Neuroendocrine Tests

The hypothalamic-pituitary-adrenocortical axis. The DST was the first, and is to date the most studied, putative biological marker in research on depressive disorders. In 1968 Carroll et al [136] showed that while depressed, patients fail to suppress plasma cortisol. This led Carroll to claim that a positive DST is a specific laboratory test for melancholia or severe forms of depression [46]. Subsequent studies confirmed the high specificity vs. normal or non-psychiatric controls (91%-93%) but not vs. dysthymic and other severe or acute psychiatric disorders as well as vs. apparently healthy individuals who had experienced a recent stressful event [137]. Moreover, high and low cortisol suppressors were found not to differ in depressive symptoms among participants in population studies [138]. However, cortisol secretion was found to be related to temperament dimensions [139]. A recent meta-analysis to determine the significance of differences in non-suppression of cortisol across studies, indicated a highly significant probability that a greater rate of cortisol non-suppression occurs in psychotic depression (64% in psychotics and 41% in non-psychotic patients) and the authors concluded that, among patients with major depression, those with psychotic depression constitute a subtype that is most closely associated with non-suppression of cortisol on the DST [53]. In another study the RDC ''endogenous/non-endogenous'' dichotomy was validated by the DST [161]. Interestingly, an enhanced negative feedback inhibition manifested by an exaggerated cortisol response to dexamethasone was observed in patients with post-traumatic stress disorder [140].

The adrenocorticotrophic hormone (ACTH) response to corticotropin releasing factor (CRF) is also a focus of investigation. There is accumulating evidence that the increased hypothalamic-pituitary drive reported in depression is primarily mediated by hypersecretion of CRF [141]. In some studies, patients with major depression show increased levels of CSF CRF as compared to matched controls or patients with schizophrenia [142, 143]. The elevation appears to be state-dependent, as CSF CRF levels normalize upon successful treatment. Studies utilizing challenge tests indicate that many depressed patients display a blunted ACTH response to exogenous CRF administration as compared to matched controls, and in at least one study this seems to be observed also in healthy subjects with a familial loading for affective disorders [142, 144]. In one study [145], the sensitivity of the DST/corticotropin-releasing hormone (CRH) test for MD was found to be about 80% greatly exceeding that of the standard DST (1 -2 mg of dexamethasone), which has been reported to average about 44% in a meta-analysis of the literature data. Since CRF is considered as one of the primary mediators of stress responses, anxiety and fear, it is not surprising that increased CRF and blunted response to ACTH have been observed in stressful anxiety-ridden conditions [140].

The hypothalamic-pituitary-thyroid axis. Concerning the hypothalamic-pit-uitary-thyroid axis, depressed patients have been reported to have: (a) alterations in TSH response to the TRH; (b) an abnormally high rate of antithyroid antibodies; and (c) elevated CSF TRH concentrations. Consistently, a subgroup of depressive patients (about 30% or more) have a decreased response of TSH, to TRH and a variable prolactin (PRL) response [146,147]. The blunted response persists in some patients after recovery and is not connected with cortisol levels or DST response. Both T4 and TSH response to TRH is reported to relate to the treatment outcome of depressed patients [148]. The significance of the pituitary-thyroid axis abnormalities in depression, however, still remains unclear.

The hypothalamic-pituitary-growth hormone system. The release of growth hormone (GH) from the anterior pituitary is regulated by hypothalamic peptides, especially GH-releasing hormone (GHRH) and somatostatin, which in turn are controlled by the classic neurotransmitters and insulin-like growth factor-1. Blunted GH response has been reported following administration of insulin, L-dopa, d-amphetamine, clonidine and GHRH, but the findings are equivocal [149]. The blunted GH secretion to clonidine is not only observed in depression and panic attacks, but also in GAD and social phobia. However, the abnormality is not observed in schizophrenia or obsessive-compulsive disorder (OCD). On the other hand, some investigators have observed no difference between depressed patients and controls in the clonidine/GH or GHRH/GH challenges [149,150]. In a recent study, an enhanced GH release in response to pyridostigmine (PYD) in subjects with major depression (sensitivity 63%), but not inpatients with schizophrenia, alcohol dependence and panic, was reported [151]. Studies on GH nocturnal secretion in depressed patients yielded conflicting results. A marked decrease in depressed patients was observed in some studies [152], while in others secretion did not differ between patients and controls [153].

Serotonin (5-HT) tests. The implication of serotonin (5-HT) in depression is based on many findings from a variety of sources, including the beneficial effects of 5-HT reuptake inhibitors on depressive symptomatology. A number of studies used a variety of 5-HT releasing agents, mainly fenfluramine, as a challenge drug in order to probe the 5-HT functional state in the brain. The response of 5-HT receptors to the 5-HT releasing agents is measured by PRL, ACTH and cortisol secretion from the pituitary. The results of fenfluramine studies are thus far inconsistent. Negative results were reported by some investigators [154] and positive results by others [155,156]. In a recent study in which strict control measures were applied, results were consistent with a blunted fenfluramine response. Moreover, the study indicated that the clinical recovery from depression is not associated with normalization of serotoninergic function [157].

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