Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Jerusalem.
J Clin Psychiatry. 2012 Jun;73(6):e728-34. doi: 10.4088/JCP.11m07031.
Observations that antagonists of the N-methyl-d-aspartate (NMDA) receptor of glutamatergic neurons can mimic symptoms of schizophrenia have raised the hope that NMDA agonists can improve symptoms. On the basis of encouraging results of trials in which NMDA agonists were added to antipsychotics, we conducted an adequately powered randomized controlled trial adding d-serine, an NMDA modulator, to antipsychotics.
This study was a 195-patient, multicenter, double-blind, randomized, placebo-controlled, 16-week trial of d-serine 2 g/d as an add-on treatment to antipsychotics. Subjects had DSM-IV schizophrenia or schizoaffective disorder and were inpatients or outpatients stabilized on antipsychotics, with persistent negative symptoms. The primary outcome measures were changes in negative symptoms and cognition as measured by the Scale for the Assessment of Negative Symptoms (SANS) and the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) battery, respectively. The study was performed between 2003 and 2007.
Mean total Positive and Negative Syndrome Scale scores at baseline were 75.5. Subjects receiving d-serine and placebo improved in scores on the SANS and MATRICS, but no significant differences were observed between groups: improvement on SANS was 11.4% for d-serine vs 14.8% for placebo, F1,147=1.18, P=.32; and improvement on MATRICS was 6.8% for d-serine vs 6.1% for placebo, F1,125=0.96, P=.39, respectively. d-Serine was well tolerated.
This study did not find a significant difference between drug and placebo. However, the results are limited by a relatively large placebo response and somewhat lower-achieved doses than in prior studies. Future studies will administer higher doses and will attempt to affect the NMDA receptor using other mechanisms, such as agonists of the presynaptic metabotropic glutamate 2/3 receptor or glycine reuptake inhibitors.
ClinicalTrials.gov identifier: NCT00138775.
观察到谷氨酸能神经元 N-甲基-D-天冬氨酸（NMDA）受体拮抗剂可模拟精神分裂症的症状，这增加了 NMDA 激动剂改善症状的希望。基于 NMDA 激动剂与抗精神病药联合使用的试验结果令人鼓舞，我们进行了一项充分有力的随机对照试验，即在抗精神病药中添加 NMDA 调节剂 D-丝氨酸。
这是一项 195 例患者、多中心、双盲、随机、安慰剂对照、为期 16 周的试验，D-丝氨酸 2g/d 作为抗精神病药的附加治疗。受试者为 DSM-IV 精神分裂症或分裂情感障碍患者，正在服用抗精神病药，病情稳定，有持续性阴性症状。主要的结局测量指标分别为阴性症状的变化和认知的变化，使用阴性症状量表（SANS）和精神分裂症认知测量与治疗研究（MATRICS）成套测验进行评估。研究于 2003 年至 2007 年进行。
基线时，阳性和阴性症状量表总分的平均值为 75.5。接受 D-丝氨酸和安慰剂的受试者在 SANS 和 MATRICS 上的评分均有所改善，但组间无显著差异：D-丝氨酸组 SANS 评分改善 11.4%，安慰剂组改善 14.8%，F1,147=1.18，P=.32；D-丝氨酸组 MATRICS 评分改善 6.8%，安慰剂组改善 6.1%，F1,125=0.96，P=.39。D-丝氨酸耐受性良好。
本研究未发现药物与安慰剂之间有显著差异。然而，结果受到安慰剂反应较大和达到的剂量略低于先前研究的限制。未来的研究将给予更高的剂量，并尝试通过其他机制影响 NMDA 受体，如前突触代谢型谷氨酸 2/3 受体激动剂或甘氨酸再摄取抑制剂。
ClinicalTrials.gov 标识符：NCT00138775。
