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Using neuroimaging to evaluate and guide pharmacological and psychotherapeutic treatments for mood disorders in children

Published online by Cambridge University Press:  09 February 2015

Manpreet K. Singh ,
Amy S. Garrett  and
Kiki D. Chang
Manpreet K. Singh*
Affiliation:
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, USA
Amy S. Garrett
Affiliation:
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, USA
Kiki D. Chang
Affiliation:
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, USA
*
*Address for correspondence: Manpreet Kaur Singh, M.D. M.S., Stanford University School of Medicine, Division of Child and Adolescent Psychiatry, 401 Quarry Road, Stanford, CA 94305-5719, USA. (Email: [email protected])
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Abstract

Mood disorders are increasing in childhood, and often require multimodal and comprehensive treatment plans to address a complex array of symptoms and associated morbidities. Pharmacotherapy, in combination with psychotherapeutic interventions, is essential for treatment and stabilization. Current evidence supports the use of a number of interventions in children and adolescents diagnosed with DSM-5 mood spectrum disorders, which are associated with impairments in prefrontal–striatal–limbic networks, which are key for emotional functioning and regulation. Yet, little is known about the neurobiological effects of interventions on the developing brain. This chapter provides a synopsis of the literature demonstrating the neural effects of psychotropic medications and psychotherapy in youth with depressive or bipolar spectrum disorders. Additional longitudinal and biological studies are warranted to characterize the effects of these interventions on all phases and stages of mood illness development in children and adolescents.

Keywords

Bipolar disorderdepressioninterventionMRIneuroimagingpediatric
Type
Review Articles
Information
CNS Spectrums , Volume 20 , Special Issue 4: Pediatric Neuroimaging , August 2015 , pp. 359 - 368
Copyright
© Cambridge University Press 2015 

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References

1. Merikangas, KR, He, J-P, Burstein, M, et al. Lifetime prevalence of mental disorders in U.S. adolescents: results from the National Comorbidity Survey Replication—Adolescent Supplement (NCS-A). J Am Acad Child Adolesc Psychiatry. 2010; 49(10): 980–989.CrossRefGoogle ScholarPubMed
2. Rocha, TBM, Zeni, CP, Caetano, SC, Kieling, C. Mood disorders in childhood and adolescence. Rev Bras Psiquiatr. 2013; 35(Suppl 1): S22–S31.CrossRefGoogle ScholarPubMed
3. Eaton, DK, Kann, L, Kinchen, S, et al. Youth risk behavior surveillance—United States, 2011. MMWR Surveill Summ. 2012; 61(4): 1–162.Google Scholar
4. Testa, CR, Steinberg, L. Depressive symptoms and health-related risk-taking in adolescence. Suicide Life Threat Behav. 2010; 40(3): 298–305.Google Scholar
5. Niederkrotenthaler, T, Floderus, B, Alexanderson, K, Rasmussen, F, Mittendorfer-Rutz, E. Exposure to parental mortality and markers of morbidity, and the risks of attempted and completed suicide in offspring: an analysis of sensitive life periods. J Epidemiol Community Health. 2012; 66(3): 233–239.Google Scholar
6. Arnett, J. Reckless behavior in adolescence: a developmental perspective. Developmental Review. 1992; 12(4): 339–373.Google Scholar
7. Casey, BJ, Jones, RM, Hare, TA. The adolescent brain. Ann N Y Acad Sci. 2008; 1124(1): 111–126.CrossRefGoogle ScholarPubMed
8. Neef, M, Weise, S, Adler, M, et al. Health impact in children and adolescents. Best Pract Res Clin Endocrinol Metab. 2013; 27(2): 229–238.CrossRefGoogle ScholarPubMed
9. Potter, R, Mars, B, Eyre, O, et al. Missed opportunities: mental disorder in children of parents with depression. Br J Gen Pract. 2012; 62(600): e487–e493.CrossRefGoogle ScholarPubMed
10. Post, RM, Leverich, GS, Kupka, RW, et al. Early-onset bipolar disorder and treatment delay are risk factors for poor outcome in adulthood. J Clin Psychiatry. 2010; 71(7): 864–872.Google Scholar
11. Merikangas, KR, Cui, L, Kattan, G, Carlson, GA, Youngstrom, EA, Angst, J. Mania with and without depression in a community sample of US adolescents. Arch Gen Psychiatry. 2012; 69(9): 943–951.CrossRefGoogle Scholar
12. Kessler, RC, Avenevoli, S, Costello, J, et al. Severity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication Adolescent Supplement. Arch Gen Psychiatry. 2012; 69(4): 381–389.Google ScholarPubMed
13. Yu, AP, Ben-Hamadi, R, Wu, EQ, et al. Impact of initiation timing of SSRI or SNRI on depressed adolescent healthcare utilization and costs. J Med Econ. 2011; 14(4): 508–515.Google Scholar
14. Merikangas, KR, He, J, Burstein, M, et al. Service utilization for lifetime mental disorders in U.S. adolescents: results of the National Comorbidity Survey–Adolescent Supplement (NCS-A). J Am Acad Child Adolesc Psychiatry. 2011; 50(1): 32–45.CrossRefGoogle ScholarPubMed
15. Mittendorfer-Rutz, E, Rasmussen, F, Lange, T. A life-course study on effects of parental markers of morbidity and mortality on offspring’s suicide attempt. PLoS ONE. 2012; 7(12): e51585.Google Scholar
16. Chang, K. Challenges in the diagnosis and treatment of pediatric bipolar depression. Dialogues Clin Neurosci. 2009; 11(1): 73–80.Google Scholar
17. 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): 107–125.CrossRefGoogle ScholarPubMed
18. Chang, K, Howe, M, Gallelli, K, Miklowitz, D. Prevention of pediatric bipolar disorder: integration of neurobiological and psychosocial processes. Ann N Y Acad Sci. 2006; 1094: 235–247.Google Scholar
19. Miklowitz, DJ, Chang, KD. Prevention of bipolar disorder in at-risk children: theoretical assumptions and empirical foundations. Dev Psychopathol. 2008; 20(3): 881–897.Google Scholar
20. Gross, JJ. The emerging field of emotion regulation: an integrative review. Review of General Psychology. 1998; 2(3): 271–299.Google Scholar
21. Singh, MK, Ketter, T, Chang, KD. Distinguishing bipolar disorder from other psychiatric disorders in children. Curr Psychiatry Rep. 2014; 16(12): 516.Google Scholar
22. Klein, DN, Glenn, CR, Kosty, DB, Seeley, JR, Rohde, P, Lewinsohn, PM. Predictors of first lifetime onset of major depressive disorder in young adulthood. J Abnorm Psychol. 2013; 122(1): 1–6.CrossRefGoogle ScholarPubMed
23. Lewinsohn, PM, Allen, NB, Seeley, JR, Gotlib, IH. First onset versus recurrence of depression: differential processes of psychosocial risk. J Abnorm Psychol. 1999; 108(3): 483–489.CrossRefGoogle ScholarPubMed
24. Lewinsohn, PM, Rohde, P, Seeley, JR, Klein, DN, Gotlib, IH. Natural course of adolescent major depressive disorder in a community sample: predictors of recurrence in young adults. Am J Psychiatry. 2000; 157(10): 1584–1591.Google Scholar
25. Savitz, JB, Rauch, SL, Drevets, WC. Clinical application of brain imaging for the diagnosis of mood disorders: the current state of play. Mol Psychiatry. 2013; 18(5): 528–539.Google Scholar
26. Tseng, W-L, Leibenluft, E, Brotman, MA. A systems neuroscience approach to the pathophysiology of pediatric mood and anxiety disorders. Curr Top Behav Neurosci. 2014; 16: 297–317.CrossRefGoogle Scholar
27. Rao, U. Biomarkers in pediatric depression. Depress Anxiety. 2013; 30(9): 787–791.Google Scholar
28. Serene, JA, Ashtari, M, Szeszko, PR, Kumra, S. Neuroimaging studies of children with serious emotional disturbances: a selective review. Can J Psychiatry. 2007; 52(3): 135–145.Google Scholar
29. Hulvershorn, LA, Cullen, K, Anand, A. Toward dysfunctional connectivity: a review of neuroimaging findings in pediatric major depressive disorder. Brain Imaging Behav. 2011; 5(4): 307–328.Google Scholar
30. Wu, M, Lu, LH, Passarotti, AM, Wegbreit, E, Fitzgerald, J, Pavuluri, MN. Altered affective, executive and sensorimotor resting state networks in patients with pediatric mania. J Psychiatry Neurosci. 2013; 38(4): 232–240.Google ScholarPubMed
31. Carlson, PJ, Singh, JB, Zarate, CA, Drevets, WC, Manji, HK. Neural circuitry and neuroplasticity in mood disorders: insights for novel therapeutic targets. NeuroRx. 2006; 3(1): 22–41.CrossRefGoogle ScholarPubMed
32. Phillips, ML, Travis, MJ, Fagiolini, A, Kupfer, DJ. Medication effects in neuroimaging studies of bipolar disorder. Am J Psychiatry. 2008; 165(3): 313–320.Google Scholar
33. Hafeman, DM, Chang, KD, Garrett, AS, Sanders, EM, Phillips, ML. Effects of medication on neuroimaging findings in bipolar disorder: an updated review. Bipolar Disord. 2012; 14(4): 375–410.Google Scholar
34. Singh, MK, Chang, KD, Chen, MC, et al. Volumetric reductions in the subgenual anterior cingulate cortex in adolescents with bipolar I disorder. Bipolar Disord. 2012; 14(6): 585–596.CrossRefGoogle ScholarPubMed
35. Singh, MK, Chang, KD, Kelley, RG, et al. Reward processing in adolescents with bipolar I disorder. J Am Acad Child Adolesc Psychiatry. 2013; 52(1): 68–83.CrossRefGoogle ScholarPubMed
36. Dickstein, DP, Gorrostieta, C, Ombao, H, et al. Fronto-temporal spontaneous resting state functional connectivity in pediatric bipolar disorder. Biol Psychiatry. 2010; 68(9): 839–846.Google Scholar
37. Singh, M, Spielman, D, Adleman, N, et al. Brain glutamatergic characteristics of pediatric offspring of parents with bipolar disorder. Psychiatry Res. 2010; 182(2): 165–171.CrossRefGoogle ScholarPubMed
38. Guyer, AE, Choate, VR, Detloff, A, et al. Striatal functional alteration during incentive anticipation in pediatric anxiety disorders. Am J Psychiatry. 2012; 169(2): 205–212.Google Scholar
39. Chantiluke, K, Halari, R, Simic, M, et al. Fronto-striato-cerebellar dysregulation in adolescents with depression during motivated attention. Biol Psychiatry. 2012; 71(1): 59–67.Google Scholar
40. Freitag, CM, Luders, E, Hulst, HE, et al. Total brain volume and corpus callosum size in medication-naïve adolescents and young adults with autism spectrum disorder. Biol Psychiatry. 2009; 66(4): 316–319.Google Scholar
41. Dickstein, DP, van der Veen, JW, Knopf, L, Towbin, KE, Pine, DS, Leibenluft, E. Proton magnetic resonance spectroscopy in youth with severe mood dysregulation. Psychiatry Res. 2008; 163(1): 30–39.Google Scholar
42. Suzuki, H, Botteron, KN, Luby, JL, et al. Structural-functional correlations between hippocampal volume and cortico-limbic emotional responses in depressed children. Cogn Affect Behav Neurosci. 2013; 13(1): 135–151.Google Scholar
43. Chen, MC, Hamilton, JP, Gotlib, IH. Decreased hippocampal volume in healthy girls at risk of depression. Arch Gen Psychiatry. 2010; 67(3): 270–276.CrossRefGoogle ScholarPubMed
44. Kerestes, R, Davey, CG, Stephanou, K, Whittle, S, Harrison, BJ. Functional brain imaging studies of youth depression: a systematic review. Neuroimage Clin. 2013; 4: 209–231.Google Scholar
45. Weir, JM, Zakama, A, Rao, U. Developmental risk I: depression and the developing brain. Child Adolesc Psychiatr Clin N Am. 2012; 21(2): 237–259; vii.Google Scholar
46. Tao, R, Calley, CS, Hart, J, et al. Brain activity in adolescent major depressive disorder before and after fluoxetine treatment. Am J Psychiatry. 2012; 169(4): 381–388.Google Scholar
47. Kondo, DG, Sung, Y-H, Hellem, TL, et al. Open-label adjunctive creatine for female adolescents with SSRI-resistant major depressive disorder: a 31-phosphorus magnetic resonance spectroscopy study. J Affect Disord. 2011; 135(1–3): 354–361.Google Scholar
48. Forbes, EE, Olino, TM, Ryan, ND, et al. Reward-related brain function as a predictor of treatment response in adolescents with major depressive disorder. Cogn Affect Behav Neurosci. 2010; 10(1): 107–118.Google Scholar
49. Croarkin, PE, Nakonezny, PA, Husain, MM, et al. Evidence for pretreatment LICI deficits among depressed children and adolescents with nonresponse to fluoxetine. Brain Stimul. 2014; 7(2): 243–251.CrossRefGoogle ScholarPubMed
50. Halari, R, Simic, M, Pariante, CM, et al. Reduced activation in lateral prefrontal cortex and anterior cingulate during attention and cognitive control functions in medication-naïve adolescents with depression compared to controls. J Child Psychol Psychiatry. 2009; 50(3): 307–316.Google Scholar
51. Rosen, HR, Rich, BA. Neurocognitive correlates of emotional stimulus processing in pediatric bipolar disorder: a review. Postgrad Med. 2010; 122(4): 94–104.Google Scholar
52. Baykara, B, Inal-Emiroglu, N, Karabay, N, et al. Increased hippocampal volumes in lithium treated adolescents with bipolar disorders: a structural MRI study. J Affect Disord. 2012; 138(3): 433–439.CrossRefGoogle ScholarPubMed
53. Mitsunaga, MM, Garrett, A, Howe, M, Karchemskiy, A, Reiss, A, Chang, K. Increased subgenual cingulate cortex volume in pediatric bipolar disorder associated with mood stabilizer exposure. J Child Adolesc Psychopharmacol. 2011; 21(2): 149–155.CrossRefGoogle ScholarPubMed
54. Chang, K, Karchemskiy, A, Barnea-Goraly, N, Garrett, A, Simeonova, DI, Reiss, A. Reduced amygdalar gray matter volume in familial pediatric bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2005; 44(6): 565–573.CrossRefGoogle ScholarPubMed
55. Barnea-Goraly, N, Chang, KD, Karchemskiy, A, Howe, ME, Reiss, AL. Limbic and corpus callosum aberrations in adolescents with bipolar disorder: a tract-based spatial statistics analysis. Biol Psychiatry. 2009; 66(3): 238–244.Google Scholar
56. Leibenluft, E, Rich, BA, Vinton, DT, et al. Neural circuitry engaged during unsuccessful motor inhibition in pediatric bipolar disorder. Am J Psychiatry. 2007; 164(1): 52–60.Google Scholar
57. Pavuluri, MN, Passarotti, AM, Lu, LH, Carbray, JA, Sweeney, JA. Double-blind randomized trial of risperidone versus divalproex in pediatric bipolar disorder: fMRI outcomes. Psychiatry Res. 2011; 193(1): 28–37.Google Scholar
58. Pavuluri, MN, Ellis, JA, Wegbreit, E, Passarotti, AM, Stevens, MC. Pharmacotherapy impacts functional connectivity among affective circuits during response inhibition in pediatric mania. Behav Brain Res. 2012; 226(2): 493–503.Google Scholar
59. Pavuluri, MN, Passarotti, AM, Fitzgerald, JM, Wegbreit, E, Sweeney, JA. Risperidone and divalproex differentially engage the fronto-striato-temporal circuitry in pediatric mania: a pharmacological functional magnetic resonance imaging study. J Am Acad Child Adolesc Psychiatry. 2012; 51(2): 157–170.CrossRefGoogle Scholar
60. Chang, KD, Wagner, C, Garrett, A, Howe, M, Reiss, A. A preliminary functional magnetic resonance imaging study of prefrontal-amygdalar activation changes in adolescents with bipolar depression treated with lamotrigine. Bipolar Disord. 2008; 10(3): 426–431.CrossRefGoogle ScholarPubMed
61. Pavuluri, MN, Passarotti, AM, Parnes, SA, Fitzgerald, JM, Sweeney, JA. A pharmacological functional magnetic resonance imaging study probing the interface of cognitive and emotional brain systems in pediatric bipolar disorder. J Child Adolesc Psychopharmacol. 2010; 20(5): 395–406.Google Scholar
62. Pavuluri, MN, Passarotti, AM, Harral, EM, Sweeney, JA. Enhanced prefrontal function with pharmacotherapy on a response inhibition task in adolescent bipolar disorder. J Clin Psychiatry. 2010; 71(11): 1526–1534.Google Scholar
63. Passarotti, AM, Sweeney, JA, Pavuluri, MN. Fronto-limbic dysfunction in mania pre-treatment and persistent amygdala over-activity post-treatment in pediatric bipolar disorder. Psychopharmacology (Berl.). 2011; 216(4): 485–499.Google Scholar
64. Yang, H, Lu, LH, Wu, M, et al. Time course of recovery showing initial prefrontal cortex changes at 16 weeks, extending to subcortical changes by 3 years in pediatric bipolar disorder. J Affect Disord. 2013; 150(2): 571–577.CrossRefGoogle ScholarPubMed
65. Schneider, MR, Adler, CM, Whitsel, R, et al. The effects of ziprasidone on prefrontal and amygdalar activation in manic youth with bipolar disorder. Isr J Psychiatry Relat Sci. 2012; 49(2): 112–120.Google Scholar
66. Wegbreit, E, Ellis, JA, Nandam, A, et al. Amygdala functional connectivity predicts pharmacotherapy outcome in pediatric bipolar disorder. Brain Connect. 2011; 1(5): 411–422.Google Scholar
67. Chang, K, Karchemskiy, A, Kelley, R, et al. Effect of divalproex on brain morphometry, chemistry, and function in youth at high-risk for bipolar disorder: a pilot study. J Child Adolesc Psychopharmacol. 2009; 19(1): 51–59.Google Scholar
68. Pavuluri, MN, O’Connor, MM, Harral, EM, Sweeney, JA. An fMRI study of the interface between affective and cognitive neural circuitry in pediatric bipolar disorder. Psychiatry Res. 2008; 162(3): 244–255.Google Scholar
69. Wegbreit, E, Passarotti, AM, Ellis, JA, et al. Where, when, how high, and how long? The hemodynamics of emotional response in psychotropic-naïve patients with adolescent bipolar disorder. J Affect Disord. 2013; 147(1–3): 304–311.Google Scholar
70. Chang, K, Adleman, N, Dienes, K, Barnea-Goraly, N, Reiss, A, Ketter, T. Decreased N-acetylaspartate in children with familial bipolar disorder. Biol Psychiatry. 2003; 53(11): 1059–1065.Google Scholar
71. Davanzo, P, Thomas, MA, Yue, K, et al. Decreased anterior cingulate myo-inositol/creatine spectroscopy resonance with lithium treatment in children with bipolar disorder. Neuropsychopharmacology. 2001; 24(4): 359–369.Google Scholar
72. Patel, NC, DelBello, MP, Cecil, KM, Stanford, KE, Adler, CM, Strakowski, SM. Temporal change in N-acetyl-aspartate concentrations in adolescents with bipolar depression treated with lithium. J Child Adolesc Psychopharmacol. 2008; 18(2): 132–139.Google Scholar
73. Patel, NC, DelBello, MP, Cecil, KM, et al. Lithium treatment effects on myo-inositol in adolescents with bipolar depression. Biol Psychiatry. 2006; 60(9): 998–1004.Google Scholar
74. Glitz, DA, Manji, HK, Moore, GJ. Mood disorders: treatment-induced changes in brain neurochemistry and structure. Semin Clin Neuropsychiatry. 2002; 7(4): 269–280.Google Scholar
75. Soeiro-de-Souza, MG, Dias, VV, Figueira, ML, et al. Translating neurotrophic and cellular plasticity: from pathophysiology to improved therapeutics for bipolar disorder. Acta Psychiatr Scand. 2012; 126(5): 332–341.Google Scholar
76. Demuro, A, Parker, I. Cytotoxicity of intracellular aβ42 amyloid oligomers involves Ca2+ release from the endoplasmic reticulum by stimulated production of inositol trisphosphate. J Neurosci. 2013; 33(9): 3824–3833.Google Scholar
77. Yildiz-Yesiloglu, A, Ankerst, DP. Neurochemical alterations of the brain in bipolar disorder and their implications for pathophysiology: a systematic review of the in vivo proton magnetic resonance spectroscopy findings. Prog Neuropsychopharmacol Biol Psychiatry. 2006; 30(6): 969–995.CrossRefGoogle ScholarPubMed
78. DelBello, MP, Cecil, KM, Adler, CM, Daniels, JP, Strakowski, SM. Neurochemical effects of olanzapine in first-hospitalization manic adolescents: a proton magnetic resonance spectroscopy study. Neuropsychopharmacology. 2006; 31(6): 1264–1273.Google Scholar
79. Manji, HK, Moore, GJ, Chen, G. Clinical and preclinical evidence for the neurotrophic effects of mood stabilizers: implications for the pathophysiology and treatment of manic-depressive illness. Biol Psychiatry. 2000; 48(8): 740–754.Google Scholar
80. Kowatch, RA, Fristad, M, Birmaher, B, et al. Treatment guidelines for children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry. 2005; 44(3): 213–235.Google Scholar
81. Hashimoto, R, Fujimaki, K, Jeong, MR, et al. [Neuroprotective actions of lithium]. Seishin Shinkeigaku Zasshi. 2003; 105(1): 81–86.Google Scholar
82. Laeng, P, Pitts, RL, Lemire, AL, et al. The mood stabilizer valproic acid stimulates GABA neurogenesis from rat forebrain stem cells. J Neurochem. 2004; 91(1): 238–251.Google Scholar
83. Moore, CM, Frazier, JA, Glod, CA, et al. Glutamine and glutamate levels in children and adolescents with bipolar disorder: a 4.0-T proton magnetic resonance spectroscopy study of the anterior cingulate cortex. J Am Acad Child Adolesc Psychiatry. 2007; 46(4): 524–534.Google Scholar
84. Moore, CM, Biederman, J, Wozniak, J, et al. Mania, glutamate/glutamine and risperidone in pediatric bipolar disorder: a proton magnetic resonance spectroscopy study of the anterior cingulate cortex. J Affect Disord. 2007; 99(1–3): 19–25.Google Scholar
85. Mayanil, T, Wegbreit, E, Fitzgerald, J, Pavuluri, M. Emerging biosignature of brain function and intervention in pediatric bipolar disorder. Minerva Pediatr. 2011; 63(3): 183–200.Google Scholar
86. Diler, RS, Segreti, AM, Ladouceur, CD, et al. Neural correlates of treatment in adolescents with bipolar depression during response inhibition. J Child Adolesc Psychopharmacol. 2013; 23(3): 214–221.Google Scholar
87. Diler, RS, Ladouceur, CD, Segreti, A, et al. Neural correlates of treatment response in depressed bipolar adolescents during emotion processing. Brain Imaging Behav. 2013; 7(2): 227–235.Google Scholar
88. Garrett, AS, Miklowitz, DJ, Howe, ME, et al. Changes in brain activation following psychotherapy for youth with mood dysregulation at familial risk for bipolar disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2015; 56: 215–220.Google Scholar
89. Dichter, GS, Sikich, L, Song, A, Voyvodic, J, Bodfish, JW. Functional neuroimaging of treatment effects in psychiatry: methodological challenges and recommendations. Int J Neurosci. 2012; 122(9): 483–493.Google Scholar
90. Goldsmith, M, Singh, M, Chang, K. Antidepressants and psychostimulants in pediatric populations: is there an association with mania? Paediatr Drugs. 2011; 13(4): 225–243.Google Scholar