Department of Psychiatry, UCSD School of Medicine, La Jolla, CA, USA.
Neuropsychopharmacology. 2018 Mar;43(4):708-717. doi: 10.1038/npp.2017.285. Epub 2017 Nov 20.
Prepulse inhibition (PPI) of startle is being explored both as an indicator of target engagement for, and a biomarker predicting the sensitivity to, procognitive effects of drugs. We now report the effects of the pro-attentional drug, d-amphetamine, on PPI and neurocognition in antipsychotic-medicated schizophrenia patients and healthy subjects (HS) who were also tested in a targeted cognitive training (TCT) module. 44 HS and 38 schizophrenia patients completed a double-blind, placebo-controlled crossover study of the effects of a single dose of amphetamine (10 mg po) on PPI and MATRICS Consensus Cognitive Battery (MCCB) performance; TCT results were previously reported from 60 of these subjects. Moderators predicting AMPH sensitivity were assessed, including the rs4680 single-nucleotide polymorphism for catechol-O-methyltransferase (COMT). After placebo, patients exhibited PPI deficits with 60 ms prepulse intervals; these deficits were 'rescued' by amphetamine. The magnitude of amphetamine-enhanced PPI was greater in patients than in HS (p<0.032), and was associated with positive symptoms (p<0.007), antipsychotic load (p<0.015), hedonic effects of AMPH (p<0.003), and with the presence of at least one methionine allele in rs4680 (p<0.008). No significant effects of amphetamine on MCCB performance were detected in either group, though pro-attentional effects of amphetamine in patients were associated with greater amphetamine-enhanced TCT learning. Amphetamine acutely 'normalized' PPI in antipsychotic-medicated schizophrenia patients; no concurrent acute neurocognitive changes were detected by the MCCB. Findings suggest that in the context of appropriate antipsychotic medication, a low dose of amphetamine enhances brain processes associated with higher function in schizophrenia patients, without accompanying changes in MCCB performance.
启动前抑制（PPI）的惊跳反应正在被探索作为一个指标，以确定药物对认知的影响，并预测药物对认知的敏感性。我们现在报告的是前注意药物苯丙胺对精神分裂症患者和健康受试者（HS）的 PPI 和神经认知的影响，这些受试者也在一个有针对性的认知训练（TCT）模块中进行了测试。44 名 HS 和 38 名精神分裂症患者完成了一项双盲、安慰剂对照的交叉研究，研究了单剂量苯丙胺（10mg 口服）对 PPI 和 MATRICS 共识认知电池（MCCB）表现的影响；TCT 的结果以前是从这些受试者中的 60 名报告的。评估了预测 AMPH 敏感性的调节剂，包括儿茶酚-O-甲基转移酶（COMT）的 rs4680 单核苷酸多态性。安慰剂后，患者表现出 60ms 预脉冲间隔的 PPI 缺陷；这些缺陷被苯丙胺“挽救”。与 HS 相比，患者的苯丙胺增强 PPI 的幅度更大（p<0.032），与阳性症状（p<0.007）、抗精神病药物负荷（p<0.015）、AMPH 的快感效应（p<0.003）以及 rs4680 中至少一个蛋氨酸等位基因（p<0.008）有关。在两组中均未检测到苯丙胺对 MCCB 表现的显著影响，尽管苯丙胺对患者的前注意作用与更大的苯丙胺增强 TCT 学习有关。苯丙胺急性“正常化”抗精神病药物治疗的精神分裂症患者的 PPI；MCCB 未检测到急性神经认知变化。研究结果表明，在适当的抗精神病药物治疗的情况下，低剂量的苯丙胺增强了精神分裂症患者与更高功能相关的大脑过程，而 MCCB 表现没有变化。
