiatry 2009; 18:240-249.

15. Wilens TE, Kratochvil C, Newcorn JH, Gao H. Do children and adolescents with ADHD respond differently to atomoxetine? J Am Acad Child Adolesc Psychiatry 2006; 45:149-157.

16. Kratochvil CJ, Wilens TE, Greenhill LL, Gao H, Baker KD, Feldman PD, Gelowitz DL. Effects of long-term atomoxetine treatment for young children with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2006; 45:919-927.

17. Bangs ME, Jin L, Zhang S, Desaiah D, Allen AJ, Read HA, Regev A, Wernicke JF. Hepatic events associated with atomoxetine treatment for attention-deficit hyperactivity disorder. Drug Saf 2008; 31:345-354.

18. Ju C, Reilly T. Role of immune reactions in drug-induced liver injury (DILI). Drug Metab Rev 2012; 44:107-115.

19. Chalasani N, Björnsson E. Risk factors for idiosyncratic drug-induced liver injury. Gastroenterology 2010; 138:2246-2259.