Relevance of endogenous 3α-reduced neurosteroids to depression and antidepressant action-猫眼课题宝

内源性 3α-还原神经类固醇与抑郁症和抗抑郁作用的相关性

DOI：

10.1007/s00213-005-0201-6

发表时间：

2006

期刊：

Psychopharmacology

影响因子：

3.4

通讯作者：

中科院分区：

医学3区

文献类型：

作者：

V. Uzunova;L. Sampson;D. Uzunov

天然存在的3α-还原型神经甾体别孕烯醇酮及其异构体孕烯醇酮是γ-氨基丁酸A型受体的最有效的正变构调节剂之一。它们在维持生理性GABA能紧张性方面发挥关键作用，并显示出广泛的神经精神药理学特性。我们回顾了内源性3α还原型神经活性类固醇与抑郁症及抗抑郁药作用机制相关性的现有证据。近年来，出现了广泛的临床前和临床证据，表明3α-减少的神经活性类固醇具有抗抑郁潜力，并且神经活性类固醇水平的缺乏和不平衡可能参与了重度抑郁症病因的病理机制。抗抑郁药可升高啮齿动物脑中3α还原型神经类固醇水平，临床有效的抗抑郁药物治疗与抑郁患者血浆和脑脊液（CSF）内源性神经活性类固醇浓度正常化相关，揭示了神经活性类固醇对抗抑郁药作用机制的可能贡献。相反，最近使用非药物抗抑郁治疗的研究表明，血浆神经活性类固醇水平的变化可能不是临床有效的抗抑郁治疗本身的一般强制性组成部分，但可能仅反映药物治疗的独特性质。虽然临床前研究提供了令人信服的证据，支持3α-还原型神经活性类固醇在啮齿动物抑郁症模型中具有抗抑郁样作用，但目前的临床研究尚未确定神经活性类固醇缺乏症是否参与抑郁症的病理生理学。此外，临床证据仅提示神经活性类固醇在临床有效的抗抑郁治疗的作用机制中的作用。为了更准确地说明3α还原型神经活性类固醇与重度抑郁症的相关性，有必要进行额外的临床研究，评价成功的药理学和非药理学抗抑郁治疗对同一患者血浆和CSF样本中神经活性类固醇水平变化的影响。最后，使用已知选择性提高脑神经类固醇水平的药物进行的概念验证研究可能会直接评估神经类固醇在治疗抑郁症中的作用。

The naturally occurring 3α-reduced neurosteroids allopregnanolone and its isomer pregnanolone are among the most potent positive allosteric modulators of γ-aminobutyric acid type A receptors. They play a critical role in the maintenance of physiological GABAergic tone and display a broad spectrum of neuropsychopharmacological properties. We have reviewed existing evidence implicating the relevance of endogenous 3α-reduced neuroactive steroids to depression and to the mechanism of action of antidepressants. A wide range of preclinical and clinical evidence suggesting the antidepressant potential of 3α-reduced neuroactive steroids and a possible involvement of a deficiency and a disequilibrium of neuroactive steroid levels in pathomechanisms underlying the etiology of major depressive disorder have emerged in recent years. Antidepressants elevate 3α-reduced neurosteroid levels in rodent brain, and clinically effective antidepressant pharmacotherapy is associated with normalization of plasma and cerebrospinal fluid (CSF) concentrations of endogenous neuroactive steroids in depressed patients, unveiling a possible contribution of neuroactive steroids to the mechanism of action of antidepressants. In contrast, recent studies using nonpharmacological antidepressant therapy suggest that changes in plasma neuroactive steroid levels may not be a general mandatory component of clinically effective antidepressant treatment per se, but may reflect distinct properties of pharmacotherapy only. While preclinical studies offer convincing evidence in support of an antidepressant-like effect of 3α-reduced neuroactive steroids in rodent models of depression, current clinical investigations are inconclusive of an involvement of neuroactive steroid deficiency in the pathophysiology of depression. Moreover, clinical evidence is merely suggestive of a role of neuroactive steroids in the mechanism of action of clinically effective antidepressant therapy. Additional clinical studies evaluating the impact of successful pharmacological and nonpharmacological antidepressant therapies on changes in neuroactive steroid levels in both plasma and CSF samples of the same patients are necessary in order to more accurately address the relevance of 3α-reduced neuroactive steroids to major depressive disorder. Finally, proof-of-concept studies with drugs that are known to selectively elevate brain neurosteroid levels may offer a direct assessment of an involvement of neurosteroids in the treatment of depressive symptomatology.