Negative symptoms and cognitive deficits contribute strongly to disability in schizophrenia, and are resistant to existing medications. Recent drug development has targeted enhanced NMDA function by increasing mGluR2/3 signaling. However, the clinical utility of such agents remains uncertain, and markers of brain circuit function are critical for clarifying mechanisms and understanding individual differences in efficacy. We conducted a double-blind, placebo-controlled, randomized cross-over (14 day washout) pilot study evaluating adjunctive use of the mGluR2 positive allosteric modulator AZD8529 (80 mg daily for 3 days), in chronic stable patients with schizophrenia (n = 26 analyzed). We focused on 3 T fMRI response in frontostriatal regions during an n-back working memory task, testing the hypothesis that AZD8529 produces fMRI changes that correlate with improvement in negative symptoms and cognition. We found that AZD8529 did not produce significant group-average effects on symptoms or cognitive accuracy. However, AZD8529 did increase n-back fMRI activation in striatum (p < 0.0001) and anterior cingulate/paracingulate (p = 0.002). Greater drug-versus-placebo effects on caudate activation significantly correlated with greater reductions in PANSS negative symptom scores (r = −0.42, p = 0.031), and exploratory correlations suggested broader effects across multiple symptom domains and regions of interest. These findings demonstrate that fMRI responses to mGluR2 positive modulation relate to individual differences in symptom reduction, and could be pursued for future biomarker development. Negative clinical results at the group level should not lead to premature termination of investigation of this mechanism, which may benefit an important subset of individuals with schizophrenia. Imaging biomarkers may reveal therapeutic mechanisms, and help guide treatment toward specific populations.

阴性症状和认知缺陷对精神分裂症的残疾有很大贡献，并且对现有药物有抵抗力。最近的药物开发通过增加 mGluR2/3 信号转导增强了 NMDA 功能。然而，此类药物的临床效用仍不确定，脑回路功能的标志物对于阐明机制和了解疗效的个体差异至关重要。我们进行了一项双盲、安慰剂对照、随机交叉（14 天清除）试验性研究，评估在慢性稳定的精神分裂症患者中辅助使用 mGluR2 正变构调节剂 AZD8529（每天 80 毫克，持续 3 天）（n = 26 分析）。我们专注于 n-back 工作记忆任务期间额纹状体区域的 3 T fMRI 反应，检验 AZD8529 产生与阴性症状和认知改善相关的 fMRI 变化的假设。我们发现 AZD8529 对症状或认知准确性没有产生显着的组平均效应。然而，AZD8529 确实增加了纹状体 ( p  < 0.0001) 和前扣带回/副扣带回 ( p  = 0.002) 中的 n-back fMRI 激活。与安慰剂相比，药物对尾状核激活的更大影响与 PANSS 阴性症状评分的更大降低显着相关（r  = −0.42，p = 0.031)，探索性相关性表明对多个症状域和感兴趣区域的影响更广泛。这些发现表明，fMRI 对 mGluR2 正调节的反应与症状减轻的个体差异有关，并且可以用于未来的生物标志物开发。组水平的阴性临床结果不应导致对该机制的调查过早终止，这可能会使精神分裂症患者的重要子集受益。成像生物标志物可能揭示治疗机制，并有助于指导针对特定人群的治疗。