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.

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.

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.

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.

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.

School start time influences melatonin and cortisol levels in children and adolescents - a community-based study.

School start time influences sleep parameters. Differences between circadian sleep parameters on weekends and weekdays have been associated with obesity, sleep, and psychiatric disorders. Moreover, circadian rhythm dysregulation affects the secretion of some hormones, such as melatonin and cortisol. In the current study, we investigate the effect of school start time on cortisol and melatonin levels in a community sample of Brazilian children and adolescents. This was a cross-sectional study of 454 students (mean age, 12.81 ± 2.56 years; 58.6% female). From this sample, 80 participants were randomly selected for saliva collection to measure melatonin and cortisol levels. Circadian sleep parameters were assessed by self-reported sleep and wake up schedules and the Morningness-Eveningness Questionnaire. The outcomes, salivary melatonin and cortisol levels, were measured in morning, afternoon and night saliva samples, and behavior problems were assessed using the Child Behavior Checklist (CBCL). The main results revealed that morning school start time decreased the secretion of melatonin. Morning melatonin levels were significantly positively correlated with the sleep midpoint on weekdays and on weekends. Afternoon melatonin levels were positively correlated with the sleep midpoint on weekends in the morning school students. Conversely, in the afternoon school students, night melatonin levels were negatively correlated with the sleep midpoint on weekdays. Cortisol secretion did not correlate with circadian sleep parameters in any of the school time groups. In conclusion, school start time influences melatonin secretion, which correlated with circadian sleep parameters. This correlation depends on the presence of psychiatric symptoms. Our findings emphasize the importance of drawing attention to the influence of school start time on the circadian rhythm of children and adolescents.

GAD1 gene polymorphisms are associated with hyperactivity in Attention-Deficit/Hyperactivity Disorder.

Attention-Deficit/Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental disorders of childhood. Recent studies suggest a role for γ-aminobutyric acid (GABA) on ADHD hyperactive/impulsive symptoms due to behavioral disinhibition resulting from inappropriate modulation of both glutamatergic and GABAergic signaling. The glutamic acid decarboxylase (GAD1) gene encodes a key enzyme of GABA biosynthesis. The aim of the present study was to investigate the possible influence of GAD1 SNPs rs3749034 and rs11542313 on ADHD susceptibility. The clinical sample consisted of 547 families with ADHD probands recruited at the ADHD Outpatient Clinics from Hospital de Clínicas de Porto Alegre. Hyperactive/impulsive symptoms were evaluated based on parent reports from the Swanson, Nolan, and Pelham Scale-version IV (SNAP-IV). The C allele of rs11542313 was significantly overtransmitted from parents to ADHD probands (P = 0.02). Hyperactive/impulsive score was higher in rs3749034G allele (P = 0.005, Cohen's D = 0.19) and rs11542313C allele (P = 0.03; Cohen's D = 0.16) carriers. GAD1 haplotypes were also associated with higher hyperactive/impulsive scores in ADHD youths (global P-value = 0.01). In the specific haplotype test, the GC haplotype was the one with the highest hyperactive/impulsive scores (P = 0.03). Our results suggest that the GAD1 gene is associated with ADHD susceptibility, contributing particularly to the hyperactive/impulsive symptom domain. © 2016 Wiley Periodicals, Inc.

NOS1 and SNAP25 polymorphisms are associated with Attention-Deficit/Hyperactivity Disorder symptoms in adults but not in children.

Several investigations documented that Attention-Deficit/Hyperactivity Disorder (ADHD) is better conceptualized as a dimensional disorder. At the same time, the disorder seems to have different neurobiological underpinnings and phenotypic presentation in children compared to adults. Neurodevelopmental genes could explain, at least partly these differences. The aim of the present study was to examine possible associations between polymorphisms in SNAP25, MAP1B and NOS1 genes and ADHD symptoms in Brazilian samples of children/adolescents and adults with ADHD. The youth sample consisted of 301 patients whereas the adult sample comprises 485 individuals with ADHD. Diagnoses of ADHD and comorbidities were based on the Diagnostic and Statistical Manual of Mental Disorders-4th edition criteria. The Swanson, Nolan and Pelham Scale-Version IV (SNAP-IV) was applied by psychiatrists blinded to genotype. The total SNAP-IV scores were compared between genotypes. Impulsivity SNAP-IV scores were also compared according to NOS1 genotypes. Adult patients homozygous for the C allele at SNAP25 rs8636 showed significantly higher total SNAP-IV scores (F = 11.215; adjusted P-value = 0.004). Impulsivity SNAP-IV scores were also significantly different according to NOS1 rs478597 polymorphisms in adults with ADHD (F = 6.282; adjusted P-value = 0.026). These associations were not observed in children and adolescents with ADHD. These results suggest that SNAP25 and NOS1 genotypes influence ADHD symptoms only in adults with ADHD. Our study corroborates previous evidences for differences in the genetic contribution to adult ADHD compared with childhood ADHD.

MAP1B and NOS1 genes are associated with working memory in youths with attention-deficit/hyperactivity disorder.

Diverse efforts have been done to improve the etiologic understanding of mental disorders, such as attention-deficit/hyperactivity disorder (ADHD). It becomes clear that research in mental disorders needs to move beyond descriptive syndromes. Several studies support recent theoretical models implicating working memory (WM) deficits in ADHD complex neuropsychology. The aim of this study was to examine the association between rs2199161 and rs478597 polymorphisms at MAP1B and NOS1 genes with verbal working memory in children and adolescents with ADHD. A total of 253 unrelated ADHD children/adolescents were included. The sample was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders-4th edition criteria. Digit Span from the Wechsler Intelligence Scale for Children-Third Edition was used to assess verbal WM. The raw scores from both forward and backward conditions of Digit Span were summed and converted into scaled scores according to age. The means of scaled Digit Span were compared according to genotypes by ANOVA. Significant differences in Digit Span scores between MAP1B genotype groups (rs2199161: F = 5.676; p = 0.018) and NOS1 (rs478597: F = 6.833; p = 0.009) genes were detected. For both polymorphisms, the CC genotype carriers showed a worse performance in WM task. Our findings suggest possible roles of NOS1 and MAP1B genes in WM performance in ADHD patients, replicating previous results with NOS1 gene in this cognitive domain in ADHD children.

Biological rhythms in bipolar and depressive disorders: A community study with drug-naïve young adults.

AIM: To assess biological rhythm disruptions among drug-naïve young adults with bipolar disorder (BD), major depressive disorder (MDD), and community controls. METHODS: This was a cross-sectional study nested in a population-based study. BD and MDD were diagnosed using the Structured Clinical Interview for DSM-IV. Biological rhythm disruptions were assessed using the Biological Rhythm Interview of Assessment in Neuropsychiatry (BRIAN). RESULTS: Two hundred seventeen subjects were assessed (49 BD, 74 MDD, and 94 community controls). Biological rhythm disruption was higher in subjects with BD (40.32±9.92; p<0.001) and MDD (36.23±8.71; p<0.001) than community controls (27.67±6.88). Subjects with BD had a higher BRIAN total score (p=0.028) and higher disruption in sleep/social domains (p=0.018) as compared to MDD. In addition, the BRIAN scores were higher in current MDD, euthymic BD, and BD in current episode group, as compared to community controls. LIMITATION: Cross-sectional design. Absence of assessment of biomarkers of biological rhythms. CONCLUSION: Bipolar disorder and major depressive disorder are associated with disruption in biological rhythm. In addition, disruption in sleep/social rhythms is higher in subjects with BD when compared to subjects with MDD. We also verified biological rhythm disruption in subjects with BD during euthymic status, but not in remitted MDD. Regulation of biological rhythm may be a means to identify patients with mood disorders and potentially differentiate MDD from BD.

Correlation between Peripheral Levels of Brain-Derived Neurotrophic Factor and Hippocampal Volume in Children and Adolescents with Bipolar Disorder.

Pediatric bipolar disorder (PBD) is a serious mental disorder that affects the development and emotional growth of affected patients. The brain derived neurotrophic factor (BDNF) is recognized as one of the possible markers of the framework and its evolution. Abnormalities in BDNF signaling in the hippocampus could explain the cognitive decline seen in patients with TB. Our aim with this study was to evaluate possible changes in hippocampal volume in children and adolescents with BD and associate them to serum BDNF. Subjects included 30 patients aged seven to seventeen years from the ProCAB (Program for Children and Adolescents with Bipolar Disorder). We observed mean right and left hippocampal volumes of 41910.55 and 41747.96 mm(3), respectively. No statistically significant correlations between peripheral BDNF levels and hippocampal volumes were found. We believe that the lack of correlation observed in this study is due to the short time of evolution of BD in children and adolescents. Besides studies with larger sample sizes to confirm the present findings and longitudinal assessments, addressing brain development versus a control group and including drug-naive patients in different mood states may help clarify the role of BDNF in the brain changes consequent upon BD.

Cadherin-13 gene is associated with hyperactive/impulsive symptoms in attention/deficit hyperactivity disorder.

Several efforts have been made to find new genetic risk variants which explain the high heritability of ADHD. At the genome level, genes involved in neurodevelopmental pathways were pointed as candidates. CDH13 and CTNNA2 genes are within GWAS top hits in ADHD and there are emerging notions about their contribution to ADHD pathophysiology. The main goal of this study is to test the association between SNPs in CDH13 and CTNNA2 genes and ADHD across the life cycle in subjects with ADHD. This study included 1,136 unrelated ADHD cases and 946 individuals without ADHD. No significant association between CDH13 and CTNNA2 was observed between cases and controls across different samples (P ≥ 0.096 for all comparisons). No allele was significantly more transmitted than expected from parents to ADHD probands. The CDH13 rs11150556 CC genotype was associated with more hyperactive/impulsive symptoms in youths with ADHD (children/adolescents clinical sample: F = 7.666, P = 0.006, FDR P-value = 0.032; Pelotas Birth Cohort sample: F = 6.711, P = 0.011, FDR P-value = 0.032). Although there are many open questions regarding the role of neurodevelopmental genes in ADHD symptoms, the present study suggests that CDH13 is associated with hyperactive/impulsive symptoms in youths with ADHD.

Attention-based classification pattern, a research domain criteria framework, in youths with bipolar disorder and attention-deficit/hyperactivity disorder.

OBJECTIVE: The National Institute of Mental Health has initiated the Research Domain Criteria (RDoC) project. Instead of using disorder categories as the basis for grouping individuals, the RDoC suggests finding relevant dimensions that can cut across traditional disorders. Our aim was to use the RDoC's framework to study patterns of attention deficit based on results of Conners' Continuous Performance Test (CPT II) in youths diagnosed with bipolar disorder (BD), attention-deficit/hyperactivity disorder (ADHD), BD+ADHD and controls. METHOD: Eighteen healthy controls, 23 patients with ADHD, 10 with BD and 33 BD+ADHD aged 12-17 years old were assessed. Pattern recognition was used to partition subjects into clusters based simultaneously on their performance in all CPT II variables. A Fisher's linear discriminant analysis was used to build a classifier. RESULTS: Using cluster analysis, the entire sample set was best clustered into two new groups, A and B, independently of the original diagnoses. ADHD and BD+ADHD were divided almost 50% in each subgroup, and there was an agglomeration of controls and BD in group B. Group A presented a greater impairment with higher means in all CPT II variables and lower Children's Global Assessment Scale. We found a high cross-validated classification accuracy for groups A and B: 95.2%. Variability of response time was the strongest CPT II measure in the discriminative pattern between groups A and B. CONCLUSION: Our classificatory exercise supports the concept behind new approaches, such as the RDoC framework, for child and adolescent psychiatry. Our approach was able to define clinical subgroups that could be used in future pathophysiological and treatment studies.

Glutamatergic copy number variants and their role in attention-deficit/hyperactivity disorder.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder with a strong genetic component. The glutamate metabotropic receptor genes (GRMs) have been considered potential candidates for ADHD susceptibility. The aim of the present study was to investigate if copy number variants (CNVs) in GRM1, GRM5, and GRM8 genes are overrepresented in ADHD subjects. A total of 1038 individuals with ADHD and 1057 subjects without this disorder were investigated. No significant difference in the total number of CNVs was found comparing the entire ADHD sample and the population sample without ADHD (P = 0.326, OR = 1.112, 95% CI = 0.762-1.624). The presence of CNVs was associated with lower intelligence quotient (IQ) scores in ADHD samples (P = 0.026, OR = 1.824, 95% CI = 1.066-3.121) but not in the sample of individuals without ADHD. CNVs in GRM5 were associated with presence of anxiety disorders in ADHD cases (P = 0.002, OR = 3.915, 95% CI = 1.631-9.402), but not in individuals without ADHD. Taken together, our results suggest a role for glutamate in ADHD as CNVs in the glutamatergic genes investigated herein were associated with cognitive and clinical characteristics of ADHD individuals.