Department of Psychiatry, Indiana University School of Medicine, James Whitcomb Riley Hospital for Children, Indianapolis, IN 46202, USA.
Brain Res. 2011 Mar 22;1380:264-70. doi: 10.1016/j.brainres.2010.10.108. Epub 2010 Nov 5.
Glutamatergic dysregulation is implicated in the pathophysiology of fragile X syndrome (FXS). Riluzole is hypothesized to have an inhibitory effect on glutamate release, block excitotoxic effects of glutamate, and potentiate postsynaptic GABA(A) receptor function. Extracellular signal-related kinase (ERK) activation is known to be delayed in humans with FXS and knockout animal models of FXS. Correction of delayed ERK activation is a potential biomarker of treatment response in FXS. We conducted a six-week open-label prospective pilot study of riluzole (100 mg/day) in six adults with FXS.
Riluzole was started at 50mg every evening and then increased to 50mg twice daily at week 2. The dose was kept constant for the final 4 weeks of the trial. Clinical response was determined by a score of 1 "very much improved" or 2 "much improved" on the Clinical Global Impressions Improvement (CGI-I) scale and a≥25% improvement on the Children's Yale-Brown Obsessive Compulsive Scale modified for Pervasive Developmental Disorders. The primary target of treatment in this study was repetitive, compulsive behavior that commonly occurs in persons with FXS. The study incorporated an ERK activation biomarker assay. Potential adverse effects were assessed in a systematic manner at all clinic visits and by phone between visits.
Riluzole treatment was associated with clinical response in 1 of 6 subjects (17%). Among a number of secondary outcome measures employed, significant improvement was only noted on the ADHD Rating Scale-IV (became non-significant when corrected for multiple comparisons). Riluzole use was associated with significant correction in ERK activation time in all subjects (mean change from 3.82±0.27 (baseline) to 2.99±0.26 (endpoint) minutes; p=0.007). Riluzole was well tolerated; mean increases in liver function tests occurred but drug discontinuation was not required.
Overall, riluzole use was not associated with significant clinical improvement despite uniform correction of peripheral ERK activation. Future directions of study include testing of riluzole in animal models of FXS and assessment of psychotropic monotherapy on ERK activation.
谷氨酸能失调与脆性 X 综合征（FXS）的病理生理学有关。利鲁唑被假设具有抑制谷氨酸释放、阻断谷氨酸的兴奋毒性作用以及增强突触后 GABA(A)受体功能的作用。已知 FXS 患者和 FXS 敲除动物模型的细胞外信号调节激酶（ERK）激活延迟。ERK 激活的纠正可能是 FXS 治疗反应的潜在生物标志物。我们对 6 名 FXS 成人进行了为期 6 周的利鲁唑（100mg/天）开放性前瞻性试验。
利鲁唑每晚 50mg 起始，第 2 周增加至 50mg 每日 2 次。试验的最后 4 周维持剂量不变。临床反应通过临床总体印象改善量表（CGI-I）评分 1“非常改善”或 2“明显改善”和广泛性发育障碍改良耶鲁-布朗强迫量表（Y-BOCS）≥25%的改善来确定。本研究的主要治疗目标是 FXS 患者常见的重复、强迫行为。该研究纳入了 ERK 激活生物标志物检测。在所有就诊时和就诊间通过电话以系统方式评估潜在的不良反应。
利鲁唑治疗与 6 名受试者中的 1 名（17%）的临床反应相关。在使用的多项次要终点测量中，仅在 ADHD 评定量表-IV 上观察到显著改善（在进行多次比较校正后变得不显著）。利鲁唑的使用与所有受试者的 ERK 激活时间的显著校正相关（从 3.82±0.27（基线）到 2.99±0.26（终点）分钟的平均变化；p=0.007）。利鲁唑耐受良好；肝功能检查的平均升高，但无需停药。
总体而言，尽管外周 ERK 激活得到一致纠正，但利鲁唑的使用与显著的临床改善无关。未来的研究方向包括在 FXS 动物模型中测试利鲁唑和评估精神药物单药治疗对 ERK 激活的影响。
