Nugent Allison C, Iadarola Nicolas D, Miller Frank G, Luckenbaugh David A, Zarate Carlos A
Experimental Therapeutics and Pathophysiology Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA.
The Department of Bioethics, Clinical Center, National Institutes of Health, Bethesda, MD, USA.
Lancet Psychiatry. 2016 May;3(5):436-42. doi: 10.1016/S2215-0366(16)00006-7. Epub 2016 Mar 10.
Placebo-controlled trials in drug-free patients have long been considered a key research component in the study of mood disorders and relevant treatment mechanisms. However, concerns have been raised about the ethics of such research, leading to an ongoing debate as to whether placebo controls are ethically acceptable. We aimed to assess the cumulative effects of research in individuals with mood disorders and to provide data to address ethical concerns regarding research in this population.
We obtained empirical data for patients screened between between Dec 13, 2001, and Jan 31, 2014, with either major depressive disorder or bipolar disorder who were enrolled in one or more of 18 clinical trials at a US National Institute of Mental Health (NIMH) inpatient or outpatient behavioural health research clinic. We assessed the cumulative effects of research in our patient population, including the effects of drug taper, drug washout, and placebo administration on mood state. Two subgroups were examined: patients enrolled in trials explicitly requiring treatment resistance and patients with a current or past history of suicidal ideation or behaviour. We used the percentage change from screening as the primary outcome measure for statistical analysis of change in mood over study periods. This study is registered with ClinicalTrials.gov, number NCT00024635.
We obtained data for 540 patients; 360 (71%) patients were enrolled in trials requiring treatment resistance, 58 (12%) of 465 patients had suicidal ideation at screening, and 191 (60%) of 321 patients had a history of suicidal ideation. Mean mood severity at screening was in the moderate to severe range. Full participation in research, including drug tapers, drug-free periods, and placebo-controlled trials, had a low risk of symptom exacerbation. Patients undergoing drug taper had a mean increase in symptom severity of 4·2% (SD 19·56, tdegrees of freedom 96=1·85; p=0·036). We recorded modest increases in the subgroup who tapered to no medications (mean percentage change 5·1% [SD 18·10], t56=2·12; p=0·039), but increases were not significant in participants enrolled in trials requiring treatment resistance (4·3% [18·60], t72=1·96; p=0·054) and those with a current or past history of suicidal ideation or behaviour (1·8% [18·78], t51=0·68; p=0·50). Six serious adverse events were reported, including one suicide attempt that occurred during the standard treatment phase and not during the clinical trial.
In general, research participation at the NIMH was not detrimental to health and safety, and conferred benefit in many cases. This finding was true not only in our entire research population, but also in treatment-resistant subgroups and subgroups with a history of suicidality. Our study provides evidence to guide ethical analysis of issues in psychiatric research, and to support continued scientific investigation.
Intramural Research Program, NIMH, National Institutes of Health.
长期以来，在未服用药物的患者中进行安慰剂对照试验一直被视为情绪障碍及相关治疗机制研究的关键组成部分。然而，此类研究的伦理问题引发了人们的关注，导致关于安慰剂对照在伦理上是否可接受的争论持续不断。我们旨在评估针对情绪障碍患者的研究的累积影响，并提供数据以解决有关该人群研究的伦理问题。
我们获取了2001年12月13日至2014年1月31日期间在美国国立精神卫生研究所（NIMH）住院或门诊行为健康研究诊所参与18项临床试验中的一项或多项试验的、患有重度抑郁症或双相情感障碍的患者的经验数据。我们评估了针对我们患者群体的研究的累积影响，包括减药、药物洗脱和给予安慰剂对情绪状态的影响。研究了两个亚组：参加明确要求有治疗抵抗性的试验的患者，以及有当前或既往自杀意念或行为史的患者。我们将筛查时的百分比变化用作研究期间情绪变化统计分析的主要结局指标。本研究已在ClinicalTrials.gov注册，编号为NCT00024635。
我们获取了540例患者的数据；360例（71%）患者参加了要求有治疗抵抗性的试验，465例患者中有58例（12%）在筛查时有自杀意念，321例患者中有191例（60%）有自杀意念史。筛查时的平均情绪严重程度处于中度至重度范围。全面参与研究，包括减药、无药期和安慰剂对照试验，症状加重的风险较低。减药患者的症状严重程度平均增加了4.2%（标准差19.56，自由度为96时t值 = 1.85；p = 0.036）。我们记录到减至未用药的亚组有适度增加（平均百分比变化5.1% [标准差18.10]，自由度为56时t值 = 2.12；p = 0.039），但在参加要求有治疗抵抗性的试验的参与者中增加不显著（4.3% [18.60]，自由度为72时t值 = 1.96；p = 0.054），在有当前或既往自杀意念或行为史的患者中也不显著（1.8% [18.78]，自由度为51时t值 = 0.68；p = 0.50）。报告了6例严重不良事件，包括1例自杀未遂，该事件发生在标准治疗阶段而非临床试验期间。
总体而言，在NIMH参与研究对健康和安全无害，并且在许多情况下带来益处。这一发现不仅在我们的整个研究人群中成立，在治疗抵抗性亚组和有自杀史亚组中也是如此。我们 的研究为指导精神病学研究问题的伦理分析以及支持持续的科学调查提供了证据。
国立卫生研究院NIMH内部研究项目。
