Targeted Vitamin D Treatment of Schizophrenia-Associated Hyperprolinemia
关键词
抽象
描述
25-hydroxyvitamin D (vitD) insufficiency is associated with cognitive decline and has long-been considered important in schizophrenia susceptibility. VitD supplementation has been suggested for those at-risk, and recent studies have demonstrated that vitD insufficiency extends into both adolescent and adult schizophrenia.
The mechanism by which vitD deficits confers risk is unknown. However, vitD is a transcriptional regulator, and the investigators recently found that vitD significantly up-regulates PRODH gene expression. This is important because the highest known genetic risk of schizophrenia is conferred by hemizygous microdeletion of chromosome 22q11, to which PRODH maps. Furthermore, PRODH encodes proline oxidase, which catalyzes proline catabolism. Proline is a neuromodulator at glutamatergic synapses, and peripheral hyperprolinemia has been associated with learning and memory deficits and neurotransmitter dysregulation in animal models, and in humans, with decreased intelligence quotient (IQ), cognitive impairment, and schizoaffective disorder. The investigators recently found that >25% of schizophrenia patients were hyperprolinemic and hypothesized a causal relationship between vitD, proline elevation, and schizophrenia, such that vitD insufficiency causes decreased PRODH expression and hyperprolinemia. Measuring fasting plasma 25hydroxyvitD and proline in 64 patients and 90 controls, the investigators found that vitD insufficiency (<30ng/ml) was significantly associated with schizophrenia (OR:2.1, p=0.044), vitD levels were negatively correlated with proline (p=0.01), and vitD insufficient subjects had three times greater odds of hyperprolinemia (p=0.046). Moreover, they demonstrated that hyperprolinemia explains >37% of the association between vitD insufficiency and schizophrenia, signifying that vitD insufficiency increases schizophrenia risk, at least in part by elevating proline. These findings advocate that targeting schizophrenia-associated hyperprolinemia by alleviating vitD insufficiency, may improve symptoms including neurocognitive deficits.
The Specific Aims of this study are:
Aim 1) To Evaluate a clinical response to vitamin D3 (vitD3) treatment, targeting patients with both vitD insufficiency and hyperprolinemia.
Aim 2) To Evaluate the relationship between fasting plasma proline change, PRODH expression, and symptoms, for development of an efficacy biomarker.
The aims will be accomplished via a ten week, double-blind, placebo controlled trial, in which schizophrenia or schizoaffective disorder subjects who are both vitD insufficient and hyperprolinemic, will be randomized to vitD3 (4,000 international units (IU)/day n=40) or placebo (n=40) as an adjunct to their antipsychotics.
日期
| 最后验证: | 09/30/2015 |
| 首次提交: | 07/15/2014 |
| 提交的预估入学人数: | 07/17/2014 |
| 首次发布: | 07/21/2014 |
| 上次提交的更新: | 10/06/2015 |
| 最近更新发布: | 10/11/2015 |
| 实际学习开始日期: | 01/31/2015 |
| 预计主要完成日期: | 11/30/2017 |
状况或疾病
干预/治疗
Drug: Vitamin D (cholecalciferol)
Drug: Placebo
相
手臂组
| 臂 | 干预/治疗 |
|---|---|
| Experimental: Vitamin D (cholecalciferol) Intervention: Capsules containing the active ingredient, cholecalciferol @ 4,000 international units (IU). One capsule daily, oral administration for 10 weeks. | Drug: Vitamin D (cholecalciferol) One capsule containing 4,000 IU of Cholecalciferol, per day |
| Placebo Comparator: Placebo Daily matching placebo gelatin capsule (also contains microcrystalline cellulose).
Capsules are identical in size, color and taste to experimental drug. | Drug: Placebo Daily dose of a single gelatin placebo capsule. |
资格标准
| 有资格学习的年龄 | 18 Years 至 18 Years |
| 有资格学习的性别 | All |
| 接受健康志愿者 | 是 |
| 标准 | Inclusion Criteria: Inclusion Criteria for Recruitment 1. Male and Female, all racial/ethnic groups, aged 18-65 years. 2. Admission diagnosis of schizophrenia, schizophreniform disorder, or schizoaffective disorder. 3. Capability to give informed consent. Inclusion Criteria for Randomization and Trial Entry 1. Fasting hyperprolinemia (defined as 2 standard deviations (SDs) above the gender-adjusted mean measured for historical controls: 203.3 micromolar (uM) for females and 327.6 uM for males). 2. 25(OH)D insufficiency (<30ng/ml). 3. Confirmed diagnosis of schizophreniform disorder, schizophrenia or schizoaffective disorder. Exclusion Criteria: Exclusion Criteria for Recruitment 1. Organic brain disorders. 2. Valproate treatment within 14 days, because of known proline up-regulatory effects. 3. Pregnant women or women of child-bearing potential, who are not surgically-sterile or who are not using appropriate methods of birth control. 4. Amino acid metabolism disorder diagnosis. 5. Hypercalcemia (>10.4mg/dL), hypercalciuria (>0.20mg/mg), hyperthyroidism (>65pg/ml) or history of renal stones, kidney disease, atherosclerosis, sarcoidosis, histoplasmosis and lymphoma. 6. Chart record of HIV positive status. 7. Treatment with clozapine, as this may reflect general treatment resistance. Exclusion Criteria for Randomization and Trial Entry 1. Abnormal serum/ urine metabolic lab values suggesting hypercalcemia (serum Calcium >10.4mg/dL), hypercalciuria (urine calcium/urine creatinine >0.20 mg/mg), or hyperthyroidism (parathyroid hormone (PTH) > 65pg/ml). 2. Initiation of Valproate treatment. 3. Continued use of dietary supplementation, such as fish oil supplementation or vitamin D supplements (>400 IU/day). |
结果
主要结果指标
1. Clinical response to supplementation with vitamin D. [Baseline (start of vitamin D supplementation) through ten weeks of treatment.]
次要成果指标
1. Biological response to supplementation with vitamin D. [Lead-in phase visit, baseline visit and then at biweekly visits through ten weeks of treatment.]
其他成果措施
1. Length of hospital stay. [Lead-in phase visit, baseline visit and then at biweekly visits until discharge, an expected average period from lead-in to discharge of seven weeks.]
2. Number of participants with adverse events as a measure of safety. [Throughout 10 week treatment study period.]
3. Clinical response to supplementation with vitamin D. [Baseline (start of vitamin D supplementation) through ten weeks of treatment.]
4. Clinical response to supplementation with vitamin D. [Baseline (start of vitamin D supplementation) through ten weeks of treatment.]
5. Clinical response to supplementation with vitamin D. [Baseline (start of vitamin D supplementation) through ten weeks of treatment.]
