深部脑刺激对抑郁有积极效果

巴塞罗那——过去10年间，在难治性抑郁(TRD)患者中进行的深部脑刺激(DBS)研究取得了积极结果，但仍处于早期研究阶段，目前全球的总治疗例数仅约为60例，包括在6个不同脑区置入DBS电极的患者。

欧洲神经精神药理学学院年会上公布的一项初步研究结果表明，伏核是置入DBS电极的较佳目标位置之一。


Bruno Millet医生

法国雷恩大学精神病学教授Bruno Millet医生及其来自另外9个法国中心的同事对2009年开始在伏核置入DBS电极的4例患者进行了研究。Millet医生表示，选择伏核作为置入位置是因为其位于参与重性抑郁障碍的回路的中心，并且在奖赏回路及其功能障碍中发挥重要作用。所有置入DBS电极的患者均患有5期TRD，这意味着患者的抑郁对所有可能的药物类别(单胺氧化酶抑制剂)均无反应。这些患者对电休克治疗也无充分反应。刺激强度为1.5~4 V。所有4例患者的抑郁在治疗后最初6个月逐渐改善。随访1年后，所有患者仍有治疗反应，定义为汉密尔顿抑郁量表(HRSD)评分相对基线降低至少50%。1例患者获得缓解，定义为HRSD评分＜10。随访15个月期间，无1例患者出现躯体不良反应，但1例患者出现情绪恶化和焦虑并有自杀企图；1例患者出现情绪和睡眠恶化及进食增加；1例患者出现感觉异常。

伏核置入DBS电极的样本量最大且随访时间最长的TRD病例系列是在德国接受治疗的11例患者。这些患者出现了轻微不良反应。11例患者中5例有治疗反应，并且治疗反应在随访4年期间保持稳定(Neuropsychopharmacology 2012;37:1975-85)。另一个产生显著结果的置入位置是内侧前脑束，同一德国研究小组在7例患者中观察到良好的DBS结果。今年早些时候，这些研究者报告7例患者中6例有治疗反应，并且4例的抑郁在随访3~7个月后获得缓解(Biol. Psychiatry 2013;73:1204-12)。被其他研究小组成功使用的另外2个目标脑区是膝下扣带回及腹侧囊和腹侧纹状体(World Neurosurg. 2013;80:S27.e17-24)。

Millet医生的研究由销售DBS治疗装置Reclaim的美敦力公司资助。该公司主要销售其DBS装置用于治疗帕金森病、原发性震颤和肌张力障碍，但在2009年，美国食品药品管理局(FDA)还在人道主义器械豁免程序下批准其用于治疗强迫性精神障碍。一些医学伦理学家、精神病科医生和神经外科医生质疑DBS在缺乏随机对照试验证实其疗效的情况下被日益用于治疗强迫性精神障碍，称这是对该装置的“误用”(Health Aff. 2011;30:302-11 )。

Millet医生表示，目前尚缺乏有关DBS的随机对照试验。他和同事目前已将研究网络扩大至12个中心(包括1个在日内瓦的中心)，他们已设计并正在开始一项美敦力资助的试验，将在所有患者中置入DBS导联，但在置入导联后的最初7个月将暂时不对半数的患者进行刺激。

Millet医生声明从美敦力公司获得资助，并且是其他9家药物或器械公司的顾问、讲师，或从这些公司获得研究资金。

爱思唯尔版权所有  未经授权请勿转载

By: MITCHEL L. ZOLER, Clinical Neurology News Digital Network

BARCELONA – Assessment of deep brain stimulation for patients with treatment-resistant depression has inched forward over the past decade with promising results but remains in its early days with a total worldwide experience of roughly 60 patients.

That total includes patients who have received deep brain stimulation (DBS) leads placed in six different brain regions. However, the results suggest that one of the better target locations for DBS in patients with treatment-resistant depression (TRD) is in the nucleus accumbens, Dr. Bruno Millet said at the annual congress of the European College of Neuropsychopharmacology.
 
"The nucleus accumbens is a very good target that we will continue to study. It is very safe, and the surgery is easy and rapid. The nucleus accumbens has a good benefit-to-risk ratio," said Dr. Millet, professor of psychiatry at the University of Rennes (France). "This is a strength of this target."

The nucleus accumbens became a target because it is "at the center of a circuit involved in major depressive disorder," and plays a "central role in reward circuitry and its dysfunctions," he added.

All patients who have received DBS had stage 5 TRD, which meant that their depression was unresponsive to all possible drug classes, including monamine oxidase inhibitors. These patients also failed to adequately respond to electroconvulsive therapy.

Dr. Millet and his associates at nine other French centers ran a pilot study with four patients who received DBS in the nuclear accumbens starting in 2009. Patients received stimulation at a level of 1.5-4 V. All four patients showed gradual improvement in their depression during the first 6 months after treatment. After 1 year of follow-up, all patients had responded, with response defined as at least a 50% decline from the baseline Hamilton Rating Scale for Depression (HRSD) score. One patient went into remission, defined as an HRSD score of less than 10. None of the patients had somatic adverse effects during 15 months of follow-up, but one patient had worsening mood and anxiety and made a suicide attempt; one patient had worsening mood and sleep and increased food intake; and one patient developed paresthesia.

The largest patient series and the longest follow-up of patients who received DBS in their nucleus accumbens for TRD involved 11 patients treated in Germany. The patients had minimal adverse effects, and 5 of the 11 responded, with the response remaining stable during 4 years of follow-up (Neuropsychopharmacology 2012;37:1975-85).

Another target that produced notable results is the medial forebrain bundle, which led to good DBS results in seven patients treated by the same German team. Earlier this year, the investigators reported that six of the seven patients had responded and four patients had reached remission of their depression after 3-7 months of follow-up (Biol. Psychiatry 2013;73:1204-12). Two other brain targets that have been used by other groups with success are the subgenual cingulate gyrus, and the ventral capsule and ventral striatum (World Neurosurg. 2013;80:S27.e17-24).

But "one of the striking things in DBS for the moment is the lack of any randomized controlled trials," Dr. Millet said. He and his French associates have expanded their network to 12 centers, including one in Geneva, and they have designed and are now starting a trial that will place DBS leads in all patients but will withhold active stimulation in half the patients for the first 7 months after lead placement. This trial is sponsored by Medtronic, a company that markets the DBS device Reclaim.

Medtronic primarily markets its DBS device for the treatment of Parkinson’s disease, essential tremor, and dystonia, but in 2009, the Food and Drug Administration also approved its use to treat obsessive-compulsive disorder under a humanitarian device exemption. Some medical ethicists, psychiatrists, and neurosurgeons have questioned the growing use of DBS for obsessive-compulsive disorder in the absence of evidence for its efficacy in a randomized controlled trial, calling this practice "misuse" of the device (Health Aff. 2011;30:302-11). One of these critics, Dr. Thomas E. Schlaepfer of Bonn, Germany, also is head of the group with perhaps the largest experience in using DBS to treat patients with depression.

Dr. Millet said he has received grant support from Medtronic, marketer of the Reclaim DBS therapy device. He also said he has been a consultant to, has been a speaker for, or has received research funding from nine other drug or device companies.