Mechanisms underlying psychosis and antipsychotic treatment response in schizophrenia: insights from PET and SPECT imaging.
Mechanisms underlying psychosis and antipsychotic treatment response in schizophrenia: insights from PET and SPECT imaging.
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DOI：
10.2174/138161209788957528
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发表时间：
2009
影响因子：
3.1
通讯作者：
Kapur S
中科院分区：
文献类型：
--
作者：
Howes OD;Egerton A;Allan V;McGuire P;Stokes P;Kapur S
分子影像学研究在体内对精神分裂症的病因及治疗反应有了重要的认识。本文首先回顾了正电子发射断层扫描（PET）和单光子发射计算机断层扫描（SPECT）的证据，这些证据表明多巴胺能功能障碍，尤其是突触前调节异常，是精神病的一种发病机制。其次，文章总结了抗精神病作用的神经化学影像学研究，重点关注D2/3受体。这些研究表明，目前所有获批的抗精神病药物在体内都会阻断纹状体D2/3受体——这是精神分裂症中可能的主要多巴胺能病理生理学的下游位点——并且抗精神病治疗反应需要D2/3受体占有率高于一个阈值。然而，在较高的占有率水平下，诸如锥体外系副作用或高泌乳素血症等不良事件发生的可能性大大增加，这表明D2/3受体占有率存在一个最佳的“治疗窗口”，并对临床实践和试验中使用高剂量抗精神病治疗提出了质疑。抗精神病药物对D2/3的充分阻断对于抗精神病反应是必要的，但并不总是足够的。氯氮平是一种被批准用于治疗难治性精神分裂症的抗精神病药物，对其进行的分子影像学研究为了解其独特疗效的潜在机制提供了思路。为了将这种药理学与疾病的症状学联系起来，我们讨论了多巴胺在动机显著性中的作用，并展示了：i）精神病如何可被视为一种异常显著性的过程，以及ii）抗精神病药物如何通过阻断这种异常显著性来缓解症状。最后，我们讨论了这些PET和SPECT研究结果对药物研发新途径的启示。
Molecular imaging studies have generated important in vivo insights into the etiology of schizophrenia and treatment response. This article first reviews the PET and SPECT evidence implicating dopaminergic dysfunction, especially presynaptic dysregulation, as a mechanism for psychosis. Second, it summarises the neurochemical imaging studies of antipsychotic action, focussing on D2/3 receptors. These studies show that all currently licensed antipsychotic drugs block striatal D2/3 receptors in vivo-a site downstream of the likely principal dopaminergic pathophysiology in schizophrenia- and that D2/3 occupancy above a threshold is required for antipsychotic treatment response. However, adverse events, such as extra-pyramidal side-effects or hyperprolactinemia, become much more likely at higher occupancy levels, which indicates there is an optimal ‘therapeutic window’ for D2/3 occupancy, and questions the use of high doses of antipsychotic treatment in clinical practice and trials. Adequate D2/3 blockade by antipsychotic drugs is necessary but not always sufficient for antipsychotic response. Molecular imaging studies of clozapine, the one antipsychotic licensed for treatment resistant schizophrenia, have provided insights into the mechanisms underlying its unique efficacy. To link this pharmacology to the phenomenology of the illness, we discuss the role of dopamine in motivational salience and show how i) psychosis could be viewed as a process of aberrant salience, and ii) antipsychotics might provide symptomatic relief by blocking this aberrant salience. Finally, we discuss the implications of these PET and SPECT findings for new avenues of drug development.
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影响因子：
3.4
作者：
FARDE, L;WIESEL, FA;SEDVALL, G
通讯作者：
SEDVALL, G
影响因子：
7.6
作者：
Gründer, G;Landvogt, C;Bartenstein, P
通讯作者：
Bartenstein, P
影响因子：
4.5
作者：
Bose, Subrata K.;Turkheimer, Federico E.;Grasby, Paul M.
通讯作者：
Grasby, Paul M.
DOI：
10.1073/pnas.97.14.8104
发表时间：
2000-07-05
影响因子：
11.1
作者：
Abi-Dargham, A;Rodenhiser, J;Laruelle, M
通讯作者：
Laruelle, M
影响因子：
--
作者：
Agid, O;Kapur, S;Zipursky, RB
通讯作者：
Zipursky, RB