Improvement in mismatch negativity generation during D-serine treatment in schizophrenia: Correlation with symptoms
Improvement in mismatch negativity generation during D-serine treatment in schizophrenia: Correlation with symptoms
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DOI：
10.1016/j.schres.2017.02.027
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发表时间：
2018-01-01
影响因子：
4.5
通讯作者：
Javitt, Daniel C.
中科院分区：
文献类型：
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作者：
Kantrowitz, Joshua T.;Epstein, Michael L.;Javitt, Daniel C.
背景：N-甲基-D-天冬氨酸型（NMDAR）功能缺陷会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症状的疗效各不相同，可能反映了功能靶点参与的局限性。我们最近证明，每周一次使用 D-丝氨酸（一种天然存在的 NMDAR 甘氨酸位点激动剂）治疗可显着改善听觉失配负性 (MMN)。本研究探讨连续（每日）NMDAR 激动剂对精神分裂症/分裂情感性障碍的影响。方法：主要分析是用 D-丝氨酸/安慰剂进行双盲交叉（60 mg/kg/d，n = 16，6 周）治疗后的 MMN。次要指标包括临床症状、神经认知以及开放标签（30-120 mg/kg/d，n = 21）D-丝氨酸和比妥汀/安慰剂（10 mg，n = 29）（一种甘氨酸转运抑制剂）的效果。结果：双盲 D-丝氨酸治疗显着改善了 MMN 频率（p = 0.001，d = 2.3）的产生和临床症状（p = 0.023，d = 0.80）。 MMN 频率与治疗类型共变后症状的变化显着相关（r = -0.63，p = 0.002）。与安慰剂相比，D-丝氨酸治疗导致诱发 a 力响应标准显着、大幅增加（p = 0.036，d = 0.81），相对于之前的对照结果，似乎使诱发力正常化。虽然开放标签的 D-丝氨酸也得到了类似的结果，但没有观察到比特哌丁对症状或 MMN 的显着影响。结论：这些发现代表了第一个使用 60 mg/kg D-丝氨酸治疗精神分裂症的随机双盲安慰剂对照研究，并且与显示 D-丝氨酸对精神分裂症显着影响的荟萃分析一致。结果总体支持表明 MMN 在预测新化合物的功效方面可能具有阴性和阳性预测价值。 (c) 2017 Elsevier B.V. 保留所有权利。
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 (60 mg/kg/d, n = 16, 6 weeks) treatment with D-serine/placebo. Secondary measures included clinical symptoms, neurocognition, and the effects of open-label (30-120 mg/kg/d, n = 21) D-serine and bitopertin/placebo (10 mg, 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 a-power in response to standards (p = 0.036, d = 0.81), appearing to normalize evoked a 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 60 mg/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. (c) 2017 Elsevier B.V. All rights reserved.