Howes Oliver D, Kambeitz Joseph, Kim Euitae, Stahl Daniel, Slifstein Mark, Abi-Dargham Anissa, Kapur Shitij
Department of Psychosis Studies, Institute of Psychiatry, King's College London, Camberwell, UK.
Arch Gen Psychiatry. 2012 Aug;69(8):776-86. doi: 10.1001/archgenpsychiatry.2012.169.
Current drug treatments for schizophrenia are inadequate for many patients, and despite 5 decades of drug discovery, all of the treatments rely on the same mechanism: dopamine D(2) 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 PsycINFO databases were searched for studies from January 1, 1960, to July 1, 2011.
A total of 44 studies were identified that compared 618 patients with schizophrenia with 606 controls, using positron emission tomography or single-photon emission computed tomography to measure in vivo striatal dopaminergic function.
Demographic, clinical, and imaging variables were extracted from each study, and effect sizes were determined for the measures of dopaminergic function. Studies were grouped into those of presynaptic function and those of 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.<001) in presynaptic dopaminergic function in schizophrenia with a large effect size (Cohen d=0.79). There was no evidence of alterations in dopamine transporter availability. There was a small elevation in D(2/3) receptor availability (Cohen d=0.26), but this was not evident in drug-naive patients and was influenced by the imaging approach used.
The locus of the largest dopaminergic abnormality in schizophrenia is presynaptic, which affects dopamine synthesis capacity, baseline synaptic dopamine levels, and dopamine release. Current drug treatments, which primarily act at D(2/3) receptors, fail to target these abnormalities. Future drug development should focus on the control of presynaptic dopamine synthesis and release capacity.
目前用于治疗精神分裂症的药物对许多患者并不充分，尽管经过了50年的药物研发，但所有治疗方法都依赖于相同的机制：多巴胺D(2)受体阻断。因此，了解该疾病的病理生理学可能对精神分裂症新治疗方法的合理开发至关重要。
通过对体内研究的荟萃分析来研究精神分裂症中多巴胺能功能障碍的本质。
检索了MEDLINE、EMBASE和PsycINFO数据库中1960年1月1日至2011年7月1日期间的研究。
共确定了44项研究，这些研究使用正电子发射断层扫描或单光子发射计算机断层扫描来测量体内纹状体多巴胺能功能，将618例精神分裂症患者与606例对照进行比较。
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测量的效应大小。研究分为突触前功能研究以及多巴胺转运体和受体可用性研究。进行敏感性分析以探讨效应的一致性以及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有极显著升高（P<0.001），效应大小较大（Cohen d=0.79）。没有证据表明多巴胺转运体可用性有改变。D(2/3)受体可用性有小幅升高（Cohen d=0.26），但在未用药患者中不明显，且受所用影像学方法影响。
精神分裂症中最大的多巴胺能异常部位是突触前，这会影响多巴胺合成能力、基线突触多巴胺水平和多巴胺释放。目前主要作用于D(2/3)受体的药物治疗未能针对这些异常。未来的药物开发应侧重于控制突触前多巴胺合成和释放能力。
