with unipolar depression and bipolar patients in the mixed state (Evans & Nemeroff, 1983; Swann et al., 1992). Upon stress exposure, neurons in the hypothalamic paraventricular nucleus (PVN) secrete corticotropin-releasing factor (CRF) into the hypothalamic-hypophyseal portal circulation, which stimulates the production and release of adrenocorticotropin (ACTH) from the anterior pituitary. Adrenocorticotropin in turn stimulates release of glucocorticoids from the adrenal cortex. Glucocorticoids have marked effects on metabolism, immune function, and the brain, adjusting physiological functions and behavior in response to the stressor. Glucocorticoids exert negative feedback control on the HPA axis by regulating hippocampal and PVN neurons. Persistent glucocorticoid exposure exerts adverse effects on hippocampal neurons, in-cluding reduction in dendritic branching, loss of dendritic spines, and impairment of neurogenesis. Such damage might progressively reduce inhibitory control of the HPA axis. Corticotropin-releasing factor neurons integrate information relevant to stress not only at the hypothalamic PVN but also in a widespread circuitry throughout the limbic system and brain stem. Direct CNS administration of CRF to laboratory animals produces endocrine, autonomic, and behavioral responses that parallel signs of stress, depression, and anxiety, including loss of appetite, sleep disruption, decreased sexual behavior, despair, increased motor activity, neophobia, and enhanced startle reactivity.

Laboratory animal studies have provided direct evidence that ELS indeed leads to heightened stress reactivity and alterations in the aforementioned neural circuits that persist into adulthood. For example, adult rats separated from their dams for 180 minutes/day on postnatal days 2–14 exhibit up to 3-fold increases in ACTH and corticosterone responses to a variety of psychological stressors compared with control rats (Ladd et al., 2000; Plotsky and Meaney, 1993). Maternally separated rats also develop marked behavioral changes, including increased anxiety-like behavior, anhedonia, alcohol preference, sleep disruption, decreased appetite, and cognitive impairment. Subsequent studies revealed multiple CNS changes that likely underlie physiologic and behavioral sensitization to stress after maternal separation or lack of maternal care. These findings include increased activity (increased CRF mRNA expression) and sensitization of CRF neurons in hypothalamic and limbic regions, decreased glucocorticoid receptor density in the hippocampus and prefrontal cor

tex, increased mineralocorticoid receptor in the hippocampus, decreased mossy fiber development and neurogenesis in the hippocampus, as well as alterations in norepinephrine, GABA, and other systems (Heim, Plotsky, & Nemeroff, 2004; Ladd, Huot, Thrivikraman, Nemeroff, & Plotsky, 2004). Behavioral sensitization to fear stimuli have been observed in nonhuman primates reared by mothers exposed to unpredictable conditions with respect to food access over 3 months (Coplan et al., 1996, 2001). Taken together, ELS induces manifold changes in multiple neurocircuits involved in neuroendocrine, autonomic, and behavioral responses to stress. If similar changes also occur in humans exposed to ELS, these changes might indeed confer an enhanced risk for depression.

As noted earlier, several clinical studies have evaluated the long-term consequences of ELS in adult humans. In astonishing parallel to findings in rodents and nonhuman primates, women abused as children, including those with and those without current depression, exhibit greater plasma ACTH responses in a standardized stress paradigm than controls. The increase was more pronounced in abused women with current depression, and these women also showed greater cortisol and heart rate responses than controls (Heim et al., 2000). Several studies have reported similar neuroendocrine and neurochemical changes in abused children, which are reviewed in detail elsewhere (Heim & Nemeroff, 2001).

Among depressed patients, magnetic resonance imaging (MRI) analysis has revealed decreased hippocampal volumes only in adult women with ELS (Vythilingam et al., 2002). Because hippocampal volume loss is not observed in abused children or young adults (Teicher, 2002) (although corpus callosum, amygdala, and cortical development seems to be impaired), some have suggested that repeated bursts of cortisol secretion over the course of time may eventually result in smaller hippocampi. Enhanced CRF secretion during development may also contribute to progressive hippocampal volume loss (Brunson, Eghbal-Ahmadi, Bender, Chen, & Baram, 2001). The fact that adult patients with major depression exhibit HPA axis hyperactivity and profound CRF hypersecretion as evidenced in studies of cerebrospinal fluid (CSF) and postmortem tissue (Flores, Alvarado, Wong, Licinio, & Flockhart, 2004; Merali et al., 2004) and that these findings are also observed after ELS raises the question as to whether the HPA axis in general and the CRF system in particular play a role in the pathogenesis of childhood mood disorders.

Steingard and colleagues (2002) found significant reductions in frontal lobe volume and increased ventricular volume in a large cohort of children and adolescents with depressive disorders. In resolving white and gray matter, they found significant reductions in frontal white matter in adolescents with major depression. Furthermore, orbitofrontal choline levels are elevated in depressed adolescents (Steingard et al., 2000), consistent with findings in adults. A single photon emission computed tomography (SPECT) study found a significant elevation of the density of serotonin transporters in the hypothalamus and midbrain, but no change in the dopamine transporter in children and adolescents with major depression. Chang and colleagues (2004) used functional magnetic resonance imaging (fMRI) to compare 12 children and adolescents with bipolar disorder who had at least one parent with bipolar disorder and 10 age-and IQ-matched healthy male controls. Significant differences in brain activation patterns in prefrontal areas were noted in the bipolar subjects, compared to patterns in the controls, when performing both cognitive and affective tasks. Brain areas affected included the anterior cingulate cortical and dorsolateral prefrontal cortex. This same group (Chang et al., 2003) had previously reported a reduction in dorsolateral and prefrontal cortical N-acetyl-aspartate concentrations, a marker of neuronal integrity, in children with bipolar disorder, as measured by magnetic resonance spectroscopy (MRS). Children during a manic episode were also reported to exhibit increased anterior cingulate concentrations of myo-inositol (Davanzo et al., 2001).

Gender is well known to be an important but poorly understood factor influencing the risk of MDD. The prevalence of MDD, while equal between boys and girls prior to puberty, doubles in young women after puberty. This increase in females has been hypothesized to be secondary to hormonal changes occurring during puberty. These endocrine changes surely influence brain function, but the attendant social and psychological factors of puberty cannot be ignored. Nevertheless, twin studies suggest that the impact of genetic risk factors become more prominent as girls pass through puberty and enter adolescence (Silberg et al., 1999).

An early and logical focus of biological studies of child and adolescent mood disorders was neuroendocrinologic, motivated by the findings described above of significant HPA dysregulation in a sizeable proportion of adults with MDD. However, the results of a number of studies have found rare and only modest abnormalities in 24-hour cortisol secretion, the dexamethasone suppression test, and the CRF stimulation test. Recently, Feder and colleages (2004) reported that of 86 children (depressed, anxious, or normal) tested, those children who exhibited an abnormally elevated cortisol concentration during the evening and an abnormal delay in the rise of cortisol during the night, whether depressed or not as children, exhibited depression as adults.

Puig-Antich and colleagues (1985a,b) observed a blunted growth hormone (GH) response in adolescents with MDD when challenged with insulin or growth hormone releasing hormone (GHRH), a finding previously reported in adults with major depression. However, the link between this abnormality and the underlying pathophysiology of depression remains obscure.

Accurate epidemiologic data are useful for determining the magnitude of the problem, identifying risk factors, monitoring changes of rates (epidemics), and identifying the underserved. Accurate estimates rest on accurate diagnosis. The explosive developments in neurosciences, genetics, and neuroimaging will undoubtedly help advance our pathophysiological understanding of these complex mood disorders afflicting the young. Such advances can help shed light on etiology, identify dysfunctional brain circuits and, most importantly, define subtypes of the disorder. This will undoubtedly lead to improved treatment of afflicted youth and their families. Longitudinal studies focusing on the biology and treatment response of childhood and adolescent mood disorders are sorely needed.