Agid Ofer, Mamo David, Ginovart Nathalie, Vitcu Irina, Wilson Alan A, Zipursky Robert B, Kapur Shitij
Schizophrenia Program, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Neuropsychopharmacology. 2007 Jun;32(6):1209-15. doi: 10.1038/sj.npp.1301242. Epub 2006 Nov 1.
Blockade of dopamine D2 receptors remains a common feature of all antipsychotics. It has been hypothesized that the extrastriatal (cortical, thalamic) dopamine D2 receptors may be more critical to antipsychotic response than the striatal dopamine D2 receptors. This is the first double-blind controlled study to examine the relationship between striatal and extrastriatal D2 occupancy and clinical effects. Fourteen patients with recent onset psychosis were assigned to low or high doses of risperidone (1 mg vs 4 mg/day) or olanzapine (2.5 mg vs 15 mg/day) in order to achieve a broad range of D2 occupancy levels across subjects. Clinical response, side effects, striatal ([11C]-raclopride-positron emission tomography (PET)), and extrastriatal ([11C]-FLB 457-PET) D2 receptors were evaluated after treatment. The measured D2 occupancies ranged from 50 to 92% in striatal and 4 to 95% in the different extrastriatal (frontal, temporal, thalamic) regions. Striatal and extrastriatal occupancies were correlated with dose, drug plasma levels, and with each other. Striatal D2 occupancy predicted response in positive psychotic symptoms (r=0.62, p=0.01), but not for negative symptoms (r=0.2, p=0.5). Extrastriatal D2 occupancy did not predict response in positive or negative symptoms. The two subjects who experienced motor side effects had the highest striatal occupancies in the cohort. Striatal D2 blockade predicted antipsychotic response better than frontal, temporal, and thalamic occupancy. These results, when combined with the preclinical data implicating the mesolimbic striatum in antipsychotic response, suggest that dopamine D2 blockade within specific regions of the striatum may be most critical for ameliorating psychosis in schizophrenia.
阻断多巴胺D2受体仍是所有抗精神病药物的一个共同特征。有假说认为，纹状体以外（皮质、丘脑）的多巴胺D2受体可能比纹状体多巴胺D2受体在抗精神病反应中更为关键。这是第一项双盲对照研究，旨在探讨纹状体和纹状体以外区域D2受体占有率与临床疗效之间的关系。14例近期发病的精神病患者被分配接受低剂量或高剂量的利培酮（1毫克/天与4毫克/天）或奥氮平（2.5毫克/天与15毫克/天）治疗，以便在受试者中实现广泛的D2受体占有率水平。治疗后评估临床反应、副作用、纹状体（[11C] - 雷氯必利 - 正电子发射断层扫描（PET））和纹状体以外区域（[11C] - FLB 457 - PET）的D2受体情况。测得的纹状体D2受体占有率范围为50%至92%，不同纹状体以外区域（额叶、颞叶、丘脑）为4%至95%。纹状体和纹状体以外区域的占有率与剂量、药物血浆水平以及彼此之间均相关。纹状体D2受体占有率可预测阳性精神病症状的反应（r = 0.62，p = 0.01），但对阴性症状无预测作用（r = 0.2，p = 0.5）。纹状体以外区域的D2受体占有率对阳性或阴性症状的反应均无预测作用。该队列中出现运动副作用的两名受试者具有最高的纹状体占有率。纹状体D2受体阻断比额叶、颞叶和丘脑的占有率能更好地预测抗精神病反应。这些结果与临床前数据表明中脑边缘纹状体参与抗精神病反应相结合，提示纹状体内特定区域的多巴胺D2受体阻断可能对改善精神分裂症的精神病症状最为关键。
