Department of Psychosis Studies, Institute of Psychiatry, Psychology, and Neuroscience, King's College London, London, United Kingdom.
Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, the Netherlands.
JAMA Psychiatry. 2019 Feb 1;76(2):199-207. doi: 10.1001/jamapsychiatry.2018.3252.
Preclinical and human data suggest that hippocampal dysfunction plays a critical role in the onset of psychosis. Neural hyperactivity in the hippocampus is thought to drive an increase in subcortical dopamine function through glutamatergic projections to the striatum.
To examine the association between hippocampal glutamate levels in individuals at clinical high risk for psychosis and their subsequent clinical outcomes.
DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study of 86 individuals at clinical high risk for psychosis and 30 healthy control individuals, with a mean follow-up of 18.5 months, was conducted between November 1, 2011, and November 1, 2017, at early detection services in London and Cambridge, United Kingdom.
Concentrations of glutamate and other metabolites were measured in the left hippocampus using 3-T proton magnetic resonance spectroscopy at the first clinical presentation. At follow-up, clinical outcomes were assessed in terms of transition or nontransition to psychosis using the Comprehensive Assessment of the At-Risk Mental State criteria and the level of overall functioning using the Global Assessment of Function scale.
Of 116 total participants, 86 were at clinical high risk for psychosis (50 [58%] male; mean [SD] age, 22.4 [3.5] years) and 30 were healthy controls (14 [47%] male; mean [SD] age, 24.7 [3.8] years). At follow-up, 12 clinical high-risk individuals developed a first episode of psychosis whereas 74 clinical high-risk individuals did not; 19 clinical high-risk individuals showed good overall functioning (Global Assessment of Function ≥65), whereas 38 clinical high-risk individuals had a poor functional outcome (Global Assessment of Function <65). Compared with clinical high-risk individuals who did not become psychotic, clinical high-risk individuals who developed psychosis showed higher hippocampal glutamate levels (mean [SD], 8.33 [1.48] vs 9.16 [1.28] glutamate levels; P = .048). The clinical high-risk individuals who developed psychosis also had higher myo-inositol levels (mean [SD], 7.60 [1.23] vs 6.24 [1.36] myo-inositol levels; P = .002) and higher creatine levels (mean [SD], 8.18 [0.74] vs 7.32 [1.09] creatine levels; P = .01) compared with clinical high-risk individuals who did not become psychotic, and higher myo-inositol levels compared with healthy controls (mean [SD], 7.60 [1.23] vs 6.19 [1.51] myo-inositol levels; P = .005). Higher hippocampal glutamate levels in clinical high-risk individuals were also associated with a poor functional outcome (mean [SD], 8.83 [1.43] vs 7.76 [1.40] glutamate levels; P = .02). In the logistic regression analyses, hippocampal glutamate levels were significantly associated with clinical outcome in terms of transition and nontransition to psychosis (β = 0.48; odds ratio = 1.61; 95% CI, 1.00-2.59; P = .05) and overall functioning (β = 0.53; odds ratio = 1.71; 95% CI, 1.10-2.66; P = .02).
The findings indicate that adverse clinical outcomes in individuals at clinical high risk for psychosis may be associated with an increase in baseline hippocampal glutamate levels, as well as an increase in myo-inositol and creatine levels. This conclusion suggests that these measures could contribute to the stratification of clinical high-risk individuals according to future clinical outcomes.
临床前和人体数据表明，海马功能障碍在精神病发病中起着关键作用。人们认为，海马体的神经活动过度通过谷氨酸能投射到纹状体来驱动皮质下多巴胺功能的增加。
研究精神病临床高危个体的海马谷氨酸水平与其后续临床结局之间的关系。
设计、地点和参与者：这项横断面研究共纳入 86 名精神病临床高危个体和 30 名健康对照个体，平均随访时间为 18.5 个月，于 2011 年 11 月 1 日至 2017 年 11 月 1 日在英国伦敦和剑桥的早期检测服务处进行。
使用 3-T 质子磁共振波谱技术在首次临床就诊时测量左海马体的谷氨酸和其他代谢物浓度。在随访时，使用风险精神状态综合评估标准评估临床结局，以确定是否发展为精神病，使用总体功能评估量表评估整体功能水平。
在 116 名参与者中，86 名患有精神病临床高危（50 名[58%]男性；平均[标准差]年龄为 22.4[3.5]岁），30 名健康对照（14 名[47%]男性；平均[标准差]年龄为 24.7[3.8]岁）。在随访时，12 名临床高危个体发展为首次精神病发作，而 74 名临床高危个体未发展为精神病；19 名临床高危个体表现出良好的整体功能（总体功能评估≥65），而 38 名临床高危个体表现出较差的功能结局（总体功能评估<65）。与未发展为精神病的临床高危个体相比，发展为精神病的临床高危个体的海马体谷氨酸水平较高（平均值[标准差]，8.33[1.48]vs 9.16[1.28]谷氨酸水平；P=0.048）。发展为精神病的临床高危个体的肌醇水平也较高（平均值[标准差]，7.60[1.23]vs 6.24[1.36]肌醇水平；P=0.002），肌酸水平也较高（平均值[标准差]，8.18[0.74]vs 7.32[1.09]肌酸水平；P=0.01），与未发展为精神病的临床高危个体相比，肌醇水平也较高（平均值[标准差]，7.60[1.23]vs 6.19[1.51]肌醇水平；P=0.005）。与功能结局较好的个体相比，临床高危个体的海马体谷氨酸水平也较高（平均值[标准差]，8.83[1.43]vs 7.76[1.40]谷氨酸水平；P=0.02）。在逻辑回归分析中，海马体谷氨酸水平与向精神病的过渡和非过渡的临床结局（β=0.48；优势比=1.61；95%CI，1.00-2.59；P=0.05）和整体功能（β=0.53；优势比=1.71；95%CI，1.10-2.66；P=0.02）显著相关。
研究结果表明，精神病临床高危个体的不良临床结局可能与基线海马体谷氨酸水平升高、肌醇和肌酸水平升高有关。这一结论表明，这些指标可能有助于根据未来的临床结果对精神病临床高危个体进行分层。
