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.
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DOI：
10.1016/j.euroneuro.2010.02.006
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发表时间：
2010-06
影响因子：
5.6
通讯作者：
Pariante, C. M.
中科院分区：
文献类型：
--
作者：
Carvalho, L. A.;Garner, B. A.;Dew, T.;Fazakerley, H.;Pariante, C. M.
关键词：
临床研究表明，重度抑郁症(GR抵抗)患者存在糖皮质激素受体(GR)介导的下丘脑-垂体-肾上腺(HPA)轴负反馈功能障碍，并通过抗抑郁治疗缓解。最近，我们发现这种损害确实是由于抑郁症患者的GR功能障碍造成的，并且在临床上对治疗有抵抗力的重度抑郁症患者中，抗抑郁剂氯丙咪嗪降低外周血细胞GR功能的能力受到损害。为了进一步研究抗抑郁药对人类GR功能的影响，我们比较了抗抑郁药氯米帕明、阿米替林、舍曲林、帕罗西汀和文拉法辛以及抗精神病药物氟哌啶醇和利培酮对33名健康志愿者外周血细胞GR功能的影响。糖皮质激素抑制脂多糖(LPS)刺激的白介素6(IL-6)水平以检测GR功能。与赋形剂处理的细胞相比，所有抗抑郁剂均可抑制地塞米松对脂多糖刺激的IL-6水平的抑制(p值在0.007~0.1nM之间)。这种作用是抗抑郁药物所特有的，因为抗精神病药物对脂多糖刺激的IL-6水平的地塞米松抑制没有影响。磷酸二酯酶(PDE)4型抑制剂罗利普兰增强抗抑郁药对GR功能的影响，而GR拮抗剂RU-486则抑制抗抑郁药对GR功能的影响。这些结果表明，抗抑郁药对GR功能的影响是这类精神药物所特有的，并涉及与GR功能和炎症相关的第二信使通路。此外，它还指出了一种可能的机制，通过这种机制，人们可能能够克服难治性抑郁症。这一领域的研究将导致对情感障碍的病理生理学和治疗的新见解。
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, 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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