Patients with endogenous depression (major affective disorder) frequently have high cortisol levels, but the diurnal rhythm is usually maintained and they do not develop the physical signs of Cushing's syndrome. On the other hand, depression is a frequent feature of Cushing's syndrome regardless of etiology, and it is often relieved when the cortisol levels are reduced, by whatever means. The mechanisms of the hypercortisolemia and resistance to dexamethasone suppression commonly found in endogenous depression are poorly understood; contrary to expectations, ACTH levels are not clearly elevated. There is striking difference in the psychiatric features seen in endogenous hypercorticism compared to those seen after exogenous administration of glucocorticoids or ACTH. This suggests that either there are other stimulating or modifying factors besides ACTH or that the steroids stimulated by ACTH or other peptides differ from those in control subjects, i.e. there may be an alteration in the metabolism of steroids in depression. Little is known about the metabolic changes or the many steroids besides glucocorticoids produced by the hyperactive steroid-producing tissue. Preliminary studies suggest that major depression may be improved by steroid suppression. It is hypothesized that steroids themselves may be important in causing and perpetuating depression.
"Chronic stress as well as high glucocorticoid levels can induce hippocampal atrophy and reduce synaptic plasticity, which in turn has been proposed to be mediated by reduced BDNF levels (Garcia, 2002). Signs of abnormal hypothalamic–pituitary–adrenal (HPA) axis activity including increased levels of cortisol are frequently reported in MDD (Murphy, 1991; Nelson and Davis, 1997). A recent meta-analysis demonstrated an association between the Val66Met BDNF polymorphism (''met-allele'') and treatment response in patients with MDD, with Val66Met heterozygous patients showing a better response rate than the Val/Val homozygotes, especially in Asian populations (Schumacher et al., 2005). "
[Show abstract][Hide abstract] ABSTRACT: Major depressive disorders (MDD) are among the most debilitating diseases worldwide and occur with a high prevalence in elderly individuals. Neurodegenerative diseases (in particular Alzheimer's disease, AD) do also show a strong age-dependent increase in incidence and prevalence among the elderly population. A high number of geriatric patients with MDD show cognitive deficits and a very high proportion of AD patients present co-morbid MDD, which poses difficult diagnostic and prognostic questions. Especially in prodromal and in very early stages of AD, it is almost impossible to differentiate between pure MDD and MDD with underlying AD. Here, we give a comprehensive review of the literature on the current state of candidate biomarkers for MDD ("positive MDD markers") and briefly refer to established and validated diagnostic AD biomarkers in order to rule out underlying AD pathophysiology in elderly MDD subjects with cognitive impairments ("negative MDD biomarkers"). In summary, to date there is no evidence for positive diagnostic MDD biomarkers and the only way to delineate MDD from AD is to use "negative MDD" biomarkers. Because of this highly unsatisfactory current state of MDD biomarker research, we propose a research strategy targeting to detect and validate positive MDD biomarkers, which is based on a complex (genetic, molecular and neurophysiological) biological model that incorporates current state of the art knowledge on the pathobiology of MDD. This model delineates common pathways and the intersection between AD and MDD. Applying these concepts to MDD gives hope that positive MDD biomarkers can be successfully identified in the near future.
Progress in Neurobiology 08/2011; 95(4):703-17. DOI:10.1016/j.pneurobio.2011.08.001 · 9.99 Impact Factor
"A dysregulation of the HPA axis in patients with major depression is seen after the dexamethasone suppression test (DST) (Pariante 2004) and the DEX/corticotrophin releasing hormone (CRH) (Holsboer 2000; Nemeroff 1996) test, indicating in depressed patients a relative impairment of glucocorticoid receptor (GR)-mediated negative feedback (glucocorticoid resistance). In further support to the notion of relative glucocorticoid resistance in depressed patients is the fact that the increased cortisol levels are not accompanied by physical signs of Cushing's Syndrome (Holsboer et al. 1992; Murphy 1991). Glucocorticoid resistance has also been described in the peripheral blood immune cells from depressed patients (Holsboer 2000; Pariante et al., 2001). "
[Show abstract][Hide abstract] ABSTRACT: Clinical studies have demonstrated an impairment of glucocorticoid receptor (GR)-mediated negative feedback on the hypothalamic-pituitary-adrenal (HPA) axis in patients with major depression (GR resistance), and its resolution by antidepressant treatment. Recently, we showed that this impairment is indeed due to a dysfunction of GR in depressed patients (Carvalho et al., 2009), and that the ability of the antidepressant clomipramine to decrease GR function in peripheral blood cells is impaired in patients with major depression who are clinically resistant to treatment (Carvalho et al. 2008). To further investigate the effect of antidepressants on GR function in humans, we have compared the effect of the antidepressants clomipramine, amytriptiline, sertraline, paroxetine and venlafaxine, and of the antipsychotics, haloperidol and risperidone, on GR function in peripheral blood cells from healthy volunteers (n=33). GR function was measured by glucocorticoid inhibition of lypopolysaccharide (LPS)-stimulated interleukin-6 (IL-6) levels. Compared to vehicle-treated cells, all antidepressants inhibited dexamethasone (DEX, 10-100nM) inhibition of LPS-stimulated IL-6 levels (p values ranging from 0.007 to 0.1). This effect was specific to antidepressants, as antipsychotics had no effect on DEX-inhibition of LPS-stimulated IL-6 levels. The phosphodiesterase (PDE) type 4 inhibitor, rolipram, potentiated the effect of antidepressants on GR function, while the GR antagonist, RU-486, inhibited the effect of antidepressants on GR function. These findings indicate that the effect of antidepressants on GR function are specific for this class of psychotropic drugs, and involve second messenger pathways relevant to GR function and inflammation. Furthermore, it also points towards a possible mechanism by which one maybe able to overcome treatment-resistant depression. Research in this field will lead to new insights into the pathophysiology and treatment of affective disorders.
European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 03/2010; 20(6):379-87. DOI:10.1016/j.euroneuro.2010.02.006 · 4.37 Impact Factor
"The presence of GR resistance in these patients is also supported by the fact that there was no difference between patients and controls in stimulated IL-6 levels, even in the presence of higher endogenous CORT levels in the in vitro assay of depressed patients. These results are consistent with the fact that patients with depression frequently have high CORT levels, but they do not develop the physical signs of Cushing's syndrome (reviewed by Murphy, 1991). Other studies have examined GR function in vitro using a different technique, glucocorticoid inhibition of lymphocyte proliferation. "
[Show abstract][Hide abstract] ABSTRACT: Previously, we have shown that in vitro antidepressants modulate glucocorticoid receptor (GR) function and expression, and have suggested that these effects could be relevant for the mechanism of action of antidepressants. To further clarify the interaction between antidepressants and glucocorticoids, we evaluated the in vitro effect of the tricyclic antidepressant, clomipramine (CMI), on the GR function in 15 treatment-resistant depressed inpatients and 28 healthy controls. Diluted whole-blood cells were incubated for 24 h in the presence or absence of CMI (10 muM). Glucocorticoid function was measured by glucocorticoid inhibition of lypopolysaccharide (LPS)-stimulated interleukin-6 (IL-6) levels. The results show that glucocorticoids (dexamethasone, prednisolone, cortisol and corticosterone) caused a concentration-dependent inhibition of LPS-stimulated IL-6 levels. In healthy controls, CMI decreased glucocorticoid inhibition of LPS-stimulated IL-6 levels, while this effect was not present in depressed patients. Therefore, depressed patients, who were clinically treatment resistant, also showed a lack of effect of the antidepressant in vitro. Upcoming studies shall test whether assessing the effects of antidepressants in vitro on GR function could predict future treatment response in a clinical setting.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 04/2008; 33(13):3182-9. DOI:10.1038/npp.2008.44 · 7.05 Impact Factor
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