PACAP associated with precise PTSD and fear extinction response in women

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_p²=.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.