The biochemistry of the blues.

The biochemistry of the blues

The blues take body and mind on a dance so complex that researchers have had trouble charting the steps. Now there's evidence that a brain hormone may be involved in the debilitating symptoms of both depression and the eating disorder anorexia nervosa. While the work, reported in the May 22 NEW ENGLAND JOURNAL OF MEDICINE, has no immediate therapeutic applications, according to a member of the research team it does provide "a clue to follow' in developing treatment strategies.

Since its discovery in 1981, corticotropin-releasing hormone (CRH) has been shown to produce behavioral and physiological changes characteristic of depression when injected into the brains of rats. But according to George Chrousos, who took part in the new study, levels of the hormone are difficult to measure in humans because it is contained in a small, closed circulatory system between the pituitary and the hypothalamus. So Chrousos and his colleagues at the National Institute of Mental Health (NIMH) and the National Institute of Child Health and Human Development (NICHD) in Bethesda, Md., teased apart a convoluted endocrine feedback loop to deduce elevated levels of CRH in depressives and anorexics.

CRH, produced by the hypothalamus in the brain, stimulates the pituitary gland to produce a hormone called adrenocorticotropic hormone (ACTH). That hormone "turns on' the adrenal glands' production of cortisol. Then, feeding back, high levels of cortisol act on both the pituitary and the hypothalamus to "turn off' further production of hormones. Scientists have known for decades that depressives and anorexics have a defect somewhere in the production cycle that results in abnormally high levels of cortisol.

The researchers injected CRH into their subjects and found that in depressed and anorexic patients the pituitary did not make much more ACTH in response; it "knew,' through feedback, that cortisol levels were adequate. But while the levels of ACTH didn't jump, the adrenals were hyperresponsive, producing large amounts of cortisol--as they would if they were constantly stimulated by ACTH. Together, the scientists say, the findings indicate that the defect in these patients occurs before the pituitary plays its part, at the level of the hypothalamus or even before that. That would mean that the high levels of cortisol seen in depressed and anorexic patients reflect abnormally high levels of CRH.

Earlier animal research has shown that the brain becomes hypersensitive to CRH; in fact, rats repeatedly injected with CRH eventually respond with seizures. That sensitization is also reflected in the natural history of depression, according to researcher Philip Gold at NIMH.

"The first episodes generally require emotional stress,' says Gold, "but they progressively require less and less. CRH might be relevant there. . . . It represents a link between biological and psychological models of depression.'

Next, the researchers plan to look for agents that suppress or block CRH, and to test them in animals.