We have identified four risk factors for the development and/or perpetuation of the eating disorders: 1) An intrinsic reduction in metabolic rate that predisposes to weight gain, and hence pathological eating behaviors; 2) correction of this reduction in metabolic rate by bingeing and vomiting via preabsorptive mechanisms that result in enhanced thyroid and sympathetic function; 3) clinical evidence of obsessive compulsive disorder and biological abnormalities that span anorexia nervosa, bulimia nervosa, and classic obsessive compulsive disorder (e.g., a profound disturbance in the secretion of arginine vasopressin, a peptide that delays the extinction of behaviors acquired during aversive conditioning; 4) secondary abnormalities in the neural mechanisms subserving hunger and satiety that occur as a consequence of pathological eating behavior that perpetuate these illnesses. We have originated the concept that the sub-type of atypical depression reflects the concomitant inactivation of the principal stress-responsive, arousal-producing neurotransmitter systems in brain, validating this concept in patients with the Chronic Fatigue Syndrome, hypothyroidism, Cushing's disease, and seasonal affective disorder. We have developed an animal model for susceptibility to inflammatory disease and abnormal behavioral responses to stress, related to a defect in regulation of hypothalamic-pituitary-adrenal responses to inflammatory and stress mediators. As a corollary, preliminary studies in clinical populations suggest that susceptibility to inflammatory disease and the frequent association of atypical depression with inflammatory disease may relate to a subtle inactivation of the CRH neuron. We have shown that patients with the tryptophan-induced eosinophilic myalgia syndrome (EMS) show abnormal activation of the enzyme indoleamine 2,3 dioxygenase, that suppression of the pituitary-adrenal axis may predispose to this illness, and that the presumed contaminant in tryptophan preparations is a benzodiazepine compound that suppresses the expression of the CRH gene. We have developed a model for the EMS syndrome in the CRH-- hyporesponsive LEWIN rat that provides the means to identify the role of specific purified contaminants, host factors that enhance susceptibility, the role of the HPA axis and of eosinophils in amplifying the syndrome, and the evaluation of new therapies. We have recently localized the cannabinoid receptor, a finding that offers for the first time a means of accounting for the acute syndrome elicited by cannabinoid administration to animals and humans.
