SummaryResearch findings on the hypothalamic-pituitary-adrenal (HPA) axis and pediatric depression reflect a variety of methodological approaches that tap different facets of HPA-axis functions. Partly owing to the methodological heterogeneity of studies, descriptive reviews of this area have produced inconsistent conclusions. Therefore, we conducted formal meta-analyses of pertinent studies in order to advance our understanding of HPA-axis dysregulation in pediatric depression. We examined: a) 17 published studies of HPA-axis response to the dexamethasone suppression test in depressed youth (DST; N=926) and b) 17 studies of basal HPA-axis functioning (N=1,332). We also examined descriptively studies that used corticotropin releasing hormone (CRH) infusion, and those that used psychological probes of the HPA-axis. The global standardized mean effect size difference in HPAaxis response to the DST between depressed and non-depressed youth was .57, z = 4.18 p< .01. The global standardized mean difference effect size in basal HPA-axis functioning was .20, z = 4.53, p < .01. Age, sex, timing of sampling, dexamethasone dosage, or type of control group was not a significant source of variability for the DST or basal studies. In addition, when compared to nondepressed peers, depressed youth have a normative response to CRH infusion but an overactive response to psychological stressors. In conclusion, the HPA-axis system tends to be dysregulated in depressed youth, as evidenced by atypical responses to the DST, higher baseline cortisol values, and an overactive response to psychological stressors. This pattern of dysregulation suggests anomalies within the axis's negative feedback system and CRH production, but intact pituitary and adrenal sensitivity. KeywordsHPA-Axis; Depression; Children; Adolescents; Dexamethasone Suppression TestIn the quest for biological markers of depression, researchers have explored the link between hypothalamic-pituitary-adrenal (HPA) axis functioning and adult depression for at least forty years, extending the inquiry to pediatric depression in more recent decades. Much of this work has involved the examination of cortisol response to biological and psychological probes or the assessment of basal cortisol levels. However, recent descriptive reviews of the pediatric literature have yielded inconsistent findings, with some reviewers concluding that the association between dysregulated HPA-axis and child depression is inconclusive at best Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptPsychoneuroendocrinology. Author ma...

Brain-derived neurotrophic factor (BDNF) is a nerve growth factor that has been implicated in the neurobiology of depression. Our group has previously reported an association between a BDNF variant and childhood-onset mood disorder (COMD) in an adult sample from Pittsburgh. We hypothesize that variants at the BDNF locus are associated with COMD. Six BDNF polymorphisms were genotyped in 258 trios having juvenile probands with childhood-onset DSM-IV major depressive or dysthymic disorder. Keywords: neurotrophic factors; mood disorder; childhood-onset; genetic association; haplotype Mood disorders rank fourth among the most significant global public health problems. 1 The prevalence of the juvenile-onset subtype of depressive disorder increases dramatically across the years of childhood and adolescence, with an estimated lifetime prevalence close to 20% by late adolescence. 2 Juvenile-onset mood disorders are associated with serious morbidity, including recurrence, impaired interpersonal functioning, and increased risks of bipolar disorder and suicide. 2,3 The influence of hereditary factors on susceptibility to major depression has been documented based on twin and adoption studies. 4 Twin studies in youth have identified significant heritability for depressive symptoms. 5,6 It has also been proposed that genetic aspects of liability to mood disorder may be more readily identified in families of childhood-and adolescentonset probands. 7 Accordingly, first-degree relatives of childhood-onset mood disorder probands have higher rates of affective disorder than do first-degree relatives of adult-onset mood disorder probands. 8 Evidence from both preclinical and clinical studies implicates brain-derived neurotrophic factor (BDNF) in mood disorders. Altered BDNF expression in stress-related depression via cellular signalling has been described in animal models. Repeated antidepressant administration, including electroconvulsive seizures, is associated with increased hippocampal BDNF expression, neuronal plasticity and neurogenesis. 9-11 Human neuroimaging 12,13 post mortem 14 and clinical [15][16][17] investigations indirectly support the hypothesis that neurotrophic factors play a key role in depression. As well, human linkage studies in

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