SSRI-INDUCED CHANGES IN CORTICAL GABA IN WOMEN WITH PMDD

SSRI 引起经前抑郁症女性皮质 GABA 的变化

• 批准号: 7156938
• 负责人: C. Neill NEILL EPPERSON
• 金额: $ 26.72万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-22 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7156938
• 关键词: 20-alpha-Dihydroprogesterone; Agonist; Allopregnanolone; Amino Acid Neurotransmitters; Animals; Brain; Budgets; Clinical; Data; Diagnosis; Disease; Exhibits; Exposure to; Fluoxetine; Functional disorder; Funding; Glutamates; Glutamine; Goals; Investigation; Luteal Phase; Magnetic Resonance Spectroscopy; Measurement; Measures; Mediator of activation protein; Menstrual cycle; Mentored Clinical Oncology Award; Mentored Clinical Scientist Award; Mentored Patient-Oriented Research Career Development Award; Metabolic Pathway; Occipital lobe; Pathogenesis; Pattern; Phase; Placebos; Plasma; Production; Progesterone; Protons; Publishing; Regulation; Research Personnel; Role; Scanning; Selective Serotonin Reuptake Inhibitor; Serotonin; Spectrum Analysis; Steroids; System; Therapeutic; Woman; Women' s Group; base; clinical efficacy; data acquisition; experience; functional disability; gamma-Aminobutyric Acid; human study; pre-clinical; premenstrual dysphoric disorder; programs; proliferative phase Menstrual cycle; receptor; response; reuptake

DESCRIPTION (provided by applicant): Premenstrual dysphoric disorder (PMDD), a distinct disorder that effects at least 3% of menstruating women, is associated with significant functional impairment. That PMDD is preferentially responsive to selective serotonin reuptake inhibitor (SSRI) treatment provides strong evidence that serotonergic dysfunction is involved in the pathophysiology, as well as, treatment of PMDD. However, there are substantial clinical and preclinical data to implicate the gamma-aminobutyric acid (GABA) system as a mediator of the clinical efficacy of SSRIs in this disorder. Using proton magnetic resonance spectroscopy (IH-MRS), our group has found that women with PMDD have abnormal central GABAergic regulation in response to menstrual cycle-related fluctuations in neuroactive steroids. Cortical GABA concentrations fluctuate across the menstrual cycle in a diagnosis- and phase-specific fashion with the greatest disparity in cortical GABA levels during the follicular phase, when women with PMDD had significantly lower cortical GABA levels than healthy menstruating controls. Presently, it is unclear whether inhibition of serotonin reuptake or alternatively SSRI modulation of GABAergic function is crucial in the therapeutic action of SSRIs in the treatment of PMDD. In support of the latter, animal and human studies have shown that SSRI administration enhances central production of the potent GABAA receptor agonist, allopregnanolone (ALLO). At baseline, women with PMDD fail to demonstrate a normal GABAergic response to endogenous or exogenous exposure to ALLO. Further, we have found that successful SSRI treatment is associated with an increase in occipital cortical GABA levels during the follicular phase in women with PMDD, essentially "righting" the abnormal cyclic changes in GABA seen in these women prior to treatment. Therefore, the overarching goal of this proposal is two-fold; to confirm these early 1H-MRS findings in a group of women undergoing fluoxetine treatment for PMDD and to determine the impact of fluoxetine treatment on the relationship between occipital cortex GABA levels and plasma ALLO levels across the menstrual cycle. We anticipate that our findings will provide further support for the role of GABA and neurosteroids in the pathogenesis and treatment of PMDD.

描述（由申请人提供）：经前烦躁不安（PMDD），一种独特的疾病，至少影响3％的月经妇女，与重大功能障碍有关。 PMDD优先响应选择性5-羟色胺再摄取抑制剂（SSRI）治疗提供了有力的证据，表明5-羟色胺能功能障碍参与了病理生理学以及PMDD的治疗。然而，有大量的临床和临床前数据暗示伽马氨基丁酸（GABA）系统是SSRI在该疾病中临床疗效的介体。使用质子磁共振光谱（IH-MRS），我们的小组发现，患有PMDD的女性对神经活性类固醇的月经周期相关的波动有异常的中央GABA能调节。皮质GABA浓度以诊断和相位特异性的方式在整个月经周期中波动，而在卵泡阶段，皮质GABA水平的差异最大，而PMDD的女性皮质GABA水平明显低于健康的月经对照组。目前，尚不清楚抑制5-羟色胺再摄取或SSRI对GABA能功能的调节是否对于SSRI在PMDD治疗中的治疗作用至关重要。为了支持后者，动物和人类研究表明，SSRI给药增强了有效的GABAA受体激动剂Allopregnanolone（Allo）的中心产生。在基线时，患有PMDD的女性未能证明对内源性或外源性暴露于Allo的正常GABA能反应。此外，我们发现成功的SSRI治疗与PM​​DD女性在卵泡相期间枕叶皮质GABA水平的增加有关，本质上是“纠正”这些女性在治疗前在这些女性中看到的GABA异常的循环变化。因此，该提议的总体目标是两倍。为了确认一组接受氟西汀治疗PMDD的妇女中的这些早期1H-MRS的发现，并确定氟西汀治疗对枕骨皮层GABA水平与血浆Allo水平之间的关系的影响。我们预计我们的发现将为GABA和神经素在PMDD的发病机理和治疗中的作用提供进一步的支持。

项目成果

Advances in the translational neuroscience of neurosteroids.

神经类固醇转化神经科学的进展。

• DOI: 10.1007/s00213-006-0310-x
• 发表时间: 2006
• 期刊: Psychopharmacology
• 影响因子: 3.4
• 作者: Epperson,CNeill;deWit,Harriet;Krystal,JohnH
• 通讯作者: Krystal,JohnH

Towards a consensus on diagnostic criteria, measurement and trial design of the premenstrual disorders: the ISPMD Montreal consensus.

• DOI: 10.1007/s00737-010-0201-3
• 发表时间: 2011-02
• 期刊: ARCHIVES OF WOMENS MENTAL HEALTH
• 影响因子: 4.5
• 作者: O'Brien, Patrick Michael Shaughn;Backstrom, Torbjorn;Brown, Candace;Dennerstein, Lorraine;Endicott, Jean;Epperson, C. Neill;Eriksson, Elias;Freeman, Ellen;Halbreich, Uriel;Ismail, Khaled M. K.;Panay, Nicholas;Pearlstein, Teri;Rapkin, Andrea;Reid, Robert;Schmidt, Peter;Steiner, Meir;Studd, John;Yonkers, Kimberley
• 通讯作者: Yonkers, Kimberley

Effect of estrogen-serotonin interactions on mood and cognition.

• DOI: 10.1177/1534582305277152
• 发表时间: 2005-03-01
• 期刊: Behavioral and cognitive neuroscience reviews
• 作者: Amin, Zenab;Canli, Turhan;Epperson, C Neill
• 通讯作者: Epperson, C Neill