Composite contributions of cerebrospinal fluid GABAergic neurosteroids, neuropeptide Y and interleukin-6 to PTSD symptom severity in men with PTSD

Abstract

Given that multiple neurobiological systems, as well as components within these systems are impacted by stress, and may interact in additive, compensatory and synergistic ways to promote or mitigate PTSD risk, severity, and recovery, we thought that it would be important to consider the collective, as well as separate effects of these neurobiological systems on PTSD risk. With this goal in mind, we conducted a proof-of-concept study utilizing cerebrospinal fluid (CSF) collected from unmedicated, tobacco- and illicit substance-free men with PTSD (n = 13) and trauma-exposed healthy controls (TC) (n = 17). Thirteen neurobiological factors thought to contribute to PTSD risk or severity based on previous studies were assayed. As the small but typical sample size of this lumbar puncture study limited the number of factors that could be considered in a hierarchical regression model, we included only those five factors with at least a moderate correlation (Spearman rho > 0.30) with total Clinician-Administered PTSD Scale (CAPS-IV) scores, and that did not violate multicollinearity criteria. Three of the five factors meeting these criteria—CSF allopregnanolone and pregnanolone (Allo + PA: equipotent GABAergic metabolites of progesterone), neuropeptide Y (NPY), and interleukin-6 (IL-6)—were found to account for over 75% of the variance in the CAPS-IV scores (R2 = 0.766, F = 8.75, p = 0.007). CSF Allo + PA levels were negatively associated with PTSD severity (β = −0.523, p = 0.02) and accounted for 47% of the variance in CAPS-IV scores. CSF NPY was positively associated with PTSD severity (β = 0.410, p = 0.04) and accounted for 14.7% of the CAPS-IV variance. There was a trend for a positive association between PTSD severity and CSF IL-6 levels, which accounted for 15.3% of the variance in PTSD severity (β = 0.423, p = 0.05). Z-scores were then computed for each of the three predictive factors and used to depict the varying relative degrees to which each contributed to PTSD severity at the individual PTSD patient level. This first of its kind, proof-of-concept study bears replication in larger samples. However, it highlights the collective effects of dysregulated neurobiological systems on PTSD symptom severity and the heterogeneity of potential biological treatment targets across individual PTSD patients—thus supporting the need for precision medicine approaches to treatment development and prescribing in PTSD.