背景:精神分裂症患者表现出NMDA谷氨酸受体依赖性听觉可塑性降低,这是听觉认知修复(AudRem)的限速。我们评估了行为和神经生理药效学靶标参与生物标志物的效用,使用d-丝氨酸+AudRem组合。
方法:45名精神分裂症或分裂情感障碍的参与者被随机分为每周3次AudRem访视+双盲d-丝氨酸(80、100或120mg/kg)或安慰剂,每组3个剂量组,每组12d-丝氨酸和3个安慰剂治疗的参与者。在AudRem,参与者指出了哪个配对音调较高。主要结果是可塑性改善,操作为AudRem音调之间的音调阈值变化[(测试音调Hz-参考音调Hz)/参考音调Hz]在初始平台音调阈值(1次治疗访问的试验20-30的平均值)到访问结束时的音调阈值之间。通过脑电图结果评估目标参与度,包括失配消极性(基音)。
结果:可塑性改善具有显着的总体治疗效果(p=.014)。80和100mg/kg组的可塑性改善最大(p<.001,d>0.67),而120mg/kg和安慰剂治疗的参与者显示无显著组内变化。在单次治疗后观察到可塑性改善,并且在随后的治疗中持续。100mg/kg剂量与安慰剂相比,明显更大的错配负(p=0.049,d=1.0)证明了目标参与。
结论:我们的结果证明了继续开发d-丝氨酸+AudRem组合和我们的目标参与方法的原则。最终的效用取决于正在进行的更大的结果,对临床相关结局的组合进行更长的研究。
Patients with schizophrenia show reduced NMDA glutamate receptor-dependent auditory plasticity, which is rate limiting for auditory cognitive remediation (AudRem). We evaluate the utility of behavioral and neurophysiological pharmacodynamic target engagement biomarkers, using a d-serine+AudRem combination.
Forty-five participants with schizophrenia or schizoaffective disorder were randomized to 3 once-weekly AudRem visits + double-blind d-serine (80, 100, or 120 mg/kg) or placebo in 3 dose cohorts of 12 d-serine and 3 placebo-treated participants each. In AudRem, participants indicated which paired tone was higher in pitch. The primary outcome was plasticity improvement, operationalized as change in pitch threshold between AudRem tones [(test tone Hz - reference tone Hz)/reference tone Hz] between the initial plateau pitch threshold (mean of trials 20-30 of treatment visit 1) to pitch threshold at the end of visit(s). Target engagement was assessed by electroencephalography outcomes, including mismatch negativity (pitch primary).
There was a significant overall treatment effect for plasticity improvement (p = .014). Plasticity improvement was largest within the 80 and 100 mg/kg groups (p < .001, d > 0.67), while 120 mg/kg and placebo-treated participants showed nonsignificant within-group changes. Plasticity improvement was seen after a single treatment and was sustained on subsequent treatments. Target engagement was demonstrated by significantly larger mismatch negativity (p = .049, d = 1.0) for the 100 mg/kg dose versus placebo.
Our results demonstrate sufficient proof of principle for continued development of both the d-serine+AudRem combination and our target engagement methodology. The ultimate utility is dependent on the results of an ongoing larger, longer study of the combination for clinically relevant outcomes.