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

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 . 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.

Effects of anti-inflammatory drugs on the expression of tryptophan-metabolism genes by human macrophages

“…This is in contrast to reports that TCAs reduce proinflammatory signaling in phagocytes,68 and SSRIs have been reported to alter macrophage differentiation and inflammatory signaling 67, 69. SSRIs have also been reported to modulate glucocorticoid actions on monocytes 70. Although we found no direct effect of SSRIs or TCAs on macrophage responses to either LPS or IFNα, we did observe significant cytotoxicity at concentrations that were <20‐fold lower than circulating blood concentrations in treated patients.…”

Bidirectional Prospective Associations of Metabolic Syndrome Components With Depression, Anxiety, and Antidepressant Use

“…This was particularly true for use of antidepressants, which compared with depressive and anxiety symptoms, negatively influenced a range of metabolic syndrome components after 2‐years. Antidepressants have pleiotropic effects across biological systems, including effects on autonomic nervous system, immune and inflammatory processes, oxidation, and cellular aging 53, 54, 55. These systems are all associated with negative consequences for cardiometabolic health and the development and maintenance cardiometabolic diseases 56, 57, 58.…”

Effects of psychotropic drugs on inflammation: consequence or mediator of therapeutic effects in psychiatric treatment?

“…Using such a strategy allows for comparison with the several meta-analyses already published on the effects of such agents on peripheral cytokine levels in vivo. We identified 17 eligible studies using antidepressants (Table 1; Xia et al 1996;Maes et al 1999;Lin et al 2000;Kubera et al 2001;Kubera et al 2002;Rudolf et al 2002;Szuster-Ciesielska et al 2003;Kubera et al 2004;Maes et al 2005;Diamond et al 2006;Carvalho et al 2008;Carvalho et al 2010;Himmerich et al 2010;Krause et al 2012;Munzer et al 2013;Tsai et al 2014;Waiskopf et al 2014) and 12 eligible studies employing antipsychotics (Table 2; Bleeker et al 1997;Leykin et al 1997;Hinze-Selch et al 1998;Moots et al 1999;Song et al 2000;Rudolf et al 2002;SzusterCiesielska et al 2004;Carvalho et al 2010;Chen et al 2011;Himmerich et al 2011;Chen et al 2013b;Krause et al 2013). …”