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.

In major depression, complex intersections between adverse childhood experiences and negative life events impact neuroticism, brooding, suicidal tendencies, insomnia, and cognitive interference

“…A factor extracted from physical and emotional maltreatment and neglect as well as family problems had a substantial, significant direct effect on the phenome, according to this analysis. These results build upon the conclusions drawn by Almulla et al, 22 which indicated that ACEs could predict the phenome of depression. Consistent with previous research (e.g., Hein et al; 50 Peckins et al; 51 Gizdic et al 52 ), our findings demonstrate that distinct subtypes of ACEs are associated with psychopathology in unique ways.…”

“…23,24,73 Furthermore, increased NLEs were found to partially mediate the effects of ACEs on rumination, SB, neuroticism, and the phenome of depression, according to the current study. Almulla et al 22 discovered that NLEs combined with ACEs substantially predict the manifestation of very severe MDD, as well as the lifetime and current suicidal behaviors. These results build upon those of Almulla et al 22 The effects of ACEs on the increases in affective symptoms during the COVID -19 pandemic are partially mediated by increased NLE scores.…”

“…Almulla et al 22 discovered that NLEs combined with ACEs substantially predict the manifestation of very severe MDD, as well as the lifetime and current suicidal behaviors. These results build upon those of Almulla et al 22 The effects of ACEs on the increases in affective symptoms during the COVID -19 pandemic are partially mediated by increased NLE scores. 74 Maes and Almulla 27 identified a similar pattern to the present study:…”

“…17,18 Cognitive dysfunction and emotional dysregulation, as well as an increased risk of developing psychopathology and late-life cognitive impairment, such as major depressive disorder (MDD), may result from daily hassles and exposure to NLEs . [19][20][21][22][23][24][25] MDD was predicted by increased daily hassles in a 14-24-year-old cohort. 23 Maybery 26 identified a correlation between perceived distress among university students and adverse interpersonal (e.g., financial, and familial) and noninterpersonal (e.g., academic) events.…”

Are abnormalities in lipid metabolism, together with adverse childhood experiences, the silent causes of immune-linked neurotoxicity in major depression?

“…Significantly, the impact of adverse childhood experiences (ACEs) on the "phenome" of severe IMDD is partially mediated by neuro-immune pathways, such as the activation of Th-1 and M1 immune cells [16]. The phenome of depression is a complex condition that encompasses the intensity of current depressive symptoms, anxiety, and suicidal tendencies [17,18,14].…”