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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 ,
Lynn E. Eberly ,
Melinda Westlund Schreiner ,
Patrick Kurkiewicz ,
Alaa Houri ,
Amanda Schlesinger ,
Kathleen M. Thomas ,
Bryon A. Mueller ,
Kelvin O. Lim  and
Kathryn R. Cullen
Bonnie Klimes-Dougan*
Affiliation:
University of Minnesota
Lynn E. Eberly
Affiliation:
University of Minnesota
Melinda Westlund Schreiner
Affiliation:
University of Minnesota
Patrick Kurkiewicz
Affiliation:
University of Minnesota
Alaa Houri
Affiliation:
University of Minnesota
Amanda Schlesinger
Affiliation:
University of Iowa
Kathleen M. Thomas
Affiliation:
University of Minnesota
Bryon A. Mueller
Affiliation:
University of Minnesota
Kelvin O. Lim
Affiliation:
University of Minnesota
Kathryn R. Cullen
Affiliation:
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: [email protected].
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Abstract

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.

Type
Regular Articles
Information
Development and Psychopathology , Volume 26 , Special Issue 4pt2: Multilevel Developmental Perspectives Toward Understanding Internalizing Psychopathology: Current Research and Future Directions , November 2014 , pp. 1321 - 1335
Copyright
Copyright © Cambridge University Press 2014 

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References

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, 245–256.Google Scholar
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, 63–70.Google Scholar
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, 163–173.Google Scholar
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, 102–113.Google Scholar
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, 940–947.Google Scholar
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, 1736–1741.Google Scholar
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, 587–595.Google 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, 227–231.Google Scholar
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, 173–183. doi:10.1016/j.jaac.2009.11.005 Google Scholar
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, 694–704.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, 847–853. doi:10.1016/j.biopsych.2010.07.025 Google Scholar
De Kloet, E. R. (2003). Hormones, brain and stress. Endocrine Regulations, 37, 51–68.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, 3839–3847.Google Scholar
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, 683–692. doi:10.1016/0960-0760(92)90294-S Google Scholar
Drevets, W. C. (1999). Prefrontal cortical–amygdalar metabolism in major depression. Annals of the New York Academy of Sciences, 877, 614–637. doi:10.1111/j.1749-6632.1999.tb09292.x Google Scholar
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, 431–447.Google Scholar
Eatough, E. M., Shirtcliff, E. A., Hanson, J. L., & Pollak, S. D. (2009). Hormonal reactivity to MRI scanning in adolescents. Psychoneuroendocrinology, 34, 1242–1246.Google Scholar
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, 1356–1364.Google Scholar
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, 892–905. doi:http://dx.doi.org/10.1016/j.psyneuen.2007.06.008 Google Scholar
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, 1156–1165. doi:10.1001/archpsyc.65.10.1156 Google Scholar
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, 1261–1279.Google 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, 224–237. doi:10.1037/0022-3514.74.1.224 Google Scholar
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, 1125–1128.Google 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, 953–967.Google 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, 317–323.Google Scholar
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, 993–1000. doi.org/10.1038/mp.2008.57 Google Scholar
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, 2336–2345.Google Scholar
Herman, J. P., Flak, J., & Jankord, R. (2008). Chronic stress plasticity in the hypothalamic paraventricular nucleus. Progress in Brain Research, 170, 353–364. doi:10.1016/S0079-6123(08)00429-9 Google Scholar
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, 733–742.Google Scholar
Insel, T. R., & Charney, D. S. (2003). Research on major depression. Journal of the American Medical Association, 289, 3167–3168. doi:10.1001/jama.289.23.3167 Google Scholar
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, 175–181.Google Scholar
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, 157–161. doi:10.1016/j.psyneuen.2011.05.009 Google Scholar
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, 980–988. doi:10.1097/00004583-199707000-00021 Google Scholar
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, 451–471.Google Scholar
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, 517–529. doi:10.1016/j.psyneuen.2008.01.010 Google Scholar
Kessler, R. C., Avenevoli, S., & Merikangus, K. R. (2001). Mood disorders in children and adolescents: An epidemiologic perspective. Biological Psychiatry, 49, 1002–1014.Google 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, 76–81.Google 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, 695–719.Google 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, 1112–1117.Google Scholar
Lenroot, R. K., & Giedd, J. N. (2006). Brain development in children and adolescents: Insights from anatomical magnetic resonance imaging. Neuroscience & Biobehavioral Reviews, 30, 718–729.Google Scholar
Leuner, B., & Shors, T. J. (2013). Stress, anxiety, and dendritic spines: What are the connections? Neuroscience, 251, 108–119. doi:10.1016/j.neuroscience.2012.04.021 Google Scholar
Levine, S. (1957). Infantile experience and resistance to physiological stress. Science, 126, 405–406.Google Scholar
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, 809–818.Google Scholar
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, 304–312.Google Scholar
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, 15–20.Google Scholar
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, 392–399.Google Scholar
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, 33–45.Google Scholar
Mason, B. L, & Pariante, C. M. (2006). The effects of antidepressants on the hypothalamic–pituitary–adrenal axis. Drug News Perspect, 19, 603.Google Scholar
Mayberg, H. S. (1997). Limbic-cortical dysregulation: A proposed model of depression. Journal of Psychiatry and Clinical Neurosciences, 9, 471–481.Google Scholar
McEwen, B. S. (1995). Stressful experience, brain, and emotions. In Gazzaniga, M. S. (Ed.), The cognitive neurosciences (pp. 1117–1136). 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, 183–192.Google Scholar
Meaney, M. J., & Szyf, M. (2005). Maternal care as a model for experience-dependent chromatin plasticity? Trends in Neuroscience, 28, 456–463.Google Scholar
Musselman, D., & Nemeroff, C. B. (1993). The role of cortisotropin-releasing factor in the pathophysiology of psychiatric disorders. Psychiatry Annals, 23, 676–681.Google Scholar
Nestler, E. J., Barrot, M., DiLeone, R. J., Eisch, A. J., Gold, S. J., & Monteggia, L. M. (2002). Neurobiology of depression. Neuron, 34, 13–25. doi:10.1016/S0896-6273(02)00653-0 Google 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, 1111–1118.Google Scholar
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, 737–741.Google Scholar
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, 515–528.Google Scholar
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, 192–216.Google Scholar
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, 179–191.Google Scholar
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, 916–931. doi:10.1016/S0306-4530(02)00108-7 Google Scholar
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, 521–526. doi:10.1016/j.biopsych.2008.05.012 Google Scholar
Reul, J., & de Kloet, E. (1985). Two receptor systems for corticosterone in rat brain: Microdistribution and differential occupation. Endocrinology, 117, 2505–2511.Google Scholar
Romeo, R. D., & McEwen, B. S. (2006). Stress and the adolescent brain. Annals of the New York Academy of Sciences, 1094, 202–214.Google Scholar
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, 429–434. doi:10.1097/WNR.0b013e328326a031 Google Scholar
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, 21–26.Google Scholar
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, 96–103.Google Scholar
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, 1226–1238. doi:10.1016/j.psyneuen.2011.02.01 Google Scholar
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, 99–114. doi:10.1016/S0306-4530(01)00038-5 Google Scholar
Tessner, K. D., Walker, E. F., Hochman, K., & Hamann, S. (2006). Cortisol responses of healthy volunteers undergoing magnetic resonance imaging. Human Brain Mapping, 27, 889–895.Google Scholar
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, 1057–1063.Google Scholar
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, 1026–1034. doi:10.1111/j.1469-7610.2011.02422.x Google Scholar
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 Google Scholar
Van de Kar, L. D., & Blair, M. L. (1999). Forebrain pathways mediating stress-induced hormone secretion. Frontiers in Neuroendocrinology, 20, 1–48.Google Scholar
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, 57–66.Google Scholar
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, 101–112.Google 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, 17804–17809.Google Scholar
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, 1707–1713.Google Scholar
World Health Organization. (2008). The Global Burden of Disease 2004 update. Retrieved June 16, 2012, from http://www.who.int/healthinfo/global_burden_disease/GBD_report_2004update_full.pdf 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, 42–51.Google Scholar
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, 827–841.Google Scholar
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, 1539–1546. doi:10.1176/appi.ajp.2007.06101757 Google Scholar