Mara L. Cordeiro

Manganese in Children with Attention-Deficit/Hyperactivity Disorder: Relationship with Methylphenidate Exposure

Attention-deficit/hyperactivity disorder (ADHD) is a common neurobehavioral disorder that affects children worldwide. The etiology of ADHD is complex and not fully understood. Earlier studies associated elevated levels of manganese (Mn) with learning problems, attention deficits, and ADHD. Furthermore, it has also been shown that the dopamine (DA) system, the primary site of action of pharmacological ADHD treatments, is influenced by high levels of Mn. Recent studies have suggested that Mn accumulates in dopaminergic neurons via the presynaptic dopamine transporter (DAT). A role for altered functioning of the dopaminergic system in the etiology of ADHD has been well established through neurochemical, neurophysiological, imaging, and genetics studies. Methylphenidate (MPH) is a psychostimulant commonly used to manage ADHD symptoms. The pharmacotherapeutic effect of MPH occurs primarily through its action of inhibiting DAT, and thus increasing dopamine, as well as other catecholamines, at the synapse. We assessed a group of children with ADHD and matched control children without psychopathology attending public schools in a southern Brazilian city and reported elevated serum concentrations of Mn in treatment-naïve children with ADHD compared to normal controls. Interestingly, children with ADHD receiving concurrent MPH showed no difference in Mn serum levels versus controls. We then prospectively assessed the impact of naturalistic treatment with MPH and determined that Mn concentrations were significantly reduced from baseline values following MPH exposure.

Lithium Ions Enhance Cysteine String Protein Gene Expression In Vivo and In Vitro

Abstract: Lithium is a well established pharmacotherapy for the treatment of recurrent manic‐depressive illness. However, the mechanism by which lithium exerts its therapeutic action remains elusive. Here we report that lithium at 1 mM significantly increased the expression of cysteine string proteins (CSPs) in a pheochromocytoma cell line (PC12 cells) differentiated by nerve growth factor. These cells concomitantly exhibited increased expression of CSPs in their cell bodies and boutons. Enhanced CSP expression was also observed in the brain of rats fed a lithium‐containing diet, which elevated serum lithium to a therapeutically relevant concentration of ∼1.0 mM. However, both in vitro and in vivo, the expression of another synaptic vesicle protein, synaptophysin, and the t‐SNARE, synaptosomal‐associated protein of 25 kDa (SNAP‐25), was not significantly altered by lithium. These observations indicate that lithium‐induced changes of CSP gene expression may contribute to the therapeutic efficacy of this monovalent cation.

Lithium ions modulate the expression of VMAT2 in rat brain

Recent work has indicated that lithium (at 1 mM, a concentration that is efficacious in the treatment of manic-depressive disorders) modulates the level of vesicular monoamine transporter 1 (VMAT1) mRNA in PC12 cells as a function of the differentiation status of these cells. To ascertain whether VMAT expression in neurons is sensitive to lithium, in vivo, rats were fed a lithium-supplemented diet for 21 days (which raised serum lithium to 0.98+/-0.1 mM). Northern analysis revealed an overall increase (199+/-27%) of the neuronal VMAT isoform (VMAT2) in rat brain after lithium. However, in situ hybridization analysis revealed regional differences in the effects of lithium. Thus, VMAT2 mRNA increased by 50-100% over control in the raphe nuclei, ventral tegmental area, and substantia nigra of rats fed the lithium diet. Concomitantly, VMAT2 mRNA declined by about 50% in the locus coeruleus. Because VMAT2 is expressed in neurons that are strongly implicated in regulating mood and behavior, these data support the hypothesis that alterations of VMAT2 expression contribute to the therapeutic effects of lithium in psychiatric disorders.

Convergent effects of lithium and valproate on the expression of proteins associated with large dense core vesicles in NGF-differentiated PC12 cells.

Lithium and valproate are chemically unrelated compounds that are used to treat manic-depressive illness. Previously, we reported that lithium ions upregulate genes encoding proteins primarily associated with large dense core vesicles (LDCV) in nerve growth factor (NGF)-differentiated PC12 cells, but not in undifferentiated PC12 cells. Moreover, lithium did not alter the expression of proteins associated with small-clear, synaptic-like vesicles (SSV) in these cells. Based on these observations, we investigated whether valproate had actions similar to those of lithium in PC12 cells. Thus, undifferentiated or NGF-differentiated PC12 cells were exposed to lithium (1 mM) or valproate (1 mM) for 48 h. Extracts from these cells were submitted to semiquantitative Northern and Western analyses. In NGF-differentiated cells, both agents increased the expression of proteins associated with LDCV, the vesicular monoamine transporter 1 (VMAT1), and cysteine string protein (CSP). These same treatments did not alter the expression of proteins primarily associated with SSV, the vesicular acetylcholine transporter (VAChT), and synaptophysin (SY). Furthermore, neither drug affected the expression of these proteins in undifferentiated cells. Interestingly, secretion of 3H-dopamine was increased in cells exhibiting the increase of VMAT1 and csp. Taken together, the convergent effects of these chemically diverse compounds suggest that altered dynamics of LDCV may play a vital role in the biochemical pathway, leading to the relief of the symptoms of manic depression.

Potential link between caffeine consumption and pediatric depression: a case-control study

BackgroundEarly-onset depressive disorders can have severe consequences both from developmental and functional aspects. The etiology of depressive disorders is complex and multi-factorial, with an intricate interaction among environmental factors and genetic predisposition. While data from studies on adults suggest that caffeine is fairly safe, effects of caffeine in children, who are in period of rapid brain development, are currently unknown. Furthermore, systematic research addressing the relationship between depressive symptoms in children and caffeine consumption is lacking.The present study examined the effects of caffeine consumption on depressed mood in children with depression and non-depressed participants.MethodsChildren and adolescents (n = 51) already enrolled in an ongoing longitudinal study, aged 9-12 years, were assessed for depressive symptoms with the Children Depressive Inventory (CDI). Psychopathological symptoms were assessed with the Child Behavioral Checklist (CBCL) and eating habits were assessed with the Nutrition-Behavior Inventory (NBI) [1]. The children were compared to control children without psychopathology attending public schools in a Southern Brazilian city.ResultsParticipants with CDI scores ≥ 15 (mean = 19; S.D. = 4) also had high NBI scores (mean = 52; S.D. = 19, p < 0.001) suggestive of a relationship between depressive symptoms and environmental factors, in this case nutrition/behavior. Additional linear regression adjusted statistical analysis, considering the factors of consumption of sweets and caffeine individually, showed that caffeine, but not sweets, was associated with depressive symptoms.ConclusionsThese findings indicate that depressed children consume more caffeinated drinks than non-depressed children. Nonetheless while a strong association between depressive symptoms and caffeine consumption among children was found, further research should investigate whether or not this association is due to a cause and effect relationship.

Co-Occurrence of ADHD and High IQ: A Case Series Empirical Study.

Objective: The validity of a diagnosis of ADHD in children with a high intelligence quotient (IQ) remains controversial. Using a multidisciplinary approach, rigorous diagnostic criteria, and worldwide-validated psychometric instruments, we identified a group of children attending public schools in southern Brazil for co-occurrence of high IQ and ADHD. Method: Students attending public schools, in the first to fifth grades, were referred to our Research Center for behavioral and/or learning difficulties. These children completed clinical, psychiatric, psychological, and pedagogical evaluations for assessment of IQ, ADHD, learning, and other emotional or behavioral disorders. Results: Fifteen of the participants were identified to have a full-scale IQ ≥ 120. Data show that 10 of these high-IQ children met the DSM-IV criteria diagnosis for ADHD combined type, 5 met criteria for current oppositional-defiant disorder, 2 had current major depression, and 2 had a learning disorder. Here we present the results as a case series. Conclusion: Our data support the hypothesis that ADHD is a valid diagnosis in children with high IQs.

Dietary lithium induces regional increases of mRNA encoding cysteine string protein in rat brain.

Lithium salts are used to treat manic‐depressive disorders; however, the mechanism by which lithium produces its therapeutic benefit remains obscure. The action of lithium may involve alterations of proteins important for regulating synaptic function. In this context, we observed recently that lithium at therapeutically relevant concentrations enhanced expression of cysteine string protein (csp) at the level of both mRNA and protein, in cell culture and in rat brain. Several lines of evidence have shown that csps are vital components of the regulated secretory pathway. We were interested whether lithium modulates expression of csp in specific brain regions. To study this issue, we analyzed the effects of chronic lithium administration (21 days) on csp mRNA levels in rat brain using in situ hybridization. Densitometric analysis revealed that lithium upregulated csp mRNA in several brain areas that are important for mood and behavior. This effect may be germane to understanding the beneficial action of lithium in mood disorders.

Mood disorders in children and adolescents: update for pediatricians

OBJECTIVES To review epidemiological and etiologic aspects of diagnosis and treatment of mood disorders (MDs) in children and adolescents, with a focus on essential information for pediatricians. SOURCES A literature search on MEDLINE, a review of the American Psychiatric Associations Diagnostic and Statistical Manual of Mental Disorders, fourth edition (text revision) (DSM-IV-TR), and a critical analysis of current diagnostic criteria and scientific evidence regarding the etiology of mood disorders were performed. SUMMARY OF THE FINDINGS We identified diverging opinions for and against the proposition of using the same criteria used for adults, as listed in the DSM-IV-TR, for diagnosing mood disorders in children and adolescents. Although there has been much debate in the literature on this topic in the last decade, there remains a concern that there may be a significant under-diagnosis of cases due to differing methods. Several epidemiological studies conducted in pediatric populations using different criteria and methods make it difficult to interpret the data currently published. Although the field of neurosciences has achieved major advances in understanding these pathologies, additional investigations are needed to gain a clearer picture of how genetic and environmental factors interact and influence the origin and severity of the disease and the patients response to treatment. CONCLUSIONS MDs have a high prevalence in childhood and adolescence and have major long-term impacts on sufferers lives. There is a need to improve diagnostic criteria, adapting them for the pediatric population, with the objective of making it simpler for clinicians, particularly pediatricians, to make diagnoses and initiate early intervention. Advances in the area of epigenetics may aid in the development of new preventative, diagnostic, and therapeutic approaches.

Brazilian adaptation of the Functioning after Pediatric Cochlear Implantation (FAPCI): comparison between normal hearing and cochlear implanted children

OBJECTIVE Enabling development of the ability to communicate effectively is the principal objective of cochlear implantation (CI) in children. However, objective and effective metrics of communication for cochlear-implanted Brazilian children are lacking. The Functioning after Pediatric Cochlear Implantation (FAPCI), a parent/caregiver reporting instrument developed in the United States, is the first communicative performance scale for evaluation of real-world verbal communicative performance of 2-5-year-old children with cochlear implants. The primary aim was to cross-culturally adapt and validate the Brazilian-Portuguese version of the FAPCI. The secondary aim was to conduct a trial of the adapted Brazilian-Portuguese FAPCI (FAPCI-BP) in normal hearing (NH) and CI children. METHODS The American-English FAPCI was translated by a rigorous forward-backward process. The FAPCI-BP was then applied to the parents of children with NH (n=131) and CI (n=13), 2-9 years of age. Test-retest reliability was verified. RESULTS The FAPCI-BP was confirmed to have excellent internal consistency (Cronbachs alpha > 0.90). The CI group had lower FAPCI scores (58.38 ± 22.6) than the NH group (100.38 ± 15.2; p<0.001, Wilcoxon test). CONCLUSION The present results indicate that the FAPCI-BP is a reliable instrument. It can be used to evaluate verbal communicative performance in children with and without CI. The FAPCI is currently the only psychometrically-validated instrument that allows such measures in cochlear-implanted children.

Transtornos do humor em crianças e adolescentes: atualização para pediatras

OBJETIVOS: Revisar aspectos epidemiologicos e etiologicos do diagnostico e tratamento dos transtornos do humor em criancas e adolescentes, com foco em conteudos essenciais para medicos pediatras. FONTES DOS DADOS: Revisao da literatura no banco de dados da MEDLINE. Utilizacao das recomendacoes da quarta edicao do texto revisado do Manual Diagnostico e Estatistico de Transtornos Mentais da Associacao Americana de Psiquiatria. Analise critica dos atuais criterios diagnosticos e teorias cientificas sobre etiologia dos transtornos do humor. SINTESE DOS DADOS: Foram identificadas opinioes discordantes e congruentes sobre a efetividade de se utilizar os mesmos criterios atualmente listados no Manual Diagnostico e Estatistico de Transtornos Mentais para diagnostico de transtornos do humor em adultos, adolescentes e criancas. Embora esse topico tenha sido muito debatido na literatura dos ultimos 10 anos, a percepcao e de que uma porcentagem significativa de casos continuam sendo subdiagnosticados devido a utilizacao dos mesmos criterios independente da faixa etaria. Os diversos estudos epidemiologicos realizados na populacao infantil fundamentam-se nesses criterios para calculos de prevalencia, o que tornam duvidosos os numeros atualmente publicados. Embora a neurociencia tenha alcancado grandes avancos no conhecimento dessas patologias, ainda e necessario um melhor entendimento sobre como os fatores geneticos e ambientais interagem e influenciam a origem, gravidade e resposta ao tratamento. CONCLUSOES: Os transtornos do humor sao patologias de alta prevalencia na infância e adolescencia, com grande impacto na vida dos portadores no longo prazo. Constatamos a necessidade de aprimorar os criterios diagnosticos, adequando-os a populacao infantil, com objetivo de facilitar ao clinico, particularmente ao pediatra, diagnostico e intervencao precoce. Avancos na area de epigenetica podem colaborar para o desenvolvimento de outras abordagens preventivas, diagnosticas e terapeuticas.