Reply: ‘Clomipramine and Glucocorticoid Receptor Function’

Carvalho, Lívia A.; Juruena, Mário F.; Papadopoulos, Andrew; Poon, Lucia; Cleare, Anthony J.; Pariante, Carmine M.

doi:10.1038/npp.2009.43

Cited by 2 publications

(6 citation statements)

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“…The concentration of DEX used in this study was based on the average IC 50 =4.5 nM found in this study. This value is within the normal values of cortisol found in the plasma of healthy subjects from 11 AM to midnight (Conceptual Framework of Adrenal Stress Index, 2010). It is of note that this concentration of antidepressants and antipsychotics is somewhat in the upper range of the values found in the plasma.…”

Section: Methodssupporting

confidence: 85%

“…Finally, we have recently found that the ability of clomipramine to decrease GR function in peripheral blood cells is impaired in patients with major depression who are clinically resistant to treatment, thus suggesting that the ability of antidepressants to regulate GR function is related to their therapeutic action (Carvalho et al, 2008). These patients also had reduced GR function in peripheral blood cells (Carvalho et al 2009) and increased levels of interleukin-6 possibly reflecting a pro-inflammatory state of monocytes (Carvalho et al, 2008). Taking together we hypothesize antidepressants correct the glucocorticoid resistance and pro-inflammatory state of monocytes in major depressive disorders.…”

Section: Introductionmentioning

confidence: 99%

“… 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).…”

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confidence: 99%

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Antidepressants, but not antipsychotics, modulate GR function in human whole blood: An insight into molecular mechanisms

Carvalho

Garner

Dew

et al. 2010

European Neuropsychopharmacology

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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 . 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, 10-100 nM) 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.

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Section: Methodssupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Antidepressants, but not antipsychotics, modulate GR function in human whole blood: An insight into molecular mechanisms

Carvalho

Garner

Dew

et al. 2010

European Neuropsychopharmacology

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“…The most commonly reported cytokine level was IL-6, which was reported by all studies (13, 45, 54–56). IL-6 levels were used from three studies (13, 55, 56) to determine effect size, whereas CRP was used for the other study (45).…”

Section: Resultsmentioning

confidence: 91%

“…Two of four studies used suppression of lipopolysaccharide (LPS)-induced IL-6 production by exogenous glucocorticoids to measure glucocorticoid resistance (13, 45, 54). Two studies used GR expression to assess glucocorticoid resistance (55, 56).…”

Section: Resultsmentioning

confidence: 99%

Glucocorticoid Resistance: Is It a Requisite for Increased Cytokine Production in Depression? A Systematic Review and Meta-Analysis

et al. 2019

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Background: Glucocorticoid resistance—reduced function of the glucocorticoid receptor (GR)—is seen in many depressed patients. It is argued that this resistance to glucocorticoids leads to failure of normal feedback regulation on the immune system. High levels of pro-inflammatory cytokines result. Purpose: We sought to identify evidence supporting or refuting a link between glucocorticoid resistance and immune dysregulation in depression and to summarize retrieved evidence in aggregate form. Methods: We systematically reviewed and meta-analyzed studies that examined cytokine levels in depressed patients compared with controls and that also reported a measure of glucocorticoid resistance. These measures included plasma cortisol, the dexamethasone suppression test (DST), GR expression levels, and the results of in vitro assays of GR function. We conducted four separate meta-analyses to test for moderating effects of glucocorticoid resistance on cytokine production in depression. Results: After sub-grouping 32 studies by the ratio of cortisol levels in patients compared with controls, we observed a trend for increasing glucocorticoid resistance (i.e., the most hypercortisolemic patients) to be associated with increased production of interleukin (IL)-6 [ d = 0.94; 95% CI (0.29, 1.59)] and tumour necrosis factor (TNF)-α [ d = 0.46; 95% CI (0.12, 0.79)]. We stratified nine studies that reported DST results by relative glucocorticoid resistance between patients and controls, identifying a trend for higher glucocorticoid resistance in patients, compared with controls, to be associated with higher cytokine production in patients (170 patients and 187 controls). This was particularly evident when studies were sub-grouped by source of cytokine—plasma ( d = 1.04; 95% CI, 0.57–1.50) versus in vitro ( d = 0.24; 95% CI, −0.20 to 0.67). Stratifying the four studies (147 patients and 118 controls) that used in vitro assays of GR function or GR expression to quantify glucocorticoid resistance revealed variable contributions to cytokine production in patients compared with controls (overall effect size: d = 1.35; 95% CI 0.53–2.18). Combining our analyses of studies that reported DST results with those that used in vitro assays of GR function or GR expression to quantify glucocorticoid resistance (302 patients and 277 controls), we noted that although depressed patients produced more cytokines than controls ( d = 1.02; 95% CI, 0.55–1.49), there was no evident positive correlation between glucocorticoid resistance and inflammation. Conclusions: Our work provides some support for a model conceptualizing glucocorticoid resistance...

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Reply: ‘Clomipramine and Glucocorticoid Receptor Function’

Cited by 2 publications

References 14 publications

Antidepressants, but not antipsychotics, modulate GR function in human whole blood: An insight into molecular mechanisms

Antidepressants, but not antipsychotics, modulate GR function in human whole blood: An insight into molecular mechanisms

Glucocorticoid Resistance: Is It a Requisite for Increased Cytokine Production in Depression? A Systematic Review and Meta-Analysis

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