Relationship between dopamine D2 occupancy, clinical response, and side effects:: A double-blind PET study of first-episode schizophrenia
Relationship between dopamine D2 occupancy, clinical response, and side effects:: A double-blind PET study of first-episode schizophrenia
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DOI：
10.1176/appi.ajp.157.4.514
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发表时间：
2000-04-01
影响因子：
17.7
通讯作者：
Houle, S
中科院分区：
文献类型：
--
作者：
Kapur, S;Zipursky, R;Houle, S
目标：由于所有抗精神病药物都能阻断多巴胺D-2受体，作者研究了体内D-2受体占有率如何预测临床反应、锥体外系副作用和高泌乳素血症。方法：采用双盲对照研究方法，将22例首发精神分裂症患者随机分为氟哌啶醇1.0或2.5mg/d组。治疗2周后，用[C-11]雷氯必利和正电子发射断层扫描测定D-2受体结合率，并测量临床反应、锥体外系副作用和催乳素水平。表现出充分反应的患者继续服用初始剂量，未反应的患者将剂量增加至5.0 mg/天，所有患者在4周时重复评价。结果：患者的D-2占据率范围很广（38%-87%）。受体结合程度预测临床改善、高泌乳素血症和锥体外系副作用。当D-2占用率分别超过65%、72%和78%时，临床反应、高泌乳素血症和锥体外系副作用的可能性显著增加。结论：本研究证实D-2占据率是抗精神病药物治疗反应和副作用的重要介质。这些数据与抗精神病药物作用的“靶点和触发”假设一致，即，抗精神病药的D-2受体特异性允许它们靶向离散的神经元，并且它们的拮抗剂性质在这些神经元内触发细胞内变化，最终引起抗精神病药反应。虽然仅限于氟哌啶醇，但本研究中D-2占用率与副作用之间的关系有助于解释典型和非典型抗精神病药之间观察到的许多临床差异。
Objective: Since all antipsychotics block dopamine D-2 receptors, the authors investigated how well D-2 receptor occupancy in vivo predicts clinical response, extrapyramidal side effects, and hyperprolactinemia. Method: In a double-blind study, 22 patients with first-episode schizophrenia were randomly assigned to 1.0 or 2.5 mg/day of haloperidol. After 2 weeks of treatment, D-2 receptor occupancy was determined with [C-11]raclopride and positron emission tomography and clinical response, extrapyramidal side effects, and prolactin levels were measured. Patients who showed adequate responses continued taking their initial doses, those who did not respond had their doses increased to 5.0 mg/day, and evaluations were repeated at 4 weeks for all patients. Results: The patients showed a wide range of D-2 occupancy (38%-87%). The degree of receptor occupancy predicted clinical improvement, hyperprolactinemia, and extrapyramidal side effects. The likelihood of clinical response, hyperprolactinemia, and extrapyramidal side effects increased significantly as D-2 occupancy exceeded 65%, 72%, and 78%, respectively. Conclusions: The study confirms that D-2 occupancy is an important mediator of response and side effects in antipsychotic treatment. The data are consistent with a "target and trigger" hypothesis of antipsychotic action, i.e., that the D-2 receptor specificity of antipsychotics permits them to target discrete neurons and that their antagonist properties trigger within those neurons intracellular changes that ultimately beget antipsychotic response. While limited to haloperidol, the relationship between D-2 occupancy and side effects in this study helps explain many of the observed clinical differences between typical and atypical antipsychotics.