Nature of Glutamate Alterations in Schizophrenia A Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies
Nature of Glutamate Alterations in Schizophrenia A Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies
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DOI：
10.1001/jamapsychiatry.2016.0442
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发表时间：
2016-07-01
期刊：
影响因子：
25.8
通讯作者：
McGuire, Philip K.
中科院分区：
文献类型：
--
作者：
Merritt, Kate;Egerton, Alice;McGuire, Philip K.
重要性谷氨酸能神经传递的改变可能是精神分裂症的病理生理学的基础，并且谷氨酸能系统是精神分裂症中新的治疗干预的靶点。目的通过对谷氨酸质子磁共振（MRS）波谱研究进行荟萃分析，研究精神分裂症中脑谷氨酸改变的性质。1980年至2015年4月1日。检索词包括磁共振波谱、精神分裂症、精神病、临床或遗传高危和情感障碍。纳入标准是报告患者或风险组与健康志愿者组相比的谷氨酸、谷氨酰胺或Glx值的单体素1H-MRS研究。研究选择确定了59项研究，其中包括1686名患者和1451名健康个体作为对照。提取平均值并独立验证。在至少3项不同研究中检查的脑区中确定谷氨酸盐、谷氨酰胺和Glx的效应量。二次分析将研究分组为那些检查处于不同疾病阶段（高风险，首次发作精神病或慢性精神分裂症）的患者的研究。年龄、抗精神病药物剂量和症状严重程度的影响采用荟萃回归分析确定。结果在精神分裂症患者中，基底神经节谷氨酸显著升高（Hedges g = 0.63; 95% CI，0.15-1.11），丘脑中的谷氨酰胺（g = 0.56; 95% CI，0.02-1.09），基底节（g = 0.39; 95% CI，0.09-0.70）和内侧颞叶（g = 0.32; 95% CI，0.12-0.52）中Glx。在精神分裂症患者中，没有一个区域显示谷氨酸代谢物减少。二次分析显示，在精神分裂症高危人群中，内侧额叶Glx水平明显升高（g = 0.26; 95%CI，0.05-0.46），但在首发精神病或慢性精神分裂症患者中没有，而在慢性精神分裂症患者中观察到内侧颞叶Glx升高（g = 0.40; 95% CI，0.08-0.71），但在高危组或首次发作组中没有。荟萃回归分析发现，年龄，症状的严重程度，或抗精神病药物dose.CONCLUSIONS和相关性精神分裂症是与几个脑区的代谢产物的升高。这一发现支持了精神分裂症与几个边缘系统区域中过量的多巴胺能神经传递相关的假设，并进一步表明减少多巴胺能传递的化合物可能具有治疗潜力。
IMPORTANCE Alterations in glutamatergic neurotransmission may be fundamental to the pathophysiology of schizophrenia, and the glutamatergic system is a target for novel therapeutic interventions in the disorder.OBJECTIVE To investigate the nature of brain glutamate alterations in schizophrenia by conducting a meta-analysis of glutamate proton magnetic resonance (MRS) spectroscopy studies.DATA SOURCES The MEDLINE database was searched for studies published from January 1, 1980, to April 1, 2015. Search terms included magnetic resonance spectroscopy, schizophrenia, psychosis, clinical or genetic high risk, and schizoaffective. Inclusion criteria were single voxel 1H-MRS studies reporting glutamate, glutamine or Glx values for a patient or risk group in comparison to a healthy volunteer group.STUDY SELECTION Fifty-nine studies were identified, which included 1686 patients and 1451 healthy individuals serving as controls.DATA EXTRACTION AND SYNTHESIS A random-effects, inverse-weighted variance model was used to calculate the pooled effect size. Mean values were extracted and verified independently. Effect sizes were determined for glutamate, glutamine, and Glx in brain regions that had been examined in at least 3 different studies. A secondary analysis grouped studies into those examining patients at different stages of illness (high risk, first-episode psychosis, or chronic schizophrenia). Effects of age, antipsychotic dose, and symptom severity were determined using meta-regression.RESULTS In schizophrenia, there were significant elevations in glutamate in the basal ganglia (Hedges g = 0.63; 95% CI, 0.15-1.11), glutamine in the thalamus (g = 0.56; 95% CI, 0.02-1.09), and Glx in the basal ganglia (g = 0.39; 95% CI, 0.09-0.70) and medial temporal lobe (g = 0.32; 95% CI, 0.12-0.52). No region showed a reduction in glutamate metabolites in schizophrenia. Secondary analyses revealed that elevated medial frontal Glx levels were evident in individuals at high risk for schizophrenia (g = 0.26; 95% CI, 0.05-0.46) but not in those with first-episode psychosis or chronic schizophrenia, whereas elevated Glx in the medial temporal lobe was seen with chronic schizophrenia (g = 0.40; 95% CI, 0.08-0.71) but not in the high-risk or first-episode groups. Meta-regression found no association with age, symptom severity, or antipsychotic dose.CONCLUSIONS AND RELEVANCE Schizophrenia is associated with elevations in glutamatergic metabolites across several brain regions. This finding supports the hypothesis that schizophrenia is associated with excess glutamatergic neurotransmission in several limbic areas and further indicates that compounds that reduce glutamatergic transmission may have therapeutic potential.