Proof of mechanism and target engagement of glutamatergic drugs for the treatment of schizophrenia: RCTs of pomaglumetad and TS-134 on ketamine-induced psychotic symptoms and pharmacoBOLD in healthy volunteers.
Proof of mechanism and target engagement of glutamatergic drugs for the treatment of schizophrenia: RCTs of pomaglumetad and TS-134 on ketamine-induced psychotic symptoms and pharmacoBOLD in healthy volunteers.
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DOI：
10.1038/s41386-020-0706-z
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发表时间：
2020-10
期刊：
影响因子：
--
通讯作者：
Lieberman JA
中科院分区：
文献类型：
--
作者：
Kantrowitz JT;Grinband J;Goff DC;Lahti AC;Marder SR;Kegeles LS;Girgis RR;Sobeih T;Wall MM;Choo TH;Green MF;Yang YS;Lee J;Horga G;Krystal JH;Potter WZ;Javitt DC;Lieberman JA
谷氨酸神经传递是抗精神病药物开发的优先靶点。两种代谢型谷氨酸受体2/3(mGluR2/3)激动剂(Pomagumetad[POMA]和TS-134)在两期Ib机制验证研究中进行了评估，这些研究采用了相同的临床评估和药物BOLD方法学。POMA在双盲条件下进行了为期10天的随机对照试验，剂量分别为80或320 mg/d，对照组为安慰剂(1：1：1)。TS-134试验是一项随机、单盲、为期6天的研究，将20或60 mg/d的TS-134与安慰剂(比例为5：5：2)进行比较。主要结果是氯胺酮引起背侧前扣带回皮质(DACC)药物BOLD的变化以及简明精神病评定量表(BPRS)反映的症状。两项试验都是同时进行的。95名健康志愿者被随机分为POMA组和63名TS-134组。组内和组间比较，高剂量组均能显著降低氯胺酮诱导的短暂性疲劳综合征的总症状(p <； 0.0 1，d = −0.4 1；p = 0.0 4，d = −0.44)，但对氯胺酮诱导的dACC药物BOLD无明显抑制作用。相比之下，使用汇集的跨研究安慰剂数据，小剂量的TS-134在组内和组间导致bprs阳性症状(分别为p = 0.02，d = −0.36；p = 0.008，d = −0.82)和dACC药物BOLD(分别为p = 0.004，d = −0.56；p = 0.079，d = −0.50)的中等到较大的减少。大剂量的POMA对临床症状有显著影响，但对靶点结合没有影响，这表明可能还需要更高的剂量，而小剂量的TS-134显示出症状减轻和靶点结合的证据。这些结果支持进一步研究mGluR2/3和其他谷氨酸靶向治疗精神分裂症的方法。
Glutamate neurotransmission is a prioritized target for antipsychotic drug development. Two metabotropic glutamate receptor 2/3 (mGluR2/3) agonists (pomaglumetad [POMA] and TS-134) were assessed in two Phase Ib proof of mechanism studies of comparable designs and using identical clinical assessments and pharmacoBOLD methodology. POMA was examined in a randomized controlled trial under double-blind conditions for 10-days at doses of 80 or 320 mg/d POMA versus placebo (1:1:1 ratio). The TS-134 trial was a randomized, single-blind, 6-day study of 20 or 60 mg/d TS-134 versus placebo (5:5:2 ratio). Primary outcomes were ketamine-induced changes in pharmacoBOLD in the dorsal anterior cingulate cortex (dACC) and symptoms reflected on the Brief Psychiatric Rating Scale (BPRS). Both trials were conducted contemporaneously. 95 healthy volunteers were randomized to POMA and 63 to TS-134. High-dose POMA significantly reduced ketamine-induced BPRS total symptoms within and between-groups (p < 0.01, d = −0.41; p = 0.04, d = −0.44, respectively), but neither POMA dose significantly suppressed ketamine-induced dACC pharmacoBOLD. In contrast, low-dose TS-134 led to moderate to large within and between group reductions in both BPRS positive symptoms (p = 0.02, d = −0.36; p = 0.008, d = −0.82, respectively) and dACC pharmacoBOLD (p = 0.004, d = −0.56; p = 0.079, d = −0.50, respectively) using pooled across-study placebo data. High-dose POMA exerted significant effects on clinical symptoms, but not on target engagement, suggesting a higher dose may yet be needed, while the low dose of TS-134 showed evidence of symptom reduction and target engagement. These results support further investigation of mGluR2/3 and other glutamate-targeted treatments for schizophrenia.
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