Adams Shane W, Neylan Thomas C, May Victor, Hammack Sayamwong E, Ressler Kerry, Inslicht Sabra S
Department of Neurosurgery, Stanford University School of Medicine, Palo Alto, CA, USA; Polytrauma System of Care, VA Palo Alto Health Care System, Palo Alto, CA, USA; VA San Francisco Medical Center, San Francisco, CA, USA.
VA San Francisco Medical Center, San Francisco, CA, USA; Weill Institute for Neurosciences, Department of Psychiatry and Behavioral Sciences, University of California, San Francisco, San Francisco, CA, USA.
Psychoneuroendocrinology. 2025 Mar;173:107375. doi: 10.1016/j.psyneuen.2025.107375. Epub 2025 Jan 28.
Behavioral, biological, and physiological reactions following posttraumatic stress disorder (PTSD) are heterogeneous, particularly between sexes. Pituitary adenylate cyclase-activating polypeptide (PACAP38) is identified as a viable sex-specific marker of PTSD and fear conditioning impairments in women. However, no studies have examined the association between PACAP38 and fear extinction in humans to inform treatment mechanisms, and the association between PACAP38 and PTSD is variable, requiring further investigation. Participants (n = 123) included representative proportions of women (48.8 %), those with ≥subthreshold PTSD (39.8 %), veterans (33.3 %), and participants of color (59.5 %). Main outcomes and measures included PTSD symptoms (CAPS-IV), peripheral serum PACAP38, differential skin conductance response during a fear conditioning paradigm. The Middle-Out Approach was applied to integrate behavioral, biological, and physiological indicators and identify precise clinical phenotypes using latent class analysis. The current study provides behavioral, biological, and physiological evidence of a homogeneous subgroup (13.8 %), composed largely of women, for whom peripheral PACAP38 levels were over twofold higher than other participants (η=.52-.56) and associated with a unique constellation of Intrusive-Hypervigilant PTSD symptoms and impairments in fear extinction retention. Results suggest specificity in the association between PACAP38, PTSD symptoms, and fear extinction retention that can inform practical targets for clinical assessment and intervention, and create viable avenues for future research.
创伤后应激障碍（PTSD）后的行为、生物学和生理反应具有异质性，尤其是在性别之间。垂体腺苷酸环化酶激活多肽（PACAP38）被确定为女性PTSD和恐惧条件化损伤的一种可行的性别特异性标志物。然而，尚无研究探讨PACAP38与人类恐惧消退之间的关联以指导治疗机制，并且PACAP38与PTSD之间的关联存在差异，需要进一步研究。参与者（n = 123）包括具有代表性比例的女性（48.8%）、患有≥阈下PTSD的人（39.8%）、退伍军人（33.3%）和有色人种参与者（59.5%）。主要结局和测量指标包括PTSD症状（CAPS-IV）、外周血清PACAP38、恐惧条件化范式期间的差异皮肤电导反应。采用中间向外法整合行为、生物学和生理指标，并使用潜在类别分析确定精确的临床表型。本研究提供了行为、生物学和生理学证据，表明存在一个主要由女性组成的同质亚组（13.8%），其外周PACAP38水平比其他参与者高出两倍多（η = 0.52 - 0.56），并且与侵入性-过度警觉PTSD症状的独特组合以及恐惧消退保持受损相关。结果表明PACAP38、PTSD症状和恐惧消退保持之间的关联具有特异性，这可为临床评估和干预的实际靶点提供信息，并为未来研究开辟可行的途径。
