The United States of America As Represented by the Department of Health

Other

The United States of America As Represented by the United States

Beth Israel Deaconess Medical Center, Inc.

Philip W Gold

Esther M Sternberg

Jeffrey S Flier

Ronald L Wilder

George P Chrousos

Ma-Li Wong

Julio Licinio De Castro Paixao

Samuel W Page

Methods of treating an affective disorder in an individual are disclosed. Affective disorders include major depression, melancholic and atypical subtypes, and dysthymia.

Methods of neuroendocrine regulation of affective disorders

The present invention is directed to a method for testing the susceptibility of a mammal to inflammatory diseases which comprises the steps of:

Evaluative means for detecting inflammatory reactivity

Inbred Lewis (LEW/N) female rats develop an arthritis in response to Group A streptococcal cell wall peptidoglycanpolysaccharide (SCW) which mimics human rheumatoid arthritis. Histocompatible Fischer (F344/N) rats, on the other hand, do not develop arthritis in response to the same SCW stimulus. To evaluate this difference in inflammatory reactivity between the two strains, the function of the hypothalamic-pituitary-adrenal axis and its ability to modulate the development of the inflammatory response was studied. It has been found that, in contrast to F344/N rats, LEW/N rats had markedly impaired plasma ACTH and corticosterone responses to SCW, recombinant human Interleukin-1 alpha (IL-1 alpha), the serotonin agonist, quipazine, and synthetic rat corticotropin-releasing hormone (CRH). In addition, LEW/N rats compared to F344/N rats had smaller adrenal glands and larger thymuses. Treatment of LEW/N rats with replacement doses of dexamethasone decreased the severity of their SCW-induced arthritis. Conversely, treatment of F344/N rats with the glucocorticoid receptor antagonist, RU 486, or the serotonin (5-HT.sub.2) antagonist, LY53857, was associated with development of severe inflammatory disease, including arthritis, in response to SCW. These findings support the concept that susceptibility of LEW/N rats to SCW arthritis is related to abnormal hypothalamic-pituitary-adrenal (HPA) axis responsiveness to inflammatory and other stress mediators and that resistance of F344/N rats to SCW arthritis is regulated by an intact HPA axis-immune system feedback loop.

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Washington, DC, United States of America

Philip W Gold