Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine.
Increase in the cerebrospinal fluid content of neurosteroids in patients with unipolar major depression who are receiving fluoxetine or fluvoxamine.
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DOI：
10.1073/pnas.95.6.3239
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发表时间：
1998-03
影响因子：
11.1
通讯作者：
V. Uzunova;Y. Sheline;John M Davis;A. Rasmusson;D. Uzunov;E. Costa;A. Guidotti
中科院分区：
文献类型：
--
作者：
V. Uzunova;Y. Sheline;John M Davis;A. Rasmusson;D. Uzunov;E. Costa;A. Guidotti
我们最近报道，氟西汀或帕罗西汀，两种选择性5-羟色胺再摄取抑制剂（SSRIs），当给予大鼠时，增加神经类固醇3 α-羟基-5 α-胆甾烷-20-酮（3 α 5 α-ALLO）的脑含量，而不改变其他神经类固醇的脑含量。ALLO（3 α 5 α和3 α 5 β异构体）以高亲和力结合各种γ-氨基丁酸（GABA）受体A亚型，并促进GABA对这些受体的作用。我们假设SSRIs治疗诱导的ALLO脑含量增加可能有助于缓解与重度单相抑郁症相关的焦虑和烦躁。我们测定了15例单相抑郁症患者在接受氟西汀或氟伏沙明治疗前和治疗后8-10周的4个脑池-腰段脑脊液（CSF）中的ALLO含量。在重度单相抑郁症患者中，ALLO的浓度（三名对照受试者的每个CSF部分中约为40 fmol/ml）约低60%。然而，在相同的患者中，氟西汀或氟伏沙明治疗使CSF ALLO含量正常化。此外，氟西汀或氟伏沙明治疗后，抑郁症改善（汉密尔顿抑郁量表评分）与CSF ALLO增加之间存在统计学显著相关性（r = 0.58; P < 0.023; n = 15）。CSF中PREG和PROG的含量在治疗后保持不变，并且与SSRI诱导的CSF ALLO增加无关。抑郁症患者CSF ALLO含量的正常化似乎足以通过GABA A型受体的正变构调节介导氟西汀或氟伏沙明的抗焦虑和抗焦虑作用。
We recently reported that fluoxetine or paroxetine, two selective serotonin reuptake inhibitors (SSRIs), when administered to rats, increase the brain content of the neurosteroid 3alpha-hydroxy-5alpha-pregnane-20-one (3alpha5alpha-ALLO) without altering the brain content of other neurosteroids. ALLO (3alpha5alpha and 3alpha5beta isomers) binds with high affinity to various gamma-aminobutyric acid (GABA) receptor A subtypes and facilitates the action of GABA at these receptors. We hypothesized that the increase of ALLO brain content induced by treatment with SSRIs could contribute to alleviating the anxiety and dysphoria associated with the symptomatology of major unipolar depression. We measured ALLO content in four cisternal-lumbar fractions of cerebrospinal fluid (CSF) before and 8-10 weeks after treatment with fluoxetine or fluvoxamine in 15 patients with unipolar major depression. The concentration of ALLO ( approximately 40 fmol/ml in each CSF fraction of three control subjects) was about 60% lower in patients with major unipolar depression. However, in the same patients, fluoxetine or fluvoxamine treatment normalized the CSF ALLO content. Moreover, a statistically significant correlation (r = 0.58; P < 0.023; n = 15) existed between symptomatology improvement (Hamilton Rating Scale for Depression scores) and the increase in CSF ALLO after fluoxetine or fluvoxamine treatment. The CSF content of PREG and PROG remained unaltered after treatment and failed to correlate with the SSRI-induced increase of CSF ALLO. The normalization of CSF ALLO content in depressed patients appears to be sufficient to mediate the anxiolytic and antidysphoric actions of fluoxetine or fluvoxamine via its positive allosteric modulation of GABA type A receptors.