Michopoulos Vasiliki, Norrholm Seth D, Stevens Jennifer S, Glover Ebony M, Rothbaum Barbara O, Gillespie Charles F, Schwartz Ann C, Ressler Kerry J, Jovanovic Tanja
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia; Yerkes National Primate Research Center, Atlanta, Georgia.
Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia; Atlanta Veterans Affairs Medical Center, Mental Health Service Line, Decatur, Georgia.
Psychoneuroendocrinology. 2017 Sep;83:65-71. doi: 10.1016/j.psyneuen.2017.05.023. Epub 2017 May 31.
Psychophysiological hallmarks of posttraumatic stress disorder (PTSD) include exaggerated fear responses, impaired inhibition and extinction of conditioned fear, and decreased discrimination between safety and fear cues. This increased fear load associated with PTSD can be a barrier to effective therapy thus indicating the need for new treatments to reduce fear expression in people with PTSD. One potential biological target for reducing fear expression in PTSD is the hypothalamic-pituitary-adrenal (HPA) axis, which is dysregulated in PTSD. Recent translational rodent studies and cross-sectional clinical studies have shown that dexamethasone administration and the resulting suppression of cortisol in individuals with PTSD leads to a decrease in the fear responses characteristic of PTSD. These data, taken together, suggest that dexamethasone may serve as a novel pharmacologic intervention for heightened fear responses in PTSD. We conducted a double-blind, placebo-controlled trial to test our hypothesis that dexamethasone administration and the concomitant suppression of HPA axis hyperactivity would attenuate fear expression and enhance fear extinction in individuals with PTSD. Study participants (n=62) were recruited from Grady Memorial Hospital in Atlanta, GA. Participants were randomized to receive dexamethasone or placebo prior to fear conditioning and extinction, in a counterbalanced design (treatments separated by a week). Both PTSD- (n=37) and PTSD+ (n=25) participants showed significant startle increases in the presence of the danger signal during placebo and dexamethasone treatments (all p<0.05). However, only PTSD- control participants showed decreases in fear-potentiated startle across extinction blocks during both conditions (p's≤0.001), with PTSD+ participants showing deficits in fear extinction and safety discrimination in the placebo condition. Notably, extinction and discrimination deficits in PTSD+ subjects were markedly reversed with dexamethasone (p<0.001). These data suggest that dexamethasone may serve as a pharmacological agent with which to facilitate fear extinction and discrimination in individuals with PTSD.
创伤后应激障碍（PTSD）的心理生理特征包括过度的恐惧反应、条件性恐惧抑制和消退受损，以及安全线索和恐惧线索之间的辨别能力下降。与PTSD相关的这种增加的恐惧负荷可能是有效治疗的障碍，因此表明需要新的治疗方法来减少PTSD患者的恐惧表达。减少PTSD患者恐惧表达的一个潜在生物学靶点是下丘脑-垂体-肾上腺（HPA）轴，该轴在PTSD中失调。最近的转化啮齿动物研究和横断面临床研究表明，给予地塞米松并由此抑制PTSD患者的皮质醇会导致PTSD特征性恐惧反应的减少。综合这些数据表明，地塞米松可能作为一种新的药物干预措施，用于减轻PTSD患者过度的恐惧反应。我们进行了一项双盲、安慰剂对照试验，以检验我们的假设，即给予地塞米松并同时抑制HPA轴的过度活跃将减轻PTSD患者的恐惧表达并增强其恐惧消退能力。研究参与者（n = 62）从佐治亚州亚特兰大的格雷迪纪念医院招募。参与者在恐惧条件化和消退之前被随机分配接受地塞米松或安慰剂，采用平衡设计（治疗间隔一周）。在安慰剂和地塞米松治疗期间，PTSD-（n = 37）和PTSD+（n = 25）参与者在危险信号出现时均表现出明显的惊吓增强（所有p<0.05）。然而，只有PTSD-对照参与者在两种情况下的消退阶段恐惧增强惊吓均有所降低（p≤0.001），PTSD+参与者在安慰剂条件下表现出恐惧消退和安全辨别缺陷。值得注意的是，地塞米松显著逆转了PTSD+受试者的消退和辨别缺陷（p<0.001）。这些数据表明，地塞米松可能作为一种药物，促进PTSD患者的恐惧消退和辨别。
