Adverse Childhood Experiences Predict the Phenome of Affective Disorders and These Effects Are Mediated by Staging, Neuroimmunotoxic and Growth Factor Profiles

Abstract

Adverse childhood experiences (ACEs) enhance pro-inflammatory and pro-oxidant responses. In affective disorders, recent precision nomothetic psychiatry studies disclosed new pathway phenotypes, including an ROI—reoccurrence of illness (ROI)—oxidative stress latent construct. The aim of the present study is to delineate a) whether ACEs sensitize the M1 macrophage, the T helper cells (Th)1, Th2, and Th17, the IRS (immune-inflammatory-responses system), the CIRS (compensatory immunoregulatory system), and the neuroimmunotoxic and growth factor (GF) profiles and whether they are associated with ROI and the phenome of affective disorders and b) the molecular pathways underpinning the effects of the ACEs. We collected supernatants of stimulated (5 μg/mL of PHA and 25 μg/mL of LPS) and unstimulated diluted whole blood in 20 healthy controls and 30 depressed patients and measured a panel of 27 cytokines/GF using a Luminex method. ACEs (comprising mental and physical trauma, mental neglect, domestic violence, family history of mental disease, and parent loss) are accompanied by the increased stimulated, but not unstimulated, production of M1, Th1, Th2, Th17, IRS, neuroimmunotoxic, and GF profiles and are strongly correlated with ROI and the phenome. A latent vector extracted from the ROI features (recurrent episodes and suicidal behaviors) and the IRS/neuroimmunotoxic/GF profiles explains 66.8% of the variance in the phenome and completely mediates the effects of ACEs on the phenome. Enrichment analysis showed that the ACE-associated sensitization of immune/GF profiles involves JAK-STAT, nuclear factor-κB, tumor necrosis factor-α, G-protein coupled receptor, PI3K/Akt/RAS/MAPK, and hypoxia signaling. In summary, the ACE-induced sensitization of immune pathways and secondary immune hits predicts the phenome of affective disorders.

The tryptophan catabolite or kynurenine pathway in major depressive and bipolar disorder: a systematic review and meta-analysis

“…Thus, it is preferable to thoroughly investigate the TRP and TRYCATs in drug-naïve patients with a first episode or to control statistically for the medication status. Moreover, future research should stratify patients according to the staging phases of affective disorders since disease staging is related to greater neurotoxicity (Maes, Moraes et al 2019, Maes, Rachayon et al 2022). Fourth, a considerable number of studies seemed to have been conducted without correcting for major confounding variables such as smoking and alcoholism and their effects on TRP (Badawy 2002) and TRYCAT (Leclercq, Schwarz et al 2021) metabolism.…”

“…Moreover, the activated IRS pathways in affective disorders are associated with activation of nitro-oxidative pathways with increased reactive oxygen and nitrogen species (RONS), and consequent lipid peroxidation and protein oxidation (Maes, Galecki et al 2011, Maes 2022). Activation of IRS and nitro-oxidative pathways are associated with the key features of affective disorders, including severity of illness, staging (reoccurrence of episodes) and suicidal behaviors including suicidal ideation and attempts (Vasupanrajit, Jirakran et al 2021, Maes 2022, Maes, Rachayon et al 2022). The current theory is that the neurotoxic effects of M1 and Th-1 cytokines and RONS cause neuro-affective toxicity with dysfunctions in brain connectome pathways that lead to staging and the phenome of MDD/BD (Maes 2022, Maes, Rachayon et al 2022).…”

Antenatal depressive symptoms are strongly predicted by the severity of pre-menstrual syndrome: results of partial least squares analysis

“…The interrelationships among the PSST affective symptoms of PMS and perinatal depressive symptoms and the effects of ACEs may be explained by the effects of adverse outcome pathways. Thus, there is evidence that a) PMS (or better MCAS) and menstrual distress are in part due to immune-inflammatory processes (Roomruangwong and Maes, 2021); b) major depression and perinatal depression are associated with activated immune-inflammatory pathways; and c) ACEs induce an immune-inflammatory and growth factor response which is a major determinant of the phenome of depression (Maes et al, 2022). Moreover, psychosocial stressors including relation dissatisfaction and abuse by the partner during pregnancy may further exacerbate those immune-inflammatory pathways.…”

“…There is also evidence that adverse childhood experiences (ACEs) are strongly associated with the onset of AD (Abe et al, 2021), major depressive disorder (Maes et al, 2019; Maes et al, 2022), and possibly premenstrual syndrome (PMS) (Jacobs et al, 2015; Yang et al, 2022). Such findings suggest that ACEs may underlie the association between PMS and AD.…”

Research and Diagnostic Algorithmic Rules (RADAR) for mood disorders, recurrence of illness, suicidal behaviors, and the patient’s lifetime trajectory

“…Recent meta-analyses demonstrated that active immune-inflammatory and nitro-oxidative pathways significantly underlie lifetime and recent suicidal behaviors (Vasupanrajit et al, 2021;2022). Recent research indicates that elevated M1 macrophage, T helper 1, and T cell growth factor responsiveness is substantially linked with lifetime and current suicidal behaviors (Maes et al, 2022b).…”