基于神经可塑性的听觉学习在精神分裂症中的剂量依赖性增强：NMDA 谷氨酸受体激动剂 D-丝氨酸的双盲、安慰剂对照、随机、靶向试验
Dose-Dependent Augmentation of Neuroplasticity-Based Auditory Learning in Schizophrenia: A Double-Blind, Placebo-Controlled, Randomized, Target Engagement Clinical Trial of the NMDA Glutamate Receptor Agonist d-serine.
机构信息
Area Psychosis, New York State Psychiatric Institute, New York, New York; Psychiatry, College of Physicians and Surgeons, Columbia University, New York, New York; Nathan Kline Institute, Orangeburg, New York.
Nathan Kline Institute, Orangeburg, New York; Psychiatry, New York University Grossman School of Medicine, New York, New York.
出版信息
Biol Psychiatry. 2023 Jul 15;94(2):164-173. doi: 10.1016/j.biopsych.2023.01.015. Epub 2023 Jan 28.
BACKGROUND
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.
METHODS
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).
RESULTS
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.
CONCLUSIONS
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.
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，这是听觉认知矫正（AudRem）的限速步骤。我们使用 d-丝氨酸+AudRem 组合评估行为和神经生理药理学靶标效价生物标志物的效用。
方法
45 名精神分裂症或分裂情感障碍患者被随机分为 3 组，每组接受每周 1 次 AudRem 治疗+3 种剂量的 d-丝氨酸（80、100 或 120 mg/kg）或安慰剂治疗，每组各有 12 名 d-丝氨酸和 3 名安慰剂治疗参与者。在 AudRem 中，参与者指出哪对音调更高。主要结局是可塑性改善，用 AudRem 音调之间的音高阈值变化来表示[（测试音 Hz-参考音 Hz）/参考音 Hz]，从治疗第 1 次就诊的初始平台音高阈值（治疗就诊 1 的第 20-30 次试验的平均值）到就诊结束时的音高阈值。通过脑电图结果评估靶标效价，包括失匹配负波（音高主波）。
结果
在可塑性改善方面，存在显著的整体治疗效果（p=0.014）。80 和 100 mg/kg 组的可塑性改善最大（p<0.001，d>0.67），而 120 mg/kg 和安慰剂组的参与者显示出无统计学意义的组内变化。单次治疗后即观察到可塑性改善，并在随后的治疗中持续存在。与安慰剂相比，100 mg/kg 剂量的失匹配负波显著增大（p=0.049，d=1.0），表明靶标效价。
结论
我们的结果证明了 d-丝氨酸+AudRem 组合及其靶标效价方法的进一步开发具有充分的原理验证。最终效用取决于正在进行的针对该组合的更大、更长时间的临床相关结局研究的结果。
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