Insomnia Polygenic Component on Attention Deficit-Hyperactivity Disorder: Exploring this Association Using Genomic Data from Brazilian Families.

Introduction Insomnia is highly prevalent among individuals with Attention-Deficit/Hyperactivity Disorder (ADHD). However, the biological mechanisms shared between both conditions is still elusive. We aimed to investigate whether insomnia's genomic component is able to predict ADHD in childhood and adolescence. Methods A Brazilian sample of 259 ADHD probands and their biological parents were included in the study. Their genomic DNA genotypes were used to construct the polygenic risk score for insomnia (Insomnia PRS), using the largest GWAS summary statistics as a discovery sample. The association was tested using logistic regression, under a case-pseudocontrol design. Results Insomnia PRS was nominally associated with ADHD (OR = 1.228, p = 0.022), showing that the alleles that increase the risk for insomnia also increase the risk for ADHD. Discussion Our results suggest that genetic factors associated with insomnia may play a role in the ADHD genetic etiology, with both phenotypes likely to have a shared genetic mechanism.

Stress-related genetic components in attention-deficit/hyperactivity disorder (ADHD): Effects of the SERPINA6 and SERPINA1 genetic markers in a family-based brazilian sample.

SERPINA6 and SERPINA1 were recently identified as the main genes associated with plasma cortisol concentration in humans. Although dysregulation in the Hypothalamus-Pituitary-Adrenal (HPA) axis has been observed in Attention Deficit/Hyperactivity Disorder (ADHD), the molecular mechanisms underlying this relationship are still unclear. Evaluation of the SERPINA6/SERPINA1 gene cluster in ADHD may provide relevant information to uncover them. We tested the association between the SERPINA6/SERPINA1 locus, including 95 single nucleotide polymorphisms (SNPs), and ADHD, using data from a Brazilian clinical sample of 259 ADHD probands and their parents. The single SNP association was tested using binary logistic regression, and we performed Classification and Regression Tree (CART) analysis to evaluate genotype combinations' effects on ADHD susceptibility. We assessed SNPs' regulatory effects through the Genotype-Tissue Expression (GTEx) v8 tool, and performed a complementary look-up analysis in the largest ADHD GWAS to date. There was a suggestive association between ADHD and eight variants located in the SERPINA6 region and one in the intergenic region between SERPINA6 and SERPINA1 after correction for multiple tests (p < 0.032). CART analysis showed that the combined effects of genotype GG in rs2144833 and CC in rs10129500 were associated with ADHD (OR = 1.78; CI95% = 1.24-2.55). The GTEx assigned the SNPs as eQTLs for genes in different tissues, including SERPINA6, and the look-up analysis revealed two SNPs associated with ADHD. These results suggest a shared genetic component between cortisol levels and ADHD. HPA dysregulation/altered stress response in ADHD might be mediated by upregulation of corticosteroid binding globulin (CBG, encoded by SERPINA6) expression.

Investigation of endophenotype potential of decreased fractional anisotropy in pediatric bipolar disorder patients and unrelated offspring of bipolar disorder patients.

BACKGROUND: Bipolar disorder (BD) is a severe psychiatric disorder associated with structural and functional brain abnormalities, some of which have been found in unaffected relatives as well. In this study, we examined the potential role of decreased fractional anisotropy (FA) as a BD endophenotype, in adolescents at high risk for BD. METHODS: We included 15 offspring of patients with BD, 16 pediatric BD patients, and 16 matched controls. Diffusion weighted scans were obtained on a 3T scanner using an echo-planar sequence. Scans were segmented using FreeSurfer. RESULTS: Our results showed significantly decreased FA in six brain areas of offspring group; left superior temporal gyrus (LSTG; P < .0001), left transverse temporal gyrus (LTTG; P = .002), left banks of the superior temporal sulcus (LBSTS; P = .002), left anterior cingulum (LAC; P = .003), right temporal pole (RTP; P = .004) and left frontal pole (LFP; P = .017). On analysis, LSTG, LAC, and RTP demonstrated a potential to be an endophenotype when comparing all three groups. FA values in three regions, LBSTS, LTTG, and LFP were increased only in controls. CONCLUSION: Our findings point at decreased FA as a possible endophenotype for BD, as they were found in children of patients with BD. Most of these areas were previously found to have morphological and functional changes in adult and pediatric BD, and are thought to play important roles in affected domains of functioning. Prospective follow up studies should be performed to detect reliability of decreased FA as an endophenotype and effects of treatment on FA.

Patterns of Youth Inpatient Psychiatric Admissions Before and After the Onset of the COVID-19 Pandemic.

To slow the spread of severe acute respiratory syndrome coronavirus 2, the virus causing 2019 novel coronavirus disease (COVID-19), many state authorities enforced extreme social distancing measures, such as closing schools, implementing online instruction, canceling major events, and limiting social contact outside families. Such measures have promoted safety but also have severely disrupted the lives of children of all ages. Many youths have missed seminal milestones; have struggled with the challenges of virtual schooling; and have isolated at home with their families, which has eroded opportunities for peer social support, relaxation, and enjoyment. While the consequences of COVID-19 on mental health are still unfolding, the psychological toll of these prolonged social distancing measures in combination with economic hardships and increased parental stress has led to worldwide reports of increased rates of mental health problems,1,2 trauma, abuse,3,4 and predicted increases in suicide5 in youths.

Alterations in plasma kynurenine pathway metabolites in children and adolescents with bipolar disorder and unaffected offspring of bipolar parents: A preliminary study.

BACKGROUND: There has been growing scientific evidence in recent years that bipolar disorder (BD) is associated with alterations in the kynurenine (KYN) pathway. However, many of these studies have been limited by their focus on adults. Thus, this preliminary study investigated differences in the peripheral levels of KYN metabolites in children and adolescents with BD, unaffected offspring of parents with BD, and healthy controls (HCs). METHODS: Plasma samples were collected from 49 youths with BD, 19 bipolar offspring, and 31 HCs. Tryptophan (TRP), KYN, and kynurenic acid (KYNA) were separated using electrospray ionization. RESULTS: One-Way ANCOVA after controlling for age, gender, race, BMI-for-age, and smoking status showed that BD had lower levels of KYN, while unaffected high-risk offspring subjects had lower levels of TRP, KYN, and KYNA when compared to HCs. Moreover, we found that KYN, KYN/TRP, and KYNA/KYN levels predicted the severity of depressive symptoms, while the YMRS score was not associated with any metabolite. CONCLUSIONS: In summary, this preliminary study has shown that KYN metabolites are decreased in both affected and unaffected subjects, strengthening the idea that the KYN pathway might underlie the familial risk of BD shown by high-risk offspring individuals. However, longitudinal studies are needed to examine whether the alterations observed in this study represent early markers of risk for later developing BD.

Life satisfaction mediates the association between childhood maltreatment and depressive symptoms: a study in a sample of Brazilian adolescents

Objective: To evaluate the interrelationships between childhood maltreatment, life satisfaction (LS), and depressive symptoms, and to investigate LS as a mediating factor in the association between childhood maltreatment and depressive symptoms. Methods: The sample consisted of 342 adolescents, aged 11 to 17 years (mean = 13.3, SD = 1.52 years), recruited from a public school in Salvador, Brazil. Participants filled out instruments for the collection of sociodemographic data and evaluation of childhood maltreatment, LS, and depressive symptoms. Structural equation modeling (SEM) was used to evaluate the mediating effect of LS. Results: We detected significant negative correlations between childhood maltreatment and LS and between LS and depressive symptoms. We observed a significant positive correlation between childhood maltreatment and depressive symptoms. LS partially mediated the association between childhood maltreatment and depressive symptoms, mitigating the impact of maltreatment. Conclusion: LS played an important mediating role in the association between childhood maltreatment and depressive symptoms. Longitudinal studies are recommended to fully elucidate these associations, reinforcing the need for attention and care of this vulnerable population.

Higher Prevalence of Metabolic Syndrome in Child-adolescent Patients with Bipolar Disorder.

OBJECTIVE: Previous studies have indicated a convergent and bidirectional relationship between metabolic syndrome (MetS) and bipolar disorder (BD). As most of these studies focused mainly on adults diagnosed with BD, our study aims to investigate and characterize metabolic disturbances in child-adolescents diagnosed with BD. METHODS: We retrospectively examined the medical records of psychiatric hospitalizations with admitting diagnosis of BD in child-adolescents (age ＜ 18 years). Body mass index (BMI), lipid profile, fasting blood glucose, and blood pressure were primary variables. National Cholesterol Education Program criteria were used to define MetS. Reference group data was obtained from the National Health and Nutrition Examination Survey study. Statistical analyses included t tests, chi-square tests, and Fisher's exact tests. RESULTS: We identified 140 child-adolescent patients with BD (mean age = 15.12 ± 1.70 years, 53% male). MetS was significantly more common in BD compared to the reference group: 14% (95% confidence interval [95% CI] 8-20) vs. 6.7% (95% CI 4.1-9.2), p = 0.001 with no significant difference by sex. MetS components were higher in the BD group, particularly BMI ≥ 95% (25% vs. 11.8%, p ＜ 0.001) and high blood pressure (17% vs. 8%, p = 0.05). Moreover, female patients had lower odds of high blood pressure (odds ratio = 0.24 [95% CI 0.08-0.69], p = 0.005). CONCLUSION: Compared with the general child-adolescent population, the prevalence of MetS was significantly higher in patients with BD of same age. This reiterates the notion of an increased risk of MetS in patients diagnosed with BD; and thus, further exploration is warranted.

Life satisfaction mediates the association between childhood maltreatment and depressive symptoms: a study in a sample of Brazilian adolescents.

OBJECTIVE: To evaluate the interrelationships between childhood maltreatment, life satisfaction (LS), and depressive symptoms, and to investigate LS as a mediating factor in the association between childhood maltreatment and depressive symptoms. METHODS: The sample consisted of 342 adolescents, aged 11 to 17 years (mean = 13.3, SD = 1.52 years), recruited from a public school in Salvador, Brazil. Participants filled out instruments for the collection of sociodemographic data and evaluation of childhood maltreatment, LS, and depressive symptoms. Structural equation modeling (SEM) was used to evaluate the mediating effect of LS. RESULTS: We detected significant negative correlations between childhood maltreatment and LS and between LS and depressive symptoms. We observed a significant positive correlation between childhood maltreatment and depressive symptoms. LS partially mediated the association between childhood maltreatment and depressive symptoms, mitigating the impact of maltreatment. CONCLUSION: LS played an important mediating role in the association between childhood maltreatment and depressive symptoms. Longitudinal studies are recommended to fully elucidate these associations, reinforcing the need for attention and care of this vulnerable population.

Clinical differences between patients with pediatric bipolar disorder with and without a parental history of bipolar disorder.

Pediatric Bipolar Disorder (PBD) is a highly heritable condition responsible for 18% of all pediatric mental health hospitalizations. Despite the heritability of this disorder, few studies have assessed potential differences in the clinical manifestation of PBD among patients with a clear parental history of BD. Additionally, while recent studies suggest that attentional deficits are a potential endophenotypic marker of PBD, it is unclear whether heritability is a relevant contributor to these symptoms. In order to address this gap, the present study assessed 61 youth with PBD (6-17 years old), corresponding to 27 offspring of BD patients, and 31 PBD patients without a parental history of the disorder. All standardized assessments, including the K-SADS-PL-W were performed by trained child and adolescent psychiatrists. We performed a logistic multivariate model using the variables of ADHD, rapid cycling, and lifetime psychosis. Rates of ADHD comorbidity were significantly higher among PBD patients who had a parent with BD. Furthermore, PBD patients who had a parent with BD showed a trend toward significance of earlier symptom onset. PBD offspring did not show increased rates of suicide attempts, rapid cycling, or psychosis. Given these findings, it appears that PBD patients who have a parent with BD may represent a distinct endophenotype of the disorder. Future longitudinal and larger studies are required to confirm our findings.

Persistence of symptoms after cognitive therapies is associated with childhood trauma: A six months follow-up study.

This study aims to assess the effect of childhood trauma on the outcomes of brief cognitive therapies for major depressive disorder. This is a follow-up clinical study nested in a randomized clinical trial of cognitive therapies. Sixty-one patients were assessed at baseline, post-intervention and six-month follow-up. The study showed that brief cognitive therapies improved depressive and anxious symptoms at post-intervention and six-month follow-up. Higher childhood trauma scores at baseline were significantly associated with higher severity of depressive and anxious symptoms at six-month follow-up. Longer courses of psychotherapy may be needed to improve the long-lasting effects of traumatic experiences.

CLOCK Polymorphisms in Attention-Deficit/Hyperactivity Disorder (ADHD): Further Evidence Linking Sleep and Circadian Disturbances and ADHD.

Circadian and sleep disorders, short sleep duration, and evening chronotype are often present in attention-deficit/hyperactivity disorder (ADHD). CLOCK, considered the master gene in the circadian rhythm, has been explored by few studies. Understanding the relationship between ADHD and CLOCK may provide additional information to understand the correlation between ADHD and sleep problems. In this study, we aimed to explore the association between ADHD and CLOCK, using several genetic markers to comprehensively cover the gene extension. A total of 259 ADHD children and their parents from a Brazilian clinical sample were genotyped for eight single nucleotide polymorphisms (SNPs) in the CLOCK locus. We tested the individual markers and the haplotype effects using binary logistic regression. Binary logistic and linear regressions considering ADHD symptoms among ADHD cases were conducted as secondary analysis. As main result, the analysis showed a risk effect of the G-A-T-G-G-C-G-A (rs534654, rs1801260, rs6855837, rs34897046, rs11931061, rs3817444, rs4864548, rs726967) haplotype on ADHD. A suggestive association between ADHD and rs534654 was observed. The results suggest that the genetic susceptibility to circadian rhythm attributed to the CLOCK gene may play an important role on ADHD.

Correlates of childhood trauma in children and adolescents with bipolar disorder spectrum: A preliminary study.

OBJECTIVE: Histories of childhood trauma (CT) are risk factors for affect dysregulation and poor clinical outcomes in women with bipolar disorder (BD). While much is known about the link between BD and CT in adult patients, there is limited data on this research topic in pediatric BD (PBD). The present study aims to investigate the impact of CT on irritability, aggressive and suicidal behaviors in PBD patients across gender types. METHODS: From 2013 to 2015, 59 PBD patients Aged 6-17 (30 female) were administered the Childhood Trauma Questionnaire (CTQ) along with scales assessing irritability (Affective Reactivity Index), aggression (Modified Overt Aggression Scale) and suicidal thoughts and behaviors (Columbia-Suicide Severity Rating Scale). We examined the severity of these behaviors across types of CT and gender using univariate regression analyses. Findings were adjusted for age, number of traumas, and CTQ denial score. RESULTS: In PBD patients, analyses showed that the effect of physical abuse depended on gender, whereby females were more likely than males to engage in suicidal thoughts and behaviors (p < 0.05). Male gender and CT were strong determinants of irritability (p < 0.05). Violence against property and people was found to be reduced in females, and increased in males with a history of emotional and sexual abuse, respectively (p < 0.05). CONCLUSION: These preliminary findings highlight the significant impact of CT in PBD and suggest that gender may predict the risk for dysfunctional behaviors in PBD patients with CT. Future large scale, longitudinal, investigations focusing on fear processing and extinction may provide a deeper understanding of these gender differences, and their role in the course of BD.

Effects of valproate on brain volumes in pediatric bipolar disorder: A preliminary study.

Sodium valproate (VPA) has well-established neuroprotective effects and is recommended as treatment in bipolar disorder patients. The neural effects of VPA in pediatric bipolar disorder (PBD) have yet to be established. This preliminary study explored the effects of VPA on brain structure in PBD. Fourteen PBD patients (10 males; mean = 13.43 ± 3.05 years old) underwent a structural MRI before and after a 6-week VPA treatment period. Bayesian linear mixed modeling explored seven brain region volumes as a function of dichotomous pre/post time. Results showed a decrease in amygdala volume over time. These findings need to be confirmed by large-scale, longitudinal studies.

Construction of a biological rhythm assessment scale for children.

Introduction Biological rhythm is associated with the level of alertness, cognitive performance and mood of the individuals. Its regularity is essential to preserve good health and quality of life. Objective To present the steps for the construction of the scale entitled Biological Rhythm Interview of Assessment in Neuropsychiatry - Kids (BRIAN-K), designed to measure biological rhythm disruptions in Brazilian children and adolescents. Methods Items were developed following the adult version of the scale. Analysis of the psychometric characteristics of the scale was based on the responses of 373 parents/caregivers of school age children (7 and 8 years old). Results A theoretical model of 17 items with the purpose of evaluating four domains (sleep, activities, social rhythm and eating pattern) was determined using exploratory factor analysis (EFA) and via identification of a general factor. The psychometric properties of the BRIAN-K showed favorable properties. Conclusion Only two items needed to be rewritten. Further studies are needed to investigate the instrument's adequacy to different age groups and additional evidence of validity and reliability.

Hippocampal subfield volumes in children and adolescents with mood disorders.

The hippocampus has been implicated in various mood disorders, with global volume deficits consistently found in patient populations. The hippocampus, however, consists of anatomically distinct subfields, and examination of specific subfield differences may elucidate the possible molecular mechanisms behind psychiatric pathologies. Indeed, adult studies have reported smaller hippocampal subfield volumes in regions within the cornu ammonis (CA1 and CA4), dentate gyrus (DG), and hippocampal tails in both patients with Major Depressive Disorder (MDD) and Bipolar Disorder (BD) compared to healthy controls. Subfield differences in pediatric patients with mood disorders, on the other hand, have not been extensively investigated. In the current study, magnetic resonance imaging scans were acquired for 141 children and adolescents between the ages of eight and eighteen (57 with BD, 30 with MDD, and 54 healthy controls). An automated segmentation method was then used to assess differences in hippocampal subfield volumes. Children and adolescents with BD were found to have significantly smaller volumes in the right CA1, CA4, and right subiculum, as well as the bilateral granule cell layer (GCL), molecular layer (ML), and hippocampal tails. The volume of the right subiculum in BD patients was also found to be negatively correlated with illness duration. Overall, the findings from this cross-sectional study provide evidence for specific hippocampal subfield volume differences in children and adolescents with BD compared to healthy controls and suggest progressive reductions with increased illness duration.

Construction of a biological rhythm assessment scale for children / Construção de uma escala de avaliação do ritmo biológico para crianças

Abstract Introduction Biological rhythm is associated with the level of alertness, cognitive performance and mood of the individuals. Its regularity is essential to preserve good health and quality of life. Objective To present the steps for the construction of the scale entitled Biological Rhythm Interview of Assessment in Neuropsychiatry - Kids (BRIAN-K), designed to measure biological rhythm disruptions in Brazilian children and adolescents. Methods Items were developed following the adult version of the scale. Analysis of the psychometric characteristics of the scale was based on the responses of 373 parents/caregivers of school age children (7 and 8 years old). Results A theoretical model of 17 items with the purpose of evaluating four domains (sleep, activities, social rhythm and eating pattern) was determined using exploratory factor analysis (EFA) and via identification of a general factor. The psychometric properties of the BRIAN-K showed favorable properties. Conclusion Only two items needed to be rewritten. Further studies are needed to investigate the instrument's adequacy to different age groups and additional evidence of validity and reliability.

Resumo Introdução O ritmo biológico está associado ao nível de alerta, desempenho cognitivo e humor dos indivíduos. Sua regularidade é essencial para preservar uma boa saúde e qualidade de vida. Objetivo Apresentar as etapas de construção da escala intitulada Biological Rhythm Interview of Assessment in Neuropsychiatry - Kids (BRIAN-K), criada para medir disrupturas do ritmo biológico em crianças e adolescentes brasileiros. Métodos Os itens foram desenvolvidos seguindo a versão adulta da escala. A análise das características psicométricas da escala se baseou nas respostas de 373 pais/cuidadores de crianças em idade escolar (7 e 8 anos). Resultados Um modelo teórico de 17 itens, com o objetivo de avaliar quatro domínios do ritmo biológico (sono, atividades, ritmo social e padrão alimentar) foi determinado usando análise fatorial exploratória (AFE) e pela identificação de um fator geral. As propriedades psicométricas da BRIAN-K mostraram-se satisfatórias. Conclusão Apenas dois itens precisaram ser reescritos. São necessários mais estudos para investigar a adequação do instrumento a diferentes faixas etárias e evidências adicionais de validade e confiabilidade.

ADHD is associated with migraine: a systematic review and meta-analysis.

An association between primary headaches and attention-deficit/hyperactivity disorder (ADHD) has long been suggested. Moreover, headache is regarded as a common side effect of stimulants, the most effective treatment for ADHD. So far, no systematic review has evaluated the potential association between ADHD and headache. We performed a systematic review of the literature and a meta-analysis of all reported studies on ADHD and primary headaches. Our analysis showed a positive association between ADHD and migraine (OR 1.322, 95% CI 1.018-1717, p value 0.036), but not with tension-type headache. There is a significant association between migraine and ADHD. The mechanisms underlying this association remain to be elucidated, warranting further studies.

Attention-Deficit/Hyperactivity Disorder And Inflammation: What Does Current Knowledge Tell Us? A Systematic Review.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a complex condition that interferes with development and/or functioning. Our objective is to investigate the potential association between ADHD and inflammation. METHODS: We conducted a systematic review of human studies measuring inflammatory markers in ADHD. The studies were identified by searching PUBMED, MEDLINE, EMBASE, PSYCHINFO, COCHRANE, and SCOPUS databases for peer-reviewed journals published until September 2016. We included cytokine gene expression and protein measured. Fourteen papers met the inclusion criteria. RESULTS: Seven studies evaluated the association of cytokine gene polymorphisms in ADHD, and six studies measured cytokines levels in blood. One study analyzed the presence of cytokines in cerebrospinal fluid in patients with ADHD. Altogether, these studies indicate a possible role of inflammation in ADHD pathogenesis, despite the significant heterogeneity and contradictory results. CONCLUSION: Evidence points to the association of ADHD with inflammatory processes, but more studies are warranted.

The International Society for Bipolar Disorders Task Force report on pediatric bipolar disorder: Knowledge to date and directions for future research.

OBJECTIVES: Over the past two decades, there has been tremendous growth in research regarding bipolar disorder (BD) among children and adolescents (ie, pediatric BD [PBD]). The primary purpose of this article is to distill the extant literature, dispel myths or exaggerated assertions in the field, and disseminate clinically relevant findings. METHODS: An international group of experts completed a selective review of the literature, emphasizing areas of consensus, identifying limitations and gaps in the literature, and highlighting future directions to mitigate these gaps. RESULTS: Substantial, and increasingly international, research has accumulated regarding the phenomenology, differential diagnosis, course, treatment, and neurobiology of PBD. Prior division around the role of irritability and of screening tools in diagnosis has largely abated. Gold-standard pharmacologic trials inform treatment of manic/mixed episodes, whereas fewer data address bipolar depression and maintenance/continuation treatment. Adjunctive psychosocial treatment provides a forum for psychoeducation and targets primarily depressive symptoms. Numerous neurocognitive and neuroimaging studies, and increasing peripheral biomarker studies, largely converge with prior findings from adults with BD. CONCLUSIONS: As data have accumulated and controversy has dissipated, the field has moved past existential questions about PBD toward defining and pursuing pressing clinical and scientific priorities that remain. The overall body of evidence supports the position that perceptions about marked international (US vs elsewhere) and developmental (pediatric vs adult) differences have been overstated, although additional research on these topics is warranted. Traction toward improved outcomes will be supported by continued emphasis on pathophysiology and novel therapeutics.

Antipsychotic-induced Tardive dyskinesia: from biological basis to clinical management.

INTRODUCTION: Tardive dyskinesia (TD) is a chronic and disabling movement disorder with a complex pathophysiological basis. A significant percentage of patients does not receive correct diagnosis, resulting in delayed or inaccurate treatment and poor outcome. Therefore, there is a critical need for prompt recognition, implementation of efficacious treatment regimens and long-term follow up of patients with TD. Areas covered: The current paper provides an overview of emerging data concerning proposed pathophysiology theories, epidemiology, risk factors, and therapeutic strategies for TD. Expert commentary: Despite considerable research efforts, TD remains a challenge in the treatment of psychosis as the available strategies remain sub-optimal. The best scenario will always be the prophylaxis or prevention of TD, which entails limiting the use of antipsychotics.