Shah Parita, Plitman Eric, Iwata Yusuke, Kim Julia, Nakajima Shinichiro, Chan Nathan, Brown Eric E, Caravaggio Fernando, Torres Edgardo, Hahn Margaret, Chakravarty M Mallar, Remington Gary, Gerretsen Philip, Graff-Guerrero Ariel
Multimodal Imaging Group, Research Imaging Centre, Centre for Addiction and Mental Health (CAMH), Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
Douglas Mental Health University Institute, Montreal, Quebec, Canada; Department of Psychiatry, McGill University, Montreal, Quebec, Canada.
J Psychiatr Res. 2020 May;124:151-158. doi: 10.1016/j.jpsychires.2020.02.032. Epub 2020 Mar 5.
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 H-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改变有关。然而，这些变化背后的机制仍不清楚。本研究有两个主要目的：（1）探讨对氯氮平无反应的难治性精神分裂症患者（超难治性精神分裂症，UTRS）、对氯氮平有反应的难治性精神分裂症患者（氯氮平反应者，Cloz-Resp）、对一线非氯氮平抗精神病药物有反应的患者（一线反应者，FL-Resp）和健康对照者（HCs）之间皮质厚度的差异；（2）通过检查背侧前扣带回皮质（dACC）中谷氨酸能神经代谢物水平（谷氨酸（Glu）和谷氨酸+谷氨酰胺（Glx））与皮质厚度之间的关系，来检验我们关于结构损害是谷氨酸（Glu）升高所致神经毒性作用表现（即谷氨酸介导的兴奋性毒性）的假设。从UTRS患者（n = 24）、Cloz-Resp患者（n = 25）、FL-Resp患者（n = 19）和HCs（n = 26）获取了T1加权图像和氢磁共振波谱（H-MRS）数据。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、顶叶和枕叶脑回存在广泛的皮质变薄。在患者组中，在校正多重比较并控制年龄、性别、抗精神病药物剂量和疾病严重程度后，发现dACC的Glx水平与右侧背外侧前额叶皮质的皮质厚度呈负相关。总之，谷氨酸介导的兴奋性毒性可能是难治性精神分裂症中所见结构损害的潜在机制之一。未来的研究应在治疗和疾病进展的背景下纵向检查谷氨酸能神经代谢物水平与皮质厚度之间的关联。
