Setiawan Elaine, Attwells Sophia, Wilson Alan A, Mizrahi Romina, Rusjan Pablo M, Miler Laura, Xu Cynthia, Sharma Sarita, Kish Stephen, Houle Sylvain, Meyer Jeffrey H
Research Imaging Centre and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada.
Research Imaging Centre and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
Lancet Psychiatry. 2018 Apr;5(4):339-347. doi: 10.1016/S2215-0366(18)30048-8. Epub 2018 Feb 26.
People with major depressive disorder frequently exhibit increasing persistence of major depressive episodes. However, evidence for neuroprogression (ie, increasing brain pathology with longer duration of illness) is scarce. Microglial activation, which is an important component of neuroinflammation, is implicated in neuroprogression. We examined the relationship of translocator protein (TSPO) total distribution volume (V), a marker of microglial activation, with duration of untreated major depressive disorder, and with total illness duration and antidepressant exposure.
In this cross-sectional study, we recruited participants aged 18-75 years from the Toronto area and the Centre for Addiction and Mental Health (Toronto, ON, Canada). Participants either had major depressive episodes secondary to major depressive disorder or were healthy, as confirmed with a structured clinical interview and consultation with a study psychiatrist. To be enrolled, participants with major depressive episodes had to score a minimum of 17 on the 17-item Hamilton Depression Rating Scale, and had to be medication free or taking a stable dose of medication for at least 4 weeks before PET scanning. Eligible participants were non-smokers; had no history of or concurrent alcohol or substance dependence, neurological illness, autoimmune disorder, or severe medical problems; and were free from acute medical illnesses for the previous 2 weeks before PET scanning. Participants were excluded if they had used brain stimulation treatments within the 6 months before scanning, had used anti-inflammatory drugs lasting at least 1 week within the past month, were taking hormone replacement therapy, had psychotic symptoms, had bipolar disorder (type I or II) or borderline antisocial personality disorder, or were pregnant or breastfeeding. We scanned three primary grey-matter regions of interest (prefrontal cortex, anterior cingulate cortex, and insula) and 12 additional regions and subregions using F-FEPPA PET to measure TSPO V. We investigated the duration of untreated major depressive disorder, and the combination of total duration of disease and duration of antidepressant treatment, as predictor variables of TSPO V, assessing their significance.
Between Sept 1, 2009, and July 6, 2017, we screened 134 participants for eligibility, of whom 81 were included in the study (current major depressive episode n=51, healthy n=30). We excluded one participant with a major depressive episode from the analysis because of unreliable information about previous medication use. Duration of untreated major depressive disorder was a strong predictor of TSPO V (p<0·0001), as were total illness duration (p=0·0021) and duration of antidepressant exposure (p=0·037). The combination of these predictors accounted for about 50% of variance in TSPO V in the prefrontal cortex, anterior cingulate cortex, and insula. In participants who had untreated major depressive disorder for 10 years or longer, TSPO V was 29-33% greater in the prefrontal cortex, anterior cingulate cortex, and insula than in participants who were untreated for 9 years or less. TSPO V was also 31-39% greater in the three primary grey-matter regions of participants with long duration of untreated major depressive disorder compared with healthy participants (p=0·00047).
Microglial activation, as shown by TSPO V, is greater in patients with chronologically advanced major depressive disorder with long periods of no antidepressant treatment than in patients with major depressive disorder with short periods of no antidepressant treatment, which is strongly suggestive of a different illness phase. Consistent with this, the yearly increase in microglial activation is no longer evident when antidepressant treatment is given.
Canadian Institutes of Health Research and Neuroscience Catalyst Fund.
重度抑郁症患者常表现出重度抑郁发作的持续时间不断增加。然而，神经进展（即随着病程延长脑病理学改变增加）的证据却很稀少。小胶质细胞激活是神经炎症的一个重要组成部分，与神经进展有关。我们研究了转运蛋白（TSPO）总分布容积（V）（一种小胶质细胞激活的标志物）与未治疗的重度抑郁症持续时间、总病程以及抗抑郁药暴露时间之间的关系。
在这项横断面研究中，我们从多伦多地区和成瘾与心理健康中心（加拿大多伦多）招募了年龄在18 - 75岁的参与者。通过结构化临床访谈并咨询研究精神科医生，确认参与者要么患有继发于重度抑郁症的重度抑郁发作，要么是健康的。要被纳入研究，患有重度抑郁发作的参与者在17项汉密尔顿抑郁量表上的得分必须至少为17分，并且在PET扫描前必须停药或服用稳定剂量的药物至少4周。符合条件的参与者不吸烟；无酒精或物质依赖、神经系统疾病、自身免疫性疾病或严重医疗问题的病史或并发情况；并且在PET扫描前的前2周内没有急性疾病。如果参与者在扫描前6个月内使用过脑刺激治疗、在过去1个月内使用过至少持续1周的抗炎药物、正在接受激素替代治疗、有精神病性症状、患有双相情感障碍（I型或II型）或边缘性反社会人格障碍，或者怀孕或正在哺乳，则将其排除。我们使用F-FEPPA PET扫描三个主要的灰质感兴趣区域（前额叶皮质、前扣带回皮质和岛叶）以及另外12个区域和亚区域，以测量TSPO V。我们研究了未治疗的重度抑郁症持续时间以及疾病总持续时间和抗抑郁药治疗持续时间的组合，作为TSPO V的预测变量，评估它们的显著性。
在2009年9月1日至20l7年7月6日期间，我们筛选了134名参与者以确定其是否符合条件，其中81名被纳入研究（当前重度抑郁发作患者n = 51，健康者n = 30）。由于关于既往用药的信息不可靠，我们将一名患有重度抑郁发作的参与者排除在分析之外。未治疗的重度抑郁症持续时间是TSPO V的一个强预测因素（p<0·0001），总病程（p = 0·0021）和抗抑郁药暴露时间（p = 0·037）也是如此。这些预测因素的组合在前额叶皮质、前扣带回皮质和岛叶中占TSPO V方差的约50%。在未治疗的重度抑郁症持续10年或更长时间的参与者中，前额叶皮质、前扣带回皮质和岛叶中的TSPO V比未治疗9年或更短时间的参与者高29 - 33%。与健康参与者相比，未治疗的重度抑郁症持续时间长的参与者的三个主要灰质区域中的TSPO V也高31 - 39%（p = 0·00047）。
如TSPO V所示，与未接受抗抑郁药治疗时间短的重度抑郁症患者相比，未接受抗抑郁药治疗时间长的病程进展较晚的重度抑郁症患者的小胶质细胞激活程度更高，这强烈提示处于不同的疾病阶段。与此一致的是，给予抗抑郁药治疗后，小胶质细胞激活的逐年增加不再明显。
加拿大卫生研究院和神经科学催化剂基金。
