Cognitive impairment associated with schizophrenia (CIAS) and related deficits in learning (plasticity) are among the leading causes of disability in schizophrenia. Despite this, there are no Food and Drug Administration–approved treatments for CIAS, and the development of treatments has been limited by numerous phase 2/3 failures of compounds that showed initial promise in small-scale studies. NMDA-type glutamate receptors (NMDARs) have been proposed to play an important role in schizophrenia; moreover, the NMDAR has a well-characterized role in cognition, learning, and neuroplasticity. We review previously published clinical trials in CIAS that focused on NMDAR modulator treatments, focusing on published and recent developments of the use of novel NMDAR-modulating treatments for CIAS both alone and combined with plasticity/learning paradigms to enhance learning. We use this discussion of previous studies to highlight the importance of incorporating pharmacodynamic target engagement biomarkers early in treatment development, which can help predict which compounds will succeed or fail in phase 3. A range of direct and indirect NMDAR modulators are covered, including D-serine, D-cycloserine, memantine, and glycine and first-generation glycine transport inhibitors (e.g., sarcosine and bitopertin), as well as recent positive studies of iclepertin, a novel glycine transport inhibitor, and luvadaxistat, a D-amino acid oxidase inhibitor that increases brain D-serine levels, and indirect noninvasive brain stimulation NMDAR-modulating treatments. Several examples of successful use of pharmacodynamic target engagement biomarkers for dose/drug discovery are emphasized, including the mismatch negativity, auditory steady state, and time-frequency event-related potential approaches.

中文翻译：

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寻找合适的剂量：NMDA 受体调节治疗精神分裂症的认知和可塑性缺陷以及药效学靶点参与的作用


与精神分裂症相关的认知障碍 （CIAS） 和相关的学习缺陷（可塑性）是精神分裂症残疾的主要原因之一。尽管如此，还没有美国食品和药物管理局批准的 CIAS 治疗方法，并且治疗方法的开发受到化合物的大量 2/3 期失败的限制，这些化合物在小规模研究中显示出初步的希望。NMDA 型谷氨酸受体 （NMDARs） 被认为在精神分裂症中起重要作用;此外，NMDAR 在认知、学习和神经可塑性方面具有明确的作用。我们回顾了以前在 CIAS 中发表的专注于 NMDAR 调节剂治疗的临床试验，重点关注已发表的和最近的 CIAS 使用新型 NMDAR 调节治疗，无论是单独使用还是与可塑性/学习范式相结合以增强学习。我们利用对先前研究的讨论来强调在治疗开发早期纳入药效学靶点参与生物标志物的重要性，这有助于预测哪些化合物将在第 3 阶段成功或失败。涵盖了一系列直接和间接 NMDAR 调节剂，包括 D-丝氨酸、D-环丝氨酸、美金刚和甘氨酸以及第一代甘氨酸转运抑制剂（例如肌氨酸和比特操作素），以及最近对 iclepertin（一种新型甘氨酸转运抑制剂）和 luvadaxistat（一种增加脑 D-丝氨酸水平的 D-氨基酸氧化酶抑制剂）的积极研究，以及间接无创脑刺激 NMDAR 调节治疗。强调了成功使用药效学靶点参与生物标志物进行剂量/药物发现的几个例子，包括错配负性、听觉稳态和时频事件相关的潜在方法。