Psychiatric Manifestations of Cushing’s Syndrome

Loosen, Peter T.

doi:10.1007/978-1-4615-1103-8_3

Cited by 5 publications

(4 citation statements)

References 59 publications

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“…Nonetheless, interference of these drugs with the action of higher glucocorticoid levels could also attenuate potential deleterious effects of these increases on mood. Secondly, tricyclic antidepressants are reportedly ineffective in glucocorticoid-induced mood disorders (7). However, these reports do not negate the significance of tricyclic effects on GR signaling in depression, because even in untreated depression GR occupancy is probably much lower, and thus more likely susceptible to tricyclic antidepressant modulation, than that produced by pharmacological levels of synthetic glucocorticoids.…”

Section: Discussionmentioning

confidence: 98%

“…Over two thirds of patients with Cushing's syndrome and up to 30% of patients treated with systemic glucocorticoids present with depression, even though many of these patients lack any history of psychiatric illness. Both Cushing's and glucocorticoid-treated patients may also exhibit psychosis and other symptoms observed in depression, including anxiety, mania, sleep and appetite disturbances, and cognitive impairment (7)(8)(9). Analogous to the localized resistance posited by Pariante and Miller (1) to reconcile the evidence for normal peripheral glucocorticoid action with impaired feedback in depression, we hypothesized that brain region-specific deficits in glucocorticoid signaling could account for defective feedback combined with the apparent effects of glucocorticoid excess on mood in psychotic and possibly other subtypes of depression.…”

Section: -4191 2004)mentioning

confidence: 98%

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Partial Glucocorticoid Agonist-Like Effects of Imipramine on Hypothalamic-Pituitary-Adrenocortical Activity, Thymus Weight, and Hippocampal Glucocorticoid Receptors in Male C57BL/6 Mice

Mukherjee¹,

Knisely²,

Jacobson³

2004

Endocrinology

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Abnormal hypothalamic-pituitary-adrenocortical (HPA) activity may provide clues to the neurochemistry of depression. Psychotic depression has one of the highest rates of elevated HPA activity and is most often responsive to the tricyclic class of antidepressants. Because successful treatment resolves HPA as well as psychiatric symptoms, we hypothesized, in light of evidence that tricyclic antidepressants can affect glucocorticoid receptor function, that these drugs would mimic glucocorticoid feedback inhibition of HPA activity. To test this hypothesis, we measured circadian nadir (morning) and peak (evening) as well as restraint stress-induced levels of plasma ACTH and corticosterone in adrenalectomized (ADX) and sham-ADX (Sham) male C57BL/6 mice after 8 wk of imipramine (20 mg/kg/d, ip) or saline treatment. Antidepressant efficacy was confirmed by decreased immobility in forced-swim testing. When glucocorticoids were low or absent, imipramine mimicked glucocorticoid action in inhibiting evening ACTH in ADX mice and tending to inhibit morning corticosterone in Shams. However, when glucocorticoid levels were high, imipramine appeared to interfere with feedback inhibition by increasing post-stress ACTH and tending to increase evening corticosterone in Sham mice. Imipramine also decreased thymus weight in ADX and increased thymus weight in Sham mice. Imipramine stimulated morning ACTH in ADX mice, possibly by mimicking facilitative effects of high glucocorticoids. Short-term imipramine treatment was capable of inducing nuclear translocation of hippocampal glucocorticoid receptors in ADX mice. We conclude that imipramine effects on glucocorticoid-sensitive endpoints in vivo resemble those of a glucocorticoid partial agonist.

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Section: Discussionmentioning

confidence: 98%

Section: -4191 2004)mentioning

confidence: 98%

Partial Glucocorticoid Agonist-Like Effects of Imipramine on Hypothalamic-Pituitary-Adrenocortical Activity, Thymus Weight, and Hippocampal Glucocorticoid Receptors in Male C57BL/6 Mice

Mukherjee¹,

Knisely²,

Jacobson³

2004

Endocrinology

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“…However, there is evidence that glucocorticoids not only reflect but may also contribute to mood and anxiety disorders. Glucocorticoids themselves have been shown to cause dysphoria (depression and anxiety) symptoms (Brown et al ., ; Loosen, ). Depression occurs in > 50% of patients with Cushing's syndrome (Kelly, ; Dimopoulou et al ., ) and up to 20% of patients that receive exogenous glucocorticoids for immunosuppressive therapy (Sirois, ; Kenna et al ., ).…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoid receptor deletion from the dorsal raphé nucleus of mice reduces dysphoria‐like behavior and impairs hypothalamic‐pituitary‐adrenocortical axis feedback inhibition

Vincent

Jacobson

2014

Eur J of Neuroscience

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Glucocorticoids can cause depression and anxiety. Mechanisms for glucocorticoid effects on mood are largely undefined. The dorsal raphé nucleus (DRN) produces the majority of serotonin in the brain, and expresses glucocorticoid receptors (GR). Since we previously showed that antidepressants used to treat depression and anxiety decrease DRN GR expression, we hypothesized that deleting DRN GR would have anxiolytic- and antidepressant-like effects. We also hypothesized that DRN GR deletion would disinhibit activity of the hypothalamic pituitary adrenal (HPA) axis. Adeno-associated virus pseudotype AAV2/9 expressing either Cre recombinase (DRNGRKO mice) or GFP (DRN-GFP mice) was injected into the DRN of floxed GR mice to test these hypotheses. Three weeks after injection, mice underwent 10d of social defeat or control handling and tested for anxiety-like behavior (open field test, elevated plus maze), depression-like behavior (sucrose preference, forced swim test (FST), tail suspension (TST)), social interaction, and circadian and stress-induced HPA activity. DRN GR deletion decreased anxiety-like behavior in control but not in defeated mice. DRN GR deletion decreased FST and tended to decrease TST despair-like behavior in both control and defeated mice, but did not affect sucrose preference. Exploration of social (a novel mouse) as well as neutral targets (an empty box) was increased in DRNGRKO mice, suggesting that DRN GR deletion also promotes active coping. DRN GR deletion increased stress-regulated HPA activity without strongly altering circadian HPA activity. We have shown a novel role for DRN GR to mediate anxiety- and despair-like behavior and to regulate HPA negative feedback during acute stress.

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“…Glucocorticoid excess, which can result from Cushing's syndrome or immunosuppressive therapy, can induce depression or symptoms associated with depression, including psychosis, anxiety, mania, sleep and appetite disturbances, and cognitive impairment. The impact of glucocorticoids on mood is unrelated to the psychiatric history of the individual or the severity of any immunologic disease for which glucocorticoids may have been prescribed (Brown et al, 1999; Loosen, 2002; Sirois, 2003; Starkman and Schteingart, 1981). Glucocorticoid receptor antagonists, such as RU 38486, or glucocorticoid synthesis inhibitors, such as ketoconazole and metyrapone, have been reported to improve mood in major depression and Cushing's syndrome (Jahn et al, 2004; Murphy, 1997; O'Dwyer et al, 1995; Wolkowitz et al, 1999), suggesting that glucocorticoid secretion might be contributing to depression symptoms in these patients.…”

Section: Introductionmentioning

confidence: 99%

Sensitivity of depression-like behavior to glucocorticoids and antidepressants is independent of forebrain glucocorticoid receptors

et al. 2013

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The location of glucocorticoid receptors (GR) implicated in depression symptoms and antidepressant action remains unclear. Forebrain glucocorticoid receptor deletion on a C57B/6×129×CBA background (FBGRKO-T50) reportedly produces increased depression-like behavior and elevated glucocorticoids. We further hypothesized that forebrain GR deletion would reduce behavioral sensitivity to glucocorticoids and to antidepressants. We have tested this hypothesis in mice with calcium calmodulin kinase IIα-Cre-mediated forebrain GR deletion derived from a new founder on a pure C57BL/6 background (FBGRKO-T29-1). We measured immobility in forced swim or tail suspension tests after manipulating glucocorticoids or after dose response experiments with tricyclic or monoamine oxidase inhibitor antidepressants. Despite forebrain GR deletion that was at least as rapid and more extensive than reported in the mixed-strain FBGRKO-T50 mice (Boyle et al. 2005), and possibly because of their different founder, our FBGRKO-T29-1 mice did not exhibit increases in depression-like behavior or adrenocortical axis hormones. Nevertheless, FBGRKO-T29-1 mice were at least as sensitive as floxed GR controls to the depressive effects of glucocorticoids and the effects of two different classes of antidepressants. FBGRKO-T29-1 mice also unexpectedly exhibited increased mineralocorticoid receptor (MR) gene expression. Our results reinforce prior evidence that antidepressant action does not require forebrain GR, and suggest a correlation between the absence of depression-like phenotype and combined MR up-regulation and central amygdala GR deficiency. Our findings demonstrate that GR outside the areas targeted in FBGRKO-T29-1 mice are involved in the depressive effects of glucocorticoids, and leave open the possibility that these GR populations also contribute to antidepressant action.

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Psychiatric Manifestations of Cushing’s Syndrome

Cited by 5 publications

References 59 publications

Partial Glucocorticoid Agonist-Like Effects of Imipramine on Hypothalamic-Pituitary-Adrenocortical Activity, Thymus Weight, and Hippocampal Glucocorticoid Receptors in Male C57BL/6 Mice

Partial Glucocorticoid Agonist-Like Effects of Imipramine on Hypothalamic-Pituitary-Adrenocortical Activity, Thymus Weight, and Hippocampal Glucocorticoid Receptors in Male C57BL/6 Mice

Glucocorticoid receptor deletion from the dorsal raphé nucleus of mice reduces dysphoria‐like behavior and impairs hypothalamic‐pituitary‐adrenocortical axis feedback inhibition

Sensitivity of depression-like behavior to glucocorticoids and antidepressants is independent of forebrain glucocorticoid receptors

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