Biol Psychiat：精神科药物影响大脑结构

作者：Beyond来源：生物谷2012-5-10 8:19:52


越来越多地人认识到慢性精神科药物治疗可能会导致大脑结构重塑。事实上，在临床研究中有一个有趣的画面：用于治疗精神分裂症和精神病的抗精神病药物可能有助于防止患者的皮质灰质损失，而用于治疗躁郁症和躁狂症的锂可以保存患者对的灰质。相关研究论文发表在Biological Psychiatry杂志上。

然而，这些结构性变化的临床意义尚不清楚。执行对照、随机研究评估这个问题需面临许多挑战，也有很多干扰因素包括疾病的严重程度、病程和其他药物的服用。

因此，开发动物模型显得非常关键。近日，伦敦大学国王学院Shitij Kapur博士领导的研究小组用临床相关的药物暴露和纵向磁共振成像匹配结合临床用药制定了一种大鼠模型。他们给予大鼠剂量相当于人剂量的锂盐或氟哌啶醇（一种常见的抗精神病药物）。大鼠每天接受这种治疗八周，相当于人接受治疗5年，并接受了治疗前后的脑部扫描。

Kapur博士解释说，使用这种方法我们观察到，治疗慢性氟哌啶醇导致灰质跌幅，而锂诱导的灰质增加，停药后效果是可逆的。氟哌啶醇治疗后灰质下降了6％，但锂治疗后灰质增加了的3％。

研究人员表示：无论大脑结构发生这些变化后是否背有利，这些药物的副作用都有待观察。虽然这些有趣的发现是与现有的临床数据是一致的，部分原因是因为这些研究在正常大鼠身上开展。此外，因为这些药物作用机制尚不清楚，进一步的研究仍很需要，在制定临床结论时应该谨慎。然而我们的研究表明，一个新的、强大的模型系统有助于进一步调查研究药物治疗对脑结构的影响。



Contrasting Effects of Haloperidol and Lithium on Rodent Brain Structure: A Magnetic Resonance Imaging Study with Postmortem Confirmation

Anthony C. Vernon, Sridhar Natesan, William R. Crum, Jonathan D. Cooper, Michel Modo, Steven C.R. Williams, Shitij Kapur

Background
Magnetic resonance imaging (MRI) studies suggest that antipsychotic -treated patients with schizophrenia show a decrease in gray-matter volumes, whereas lithium-treated patients with bipolar disorder show marginal increases in gray-matter volumes. Although these clinical data are confounded by illness, chronicity, and other medications, they do suggest that typical antipsychotic drugs and lithium have contrasting effects on brain volume.

Methods
Rodent models offer a tractable system to test this hypothesis, and we therefore examined the effect of chronic treatment (8 weeks) and subsequent withdrawal (8 weeks) with clinically relevant dosing of an antipsychotic (haloperidol, HAL) or lithium (Li) on brain volume using longitudinal in vivo structural MRI and confirmed the findings postmortem using unbiased stereology.

Results
Chronic HAL treatment induced decreases in whole brain volume (−4%) and cortical gray matter (−6%), accompanied by hypertrophy of the corpus striatum (+14%). In contrast, chronic Li treatment induced increases in whole-brain volume (+5%) and cortical gray matter (+3%) without a significant effect on striatal volume. Following 8 weeks of drug withdrawal, HAL-induced changes in brain volumes normalized, whereas Li-treated animals retained significantly greater total brain volumes, as confirmed postmortem. However, the distribution of these contrasting changes was topographically distinct: with the haloperidol decreases more prominent rostral, the lithium increases were more prominent caudal.

Conclusions
The implications of these findings for the clinic, potential mitigation strategies, and further drug development are discussed.