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

被引:39
作者
Carvalho, L. A. [1 ]
Garner, B. A. [2 ]
Dew, T. [3 ]
Fazakerley, H.
Pariante, C. M.
机构
[1] Kings Coll London, Inst Psychiat, Ctr Cellular Basis Behav,James Black Ctr, Sect Perinatal Psychiat & Stress,Psychiat & Immun, London SE5 9NU, England
[2] Univ Melbourne, Royal Melbourne Hosp, Dept Psychiat, Melbourne Neuropsychiat Ctr, Melbourne, Vic 3050, Australia
[3] Kings Coll London, Biochem Lab, London SE5 9NU, England
基金
英国医学研究理事会;
关键词
Hypothalamic-pituitary-adrenal axis; Mood disorders; cAMP; Corticosteroids; Corticosteroid sensitivity; Protein-kinase A; Schizophrenia; Neuroinflammation; TNF; GLUCOCORTICOID-RECEPTOR FUNCTION; MEDIATED GENE-TRANSCRIPTION; FUNCTION IN-VITRO; MEMBRANE STEROID TRANSPORTERS; MAJOR DEPRESSIVE DISORDER; PITUITARY-ADRENAL AXIS; C6; GLIOMA-CELLS; PROTEIN-KINASE; CYTOKINE PRODUCTION; ADENYLYL-CYCLASE;
D O I
10.1016/j.euroneuro.2010.02.006
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
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, 10-100 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. (C) 2010 Elsevier B.V. and ECNP. All rights reserved.
引用
收藏
页码:379 / 387
页数:9
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