Background

The glutamate (Glu) and gamma aminobutyric acid (GABA) hypotheses of schizophrenia were proposed in the 1980s. However, current findings on those metabolite levels in schizophrenia have been inconsistent, and the relationship between their abnormalities and the pathophysiology of schizophrenia remains unclear. To summarize the nature of the alterations of glutamatergic and GABAergic systems in schizophrenia, we conducted meta-analyses of proton magnetic resonance spectroscopy (¹H-MRS) studies examining these metabolite levels.

Methods

A systematic literature search was conducted using Embase, Medline, PsycINFO, and PubMed. Original studies that compared four metabolite levels (Glu, glutamine [Gln], Glx [Glu+Gln], and GABA), as measured by ¹H-MRS, between individuals at high risk for psychosis, patients with first-episode psychosis, or patients with schizophrenia and healthy controls (HC) were included. A random-effects model was used to calculate the effect sizes for group differences in these metabolite levels of 18 regions of interest between the whole group or schizophrenia group and HC. Subgroup analysis and meta-regression were performed based on the status of antipsychotic treatment, illness stage, treatment resistance, and magnetic field strength.

Results

One-hundred-thirty-four studies met the eligibility criteria, totaling 7993 participants with SZ-spectrum disorders and 8744 HC. 14 out of 18 ROIs had enough numbers of studies to examine the group difference in the metabolite levels. In the whole group, Glx levels in the basal ganglia (g = 0.32; 95% CIs: 0.18–0.45) were elevated. Subgroup analyses showed elevated Glx levels in the hippocampus (g = 0.47; 95% CIs: 0.21–0.73) and dorsolateral prefrontal cortex (g = 0.25; 95% CIs: 0.05–0.44) in unmedicated patients than HC. GABA levels in the MCC were decreased in the first-episode psychosis group compared with HC (g = −0.40; 95% CIs: −0.62 to −0.17). Treatment-resistant schizophrenia (TRS) group had elevated Glx and Glu levels in the MCC (Glx: g = 0.7; 95% CIs: 0.38–1.01; Glu: g = 0.63; 95% CIs: 0.31–0.94) while MCC Glu levels were decreased in the patient group except TRS (g = −0.17; 95% CIs: −0.33 to −0.01).

Conclusions

Increased glutamatergic metabolite levels and reduced GABA levels indicate that the disruption of excitatory/inhibitory balance may be related to the pathophysiology of schizophrenia-spectrum disorders.

中文翻译：

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精神分裂症谱系障碍中的谷氨酸能和 GABA 能代谢物水平：1H-磁共振波谱研究的荟萃分析

背景

精神分裂症的谷氨酸 (Glu) 和γ-氨基丁酸 (GABA) 假说在 1980 年代被提出。然而，目前关于精神分裂症中这些代谢物水平的研究结果并不一致，其异常与精神分裂症病理生理学之间的关系仍不清楚。为了总结精神分裂症中谷氨酸能和氨基丁酸能系统改变的性质，我们对检查这些代谢物水平的质子磁共振波谱 ( ¹ H-MRS) 研究进行了荟萃分析。

方法

使用 Embase、Medline、PsycINFO 和 PubMed 进行了系统的文献检索。比较四种代谢物水平（Glu、谷氨酰胺 [Gln]、Glx [Glu+Gln] 和 GABA）的原始研究，通过¹ H-MRS 测量，在精神病高风险个体、首发精神病患者或包括精神分裂症患者和健康对照者 (HC)。使用随机效应模型计算整个组或精神分裂症组与 HC 之间 18 个感兴趣区域的这些代谢物水平的组间差异的效应大小。根据抗精神病药物治疗状况、疾病分期、治疗抵抗力和磁场强度进行亚组分析和元回归分析。

结果

一百三十四项研究符合资格标准，共有 7993 名患有 SZ 谱障碍的参与者和 8744 名 HC。18 个 ROI 中有 14 个有足够数量的研究来检查代谢物水平的组间差异。在整个组中，基底神经节中的 Glx 水平（g  = 0.32；95% CI：0.18–0.45）升高。亚组分析显示，与 HC 相比，未接受药物治疗的患者海马体（ g  = 0.47；95% CI：0.21-0.73）和背外侧前额叶皮质（g  = 0.25；95% CI：0.05-0.44）的Glx 水平升高。与 HC 相比，首发精神病组 MCC 中的 GABA 水平降低（g = −0.40；95% CI：-0.62 至 -0.17）。难治性精神分裂症 (TRS) 组 MCC 中的 Glx 和 Glu 水平升高（Glx：g  = 0.7；95% CI：0.38-1.01；Glu：g  = 0.63；95% CI：0.31-0.94），而 MCC Glu 水平除 TRS 外，患者组均降低（g  = -0.17；95% CI：-0.33 至 -0.01）。

结论

谷氨酸能代谢物水平升高和 GABA 水平降低表明兴奋性/抑制性平衡的破坏可能与精神分裂症谱系障碍的病理生理学有关。