Corticotropin releasing hormone in the pathophysiology of melancholic & atypical depression & in the mech. of action of antidepressant drugs

Hypercortisolism in depression seems to preferentially reflect
activation of hypothalamic CRH secretion. Although it has been
postulated that this hypercortisolism is an epiphenomenon of
the pain and stress of major depression, our data showing
preferential participation of AVP in the hypercortisolism of
chronic inflammatory disease suggest specificity for the
pathophysiology of hypercortisolism in depression.

Our findings that imipramine causes a down-regulation of the HPA
axis in experimental animals and healthy controls support an
intrinsic role for CRH in the pathophysiology of melancholia
and in the mechanism of action of psychotropic agents. Our
data suggest that hypercortisolism is not the only form of HPA
dysregulation in major depression.

In a series of studies, commencing in patients with Cushing's disease,
and extending to hyperimmune fatigue states such as chronic fatigue
syndrome and examples of atypical depression such as seasonal
affective disorder, we have advanced data suggesting hypofunction
of hypothalamic CRH neurons. These data raise the question that
the hyperphagia, hypersomnia, and fatigue associated with
syndromes of atypical depression could reflect a central
deficiency of a potent arousal-producing anorexogenic

In the light of data presented elsewhere in this symposium
regarding the role of a hypofunctioning hypothalamic
CRH neuron in susceptibility to inflammatory disease, these
data also raise the question of a common pathophysiological
mechanism in syndromes associated both with inflammatory
manifestations and atypical depressive symptoms. This concept
of hypofunctioning of hypothalamic CRH neurons in these
disorders also raises the question of novel forms of
neuropharmacological intervention in both inflammatory
diseases and atypical depressive syndromes. [References: 53]

Gold PW, Licinio J, Wong ML, Chrousos GP

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