Utility of Imaging-Based Biomarkers for Glutamate-Targeted Drug Development in Psychotic Disorders A Randomized Clinical Trial
Utility of Imaging-Based Biomarkers for Glutamate-Targeted Drug Development in Psychotic Disorders A Randomized Clinical Trial
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DOI：
10.1001/jamapsychiatry.2017.3572
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发表时间：
2018-01-01
期刊：
影响因子：
25.8
通讯作者：
Lieberman, Jeffrey A.
中科院分区：
文献类型：
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作者：
Javitt, Daniel C.;Carter, Cameron S.;Lieberman, Jeffrey A.
重要性尽管有强有力的理论依据和临床前证据，精神分裂症的几种谷氨酸靶向治疗在最近的关键性试验中失败了，引发了关于靶向有效性、化合物不足或缺乏靶向参与的问题。基于谷氨酸的治疗开发的一个关键限制是缺乏用于临床前和早期临床研究之间转换的功能性靶点结合生物标志物。我们评估了3种潜在的生物标志物-氯胺酮诱发的功能磁成像（fMRI）血氧水平依赖性反应的变化的实用性（pharmacoBOLD）、谷氨酸质子磁共振波谱（H-1 MRS），和基于任务的fMRI-用于检测脑谷氨酸中氯胺酮相关的改变。在早期临床研究中作为靶向结合生物标志物的位点可靠性。设计，环境，这项随机临床试验于2014年5月至2015年10月在一家学术研究机构进行，作为国家精神健康研究所资助的精神病谱系障碍快速失败试验项目。所有评估者均对研究组设盲。从3个研究中心招募了18至55岁的健康志愿者，不分性别，无重大病史或精神病史。分析了2015年11月至2016年12月期间的数据。干预（在1分钟内输注0.23 mg/kg，随后在30分钟内输注0.58 mg/kg/h，然后在29分钟内输注0.29 mg/kg/h）或安慰剂输注。沿着症状评级。在65名志愿者中，41名（63%）为男性，平均（SD）年龄为31.1（9.6）岁; 59名（91%）至少有1次有效扫描。共有53名志愿者（82%）完成了两次氯胺酮输注。在pharmacoBOLD中，观察到fMRI反应的高度稳健的增加（Cohen d = 5.4; P < .001），并且在各个部位具有一致的反应。氯胺酮输注后立即在H-1 MRS测定的谷氨酸盐+谷氨酰胺水平中也观察到较小但显著的信号（Cohen d = 0.64; P = 0.04）。相比之下，任务激活的功能磁共振成像反应没有显着差异，发现groups.CONCLUSIONS和RELEVANCE这些研究结果表明强大的影响氯胺酮pharmacoBOLD跨网站，支持其效用的功能性目标参与的明确评估。其他指标虽然对氯胺酮效应敏感，但用作跨部位靶向结合指标时不够稳健。
IMPORTANCE Despite strong theoretical rationale and preclinical evidence, several glutamate-targeted treatments for schizophrenia have failed in recent pivotal trials, prompting questions as to target validity, compound inadequacy, or lack of target engagement. A key limitation for glutamate-based treatment development is the lack of functional target-engagement biomarkers for translation between preclinical and early-stage clinical studies. We evaluated the utility of 3 potential biomarkers-ketamine-evoked changes in the functional magnetic imaging (fMRI) blood oxygen level-dependent response (pharmacoBOLD), glutamate proton magnetic resonance spectroscopy (H-1 MRS), and task-based fMRI-for detecting ketamine-related alterations in brain glutamate.OBJECTIVE To identify measures with sufficient effect size and cross-site reliability to serve as glutamatergic target engagement biomarkers within early-phase clinical studies.DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial was conducted at an academic research institution between May 2014 and October 2015 as part of the National Institute of Mental Health-funded Fast-Fail Trial for Psychotic Spectrum Disorders project. All raters were blinded to study group. Healthy volunteers aged 18 to 55 years of either sex and free of significant medical or psychiatric history were recruited from 3 sites. Data were analyzed between November 2015 and December 2016.INTERVENTIONS Volunteers received either sequential ketamine (0.23 mg/kg infusion over 1 minute followed by 0.58 mg/kg/h infusion over 30 minutes and then 0.29 mg/kg/h infusion over 29 minutes) or placebo infusions.MAIN OUTCOMES AND MEASURES Ketamine-induced changes in pharmacoBOLD, 1H MRS, and task-based fMRI measures, along with symptom ratings. Measures were prespecified prior to data collection.RESULTS Of the 65 volunteers, 41 (63%) were male, and the mean (SD) age was 31.1 (9.6) years; 59 (91%) had at least 1 valid scan. A total of 53 volunteers (82%) completed both ketamine infusions. In pharmacoBOLD, a highly robust increase (Cohen d = 5.4; P < .001) in fMRI response was observed, with a consistent response across sites. A smaller but significant signal (Cohen d = 0.64; P = .04) was also observed in H-1 MRS-determined levels of glutamate+glutamine immediately following ketamine infusion. By contrast, no significant differences in task-activated fMRI responses were found between groups.CONCLUSIONS AND RELEVANCE These findings demonstrate robust effects of ketamine on pharmacoBOLD across sites, supporting its utility for definitive assessment of functional target engagement. Other measures, while sensitive to ketamine effects, were not sufficiently robust for use as cross-site target engagement measures.