Biological Rhythm and Bipolar Disorder: Twelve-Month Follow-Up of a Randomized Clinical Trial.

The objective was to evaluate the effect of psychoeducation on biological rhythm and in the reduction of depressive, anxious, and manic symptoms at 12 months' follow-up. This was a randomized clinical trial with young adults aged 18 to 29 years, diagnosed with bipolar disorder. Biological rhythm was assessed with the Biological Rhythm Interview Assessment in Neuropsychiatry (BRIAN). Participants were randomized for combined intervention (psychoeducation plus medication) or treatment-as-usual (medication alone). The sample consisted of 61 patients (29 TAU; 32 combined intervention). Although it failed to separate by a marginal difference, the combined intervention seems to be more effective than TAU in relation to improvement of depressive symptoms at post-intervention (p = 0.074) and regulation of sleep/social domain at 6 months' follow-up (p = 0.057). Improvement of depressive symptoms as well as regulation of sleep and social activities are known to prevent episode onset and thus improve long-term outcomes.

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.

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.

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.

Brief report: Accuracy of a 16-item questionnaire based on the HEADSS approach (QBH-16) in the screening of mental disorders in adolescents with behavioral problems in secondary care.

OBJECTIVE: Compare a questionnaire based on the HEADSS approach (QBH-16) and the Child Behavior Checklist (CBCL) in the screening of mental disorder in adolescents with behavioral problems. METHODS: Adolescents from both genders 12-17 years-old presenting behavioral problems without a previous diagnosis of mental disorder were referred from primary services to a specialized outpatient program for adolescent behavioral problems and evaluated with the QBH-16, CBCL, and the Wechsler Intelligence Scale for Children. This program is located in a secondary and tertiary university hospital, Hospital de Clínicas de Porto Alegre, in the capital city of the southernmost state of Brazil. RESULTS: 98 adolescents and their families were interviewed. Scores > or =9 in the QBH-16 had a likelihood ratio (LR) >5.5 and scores under 6 had a LR of 0.13, identifying adequately 62 patients (71%) according to the CBCL. Cognitive performance was similar among all patients. DISCUSSION: Our findings suggest the QBH-16 has a good accuracy for screening mental disorders and may help prioritize or choose which patients will benefit from psychiatric services.

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.

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.

Aripiprazole in juvenile bipolar disorder comorbid with attention-deficit/hyperactivity disorder: an open clinical trial.

INTRODUCTION: Juvenile bipolar disorder (JBD) is a highly impairing chronic mental health condition that affects children and adolescents' overall functioning. Comorbidity with attention-deficit/hyperactivity disorder (ADHD) is extremely prevalent and may determine worse response to treatment. Few investigations have addressed the use of recent atypical antipsychotics in JBD, although several guidelines suggest their use. METHODS: We conducted a 6-week open trial with aripiprazole in 10 children and adolescents with JBD comorbid with ADHD to assess impact on mania and ADHD symptoms, respectively, by means of the Young Mania Rating Scale and the Swanson, Nolan and Pelham Scale, as well as on global functioning (Clinical Global Impressions-Severity), and adverse events. RESULTS: Significant improvement in global functioning scores (F=3.17, P=.01, effect size=0.55), manic symptoms (F=5.63, P<.01; ES=0.93), and ADHD symptoms (t=3.42, P<.01;ES=1.05) were detected. Although an overall positive tolerability was reported, significant weight gain (F=3.07, P=.05) was observed. CONCLUSION: Aripiprazole was effective in improving mania and ADHD symptoms, but neither JBD nor ADHD symptom remission was observed in most of the cases. Randomized placebo-controlled trials for JBD and ADHD are needed.

Topiramate in adolescents with juvenile bipolar disorder presenting weight gain due to atypical antipsychotics or mood stabilizers: an open clinical trial.

BACKGROUND: Many children and adolescents with bipolar disorder (BD) do not adhere to the pharmacological treatment due to weight gain. This investigation aims to describe response, side effects, and weight changes in a sample of youths with BPD while receiving topiramate for 11 weeks during the treatment maintenance phase. METHODS: Ten consecutive outpatients with BPD (11-17 years) using a single mood stabilizer and/or an antipsychotic presenting weight gain over 5% of their baseline weight were enrolled in this 11-week protocol. Their medication was switched to topiramate during the first 4 weeks. The Young Mania Rating Scale (Y-MRS) was the main outcome measure to assess response to the treatment in a weekly basis. Side effects and weight were also assessed weekly. RESULTS: In repeated-measure analysis of variance (ANOVA), we found a significant reduction in both the YMRS scores (F = 10.21; p ,0.01) and in weight (F = 8.04; p ,0.01) during the trial. CONCLUSIONS: These initial findings suggesting antimanic effects for topiramate during the treatment maintenance phase associated with weight reductions indicate the need of randomized clinical trials assessing this clinical relevant issue.

Clinical Outcomes in Children and Adolescents With Bipolar Disorder and Substance Use Disorder Comorbidity.

OBJECTIVE: To assess the global functioning and clinical outcomes of children and adolescents with bipolar disorder, children and adolescents with bipolar disorder and substance use disorder (SUD) comorbidity and healthy controls. METHODS: This study had a cross-sectional design. Participants were children and adolescents aged between 6 and 17 years, and data were collected between 2003 and 2015. Psychiatric diagnosis was established according to DSM-IV criteria using the Kiddie-SADS-Present and Lifetime Version or the Mini-International Neuropsychiatric Interview for Children and Adolescents. Global functioning was assessed using the Children's Global Assessment Scale. Depressive symptoms were assessed using the Children's Depression Rating Scale. Manic symptoms were measured using the Young Mania Rating Scale, and the severity of anxious symptoms was assessed using the Screen for Child Anxiety Related Disorders. RESULTS: The sample included 187 children and adolescents with bipolar disorder, 29 with BD and SUD comorbidity, and 115 healthy controls. Children and adolescents with BD and SUD comorbidity presented later onset of mood disorder (P < .001); higher rates of lifetime history of suicide attempt (P < .001), lifetime history of psychosis (trend toward significance: P = .076), and lifetime hospitalization (P < .001); and higher severity of depressive symptoms (trend toward significance: P = .080) as compared to those with BD without SUD comorbidity. In addition, both diagnosis groups presented higher rates of functional impairment when compared to controls (P < .001). Moreover, BD and SUD comorbidity presented higher functional impairment, as compared to BD without SUD comorbidity (P = .020). CONCLUSIONS: Children and adolescents with bipolar disorder and substance use disorder comorbidity present a worse clinical course than those with bipolar disorder but without substance use disorder comorbidity.

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.

Interaction between BDNF rs6265 Met allele and low family cohesion is associated with smaller left hippocampal volume in pediatric bipolar disorder.

BACKGROUND: Genetic and environmental factors are implicated in the onset and evolution of pediatric bipolar disorder, and may be associated to structural brain abnormalities. The aim of our study was to assess the impact of the interaction between the Brain-Derived Neurotrophic Factor (BDNF) rs6265 polymorphism and family functioning on hippocampal volumes of children and adolescents with bipolar disorder, and typically-developing controls. METHODS: We evaluated the family functioning cohesion subscale using the Family Environment Scale-Revised, genotyped the BDNF rs6265 polymorphism, and performed structural brain imaging in 29 children and adolescents with bipolar disorder, and 22 healthy controls. RESULTS: We did not find significant differences between patients with BD or controls in left or right hippocampus volume (p=0.44, and p=0.71, respectively). However, we detected a significant interaction between low scores on the cohesion subscale and the presence of the Met allele at BNDF on left hippocampal volume of patients with bipolar disorder (F=3.4, p=0.043). None of the factors independently (BDNF Val66Met, cohesion scores) was significantly associated with hippocampal volume differences. LIMITATIONS: small sample size, cross-sectional study. CONCLUSIONS: These results may lead to a better understanding of the impact of the interaction between genes and environment factors on brain structures associated to bipolar disorder and its manifestations.

Behavioral inhibition and history of childhood anxiety disorders in Brazilian adult patients with panic disorder and social anxiety disorder.

PURPOSE: To evaluate the presence of behavioral inhibition and anxiety disorders during childhood in Brazilian adult patients with panic disorder and social anxiety disorder compared to a control group. METHODS: Fifty patients with panic disorder, 50 patients with social anxiety disorder, and 50 control subjects were included in the study. To assess the history of childhood anxiety, the Schedule for Affective Disorders and Schizophrenia for School Age Children, Epidemiologic Version (K-SADS-E), and the Diagnostic Interview for Children and Adolescents-Parent Version (DICA-P) were used. The presence of behavioral inhibition in childhood was assessed by the self-reported scale of Behavioral Inhibition Retrospective Version (RSRI-30). RESULTS: Patients showed significantly higher prevalence of anxiety disorders and behavioral inhibition in childhood compared to the control group. Patients with social anxiety disorder also showed significantly higher rates of avoidance disorder (46% vs. 18%, p = 0.005), social anxiety disorder (60% vs. 26%, p = 0.001), presence of at least one anxiety disorder (82% vs. 56%, p = 0.009) and global behavioral inhibition (2.89 +/- 0.61 vs. 2.46 +/- 0.61, p < 0.05) and school/social behavioral inhibition (3.56 +/- 0.91 vs. 2.67 +/- 0.82, p < 0.05) in childhood compared to patients with panic disorder. CONCLUSION: Our data are in accordance to the literature and corroborates the theory of an anxiety diathesis, suggesting that a history of anxiety disorders in childhood is associated with an anxiety disorder diagnosis, mainly social anxiety disorder, in adulthood.

Mood disorders in childhood and adolescence.

The identification and treatment of mood disorders in children and adolescents has grown over the last decades. Major depression is one of the most common and debilitating disorders worldwide, imposing a massive burden to the youth population. Bipolar disorder is being increasingly recognized as having its roots early in life, and its presentation during childhood and adolescence has been submitted to extensive research. This review aims to highlight clinical aspects of the current knowledge on mood disorders in the pediatric population, presenting updated information on epidemiology, diagnostic procedures, and management strategies. Limitations of available evidence and future directions of research in the field are also discussed.

Pharmacotherapy of bipolar disorder in children and adolescents: an update.

OBJECTIVE: To review the options for acute and maintenance pharmacological treatment of bipolar disorder in children and adolescents, including the treatment of bipolar depression and comorbid attention deficit/hyperactivity disorder (ADHD). METHODS: Narrative review of randomized clinical trials and open-label studies published from 2000 to 2012. The PubMed and PsycINFO websites were queried. Case series were included when a higher level of evidence was not available. RESULTS: Published data from randomized controlled trials (RCTs) in acute mania/hypomania with significant responses are available for lithium, topiramate, risperidone, olanzapine, and aripiprazole. Open trials of lithium and lamotrigine show that these drugs may be effective in the treatment of depressive episodes. No trials of selective serotonin reuptake inhibitors (SSRIs) have been conducted. In the treatment of comorbid ADHD, there are encouraging findings with mixed amphetamine salts and atomoxetine; conflicting results are observed with methylphenidate. CONCLUSIONS: Published RCTs of traditional mood stabilizers are scarce, but the best available evidence (results from meta-analytic regression) suggests that second-generation antipsychotics (SGAs) as a group are more effective in reducing manic symptoms. Risperidone was the only one included in head-to-head comparisons (vs. lithium and divalproex), showing superiority in terms of efficacy, but with more metabolic side effects, which were also more common in most of the SGAs. There are few studies addressing the treatment of ADHD and depression. Brazilian guidelines for the treatment of pediatric bipolar disorder should also include some SGAs (especially risperidone and aripiprazole) as first-line treatment, and these drugs should be provided by the public health services.

The Val66Met polymorphism at the BDNF gene does not influence Wisconsin Card Sorting Test results in children and adolescents with bipolar disorder.

OBJECTIVES: To assess the role of the Val66Met polymorphism at the brain-derived neurotrophic factor (BDNF) gene on the performance of children and adolescents with bipolar disorder [juvenile bipolar disorder (JBD)] on the Wisconsin Card Sorting Test (WCST). METHODS: Children and adolescents were assessed by the K-SADS-PL and a clinical evaluation for BD and comorbid conditions. Manic and depressive symptoms were assessed with the Young Mania Rating Scale and the Children Depression Rating Scale - Reviewed. The Val66Met polymorphism at the BDNF was genotyped from a blood sample. Patients' IQ and executive functions were assessed by a standard cognitive flexibility test (WCST). RESULTS: Fifty-three subjects were included in the study. No significant difference was observed between the Val/Val and Val/Met+Met/Met groups on any WCST scores in the MANCOVA (F48,5 = .76; p = .59; Perseverative Errors, p = .66; Nonperseverative Errors, p = .58; Categories Completed, p = .34; Attempts to Reach First Category, p=.64; and Percentage of Conceptual Level Responses, p = .99). CONCLUSIONS: Our findings from this sample of children and adolescents with BD do not replicate results from studies of adults and suggest the existence of differences in the neurobiology of this disorder across the life cycle. Investigations of larger samples are necessary to confirm these data.

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.