Adverse childhood experiences and recent negative events activate immune and growth factor pathways, which are associated with first episode major depression and suicidal behaviours

Abstract Background Adverse Childhood Experiences (ACEs) and Negative Life Events (NLEs) may activate immune-inflammatory pathways, which play a role in the onset of Major Depressive Disorder and its severe phenotype Major Dysmood disorder (MDMD). Objectives To assess if elevated ACEs and NLEs in first episode (FE)-MDMD predict activation of the immune-inflammatory response system (IRS), chemokines, and growth factors that participate in the pathophysiology of MDMD. Methods This research assessed the effects of ACEs and NLEs on forty-eight cytokines/chemokines/growth factors, in 71 FE-MDMD patients and forty heathy controls. Results ACEs are highly significantly associated with the classical M1 macrophage, T helper (Th)-1, Th-1 polarization, IRS, and neurotoxicity immune profiles, and not with the alternative M2, and Th-2 immune profiles. There are highly significant correlations between ACEs and NLEs and different cytokines/chemokines/growth factors, especially with interleukin (IL)-16, CCL27, stem cell growth factor, and platelet-derived growth factor. Partial Least Squares analysis showed that 62.3% of the variance in the depression phenome (based on severity of depression, anxiety and suicidal behaviors) was explained by the regression on IL-4 (p=0.001, inversely), the sum of ACEs + NLEs (p<0.0001), and a vector extracted from 10 cytokines/chemokines/growth factors (p<0.0001; both positively associated). The latter partially mediated (p<0.0001) the effects of ACE + NLEs on the depression phenome. Conclusions Part of the effects of ACEs and NLEs on the depression phenome is mediated via activation of immune and growth factor networks. These pathways have a stronger impact in subjects with lowered activities of the compensatory immune-regulatory system.