Folate in Schizophrenia

描述（由申请方提供）：几项研究表明，与对照组相比，精神分裂症患者的血清叶酸浓度较低，并且与常见的亚甲基四氢叶酸还原酶（MTHFR）C677T突变相关，该突变导致叶酸代谢活性降低。我们将阴性症状和认知障碍与低叶酸血清浓度和精神分裂症的MTHFR C677多态性联系起来。此外，最近有报道称，在一项为期12周的安慰剂对照试验中，叶酸2 mg/d和B12可改善42例同型半胱氨酸升高的精神分裂症患者的症状。这一发现是非常有前途的，但需要复制和进一步表征。我们对我们的研究设计进行了几次修改，以回应评论者的意见，包括增加样本量以允许脱落，将试验延长至6个月，以及在叶酸补充剂中添加B12。研究方法：我们提出了一个为期24周，随机，安慰剂对照，平行组添加试验叶酸2 mg/d + B12 400微克在144例精神分裂症患者中度或以上的阴性症状治疗第二代抗精神病药。我们的主要终点是阴性症状的减少。我们还将评估认知功能。将评估反应的潜在预测因素，包括基线血清和红细胞叶酸浓度、同型半胱氨酸和B12浓度、MTHFR C677多态性状态以及治疗期间叶酸和B12浓度的变化。通过排除血浆同型半胱氨酸水平升高或巨幼细胞性贫血患者以及妊娠女性，解决了之前提出的关于使用安慰剂组的伦理问题。重要性：这项研究检查了两种非常安全和廉价的维生素，它们具有与大脑发育和功能相关的多种作用，包括保护神经毒性，神经递质的合成和DNA的甲基化。最近的研究结果表明，叶酸补充剂可以改善阴性症状和认知缺陷的精神分裂症症状，赋予实质性的残疾，目前没有有效的治疗方法。这将是第一个充分把握度的研究，以评估疗效和确定反应的预测因素。

DESCRIPTION (provided by applicant): Several studies have demonstrated low serum folate concentrations in patients with schizophrenia compared to controls and an association with the common methylenetetrahydrofolate reductase (MTHFR) C677T mutation which results in decreased folate metabolic activity. We have linked negative symptoms and cognitive impairment to low folate serum concentrations and to the MTHFR C677 polymorphism in schizophrenia. In addition, folate 2 mg/d and B12 were recently reported to improve symptoms in 42 schizophrenia patients with elevated homocysteine in a placebo-controlled 12 week trial. This finding is very promising but requires replication and further characterization. We have made several revisions to our study design in response to reviewers' comments, including increasing the sample size to allow for drop-outs, extending the trial to 6 months, and adding B12 to the folate supplementation. Methods: We propose a 24-week, randomized, placebo-controlled, parallel group add-on trial of folate 2 mg/d plus B12 400 micrograms in 144 schizophrenia patients with moderate-or-greater negative symptoms treated with second generation antipsychotics. Our primary endpoint is reduction in negative symptoms. We will also assess cognitive functioning. Potential predictors of response will be assessed, including baseline serum and red blood cell folate concentrations, homocysteine and B12 concentrations, MTHFR C677 polymorphism status and change in folate and B12 concentrations during treatment. Previously-raised ethical concerns about the use of a placebo group will be addressed by excluding patients with elevated plasma homocysteine levels or with megaloblastic anemia, and women who are pregnant. Significance: This study examines two very safe and inexpensive vitamins which serve multiple roles related to brain development and function, including protection against neurotoxicity, synthesis of neurotransmitters and methylation of DNA. Recent findings suggest that folate supplementation may improve negative symptoms and cognitive deficits of schizophrenia-symptoms which confer substantial disability and for which no effective treatments are currently available. This will be the first adequately-powered study to assess efficacy and identify predictors of response.