BACKGROUND Up to 30% of patients with schizophrenia are resistant to antipsychotic drug treatment, with 60% of such cases also failing to respond to clozapine. Deep brain stimulation (DBS) has been used in treatment resistant patients with other psychiatric disorders, but there is a lack of trials in schizophrenia, partly due to uncertainties over where to site the electrodes. This trial aimed to examine the effectiveness of nucleus accumbens (NAcc) and subgenual anterior cingulate cortex (subgenual ACC) targeted DBS; the primary outcome measure was PANSS total score, as assessed fortnightly. METHODS Eight patients with schizophrenia, who met criteria for treatment resistance and were also resistant to/intolerant of clozapine, were randomly assigned using central allocation to receive DBS in the NAcc or subgenual ACC. An open stabilization phase lasting at least six months was followed by a randomized double-blind crossover phase lasting 24 weeks in those who met symptomatic improvement criteria. The primary end-point was a 25% improvement in PANSS total score. (ClinicalTrials.gov Identifier: NCT02377505; trial completed). FINDINGS One implanted patient did not receive DBS due to complications of surgery. Of the remaining 7 patients, 2/3 with NAcc and 2/4 with subgenual ACC electrode placements met the symptomatic improvement criteria (58% and 86%, and 37% and 68% improvement in PANSS total score, respectively). Three of these patients entered the crossover phase and all showed worsening when the stimulation was discontinued. The fourth patient worsened after the current was switched off accidentally without her or the investigators' knowledge. Physical adverse events were uncommon, but two patients developed persistent psychiatric adverse effects (negative symptoms/apathy and mood instability, respectively). INTERPRETATION These preliminary findings point to the possibility of DBS having therapeutic effects in patients with schizophrenia who do not respond to any other treatment. Larger trials with careful attention to blinding will be necessary to establish the extent of the benefits and whether these can be achieved without psychiatric side-effects.

中文翻译：

---

在抗药性精神分裂症中进行深部脑刺激：一项先导性随机交叉临床试验。

背景技术高达30％的精神分裂症患者对抗精神病药物治疗有抗药性，其中60％的患者对氯氮平也无反应。深部脑刺激（DBS）已用于治疗其他精神疾病的耐药患者，但是精神分裂症缺乏试验，部分原因是电极位置的不确定性。该试验旨在检查伏隔核（NAcc）和舌下前扣带回皮层（subgenual ACC）靶向DBS的有效性；每两周评估一次的主要结局指标是PANSS总分。方法八名精神分裂症患者符合治疗耐药性标准，同时对氯氮平具有耐药性/不耐受性，采用中心分配法随机分配其在NAcc或亚属ACC中接受DBS。对于符合症状改善标准的患者，开放稳定阶段持续至少六个月，然后是随机双盲交叉阶段，持续24周。主要终点是PANSS总得分提高了25％。（ClinicalTrials.gov标识符：NCT02377505；试验已完成）。结果由于手术并发症，一名植入患者未接受DBS。其余7例患者中，有2/3的NAcc和2/4的ACC电极放置在次下，符合症状改善标准（PANSS总评分分别改善了58％和86％，37％和68％）。这些患者中有3个进入交叉阶段，停止刺激后所有患者均恶化。第四名病人在电流不小心被她或研究人员所知关闭后，病情恶化。身体不良事件很少见，但两名患者持续出现精神病不良反应（分别为阴性症状/平静和情绪不稳定）。解释这些初步发现表明，DBS在对任何其他疗法无反应的精神分裂症患者中具有治疗作用的可能性。为了确定其获益的程度以及是否可以在没有精神病副作用的情况下实现这些益处，有必要特别注意盲法的大型试验。