Treatment-resistant schizophrenia may be related to structural brain alterations. However, the mechanisms underlying these changes remain unclear. The present study had two main aims: (1) to explore differences in cortical thickness between patients with treatment-resistant schizophrenia non-responsive to clozapine (ultra-treatment-resistant schizophrenia, UTRS), patients with treatment-resistant schizophrenia responsive to clozapine (Cloz-Resp), patients responsive to first-line non-clozapine antipsychotics (FL-Resp), and healthy controls (HCs); and (2) to test our hypothesis of structural compromise as a manifestation of neurotoxic effects from elevated glutamate (Glu) (i.e. glutamate-mediated excitotoxicity) by examining the relationships between glutamatergic neurometabolite levels (Glu and glutamate + glutamine (Glx)) in the dorsal anterior cingulate cortex (dACC) and cortical thickness. T1-weighted images and ¹H-MRS data were obtained from UTRS (n = 24), Cloz-Resp (n = 25), FL-Resp (n = 19), and HCs (n = 26). Vertex-wise analyses showed that patients with UTRS had widespread cortical thinning in the bilateral frontal, temporal, parietal, and occipital gyri compared to HCs and FL-Resp patients. In the patient group, negative associations were found between dACC Glx levels and cortical thickness in the right dorsolateral prefrontal cortex after correcting for multiple comparisons and controlling for age, sex, antipsychotic dose, and illness severity. In conclusion, glutamate-mediated excitotoxicity may be one of the mechanisms underlying structural compromise seen in treatment-resistant schizophrenia. Future studies should longitudinally examine the associations between glutamatergic neurometabolite levels and cortical thickness in the context of treatment and illness progression.

难治性精神分裂症可能与大脑结构的改变有关。但是，这些变化的潜在机制仍不清楚。本研究的两个主要目标是：（1）探讨对氯氮平无反应的治疗耐药性精神分裂症患者（对氯氮平有超治疗抵抗力的精神分裂症患者，对氯氮平有耐药性的精神分裂症患者之间的皮质厚度差异）。 Cloz-Resp），对一线非氯氮平抗精神病药有反应的患者（FL-Resp）和健康对照（HCs）；和（2）检验我们的结构妥协假说，认为是谷氨酸（Glu）升高引起的神经毒性作用（即 通过检查背扣带回皮层（dACC）中的谷氨酸能神经代谢产物水平（Glu和谷氨酸+谷氨酰胺（Glx））与皮质厚度之间的关系来评估谷氨酸介导的兴奋性毒性）。T1加权图像和^1个H-MRS数据是从UTRS（n = 24），Cloz-Resp（n = 25），FL-Resp（n = 19）和HCs（n = 26）获得的。逐点分析显示，与HCs和FL-Resp患者相比，UTRS患者在双侧额叶，颞叶，顶叶和枕叶回具有广泛的皮质变薄。在患者组中，在校正了多个比较并控制了年龄，性别，抗精神病剂量和疾病严重程度之后，发现右后外侧前额叶皮层中的dACC Glx水平与皮层厚度之间呈负相关。总之，谷氨酸介导的兴奋性毒性可能是在抗药性精神分裂症中所见的结构受损的潜在机制之一。