Development of a Novel Staging Model for Affective Disorders Using Partial Least Squares Bootstrapping: Effects of Lipid-Associated Antioxidant Defenses and Neuro-Oxidative Stress

Abstract

Although, staging models gained momentum to stage define affective disorders, no attempts were made to construct mathematical staging models using clinical and biomarker data in patients with major depression and bipolar disorder.The aims of this study were to use clinical and biomarker data to construct statistically-derived staging models, which are associated with early lifetime traumata (ELTs), affective phenomenology and biomarkers.In the current study, 172 subjects participated, 105 with affective disorders (both bipolar and unipolar) and 67 controls. Staging scores were computed by extracting latent vectors (LVs) from clinical data including ELTs, recurring flare ups and suicidal behaviors, outcome data such as disabilities and health-related quality of life (HR-QoL), and paraoxonase (PON)1 actvities and nitro-oxidative stress biomarkers.Recurrence of episodes and suicidal behaviors could reliably be combined into a LV with adequate composite reliability (the “recurrence LV”), which was associated with female sex, the combined effects of multiple ELTs, disabilities, HR-QoL and impairments in cognitive tests. All those factors could be combined into a reliable “ELT-staging LV” which was significantly associated with nitro-oxidative stress biomarkers. A reliable LV could be extracted from serum PON1 activities, recurrent flare ups, disabilities and HR-QoL.Our ELT-staging index scores the severity of a relevant affective dimension, shared by both major depression and bipolar disorder, namely the trajectory from ELTs, a relapsing course and suicidal behaviors to progressive disabilities. Patients were classified into three stages, namely an early stage; a relapse-regression stage; and a suicidal-regression stage. Lowered lipid-associated antioxidant defenses may be a drug target to prevent the transition from the early to the later regression stages.

The Neuro-Immune Fingerprint of Major Neuro-Cognitive Psychosis or Deficit Schizophrenia: A Supervised Machine Learning Study

“…The results of the current study show that not only schizophrenia [5,11], but also MNP is accompanied by a simultaneous activation of the IRS and the CIRS whereby CIRS products released during an immuneinflammatory response attenuate the IRS. Moreover, previous research showed that MNP is characterized by specific deficits in the CIRS, as for example lowered levels of natural IgM responses to OSEs including malondialdehyde and azelaic acid [6,7,28].…”

“…SNP and MNP are both defined by different neurocognitive and neuro-immune features with MNP being the more severe illness characterized by IRS activation and deficits in the CIRS, including in natural IgM [6]. Moreover, in MNP, indices of immune activation coupled with deficits in the CIRS explain a large part of the variance in executive functions, memory and attention deficits, as well as psychotic, hostility, excitation, mannerism (PHEM) and negative symptoms [28,29]. Nevertheless, no studies have examined the neuro-immune fingerprint of MNP or deficit schizophrenia in association with its phenomenology using M1 macrophage cytokines in combination with chemokines such as CCL-2 and CCL-11.…”

Upregulation of the Nitrosylome in Bipolar Disorder Type 1 (BP1), but not BP2, and Major Depression: Increased IgM Antibodies to Nitrosylated Conjugates are Associated with Indicants of Leaky Gut

“…Another finding of this study is that women show increased levels of peroxides and IgM to NOW and NO-arginine indicating that ROS/RNS and nitrosative stress may in part contribute to sex differences in depression and BP1 for example to the increased incidence of depression in females. 8 Such effects could be associated with increased early life trauma and other psychosocial triggers that are associated with nitro-oxidative processes and with staging of depression and mood disorders.…”

“…It is understood that MDD and BP disorder are progressive disorders whereby increasing recurrent depressive/manic episodes and suicidal behaviors are associated with disabilities, lowered quality of life, neurocognitive decline and increased suicidal ideation and suicide attempts. 8 Furthermore, a new staging model of MDD and BP disorder indicates that this staging dimension (recurrent episodes and recurrent suicidal behaviors, increasing disabilities and lowered quality of life) is strongly associated with deficits in paraoxonase 1 (PON1), a strong antioxidant, and indicants of increased oxidative stress including aldehyde formation and protein oxidation. 8 Activated immune-inflammatory and oxidative pathways are usually accompanied by increased nitrosylation of proteins.…”

“…8 Furthermore, a new staging model of MDD and BP disorder indicates that this staging dimension (recurrent episodes and recurrent suicidal behaviors, increasing disabilities and lowered quality of life) is strongly associated with deficits in paraoxonase 1 (PON1), a strong antioxidant, and indicants of increased oxidative stress including aldehyde formation and protein oxidation. 8 Activated immune-inflammatory and oxidative pathways are usually accompanied by increased nitrosylation of proteins. [9][10][11] Nitrosylation involves the covalent addition of a nitroso (NO) group to cysteine thiolate anions (S-nitrosylation) or NH2 groups (Nnitrosylation), reactions that are reversible and mediated by increased levels of mainly N2O3.…”