Wang Yun, Bernanke Joel, Peterson Bradley S, McGrath Patrick, Stewart Jonathan, Chen Ying, Lee Seonjoo, Wall Melanie, Bastidas Vanessa, Hong Susie, Rutherford Bret R, Hellerstein David J, Posner Jonathan
New York State Psychiatric Institute, Columbia University, New York, NY, USA; Columbia University College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Columbia University College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Lancet Psychiatry. 2019 Aug;6(8):667-674. doi: 10.1016/S2215-0366(19)30179-8. Epub 2019 Jun 24.
Antidepressant medications offer an effective treatment for depression, yet nearly 50% of patients either do not respond or have side-effects rendering them unable to continue the course of treatment. Mechanistic studies might help advance the pharmacology of depression by identifying pathways through which treatments exert their effects. Toward this goal, we aimed to identify the effects of antidepressant treatment on neural connectivity, the relationship with symptom improvement, and to test whether these effects were reproducible across two studies.
We completed two double-blind, placebo-controlled trials of SNRI antidepressant medications with MRI scans obtained before and after treatment. One was a 10-week trial of duloxetine (30-120 mg daily; mean 92·1 mg/day [SD 30·00]) and the other was a 12-week trial of desvenlafaxine (50-100 mg daily; 93·6 mg/day [16·47]). Participants consisted of adults with persistent depressive disorder. Adjusting for sex and age, we examined the effect of treatment on whole-brain functional connectivity. We also examined correlations between change in functional connectivity and improvement in symptoms of depression (24-item Hamilton Depression Rating Scale) and pain symptom severity (Symptom Checklist-90-Revised).
Participants were enrolled between Jan 26, 2006, and Nov 22, 2011, for the duloxetine RCT and Aug 5, 2012, and Jan 28, 2016, for the desvenlafaxine RCT. Before and after treatment MRI scans were collected in 32 participants for the duloxetine RCT and 34 participants for the desvenlafaxine RCT. In both studies, antidepressants decreased functional connectivity compared with placebo (duloxetine study: β=-0·06; 95% CI -0·08 to -0·03; p<0·0001, η=0·44; desvenlafaxine study: -0·06, -0·09 to -0·03; p<0·0001, η=0·35) within a thalamo-cortico-periaqueductal network that has previously been associated with the experience of pain. Within the active drug groups, reductions in functional connectivity within this network correlated with improvements in depressive symptom severity in both studies (duloxetine study: r=0·38, 95% CI 0·01-0·65; p=0·0426; desvenlafaxine study: 0·44, 0·10-0·69; p=0·0138) and pain symptoms in the desvenlafaxine study (0·39, 0·04 to 0·65; p=0·0299).
The findings suggest the thalamo-cortico-periaqueductal network associated with the experience of pain is a new and potentially important target for novel antidepressant therapeutics.
National Mental Health Institute, Eli Lilly and Company, Pfizer Pharmaceuticals, and the Edwin S Webster Foundation.
抗抑郁药物为抑郁症提供了一种有效的治疗方法，但近50%的患者要么没有反应，要么出现副作用，导致他们无法继续治疗过程。机制研究可能有助于通过确定治疗发挥作用的途径来推进抑郁症药理学的发展。为了实现这一目标，我们旨在确定抗抑郁治疗对神经连接的影响、与症状改善的关系，并测试这些影响在两项研究中是否可重复。
我们完成了两项关于5-羟色胺再摄取抑制剂（SNRI）抗抑郁药物的双盲、安慰剂对照试验，并在治疗前后进行了磁共振成像（MRI）扫描。一项是为期10周的度洛西汀试验（每日30-120毫克；平均92.1毫克/天[标准差30.00]），另一项是为期12周的去甲文拉法辛试验（每日50-100毫克；93.6毫克/天[16.47]）。参与者为患有持续性抑郁症的成年人。在调整性别和年龄后，我们研究了治疗对全脑功能连接的影响。我们还研究了功能连接变化与抑郁症状改善（24项汉密尔顿抑郁量表）和疼痛症状严重程度（症状自评量表-90修订版）之间的相关性。
度洛西汀随机对照试验的参与者于2006年1月26日至2011年11月22日入组，去甲文拉法辛随机对照试验的参与者于2012年8月5日至2016年1月28日入组。度洛西汀随机对照试验的32名参与者和去甲文拉法辛随机对照试验的34名参与者在治疗前后进行了MRI扫描。在两项研究中，与安慰剂相比，抗抑郁药物均降低了功能连接（度洛西汀研究：β=-0.06；95%置信区间-0.08至-0.03；p<0.0001，η=0.44；去甲文拉法辛研究：-0.06，-0.09至-0.03；p<0.0001，η=0.35），该功能连接存在于一个先前与疼痛体验相关的丘脑-皮质-导水管周围网络中。在活性药物组中，两项研究中该网络内功能连接的降低均与抑郁症状严重程度的改善相关（度洛西汀研究：r=0.38，95%置信区间0.01-0.65；p=0.0426；去甲文拉法辛研究：0.44，0.10-0.69；p=0.0138），而去甲文拉法辛研究中还与疼痛症状相关（r=0.39，0.04至0.65；p=0.0299）。
研究结果表明，与疼痛体验相关的丘脑-皮质-导水管周围网络是新型抗抑郁治疗的一个新的且可能重要的靶点。
美国国立精神卫生研究所、礼来公司、辉瑞制药公司和埃德温·S·韦伯斯特基金会。
