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Clinical Usefulness of Second-Generation Antipsychotics in Treating Children and Adolescents Diagnosed with Bipolar or Schizophrenic Disorders

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Abstract

The onset of severe, chronic or recurrent psychiatric illnesses, such as schizophrenia-spectrum and bipolar disorders, is a dramatic clinical event often detectable during adolescence and even in childhood. At any age, pharmacotherapy, along with enhancement of social skills and family support, is the mainstay for the management of such disorders. The aim of this review is to critically analyze findings from randomized controlled trials (RCTs) that have investigated the clinical utility of second-generation antipsychotics (SGAs) for the treatment of early-onset schizophrenia and bipolar disorders. Eighteen studies were considered, all of which were unfortunately impaired by methodologic limitations, such as the paucity of long-term data and lack of a three-arm comparison (SGA vs SGA vs placebo).

Nevertheless, the results of this review allow us to suggest the effectiveness of three SGAs (aripiprazole, olanzapine, and risperidone) in the short-term treatment of both early-onset schizophrenia and bipolar mania, although such agents show different safety profiles. The use of clozapine should be strictly limited to patients with non-affective, psychotic symptoms who do not respond to any of these three SGAs. In contrast, the use of quetiapine and ziprasidone in young patients with either affective or non-affective psychosis is not yet supported by evidence-based information.

Given our findings, further studies are urgently required to identify the best treatment option(s) for pediatric bipolar disorder (especially the depressive phase) and the long-term management of early-onset schizophrenia.

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References

  1. Homburger A. Vorlesungen über psychpathologie des kindersalters. Berlin: Springer, 1926

    Book  Google Scholar 

  2. Hafner H, van der Heiden W. Epidemiology of schizophrenia. Can J Psychiatry 1997; 42: 139–51

    PubMed  CAS  Google Scholar 

  3. Hafner H, Nowotny B. Epidemiology of early-onset schizophrenia. Eur Arch Clin Neurosci 1995; 245: 80–92

    Article  CAS  Google Scholar 

  4. Madaan V, Dvir Y, Wilson DR. Child and adolescent psychiatry: pharmacological approach. Expert Opin Pharmacother 2008; 9(12): 2053–68

    Article  PubMed  CAS  Google Scholar 

  5. Masi G, Mucci M, Pari C. Children with schizophrenia: clinical picture and pharmacological management. CNS Drugs 2006; 20(10): 841–66

    Article  PubMed  CAS  Google Scholar 

  6. Harris M, Henry L, Harrigan S. The relationship between the duration of untreated psychosis and outcome: an eight-year prospective study. Schizophr Res 2005; 79: 85–93

    Article  PubMed  Google Scholar 

  7. Cannon TD, Cadenhead K, Cornblatt B, et al. Prediction of psychosis in youth at high clinical risk: a multisite longitudinal study in North America. Arch Gen Psychiatry 2008; 65: 28–37

    Article  PubMed  Google Scholar 

  8. Pencer A, Addington J, Addington D. Outcome of a first episode of psychosis in adolescence: a 2-year follow-up. Psychiatr Res 2005; 33: 35–43

    Article  Google Scholar 

  9. Luby JL, Tandon M, Belden A. Preschool bipolar disorder. Child Adolesc Psychiatric Clin N Am 2009; 18: 391–403

    Article  Google Scholar 

  10. Youngstrom EA, Birmaher B, Findling RL. Pediatric bipolar disorder: validity, phenomenology, and recommendations for diagnosis. Bipolar Disord 2008; 10: 194–214

    Article  PubMed  Google Scholar 

  11. Moreno C, Laje G, Blanco C, et al. National trends in the outpatients diagnosis and treatment of bipolar disorder in youth. Arch Gen Psychiatry 2007; 64(9): 1032–9

    Article  PubMed  Google Scholar 

  12. McClellan J, Kowatch R, Findling RL. Practice parameter for the assessment and treatment of children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 2007; 46(1): 107–25

    Article  PubMed  Google Scholar 

  13. Axelson D, Birmaher B, Strober M, et al. Phenomenology of children and adolescents with bipolar spectrum disorders. Arch Gen Psychiatry 2006; 63(10): 1139–48

    Article  PubMed  Google Scholar 

  14. Nandagopal JJ, Delbello MP, Kowatch R. Pharmacological treatment of pediatric bipolar disorder. Child Adolesc Psychiatric Clin N Am 2009; 18: 455–69

    Article  Google Scholar 

  15. Pathak P, West D, Martin BC, et al. Evidence-based use of second-generation antipsychotics in a state Medicaid pediatric population, 2001–2005. Psychiatr Serv 2010; 61(2): 123–9

    Article  PubMed  Google Scholar 

  16. Lowry F. FDA expert panel approves use of atypical antipsychotic drugs in kids [online]. Available from URL: http://www.medscape.com/viewarticle/704271 [Accessed 2009 Nov 27]

  17. Pfeifer JC, Kowatch RA, DelBello MP. Pharmacotherapy of bipolar disorder in children and adolescents: recent progress. CNS Drugs 2010; 24(7): 575–93

    Article  PubMed  CAS  Google Scholar 

  18. Waknine Y. FDA approves quetiapine for pediatric schizophrenia and bipolar disorder [online]. Available from URL: http://www.medscape.com/viewarticle/713530 [Accessed 2010 Nov 11]

  19. Waknine Y. FDA approves olanzapine for pediatric schizophrenia and bipolar disorder [online]. Available from URL: http://www.medscape.com/viewarticle/713484 [Accessed 2010 Nov 11]

  20. Therapeutics Initiative, Evidence Based Drug Therapy. Increasing use of newer antipsychotics in children: a cause of concern? Ther Lett 2009 Apr–Jun: 74 [online]. Available from URL: http://www.ti.ubc.ca/newsletter/increasing-use-newer-antipsychotics-children-cause-concern [Accessed 2011 Jul 6]

  21. Il network di Pagine Sanitarie. Monografia di risperdal 60CPR 4mg verdi [online]. Available from URL: http://www.paginesanitarie.com/skfarmaci/monografia%20di%20RISPERDAL%2060CPR%204MG%20VERDI.htm [Accessed 2011 Jul 7]

  22. Il network di Pagine Sanitarie. Monografia di Abilify IM FL 1,3ML 7,5MG ML [online]. Available from URL: http://www.paginesanitarie.com/skfarmaci/monografia%20di%20ABILIFY%20IM%20FL%201,3ML%207,5MG%20ML.htm [Accessed 2011 Jul 6]

  23. Piscitelli SC, Frazier JA, McKenna K, et al. Plasma clozapine and haloperidol concentrations in adolescents with childhood-onset schizophrenia: association with response. J Clin Psychiatry 1994; 55 (9 Suppl. B): 94–7

    PubMed  Google Scholar 

  24. Sporn AL, Vermani A, Greenstein DK, et al. Clozapine treatment of childhood-onset schizophrenia: evaluation of effectiveness, adverse effects, and long-term outcome. J Am Acad Child Adolesc Psychiatry 2007; 46(10): 1349–56

    Article  PubMed  Google Scholar 

  25. Findling RL, Nyilas M, Forbes RA, et al. Acute treatment of pediatric disorder, manic or mixed episode, with aripiprazole: a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2009; 70(10): 1441–51

    Article  PubMed  CAS  Google Scholar 

  26. Gentile S. Contributing factors to weight gain during long-term treatment with second-generation antipsychotics: a systematic appraisal and clinical implications. Obesity Rev 2009; 10(5): 527–42

    Article  CAS  Google Scholar 

  27. Tramontina S, Zeni CP, Ketzer CR, et al. Aripiprazole in children and adolescents with bipolar disorder comorbid with attention-deficit/hyperactivity disorder: a pilot randomized trial. J Clin Psychiatry 2009; 70(5): 756–64

    Article  PubMed  CAS  Google Scholar 

  28. Tohen M, Kryshanovskaya L, Carlson G, et al. Olanzapine versus placebo in the treatment of adolescents with bipolar mania. Am J Psychiatry 2007; 164: 1547–56

    Article  PubMed  Google Scholar 

  29. Delbello M, Kowatch RA, Adler CM, et al. A double-blind randomized pilot study comparing quetiapine and divalproex for adolescent mania. J Am Acad Child Adolesc Psychiatry 2006; 45(3): 305–13

    Article  PubMed  Google Scholar 

  30. Delbello M, Welge JA, Adler CM, et al. A double-blind placebo-controlled study of quetiapine for depressed adolescents with bipolar disorder. Bipolar Disord 2009; 11: 483–93

    Article  PubMed  CAS  Google Scholar 

  31. Delbello M, Schwiers MS, Rosenberg HL, et al. A double-blind, randomized, placebo-controlled study of quetiapine as adjunctive treatment for adolescent mania. J Am Acad Child Adolesc Psychiatry 2002; 41(10): 1216–23

    Article  PubMed  Google Scholar 

  32. Haas M, Delbello M, Pandina G, et al. Risperidone for the treatment of acute mania in children and adolescents with bipolar disorder: a randomized, double-blind placebo-controlled study. Bipolar Disord 2009; 11: 687–700

    Article  PubMed  CAS  Google Scholar 

  33. Pavuluri MN, Henry DB, Findling RL, et al. Double-blind, randomized trial of risperidone versus divalproex in pediatric bipolar disorder. Bipolar Disord 2010; 12: 593–605

    Article  PubMed  CAS  Google Scholar 

  34. Gentile S. Second-generation antipsychotics in bipolar disorder, two years later: the song remains the same. Sociedad Iberoamericana de Información Cientifica, June 2009 [online]. Available from URL: http://www.trabajosdistinguidos.com/smental/td_saludmental_12_2_d179.pdf. [Accessed 2011 Jul 6]

    Google Scholar 

  35. Findling RL, Robb A, Nyilas M, et al. A multiple-center, randomized, double-blind, placebo-controlled study of oral aripiprazole for treatment of adolescents with schizophrenia. Am J Psychiatry 2008; 165(11): 1432–41

    Article  PubMed  Google Scholar 

  36. Kumra S, Frazier JA, Jacobsen LK, et al. Childhood onset schizophrenia: a double-blind clozapine-haloperidol comparison. Arch Gen Psychiatry 1996; 53: 1090–7

    Article  PubMed  CAS  Google Scholar 

  37. Shaw P, Sporn A, Gogtay N, et al. Childhood onset schizophrenia: a double-blind clozapine-olanzapine comparison. Arch Gen Psychiatry 2006; 63: 721–30

    Article  PubMed  CAS  Google Scholar 

  38. Kumra S, Kranzler H, Gerbino-Rosen G, et al. Clozapine and “high dose” olanzapine in refractory early-onset schizophrenia: a 12-week randomized and double-blind comparison. Biol Psychiatry 2008; 63: 524–9

    Article  PubMed  Google Scholar 

  39. Kryshanovskaya L, Schulz C, McDoulgle C, et al. Olanzapine versus placebo in adolescents with schizophrenia: a 6-week, randomized, double-blind, placebo-controlled trial. J Am Acad Child Adolesc Psychiatry 2009; 48(1): 60–70

    Article  Google Scholar 

  40. Haas M, Unis AS, Armenteros J, et al. A 6-week, randomized, double-blind placebo-controlled study of the efficacy and safety of risperidone in adolescents with schizophrenia. J Child Adolesc Psychopharmacol 2009; 19(6): 611–21

    Article  PubMed  Google Scholar 

  41. Haas M, Eerdekens M, Kushner SF, et al. Efficacy, safety, and tolerability of two risperidone dosing regimens in adolescent schizophrenia: double-blind study. Br J Psychiatry 2009; 194: 158–64

    Article  PubMed  Google Scholar 

  42. Sikich L, Frazier JA, Findling RL, et al. Double-blind comparison of first-and second generation antipsychotics in early onset schizophrenia and schizoaffective disorders: findings from the treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS) Study. Am J Psychiatry 2008; 165: 1420–31

    Article  PubMed  Google Scholar 

  43. Findling RL, Johnson JL, McClellan J, et al. Double-blind maintenance safety and effectiveness findings from the Treatment of Early-Onset Schizophrenia Spectrum (TEOSS) Study. J Am Acad Child Adolesc Psychiatry 2010; 49(6): 583–94

    PubMed  Google Scholar 

  44. McClellan J, Sikich L, Findling RL, et al. Treatment of early onset schizophrenia spectrum disorders (TEOSS): rationale, design, and methods. J Am Acad Child Adolesc Psychiatry 2007; 46(8): 969–78

    Article  PubMed  Google Scholar 

  45. Sikich L, Harmer RM, Bashford RA, et al. A pilot study of risperidone, olanzapine, and haloperidol in psychotic youth: a double-blind, randomized, 8-week trial. Neuropsychopharmacology 2004; 29: 133–45

    Article  PubMed  CAS  Google Scholar 

  46. Word Health Organization. Clinical trials in children [online]. Available from URL: http://www.who.int/ictrp/child/en/ [Accessed 2011 Feb 15]

  47. Gennery B. Clinical research in children: a pharmaceutical industry view. Paed Perinatal Drug Ther 2000; 4(2): 35–8

    Article  Google Scholar 

  48. Caldwell P, Murphy S, Butow P, et al. Clinical trials in children. Lancet 2004; 364(9436): 803–11

    Article  PubMed  Google Scholar 

  49. Crocetti MT, Amin DD, Scherer R. Assessment of the risk of bias among pediatric randomized controlled trials. Pediatrics 2010; 126(2): 298–305

    Article  PubMed  Google Scholar 

  50. Gentile S. Long term atypical antipsychotics treatment and risk of weight gain: a literature analysis. Drug Saf 2006; 29(4): 303–19

    Article  PubMed  CAS  Google Scholar 

  51. Gentile S. Quality of life and weight related issues in patients treated for schizophrenia: focus on aripiprazole. Neuropsychiatr Dis Treat 2009; 5: 117–25

    Article  PubMed  CAS  Google Scholar 

  52. Gentile S. Atypical antipsychotic for the treatment of bipolar disorder: more shadows than lights. CNS Drugs 2007; 21(5): 367–87

    Article  PubMed  CAS  Google Scholar 

  53. Dittmann RW, Meyer E, Freisleder FJ, et al. Olanzapine in male and female patients with schizophrenia and related disorders: minor sex differences in outcomes. J Clin Psychopharmacol 2010; 30(3): 328–31

    Article  PubMed  Google Scholar 

  54. Calabrese JR, Keck Jr PE, Macfadden W, et al. A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression. Am J Psychiatry 2005; 162: 1351–60

    Article  PubMed  Google Scholar 

  55. Thase ME, MacFadden W, Weisler RH, et al., the BOLDER II Study Group. Efficacy of quetiapine monotherapy in bipolar I and II depression: a double-blind, placebo-controlled study (The BOLDER II Study). J Clin Psychopharmacol 2006; 26(6): 600–9

    Article  PubMed  CAS  Google Scholar 

  56. Pfizer. Safety and tolerability of ziprasidone in adolescents with schizophrenia [Clinical Trials.gov identifier NCT00265382]. US National Institutes of Health, Clinical Trials.gov [online]. Available from URL: http://clinicaltrials.gov/ct2/show/NCT00265382 [Accessed 2010 Mar 9]

  57. 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. Eur Neuropsychopharmacol. Epub 2010 Aug 9

    Google Scholar 

  58. Dickstein DP, Towbin KE, Van Der Veen JW. Randomized double-blind placebo-controlled trial of lithium in youths with severe mood dysregulation. J Child Adolesc Psychopharmacol 2009; 19(1): 61–73

    Article  PubMed  Google Scholar 

  59. Findling RL, Frazier TW, Youngstrom EA. Double-blind, placebo-controlled trial of divalproex monotherapy in the treatment of symptomatic youth at high risk for developing bipolar disorder. J Clin Psychiatry 2007; 68(5): 781–8

    Article  PubMed  CAS  Google Scholar 

  60. Kowatch RA, Sethuraman RA, Hume JH, et al. Combination pharmacotherapy in children and adolescents with bipolar disorder. Biol Psychiatry 2003; 53(11): 978–84

    Article  PubMed  CAS  Google Scholar 

  61. Kowatch RA, Fristad M, Birmaher B, and the Workgroup Members. Treatment guidelines for children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 2005; 44(3): 213–35

    Article  PubMed  Google Scholar 

  62. Yatham LN, Kennedy SH, O’Donovan C. Canadian Network for Mood and Anxiety Treatments (CANMAT) guidelines for the management of patients with bipolar disorder: update 2007. Bipolar Disord 2006; 8: 721–39

    Article  PubMed  CAS  Google Scholar 

  63. Moreno C, Merchán-Naranjo J, Alvarez M, et al. Metabolic effects of second-generation antipsychotics in bipolar youths. Bipolar Disord 2010; 12: 172–84

    Article  PubMed  Google Scholar 

  64. Maayan LA, Vakhrushava J. Risperidone associated weight gain, leptin, and anthropometric changes in children and adolescents with psychotic disorders in early treatment. Hum Psychopharmacol 2010; 25(2): 133–8

    Article  PubMed  CAS  Google Scholar 

  65. Correll CY, Sheridan EM, DelBello MP. Antipsychotics and mood stabilizers efficacy and tolerability in pediatric and adult patients with bipolar I mania: a comparative analysis of acute, randomised, placebo-controlled trials. Bipolar Disord 2010; 12: 116–41

    Article  PubMed  CAS  Google Scholar 

  66. Panangiotopoulos C, Ronsley R, Elbe D, et al. First do not harm: promoting an evidence-based approach to atypical antipsychotic use in children and adolescents. J Can Acad Child Adolesc Psychiatry 2010; 19(2): 124–37

    Google Scholar 

  67. Gracious BL, Cook SR, Meyer AE, et al. Prevalence of overweight and obesity in adolescents with severe mental illness: a cross-sectional chart review. J Clin Psychiatry 2010; 7(17): 949–54

    Article  Google Scholar 

  68. Morrato EH, Nicol GE, Maahs D, et al. Metabolic screening in children receiving antipsychotic drug treatment. Arch Pediatr Adolesc Med 2010; 164(4): 344–51

    Article  PubMed  Google Scholar 

  69. Constantine RJ, Boaz T, Tandon R. Antipsychotic polypharmacy in the treatment of children and adolescents in the fee-for-service component of a large state Medicaid program. Clin Ther 2010; 32(5): 949–59

    Article  PubMed  Google Scholar 

  70. American Academy of Child and Adolescent Psychiatry. Practice parameters for the assessment and treatment of children and adolescents with schizophrenia. J Am Acad Child Adolesc Psychiatry 2001; 40: S4–23

    Article  Google Scholar 

  71. Shirkey H. Therapeutic orphans. J Pediatr 1968; 72: 119–20

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

Dr Gentile has received speakers’ bureau/consultant honoraria from Almirall, Boehringer Ingelheim, and Eli Lilly Italia SpA. During the last 5 years, Dr Gentile has also received travel funds from Almirall, Bristol-Myers Squibb, Eli Lilly, Lundbeck, and Novartis. He has no potential conflicts of interest that are directly related to the subject of this review. No financial support for the study has been received.

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  1. Department of Mental Health, ASL Salerno, Mental Health Center Cava de’ Tirreni, Piazza Galdi, 84013, Cava de’ Tirreni, Salerno, Italy

    Salvatore Gentile

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Gentile, S. Clinical Usefulness of Second-Generation Antipsychotics in Treating Children and Adolescents Diagnosed with Bipolar or Schizophrenic Disorders. Pediatr-Drugs 13, 291–302 (2011). https://doi.org/10.2165/11591250-000000000-00000

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