A PET study of dopamine D2 and serotonin 5-HT2 receptor occupancy in patients with schizophrenia treated with therapeutic doses of ziprasidone
A PET study of dopamine D2 and serotonin 5-HT2 receptor occupancy in patients with schizophrenia treated with therapeutic doses of ziprasidone
复制标题
DOI：
10.1176/appi.ajp.161.5.818
复制
发表时间：
2004-05-01
影响因子：
17.7
通讯作者：
Remington, G
中科院分区：
文献类型：
--
作者：
Mamo, D;Kapur, S;Remington, G
目的：齐拉西酮是一种非典型抗精神病药物，与多巴胺D-2受体相比，齐拉西酮对体外5-羟色胺5-HT2受体具有更高的亲和力。在正电子发射断层扫描（PET）研究中，齐拉西酮对患者体内这些受体的亲和力进行了检查。方法：作者对16例精神分裂症或分裂情感障碍患者进行了PET研究，以评估D-2占用（使用[C-11]raclopride）和5-HT2占用（使用[F-18]setoperone）在感兴趣的脑区域的占用，这些患者被随机分配接受40,80,120或160mg /天的齐拉西酮，这反映了推荐的剂量范围。PET扫描在给药3周后，在低谷血浆水平，即最后一次给药后12-16小时进行。结果：5-HT2受体的平均占用率显著高于D-2受体的平均占用率（平均值为76%，SD=15%，平均值为56%，SD=18%）。估计血浆齐拉西酮浓度与最大5-HT2受体占用率50%相关，几乎比D-2受体占用率低4倍。结论：这些数据证实齐拉西酮与其他新型抗精神病药物相似，在治疗剂量下，齐拉西酮的5-HT2受体占用率高于D-2受体占用率，并表明齐拉西酮的最佳有效剂量接近120mg /天，而不是先前PET研究建议的较低剂量。相对较高的D2受体占用，即使在低谷血浆水平，表明齐拉西酮在受体占用谱上更类似于利培酮和奥氮平，而不是氯氮平和喹硫平。由于齐拉西酮血浆水平在单剂量周期内表现出显著（两倍以上）变化，因此需要针对峰值血浆水平（最后一次给药后6小时）和检查肠外区域的研究，以充分表征齐拉西酮在体内的占用情况。
Objective: Ziprasidone is an atypical antipsychotic drug that shows a higher affinity for serotonin 5-HT2 receptors compared with dopamine D-2 receptors in vitro. The affinity of ziprasidone for these receptors in vivo in patients was examined in a positron emission tomography (PET) study.method: The authors conducted a PET study to evaluate D-2 occupancy (using [C-11]raclopride) and 5-HT2 occupancy (using [F-18]setoperone) in brain regions of interest in 16 patients with schizophrenia or schizoaffective disorder randomly assigned to receive 40, 80, 120, or 160 mg/ day of ziprasidone, which reflected the recommended dose range. PET scanning was done after 3 weeks of administration and at trough plasma levels, i.e., 12-16 hours after the last dose.Results: The mean 5-HT2 receptor occupancy was significantly higher than the mean D-2 receptor occupancy (mean=76%, SD=15%, and mean=56%, SD=18%, respectively). The estimated plasma ziprasidone concentration associated with 50% maximal 5-HT2 receptor occupancy was almost four times lower than that for D-2 receptor occupancy.Conclusions: These data affirm that ziprasidone is similar to other novel antipsychotics in having greater 5-HT2 than D-2 receptor occupancy at therapeutic doses and suggest that the optimal effective dose of ziprasidlone is closer to 120 mg/day than to the lower doses suggested by previous PET studies. The relatively high D2 receptor occupancy, even at trough plasma levels, suggests that ziprasidone is more similar to risperidone and olanzapine in receptor occupancy profile than to clozapine and quetiapine. Since ziprasidone plasma levels show significant (more than twofold) variation within a single dose cycle, studies that are aimed at peak plasma levels (6 hours after the last dose) and that examine extrastriatal regions are required to fully characterize the in vivo occupancy profile of ziprasidone.