D-serine for the treatment of negative symptoms in individuals at clinical high risk of schizophrenia: a pilot, double-blind, placebo-controlled, randomised parallel group mechanistic proof-of-concept trial
D-serine for the treatment of negative symptoms in individuals at clinical high risk of schizophrenia: a pilot, double-blind, placebo-controlled, randomised parallel group mechanistic proof-of-concept trial
复制标题
DOI：
10.1016/s2215-0366(15)00098-x
复制
发表时间：
2015-05-01
影响因子：
64.3
通讯作者：
Javitt, Daniel C.
中科院分区：
文献类型：
--
作者：
Kantrowitz, Joshua T.;Woods, Scott W.;Javitt, Daniel C.
n -甲基- d -天冬氨酸型谷氨酸受体拮抗剂（NMDAR）诱导的症状与精神分裂症非常相似，包括阴性症状。d -丝氨酸是一种天然存在的NMDAR调节剂，在精神分裂症动物模型中逆转NMDAR拮抗剂的作用。d -丝氨酸在治疗已确诊的精神分裂症方面的作用已经被评估过，但没有在精神分裂症的早期阶段进行评估。我们的目的是评估d -丝氨酸对高危个体阴性症状的影响。方法：我们在美国四个学术中心进行了一项双盲、安慰剂对照、平行组随机临床试验。年龄在13-35岁之间、前驱症状量表（SOPS）总分超过20分、有兴趣参加临床试验的精神分裂症临床高风险个体符合纳入研究的条件。排除标准包括有超阈值精神病症状史（即不再符合前驱症状）或临床判断sop报告的症状可以更好地由另一种疾病（如抑郁症）解释。随机化使用生成的列表，块大小为4。参与者按地点分层，参与者、调查人员和评估人员都通过使用相同的安慰剂和集中的药物分配来掩盖研究分配。d -丝氨酸（60 mg/kg）每日分次口服，连续16周。主要终点为SOPS阴性，前6周每周测量一次，然后每2周测量一次。至少接受过一次基线后评估的参与者被纳入分析。在基线、中点和终点收集血清细胞因子浓度，以评估作用机制。获得了所有个体的安全性结果，包括实验室评估。该试验已在ClinicalTrials.gov注册，注册号为NCT0082620。我们在2009年4月2日至2012年7月23日期间招募了参与者。44名参与者被随机分配接受d -丝氨酸（n=20）或安慰剂（n=24）；35例有可评估的数据（d -丝氨酸15例，安慰剂20例）。d -丝氨酸诱导阴性症状改善35.7% (SD 17.8)，与安慰剂相比具有显著性（d -丝氨酸组最终SOPS平均阴性评分为7.6 [SEM 1.4]，安慰剂组为11.3 [1.2];d=0.68, p=0.03）。接受d -丝氨酸治疗的5名参与者和接受安慰剂治疗的9名参与者因撤回同意或失去随访（n=8）、转化为精神病（n=2）、实验室确认的不良事件（n=2）或方案偏差（n=2）而提前终止研究。这项研究支持使用基于nmdar的干预措施，如d -丝氨酸，来治疗精神分裂症的前驱症状。根据观察到的效应量，未来需要每个治疗组约40个样本量的研究来确认对症状和nmdar相关炎症变化的有益影响。需要长期研究来评估对精神分裂症临床高风险个体的精神病转化的影响。
Background Antagonists of N-methyl-D-aspartate-type glutamate receptors (NMDAR) induce symptoms that closely resemble those of schizophrenia, including negative symptoms. D-serine is a naturally occurring NMDAR modulator that reverses the effects of NMDAR antagonists in animal models of schizophrenia. D-serine effects have been assessed previously for treatment of established schizophrenia, but not in the early stages of the disorder. We aimed to assess effects of D-serine on negative symptoms in at risk individuals.Methods We did a double-blind, placebo-controlled, parallel-group randomised clinical trial at four academic US centres. Individuals were eligible for inclusion in the study if they were at clinical high risk of schizophrenia, aged between 13-35 years, had a total score of more than 20 on the Scale of Prodromal Symptoms (SOPS), and had an interest in participation in the clinical trial. Exclusion criteria included a history of suprathreshold psychosis symptoms (ie, no longer qualifying as prodromal) or clinical judgment that the reported symptoms from the SOPS were accounted for better by another disorder (eg, depression). Randomisation was done using a generated list with block sizes of four. Participants were stratified by site, with participants, investigators, and assessors all masked through use of identical looking placebos and centralised drug dispensation to study assignment. D-serine (60 mg/kg) was given orally in divided daily doses for 16 weeks. The primary endpoint was for negative SOPS, measured weekly for the first 6 weeks, then every 2 weeks. Participants who received at least one post-baseline assessment were included in analysis. Serum cytokine concentrations were collected at baseline, midpoint, and endpoint to assess the mechanism of action. Safety outcomes including laboratory assessments were obtained for all individuals. This trial is registered with ClinicalTrials.gov, number NCT0082620.Findings We enrolled participants between April 2, 2009, and July 23, 2012. 44 participants were randomly assigned to receive either D-serine (n=20) or placebo (n=24); 35 had assessable data (15 D-serine, 20 placebo). D-serine induced a 35.7% (SD 17.8) improvement in negative symptoms, which was significant compared with placebo (mean final SOPS negative score 7.6 [SEM 1.4] for D-serine group vs 11.3 [1.2] for placebo group; d=0.68, p=0.03). Five participants who received D-serine and nine participants who received placebo discontinued the study early because of withdrawn consent or loss to follow-up (n=8), conversion to psychosis (n=2), laboratory-confirmed adverse events (n=2), or protocol deviations (n=2).Interpretation This study supports use of NMDAR-based interventions, such as D-serine, for treatment of prodromal symptoms of schizophrenia. On the basis of observed effect sizes, future studies with sample sizes of about 40 per treatment group would be needed for confirmation of beneficial effects on symptoms and NMDAR-related inflammatory changes. Long-term studies are needed to assess effects on psychosis conversion in individuals at clinical high risk of schizophrenia.