Özden Şükran ÜNERİ, MAZLUM ÇÖPÜR, CANAN TANIDIR, Hatice GÜNEŞ, Ayten ERDOĞAN

Liver enzymes and bilirubin levels during atomoxetine treatment in children and adolescents

Amaç: Atomoksetin, Dikkat Eksikliği Hiperaktivite Bozukluğu (DEHB) tedavisinde FDA tarafından kullanım onayı alan, stimulan olmayan ilk ajandır. Bu çalışmanın amacı, DEHB’si olan çocuk ve ergenlerde bir aylık atomoksetin kullanımıyla ilişkili olarak karaciğer enzim düzeylerindeki değişikliklerin araştırılmasıdır. Yöntem: Çalışmaya, Bakırköy Ruh ve Sinir Hastalıkları Eğitim ve Araştırma Hastanesi Çocuk ve Ergen Psikiyatri Polikliniğinde, Eylül 2010 ve Aralık 2010 arasında muayene edilen, DEHB tanısı konup atomoksetin başlanan tüm hastalar dahil edilmiştir. Toplamda, 6-15 yaş arası 62 hasta çalışma için uygun bulunmuştur. Dosyalardan geriye yönelik olarak, hastaların tedavi öncesi ve bir aylık takipleri sonrasındaki alanin aminotransferaz (ALT), aspartat aminotransferaz (AST), gamma glutamil transferaz (GGT), alkalin fosfataz (ALP) ve total bilirubin seviyesi not edilmiştir. Bulgular: Bir aylık tedavi sırasında karaciğer yetmezliği veya sarılık gelişen hiçbir vakaya rastlanmamıştır. İlk ayda ölçülen ALT değerleri, bazal ALT düzeylerine göre anlamlı olarak düşük bulunmuştur. Birinci ayın sonundaki diğer karaciğer enzim düzey ortalamaları ve bilirubin düzeyleri ile bazal düzeyler arasında anlamlı bir fark bulunmamıştır. Sekiz hastada (%12.9) karaciğer enzimlerinde ve bilirubin düzeyinde, tanımlanan normal değerlere göre klinik olarak önemli olmayan yükselmeler saptanmıştır. Sonuç: Randomize olmayan bir örneklemde geriye dönük dosya taramasının kısıtlılıkları olmakla birlikte, atomoksetin tedavisi kısa dönemde terapotik dozlarda çocuk ve ergenlerde karaciğer fonksiyonlarında bir değişime yol açmıyor gibi görünmektedir. Ancak atomoksetin kullanan genç popülasyonda karaciğer fonksiyon testlerindeki değişimleri ve bu değişimler üzerinde diğer değişkenlerin rolünü inceleyen ileri çalışmalara ihtiyaç vardır.

Atomoksetin tedavisi alan çocuk ve ergenlerde karaciğer enzimleri ve bilirubin düzeyleri

Objective: Atomoxetine is the first non stimulant medication approved by FDA for the treatment of Attention Deficit Hyperactivity Disorder (ADHD). The objective of this study was to investigate the changes in the liver enzymes levels associated with one month atomoxetine treatment in children with ADHD. Method: A retrospective chart review was done to evaluate patients treated with only atomoxetine in Bakırköy Prof. Dr. Mazhar Osman Research and Training Hospital for Psychiatry and Neurological Disease, Child and Adolescent Psychiatry Clinic outpatient unit between September 2010 and December 2010. A total of 62 patients between 6-15 years of age were eligible for the study. Patients’ baseline and one month follow-up hepatobiliary function tests including alanine aminotransferase (ALT) and aspartat aminotransferase (AST), gamma glutamyl transferase (GGT), alkaline phosphatase (ALP) and total serum bilirubin levels were noted. Results: No case of jaundice or hepatic failure was seen during the one month treatment period. ALT levels in the first month were significantly lower than baseline. The mean levels of other liver enzymes and bilirubin levels of the patients at the first month were not significantly different than baseline. Clinically nonsignificant elevation of liver enzymes and bilirubin from the defined normal levels were observed in 8 (12.9%) patients. Conclusion: Taking into account the limitations of a retrospective chart review in nonrandomized samples, it appears that atomoxetine treatment in short term does not lead to abnormal liver function changes at therapeutic doses in children and adolescents. Prospective studies are needed to assess liver function tests abnormalities in youth population using atomoxetine.

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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.