Fadgyas-Stanculete Mihaela, Capatina Octavia Oana
Department of Neurosciences, Discipline of Psychiatry and Pediatric Psychiatry, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400394 Cluj-Napoca, Romania.
Int J Mol Sci. 2025 May 2;26(9):4331. doi: 10.3390/ijms26094331.
Schizophrenia is a complex neuropsychiatric disorder composed of primary cluster-positive symptoms, negative symptoms, disorganization, neurocognitive deficits, and social cognitive impairments. While traditional antipsychotics primarily target dopamine pathways, they provide limited efficacy against cognitive deficits and negative symptoms. Growing evidence implicates glutamatergic dysregulation, particularly N-methyl-D-aspartate receptor (NMDA-R) hypofunction, in the pathophysiology of schizophrenia, making glutamate modulation a promising therapeutic approach. This review explores emerging glutamate-based treatment strategies, including NMDA receptor modulators, metabotropic glutamate receptor (mGluR) agents, glutamate transporter regulators, and kynurenine pathway inhibitors. We summarize preclinical and clinical findings on NMDA co-agonists (D-serine and glycine), glycine transporter inhibitors, D-amino acid oxidase inhibitors, and mGluR-targeted therapies, highlighting their mechanisms, efficacy, and limitations. In addition, we discuss novel interventions aimed at restoring glutamate homeostasis, including neuroinflammatory modulation and synaptic plasticity enhancers. Despite promising results, many glutamate-targeting therapies have yielded inconsistent clinical outcomes, underscoring the need for biomarker-driven patient selection and optimized treatment protocols. We propose that integrating glutamate modulators with existing antipsychotic regimens may enhance therapeutic response while minimizing side effects. Future research should focus on refining glutamate-based interventions, identifying predictive biomarkers, and addressing the heterogeneity in schizophrenia pathology. With continued advancements, glutamate modulation has the potential to transform schizophrenia treatment, particularly for cognitive and negative symptoms that remain largely unaddressed by current therapies.
精神分裂症是一种复杂的神经精神疾病，由原发性阳性症状群、阴性症状、紊乱、神经认知缺陷和社会认知障碍组成。虽然传统抗精神病药物主要作用于多巴胺通路，但它们对认知缺陷和阴性症状的疗效有限。越来越多的证据表明，谷氨酸能调节异常，尤其是N-甲基-D-天冬氨酸受体（NMDA-R）功能低下，在精神分裂症的病理生理学中起作用，这使得谷氨酸调节成为一种有前景的治疗方法。本文综述探讨了新兴的基于谷氨酸的治疗策略，包括NMDA受体调节剂、代谢型谷氨酸受体（mGluR）药物、谷氨酸转运体调节剂和犬尿氨酸途径抑制剂。我们总结了NMDA共激动剂（D-丝氨酸和甘氨酸）、甘氨酸转运体抑制剂、D-氨基酸氧化酶抑制剂和mGluR靶向治疗的临床前和临床研究结果，突出了它们的作用机制、疗效和局限性。此外，我们还讨论了旨在恢复谷氨酸稳态的新型干预措施，包括神经炎症调节和突触可塑性增强剂。尽管取得了令人鼓舞的结果，但许多针对谷氨酸的治疗方法临床疗效并不一致，这凸显了基于生物标志物进行患者选择和优化治疗方案的必要性。我们建议将谷氨酸调节剂与现有的抗精神病治疗方案相结合，可能会增强治疗反应，同时将副作用降至最低。未来的研究应专注于优化基于谷氨酸的干预措施、识别预测性生物标志物以及解决精神分裂症病理的异质性问题。随着不断进步，谷氨酸调节有可能改变精神分裂症的治疗方式，特别是对于目前治疗方法基本未涉及的认知和阴性症状。
