The nature of dopamine dysfunction in schizophrenia and what this means for treatment.
The nature of dopamine dysfunction in schizophrenia and what this means for treatment.
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多巴胺功能障碍在精神分裂症中的性质，这对治疗意味着什么。
DOI：
10.1001/archgenpsychiatry.2012.169
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发表时间：
2012-08
影响因子：
--
通讯作者：
Kapur, Shitij
中科院分区：
文献类型：
--
作者：
Howes, Oliver D.;Kambeitz, Joseph;Kim, Euitae;Stahl, Daniel;Slifstein, Mark;Abi-Dargham, Anissa;Kapur, Shitij
目前精神分裂症的药物治疗对许多患者来说是不够的，尽管有50年的药物发现，但都使用相同的机制-多巴胺D2受体阻滞剂。因此，了解这种疾病的病理生理学可能对合理开发精神分裂症的新疗法至关重要。采用体内研究的荟萃分析探讨精神分裂症多巴胺能功能障碍的本质。检索MEDLINE、EMBASE和PsychINFO数据库中1960年1月1日至2011年7月1日的研究。确定了44项研究，采用正电子发射断层扫描或单光子发射计算机断层扫描比较了618例精神分裂症患者和606例对照者的体内纹状体多巴胺能功能。从每项研究中提取人口统计学、临床和影像学变量，并确定多巴胺能功能指标的效应量。研究分为突触前功能，多巴胺转运蛋白和受体的可用性。进行敏感性分析，以探讨效果的一致性和临床和影像学变量的影响。精神分裂症患者的突触前多巴胺能功能显著升高（p<0.0001），效应量较大（Cohen's d=0.79）。没有证据表明多巴胺转运蛋白的可用性发生改变。D2/3受体可用性略有升高（Cohen d=0.26），但这在药物初治患者中并不明显，并且受到所用成像方法的影响。精神分裂症中最大的多巴胺能异常的位点是突触前影响多巴胺合成能力、基线突触多巴胺水平和多巴胺释放。目前的药物治疗--主要作用于D2/3受体--未能针对这些异常。未来的药物开发应集中在控制突触前多巴胺的合成和释放能力。
Current drug treatments for schizophrenia are inadequate for many patients and, despite five decades of drug discovery, all use the same mechanism-dopamine D2 receptor blockade. Understanding the pathophysiology of the disorder is thus likely to be critical to the rational development of new treatments for schizophrenia. To investigate the nature of the dopaminergic dysfunction in schizophrenia using meta-analysis of in vivo studies. The MEDLINE, EMBASE and PsychINFO databases were searched for studies from January 1, 1960, to July 1, 2011. Forty-four studies were identified that compared in vivo striatal dopaminergic function in 618 patients with schizophrenia with 606 controls using positron emission tomography or single photon emission computed tomography. Demographic, clinical and imaging variables were extracted from each study and effect sizes determined for the measures of dopaminergic function. Studies were grouped into those of presynaptic function, and dopamine transporter and receptor availability. Sensitivity analyses were conducted to explore the consistency of effects and the effect of clinical and imaging variables. There was a highly significant elevation (p<0.0001) in presynaptic dopaminergic function in schizophrenia with a large effect size (Cohen’s d=0.79). There was no evidence of alterations in dopamine transporter availability. There was a small elevation in D2/3 receptor availability (Cohen’s d=0.26), but this was not evident in drug-naïve patients and was influenced by the imaging approach used. The locus of the largest dopaminergic abnormality in schizophrenia is presynaptic-affecting dopamine synthesis capacity, baseline synaptic dopamine levels and dopamine release. Current drug treatments - which primarily act at D2/3 receptors - fail to target these abnormalities. Future drug development should focus on the control of presynaptic dopamine synthesis and release capacity.
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影响因子：
4.5
作者：
DaoCastellana, MH;PaillereMartinot, ML;Martinot, JL
通讯作者：
Martinot, JL
影响因子：
4.1
作者：
Abi-Dargham, Anissa;Xu, Xiaoyan;Slifstein, Mark
通讯作者：
Slifstein, Mark
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
DOI：
10.3109/10799899709036618
发表时间：
1997-01-01
期刊：
JOURNAL OF RECEPTOR AND SIGNAL TRANSDUCTION RESEARCH
影响因子：
--
作者：
Bischoff, S;Gunst, F
通讯作者：
Gunst, F
DOI：
10.1017/s1461145704004110
发表时间：
2004-03-01
影响因子：
4.8
作者：
Abi-Dargham, A
通讯作者：
Abi-Dargham, A