Kapur S, Zipursky R, Jones C, Remington G, Houle S
Department of Psychiatry, University of Toronto, ON, Canada.
Am J Psychiatry. 2000 Apr;157(4):514-20. doi: 10.1176/appi.ajp.157.4.514.
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.
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 [(11)C]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.
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.
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.
由于所有抗精神病药物均会阻断多巴胺D(2)受体，作者研究了体内D(2)受体占有率对临床反应、锥体外系副作用及高催乳素血症的预测效果。
在一项双盲研究中，22例首发精神分裂症患者被随机分配至每日服用1.0或2.5mg氟哌啶醇的治疗组。治疗2周后，使用[11C]雷氯必利和正电子发射断层扫描测定D(2)受体占有率，并测量临床反应、锥体外系副作用及催乳素水平。反应充分的患者继续服用初始剂量，无反应者将剂量增至每日5.0mg，所有患者在4周时重复评估。
患者的D(2)占有率范围较广（38%-87%）。受体占有率程度可预测临床改善情况、高催乳素血症及锥体外系副作用。当D(2)占有率分别超过65%、72%和78%时，临床反应、高催乳素血症及锥体外系副作用的可能性显著增加。
该研究证实，D(2)占有率是抗精神病治疗中反应及副作用的重要介导因素。数据与抗精神病作用的“靶向和触发”假说一致，即抗精神病药物的D(2)受体特异性使其能够靶向离散神经元，且其拮抗特性在这些神经元内触发细胞内变化，最终产生抗精神病反应。尽管该研究仅限于氟哌啶醇，但D(2)占有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物之间许多已观察到的临床差异。
