Striatal Activation Predicts Differential Therapeutic Responses to Methylphenidate and Atomoxetine
Striatal Activation Predicts Differential Therapeutic Responses to Methylphenidate and Atomoxetine
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DOI：
10.1016/j.jaac.2017.04.005
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发表时间：
2017-07-01
影响因子：
13.3
通讯作者：
Newcorn, Jeffrey H.
中科院分区：
文献类型：
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作者：
Schulz, Kurt P.;Bedard, Anne-Claude V.;Newcorn, Jeffrey H.
目的：哌甲酯在富含多巴胺的纹状体中具有显著的作用，而选择性去甲肾上腺素转运蛋白抑制剂托莫西汀则不存在这种作用。本研究测试是否基线纹状体激活将预测差异反应的两种药物在青少年注意力缺陷/多动障碍（ADHD）。方法：共36名青少年与ADHD进行了去/不去测试在基线功能磁共振成像和哌甲酯和托莫西汀使用随机交叉设计。结果：右尾状核中的任务相关激活通过对哌甲酯和托莫西汀的临床反应的相互作用来预测（F-1，F-30 = 17.00; p <0.001）。尾状核激活升高与哌甲酯的稳健改善相关，而托莫西汀的改善很小。在高（94.4% vs. 38.8%; p = 0.003;需要治疗的人数= 2，95% CI = 1.31-3.73）但不低（33.3% vs. 50.0%; p = 0.375）尾状核激活的青年中，哌甲酯的稳健缓解率高于托莫西汀。此外，对托莫西汀的反应预测了运动皮层激活（F-1，F-30 = 14.99; p < .001）。反应抑制的尾状核激活增强可能是ADHD青少年中哌甲酯反应优于托莫西汀的上级候选生物标志物，据称反映了哌甲酯而非托莫西汀在纹状体中的多巴胺能效应，而运动皮层激活可以预测对托莫西汀的反应。这些数据尚未直接转化为临床环境，但该方法对于为未来的研究提供信息具有潜在的重要性，并表明可以使用生物标志物驱动的方法预测差异治疗反应。
Objective: Methylphenidate has prominent effects in the dopamine-rich striatum that are absent for the selective norepinephrine transporter inhibitor atomoxetine. This study tested whether baseline striatal activation would predict differential response to the two medications in youth with attention-deficit/hyperactivity disorder (ADHD).Method: A total of 36 youth with ADHD performed a Go/No-Go test during functional magnetic resonance imaging at baseline and were treated with methylphenidate and atomoxetine using a randomized cross-over design. Whole-brain task-related activation was regressed on clinical response.Results: Task-related activation in right caudate nucleus was predicted by an interaction of clinical responses to methylphenidate and atomoxetine (F-1,F-30 = 17.00; p < .001). Elevated caudate activation was associated with robust improvement for methylphenidate and little improvement for atomoxetine. The rate of robust response was higher for methylphenidate than for atomoxetine in youth with high (94.4% vs. 38.8%; p = .003; number needed to treat = 2, 95% CI = 1.31-3.73) but not low (33.3% vs. 50.0%; p = .375) caudate activation. Furthermore, response to atomoxetine predicted motor cortex activation (F-1,F-30 = 14.99; p < .001).Conclusion: Enhanced caudate activation for response inhibition may be a candidate biomarker of superior response to methylphenidate over atomoxetine in youth with ADHD, purportedly reflecting the dopaminergic effects of methylphenidate but not atomoxetine in the striatum, whereas motor cortex activation may predict response to atomoxetine. These data do not yet translate directly to the clinical setting, but the approach is potentially important for informing future research and illustrates that it may be possible to predict differential treatment response using a biomarker-driven approach.