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Management of Treatment-Resistant Depression in Children and Adolescents

  • Therapy in Practice
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Abstract

Depression is a relatively common diagnosis in children and adolescents, and is associated with significant morbidity and suicidality in this population. Evidence-based treatment of the acute illness is imperative to try to prevent the development of treatment-resistant depression or other complications. In situations where response to acute treatment is inadequate, clinicians should first consider factors that may influence outcome, such as psychiatric or medical comorbidities, psychosocial stressors, and treatment noncompliance. Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for depression in children and adolescents. For treatment-resistant depression, a switch to an alternate SSRI is recommended before trials of other antidepressants. Psychotherapy, such as cognitive behavioral therapy or interpersonal therapy, may improve treatment response. More research is needed examining medication augmentation strategies for treatment-resistant depression in children and adolescents.

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References

  1. Merikangas KR, He J, Burstein M, Swanson SA, Avenevoli S, Cui L, Benjet C, Georgiades K, Swendsen J. Lifetime prevalence of mental disorders in US adolescents: Results from the National Comorbidity Study-Adolescent Supplement (NCS-A). J Am Acad Child Adolesc Psychiatry. 2010;49(10):980–9.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Melvin GA, Dudley AL, Gordon MS, Ford S, Taffe J, Tonge BJ. What happens to depressed adolescents? A follow-up study into early adulthood. J Affective Disorders. 2013;151:298–305.

    Article  Google Scholar 

  3. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Arlington, VA: American Psychiatric Association; 2013.

  4. Williams JM, et al. Pre-adult onset and patterns of suicidality in patients with a history of recurrent depression. J Affect Disord. 2012;138(1–2):173–9.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Brent D, et al. Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression: The TORDIA randomized controlled trial. JAMA. 2008;299(8):901–13.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Wagner KD, Pliszka SR. Treatment of child and adolescent disorders. In: Schatzberg AF, Nemeroff CB, editors. Essentials of clinical psychopharmacology, 3rd ed. Arlington, VA: American Psychiatric Publishing; 2013. p. 693–750.

  7. Malouf FT, Atwi M, Brent DA. Treatment-resistant depression in adolescents: review and updates on clinical management. Depress Anxiety. 2011;28:946–54.

    Article  Google Scholar 

  8. Lewinsohn PM, et al. Cross-sectional and prospective relationships between physical morbidity and depression in older adolescents. J Am Acad Child Adolesc Psychiatry. 1996;35:1120–9.

    Article  PubMed  CAS  Google Scholar 

  9. Kovacs M, et al. Psychiatric disorder and metabolic control among youths with IDDM. A longitudinal study. Diabetes Care. 1996;19:318–23.

    Article  PubMed  CAS  Google Scholar 

  10. Schosser A, Kasper S. The role of pharmacogenetics in the treatment of depression and anxiety disorders. Int Clin Psychopharmacol. 2009;24:277–88.

    Article  PubMed  Google Scholar 

  11. Emslie GJ, et al. A double-blind, randomized, placebo-controlled trial of fluoxetine in children and adolescents with depression. Arch Gen Psychiatry. 1997;54(11):1031–7.

    Article  PubMed  CAS  Google Scholar 

  12. Guy W. ECDEU Assessment Manual for Psychopharmacology-Revised (DHEW Publ No ADM 76-338). Rockville, MD, U.S. Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, NIMH Psychopharmacology Research Branch, Division of Extramural Research Programs; 1976. p. 218–22.

  13. Emslie GJ, et al. Fluoxetine for acute treatment of depression in children and adolescents: a placebo-controlled, randomized clinical trial. J Am Acad Child Adolesc Psychiatry. 2002;41(10):1205–15.

    Article  PubMed  Google Scholar 

  14. Poznanski EO, Mokros H. Children’s Depression Rating Scale Revised (CDRS-R)Western Psychological Services, Los Angeles; 1996.

  15. March J, Silva S, Petrycki S, Curry J, Wells K, Fairbank J, Burns B, Domino M, McNulty S, Vitiello B, Severe J. Treatment for Adolescents With Depression Study (TADS) Team. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) randomized controlled trial. JAMA. 2004;292(7):807–20.

    Article  PubMed  CAS  Google Scholar 

  16. Emslie GJ, Ventura D, Korotzer A, Tourkodimitris S. Escitalopram in the treatment of adolescent depression: a randomized placebo-controlled multisite trial. J Am Acad Child Adolesc Psychiatry. 2009;48(7):721–9.

    Article  PubMed  Google Scholar 

  17. Wagner KD, et al. A double-blind, randomized, placebo-controlled trial of escitalopram in the treatment of pediatric depression. J Am Acad Child Adolesc Psychiatry. 2006;45(3):280–8).

  18. Wagner KD, et al. Efficacy of sertraline in the treatment of children and adolescents with major depressive disorder: two randomized controlled trials. Sertraline Pediatric Depression Study Group. JAMA. 2003;290(8):1033–41.

    Article  PubMed  CAS  Google Scholar 

  19. Wagner KD, et al. A randomized, placebo-controlled trial of citalopram for the treatment of major depression in children and adolescents. Am J Psychiatry. 2004;161(6):1079–83.

    Article  PubMed  Google Scholar 

  20. FDA Drug Safety Communication. Abnormal heart rhythms associated with high doses of Celexa (citalopram hydrobromide). FDA Web site. http://www.fda.gov/Drugs/DrugSafety/ucm269086.

  21. Emslie GJ, et al. Paroxetine treatment in children and adolescents with major depressive disorder: a randomized, multicenter, double-blind, placebo-controlled trial. J Am Acad Child Adolesc Psychiatry. 2006;45(6):709–19.

    Article  PubMed  Google Scholar 

  22. von Knorring AL, et al. A randomized, double-blind, placebo-controlled study of citalopram in adolescents with major depressive disorder. J Clin Psychopharmacol. 2006;26(3):311–5.

    Article  Google Scholar 

  23. Emslie GJ, et al. Paroxetine treatment in children and adolescents with major depressive disorder: a randomized, multicenter, placebo-controlled trial. J Am Acad Child Adolesc Psychiatry. 2006;45(6):709–19.

    Article  PubMed  Google Scholar 

  24. Berard R, et al. An international, multicenter, placebo-controlled trial of paroxetine in adolescents with major depressive disorder. J Child Adolesc Psychopharmacol. 2006;16(1–2):59–75.

    Article  PubMed  Google Scholar 

  25. Keller MB, et al. Efficacy of paroxetine in the treatment of adolescent major depression: a randomized, controlled trial. J Am Acad Child Adolesc Psychiatry. 2001;40(7):762–72.

    Article  PubMed  CAS  Google Scholar 

  26. Emslie, Yeung, and Kunz. Long-term, open-label venlafaxine extended-release treatment in children and adolescents with major depressive disorder. CNS Spectrums. 2007;12(3):223-233.

  27. Cheung AH, Emslie GJ, Mayes TL. Review of the efficacy and safety of antidepressants in youth depression. J Child Psychol Psychiatry. 2005;46:735–54.

    Article  PubMed  Google Scholar 

  28. A Study in the Treatment of Children and Adolescents with Major Depressive Disorder, Clinicaltrials.gov Study NCT00849901 and Study NCT00849693.

  29. Delbello MP, et al. A double-blind, placebo-controlled study of selegeline transdermal system (EMSAS) in depressed adolescents. In: Presented at Annual Meeting of American Academy of Child and Adolescent Psychiatrists Annual Meeting, Toronto, Canada, 18–23 Oct 2011.

  30. Daviss WB, et al. Bupropion sustained release in adolescents with comorbid attention-deficit/hyperactivity disorder and depression. J Am Acad Child Adolesc Psychiatry. 2001;40(3):307–14.

    Article  PubMed  CAS  Google Scholar 

  31. Bridge JA, et al. Clinical response and risk for reported suicidal ideation and suicide attempts in pediatric antidepressant treatment: a meta analysis of randomized controlled trials. JAMA. 2007;297(15):1683–96.

    Article  PubMed  CAS  Google Scholar 

  32. Hetrick SE, McKenzie JE, Cox GR, Simmons MB, Merry SN. Newer generation antidepressants for depressive disorders in children and adolescents. Cochrane Database Syst Rev. 2012;11:CD004851. doi:10.1002/14651858.CD004851.pub3.

  33. Kennard BD, Silva SG, Tonev S, Rohde P, Hughes JL, Vitiello B, Kratochvil CJ, Curry JF, Emslie GJ, Reinecke M, March J. Remission and recovery in the Treatment for Adolescents with Depression Study (TADS): acute and long-term outcomes. J Am Acad Child Adolesc Psychiatry. 2009;48(2):186–95.

    Article  PubMed  PubMed Central  Google Scholar 

  34. The TADS Team. The treatment for adolescents with depression study (TADS). Arch Gen Psychiatry. 2007;64:1132–44.

    Article  Google Scholar 

  35. Emslie GJ, Kennard BD, Mayes TL, Nightingale-Teresi J, Carmody T, Hughes CW, Rush AJ, Tao R, Rintelmann JW. Fluoxetine versus placebo in preventing relapse of major depression in children and adolescents. Am J Psychiatry. 2008;165(4):459–67.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Cox GR, et al. Interventions for preventing relapse and recurrence of a depressive disorder in children and adolescents. Cochrane Database Syst Rev. 2012;11:CD007504. doi:10.1002/14651858.CD007504.pub2.

  37. Birmaher B. Brent D; AACAP Work Group on Quality Issues, Bernet W, Bukstein O, Walter H, Benson RS, Chrisman A, Farchione T, Greenhill L, Hamilton J, Keable H, Kinlan J, Schoettle U, Stock S, Ptakowski KK, Medicus J. Practice parameter for the assessment and treatment of children and adolescents with depressive disorders. J Am Acad Child Adolesc Psychiatry. 2007;46(11):1503–26.

    Article  PubMed  Google Scholar 

  38. Hughes CW, Emslie GJ, Crismon ML, Posner K, Birmaher B, Ryan N, Jensen P, Curry J, Vitiello B, Lopez M, Shon SP, Pliszka SR, Trivedi MH. Texas consensus conference panel on medication treatment of childhood major depressive disorder. Texas children’s medication algorithm project: update from Texas consensus conference panel on medication treatment of childhood major depressive disorder. J Am Acad Child Adolesc Psychiatry. 2007;46(6):667–86.

    Article  PubMed  Google Scholar 

  39. Emslie GJ, Kennard BD, Mayes TL. Predictors of treatment response in adolescent depression. Pediatr Ann. 2011;40(6):300–6.

    Article  PubMed  Google Scholar 

  40. Curry J, Silva S, et al. Recovery and recurrence following Treatment for Adolescent Major Depression. Arch Gen Psychiatry. 2011;68(3):263–9.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Emslie GJ, Mayes T, Porta G, et al. Treatment of Resistant Depression in Adolescents (TORDIA): week 24 outcomes. Am J Psychiatry. 2010;167(7):782–91.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Beach SR, et al. Meta-analysis of selective serotonin reuptake inhibitor-associated QTc prolongation. J Clin Psychiatry. 2014;75(5):e441–9.

    Article  PubMed  Google Scholar 

  43. Zivin K, et al. Evaluation of the FDA warning against prescribing citalopram at doses exceeding 40mg. Am J Psychiatry. 2013;170:642–50.

    Article  PubMed  Google Scholar 

  44. Van Haelst IMM, et al. QT interval prolongation in users of selective serotonin reuptake inhibitors in an elderly surgical population: a cross-sectional study. J Clin Psychiatry. 2014; 75(1):15-21

  45. Rizzoli R, et al. Antidepressant medications and osteoporosis. Bone. 2012;51:606–13.

    Article  PubMed  CAS  Google Scholar 

  46. Jerrell JM. Neuroendocrine-related adverse events associated with antidepressant treatment in children and adolescents. CNS Neurosci Therapeutics. 2010;16:83–90.

    Article  CAS  Google Scholar 

  47. Voican CS, et al. Antidepressant-induced liver injury: a review for clinicians. Am J Psychiatry. 2014;171(4):404–15.

    Article  PubMed  Google Scholar 

  48. Hammerness PG, et al. Selective serotoinin reuptake inhibitors in pediatric psychopharmacology: a review of the evidence. J Pediatrics. 2006;148:158–65.

    Article  CAS  Google Scholar 

  49. U.S. Food and Drug Administration: FDA News: FDA launches a multi-pronged strategy to strengthen safeguards for children treated with antidepressant medication. October 15, 2004a. http://www.fda.gov/newsevents/newsroom/pressannouncements/2004/ucm108363.htm. Accessed July 2014.

  50. Cooper WO, et al. Antidepressants and suicide attempts in children. Pediatrics. 2014;133(2):204–10.

    Article  PubMed  Google Scholar 

  51. Miller M, et al. Antidepressant dose, age, and the risk of deliberate self-harm. JAMA Intern Med. 2014;174(6):899–909.

    Article  PubMed  Google Scholar 

  52. Pathak S, Johns ES, Kowatch RA. Adjunctive quetiapine for treatment-resistant adolescent major depressive disorder: a case series. J Child Adolesc Psychopharmacol. 2005;15(4):696–702.

    Article  PubMed  Google Scholar 

  53. Nemets H, et al. Omega-3 treatment of childhood depression: a controlled, double-blind pilot study. Am J Psychiatry. 2006;163(6):1098–100.

    Article  PubMed  Google Scholar 

  54. Bloch Y, et al. Repetitive transcranial magnetic stimulation in the treatment of depression in adolescents: an open-label study. J ECT. 2008;24(2):156–9.

    Article  PubMed  Google Scholar 

  55. Mayer G, et al. Long-term follow-up of adolescents with resistant depression treated with repetitive transcranial magnetic stimulation. J ECT. 2012;28(2):84–6.

    Article  PubMed  Google Scholar 

  56. Walter G, et al. Transcranial magnetic stimulation in young persons: a review of known cases. J Child Adolsec Psychopharmacol. 2001;11(1):69–75.

    Article  CAS  Google Scholar 

  57. Hegeman JM, et al. The efficacy of electroconvulsive therapy in adolescents. A restrospective study. Tijdschr Psychiatr. 2008;50(1):23–51.

    PubMed  CAS  Google Scholar 

  58. Ghaziuddin N, et al. Use of continuation or maintenance electroconvulsive therapy in adolescents with severe treatment-resistant depression. J ECT. 2011;27(2)168–74.

  59. Ghaziuddin N, et al. Work Group on Quality Issues; AACAP. Practice parameter for use of electroconvulsive therapy with adolescents. J Am Acad Child Adoles Psychiatry. 2004;43:1521–39.

    Article  Google Scholar 

  60. Brent DA, et al. A clinical psychotherapy trial for adolescent depression comparing cognitive, family, and supportive therapy. Arch Gen Psychiatry. 1997;54(9):877–85.

    Article  PubMed  CAS  Google Scholar 

  61. Clarke GN, Rohde P, Lewinsohn PM, Hops H, Seeley JR. Cognitive-behavioral treatment of adolescent depression: efficacy of acute group treatment and booster sessions. J Am Acad Child Adolesc Psychiatry. 1999;38(3):272–9.

    Article  PubMed  CAS  Google Scholar 

  62. Lewinsohn PM, Clarke GN, Hops H, Andrews J. Cognitive-behavioral treatment for depressed adolescents. Behavioral Therapy. 1990;21:385–401.

    Article  Google Scholar 

  63. Rosselló J, Bernal G. The efficacy of cognitive-behavioral and interpersonal treatments for depression in Puerto Rican adolescents. J Consult Clin Psychol. 1999;67(5):734–45.

    Article  PubMed  Google Scholar 

  64. Wood A, Harrington R, Moore A. Controlled trial of a brief cognitive-behavioural intervention in adolescent patients with depressive disorders. J Child Psychol Psychiatry. 1996;37(6):737–46.

    Article  PubMed  CAS  Google Scholar 

  65. Weisz JR, McCarty CA, Valeri SM. Effects of psychotherapy for depression in children and adolescents: a meta-analysis. Psychol Bull. 2006;132(1):132–49.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Merry SN, et al. The effectiveness of SPARX, a computerized self help intervention for adolescents seeking help for depression: randomized controlled non-inferiority trial. BMJ. Published online Apr 18 2012. doi:10.1136/bmj.e2598.

  67. Mufson L, Dorta KP, Wickramaratne P, Nomura Y, Olfson M, Weissman MM. A randomized effectiveness trial of interpersonal psychotherapy for depressed adolescents. Arch Gen Psychiatry. 2004;61(6):577–84.

    Article  PubMed  Google Scholar 

  68. Mufson L, Weissman MM, Moreau D, Garfinkel R. Efficacy of interpersonal psychotherapy for depressed adolescents. Arch Gen Psychiatry. 1999;56(6):573–9.

    Article  PubMed  CAS  Google Scholar 

  69. Tang TC, Jou SH, Ko CH, Huang SY, Yen CF. Randomized study of school-based intensive interpersonal psychotherapy for depressed adolescents with suicidal risk and parasuicide behaviors. Psychiatry Clin Neurosci. 2009;63(4):463–70.

    Article  PubMed  Google Scholar 

  70. Young JF, Mufson L, Gallop R. Preventing depression: a randomized trial of interpersonal psychotherapy-adolescent skills training. Depress Anxiety. 2010;27(5):426–33.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Kratochvil C, et al. Acute time to response in the Treatment for Adolescents with Depression Study (TADS). J Am Acad Child Adolesc Psychiatry. 2006;45(12):1412–8.

    Article  PubMed  Google Scholar 

  72. Curry J, et al. Predictors and moderators of acute outcome in the Treatment for Adolescents with Depression Study (TADS). J Am Acad Child Adolesc Psychiatry. 2006;45(12):1427–39.

    Article  PubMed  Google Scholar 

  73. Kennard BD, et al. Cognitive-behavioral therapy to prevent relapse in pediatric responders to pharmacotherapy for major depressive disorder. J Am Acad Child Adolesc Psychiatry. 2008;47(12):1395–404.

    Article  PubMed  PubMed Central  Google Scholar 

  74. Goodyer IM, et al. A randomised controlled trial of cognitive behaviour therapy in adolescents with major depression treated by selective serotonin reuptake inhibitors. The ADAPT trial. Health Technol Assess. 2008;12(14):iii–iv, ix-60.

  75. Dubicka B, Elvins R, Roberts C, Chick G, Wilkinson P, Goodyer I. Combined treatment with cognitive-behavioural therapy in adolescent depression: meta-analysis. B J Psych. 2010;197:433–40.

    Article  Google Scholar 

  76. Cox GR et al. Psychological therapies versus antidepressant medication, alone and in combination for depression in children and adolescents (Review). Cochrane Database Syst Rev. 2012;11:CD008324. doi:10.1002/14651858.CD008324.pub2.

  77. Diamond GS, et al. Attachment-based family therapy for adolescents with suicidal ideation: a randomized controlled trial. J Am Acad Child Adolesc Psychiatry. 2010;49(2):122–31.

    PubMed  Google Scholar 

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Acknowledgments

No sources of funding were used to assist in the preparation of this manuscript. Dr Defillippis has no conflicts of interest to disclose. For the period May 2013 to May 2014, Dr Wagner received honoraria from UBM Medica, American Psychiatric Association, Las Vegas Psychiatric Society, NAC CME, University of Wisconsin, Doctors Hospital at Renaissance, Oxford University Press, University of California San Diego, and Partners Healthcare. She has been a consultant for Lundbeck (no financial compensation).

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  1. Department of Child and Adolescent Psychiatry, The University of Texas Medical Branch, 301 University Blvd, Galveston, TX, 77555-0188, USA

    Melissa DeFilippis & Karen Dineen Wagner

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  1. Melissa DeFilippis
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  2. Karen Dineen Wagner
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Correspondence to Karen Dineen Wagner.

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DeFilippis, M., Wagner, K.D. Management of Treatment-Resistant Depression in Children and Adolescents. Pediatr Drugs 16, 353–361 (2014). https://doi.org/10.1007/s40272-014-0088-y

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