Rosenblum, Owens, Friedman, Gorman, and defect at or above the hypothalamus, presum-Nemeroff (1996) studied monkeys who were ably resulting the hypersecretion of hypo-raised by mothers who were forced to spend thalamic CRH. The first data support a role a great deal of time and effort foraging for for CRH the hypercortisolism of major de-food. They found that these infants exhibited pression carne from studies in which ovine emotional dysregulation, well as elevated CRH (oCRH) was given a stimulus to levels of CRH, response to challenge. As ACTH secretion (Gold, Chrousos, Kellner, adults, they continued to display adjustment Post, Roy, Augerinos, Schulte, Oldfield, & Lo-problems, well as heightened CRH and NE riaux, 1984; Gold, Loriaux, Roy, Kling, Cala-activity. King and Edwards (1999) explored brese, Kellner, Nieman, Post, Pickar, Gallucci, the impact of early stress and genetic compo-A vgerinos, Paul, Oldfield, Cutler, sition on the long-term reactivity of the endo- Holsboer, Vonbardeleben, Girken, Stalla, crine system rats. The investigators studied rats that had a genetic vulnerability develop sessment of the functional integrity of gluco-learned helpless behaviors (cLH) and rats that corticoid negative feedback at the pituitary. were congenitally resistant developing Adult patients with melancholic depression learned helpless tendencies (cNLH). They showed basal hypercortisolism and normal found that the timing of stress exposure, along basal plasma ACTH levels. In response with genetic composition, were both impor-oCRH, they exhibited blunted plasma ACTH, tant in shaping neuroendocrine response and their cortisol responses were proportion-ture challenge. Early stress had a larger influ-ally greater than were those of nondepressed ence on future functioning when it occurred controls. The more hypercortisolemic the pa-after, rather that during, the stress hypore-tients, the more blunted were the ACTH re-sponsive period. There was also a clear inter-sponses oCRH (Gold et al., 1986). These action between genes and experience. Specifi-data suggested that a stimulus such sympa-cally, cLH animals who had been exposed thetic innervation of the adrenal melan-early stress showed hyperreactivity of the pi-cholic depression either directly released NE tuitary response to challenge, with a independent of ACTH or led to hypertrophy marked decrease in corticosterone levels com-and hyperplasia of the adrenal cortex and glu-pared to nonstressed cLH controls, while the cocorticoid hyperresponsiveness ACTH. cNLH animals exhibited hyporeactivity of the Some of the blunting may also have been due pituitary and adrenal systems compared a CRH-mediated down-regulation of pitu-their nonstressed peers. itary CRH receptors. Several other lines of in-As with prenatal experience, exposure to direct evidence are compatible with a role for stress during early postnatal life may interact CRH the hypercortisolism of melancholia with genetic predisposition to increase individ- adults. For example, when healthy controls uals' susceptibility to psychopathologic out-were given a continuous infusion of oCRH for comes (De Bellis et al., 1994; Meaney, Diorio, 24 hr, they showed the pattern and magnitude Francis, Widdowson, LaPlante, Caldji, Shar-of plasma ACTH and cortisol levels that typi-ma, Seckl, & Plotsky, 1996), including depres-cally occur in patients with melancholic sion (Plotsky, Owens, well as chronic medical illness (Francis, Caldji, Oldfield, Cutler, Champagne, Plotsky, individuals who had a history of major de-Melancholic Depression d pression during their lifetimes showed an an he Stress System increase in CRH-containing neurons in the t hypothalamus (Raadsheer, van Heerikhuize, Thousands of papers have been written on the Lucassen, Hoogendijk, Tilders, hypercortisolism of melancholic depression in 1995). Another study conducted on brains adulthood. Several lines of evidence suggest taken from individuals who had died of sui-that this represents a central nervous system cide showed a significant decrease frontal

DOI link for Rosenblum, Owens, Friedman, Gorman, and defect at or above the hypothalamus, presum-Nemeroff (1996) studied monkeys who were ably resulting the hypersecretion of hypo-raised by mothers who were forced to spend thalamic CRH. The first data support a role a great deal of time and effort foraging for for CRH the hypercortisolism of major de-food. They found that these infants exhibited pression carne from studies in which ovine emotional dysregulation, well as elevated CRH (oCRH) was given a stimulus to levels of CRH, response to challenge. As ACTH secretion (Gold, Chrousos, Kellner, adults, they continued to display adjustment Post, Roy, Augerinos, Schulte, Oldfield, & Lo-problems, well as heightened CRH and NE riaux, 1984; Gold, Loriaux, Roy, Kling, Cala-activity. King and Edwards (1999) explored brese, Kellner, Nieman, Post, Pickar, Gallucci, the impact of early stress and genetic compo-A vgerinos, Paul, Oldfield, Cutler, sition on the long-term reactivity of the endo- Holsboer, Vonbardeleben, Girken, Stalla, crine system rats. The investigators studied rats that had a genetic vulnerability develop sessment of the functional integrity of gluco-learned helpless behaviors (cLH) and rats that corticoid negative feedback at the pituitary. were congenitally resistant developing Adult patients with melancholic depression learned helpless tendencies (cNLH). They showed basal hypercortisolism and normal found that the timing of stress exposure, along basal plasma ACTH levels. In response with genetic composition, were both impor-oCRH, they exhibited blunted plasma ACTH, tant in shaping neuroendocrine response and their cortisol responses were proportion-ture challenge. Early stress had a larger influ-ally greater than were those of nondepressed ence on future functioning when it occurred controls. The more hypercortisolemic the pa-after, rather that during, the stress hypore-tients, the more blunted were the ACTH re-sponsive period. There was also a clear inter-sponses oCRH (Gold et al., 1986). These action between genes and experience. Specifi-data suggested that a stimulus such sympa-cally, cLH animals who had been exposed thetic innervation of the adrenal melan-early stress showed hyperreactivity of the pi-cholic depression either directly released NE tuitary response to challenge, with a independent of ACTH or led to hypertrophy marked decrease in corticosterone levels com-and hyperplasia of the adrenal cortex and glu-pared to nonstressed cLH controls, while the cocorticoid hyperresponsiveness ACTH. cNLH animals exhibited hyporeactivity of the Some of the blunting may also have been due pituitary and adrenal systems compared a CRH-mediated down-regulation of pitu-their nonstressed peers. itary CRH receptors. Several other lines of in-As with prenatal experience, exposure to direct evidence are compatible with a role for stress during early postnatal life may interact CRH the hypercortisolism of melancholia with genetic predisposition to increase individ- adults. For example, when healthy controls uals' susceptibility to psychopathologic out-were given a continuous infusion of oCRH for comes (De Bellis et al., 1994; Meaney, Diorio, 24 hr, they showed the pattern and magnitude Francis, Widdowson, LaPlante, Caldji, Shar-of plasma ACTH and cortisol levels that typi-ma, Seckl, & Plotsky, 1996), including depres-cally occur in patients with melancholic sion (Plotsky, Owens, well as chronic medical illness (Francis, Caldji, Oldfield, Cutler, Champagne, Plotsky, individuals who had a history of major de-Melancholic Depression d pression during their lifetimes showed an an he Stress System increase in CRH-containing neurons in the t hypothalamus (Raadsheer, van Heerikhuize, Thousands of papers have been written on the Lucassen, Hoogendijk, Tilders, hypercortisolism of melancholic depression in 1995). Another study conducted on brains adulthood. Several lines of evidence suggest taken from individuals who had died of sui-that this represents a central nervous system cide showed a significant decrease frontal

Rosenblum, Owens, Friedman, Gorman, and defect at or above the hypothalamus, presum-Nemeroff (1996) studied monkeys who were ably resulting the hypersecretion of hypo-raised by mothers who were forced to spend thalamic CRH. The first data support a role a great deal of time and effort foraging for for CRH the hypercortisolism of major de-food. They found that these infants exhibited pression carne from studies in which ovine emotional dysregulation, well as elevated CRH (oCRH) was given a stimulus to levels of CRH, response to challenge. As ACTH secretion (Gold, Chrousos, Kellner, adults, they continued to display adjustment Post, Roy, Augerinos, Schulte, Oldfield, & Lo-problems, well as heightened CRH and NE riaux, 1984; Gold, Loriaux, Roy, Kling, Cala-activity. King and Edwards (1999) explored brese, Kellner, Nieman, Post, Pickar, Gallucci, the impact of early stress and genetic compo-A vgerinos, Paul, Oldfield, Cutler, sition on the long-term reactivity of the endo- Holsboer, Vonbardeleben, Girken, Stalla, crine system rats. The investigators studied rats that had a genetic vulnerability develop sessment of the functional integrity of gluco-learned helpless behaviors (cLH) and rats that corticoid negative feedback at the pituitary. were congenitally resistant developing Adult patients with melancholic depression learned helpless tendencies (cNLH). They showed basal hypercortisolism and normal found that the timing of stress exposure, along basal plasma ACTH levels. In response with genetic composition, were both impor-oCRH, they exhibited blunted plasma ACTH, tant in shaping neuroendocrine response and their cortisol responses were proportion-ture challenge. Early stress had a larger influ-ally greater than were those of nondepressed ence on future functioning when it occurred controls. The more hypercortisolemic the pa-after, rather that during, the stress hypore-tients, the more blunted were the ACTH re-sponsive period. There was also a clear inter-sponses oCRH (Gold et al., 1986). These action between genes and experience. Specifi-data suggested that a stimulus such sympa-cally, cLH animals who had been exposed thetic innervation of the adrenal melan-early stress showed hyperreactivity of the pi-cholic depression either directly released NE tuitary response to challenge, with a independent of ACTH or led to hypertrophy marked decrease in corticosterone levels com-and hyperplasia of the adrenal cortex and glu-pared to nonstressed cLH controls, while the cocorticoid hyperresponsiveness ACTH. cNLH animals exhibited hyporeactivity of the Some of the blunting may also have been due pituitary and adrenal systems compared a CRH-mediated down-regulation of pitu-their nonstressed peers. itary CRH receptors. Several other lines of in-As with prenatal experience, exposure to direct evidence are compatible with a role for stress during early postnatal life may interact CRH the hypercortisolism of melancholia with genetic predisposition to increase individ- adults. For example, when healthy controls uals' susceptibility to psychopathologic out-were given a continuous infusion of oCRH for comes (De Bellis et al., 1994; Meaney, Diorio, 24 hr, they showed the pattern and magnitude Francis, Widdowson, LaPlante, Caldji, Shar-of plasma ACTH and cortisol levels that typi-ma, Seckl, & Plotsky, 1996), including depres-cally occur in patients with melancholic sion (Plotsky, Owens, well as chronic medical illness (Francis, Caldji, Oldfield, Cutler, Champagne, Plotsky, individuals who had a history of major de-Melancholic Depression d pression during their lifetimes showed an an he Stress System increase in CRH-containing neurons in the t hypothalamus (Raadsheer, van Heerikhuize, Thousands of papers have been written on the Lucassen, Hoogendijk, Tilders, hypercortisolism of melancholic depression in 1995). Another study conducted on brains adulthood. Several lines of evidence suggest taken from individuals who had died of sui-that this represents a central nervous system cide showed a significant decrease frontal