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Multilevel assessment of the neurobiological threat system in depressed adolescents: Interplay between the limbic system and hypothalamic–pituitary–adrenal axis

Published online by Cambridge University Press:  25 November 2014

Bonnie Klimes-Dougan*
University of Minnesota
Lynn E. Eberly
University of Minnesota
Melinda Westlund Schreiner
University of Minnesota
Patrick Kurkiewicz
University of Minnesota
Alaa Houri
University of Minnesota
Amanda Schlesinger
University of Iowa
Kathleen M. Thomas
University of Minnesota
Bryon A. Mueller
University of Minnesota
Kelvin O. Lim
University of Minnesota
Kathryn R. Cullen
University of Minnesota
Address correspondence and reprint requests to: Bonnie Klimes-Dougan, Department of Psychology, University of Minnesota, N412 Elliot Hall, 75 East River Road, Minneapolis, MN 55455; E-mail:


Integrative, multilevel approaches investigating neurobiological systems relevant to threat detection promise to advance understanding of the pathophysiology of major depressive disorder (MDD). In this study we considered key neuronal and hormonal systems in adolescents with MDD and healthy controls (HC). The goals of this study were to identify group differences and to examine the association of neuronal and hormonal systems. MDD and HC adolescents (N = 79) aged 12–19 years were enrolled. Key brain measures included amygdala volume and amygdala activation to an emotion face-viewing task. Key hormone measures included cortisol levels during a social stress task and during the brain scan. MDD and HC adolescents showed group differences on amygdala functioning and patterns of cortisol levels. Amygdala activation in response to emotional stimuli was positively associated with cortisol responses. In addition, amygdala volume was correlated with cortisol responses, but the pattern differed in depressed versus healthy adolescents, most notably for unmedicated MDD adolescents. The findings highlight the value of using multilevel assessment strategies to enhance understanding of pathophysiology of adolescent MDD, particularly regarding how closely related biological threat systems function together while undergoing significant developmental shifts.

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Aihara, M., Ida, I., Yuuki, N., Oshima, A., Kumano, H., Takahashi, K., et al. (2007). HPA axis dysfunction in unmedicated major depressive disorder and its normalization by pharmacotherapy correlates with alteration of neural activity in prefrontal cortex and limbic/paralimbic regions. Psychiatry Research, 155, 245256.CrossRefGoogle ScholarPubMed
Axelson, D. A., Doraiswamy, P. M., Boyko, O. B., Rodrigo Escalona, P., McDonald, W. M., Ritchie, J. C., et al. (1992). In vivo assessment of pituitary volume with magnetic resonance imaging and systematic stereology: Relationship to dexamethasone suppression test results in patients. Psychiatry Research, 44, 6370.CrossRefGoogle ScholarPubMed
Axelson, D. A., Doraiswamy, P. M., McDonald, W. M., Boyko, O. B., Tupler, L. A., Patterson, L. J., et al. (1993). Hypercortisolemia and hippocampal changes in depression. Psychiatry Research, 47, 163173.CrossRefGoogle ScholarPubMed
Bauer, A. M., Quas, J. A., & Boyce, W. T. (2002). Associations between physiological reactivity and children's behavior: Advantages of a multisystem approach. Journal of Developmental and Behavioral Pediatrics, 23, 102113.CrossRefGoogle ScholarPubMed
Beck, A. T., Steer, R. A., & Brown, K. B. (1996). Beck Depression Inventory II. San Antonio, TX: Harcourt Brace.Google Scholar
Berndt, E. R., Koran, L. M., Finkelstein, S. N., Gelenberg, A. J., Kornstein, S. G., Miller, I. M., et al. (2000). Lost human capital from early-onset chronic depression. American Journal of Psychiatry, 157, 940947.CrossRefGoogle ScholarPubMed
Burghy, C. A., Stodola, D. E., Ruttle, P. L., Molloy, E. K., Armstrong, J. M., Oler, J. A., et al. (2012). Developmental pathways to amygdala–prefrontal function and internalizing symptoms in adolescence. Nature Neuroscience, 15, 17361741.CrossRefGoogle ScholarPubMed
Colla, M., Kronenberg, G., Deuschle, M., Meichel, K., Hagen, T., Bohrer, M., et al. (2007). Hippocampal volume reduction and HPA-system activity in major depression. Journal of Psychiatric Research, 42, 587595.CrossRefGoogle Scholar
Compas, B. E., & Wagner, B. M. (1991). Psychosocial stress during adolescence: Intrapersonal and interpersonal processes. In Gore, S. & Colton, M. E. (Eds.), Adolescence, stress and coping. New York: Aldine de Gruyter.Google Scholar
Cullen, K. R., Gee, D. G., Klimes-Dougan, B., Gabbay, V., Hulvershorn, L. Mueller, B. A., et al. (2009). A preliminary study of functional connectivity in comorbid adolescent depression. Neuroscience Letters, 460, 227231.CrossRefGoogle ScholarPubMed
Cullen, K. R., Klimes-Dougan, B., Muetzel, R., Mueller, B. A. Camchong, J., Houri, A., et al. (2010). Altered white matter microstructure in adolescents with major depression: A preliminary study. Journal of the American Academy of Child & Adolescent Psychiatry, 49, 173183. doi:10.1016/j.jaac.2009.11.005 Google ScholarPubMed
Cunningham-Bussel, A. C., Root, J. C., Butler, T., Tuescher, O., Pan, H., Epstein, J., et al. (2009). Diurnal cortisol amplitude and fronto-limbic activity in response to stressful stimuli. Psychoeuroendocrinology, 34, 694704.CrossRefGoogle ScholarPubMed
Dedovic, K., Engert, V., Duchesne, A., Lue, S. D., Andrews, J., Efanov, S. I., et al. (2010). Cortisol awakening response and hippocampal volume: Vulnerability for major depressive disorder? Biological Psychiatry, 68, 847853. doi:10.1016/j.biopsych.2010.07.025 CrossRefGoogle ScholarPubMed
De Kloet, E. R. (2003). Hormones, brain and stress. Endocrine Regulations, 37, 5168.Google Scholar
Diorio, D., Viau, V., & Meaney, M. J. (1993). The role of the medial prefrontal cortex (cingulate gyrus) in the regulation of hypothalamic–pituitary–adrenal responses to stress. Journal of Neuroscience, 13, 38393847.Google ScholarPubMed
Dressendörfer, R. A., Kirschbaum, C., Rohde, W., Stahl, F., & Strasburger, C. J. (1992). Synthesis of a cortisol-biotin conjugate and evaluation as a tracer in an immunoassay for salivary cortisol measurement. Journal of Steroid Biochemistry and Molecular Biology, 43, 683692. doi:10.1016/0960-0760(92)90294-S CrossRefGoogle Scholar
Drevets, W. C. (1999). Prefrontal cortical–amygdalar metabolism in major depression. Annals of the New York Academy of Sciences, 877, 614637. doi:10.1111/j.1749-6632.1999.tb09292.x CrossRefGoogle ScholarPubMed
Drevets, W. C., Price, J. L., Bardgett, M. E., Reich, T., Todd, R. D., Raichle, M. E., et al. (2002). Glucose metabolism in the amygdala in depression: Relationship to diagnostic subtype and plasma cortisol levels. Pharmacology Biochemistry and Behavior, 71, 431447.CrossRefGoogle ScholarPubMed
Eatough, E. M., Shirtcliff, E. A., Hanson, J. L., & Pollak, S. D. (2009). Hormonal reactivity to MRI scanning in adolescents. Psychoneuroendocrinology, 34, 12421246.CrossRefGoogle ScholarPubMed
Ekman, P., & Friesen, W. V. (1976). Pictures of facial affect. Palo Alto, CA: Consulting Psychologists Press.Google Scholar
Fisher, P. A., Gunnar, M. R., Chamberlain, P., & Reid, J. B. (2000). Preventive intervention for maltreated preschool children: Impact on children's behavior, neuroendocrine activity, and foster parent functioning. Journal of the American Academy of Child & Adolescent Psychiatry, 39, 13561364.CrossRefGoogle ScholarPubMed
Fisher, P. A., Stoolmiller, M., Gunnar, M. R., & Burraston, B. O. (2007). Effects of a therapeutic intervention for foster preschoolers on diurnal cortisol activity. Psychoneuroendocrinology, 32, 892905. doi: CrossRefGoogle ScholarPubMed
Frodl, T. S., Koutsouleris, N., Bottlender, R., Born, C., Jäger, M., Scupin, I., et al. (2008). Depression-related variation in brain morphology over 3 years: Effects of stress? Archives of General Psychiatry, 65, 11561165. doi:10.1001/archpsyc.65.10.1156 CrossRefGoogle ScholarPubMed
Ghashghaei, H. T., & Barbas, H. (2002). Pathways for emotion: Integration of prefrontal and anterior temporal pathways in the amygdala of the rhesus monkey. Neuroscience, 115, 12611279.CrossRefGoogle Scholar
Gross, J. J. (1998). Antecedent- and response-focused emotion regulation: Divergent consequences for experience, expression, and physiology. Journal of Personality and Social Psychology, 74, 224237. doi:10.1037/0022-3514.74.1.224 CrossRefGoogle ScholarPubMed
Gunlicks-Stoessel, M., Mufson, L., Cullen, K. R., & Klimes-Dougan, B. (2013). Depressed adolescents' cortisol reactivity during parent–adolescent conflict and response to interpersonal psychotherapy (IPT-A). Journal of Affective Disorders, 150, 11251128.CrossRefGoogle Scholar
Gunnar, M. R., Talge, N. M., & Herrera, A. (2009). Stressor paradigms in developmental studies: What does and does not work to produce mean increases in salivary cortisol. Psychoneuroendocrinology, 34, 953967.CrossRefGoogle Scholar
Hariri, A. R., Tessitore, A., Mattay, V. S., Fera, F., & Weinberger, D. R. (2002). The amygdala response to emotional stimuli: A comparison of faces and scenes. NeuroImage, 17, 317323.CrossRefGoogle ScholarPubMed
Hamilton, J. P., Siemer, M., & Gotlib, I. H. (2008). Amygdala volume in major depressive disorder: A meta-analysis of magnetic resonance imaging studies. Molecular Psychiatry, 13, 9931000. CrossRefGoogle ScholarPubMed
Hebb, D. O. (1949). The organization of behavior. New York: Wiley.Google Scholar
Henckens, M. J. A. G., van Wingen, A. G., Joels, M., & Fernadez, G. (2012). Cortiscosteriod induced decouping of the amygdala in men. Cerbral Cortex, 22, 23362345.CrossRefGoogle Scholar
Herman, J. P., Flak, J., & Jankord, R. (2008). Chronic stress plasticity in the hypothalamic paraventricular nucleus. Progress in Brain Research, 170, 353364. doi:10.1016/S0079-6123(08)00429-9 CrossRefGoogle ScholarPubMed
Holsen, L. M, Lancaster, K., Klibanski, A., Whitfield-Babrieli, S., Cherkerzian, S., Ubka, S., et al. (2013). HPA-axis hormone modulation of stress response circuitry activity in women with remitted major depression. Neuroscience, 250, 733742.CrossRefGoogle ScholarPubMed
Insel, T. R., & Charney, D. S. (2003). Research on major depression. Journal of the American Medical Association, 289, 31673168. doi:10.1001/jama.289.23.3167 CrossRefGoogle ScholarPubMed
Jahn, A. L., Fox, A. S., Abercrombie, H. C., Shelton, S. E., Oakes, T. R., Davidson, R. J., et al. (2010). Subgenual prefrontal cortex activity predicts individual differences in hypothalamic–pituitary–adrenal activity across different contexts. Biological Psychiatry, 67, 175181.CrossRefGoogle ScholarPubMed
Kaess, M., Hille, M., Parzer, P., Maser-Gluth, C., Resch, F., & Brunner, R. (2011). Alterations in the neuroendocrinological stress response to acute psychosocial stress in adolescents engaging in nonsuicidal self-injury. Psychoneuroendocrinology, 37, 157161. doi:10.1016/j.psyneuen.2011.05.009 CrossRefGoogle ScholarPubMed
Kaufman, J., Birmaher, B., Brent, D., Rao, U., Flynn, C., Moreci, P., et al. (1997). Schedule for Affective Disorders and Schizophrenia for School-Age Children—Present and lifetime version (K-SADS-PL): Initial reliability and validity data. Journal of the American Academy of Child & Adolescent Psychiatry, 36, 980988. doi:10.1097/00004583-199707000-00021 CrossRefGoogle ScholarPubMed
Kaufman, J., & Charney, D. (2001). Effects of early stress on brain structure and function: Implications for understanding the relationship between child maltreatment and depression. Development and Psychopathology, 13, 451471.CrossRefGoogle ScholarPubMed
Kern, S., Oakes, T. R., Stone, C. K., McAuliff, E. M., Kirschbaum, C., & Davidson, R. J. (2008). Glucose metabolic changes in the prefrontal cortex are associated with HPA axis response to a psychosocial stressor. Psychoneuroendocrinology, 33, 517529. doi:10.1016/j.psyneuen.2008.01.010 CrossRefGoogle ScholarPubMed
Kessler, R. C., Avenevoli, S., & Merikangus, K. R. (2001). Mood disorders in children and adolescents: An epidemiologic perspective. Biological Psychiatry, 49, 10021014.CrossRefGoogle Scholar
Kirschbaum, C., Pirke, K., & Hellhammer, D. H. (1993). The “Trier Social Stress Test”—A tool for investigating psychobiological stress responses in a laboratory setting. Neuropshcobiology, 28, 7681.CrossRefGoogle Scholar
Klimes-Dougan, B., Hastings, P. D., Granger, D. A., Usher, B. A., & Zahn-Waxler, C. (2001). Adrenocortical activity in at-risk and normally developing adolescents: Individual difference in salivary cortisol basal levels, diurnal variation, and responses to social challenges. Development and Psychopathology, 13, 695719.CrossRefGoogle Scholar
Klimes-Dougan, B., Klingbeil, D. K., & August, G. (2009, April). HPA axis functioning of children enrolled in Early Risers Prevention Program. Paper presented at the Society for Research in Child Development, Denver, CO.Google Scholar
Kronenberg, G., Tebartz van Elst, L., Regaen, F., Deuschle, M., Heuser, I., & Colla, M. (2009). Reduced amygdala volume in newly admitted psychiatric in-patients with unipolar major depression. Journal of Psychiatric Research, 43, 11121117.CrossRefGoogle ScholarPubMed
Lenroot, R. K., & Giedd, J. N. (2006). Brain development in children and adolescents: Insights from anatomical magnetic resonance imaging. Neuroscience & Biobehavioral Reviews, 30, 718729.CrossRefGoogle ScholarPubMed
Leuner, B., & Shors, T. J. (2013). Stress, anxiety, and dendritic spines: What are the connections? Neuroscience, 251, 108119. doi:10.1016/j.neuroscience.2012.04.021 CrossRefGoogle ScholarPubMed
Levine, S. (1957). Infantile experience and resistance to physiological stress. Science, 126, 405406.CrossRefGoogle ScholarPubMed
Lewinsohn, P. M., Clarke, G. N., Seeley, J. R., & Rohde, D. (1994). Major depression in community adolescents: Age at onset, episode duration, and time to recurrence. Journal of the American Academy of Child & Adolescent Psychiatry, 33, 809818.CrossRefGoogle ScholarPubMed
Liu, J., Chaplin, T. M., Wang, F., Sinha, R., Mayes, L. C., & Blumberg, H. P. (2012). Stress reactivity and corticolimbic response to emotional faces in adolescents. Journal of the American Academy of Child & Adolescent Psychiatry, 51, 304312.CrossRefGoogle ScholarPubMed
Lovallo, W. R., Robinson, J. L., Glahn, D. C., & Fox, P. T. (2010). Acute effects of hydrocortisone on the human brain: An fMRI study. Psychoneuroendocrinology, 35, 1520.CrossRefGoogle ScholarPubMed
Luciana, M., & Collins, P. F. (2012). Incentive motivation, cognitive control, and the adolescent brain: Is it time for a paradigm shift? Child Development Perspectives, 6, 392399.Google ScholarPubMed
Marceau, K., Shirtcliff, E. A., Hastings, P. D., Klimes-Dougan, B., Zahn-Waxler, C., Dorn, L. D., et al. (2014). Within-adolescent coupled changes in cortisol with DHEA and testosterone in response to three stressors during adolescence. Psychoneuroendocrinology, 41, 3345.CrossRefGoogle ScholarPubMed
Mason, B. L, & Pariante, C. M. (2006). The effects of antidepressants on the hypothalamic–pituitary–adrenal axis. Drug News Perspect, 19, 603.CrossRefGoogle ScholarPubMed
Mayberg, H. S. (1997). Limbic-cortical dysregulation: A proposed model of depression. Journal of Psychiatry and Clinical Neurosciences, 9, 471481.Google Scholar
McEwen, B. S. (1995). Stressful experience, brain, and emotions. In Gazzaniga, M. S. (Ed.), The cognitive neurosciences (pp. 11171136). Cambridge, MA: MIT Press.Google Scholar
McKay, M. S., & Zakzanis, K. K. (2010). The impact of treatment on HPA axis activity in unipolar major depression. Journal of Psychiatric Research, 44, 183192.CrossRefGoogle ScholarPubMed
Meaney, M. J., & Szyf, M. (2005). Maternal care as a model for experience-dependent chromatin plasticity? Trends in Neuroscience, 28, 456463.CrossRefGoogle Scholar
Musselman, D., & Nemeroff, C. B. (1993). The role of cortisotropin-releasing factor in the pathophysiology of psychiatric disorders. Psychiatry Annals, 23, 676681.CrossRefGoogle Scholar
Nestler, E. J., Barrot, M., DiLeone, R. J., Eisch, A. J., Gold, S. J., & Monteggia, L. M. (2002). Neurobiology of depression. Neuron, 34, 1325. doi:10.1016/S0896-6273(02)00653-0 CrossRefGoogle Scholar
Pariante, C. M., Kim, R. B., Makoff, A., & Kerwin, R. W. (2003). Antidepressant fluoxetine enhances glucocorticoid receptor function in vitro by modulating membrane steroid transporters. British Journal of Pharmacology, 139, 11111118.CrossRefGoogle ScholarPubMed
Peters, S., Cleare, A. J., Papadopoulos, A., & Fu, C. H. (2011). Cortisol responses to serial MRI scans in healthy adults and in depression. Psychoeuroendocrinology, 36, 737741.CrossRefGoogle ScholarPubMed
Phillips, M. L., Drevets, W. C., Rauch, S. L., & Lane, R. (2003). Neurobiology of emotion perception: II. Implications for major psychiatric disorders. Biological Psychiatry, 54, 515528.CrossRefGoogle ScholarPubMed
Poznanski, E. O., & Mokros, H. B. (1996). The Children's Depression Rating Scale—Revised (CDRS-R). Los Angeles: Western Psychological Services.Google Scholar
Price, J. L., & Drevets, W. C. (2010). Neurocircuitry of mood disorders. Neuropsychopharmacology, 35, 192216.CrossRefGoogle ScholarPubMed
Pruessner, J. C., Dedovic, K., Pruessner, M., Lord, C., Buss, C., Collins, L., et al. (2010). Stress regulation in the central nervous system: Evidence from structural and functional neuroimaging studies in human populations. Psychoeuroendocrinology, 35, 179191.CrossRefGoogle ScholarPubMed
Pruessner, J. C., Kirschbaum, C., Meinlschmid, G., & Hellhammer, D. H. (2003). Two formulas for computation of the area under the curve represent measures of total hormone concentration versus time-dependent change. Psychoeuroendocrinology, 28, 916931. doi:10.1016/S0306-4530(02)00108-7 CrossRefGoogle ScholarPubMed
Rao, U., Hammen, H., Ortiz, L. R., Chen, L., & Poland, R. E. (2008). Effects of early and recent adverse experiences on adrenal response to psychosocial stress in depressed adolescents. Biological Psychiatry, 64, 521526. doi:10.1016/j.biopsych.2008.05.012 CrossRefGoogle ScholarPubMed
Reul, J., & de Kloet, E. (1985). Two receptor systems for corticosterone in rat brain: Microdistribution and differential occupation. Endocrinology, 117, 25052511.CrossRefGoogle ScholarPubMed
Romeo, R. D., & McEwen, B. S. (2006). Stress and the adolescent brain. Annals of the New York Academy of Sciences, 1094, 202214.CrossRefGoogle ScholarPubMed
Root, J. C., Tuescher, O., Cunningham-Bussel, A., Pan, H., Epstein, J., Silbersweig, D., et al. (2009). Frontolimbic function and cortisol reactivity in response to emotional stimuli. NeuroReport, 20, 429434. doi:10.1097/WNR.0b013e328326a031 CrossRefGoogle ScholarPubMed
Rosso, I. M., Cintron, C. M., Steingard, R. J., Renshaw, P. F., Young, A. D., & Yurgelun-Todd, D. A. (2005). Amygdala and hippocampus volumes in pediatric major depression. Biological Psychiatry, 57, 2126.CrossRefGoogle ScholarPubMed
Schuhmacher, A., Mössner, R., Jessen, F., Scheef, L., Block, W., Belloche, A. C., et al. (2012). Association of amygdala volumes with cortisol secretion in unipolar depressed patients. Psychiatry Research, 202, 96103.CrossRefGoogle ScholarPubMed
Stroud, L. R., Papandonatos, G. D., Williamson, D. E., & Dahl, R. E. (2011). Sex differences in cortisol response to corticotropin releasing hormone challenge over puberty: Pittsburgh pediatric neurobehavioral studies. Psychoneuroendocrinology, 36, 12261238. doi:10.1016/j.psyneuen.2011.02.01 CrossRefGoogle ScholarPubMed
Sullivan, R. M., & Gratton, A. (2002). Prefrontal cortical regulation of hypothalamic–pituitary–adrenal function in the rat and implications for psychopathology: Side matters. Psychoneuroendocrinology, 27, 99114. doi:10.1016/S0306-4530(01)00038-5 CrossRefGoogle ScholarPubMed
Tessner, K. D., Walker, E. F., Hochman, K., & Hamann, S. (2006). Cortisol responses of healthy volunteers undergoing magnetic resonance imaging. Human Brain Mapping, 27, 889895.CrossRefGoogle ScholarPubMed
Thomas, K. M., Drevets, W. C., Dahl, R. E., Ryan, N. D., Birmaher, B., Eccard, C. H., et al. (2001). Amygdala response to fearful faces in anxious and depressed children. Archives of General Psychiatry, 58, 10571063.CrossRefGoogle ScholarPubMed
Thomason, M. E., Hamilton, J. P., & Gotlib, I. H. (2011). Stress-induced activation of the HPA axis predicts connectivity between subgenual cingulate and salience network during rest in adolescents. Journal of Child Psychology and Psychiatry, 52, 10261034. doi:10.1111/j.1469-7610.2011.02422.x CrossRefGoogle ScholarPubMed
Treadway, M. T., Grant, M. M., Ding, Z., Hollon, S. D., Gore, J. C., & Shelton, R. C. (2009). Early adverse events, HPA activity and rostral anterior cingulate volume in MDD. PLOS One, 4, e4887. doi:10.1371/journal.pone.0004887 CrossRefGoogle ScholarPubMed
Van de Kar, L. D., & Blair, M. L. (1999). Forebrain pathways mediating stress-induced hormone secretion. Frontiers in Neuroendocrinology, 20, 148.CrossRefGoogle ScholarPubMed
van Stegeren, A. H., Wolf, O. T., Everaerd, W., Scheltens, P., Barkhof, F., & Rombouts, S. A. (2007). Endogenous cortisol level interacts with noradrenergic activation in the human amygdala. Neurobiological Learning and Memory, 87, 5766.CrossRefGoogle ScholarPubMed
Vythilingam, M., Vermetten, E., Anderson, G. M., Luckenbaugh, D., Anderson, E. R., Snow, J., et al. (2004). Hippocampal volume, memory, and cortisol status in major depressive disorder: Effects of treatment. Biological Psychiatry, 56, 101112.CrossRefGoogle Scholar
Wang, J., Rao, H., Wetmore, G. S., Furlan, P. M., Korczykowski, M., Dinges, D. F., et al. (2005). Perfusion functional MRI reveals cerebral blood flow pattern under psychological stress. Proceedings of the National Academy of Sciences, 102, 1780417809.CrossRefGoogle ScholarPubMed
Wechsler, D. (1999). Wechsler Abbreviated Scale of Intelligence (WASI). San Antonio, TX: American Psychological Association.Google Scholar
Weissman, M. M., Wolk, S., Goldstein, R. B., Moreau, D., Adams, P., Greenwald, S., et al. (1999). Depressed adolescents grown up. Journal of the American Medical Association, 281, 17071713.CrossRefGoogle ScholarPubMed
World Health Organization. (2008). The Global Burden of Disease 2004 update. Retrieved June 16, 2012, from Google Scholar
Yang, T. T., Simmons, A. N., Matthews, S. C., Tapert, S. F., Frank, G. K., Max, J. E., et al. (2010). Adolescents with major depression demonstrate increased amygdala activation. Journal of the American Academy of Child & Adolescent Psychiatry, 49, 4251.Google ScholarPubMed
Zalsman, G., Brent, D. A., & Weersing, V. R. (2006). Depressive disorders in childhood and adolescence: An overview: Epidemiology, clinical manifestation and risk factors. Child and Adolescent Psychiatric Clinics of North America, 15, 827841.CrossRefGoogle ScholarPubMed
Zisook, S., Lesser, I., Stewart, J. W., Wisniewski, S. R., Balasubramani, G. K., Fava, M., et al. (2007). Effect of age at onset on the course of major depressive disorder. American Journal of Psychiatry, 164, 15391546. doi:10.1176/appi.ajp.2007.06101757 CrossRefGoogle ScholarPubMed
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Multilevel assessment of the neurobiological threat system in depressed adolescents: Interplay between the limbic system and hypothalamic–pituitary–adrenal axis
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