Çocuk ve Ergenlerde Antipsikotik Kullanımı
Özet
Çocuk ve ergenlerde antipsikotik (AP) ilaç kullanımı son on yılda, özellikle Amerikan Gıda ve İlaç Dairesi'nin (FDA) onayladığı şizofreni, bipolar bozukluk, otizm spektrum bozukluğu ve Tourette sendromu gibi temel endikasyonların dışındaki "etiket dışı" kullanımlarla belirgin şekilde artmıştır. Birinci kuşak antipsikotikler dopamin D2 reseptörlerini bloke ederek etki gösterirken yüksek ekstrapiramidal yan etki riski taşırlar; ikinci kuşak antipsikotikler ise serotonerjik reseptörlere de etki ederek daha düşük hareket bozukluğu riski sunmakla birlikte kilo alımı, dislipidemi ve prolaktin yüksekliği gibi ciddi metabolik yan etkilere yol açmaktadır. Bu avantajları nedeniyle dünya genelinde ikinci kuşak ilaçların tercih edilme oranında belirgin bir artış yaşanmıştır. Klinik çalışmalarda antipsikotiklerin yıkıcı/saldırgan davranış bozuklukları, yıkıcı duygudurum düzensizliği bozukluğu ve dikkat eksikliği ve hiperaktivite bozukluğu (DEHB) gibi durumlarda da etiket dışı olarak yaygın şekilde reçete edildiği görülmektedir. Güncel kılavuzlar, etiket dışı vakalarda öncelikle psikososyal ve davranışsal terapilerin uygulanmasını, bu yaklaşımların yetersiz kalması durumunda ise hastanın kâr-zarar dengesi ile metabolik değerleri yakından takip edilerek en düşük dozda antipsikotik tedavisine başlanmasını ve ilaç sonlandırılacağı zaman dozun kademeli olarak azaltılmasını önermektedir.
Antipsychotic (AP) drug use in children and adolescents has significantly increased over the last decade, particularly due to "off-label" prescribing outside of the core indications approved by the U.S. Food and Drug Administration (FDA) such as schizophrenia, bipolar disorder, autism spectrum disorder, and Tourette syndrome. While first-generation antipsychotics exert their effects by blocking dopamine D2 receptors and carry a high risk of extrapyramidal side effects, second-generation antipsychotics also affect serotonergic receptors, offering a lower risk of movement disorders but causing serious metabolic side effects such as weight gain, dyslipidemia, and elevated prolactin levels. Due to these advantages, a distinct shift toward utilizing second-generation medications has occurred worldwide. Clinical studies show that antipsychotics are also frequently prescribed off-label for conditions such as disruptive/aggressive behavior disorders, disruptive mood dysregulation disorder, and attention-deficit/hyperactivity disorder (ADHD). Current guidelines recommend implementing psychosocial and behavioral therapies first in off-label cases, and if these approaches prove insufficient, initiating antipsychotic treatment at the lowest possible dose while closely monitoring the patient's risk-benefit ratio and metabolic parameters, and gradually tapering the dose when discontinuing the medication.
Referanslar
Crystal S, Olfson M, Huang C, et al. Broadened Use Of Atypical Antipsychotics: Safety, Effectiveness, And Policy Challenges. Health affairs (Project Hope). 2009;28(5): w770–w781. doi:10.1377/hlthaff.28.5.w770
Erskine HE, Baxter AJ, Patton G, et al. The global coverage of prevalence data for mental disorders in children and adolescents. Epidemiology and Psychiatric Sciences. 2017;26(4): 395–402. doi:10.1017/S2045796015001158
Varimo E, Saastamoinen LK, Rättö H, et al. New Users of Antipsychotics Among Children and Adolescents in 2008–2017: A Nationwide Register Study. Frontiers in Psychiatry. 2020;11. https://www.frontiersin.org/articles/10.3389/fpsyt.2020.00316
Hartz I, Skurtveit S, Steffenak AKM, et al. Psychotropic drug use among 0-17 year olds during 2004-2014: a nationwide prescription database study. BMC psychiatry. 2016;16: 12. doi:10.1186/s12888-016-0716-x
Alessi-Severini S, Biscontri RG, Collins DM, et al. Ten years of antipsychotic prescribing to children: a Canadian population-based study. Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie. 2012;57(1): 52–58. doi:10.1177/070674371205700109
Hálfdánarson Ó, Zoëga H, Aagaard L, et al. International trends in antipsychotic use: A study in 16 countries, 2005-2014. European Neuropsychopharmacology: The Journal of the European College of Neuropsychopharmacology. 2017;27(10): 1064–1076. doi:10.1016/j.euroneuro.2017.07.001
Kaguelidou F, Holstiege J, Schink T, et al. ‘Use of antipsychotics in children and adolescents: a picture from the ARITMO population-based European cohort study’. Epidemiology and Psychiatric Sciences. 2020;29: e117. doi:10.1017/S2045796020000293
Penfold RB, Stewart C, Hunkeler EM, et al. Use of antipsychotic medications in pediatric populations: what do the data say? Current Psychiatry Reports. 2013;15(12): 426. doi:10.1007/s11920-013-0426-8
Pillay J, Boylan K, Carrey N, et al. Introduction. [Online] First- and Second-Generation Antipsychotics in Children and Young Adults: Systematic Review Update [Internet]. Agency for Healthcare Research and Quality (US); 2017. https://www.ncbi.nlm.nih.gov/books/NBK442340/
Stone JM, Davis JM, Leucht S, et al. Cortical dopamine D2/D3 receptors are a common site of action for antipsychotic drugs--an original patient data meta-analysis of the SPECT and PET in vivo receptor imaging literature. Schizophrenia Bulletin. 2009;35(4): 789–797. doi:10.1093/schbul/sbn009
Vanover KE, Weiner DM, Makhay M, et al. Pharmacological and behavioral profile of N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N’-(4-(2-methylpropyloxy)phenylmethyl) carbamide (2R,3R)-dihydroxybutanedioate (2:1) (ACP-103), a novel 5-hydroxytryptamine(2A) receptor inverse agonist. The Journal of Pharmacology and Experimental Therapeutics. 2006;317(2): 910–918. doi:10.1124/jpet.105.097006
Patten SB, Waheed W, Bresee L. A review of pharmacoepidemiologic studies of antipsychotic use in children and adolescents. Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie. 2012;57(12): 717–721. doi:10.1177/070674371205701202
Pringsheim T, Lam D, Ching H, et al. Metabolic and neurological complications of second-generation antipsychotic use in children: a systematic review and meta-analysis of randomized controlled trials. Drug Safety. 2011;34(8): 651–668. doi:10.2165/11592020-000000000-00000
Fraguas D, Correll CU, Merchán-Naranjo J, et al. Efficacy and safety of second-generation antipsychotics in children and adolescents with psychotic and bipolar spectrum disorders: comprehensive review of prospective head-to-head and placebo-controlled comparisons. European Neuropsychopharmacology: The Journal of the European College of Neuropsychopharmacology. 2011;21(8): 621–645. doi:10.1016/j.euroneuro.2010.07.002
Man KKC, Shao S-C, Chang Y-C, et al. Cardiovascular and metabolic risk of antipsychotics in children and young adults: a multinational self-controlled case series study. Epidemiology and Psychiatric Sciences. 2021;30: e65. doi:10.1017/S2045796021000494
AACAP_Psychotropic_Medication_Recommendations_2015_FINAL.pdf. [Online] https://www.aacap.org/App_Themes/AACAP/docs/clinical_practice_center/systems_of_care/AACAP_Psychotropic_Medication_Recommendations_2015_FINAL.pdf
Second-Generation Antipsychotic Drug Use Among Med.pdf. [Online] https://oig.hhs.gov/oei/reports/oei-07-12-00320.pdf
Otsuka and Lundbeck Announce FDA Approval of Supplemental New Drug Application for REXULTI® (brexpiprazole) to Treat Schizophrenia in Pediatric Patients Ages 13-17. [Online] BioSpace. https://www.biospace.com/article/otsuka-and-lundbeck-announce-fda-approval-of-supplemental-new-drug-application-for-rexulti-brexpiprazole-to-treat-schizophrenia-in-pediatric-patients-ages-13-17/
Rettew DC, Greenblatt J, Kamon J, et al. Antipsychotic medication prescribing in children enrolled in Medicaid. Pediatrics. 2015;135(4): 658–665. doi:10.1542/peds.2014-2260
Findling RL, Steiner H, Weller EB. Use of antipsychotics in children and adolescents. The Journal of Clinical Psychiatry. 2005;66 Suppl 7: 29–40.
Sohn M, Moga DC, Blumenschein K, et al. National trends in off-label use of atypical antipsychotics in children and adolescents in the United States. Medicine. 2016;95(23): e3784. doi:10.1097/MD.0000000000003784
Kornø KT, Aagaard L. Off-Label Prescribing of Antipsychotics in a Danish Child and Adolescent Mental Health Center: A Register-Based Study. Journal of Research in Pharmacy Practice. 2018;7(4): 205–209. doi:10.4103/jrpp.JRPP_18_42
Olfson M, King M, Schoenbaum M. Treatment of Young People With Antipsychotic Medications in the United States. JAMA psychiatry. 2015;72(9): 867–874. doi:10.1001/jamapsychiatry.2015.0500
Ganos C, Martino D, Pringsheim T. Tics in the Pediatric Population: Pragmatic Management. Movement Disorders Clinical Practice. 2016;4(2): 160–172. doi:10.1002/mdc3.12428
Siafis S, Tzachanis D, Samara M, et al. Antipsychotic Drugs: From Receptor-binding Profiles to Metabolic Side Effects. Current Neuropharmacology. 2018;16(8): 1210–1223. doi:10.2174/1570159X15666170630163616
Kaar SJ, Natesan S, McCutcheon R, et al. Antipsychotics: Mechanisms underlying clinical response and side-effects and novel treatment approaches based on pathophysiology. Neuropharmacology. 2020;172: 107704. doi:10.1016/j.neuropharm.2019.107704
Meltzer HY. What’s atypical about atypical antipsychotic drugs? Current Opinion in Pharmacology. 2004;4(1): 53–57. doi:10.1016/j.coph.2003.09.010
Brandl EJ, Kennedy JL, Müller DJ. Pharmacogenetics of Antipsychotics. Canadian Journal of Psychiatry. Revue Canadienne de Psychiatrie. 2014;59(2): 76–88. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4079237/
A multi-national comparison of antipsychotic drug use in children and adolescents, 2005-2012 - PubMed. [Online] https://pubmed.ncbi.nlm.nih.gov/29046716/
Correll CU, Penzner JB, Parikh UH, et al. Recognizing and monitoring adverse events of second-generation antipsychotics in children and adolescents. Child and Adolescent Psychiatric Clinics of North America. 2006;15(1): 177–206. doi:10.1016/j.chc.2005.08.007
Marder SR, Cannon TD. Schizophrenia. The New England Journal of Medicine. 2019;381(18): 1753–1761. doi:10.1056/NEJMra1808803
Abidi S, Mian I, Garcia-Ortega I, et al. Canadian Guidelines for the Pharmacological Treatment of Schizophrenia Spectrum and Other Psychotic Disorders in Children and Youth. Canadian Journal of Psychiatry. Revue Canadienne De Psychiatrie. 2017;62(9): 635–647. doi:10.1177/0706743717720197
Salamon S, Santelmann H, Franklin J, et al. Test-retest reliability of the diagnosis of schizoaffective disorder in childhood and adolescence - A systematic review and meta-analysis. Journal of Affective Disorders. 2018;230: 28–33. doi:10.1016/j.jad.2017.12.070
Nesvåg R. Antipsychotic treatment of children and adolescents is a double-edged sword. The Lancet. Psychiatry. 2017;4(8): 576–577. doi:10.1016/S2215-0366(17)30289-4
Pillay J, Boylan K, Carrey N, et al. First- and Second-Generation Antipsychotics in Children and Young Adults: Systematic Review Update. [Online] Rockville (MD): Agency for Healthcare Research and Quality (US); 2017. http://www.ncbi.nlm.nih.gov/books/NBK442352/
Krause M, Zhu Y, Huhn M, et al. Efficacy, acceptability, and tolerability of antipsychotics in children and adolescents with schizophrenia: A network meta-analysis. European Neuropsychopharmacology: The Journal of the European College of Neuropsychopharmacology. 2018;28(6): 659–674. doi:10.1016/j.euroneuro.2018.03.008
Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disorders. 2018;20(2): 97–170. doi:10.1111/bdi.12609
American Psychiatric Association, American Psychiatric Association, editors. Diagnostic and statistical manual of mental disorders: DSM-5.. 5th ed. Washington, D.C: American Psychiatric Association; 2013. 947 p.
Scahill L, Hallett V, Aman MG, et al. Brief Report: social disability in autism spectrum disorder: results from Research Units on Pediatric Psychopharmacology (RUPP) Autism Network trials. Journal of Autism and Developmental Disorders. 2013;43(3): 739–746. doi:10.1007/s10803-012-1689-3
Aman MG, Kasper W, Manos G, et al. Line-item analysis of the Aberrant Behavior Checklist: results from two studies of aripiprazole in the treatment of irritability associated with autistic disorder. Journal of Child and Adolescent Psychopharmacology. 2010;20(5): 415–422. doi:10.1089/cap.2009.0120
Howes OD, Rogdaki M, Findon JL, et al. Autism Spectrum Disorder: consensus guidelines on assessment, treatment and research from the British Association for Psychopharmacology. Journal of psychopharmacology (Oxford, England). 2018;32(1): 3–29. doi:10.1177/0269881117741766
American Psychiatric Association, American Psychiatric Association, editors. Diagnostic and statistical manual of mental disorders: DSM-5.. 5th ed. Washington, D.C: American Psychiatric Association; 2013. 947 p.
Hirschtritt ME, Lee PC, Pauls DL, et al. Lifetime Prevalence, Age of Risk, and Etiology of Comorbid Psychiatric Disorders in Tourette Syndrome. JAMA psychiatry. 2015;72(4): 325–333. doi:10.1001/jamapsychiatry.2014.2650
Pringsheim T, Okun MS, Müller-Vahl K, et al. Practice guideline recommendations summary: Treatment of tics in people with Tourette syndrome and chronic tic disorders. Neurology. 2019;92(19): 896–906. doi:10.1212/WNL.0000000000007466
Roessner V, Plessen KJ, Rothenberger A, et al. European clinical guidelines for Tourette syndrome and other tic disorders. Part II: pharmacological treatment. European Child & Adolescent Psychiatry. 2011;20(4): 173–196. doi:10.1007/s00787-011-0163-7
Farag M, Stern JS, Simmons H, et al. Serial pharmacological prescribing practices for tic management in Tourette syndrome. Human Psychopharmacology. 2015;30(6): 435–441. doi:10.1002/hup.2495
Cothros N, Martino D, McMorris C, et al. Prescriptions for Alpha Agonists and Antipsychotics in Children and Youth with Tic Disorders: A Pharmacoepidemiologic Study. Tremor and Other Hyperkinetic Movements (New York, N.Y.). 2019;9. doi:10.7916/tohm.v0.645
Schmid I, Burcu M, Zito JM. Medicaid prior authorization policies for pediatric use of antipsychotic medications. JAMA. 2015;313(9): 966–968. doi:10.1001/jama.2015.0763
Connor DF, Newcorn JH, Saylor KE, et al. Maladaptive Aggression: With a Focus on Impulsive Aggression in Children and Adolescents. Journal of Child and Adolescent Psychopharmacology. 2019;29(8): 576–591. doi:10.1089/cap.2019.0039
Crystal S, Mackie T, Fenton MC, et al. Rapid Growth Of Antipsychotic Prescriptions For Children Who Are Publicly Insured Has Ceased, But Concerns Remain. Health Affairs (Project Hope). 2016;35(6): 974–982. doi:10.1377/hlthaff.2016.0064
Scotto Rosato N, Correll CU, Pappadopulos E, et al. Treatment of maladaptive aggression in youth: CERT guidelines II. Treatments and ongoing management. Pediatrics. 2012;129(6): e1577-1586. doi:10.1542/peds.2010-1361
Tourian L, LeBoeuf A, Breton J-J, et al. Treatment Options for the Cardinal Symptoms of Disruptive Mood Dysregulation Disorder. Journal of the Canadian Academy of Child and Adolescent Psychiatry. 2015;24(1): 41–54. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4357333/
Pappadopulos E, Woolston S, Chait A, et al. Pharmacotherapy of aggression in children and adolescents: efficacy and effect size. Journal of the Canadian Academy of Child and Adolescent Psychiatry = Journal De l’Academie Canadienne De Psychiatrie De L’enfant Et De L’adolescent. 2006;15(1): 27–39.
ADHD: Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents. Pediatrics. 2011;128(5): 1007–1022. doi:10.1542/peds.2011-2654
Chaplin S. Attention deficit hyperactivity disorder: diagnosis and management. Progress in Neurology and Psychiatry. 2018;22(3): 27–29. doi:10.1002/pnp.511
Gorman DA, Gardner DM, Murphy AL, et al. Canadian Guidelines on Pharmacotherapy for Disruptive and Aggressive Behaviour in Children and Adolescents With Attention-Deficit Hyperactivity Disorder, Oppositional Defiant Disorder, or Conduct Disorder. Canadian Journal of Psychiatry. Revue Canadienne de Psychiatrie. 2015;60(2): 62–76. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4344948/
