Discussion and summary

Although the hypothesis that the neuroendocrine window strategy would ultimately provide the long-searched for information concerning the nature of monoamine circuit alterations in patients with psychiatric disorders has never been realized, the approach has led to major advances in biological psychiatry. It has led to the CRF hypothesis of depression, which is supported by a considerable multidisciplinary database, and this in turn has directed the field towards the development of novel therapeutic approaches, namely CRF-receptor antagonists. It also apparently explains the neurobiological mechanisms responsible for the increase in depression (first postulated by Freud in the early part of the twentieth century) in patients exposed to trauma during their early life. If CRF is indeed the 'black bile' of depression—responsible for the endocrinopathy of depression, as well as several of the other cardinal features of this disorder—then CRF-receptor antagonists should represent a novel class of antidepressants that will be a welcome addition to the armamentarium. Indeed, a number of pharmaceutical companies are now testing CRF-receptor antagonists as novel anxiolytics and antidepressants in preclinical and clinical trials.

In addition to the now widely replicated HPA axis and CRF alterations in depression, are the HPT axis abnormalities. Most depressed patients, in fact, exhibit alterations in one of these two axes. Furthermore, there is the widely replicated blunting of the growth-hormone response to clonidine and other provocative stimuli and the blunted prolactin response to serotonergic stimuli in depressed patients. It is obvious from these studies that the vast majority of studies have focused on patients with mood disorders, particularly unipolar depression. Clearly other disorders, including eating disorders, anxiety disorders, schizophrenia, and axis II diagnoses should also be critically evaluated and compared to the literature on depression. The original neuroendocrine window strategy may well have failed in terms of gleaning information about monoamine-circuit activity, but the mechanistic studies that have followed have been remarkably fruitful. As repeatedly noted above, the availability of ligands that can be utilized with positron-emission tomography to determine peptide-receptor alterations in the brain and pituitary of patients with psychiatric disorders will advance the field, as will the long-elusive ability to measure receptors for the endocrine target hormones (glucocorticoids, oestrogens, thyroid hormones, etc.) in the brains of patients with these severe mental illnesses

Finally it is important to note the increasing database suggesting that depression is a systemic disease with major implications for vulnerability to other disorders. Thus depressed patients are much more likely to develop coronary artery disease and stroke, and perhaps cancer. They have been shown to have reduced bone density, rendering them more at risk for hip fracture. Such findings may well be mediated by the described endocrine alterations in depression. This should provide a further impetus for investigating the neuroendocrinology of psychiatric disorders.

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