Kessler Robert M, Ansari M Sib, Riccardi Patrizia, Li Rui, Jayathilake Karuna, Dawant Benoit, Meltzer Herbert Y
Department of Radiology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Neuropsychopharmacology. 2006 Sep;31(9):1991-2001. doi: 10.1038/sj.npp.1301108. Epub 2006 May 31.
Clozapine and quetiapine have a low incidence of extrapyramidal side effects at clinically effective doses, which appears to be related to their significantly lower occupancy of striatal dopamine D2 receptors (DA D2r) compared to typical antipsychotic drugs (APDs). Animal studies have indicated that clozapine and quetiapine produce selective effects on cortical and limbic regions of the brain and in particular on dopaminergic neurotransmission in these regions. Previous PET and SPECT studies have reported conflicting results regarding whether clozapine produces preferential occupancy of cortical DA D2r. To examine whether clozapine and/or quetiapine produce preferential occupancy of DA D2r in cortex and limbic regions, we studied the occupancy of putamenal, ventral striatal, thalamic, amygdala, substantia nigra, and temporal cortical DA D2r using PET with [18F]fallypride in six schizophrenic subjects receiving clozapine monotherapy and in seven schizophrenic subjects receiving quetiapine monotherapy. Doses were chosen clinically to minimize psychopathology at tolerable levels of side effects such as drowsiness. All had minimal positive symptoms at the time of the study. Regional receptor occupancies were estimated using mean regional DA D2r levels calculated for 10 off-medication schizophrenic subjects. Both clozapine and quetiapine produced lower levels of putamenal DA D2r occupancy than those reported for typical APDs, 47.8 and 33.5%, respectively. Clozapine produced preferential occupancy of temporal cortical vs putamenal DA D2r, 59.8% (p=0.05, corrected for multiple comparisons), and significantly lower levels of occupancy in the substantia nigra, 18.4% (p=0.0015, corrected for multiple comparisons). Quetiapine also produced preferential occupancy of temporal cortical DA D2r, 46.9% (p=0.03, corrected for multiple comparisons), but did not spare occupancy of substantia nigra DA D2r. The therapeutic effects of clozapine and quetiapine appear to be achieved at less than the 65% threshold for occupancy seen with typical APDs, consistent with the involvement of non-DA D2r mechanisms in at least partially mediating the therapeutic effects of these drugs. Preferential occupancy of cortical DA D2r, sparing occupancy of substantia nigra receptors, and non-DA D2r-mediated actions may contribute to the antipsychotic actions of these and other atypical APDs.
氯氮平和喹硫平在临床有效剂量下锥体外系副作用的发生率较低，这似乎与其与典型抗精神病药物（APD）相比，纹状体多巴胺D2受体（DA D2r）占有率显著降低有关。动物研究表明，氯氮平和喹硫平对大脑皮质和边缘区域产生选择性作用，特别是对这些区域的多巴胺能神经传递产生选择性作用。先前的PET和SPECT研究报告了关于氯氮平是否优先占据皮质DA D2r的相互矛盾的结果。为了研究氯氮平和/或喹硫平是否优先占据皮质和边缘区域的DA D2r，我们使用[18F]氟哌利多PET研究了6例接受氯氮平单一疗法的精神分裂症患者和7例接受喹硫平单一疗法的精神分裂症患者的壳核、腹侧纹状体、丘脑、杏仁核、黑质和颞叶皮质DA D2r的占有率。临床选择剂量以在可耐受的副作用水平（如嗜睡）下使精神病理学最小化。在研究时，所有患者的阳性症状均最少。使用为10例未服药的精神分裂症患者计算的平均区域DA D2r水平估计区域受体占有率。氯氮平和喹硫平产生的壳核DA D2r占有率均低于典型APD报告的水平，分别为47.8%和33.5%。氯氮平产生颞叶皮质DA D2r相对于壳核DA D2r的优先占有率，为59.8%（p=0.05，经多重比较校正），黑质的占有率显著较低，为18.4%（p=0.0015，经多重比较校正）。喹硫平也产生颞叶皮质DA D2r的优先占有率，为46.9%（p=0.03，经多重比较校正），但未使黑质DA D2r的占有率降低。氯氮平和喹硫平的治疗效果似乎是在低于典型APD所见的65%占有率阈值时实现的，这与非DA D2r机制至少部分介导这些药物的治疗效果一致。皮质DA D2r的优先占有率、黑质受体占有率的降低以及非DA D2r介导的作用可能有助于这些及其他非典型APD的抗精神病作用。
