Steroids and Depression

Psychoendocrinology Unit, Research and Training Building, McGill University, Montreal, Canada
The Journal of Steroid Biochemistry and Molecular Biology (Impact Factor: 3.63). 06/1991; 38(5):537-559. DOI: 10.1016/0960-0760(91)90312-S


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.

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    • "Taken together, the chronic low-grade inflammatory state in BD may lead to chronic hypercortisolemia. Hypercortisolemia subsequently leads to impaired neuroplasticity with resultant negative cognitive and mood effects associated with chronic exposure to elevated levels of cortisol (Murphy, 1991). Elevated cortisol levels may also impact mood and cognition through increasing hepatic tryptophan 2,3-dioxygenase (TDO) activity thereby increasing the breakdown of tryptophan to TRYCATs (Hoes and Sijben, 1981;Maes et al., 2011). "
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    ABSTRACT: Background: Bipolar disorder (BD) has been associated with cognitive impairment during depressed, manic and euthymic periods. Inflammation has been shown to be involved in the pathophysiology of BD and cognitive impairment. Methods: For this systematic review, the MEDLINE/PubMed, Embase, Google Scholar and databases were searched for relevant articles assessing the association between cognitive function and inflammatory markers in BD subjects. A discussion of potential mechanisms and therapeutic implications is also included to provide further context to the subject matter. Results: Eight studies, including a total of 555 BD subjects, assessing the association between cognitive function and inflammatory markers were identified. Cognitive dysfunction was associated with elevated levels of pro-inflammatory markers YKL40, IL-6, sCD40L, IL-1Ra, hsCRP and TNF-α. Mechanistically, elevation in inflammatory cytokines alters monoamine levels leading to cognitive and affective dysfunction. Neuro-inflammation, manifesting as microglial activation, leads to increased oxidative stress, pathologic synaptic pruning and impaired neuroplasticity in key brain regions sub-serving mood and cognition. Immune dysfunction also activates the hypothalamic-pituitary-adrenal (HPA) axis leading to hypercortisolemia and metabolic dysfunction, further promoting neuronal dysfunction. Anti-inflammatory agents are therefore currently being investigated in the treatment of BD and appear to exert an antidepressant effect; however, cognitive outcomes have yet to be reported. Conclusion: Several studies suggest that immune dysfunction is associated with cognitive impairment in BD. Several neurobiological pathways have been identified whereby immune dysfunction may promote cognitive impairment in BD. Future investigations of anti-inflammatory agents targeting cognitive function as a treatment outcome are merited.
    No preview · Article · Sep 2015 · Journal of Affective Disorders
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    • "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). "
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    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.
    Full-text · Article · Aug 2011 · Progress in Neurobiology
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    • "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). "
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    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.
    Full-text · Article · Mar 2010 · European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology
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