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

The top-down Diagnostic and Statistical Manual/International Statistical Classification of Diseases categories of mood disorders are inaccurate, and their dogmatic nature precludes both deductive (as indisputable) and inductive (as top-down) remodelling of case definitions. In trials, psychiatric rating scale scores employed as outcome variables are invalid and rely on folk psychology-like narratives. Using machine learning techniques, we developed a new precision nomothetic model of mood disorders with a recurrence of illness (ROI) index, a new endophenotype class, namely Major Dysmood Disorder (MDMD), characterised by increased ROI, a more severe phenome, and more disabilities. Nonetheless, our previous studies did not compute Research and Diagnostic Algorithmic Rules (RADAR) to diagnose MDMD and score ROI, lifetime (LT), and current suicidal behaviours, as well as the phenome of mood disorders. Here, we provide rules to compute bottom-up RADAR scores for MDMD, ROI, LT and current suicidal ideation and attempts, the phenome of mood disorders, and the lifetime trajectory of mood disorder patients from a family history of mood disorders and substance abuse to adverse childhood experiences, ROI, and the phenome. We also demonstrate how to plot the 12 major scores in a single RADAR graph, which displays all features in a two-dimensional plot. These graphs allow the characteristics of a patient to be displayed as an idiomatic fingerprint, allowing one to estimate the key traits and severity of the illness at a glance. Consequently, biomarker research into mood disorders should use our RADAR scores to examine pan-omics data, which should be used to enlarge our precision models and RADAR graph.

Towards a new model and classification of mood disorders based on risk resilience, neuro-affective toxicity, staging, and phenome features using the nomothetic network psychiatry approach.

Current diagnoses of mood disorders are not cross validated. The aim of the current paper is to explain how machine learning techniques can be used to a) construct a model which ensembles risk/resilience (R/R), adverse outcome pathways (AOPs), staging, and the phenome of mood disorders, and b) disclose new classes based on these feature sets. This study was conducted using data of 67 healthy controls and 105 mood disordered patients. The R/R ratio, assessed as a combination of the paraoxonase 1 (PON1) gene, PON1 enzymatic activity, and early life time trauma (ELT), predicted the high-density lipoprotein cholesterol - paraoxonase 1 complex (HDL-PON1), reactive oxygen and nitrogen species (RONS), nitro-oxidative stress toxicity (NOSTOX), staging (number of depression and hypomanic episodes and suicidal attempts), and phenome (the Hamilton Depression and Anxiety scores and the Clinical Global Impression; current suicidal ideation; quality of life and disability measurements) scores. Partial Least Squares pathway analysis showed that 44.2% of the variance in the phenome was explained by ELT, RONS/NOSTOX, and staging scores. Cluster analysis conducted on all those feature sets discovered two distinct patient clusters, namely 69.5% of the patients were allocated to a class with high R/R, RONS/NOSTOX, staging, and phenome scores, and 30.5% to a class with increased staging and phenome scores. This classification cut across the bipolar (BP1/BP2) and major depression disorder classification and was more distinctive than the latter classifications. We constructed a nomothetic network model which reunited all features of mood disorders into a mechanistically transdiagnostic model.

Increased nitro-oxidative stress toxicity as a major determinant of increased blood pressure in mood disorders.

BACKGROUND: Hypertension, atherogenicity and insulin resistance are major risk factors of cardiovascular disorder (CVD), which shows a strong comorbidity with major depression (MDD) and bipolar disorder (BD). Activated oxidative and nitrosative stress (O&NS), inflammatory pathways, and increased atherogenicity are shared pathways underpinning CVD and mood disorders. METHODS: The current study examined the effects of lipid hydroperoxides (LOOH), superoxide dismutase (SOD), nitric oxide metabolites (NOx), advanced oxidation protein products (AOPP), and malondialdehyde (MDA) on systolic (SBP) and diastolic (DBP) blood pressure in 96 mood disordered patients and 60 healthy controls. RESULTS: A large part of the variance in SBP (31.6%) was explained by the regression on a z unit-weighted composite score (based on LOOH, AOPP, SOD, NOx) reflecting nitro-oxidative stress toxicity (NOSTOX), coupled with highly sensitive C-reactive protein, body weight and use of antihypertensives. Increased DBP was best predicted (23.8%) by body mass index and NOSTOX. The most important O&NS biomarkers predicting an increased SBP were in descending order of significance: LOOH, AOPP and SOD. Higher levels of the atherogenic index of plasma, HOMA2 insulin resistance index and basal thyroid-stimulating hormone also contributed to increased SBP independently from NOSTOX. Although there were no significant changes in SBP/DBP in mood disorders, the associations between NOSTOX and blood pressure were significant in patients with mood disorders but not in healthy controls. CONCLUSIONS: Activated O&NS pathways including increased lipid peroxidation and protein oxidation, which indicates hypochlorous stress, are the most important predictors of an increased BP, especially in patients with mood disorders.

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

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.

Lowered PON1 activities are strongly associated with depression and bipolar disorder, recurrence of (hypo)mania and depression, increased disability and lowered quality of life.

Objectives: Mood disorders (MDs) frequently co-exist with cardiovascular disease (CVD) and immune-inflammatory and oxidative stress are important shared pathophysiological pathways. Even though there has been an extensive investigation of the enzyme paraoxonase 1 (PON1) as a biomarker of susceptibility for CVD, there are few reports studying PON1 in MDs. The aim of this study was to determine the association between PON1 activities as well as functional genotypes and MD diagnosis, clinical characteristics and outcomes. Methods: PON1 activities and functional genotypes were assayed in 58 bipolar disorder (BD) and 32 major depressed patients (MDD) and compared with 59 controls. Results: Our findings show significantly lower PON1 total and CMPAase activities in MDs, which are partly related to the number of previous depressive and manic episodes. Lowered CMPAase activity is associated with a worse outcome of MDs as indicated by lowered quality of life (WHOQoL-BREF scale) and increased disability in the Sheeham scale. Conclusions: We hypothesise that lowered PON1 total and CMPAase activities may play a role in the pathophysiology of MDs by lowering antioxidant defences thereby increasing the risk of lipid peroxidation and inflammation; lowered inhibition of quorum-sensing lactones thereby increasing bacterial proliferation; and attenuated homocysteine thiolactone catabolism which may trigger immune-inflammatory response and/or induce neurotoxicity.

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

Background Early life trauma (ELT) may drive mood disorder phenomenology, nitro-oxidative pathways and impairments in semantic memory. 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 into with increased risk for mood and comorbid anxiety disorders and a more severe phenomenology, including staging characteristics, depression and anxiety severity, suicidal behaviours, type of treatments, disabilities, body mass index, smoking behaviour and hsCRP, as well as lowered health-related quality of life, 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 and oxidative stress. Moreover, the effects of female sex on mood disorders and affective phenomenology are mediated by ELT. Discussion The cumulative effects of different 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.

Lowered quality of life in mood disorders is associated with increased neuro-oxidative stress and basal thyroid-stimulating hormone levels and use of anticonvulsant mood stabilizers.

RATIONALE, AIMS: Major affective disorders including bipolar disorder (BD) and major depressive disorder (MDD) are associated with impaired health-related quality of life (HRQoL). Oxidative stress and subtle thyroid abnormalities may play a pathophysiological role in both disorders. Thus, the current study was performed to examine whether neuro-oxidative biomarkers and thyroid-stimulating hormone (TSH) levels could predict HRQoL in BD and MDD. METHODS: This cross-sectional study enrolled 68 BD and 37 MDD patients and 66 healthy controls. The World Health Organization (WHO) QoL-BREF scale was used to assess 4 QoL subdomains. Peripheral blood malondialdehyde (MDA), advanced oxidation protein products, paraoxonaxe/CMPAase activity, a composite index of nitro-oxidative stress, and basal TSH were measured. RESULTS: In the total WHOQoL score, 17.3% of the variance was explained by increased advanced oxidation protein products and TSH levels and lowered CMPAase activity and male gender. Physical HRQoL (14.4%) was associated with increased MDA and TSH levels and lowered CMPAase activity. Social relations HRQoL (17.4%) was predicted by higher nitro-oxidative index and TSH values, while mental and environment HRQoL were independently predicted by CMPAase activity. Finally, 73.0% of the variance in total HRQoL was explained by severity of depressive symptoms, use of anticonvulsants, lower income, early lifetime emotional neglect, MDA levels, the presence of mood disorders, and suicidal ideation. CONCLUSIONS: These data show that lowered HRQoL in major affective disorders could at least in part result from the effects of lipid peroxidation, protein oxidation, lowered antioxidant enzyme activities, and higher levels of TSH.

In major affective disorders, early life trauma predict increased nitro-oxidative stress, lipid peroxidation and protein oxidation and recurrence of major affective disorders, suicidal behaviors and a lowered quality of life.

Early life trauma (ELT) may increase the risk towards bipolar disorder (BD) and major depression (MDD), disorders associated with activated neuro-oxidative and neuro-nitrosative stress (O&NS) pathways. It has remained elusive whether ELTs are associated with O&NS and which ELTs are associated with distinct affective disorder phenotypes. This case-control study examined patients with BD (n = 68) and MDD (n = 37) and healthy controls (n = 66). The Child Trauma Questionnaire (CTQ) was used to assess specific ELT. We measured malondialdehyde (MDA), lipid hydroperoxides (LOOH), superoxide dismutase (SOD), catalase, advanced oxidation protein products (AOPP); NO metabolites (NOx), paraoxonase 1 activity, zinc, albumin, high density lipoprotein cholesterol and -SH groups and computed z-unit weighted composite scores. Physical neglect significantly predicts higher z-unit weighted composite scores of LOOH+SOD, LOOH+SOD+NOx, LOOH+SOD+NOx + MDA and LOOH+SOD+NOx + AOPP. Sexual abuse was associated with a significantly lower composite score of zinc+albumin+SH. Emotional abuse was associated with severity of depression and anxiety, number of depressive and manic episodes, alcohol and hypnotics use, lifetime suicidal behavior and lowered quality of life. Sexual abuse was associated with an increased risk towards BD, but not MDD. ELT, especially physical neglect, may drive increased (nitro-)oxidative stress coupled with lipid and protein oxidation, which - together with emotional abuse - may play a role in severity of illness, lowered quality of life and MDD. ELTs are also associated with the onset of BD, but this link did not appear to be related to activated O&NS pathways. These novel findings deserve confirmation in prospective studies.

Elevated C-reactive Protein Levels in Women with Bipolar Disorder may be Explained by a History of Childhood Trauma, Especially Sexual Abuse, Body Mass Index and Age.

OBJECTIVE AND BACKGROUND: To evaluate whether increased levels of high-sensitivity C- reactive protein (hs-CRP) observed in individuals with bipolar disorder (BD) compared to healthy controls (HCs) could be influenced by a previous exposure to early life stress (ELS) independently from other explanatory or background variables, including age, body mass index (BMI), and the presence of cooccurring mental disorders. METHOD: In this case-control study, we included 142 healthy controls and 92 bipolar I and II patients. The Childhood Trauma Questionnaire was administered in a subset of 30 female patients with BD and 31 female HCs, and plasma hs-CRP was measured in all subjects. Multivariable models adjusted the data for the possible confounding variables. RESULTS: Serum hs-CRP levels were significantly higher in patients with BD compared to HCs. However, after controlling for BMI, these differences were no longer significant. Around 55% of the variance in hs-CRP was explained by cumulative and independent effects of age, BMI and childhood trauma, especially sexual abuse. CONCLUSION: Our results show that increased hs-CRP levels in BD patients are more related to childhood trauma, especially sexual abuse, age and BMI than to a diagnosis of BD per se. These data suggest that peripheral inflammation may underpin the well-known detrimental effects of childhood maltreatment and obesity in the course of BD. Hs-CRP data are difficult to interpret if they are not adjusted for effects of BMI and age.

Transtorno depressivo e fibromialgia: associação com estresse de vida precoce. Relato de caso / Depressive disorder and fibromyalgia: association to early life stress. Case report

JUSTIFICATIVA E OBJETIVOS: A associação entre depressão, fibromialgia e maus tratos infantis sugere que ambas, dividem o modelo de traumatologia do desenvolvimento. O objetivo deste estudo foi apresentar um caso do transtorno depressivo e fibromialgia relacionado aos maus tratos na infância, bem como discutir as causas e as consequências de ambos os diagnósticos. RELATO DO CASO: Paciente do sexo feminino, 54 anos, apresenta fibromialgia e transtorno depressivo recorrente, episódio atual grave, sem sintomas psicóticos, com sintomas somáticos há cerca de seis meses. Com história de eventos de vida negativos na infância com perda de relação afetiva, problemas relacionados com abuso físico alegado da criança e experiência pessoal amedrontadora na infância. CONCLUSÃO: O estresse de vida precoce pode ser responsabilizado como fator causal dos sintomas dolorosos na depressão e fibromialgia.

BACKGROUND AND OBJECTIVES: The association between depression, fibromyalgia and child abuse suggests that they divide the model of developmental traumatology. This study aimed at presenting a case of depressive disorder and fibromyalgia, associated to child abuse, as well as at discussing causes and consequences of both diagnoses. CASE REPORT: Female patient, 54 years old, with fibromyalgia and recurrent depressive disorder, current severe episode, without psychotic symptoms, with somatic symptoms for approximately six months. With history of negative childhood events with loss of affective relationship, problems related to alleged child abuse and frightening childhood experience. CONCLUSION: Early life stress may be the causal factor of painful symptoms in depression and fibromyalgia.

A criança agitada nem sempre é um problema / The agitated child is not always a problem

O termo agitação pode englobar muitos comportamentos diferentes, geralmente associados a algum transtorno psiquiátrico, como transtorno de déficit de atenção e hiperatividade (TDAH), transtorno de conduta, transtorno afetivo bipolar (TAB). Uma dúvida frequente é quando considerar a agitação psicomotora parte do desenvolvimento normal infantil ou de alguma doença psiquiátrica. A patologia existe quando a fase de agitação persiste além do esperado para a idade e circunstância, há prejuízo funcional importante nas relações sociais dentro da família, com pares e no desempenho escolar, além da presença de outros sintomas. Apesar da influência genética, a grande capacidade de adaptação do cérebro na infância e adolescência permite que as experiências infantis tenham efeito duradouro nos circuitos neurais por toda a vida, reforçando a importância de um ambiente favorável e do tratamento medicamentoso e psicoterápico adequado, nesta faixa etária. O foco da intervenção deve ser ensinar comportamentos pró-sociais, para que a criança/adolescente lide adequadamente com as situações que anteriormente provocavam agitação, envolvendo a colaboração de pais, pares, escola e demais profissionais.