Superolateral medial forebrain bundle deep brain stimulation in major depression: a gateway trial
Superolateral medial forebrain bundle deep brain stimulation in major depression: a gateway trial
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DOI：
10.1038/s41386-019-0369-9
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发表时间：
2019-06-01
影响因子：
7.6
通讯作者：
Schlaepfer, Thomas E.
中科院分区：
文献类型：
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作者：
Coenen, Volker A.;Bewernick, Bettina H.;Schlaepfer, Thomas E.
在开放标签研究中，脑深部电刺激（DBS）对难治性抑郁症（TRD）的短期和长期抗抑郁作用已被证明适用于几个脑靶点。对于两个刺激目标，已经进行了关键随机试验;两者都未能通过徒劳分析。我们在一项小型I期临床研究中评估了内侧前脑束（slMFB）上外侧分支DBS的有效性和安全性，该研究采用随机对照刺激开始，以获得大型RCT计划的数据。16名TRD患者接受了slMFB的DBS，并在植入后2个月内随机接受假刺激或真实的刺激。主要结局指标为DBS治疗12个月期间蒙哥马利-艾斯伯格抑郁评定量表（MADRS）的平均降低（时间轴分析）。次要结局是8周时和刺激阶段期间假刺激和真实的刺激之间的几项临床指标差异。MADRS评分从基线时的29.6（SD +/- 4）显著下降至DBS治疗12个月期间的12.9（SD +/-9）（平均MADRS，n = 16）。所有患者均达到缓解标准，大多数患者（n = 10）在1周内缓解; 50%的患者在刺激1年后被归类为缓解者。最常见的副作用是暂时性斜视。两组（活性组/假组）均表现出抗抑郁微损伤作用，但患者在开始刺激后具有额外的抗抑郁作用。在我们之前的初步研究中，证明了slMFB-DBS的抗抑郁作用的快速起效和稳定性。鉴于DBS治疗MDD的关键性试验的最新经验，我们认为缓慢、仔细和适应性的研究开发是有关系的。在我们的探索性研究和大规模研究之后，我们进行了这项网关试验，以便更好地为后者的规划提供信息。讨论了严重和慢性疾病DBS领域RCT规划的重要方面，包括个体内和组间比较的有意义阶段以及时间轴而不是单终点分析。
Short-and long-term antidepressant effects of deep brain stimulation (DBS) in treatment-resistant depression (TRD) have been demonstrated for several brain targets in open-label studies. For two stimulation targets, pivotal randomized trials have been conducted; both failed a futility analysis. We assessed efficacy and safety of DBS of the supero-lateral branch of the medial forebrain bundle (slMFB) in a small Phase I clinical study with a randomized-controlled onset of stimulation in order to obtain data for the planning of a large RCT. Sixteen patients suffering from TRD received DBS of the slMFB and were randomized to sham or real stimulation for the duration of 2 months after implantation. Primary outcome measure was mean reduction in Montgomery-Asberg Depression Rating Scale (MADRS) during 12 months of DBS (timeline analysis). Secondary outcomes were the difference in several clinical measures between sham and real stimulation at 8 weeks and during stimulation phases. MADRS ratings decreased significantly from 29.6 (SD +/- 4) at baseline to 12.9 (SD +/-9) during 12 months of DBS (mean MADRS, n = 16). All patients reached the response criterion, most patients (n = 10) responded within a week; 50% of patients were classified as remitters after 1 year of stimulation. The most frequent side effect was transient strabismus. Both groups (active/sham) demonstrated an antidepressant micro-lesioning effect but patients had an additional antidepressant effect after initiation of stimulation. Both rapid onset and stability of the antidepressant effects of slMFB-DBS were demonstrated as in our previous pilot study. Given recent experiences from pivotal trials in DBS for MDD, we believe that slow, careful, and adaptive study development is germane. After our exploratory study and a large-scale study, we conducted this gateway trial in order to better inform planning of the latter. Important aspects for the planning of RCTs in the field of DBS for severe and chronic diseases are discussed including meaningful phases of intra-individual and between-group comparisons and timeline instead of single endpoint analyses.