While clinical data show that melancholic depression reflects an organized state of hyperarousal and anxiety, our clinical data show that the depressive syndrome associated with Cushing's disease is almost universally an atypical depressive syndrome, associated with lethargy, fatigue, hypersomnia and hyperphagia. Moreover, follow-up studies of post-operative Cushing's disease patients whose PVN CRH neurons can remain suppressed for several months following surgically-induced remission of hypercortisolism show that as CRH neuron function returns, patients begin manifesting evidence of severe melancholic depression. Studies of other medical syndromes associated with atypical depression also suggest a subtle central pituitary-adrenal insufficiency as a consequence of a PVN CRH deficiency. These include the chronic fatigue syndrome, seasonal affective disorder, fibromyalgia and hypothyroidism. Our data in patients with multiple sclerosis also show reorganization of hypothalamic-pituitary-adrenal function similar to that seen in chronically inflamed experimental animals. Specifically, patients with multiple sclerosis show a pattern of responses to a variety of stimuli to the HPA axis that indicate a shift from CRH to arginine-vasopressin mediated modulation of pituitary adrenal function. While the functional significance of this shift has not been definitely elucidated, these data indicate that pituitary-adrenal-responsiveness to a repertoire of physical and emotional stressors (including inflammatory stimuli) may produce different responses in patients with multiple sclerosis than in controls that could contributieto sustaining a chronic inflammatory disease. In our studies of patients with eating disorders, we have developed a model suggesting that a confluence of the following four factors contribute to the susceptibility and natural history of anorexia nervosa and bulimia nervosa: (l) clinical and biochemical manifestations of obsessionalism; (2) a reduction in metabolic rate that interacts with obsessional features to produce a perseverative preoccupation with food intake and body image; (3) primary and/or secondary alterations in the neural mechanisms subserving hunger and satiety that reinforce pathological eating behaviors; and (4) an underlying depression that heightens the eating disordered patient's need to enhance low self-esteem by achieving an idealized body weight. In addition, we postulate that the abstinent bulimic experiences an unpleasant state of hyperarousal not dissimilar from that seen in the various forms of atypical depression that is ameliorated by the bingeing and purging process.