Equivalent occupancy of dopamine D1 and D2 receptors with clozapine:: Differentiation from other atypical antipsychotics
Equivalent occupancy of dopamine D1 and D2 receptors with clozapine:: Differentiation from other atypical antipsychotics
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DOI：
10.1176/appi.ajp.161.9.1620
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发表时间：
2004-09-01
影响因子：
17.7
通讯作者：
Kapur, S
中科院分区：
文献类型：
--
作者：
Tauscher, J;Hussain, T;Kapur, S
目的：氯氮平作为非典型抗精神病药的原型，在治疗难治性精神分裂症方面仍有独特的疗效。其对多巴胺D（4）受体的亲和力、5-羟色胺5-HT（2A）受体拮抗作用、对去甲肾上腺素能系统的影响以及相对中等的D（2）受体占用率不太可能是其疗效的关键机制。为了阐明氯氮平治疗难治性精神分裂症的分子/突触机制，作者研究了氯氮平与其他非典型抗精神病药的体内D（1）和D（2）受体谱。放射性配体[（11）C] SCH 23390和[（11）C]雷氯必利的正电子发射断层扫描用于研究D，结果：平均纹状体D_1占据率范围从氯氮平组的55%到奎替尼组的12%（排序：氯氮平>奥氮平>利培酮>奎替尼）。纹状体D（2）占据率从利培酮的81%到奎替利的30%不等（排序：利培酮>奥氮平>氯氮平>奎替利）。纹状体D（1）/D（2）占有率的比值氯氮平（0.88）显著高于奥氮平（0.54）、奎替鲁（0.41）或利培酮（0.31）。结论：在非典型抗精神病药中，氯氮平似乎具有多巴胺D（1）和D（2）受体的同时和相等的占有率。其对D（1）受体的作用是激动还是拮抗尚不清楚，因为这一问题在临床前竞技场中仍未解决。这种对D（1）/D（2）受体的独特作用可能是氯氮平对其他典型和非典型抗精神病药难治性精神分裂症患者独特疗效的原因。
Objective: Clozapine, the prototype of atypical antipsychotics, remains unique in its efficacy in the treatment of refractory schizophrenia. Its affinity for dopamine D(4) receptors, serotonin 5-HT(2A) receptor antagonism, effects on the noradrenergic system, and its relatively moderate occupancy of D(2) receptors are unlikely to be the critical mechanism underlying its efficacy. In an attempt to elucidate the molecular/synaptic mechanism underlying clozapine's distinctiveness in refractory schizophrenia, the authors studied the in vivo D(1) and D(2) receptor profile of clozapine compared with other atypical antipsychotics.Method: Positron emission tomography with the radioligands [(11)C]SCH23390 and [(11)C]raclopride was used to investigate D, and D(2) receptor occupancy in vivo in 25 schizophrenia patients receiving atypical antipsychotic treatment with clozapine, olanzapine, quetiapine, or risperidone.Results: Mean striatal D, occupancies ranged from 55% with clozapine to 12% with quetiapine (rank order: clozapine > olanzapine > risperidone > quetiapine). The striatal D(2) occupancy ranged from 81% with risperidone to 30% with quetiapine (rank order: risperidone > olanzapine > clozapine > quetiapine). The ratio of striatal D(1)/D(2) occupancy was significantly higher for clozapine (0.88) relative to olanzapine (0.54), quetiapine (0.41), or risperidone (0.31).Conclusions: Among the atypical antipsychotics, clozapine appears to have a simultaneous and equivalent occupancy of dopamine D(1) and D(2) receptors. Whether its effect on D(1) receptors represents agonism or antagonism is not yet clear, as this issue is still unresolved in the preclinical arena. This distinctive effect on D(1)/D(2) receptors may be responsible for clozapine's unique effectiveness in patients with schizophrenia refractory to other typical and atypical antipsychotics.