Pei Ju-Chun, Luo Da-Zhong, Gau Shiang-Shin, Chang Chia-Yuan, Lai Wen-Sung
Department of Psychology, National Taiwan University, Taipei, Taiwan.
Neurobiology and Cognitive Science Center, National Taiwan University, Taipei, Taiwan.
Front Psychiatry. 2021 Oct 1;12:742058. doi: 10.3389/fpsyt.2021.742058. eCollection 2021.
Schizophrenia is a severe mental illness that affects ~1% of the world's population. It is clinically characterized by positive, negative, and cognitive symptoms. Currently available antipsychotic medications are relatively ineffective in improving negative and cognitive deficits, which are related to a patient's functional outcomes and quality of life. Negative symptoms and cognitive deficits are unmet by the antipsychotic medications developed to date. In recent decades, compelling animal and clinical studies have supported the NMDA receptor (NMDAR) hypofunction hypothesis of schizophrenia and have suggested some promising therapeutic agents. Notably, several NMDAR-enhancing agents, especially those that function through the glycine modulatory site (GMS) of NMDAR, cause significant reduction in psychotic and cognitive symptoms in patients with schizophrenia. Given that the NMDAR-mediated signaling pathway has been implicated in cognitive/social functions and that GMS is a potential therapeutic target for enhancing the activation of NMDARs, there is great interest in investigating the effects of direct and indirect GMS modulators and their therapeutic potential. In this review, we focus on describing preclinical and clinical studies of direct and indirect GMS modulators in the treatment of schizophrenia, including glycine, D-cycloserine, D-serine, glycine transporter 1 (GlyT1) inhibitors, and D-amino acid oxidase (DAO or DAAO) inhibitors. We highlight some of the most promising recently developed pharmacological compounds designed to either directly or indirectly target GMS and thus augment NMDAR function to treat the cognitive and negative symptoms of schizophrenia. Overall, the current findings suggest that indirectly targeting of GMS appears to be more beneficial and leads to less adverse effects than direct targeting of GMS to modulate NMDAR functions. Indirect GMS modulators, especially GlyT1 inhibitors and DAO inhibitors, open new avenues for the treatment of unmet medical needs for patients with schizophrenia.
精神分裂症是一种严重的精神疾病，影响着全球约1%的人口。其临床特征为阳性、阴性和认知症状。目前可用的抗精神病药物在改善阴性和认知缺陷方面相对无效，而这些缺陷与患者的功能预后和生活质量相关。迄今为止开发的抗精神病药物未能解决阴性症状和认知缺陷问题。近几十年来，令人信服的动物和临床研究支持了精神分裂症的N-甲基-D-天冬氨酸受体（NMDAR）功能低下假说，并提出了一些有前景的治疗药物。值得注意的是，几种增强NMDAR的药物，尤其是那些通过NMDAR的甘氨酸调节位点（GMS）发挥作用的药物，可使精神分裂症患者的精神病性和认知症状显著减轻。鉴于NMDAR介导的信号通路与认知/社会功能有关，且GMS是增强NMDAR激活的潜在治疗靶点，人们对研究直接和间接GMS调节剂的作用及其治疗潜力非常感兴趣。在本综述中，我们重点描述直接和间接GMS调节剂治疗精神分裂症的临床前和临床研究，包括甘氨酸、D-环丝氨酸、D-丝氨酸、甘氨酸转运体1（GlyT1）抑制剂和D-氨基酸氧化酶（DAO或DAAO）抑制剂。我们重点介绍了一些最近开发的最有前景的药理化合物，这些化合物旨在直接或间接靶向GMS，从而增强NMDAR功能以治疗精神分裂症的认知和阴性症状。总体而言，目前的研究结果表明，间接靶向GMS似乎比直接靶向GMS调节NMDAR功能更有益，且副作用更少。间接GMS调节剂，尤其是GlyT1抑制剂和DAO抑制剂，为满足精神分裂症患者未满足的医疗需求开辟了新途径。
