An integrative approach to investigate the respective roles of single-nucleotide variants and copy-number variants in Attention-Deficit/Hyperactivity Disorder.

Many studies have attempted to investigate the genetic susceptibility of Attention-Deficit/Hyperactivity Disorder (ADHD), but without much success. The present study aimed to analyze both single-nucleotide and copy-number variants contributing to the genetic architecture of ADHD. We generated exome data from 30 Brazilian trios with sporadic ADHD. We also analyzed a Brazilian sample of 503 children/adolescent controls from a High Risk Cohort Study for the Development of Childhood Psychiatric Disorders, and also previously published results of five CNV studies and one GWAS meta-analysis of ADHD involving children/adolescents. The results from the Brazilian trios showed that cases with de novo SNVs tend not to have de novo CNVs and vice-versa. Although the sample size is small, we could also see that various comorbidities are more frequent in cases with only inherited variants. Moreover, using only genes expressed in brain, we constructed two "in silico" protein-protein interaction networks, one with genes from any analysis, and other with genes with hits in two analyses. Topological and functional analyses of genes in this network uncovered genes related to synapse, cell adhesion, glutamatergic and serotoninergic pathways, both confirming findings of previous studies and capturing new genes and genetic variants in these pathways.

Refinando o diagnóstico de Transtorno de Oposição e Desafio na infância e adolescência: validação e caracterização da dimensão irritável / Refining Oppositional Defiant Disorder diagnosis in children and adolescents: validation and characterization of the irritable dimension

O Transtorno de Oposição e Desafio (TOD) é definido por um padrão recorrente de comportamento desafiante, desobediente e hostil com início na infância e adolescência e caracteriza-se por uma alta taxa de comorbidades. Estudos longitudinais apontam o TOD na infância como um dos principais preditores de psicopatologia na idade adulta. Uma possível explicação para a grande heterogeneidade de comorbidades e trajetórias longitudinais é de que o diagnóstico de TOD abrange distintas dimensões de sintomas, cada qual com seu desfecho. O primeiro objetivo desta tese foi a validação das distintas dimensões do TOD em uma amostra comunitária Brasileira composta de 2512 sujeitos. Através de análise fatorial confirmatória, demonstramos que o modelo que melhor representa a heterogeneidade do TOD é composto por três dimensões: a dimensão "argumentative/defiant" que está associada com transtorno de déficit de atenção/hiperatividade (TDAH); a dimensão "vindictiveness" que possui associação com transtorno de conduta (TC); e a dimensão "angry/irritable mood" onde predominam as associações com transtornos depressivos e de ansiedade. O objetivo seguinte foi investigar o papel da dimensão irritável na classificação nosológica dos transtornos mentais na infância e adolescência. A apresentação da irritabilidade é um aspecto crucial: irritabilidade crônica caracterizada por baixa tolerância à frustração e frequentes explosões de raiva, que é distinta da apresentação episódica, associada ao diagnóstico Transtorno de Humor Bipolar (TB). "Severe mood dysregulation", "disruptive mood dysregulation disorder", ou dimensão irritável do TOD são formas distintas de classificar o fenótipo de irritabilidade crônica. Entretanto, independente da classificação utilizada, a alta taxa de comorbidades é invariavelmente o denominador comum em estudos sobre irritabilidade. Neste sentido, examinamos o impacto da irritabilidade como uma dimensão subjacente a vários transtornos. Para tanto, avaliamos o...

The Oppositional Defiant Disorder (ODD) is defined as a pattern of disobedient, hostile and defiant behavior beginning in childhood or adolescence and often accompanied by a wide range of comorbidities. Longitudinal studies support ODD as a predictor of psychopathology in adulthood. A potential explanation for such heterogeneity of comorbidities and longitudinal trajectories is that ODD diagnosis encompasses distinct clusters of symptoms, each with its outcome. The first aim of this work was the validation of ODD dimensions in a Brazilian community sample of 2512 subjects. Confirmatory factorial analysis showed that the best model for ODD comprised three dimensions: an "argumentative/defiant" dimension, which associates with attention deficit/hyperactivity disorder (ADHD); a "vindictiveness" dimension, which associates with conduct disorder (CD); and an "angry/irritable" dimension where emotional disorders such as depression and anxiety are the most common associations. The next step was the investigation of the role of the irritable dimension of oppositionality in diagnostic classifications of childhood mental disorders. The pattern of irritability is a crucial point: its chronic presentation as easy annoyance and frequent temper outbursts should be differentiated from the episodic course of irritability associated with the specific diagnosis of Bipolar Disorder (BD). "Severe mood dysregulation", "disruptive mood dysregulation disorder", and the irritable dimension of oppositionality are different ways to classify the chronic irritability phenotype. However, regardless of the classification, the high rate of comorbidities is invariably the common denominator in studies of irritability. Therefore, we examined the impact of irritability as a dimension cutting across multiple settings: individuals without any diagnosis, subjects with ADHD, and also those with emotional disorders. For that we used two samples, one from Brazil, with 2.512 subjects, and one...

Transtornos de humor na infância e na adolescência: uma atualização / Mood disorders in childhood and adolescence: an update

O atual reconhecimento de que os transtornos mentais são resultados de interações entre aspectos biológicos e ambientais que ocorrem ao longo do desenvolvimento baliza a relevância das apresentações clínicas durante a infância e adolescência. O presente artigo tem por objetivo prover uma atualização em transtornos de humor em crianças e adolescentes. Para tanto, abordaremos aspectos específicos de desenvolvimento nos transtornos de humor enfatizando como a identificação precoce e a terapêutica adequada podem potencialmente modificar alterações a longo prazo. O processo diagnóstico dos transtornos de humor em crianças e adolescentes possui peculiaridades próprias da idade que necessitam ser contempladas durante a avaliação. Isso é especialmente importante na diferenciação dos transtornos depressivos e do transtorno de humor bipolar, o que constitui hoje um dos focos de maior estudo na área. Em relação ao tratamento, hoje dispomos de inúmeros métodos terapêuticos, como a psicoeducação, a terapia de orientação psicodinâmica, a terapia cognitivo-comportamental e a terapia farmacológica, além da inclusão familiar como importante recurso na determinação do sucesso terapêutico. Uma escolha terapêutica acertada depende de um processo diagnóstico criterioso e visa proporcionar para a criança e o adolescente com transtorno de humor recursos para seu desenvolvimento pessoal e sua participação social na família e na escola.(AU)

The current recognition that mental disorders are the result of interactions between biological and environmental aspects that occur throughout development goal relevance of clinical presentations during childhood and adolescence. This article aims to provide an update on mood disorders in children and adolescents. To do so, we discuss specific aspects of the development of mood disorders emphasizing how early identification and appropriate therapy can potentially modify long-term changes. The diagnostic process of mood disorders in children and adolescents age has its own peculiarities that need to be addressed during the evaluation. This is especially important in the differentiation of depressive disorders and bipolar disorder, which is now a focus of further study in the area. Regarding treatment, we now have numerous therapeutic methods, such as psycho-education, psychodynamic orientation therapy, cognitive behavioural therapy and drug therapy, as well as family inclusion as an important feature in determining therapeutic success. A therapeutic right choice depends on a careful diagnostic process and aims to provide for the child and adolescent with mood disorder resources for personal development and social participation in family and school.(AU)

Irritability in children and adolescents: past concepts, current debates, and future opportunities.

Irritability is defined as a low threshold to experience anger in response to frustration. It is one of the most common symptoms in youth and is part of the clinical presentation of several disorders. Irritability can present early in life and is a predictor of long-term psychopathology; yet, the diagnostic status of irritability is a matter of intense debate. In the present article, we address two main components of the debate regarding irritability in youth: the misdiagnosis of chronic irritability as pediatric bipolar disorder, and the proposal of a new diagnosis in the DSM-5, disruptive mood dysregulation disorder, whose defining symptoms are chronic irritability and temper outbursts.

Dimensions of oppositionality in a Brazilian community sample: testing the DSM-5 proposal and etiological links.

OBJECTIVE: Investigating dimensions of oppositional symptoms may help to explain heterogeneity of etiology and outcomes for mental disorders across development and provide further empirical justification for the DSM-5-proposed modifications of oppositional defiant disorder (ODD). However, dimensions of oppositionality have not previously been tested in samples outside Europe or the United States. In this study, we used a large Brazilian community sample to compare the fit of different models for dimensions of oppositional symptoms; to examine the association of psychiatric diagnoses and symptoms with dimensions of oppositionality; and to examine the associations between dimensions of oppositionality and parental history of mental disorders. METHOD: A Brazilian community sample of 2,512 children 6 through 12 years old were investigated in this study. Confirmatory factorial analyses were performed to compare the fit of alternative models, followed by linear and logistic regression analyses of associations with psychiatric diagnosis and parental history of psychopathology. RESULTS: A three-factor model with irritable, headstrong, and hurtful dimensions fitted best. The irritable dimension showed a strong association with emotional disorders in the child (p<.001) and history of depression (p<.01) and suicidality (p<.05) in the mother. The headstrong dimension was uniquely associated with attention-deficit/hyperactivity disorder (ADHD) in the child (p<.001) and with maternal history of ADHD symptoms (p<.05). The hurtful dimension was specifically associated with conduct disorder (p< .05). CONCLUSIONS: Our findings from a large community sample of Brazilian children support a distinction between dimensions of oppositionality consistent with current DSM-5 recommendations and provide further evidence for etiological distinctions between these dimensions.

Irritability in children and adolescents: past concepts, current debates, and future opportunities

Irritability is defined as a low threshold to experience anger in response to frustration. It is one of the most common symptoms in youth and is part of the clinical presentation of several disorders. Irritability can present early in life and is a predictor of long-term psychopathology; yet, the diagnostic status of irritability is a matter of intense debate. In the present article, we address two main components of the debate regarding irritability in youth: the misdiagnosis of chronic irritability as pediatric bipolar disorder, and the proposal of a new diagnosis in the DSM-5, disruptive mood dysregulation disorder, whose defining symptoms are chronic irritability and temper outbursts.

An open-label trial of risperidone in children and adolescents with severe mood dysregulation.

OBJECTIVE: The diagnosis and treatment of youth with severe nonepisodic irritability and hyperarousal, a syndrome defined as severe mood dysregulation (SMD), has been the focus of increasing concern and debate among clinicians and researchers. Our main objective was to assess the effectiveness of risperidone for youths with SMD. METHODS: An 8-week open label trial with risperidone was conducted. We extensively assessed 97 subjects with semistructured and clinical interviews and enrolled 21 patients in the study. Risperidone was titrated from 0.5 to 3 mg/day in the first 2 weeks. Evaluations were performed at baseline and weeks 2, 4, 6, and 8. Clinical outcome measures were (1) Aberrant Behavior Checklist-Irritability Subscale, (2) Clinical Global Impressions, and (3) severity of co-morbid conditions. RESULTS: We found a significant reduction of the Aberrant Behavior Checklist-Irritability scores during the trial after risperidone use (p < 0.001). The scores at week 2 (mean = 12.03; standard error [SE] = 2.94), week 4 (mean = 15.48; SE = 2.93), week 6 (mean = 12.29; SE = 2.86), and week 8 (mean = 11.28; SE = 3.06) were significantly reduced compared with the baseline mean score (mean = 25.89; SE = 2.76) (p < 0.001). We also found an improvement in attention-deficit/hyperactivity disorder, depression, and global functioning (p < 0.001). CONCLUSION: Risperidone was effective in reducing irritability in SMD youth. To the best of our knowledge, this is the first psychopharmacological trial in this group of patients with positive results. Further randomized, controlled studies are needed.

Psicose reacional / Reactive psychosis

Os autores fazem uma revisão na literatura sobre psicose reacional, enfatizando seus aspectos sociais, etiológicos, prognósticos, dando prioridade à dificuldade de seu diagnóstico