Iwata Yusuke, Nakajima Shinichiro, Plitman Eric, Truong Peter, Bani-Fatemi Ali, Caravaggio Fernando, Kim Julia, Shah Parita, Mar Wanna, Chavez Sofia, Remington Gary, Gerretsen Philip, De Luca Vincenzo, Sailasuta Napapon, Graff-Guerrero Ariel
Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
Schizophr Bull Open. 2021 Mar 8;2(1):sgab006. doi: 10.1093/schizbullopen/sgab006. eCollection 2021 Jan.
Treatment-resistant schizophrenia (TRS) has been suggested to involve glutamatergic dysfunction. Glutathione (GSH), a dominant antioxidant, is known to be involved in glutamatergic neurotransmission. To date, no study has examined GSH levels in patients with TRS. The aim of this study was to examine GSH levels in the dorsal anterior cingulate cortex (dACC) of patients with TRS. Patients with schizophrenia were categorized into 3 groups with respect to their antipsychotic response: (1) clozapine (CLZ) nonresponders, (2) CLZ responders, and (3) first-line responders (FLR). GSH and glutamine + glutamate (Glx) levels were measured using 3T proton magnetic resonance spectroscopy. Firstly, dACC GSH levels were compared among the patient groups and healthy controls (HCs). Further, relationships between GSH and Glx levels were compared between the groups and GSH levels were explored stratifying the patient groups based on the glutamate-cysteine ligase catalytic (GCLC) subunit polymorphism. There was no difference in GSH levels between the groups. FLR showed a more negative relationship between GSH and Glx levels in the dACC compared to HCs. There were no effects of GCLC genotype on the GSH levels. However, CLZ responders had a higher ratio of high-risk GCLC genotype compared to CLZ nonresponders. This study demonstrated different relationships between GSH and Glx in the dACC between groups. In addition, the results suggest a potential link between CLZ response and GCLC genotype. However, it still remains unclear how these differences are related to the underlying pathophysiology of schizophrenia subtypes or the mechanisms of action of CLZ.
难治性精神分裂症（TRS）被认为涉及谷氨酸能功能障碍。谷胱甘肽（GSH）是一种主要的抗氧化剂，已知其参与谷氨酸能神经传递。迄今为止，尚无研究检测TRS患者的GSH水平。本研究的目的是检测TRS患者背侧前扣带回皮质（dACC）中的GSH水平。根据抗精神病药物反应，将精神分裂症患者分为3组：（1）氯氮平（CLZ）无反应者，（2）CLZ反应者，（3）一线反应者（FLR）。使用3T质子磁共振波谱测量GSH和谷氨酰胺+谷氨酸（Glx）水平。首先，比较患者组与健康对照（HCs）之间的dACC GSH水平。此外，比较组间GSH与Glx水平之间的关系，并基于谷氨酸-半胱氨酸连接酶催化（GCLC）亚基多态性对患者组进行分层，探索GSH水平。组间GSH水平无差异。与HCs相比，FLR的dACC中GSH与Glx水平之间的负相关关系更强。GCLC基因型对GSH水平无影响。然而，与CLZ无反应者相比，CLZ反应者的高风险GCLC基因型比例更高。本研究证明了组间dACC中GSH与Glx之间存在不同的关系。此外，结果提示CLZ反应与GCLC基因型之间可能存在联系。然而，这些差异如何与精神分裂症亚型的潜在病理生理学或CLZ的作用机制相关仍不清楚。
