Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, and Michael E. DeBakey V.A. Medical Center, MEDVAMC, 2002 Holcombe Blvd., Research 151, Houston, TX 77030, United States.
Neurosci Lett. 2013 Apr 29;541:29-33. doi: 10.1016/j.neulet.2013.02.037. Epub 2013 Feb 28.
We examined a pharmacogenetic association of the dopamine β-hydroxylase (DBH) gene with a response to an anti-cocaine vaccine that was tested in a recent clinical trial. This gene is associated with cocaine-induced paranoia, which has a slower onset than the euphoria from cocaine. The vaccine reduced euphoria by slowing the entry of cocaine into the brain, but it may not reduce aversive symptoms like paranoia. A 16-week Phase IIb randomized double-blind placebo-controlled trial of 114 cocaine and opioid dependent subjects who received five vaccinations over the first 12 weeks was examined. We genotyped 71 subjects for the rs1611115 (-1021C>T) variant of the DBH gene and compared vaccine to placebo subjects on cocaine-free urines. Using repeated measures analysis of variance, corrected for population structure, vaccine pharmacotherapy reduced cocaine positive urines significantly based on DBH genotype. Patients with the low DβH level genotype dropped from 77% to 51% on vaccine (p=0.0001), while those with the normal DβH level genotype dropped from 83% to 72%. Placebo showed no effect on cocaine use overall or by genotype. This study indicates that a patient's DBH genotype could be used to identify a subset of individuals for whom vaccine treatment may be an effective pharmacotherapy for cocaine dependence.
我们研究了多巴胺 β-羟化酶 (DBH) 基因与最近临床试验中抗可卡因疫苗反应的遗传关联。该基因与可卡因引起的妄想有关，其发病比可卡因引起的欣快感慢。疫苗通过减缓可卡因进入大脑的速度来减少欣快感，但它可能不会减少妄想等令人不快的症状。对接受五次疫苗接种的 114 名可卡因和阿片类药物依赖者进行了为期 16 周的 IIb 期随机双盲安慰剂对照试验，这些患者在前 12 周内接受了五次疫苗接种。我们对 71 名受试者的 DBH 基因 rs1611115(-1021C>T) 变体进行了基因分型，并在可卡因阴性尿液中比较了疫苗与安慰剂受试者。通过重复测量方差分析，并针对人群结构进行了校正，疫苗药理学治疗根据 DBH 基因型显著减少了可卡因阳性尿液。疫苗组低 DβH 水平基因型患者的比例从 77%降至 51%（p=0.0001），而正常 DβH 水平基因型患者的比例从 83%降至 72%。安慰剂对可卡因使用总体或按基因型均无影响。这项研究表明，患者的 DBH 基因型可以用于识别对疫苗治疗可能有效的可卡因依赖者亚组。
