Early Life Trauma Predicts Affective Phenomenology and the Effects are Partly Mediated by Staging Coupled with Lowered Lipid-Associated Antioxidant Defences

Abstract

Background: Early life trauma (ELT) may drive mood disorder phenomenology, neuro-oxidative and neuro-immune pathways and impairments in semantic memory. Nevertheless, there are no data regarding the impact of ELT on affective phenomenology and whether these pathways are mediated by staging or lowered lipid-associated antioxidant defences.Methods: This study examined healthy controls (n=54) and patients with affective disorders including major depression, bipolar disorder and anxiety disorders (n=118). ELT was assessed using the Child Trauma Questionnaire. In addition, we measured affective phenomenology and assayed advanced oxidation protein products; malondialdehyde, paraoxonase 1 (CMPAase) activity, high-sensitivity C-reactive protein (hsCRP), and high-density lipoprotein (HDL) cholesterol.Results: ELT was associated with increased risk for mood and comorbid anxiety disorders and a more severe phenomenology, including staging characteristics (number of mood episodes), severity of depression and anxiety, suicide attempts, suicidal ideation, type of treatments received, disabilities, body mass index, smoking behaviour and hsCRP, as well as lowered healthrelated quality of life, socio-economic status, antioxidant defences and semantic memory. The number of mood episodes and CMPAase/HDL-cholesterol levels could be reliably combined into a new vulnerability staging-biomarker index, which mediates in part the effects of ELT on affective phenomenology, while lowered antioxidant defences are associated with increased oxidative stress. Moreover, the effects of female sex on mood disorders and affective phenomenology are mediated by ELT.Discussion: The cumulative effects of different types of ELT drive many aspects of affective phenomenology either directly or indirectly through effects of staging and/or lipid-associated antioxidant defences. The results show that children, especially girls, with ELT are at great risk to develop mood disorders and more severe phenotypes of affective disorders. 4Both major depressive disorder (MDD) and bipolar disorder (BD) are highly recurrent disorders that are characterized by increased risk for suicidal behaviours [1-3], lowered healthrelated quality of life (HR-QoL), increased disabilities [4][5][6][7], lowered socio-economic status [8][9][10][11], smoking behaviours [12][13][14], increased incidence of metabolic syndrome [15] and cognitive impairments including semantic memory deficits [16].There is also evidence that neuro-immune, neuro-oxidative and neuro-nitrosative pathways play a key role in the pathophysiology of both . Both mood disorders are associated with lowered lipid-associated antioxidant defences, which protect against the detrimental effects of reactive oxygen species (ROS), including lowered lecithin cholesterol acyltransferase (LCAT) and paraoxonase (PON1) activities and lowered high-density lipoprotein (HDL)-cholesterol, vitamin E and coenzyme Q10 levels [21][22][23][24][25][26][27][28][29][30]. These lowered lipid-associated antioxidant defences contribute to incr...

Impairments in Peripheral Blood T Effector and T Regulatory Lymphocytes in Bipolar Disorder Are Associated with Staging of Illness and Anti-cytomegalovirus IgG Levels

“…Bipolar disorder (BD) is a progressive disorder with recurrent manic, hypomanic, and depressive episodes which alternate with remitted phases, whereby the number of mood episodes is associated with increasing severity of symptoms, increased risk of future episodes, functional decline in the performance of daily tasks, and deficits in memory and executive functions [1][2][3][4][5][6][7]. Based on staging characteristics including recurrence of episodes and past suicidal behaviors, BD patients may be classified into three stages: (a) an early stage when patients show only a few recurrent episodes and increased suicidal ideation; (b) the relapse-regression stage with increased recurrent episodes, more disabilities, lower health-related quality of life and socioeconomic status, and cognitive deficits in memory and executive functions; and (c) the suicidal-regression stage with all hallmarks of stage 2 combined with highly increased suicidal behaviors [7].…”

Towards a major methodological shift in depression research by assessing continuous scores of recurrence of illness, lifetime and current suicidal behaviors and phenome features: focus on atherogenicity and adverse childhood experiences

“…The ROI index is the most significant component of MDD in precision models because it is a continuous variable that predicts current SI and SA, the phenome and phenomenome of MDD, with high accuracy [1,5,6,7]. In addition, the ROI index is strongly associated with numerous biomarkers, such as genetic variants in Q192R paraoxoase 1 (PON1), PON1 activity, high density lipoprotein cholesterol (HDLc), lipid peroxidation, and immune activation [6,8,9,10,11].…”

“…New structures of reasoning, theoretical approaches, and methodologies are required to solve the mystery of depression and the role of its pathways. To accomplish this, we created precision nomothetic psychiatry, a new clinimetrics method based on (un)supervised ML (1,2,5,6,7,(9)(10)(11). The term "nomothetic" denotes that our method permits the extraction of mathematical laws or algorithms from a set of independent variables, including gene variants, early lifetime trauma, and adverse outcome pathways (AOPs), that explain the variability in the correct outcome models, consisting of the continuous ROI and phenome variables [1,2,5,7,[9][10][11].…”

“…As previously described, this method allowed us to construct a) new pathway phenotypes, a combination of biomarkers and clinical phenome data into one validated construct, and b) new phenotype or endophenotype classes, which are groups of patients based on different features (e.g., a combination of ROI and phenome data) or phenotype and biomarker data, respectively [1,2,5,7,[9][10][11]. For instance, we were able to establish a new phenotype class, namely major dysmood disorder (MDMD), which is distinguished from simple dysmood disorder (SDMD) by highly elevated ROI, LT, cognitive disorders, biomarkers, current SB, phenome and disability scores, and lowered HR-QoL [1,5,7].…”

“…A first nomothetic model was a clinical precision model that incorporated the effects of ACEs on ROI and the current phenome, such as physical and emotional abuse, physical and emotional neglect, and sexual abuse [1,5,6,7,11,15]. The second model included the effects of PON1 genetic variants, decreased PON1 enzymatic activity (gene-determined), decreased HDLc, and increased lipid peroxidation as trait and state biomarkers of ROI or the current phenome scores [9][10][11]. A third nomothetic model was constructed which linked elevated bacterial translocation with leaky gut and the subsequent autoimmune responses to lipid-associated neoepitopes (such as malondialdehyde) with ROI and the phenome [16].…”