The satiety-inducing effects of centrally and peripherally administered cholecystokinin (CCK) in experimental animals have been well documented. Recently, studies in humans showed that CCK is released into plasma following food ingestion, a phenomenon postulated to promote meal-related satiety. To explore whether abnormal CCK secretion during feeding may be related to pathophysiological mechanisms in disorders associated with appetite abnormalities, we report here studies of the plasma CCK response to a test meal in patients with bulimia nervosa, as well as seasonal (hyperphagic) and melancholic (anorexic) depression. Compared to controls, bulimic patients had impaired meal-related CCK secretion, correlated with an impaired sense of postprandial satiety. This defect resolved with tricyclic antidepressant-induced amelioration of bulimic behavior, suggesting that deficient CCK secretion may constitute a fundamental pathophysiologic derangement in this disorder. In contrast to patients with bulimia nervosa, hyperphagic patients with seasonal affective disorder failed to show abnormal meal-related CCK secretion. Preliminary evidence shows robust meal-related CCK secretion in melancholic depression with anorexia. We have also begun to explore the dynamics of CCK secretion into cerebrospinal fluid (CSF) utilizing an indwelling lumbar catheter. From studies in humans, we note that this peptide is secreted into the CSF in large (ng/ml) quantities in an episodic fashion that may bear some relationship to food ingestion. Further study of this parameter in volunteers and patients is now underway.