Metabolic and Endocrine Side Effects of Atypical Antipsychotic Drugs in Children and Adolescents

Abstract

Comorbid psychiatric disorders, frequent hospitalization, multiple outpatient treatment, prior history of hypertension, obesity and lipid dysregulation are associated with higher risk of metabolic syndrome in children. Side effects of antipsychotic drugs and their management have recently become a major subject of research due to enhanced antipsychotic drug usage in child and adolescents. Prevention strategies are usually preferred to secondary or tertiary strategies in the management of metabolic syndrome associated with antipsychotic drugs. Clinicians should present multidisciplinary approach to endocrine and metabolic side effects due to antipsychotic use in pediatric patient groups and avoid multiple drug use in such patients. In this paper, we briefly reviewed metabolic side effects of second generation antipsychotic drugs in child and adolescent population, possible mechanisms of susceptibility to metabolic syndrome and pharmacological and non pharmacological treatment approach to prevention of weight gain.

Keywords

• Metabolic syndrome, second generation antipsychotic, child and adolescent

Çocuk ve Ergenlerde Atipik Antipsikotik İlaçların Metabolik ve Endokrin Yan Etkileri

Öz

Çocuklarda eş tanılı psikiyatrik bozukluklar, sık hastaneye yatış, ayaktan tedavi başvurularının fazlalığı ve hipertansiyon, obezite ve lipid bozuklukları öyküsü yüksek metabolik sendrom riski ile ilişkilendirilmiştir. Çocuk ve ergenlerde antipsikotik ilaç kullanımının artması nedeniyle ilaç yan etkileri ve bu yan etkilerin yönetimi de önem kazanmaktadır. Literatürde genel olarak antipsikotiklerle ilişkili metabolik sendromda önleyici yaklaşımların ikincil ve üçüncül yaklaşımlara göre daha çok tercih edildiği vurgulanmıştır. Klinisyenlerin çocuk ve ergen hasta grubunda antipsikotik ilaç kullanımına bağlı endokrin ve metabolik yan etkilere multidisipliner yaklaşım sergilemeleri ve çoklu ilaç kullanımından kaçınmaları önerilmektedir. Bu yazıda çocuk ve ergen hasta grubunda ikinci kuşak antipsikotik ilaçların metabolik yan etkileri, metabolik sendroma yatkınlığın olası nedenleri ve kilo artışını önlemeye yönelik farmakolojik ve farmakolojik olmayan tedavi yaklaşımları kısaca gözden geçirilmiştir.

Anahtar Kelimeler

• metabolik sendrom, atipik antipsikotikler, yan etkiler, çocuk, ergen

Kaynakça

1. Zito JM, Safer DJ, de Jong-van den Berg LT, Janhsen K, Fegert JM, Gardner JF et al. A three-country comparison of psychotropic medication prevalence in youth. Child Adolesc Psychiatry Ment Health 2008; 2:26.
2. Pappadopulos E, Macintyre Ii JC, Crismon ML, Findling RL, Malone RP, Derivan A et al.Treatment recommendations for the use of antipsychotics for aggressive youth (TRAAY). Part II. J Am Child Adolesc Psychiatry. 2003; 42:145-161.
3. Keefe RS, Silva SG, Perkins DO, Lieberman J. Effects of atypical antipsychotic drugs on neurocognitive impairment in schizophrenia: a review and metaanalysis. Schizophr Bull 1999; 25:201-222.
4. Cooper WO, Arbogast PG, Ding H, Hickson GB, Fuchs DC, Ray WA. Trends in prescribing of antipsychotic medications for US children. Ambul Pediatr 2006; 6:79
5. Olfson M, Blanco C, Lui L, Moreno C, Laje G. National trends in the outpatient treatment of children and adolescents with antipsychotic drugs. Arch Gen Psychiatry 2006; 63: 679- 685.
6. Taş F, Güvenir T, Miral S. Bir çocuk ve ergen psikiyatrisi kliniğinde yatarak tedavi gören hastalarda ilaç kullanımı. Çocuk ve Gençlik Ruh Sağlığı Dergisi 2007; 14:139- 150.
7. McIntyre RS, Jerrell JM. Metabolic and cardiovascular adverse events associated with antipsychotic treatment in children and adolescents. Arch Pediatr Adolesc Med 2008;
8. Alberti KG, Zimmet P, Shaw J. IDF Epidemiology Task Force Consensus Group. The metabolic syndrome-a new world wide definition. Lancet 2005; 366(9491):1059-1062.

9. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 2002; 287:356-359.
10. Öyekçin DG. Bir grup şizofreni ve şizoaffektif bozukluk hastasında metabolik send- rom sıklığı. Anadolu Psikiyatri Dergisi 2009; 10:26-33.
11. Cook S, Weitzman M, Auinger P, Nguyen M, Dietz WH. Prevalence of a metabolic syndrome phenotype in adolescents: findings from the third National Health and Nutrition Examination Survey, 1988-1994. Arch Pediatr Adolesc Med 1994; 157:821- 827.
12. Dhillo WS. Appetite regulation: an overview. Thyroid 2007; 17: 433-445.
13. Fernandez JR, Redden DT, Pietrobelli A, Allison DB. Waist circumference percentiles in nationally representative samples of African American, European- American, and Mexican-American children and adolescents. J Pediatr 2004; 145:439- 444.
14. Correll CU, Carlson HE. Endocrin and metabolic adverse effects of psychotropic medications in children and adolescents. J Am Acad Child Adolesc Psychiatry 2006; 45: 771- 791.
15. Correll CU. Multiple antipsychotic use associated with metabolic and cardiovascular adverse events in children and adolescents. Evid Based Ment Health 2009; 12:93.
16. Bjorntorp P Heart and soul: stress and the metabolic syndrome. Scand Cardiovasc J 2001; 35:172-177.
17. Dwyer DS, Weeks KR, Aamodt EJ. Drug discovery based on genetic and metabolic findings in schizophrenia. Expert Rev Clin Pharmacol 2008; 1:773-789.
18. Ellingrod VL, Miller D, Taylor S, Moline J, Holman T, Kerr J. Metabolic syndrome and insulin resistance in schizophrenia patients receiving antipsychotics genotyped for the Methylene tetrahydro folate Reductase (MTHFR) 677C/T and 1298A/C Variants. Schizophr Res 2008; 98:47-54.
19. Burkart J, Fox R, Rotatori A. Obesity of mentally retarded individuals: prevalence, characteristics, and intervention. Am J Ment Defic 1985; 90:303-312.
20. Kang SG, Lee HJ, Park YM, Choi JE, Han C, Kim YK et al. Possible association between the 2548 A/G polymorphism of the leptin gene and olanzapin induced weight gain. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32:160-163.
21. Pena R, Marquiana D, Serrano A, Elfakih Y, de Baptista EA, Carrizo E et al. Frequency of abnormal correlation between leptin and body mass index during first and second generation antipsychotic drug treatment Schizophr Res 2008; 106:315- 319.
22. Jerrell JM, McInytre RS. Adverse events in children and adolescents treated with antipsychotic medications. Hum Psychopharmacol Clin Exp 2008; 23:283-290.
23. Kelly DL, Love RC, Mackowick M, McMahon RP, Conley RR. Atypical antipsychotic use in a state hospital inpatient adolescent population. J Child Adolesc Psychopharmacol 2004; 14:75-85.
24. Mayo Clinic Staff. Metabolic syndrome and risk factors. http:// www.mayoclinic.com/health/metabolic%20syndrome/DS00522/DSECTION=risk- factors (10 Ocak 2011’de ulaşıldı).
25. Cerit C, Özten E, Yıldız M. Şizofreni hastalarında metabolik Sendrom sıklığı ve ilişkili etmenler. Turk Psikiyatri Derg 2008; 19:124-132.
26. Gothelf D, Falk B, Singer P, Kairi M, Phillip M, Zigel L et al. Weight gain associated with increased food intake and low habitual activity levels in male adolescent schizophrenic inpatients treated with olanzapine. Am J Psychiatry 2002; 159:1055- 1057
27. Allison D, Mentore J, Heo M, Chandler LP, Cappelleri JC, Infante MC et al. Antipsychotic-induced weight gain: a comprehensive research synthesis. Am J Psychiatry 1999; 156:1686-1696.
28. Lin SK, Chen CK. Reversal of antipsychotic-ınduced hyperprolactinemia, weight gain, and dyslipidemia by aripiprazole: A case report. J Clin Psychiatry 2006; 67:1307.
29. Kirk S, Neill JC, Jones DN, Reynolds GP. Ziprasidone suppresses olanzapine- induced increases in ingestive behaviour in the rat. Eur J Pharmacol 2004; 505:253- 254.
30. Kroeze WK, Hufeisen SJ, Popadak BA, Renock SM, Steinberg S, Ernsberger P et al. H1-histamine, receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs. Neuropsychopharmacology 2003; 28:519-526.
31. Nasrallah HA. Atypical antipsychotic-induced metabolic side effects: Insights from receptor-binding profiles. Mol Psychiatry 2008; 13:27-35.
32. Casey DE, Sands EE, Heisterberg J, Yang HM. Efficacy and safety of bifeprunox in patients with an acute exacerbation of schizophrenia: results from a randomized, double-blind, placebo-controlled, multicenter, dose-finding study. Psychopharmacology (Berl) 2008; 200:317-331.
33. Patel NC, Hariparsad M, Matias-Akthar M, Sorter MT, Barzman DH, Morrison JA, Body mass indexes and lipid profiles in hospitalized children and adolescents exposed to atypical antipsychotics. J Child Adolesc Psychopharmacol 2007; 17:303-311.
34. Tohen M, Kryzhanovskaya L, Carlson G, Delbello M, Wozniak J, Kowatch R et al. Olanzapine versus placebo in the treatment of adolescents with bipolar mania. Am J Psychiatry 2007; 164:1547-1556.
35. Hoffman RP. Indices of insulin action calculated from fasting glucose and insulin reflect hepatic, not peripheral, insulin sensitivity in African-American and Caucasian adolescents. Pediatr Diabetes 2008; 9:57-61.
36. McLaughlin T, Reaven G, Abbasi F, Lamendola C, Saad M, Waters D et al. Is there a simple way to identify insulin-resistant individuals at increased risk of cardiovascular disease? Am J Cardiol 2005; 96:399-404.
37. Woods SW, Martin A, Spector SG, McGlashan TH. Effects of development on olanzapine-associated adverse events. J Am Acad Child Adolesc Psychiatry 2002;
38. Erdogan A, Atasoy N, Akkurt H, Ozturk D, Karaahmet E, Yalug I et al. Risperidone and liver function tests in children and adolescents: A short-term prospective study. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32:849-857.
39. Zhang ZJ, Yao ZJ, Liu W, Fang Q, Reynolds GP. Effects of antipsychotics on fat deposition and changes in leptin and insulin levels: Magnetic resonance imaging study of previously untreated people with schizophrenia. Br J Psychiatry 2004; 184:58-62.
40. Rutters F, Nieuwenhuizen AG, Verhoef SP, Lemmens SG, Vogels N, Westerterp- Plantenga MS. The relationship between leptin, gonadotropic hormones, and body composition during puberty in a Dutch children cohort. Eur J Endocrinol 2009; 160:973-978.
41. Farooqi IS, Jebb SA, Langmack G, Lawrence E, Cheetham CH, Prentice AM et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999; 341:879-884.
42. Mayan L, Wakrusheva J. Risperidone associated weight, leptin, and anthropometric changes in children and adolescents with psychotic disorders in early treatment. Hum Psychopharmacol Clin Exp 2010; 25:133-138.
43. Krügel U, Schraft T, Kittner H, Kiess W, Illes P. Basal and feeding-evoked dopamine release in the rat nucleus accumbens is depressed by leptin. Eur J Pharmacol 2003; 482:185-187.
44. Matsui-Sakata A, Ohtani H, Sawada Y. Receptor occupancy-based analysis of the contributions of various receptors to antipsychotics-induced weight gain and diabetes mellitus. Drug Metab Pharmacokinet 2005; 20:368-378.
45. Mizrahi R, Rusjan, P, Agid O, Graff A, Mamo DC, Zipursky RB et al. Adverse subjective experience with antipsychotics and its relationship to striatal andextra striatal D2 receptors: a PET study in schizophrenia. Am J Psychiatry 2007; 164:630- 637.
46. Templeman LA, Reynolds GP, Arranz B, San L. Polymorphisms of the 5- HT2C receptor and leptin genes are associated with antipsychotic drug-induced weight gain in Caucasian subjects with a first-episode psychosis. Pharmacogenet Genomics 2005; 15:195-200.
47. Miyamoto S, Duncan G, Marx C, Lierberman J. Treatments for schizophrenia: a critical review of pharmacology and mechanisms of action of antipsychotic drugs. Mol Psychiatry 2005; 10:79-104.
48. American Academy of Child and Adolescent Psychiatry. AACAP official action. Summary of the practice parameters for the assessment and treatment of children and adolescents with schizophrenia. American Academy of Child and Adolescent Psychiatry. J Am Acad Child Adolesc Psychiatry 2000; 39:1580-1582.
49. Bromel T, Blum WF, Ziegler A, Schulz E, Bender M, Fleischhaker C et al. Serum leptin levels increase rapidly after initiation of clozapine therapy. Mol Psychiatry 1998; 3:76-80.
50. Martin A, Scabill L, Anderson GM, Aman M, Arnold LE, Mc Cracken JT et al. Weight and leptin changes among risperidone-treated youths with autism: 6 month prospective data. Am J Psychiatry 2004; 161:1125-1127.
51. Chagnon YC, Bureau A, Gendron D, Bouchard RH, Merette C, Roy MA et al. Possible association of the pro-melanin-concentrating hormone gene with a greater body mass index as a side effect of the antipsychotic olanzapine. Am J Med Genet B Neuropsychiatr Genet 2007; 144:1063-1069.
52. Correll CU. Weight gain and metabolic effects of mood stabilizers and antipsychotics in pediatric bipolar disorder: a systematic review and pooled analysis of short-term trials. J Am Acad Child Adolesc Psychiatry 2007; 46: 687-700.
53. Smith RC, Segman RH, Golcer-Dubner T, Pavlov V, Lerer B. Allelic variationin ApoC3, ApoA5 and LPL genes and first and second generation antipsychotic effects on serum lipids in patients with schizophrenia. Pharmacogenomics 2008; 8:228-236.
54. De Leon J, Correa JC, Ruano G, Windemuth A, Arranz MJ, Diaz FJ. Exploring genetic variations that may be associated with the direct effects of some antipsychotics on lipid levels. Schizophr Res 2008; 98: 40-46.
55. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 402:656- 660
56. Haddad PM, Wieck A. Antipsychotic-induced hyperprolactinaemia: Mechanisms, cinical features and management. Drugs 2004; 64:2291-2314.
57. Kinon BJ, Gilmore JA, Liu H, Halbreich UM. Hyperprolactinemia in response to antipsychotic drugs: characterization across comparative clinical trials. Psychoneuroendocrinology 2003; 28:69-82.
58. Kinon BJ, Gilmore JA, Liu H, Halbreich UM. Prevalence of hyperprolactinemia in schizophrenic patients treated with conventional antipsychotic medications or risperidone. Psychoneuroendocrinology 2003; 28:55- 68.
59. Duan J, Wainwright MS, Comeron JM, Saitou N, Sanders AR, Gelernter J et al. Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor. Hum Mol Genet 2003; 12:205-216.
60. Kelly DL, Love RC, Mackowick M, McMahon RP, Conley RR. Atypical antipsychotic use in a state hospital inpatient adolescent population. J Child Adolesc Psychopharmacol 2004; 14:75-85.
61. Findling, RL, Kusumakar V, Daneman D., Moshang, T, De Smedt G., & Binder C Prolactin levels during longterm risperidone treatment in children and adolescents. J Clin Psychiatry, 2003; 64:1362-1369.
62. Anderson GM, Scahill L, McCracken JT, Mcdougle CJ, Aman MG, Tierney E et al. Effects of short and long term risperidone treatment on prolactin levels in children with autism. Biol Psychiatry 2007; 61:545-550.
63. Madhusoodanan S, Moise D. Risperidone-induced hyperprolactinemia in adolescents: A case series. J Clin Psychiatry 2006; 67:1110-1113.
64. Shim JC, Shin JG, Kelly DL, Jung DU, Seo YS, Liu KH et al. Adjunctive treatment with a dopamine partial agonist, aripiprazole, for antipsychotic-induced hyperprolactinemia: A placebo controlled trial. Am J Psychiatry 2007; 164:1404- 1410.
65. Dunbar F, Kusumakar V, Daneman D, Schulz M. Growth and sexual maturation during long term treatment with risperidone Am J Psychiatry 2004; 161:918-920.
66. Correll C. Antipsychotic use in children and adolescents: Minimizing adverse effects to maximize outcome. J Am Child Adolesc Psychiatry 2008; 47:9-20.
67. Hammerman A, Dreiher J, Klang S, Munitz H, Cohen A, Goldfracht M. Antipsychotics and diabetes: an age-related association. Ann Pharmacother 2008; 42:1316-1322.
68. US Food and Drug Administration. Zyprexa (olanzapine): Use in adolescents. http://www.fda.gov/ Safety/ MedWatch/ SafetyInformation/ Safety Alerts for Human Medical Products /ucm 198402. Htm (Retrieved 02.02.2010).
69. Koller EA, Weber J, Doraiswamy PM, Schneider BS. A survey of reports of quetiapine-associated Hyperglycemia and diabetes mellitus. J Clin Psychiatry 2004; 65:857-863.
70. Chintoh AF, Mann SW, Lam L, Lam C., Cohn TA,Fletcher PJ et al. Insulin resistance and decreased glucose-stimulated insulin secretion after acute olanzapine administration. J Clin Psychopharmacol 2008; 28:494-499.
71. Morrato EH, Cuffel B, Newcomer JW, Lombardo I, Kamat S, Barron J. Metabolic risk status and second-generation antipsychotic drug selection: a retrospective study of commercially insured patients. J Clin Psychopharmacol 2009; 29:26-32.
72. Haupt D, Newcomer J. Hyperglycemia and antipsychotic medications. J Clin Psychiatry 2001; 62 (suppl 27):15-26.
73. Meltzer H. Putting metabolic side effects into perspective: Risk versus benefits of atypical antipsychotics. J Clin Psychiatry 2001; 62(suppl 27):35-39.
74. Lee JM, Okumura MJ, Davis MM, Herman WH, Gurney JG. Prevalence and determinants of insulin resistance among US adolescents: a population-based study. Diabetes Care 2006; 29:2427-2432
75. Henderson D, Louie P, Koul P, Maney L, Daley T, Nguyen D. Modafinil-associated weight loss in a clozapine treated schizo affective disorder patient. Ann Clin Psychiatry 2005; 17:95-97.
76. de Haan L, Amelsvoort T, Rosien K, Linszen D. Weight loss after switching from conventional olanzapine tablets to orally disintegrating olanzapine tablets. Psychopharmacology(Berl) 2004; 175:389-390.
77. Molnar D. New drug policy in childhood obesity. Int J Obes (Lond) 2005; 29:562
78. Chanoine J, Hampl S, Jensen C, Boldrin M, Hauptman J. Effect of orlistat on weight and body composition in obese adolescents. JAMA 2005; 293:2873-2934.
79. Maahs D, de Serna D, Kolotkin R, Ralston S, Sandate J, Qualls C et al. Randomized, double blind, placebo-controlled trial of orlistat for weight loss in adolescents. Endocr Pract 2006; 12:18-28.
80. Hilgar E, Quiner S, Ginzel I, Walter H, Saria L, Barnas C. The effect of orlistat on plasma levels of psychotropic drugs in patients with long-term psychopharmacotherapy. J Clin Psychopharmacol 2002; 22:68-70.
81. Cerulli J, Lomaestro B, Malone M. Update on the pharmacotherapy of obesity. Ann Pharmacother 1998; 32:88-102.
82. Azar S, Zantout M. Diabetic ketoacidosis associated with orlistat treatment. Diabetes Care 2001; 25:602.
83. Canitano R. Cllinical experience with topiramate to counteract neuroleptic-induced weight gain in 10 individuals with autistic spectrum disorders. Brain Dev 2005; 27:228-232.
84. Aarsen F, Akker E. Effect of topiramate on cognition in obese children. Neurology 2006; 67:1307-1308.
85. Deberdt W, Winokur A, Cavazzoni P, Trzaskoma QN, Carlson CD, Bymaster FP et al. Amantadine for weight gain associated with olanzapine treatment. Eur Neuropsychopharmacol 2005; 15:13-21.
86. Gracious B, Krysiak T, Youngstrom E. Amantadine treatment of psychotropic- induced weight gain in children and adolescents: case series. J Child Adolesc Psychopharmacol 2002; 12:249-257.
87. Klein DJ, Cottingham EM, Sorter M, Barton BA, Morrison JA. A randomized, double-blind, placebo-controlled trial of metformin treatment of weight gain associated with ınitiation of atypical antipsychotic therapy in children and adolescents. Am J Psychiatry 2006; 163:2072-2079.
88. Aman MG, Binder C, Turgay A Risperidone effects in the presence/absence of psychostimulant medicine in children with ADHD, other disruptive behavior disorders, and subaverage IQ. J Child Adolesc Psychopharmacol 2004; 14:243-254.
89. Jiang J, Xia X, Greiner T, Lian G, Rosenqvist U. A two-year family-based behaviour treatment for obese children. Arch Dis Child 2005; 90:1235-1238.
90. Zimmet P, Alberti KG, Kaufman F, Tajima N, Silink M, Arslanian S et al. The metabolic syndrome in children and adolescents—An IDF consensus report. Pediatr Diabetes 2007; 8:299-306.
91. Correll C Assessing and maximizing the safety and tolerability of antipsychotics used in the treatment of children and adolescents J Clin Psychiatry 2008; 69(Suppl 4):26- 36.
92. Walter G, DeLaroche A, Soh N, Hunt G, Cleary M, Malhi G et al. Side effects of second generation antipsychotics: the experiences, views and monitoring practices of Australian child psychiatrists. Australas Psychiatry 2008; 16:253-262.