Barone Annarita, Vellucci Licia, Ciccarelli Mariateresa, Matrone Marta, De Simone Giuseppe, Iannotta Federica, Iasevoli Felice, de Bartolomeis Andrea
Section of Psychiatry, Laboratory of Translational and Molecular Psychiatry, Unit of Treatment-Resistant Psychosis, Department of Neuroscience, Reproductive Sciences and Dentistry, University Medical School of Naples "Federico II", Via Pansini 5, 80131 Naples, Italy.
Department of Translational Medical Sciences, University of Naples "Federico II", Via S. Pansini 5, 80131 Naples, Italy.
Int J Mol Sci. 2025 Sep 4;26(17):8598. doi: 10.3390/ijms26178598.
Treatment-resistant schizophrenia (TRS) affects up to one in three individuals with schizophrenia and is associated with a significant clinical, social, and economic burden. Different from treatment-responsive forms, TRS appears to involve other biological mechanisms extending beyond dopaminergic dysfunctions. This review outlines current knowledge on the molecular and cellular basis of TRS, focusing on alterations in glutamate signaling, imbalances between excitatory and inhibitory activity, disruptions in D-amino acid metabolism, and evidence of neuroinflammation, oxidative stress, and mitochondrial or endoplasmic reticulum dysfunction. Data from genomics, proteomics, metabolomics, preclinical models, and postmortem studies suggest that TRS may have a peculiar neurobiological substrate. Further, multimodal brain imaging studies reveal differences in brain structure, white matter integrity, and network connectivity when compared to treatment-responsive individuals. Altogether, these findings support a shift from the traditional dopamine hypothesis toward a more comprehensive model that includes multiple immune, metabolic, and synaptic factors. Understanding the possible interplay of these complex mechanisms may lead to the identification of potential biomarkers that may help to predict antipsychotic response, as well as the development of more targeted treatments. Early recognition and a deeper biological insight into TRS are essential for improving care and guiding personalized therapeutic strategies.
难治性精神分裂症（TRS）影响着多达三分之一的精神分裂症患者，并带来了巨大的临床、社会和经济负担。与治疗反应性形式不同，TRS似乎涉及多巴胺能功能障碍之外的其他生物学机制。本综述概述了目前关于TRS分子和细胞基础的知识，重点关注谷氨酸信号传导的改变、兴奋性和抑制性活动之间的失衡、D-氨基酸代谢的紊乱，以及神经炎症、氧化应激、线粒体或内质网功能障碍的证据。来自基因组学、蛋白质组学、代谢组学、临床前模型和尸检研究的数据表明，TRS可能具有独特的神经生物学基础。此外，多模态脑成像研究显示，与治疗反应性个体相比，TRS患者在脑结构、白质完整性和网络连通性方面存在差异。总之，这些发现支持从传统的多巴胺假说转向一个更全面的模型，该模型包括多种免疫、代谢和突触因素。了解这些复杂机制之间可能的相互作用，可能会识别出有助于预测抗精神病药物反应的潜在生物标志物，以及开发更具针对性的治疗方法。对TRS的早期识别和更深入的生物学洞察对于改善护理和指导个性化治疗策略至关重要。
