精神分裂症患者中 D-丝氨酸治疗后错配负波生成的改善：与症状的相关性。
Improvement in mismatch negativity generation during d-serine treatment in schizophrenia: Correlation with symptoms.
机构信息
Schizophrenia Research Center, Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, United States; Department of Psychiatry, Columbia University, 1051 Riverside Drive, New York, NY 10032, United States.
Schizophrenia Research Center, Nathan Kline Institute, 140 Old Orangeburg Road, Orangeburg, NY 10962, United States; Department of Psychiatry, Columbia University, 1051 Riverside Drive, New York, NY 10032, United States; Graduate Center, City University of New York, 365 5th Ave, New York, NY, United States.
出版信息
Schizophr Res. 2018 Jan;191:70-79. doi: 10.1016/j.schres.2017.02.027. Epub 2017 Mar 18.
BACKGROUND
Deficits in N-methyl-d-aspartate-type (NMDAR) function contribute to symptoms and cognitive dysfunction in schizophrenia. The efficacy of NMDAR agonists in the treatment of persistent symptoms of schizophrenia has been variable, potentially reflecting limitations in functional target engagement. We recently demonstrated significant improvement in auditory mismatch negativity (MMN) with once-weekly treatment with d-serine, a naturally occurring NMDAR glycine-site agonist. This study investigates effects of continuous (daily) NMDAR agonists in schizophrenia/schizoaffective disorder.
METHODS
Primary analysis was on MMN after double-blind crossover (60mg/kg/d, n=16, 6weeks) treatment with d-serine/placebo. Secondary measures included clinical symptoms, neurocognition, and the effects of open-label (30-120mg/kg/d, n=21) d-serine and bitopertin/placebo (10mg, n=29), a glycine transport inhibitor.
RESULTS
Double-blind d-serine treatment led to significant improvement in MMN frequency (p=0.001, d=2.3) generation and clinical symptoms (p=0.023, d=0.80). MMN frequency correlated significantly with change in symptoms (r=-0.63, p=0.002) following co-variation for treatment type. d-Serine treatment led to a significant, large effect size increase vs. placebo in evoked α-power in response to standards (p=0.036, d=0.81), appearing to normalize evoked α power relative to previous findings with controls. While similar results were seen with open-label d-serine, no significant effects of bitopertin were observed for symptoms or MMN.
CONCLUSIONS
These findings represent the first randomized double-blind placebo-controlled study with 60mg/kg d-serine in schizophrenia, and are consistent with meta-analyses showing significant effects of d-serine in schizophrenia. Results overall support suggest that MMN may have negative, as well as positive, predictive value in predicting efficacy of novel compounds.
CLINICAL TRIALS REGISTRATION
Clinicaltrials.gov: NCT00322023/NCT00817336 (d-serine); NCT01116830 (bitopertin).
背景
N-甲基-D-天冬氨酸型（NMDAR）功能缺陷导致精神分裂症的症状和认知功能障碍。NMDAR 激动剂治疗精神分裂症持续性症状的疗效各不相同，这可能反映了功能靶点结合的局限性。我们最近的研究表明，每周一次使用天然存在的 NMDAR 甘氨酸位点激动剂 D-丝氨酸治疗可显著改善听觉失匹配负波（MMN）。本研究探讨了连续（每日）NMDAR 激动剂在精神分裂症/分裂情感障碍中的作用。
方法
主要分析是在双盲交叉（60mg/kg/d，n=16，6 周）D-丝氨酸/安慰剂治疗后 MMN。次要指标包括临床症状、神经认知以及开放标签（30-120mg/kg/d，n=21）D-丝氨酸和双氢苯并噻嗪/安慰剂（10mg，n=29）的作用，一种甘氨酸转运抑制剂。
结果
双盲 D-丝氨酸治疗导致 MMN 频率显著改善（p=0.001，d=2.3）和临床症状改善（p=0.023，d=0.80）。MMN 频率与治疗类型的变化显著相关（r=-0.63，p=0.002）。与安慰剂相比，D-丝氨酸治疗显著增加了标准刺激诱发的 α 功率的大效应量（p=0.036，d=0.81），与对照组的先前发现相比，似乎使诱发的 α 功率正常化。虽然开放标签 D-丝氨酸也有类似的结果，但双氢苯并噻嗪对症状或 MMN 没有显著影响。
结论
这些发现代表了首次在精神分裂症患者中进行的随机双盲安慰剂对照研究，与荟萃分析显示 D-丝氨酸在精神分裂症中具有显著疗效一致。总的来说，结果支持 MMN 可能具有负面和正面的预测价值，预测新型化合物的疗效。
临床试验注册
Clinicaltrials.gov：NCT00322023/NCT00817336（D-丝氨酸）；NCT01116830（双氢苯并噻嗪）。
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