Effects of methylphenidate on mitochondrial dynamics and bioenergetics in the prefrontal cortex of juvenile rats are sex-dependent.

Methylphenidate (MPH) is a central nervous system stimulant drug and a first order prescription in the treatment of Attention Deficit Hyperactivity Disorder (ADHD). Although MPH biochemistry in neurodevelopment is not completely understood, studies showed it alters energy metabolism in rat brains. ADHD prevalence during neurodevelopment is related to males and the investigation has been mainly done in these subjects, therefore, little is known about MPH action in females and, consequently, about sexual dimorphism. In the present study we evaluated markers of mitochondrial dynamics (DRP1 and MFN2, fission and fusion, respectively), biogenesis (mtTFA) and bioenergetics (respiratory chain complexes) in prefrontal cortex of male and female juvenile rats submitted to exposure to MPH to better understand MPH effect during postnatal neurodevelopment. ATP and oxidative stress levels were also evaluated. Wistar rats received intraperitoneal injection of MPH (2.0 mg/kg) or control (saline), once a day, from 15th to 45th day of age. Results showed that MPH increased DRP1 and decreased MFN2, as well as increased mtTFA in prefrontal cortex of male rats. In female, MPH decreased NRF1 and increased Parkin, which are mitochondrial regulatory proteins. Respiratory chain complexes (complex I, SDH, complexes III and IV), ATP production and oxidative stress parameters were altered and shown to be sex-dependent. Taken together, results suggest that chronic MPH exposure at an early age in healthy animals changes mitochondrial dynamics, biogenesis and bioenergetics differently depending on the sex of the subjects.

Evaluation of ocular surface in children with attention deficit hyperactivity disorder with respect to methylphenidate treatment / Avaliação da superfície ocular em crianças com transtorno de déficit de atenção com hiperatividade em relação ao tratamento com metilfenidato

ABSTRACT Purpose: This study aimed to screen the ocular surface of children with attention deficit hyperactivity disorder and identify the adverse effects of methylphenidate related to dry eye disease. Methods: This cross-sectional study included children with attention deficit hyperactivity disorder and healthy children (all aged 5-18 years). They were randomized into Group A (without methylphenidate treatment), Group B (with methylphenidate treatment), and Group C (healthy children). Tear film break-up time, Ocular Surface Disease Index questionnaire, tear meniscus height, tear meniscus area, and Schirmer test results were evaluated. Furthermore, symptom severity in attention deficit hyperactivity disorder was assessed by Turgay DSM-IV-based Child and Adolescent Behavioral Disorders Screening and Rating Scale and Conners Parent Rating Scale-48. Results: Groups A, B, and C consisted of 34, 40, and 60 individuals (n=34, 40, and 60 eyes; age=11.44 ± 2.79, 11.70 ± 2.83, and 11.96 ± 3.63 years, median age=12, 12, and 11.5 years), respectively. Tear film break-up time, Ocular Surface Disease Index, tear meniscus height, tear meniscus area, and Schirmer test results were not significantly different between Groups A and C (p=0.964, 0.336, 0.445, 0.439, and 0.759, respectively). However, Group B showed a significant decrease in tear film break-up time (10.50 ± 3.39 vs. 12.52 ± 2.46 s; p=0.005), tear meniscus height (307.40 ± 5.53 vs. 310.82 ± 7.30 µm; p=0.025), tear meniscus area (0.024 ± 0.0037 vs. 0.026 ± 0.0046 mm2; p=0.010) and Schirmer test (12.75 ± 3.96 vs. 15.41 ± 3.75 mm; p=0.004) results compared with Group A. Conclusion: Compared with healthy children, children with attention deficit hyperactivity disorder showed ocular surface parameters suggestive of dry eye disease despite taking methylphenidate. Thus, they require close ophthalmologic follow-up to prevent sight-threatening dry eye complications.

RESUMO Objetivos: Este estudo teve como objetivo examinar a superfície ocular de crianças com transtorno de déficit de atenção com hiperatividade e identificar os efeitos adversos do metilfenidato relacionados à síndrome do olho seco. Métodos: Este estudo transversal incluiu crianças com transtorno de déficit de atenção e hiperatividade e crianças saudáveis (todas entre 5-18 anos de idade). Elas foram randomizadas no Grupo A (sem tratamento com metilfenidato), Grupo B (com tratamento com metilfenidato) e Grupo C (crianças saudáveis). Foram avaliados o tempo de ruptura do filme lacrimal, questionário sobre Índice de Doenças de Superfície Ocular (IDSO), altura do menisco lacrimal, área do menisco lacrimal e os resultados do teste de Schirmer. Além disso, a gravidade dos sintomas no transtorno de déficit de atenção com hiperatividade foi avaliada usando a Turgay DSM-IV-based Child and Adolescent Behavioral Disorders Screening and Rating Scale com base na escala de Conners Parent Rating Scale-48. Resultados: Os Grupos A, B e C consistiram de 34, 40 e 60 indivíduos (n=34, 40 e 60 olhos; idade=11,44 ± 2,79, 11,70 ± 2,83 e 11,96 ± 3,63 anos, idade média=12, 123 e 11,5 anos), respectivamente. O tempo de ruptura do filme lacrimal, o Índice de Doença da Superfície Ocular, as altura do menisco lacrimal, a área do menisco lacrimal e o teste de Schirmer não foram significativamente diferentes entre os Grupo A e C (p=0,964, 0,336, 0,445, 0,439 e 0,759, respectivamente). Entretanto, o Grupo B mostrou uma redução significativa no tempo de ruptura do filme lacrimal (10,50 ± 3,39 vs 12,52 ± 2,46 seg; p=0,005), altura do menisco lacrimal (307,40 ± 5,53 vs 310,82 ± 7,30 µm; p= 0,025), área do menisco lacrimal (0,024 ± 0,0037 vs 0,026 ± 0,0046 mm2; p=0,010) e teste de Schirmer (12,75 ± 3,96 vs 15,41 ± 3,75 mm; p=0,004), resultados com0arados com o Grupo A. Conclusão: Em comparação com crianças saudáveis, crianças com transtorno de déficit de atenção com hiperatividade apresentaram parâmetros de superfície ocular sugestivos de olho seco, apesar do uso de metilfenidato. Assim, elas requerem um acompanhamento oftalmológico próximo para evitar complicações oculares de olho seco que ameaçam a visão.

Methylphenidate Multiphasic Release Tablet: Bioequivalence Assessment between Two Formulations Administered under Fasting and Fed Conditions.

Methylphenidate hydrochloride is used to treat children, adolescents, and adults with attention deficit/hyperactivity disorder (ADHD). Multiphasic release formulation has been used to control drug levels, mainly during children's school period. This study aimed to evaluate the bioequivalence between two methylphenidate hydrochloride extended-release tablets to meet regulatory requirements for registration in Brazil. Two independent studies (under fasting and fed conditions) designed as open-label, randomized, single-dose, two-period, two-way crossover trials were conducted in healthy subjects of both genders. Subjects were enrolled and randomly received a single dose of the test formulation methylphenidate hydrochloride 54 mg extended-release tablet (Consiv®, Adium S.A., São Paulo, Brazil) or the reference formulation (Concerta®, Janssen-Cilag Farmacêutica Ltd., São Paulo, Brazil), in each period, with a 7-day washout interval. Serial blood samples were collected up to 24 h post dose and methylphenidate plasma concentrations were obtained using a validated LC-MS/MS method. A total of 96 healthy subjects were enrolled in the fasting study, of which 80 completed the study. For the fed study, 52 healthy subjects were enrolled, and 46 subjects completed it. In both studies, 90% confidence intervals for Cmax, AUC0-t, AUC0-inf, and partial AUCs were within the acceptable limits of 80.00 to 125.00%. Thus, according to regulatory requirements, the test formulation (Consiv®) was considered to be bioequivalent to the reference formulation (Concerta®) in both conditions (fasting and fed) and, therefore, it can be considered interchangeable in clinical practice. Both formulations were safe and well tolerated in single-dose administration.

Pre-clinical evidence that methylphenidate increases motivation and/or reward preference to search for high value rewards.

Methylphenidate is a stimulant used to treat attention deficit and hyperactivity disorder (ADHD). In the last decade, illicit use of methylphenidate has increased among healthy young adults, who consume the drug under the assumption that it will improve cognitive performance. However, the studies that aimed to assess the methylphenidate effects on memory are not consistent. Here, we tested whether the effect of methylphenidate on a spatial memory task can be explained as a motivational and/or a reward effect. We tested the effects of acute and chronic i.p. administration of 0.3, 1 or 3 mg/kg of methylphenidate on motivation, learning and memory by using the 8-arm radial maze task. Adult male Wistar rats learned that 3 of the 8 arms of the maze were consistently baited with 1, 3, or 6 sucrose pellets, and the number of entries and reentries into reinforced and non-reinforced arms of the maze were scored. Neither acute nor chronic (20 days) methylphenidate treatment affected the number of entries in the non-baited arms. However, chronic, but not acute, 1-3 mg/kg methylphenidate increased the number of reentries in the higher reward arms, which suggests a motivational/rewarding effect rather than a working memory deficit. In agreement with this hypothesis, the methylphenidate treatment also decreased the approach latency to the higher reward arms, increased the approach latency to the low reward arm, and increased the time spent in the high, but not low, reward arm. These findings suggest that methylphenidate may act more as a motivational enhancer rather than a cognitive enhancer in healthy people.

Impacto do metilfenidato no estresse oxidativo e na plasticidade cerebral / Methylphenidate impact on oxidative stress and brain plasticity

Esse estudo avaliou o impacto do tratamento com cloridrato de metilfenidato (MFD) em crianças com Transtorno de Déficit de Atenção e Hiperatividade. O estudo incluiu metodologia variada, contendo estudo de revisão sobre efeito de metilfenidato sobre BDNF e estudo de coorte experimental. O estudo de revisão seguiu as diretrizes do PRISMA e foi registrado no PROSPERO. No estudo experimental, coorte aberta de centro único foi desenhada, com amostra de conveniência recrutada entre os anos de 2020 e 2022, no ambulatório de ensino da faculdade de Medicina da Universidade Federal de Viçosa (MG). Amostra de 62 crianças, 6 a 14 anos incompletos, sem tratamento prévio, diagnosticadas por psiquiatra infantil segundo os critérios do Manual Diagnóstico e Estatístico dos Transtornos Mentais (DSM5). Média de 8 consultas de acompanhamento clínico realizadas, com coletas de amostras biológicas em 3 delas: antes do início do MFD, com 12 e 24 semanas após uso da medicação. Amostra caracterizada quanto a dados sociodemográficos, sintomas de TDAH, avaliações clínica e psiquiátrica e testagem de inteligência pela psicologia. Amostras biológicas para dosagens séricas de marcadores oxidativos (níveis de capacidade antioxidante total -FRAP -, atividade de superóxido dismutase ­ SOD-, catalase ­ CAT -, glutathione -S-transferase -GST-, níveis de peroxidação lipídica e de proteínas carboniladas) foram coletadas de cada criança nos três momentos da avaliação. Metilfenidato de liberação imediata foi administrado na dosagem de média de 0,65mg/kg/dia. Usou-se o teste de Shapiro-Wilk e Kolmogorov-Smirnov para análise de normalidade. Frequências absolutas e relativas foram determinadas para as variáveis numéricas que foram descritas por suas médias e desvios padrões. Para comparações múltiplas dos parâmetros oxidativos foi realizado pós teste paramétrico de Tukey e para as demais variáveis análise de variância ANOVA (f). Análises dos parâmetros oxidativos foram realizadas no programa GraphPad Prism 7.0 (GraphPad Software, Inc. San Diego, CA, USA) e dos dados sociodemográficos e clínicos no software SPSS (versão 23.0 para Windows). Significância estatística foi considerada com p <0.05. Os resultados mostram: Sexo masculino predominante (71%), idade média 8,58 ± 1,91, predominância de apenas um cuidador - mãe e/ou pai biológico como chefe de família e maior frequência de tipo combinado de TDAH. Pressão arterial sistólica, frequência cardíaca e temperatura corporal alterações significativas, porém sem significância clínica. Índice massa corporal com diferença estatística, 37%, 19,3% e 21% das crianças apresentaram IMC acima do esperado para idade na avaliação 1, 2 e 3 respectivamente. Adesão ao tratamento medicamentoso permaneceu acima de 93,5% na 24ª semana. Durante o tratamento: FRAP não se alterou; atividade de SOD reduziu na 12ª semana em comparação à linha de base; atividade de CAT aumento significativo à 24ª em comparação 12ª semana; aumento significativo dos níveis de peroxidação lipídica à 24ª semana em comparação à 12ª semana. Aumento significativo das proteínas carboniladas na linha de base em comparação aos níveis da 12ª e 24ª semanas. O metilfenidato parece influenciar os parâmetros redox de crianças com TDAH, aumentando o estresse oxidativo. Porém, mecanismos cerebrais tamponam e desconhecemos o resultado dessas interações na estrutura cerebral. Níveis de BDNF não foram influenciados significativamente por metilfenidato em crianças com TDAH, quando comparados a controles em nossa metanálise.

This study evaluated the impact of methylphenidate hydrochloride (MFD) treatment (MFD) in children with Attention Deficit Hyperactivity Disorder. The study included varied methodology, including a review study about methylphenidate effects on BDNF and an experimental cohort study. The review study followed the PRISMA guidelines and was registered in PROSPERO. In the experimental study, a single-center open cohort was designed, with a convenience sample recruited between the years 2020 and 2022, at the teaching outpatient clinic of the Faculty of Medicine at Viçosa Federal University (UFV-MG). Sample with 62 children, 6 to 14 years old, without previous treatment, diagnosed by a child psychiatrist according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM5). Eight clinical follow-up visits were carried out, and biological samples were collected in 3 visits: before MFD beginning and after 12- and 24-weeks medication. Sociodemographic data, ADHD symptoms, clinical and psychiatric assessments were performed, as well as intelligence testing by psychology. Biological samples for oxidative markers serum dosages (total antioxidant capacity levels -FRAP -, superoxide dismutase activity - SOD-, catalase - CAT -, glutathione S transferase -GST-, lipid peroxidation and carbonyl proteins levels) were collected of each child in the 3 evaluation moments. Immediate-release methylphenidate was administered at approximately 0.65mg/kg/day. The Shapiro-Wilk and Kolmogorov-Smirnov test was used for normality analysis. Absolute and relative frequencies were used for numeric variables that were described by their means and standard deviations. Tukey's parametric test and variance analysis ANOVA (f) were performed for multiple comparisons in redox parameters and other variables respectively. Redox parameters analysis was performed using GraphPad Prism 7.0 program (GraphPad Software, Inc. San Diego, CA, USA) and other variables using SPSS software (version 23.0 for Windows). Statistical significance was considered at p<0.05. Male was predominant (71%), with a mean age of 8.58 ± 1.91, mother and/or biological father were the householder in most homes. Systolic blood pressure, heart rate and body temperature had significant changes, but without clinical significance. Body mass index showed a statistical difference, with 37%, 19.3% and 21% of the children having a BMI above the expected for their age in assessment 1, 2 and 3 respectively. Combined-ADHD occurred in 58.1% of the children, inattentive in 32.3% and hyperactive/impulsive in 9.7%. Drug treatment adherence was 98.4% (12th week) and 93.5% (24th week). There were no changes in FRAP levels; SOD activity had significant decreased at week 12 compared to baseline activity; CAT activity showed a significant increase at the 24th week compared to 12th week; Significant increase in lipid peroxidation levels at 24th week compared to 12th week. Significant increase in protein carbonyls levels at baseline (before methylphenidate use) compared to levels at 12 and 24 weeks. Methylphenidate can influence the oxidative and antioxidative parameters of ADHD children, increasing oxidative stress. However, buffer brain mechanisms may act and the result of these interactions in brain structure is not completely known. BDNF levels were not significantly affected by methylphenidate treatment in ADHD children and do not differ from controls in our meta-analysis.

Respuesta clínica al tratamiento por trastorno de déficit atencional en niños con y sin hallazgos epileptiformes / Clinical response to treatment of attention-deficit disorder in children with and without epileptiform activity / Resposta clínica ao tratamento para transtorno de déficit de atenção em crianças com e sem achados epileptiformes

Introducción: El Trastorno de Déficit de Atención con o sin Hiperactividad se asocia a un compromiso funcional en diversas áreas de la vida académica, profesional, social y afectiva. Las causas de este trastorno son atribuidas a una combinación de factores genéticos, biológicos y ambientales. Objetivos: Evaluar la respuesta clínica al tratamiento por Trastorno de Déficit Atencional en niños con y sin hallazgos epileptiformes al ECG, mediante el test de Conners para maestros. Metodología: Estudio analítico, que trabajó con 2 cohortes de niños diagnosticados con Trastorno por Déficit de Atención, separados en grupos con y sin signos de electroencefalograma epileptiforme. Evaluados con el Test de Conners para maestros aplicado al inicio, seis meses y al año de tratamiento médico integral y farmacológico. Resultados: La presencia de electroencefalograma epileptiforme no tiene relación con la variable hiperactividad (p=0,804) ni con la variable sexo (p=0,077). Ambos grupos presentan descensos significativos en los valores del test de Conners aplicado a maestros, durante los periodos inicial, a los 6 meses y al año (p<0,050). Discusión y conclusión: El tratamiento médico integral y farmacológico permite reducir las manifestaciones del TDA a lo largo del tratamiento de un año, tanto en niños con rasgos epileptiformes como no epileptiformes. La disminución más notable en la puntuación del test de Conners para maestros se observó durante el período de tratamiento inicial a seis meses en niños sin actividad epileptiforme. Por lo tanto, la presencia de actividad epileptiforme redujo la efectividad del tratamiento.

Background: Attention Deficit Hyperactivity Disorder (ADHD) is associated to a functional compromise in a variety of areas in academic, professional and social life. The causes of this disorder are attributed to genetic, biologic, and environmental factors. Objective: To evaluate the clinical response to methylphenidate treatment in children with ADHD with and without epileptiform activity through the Conners Teacher Assessment. Methods: analytical study involving two cohorts of children diagnosed with ADHD, separated into groups for those with or without epileptiform activity, evaluated with the Conners Teacher Assessment applied at the beginning, after six months and after a year of the methylphenidate treatment. Results: The presence of epileptiform activity on electroencephalogram (EEG) shows no relation to either the variable of hyperactivity (p=0.804) or sex (p=0.077). When comparing children with and without epileptiform activity with the Conners Teacher Assessment at the starting, 6-month and year-long periods of time, statistically significant results could be noted on all compared groups. Discussion and conclusions: The methylphenidate treatment reduced the effects of ADHD through the year-long period of treatment, both in children with and without epileptiform activity. The most notable decrease in the Conners Teacher Assessment's score appeared during the initial-to-six-month treatment period in children without epileptiform activity. As such, the presence of epileptiform activity reduced the effectiveness of the treatment.

Introdução: O Transtorno de Déficit de Atenção com ou sem Hiperatividade está associado a um comprometimento funcional em várias áreas da vida acadêmica, profissional, social e afetiva. As causas deste transtorno são atribuídas a uma combinação de fatores genéticos, biológicos e ambientais. Objetivos: Avaliar a resposta clínica ao tratamento para Transtorno de Déficit Atencional em crianças com e sem achados epileptiformes no EEG, utilizando o teste de Conners para professores. Metodologia: Estudo analítico com duas coortes de crianças diagnosticadas com Transtorno de Déficit de Atenção, divididas em grupos com e sem sinais de EEG epileptiforme. Foram avaliadas com o Teste de Conners para professores no início, aos seis meses e ao ano do tratamento médico integral e farmacológico. Resultados: A presença de EEG epileptiforme não está relacionada com a variável hiperatividade (p=0,804) nem com a variável sexo (p=0,077). Ambos os grupos apresentaram reduções significativas nos valores do teste de Conners aplicado pelos professores nos períodos inicial, aos seis meses e ao ano (p<0,050). Discussão e conclusão: O tratamento médico integral e farmacológico permite reduzir as manifestações do TDA ao longo de um ano de tratamento, tanto em crianças com traços epileptiformes como não epileptiformes. A diminuição mais notável na pontuação da teste de Conners para professores ocorreu durante o período de tratamento de inicial a seis meses em crianças sem atividade epileptiforme. Assim, a presença de atividade epileptiforme reduziu a eficácia do tratamento.

Características das prescrições de metilfenidato em ambulatório de neuropediatria / Characteristics of methylphenidate prescriptions in a pediatric neurology outpatient clinic

RESUMO O metilfenidato não é disponibilizado pelo Sistema Único de Saúde (SUS), pois não faz parte da Relação Nacional de Medicamentos Essenciais. Todavia, o metilfenidato 10 mg é disponibilizado pela rede pública em Maringá-PR de acordo com a Política da Assistência Farmacêutica do município. Objetivou-se analisar as características das prescrições médicas de metilfenidato para crianças em ambulatório de neuropediatria vinculado ao SUS no município. Estudo transversal observacional retrospectivo de caráter quantitativo, realizado por meio da coleta de dados dos prontuários cadastrados no Sistema Gestor da rede pública de saúde do município, pelo ambulatório de neuropediatria na Unidade Básica de Saúde, Zona 7, entre janeiro de 2017 e novembro de 2019. Analisaram-se os dados por frequência relativa e absoluta. Emitiram-se 339 prescrições pelo neuropediatra responsável do ambulatório para 107 pacientes de 6 a 11 anos. Notou-se distribuição geográfica desigual das crianças atendidas conforme bairro da cidade, o que denota influência socioeconômica na prescrição de medicamentos. Ressaltam-se picos de prescrições coincidindo com o período do ano letivo escolar. Concluiu-se que o acompanhamento especializado adequado é premissa para o tratamento, não dispensando a rede longitudinal de assistência. Ademais, evidencia-se o impacto das condições socioeconômicas, tanto na prescrição como na aquisição do medicamento.

ABSTRACT Methylphenidate is not available through the Unified Health System (SUS), as it is not part of the National List of Essential Medicines. However, methylphenidate 10 mg is available through the public system in Maringá-PR, according to the Pharmaceutical Assistance Policy of the municipality. Retrospective cross-sectional observational study of a quantitative character occurred through the collection of data from the medical records registered in the Management System of the public health network in Maringá-PR, Brazil, by the neuropediatric outpatient clinic in the Basic Health Unit, between January 2017 and November 2019. Data were analyzed by relative and absolute frequency. 339 prescriptions were issued by the responsible neuropediatrician for 107 patients aged 6 to 11 years. There was an uneven geographic distribution of the number of children attended according to the neighborhood of the city, which points to a socioeconomic influence on the medication prescription. It is worth noting peaks of prescriptions coinciding with the period of the school year, following to a national trend. It was concluded that adequate specialized monitoring is a premise for better treatment, not dispensing the longitudinal assistance network. The impact of socioeconomic conditions is significant in the prescription and purchase of the medication.

Methylphenidate Restores Behavioral and Neuroplasticity Impairments in the Prenatal Nicotine Exposure Mouse Model of ADHD: Evidence for Involvement of AMPA Receptor Subunit Composition and Synaptic Spine Morphology in the Hippocampus.

In ADHD treatment, methylphenidate (MPH) is the most frequently used medication. The present work provides evidence that MPH restored behavioral impairments and neuroplasticity due to changes in AMPAR subunit composition and distribution, as well as maturation of dendritic spines, in a prenatal nicotine exposure (PNE) ADHD mouse model. PNE animals and controls were given a single oral dose of MPH (1 mg/kg), and their behavior was tested for attention, hyperactivity, and working memory. Long-term potentiation (LTP) was induced and analyzed at the CA3/CA1 synapse in hippocampal slices taken from the same animals tested behaviorally, measuring fEPSPs and whole-cell patch-clamp EPSCs. By applying crosslinking and Western blots, we estimated the LTP effects on AMPAR subunit composition and distribution. The density and types of dendritic spines were quantified by using the Golgi staining method. MPH completely restored the behavioral impairments of PNE mice. Reduced LTP and AMPA-receptor-mediated EPSCs were also restored. EPSC amplitudes were tightly correlated with numbers of GluA1/GluA1 AMPA receptors at the cell surface. Finally, we found a lower density of dendritic spines in hippocampal pyramidal neurons in PNE mice, with a higher fraction of thin-type immature spines and a lower fraction of mushroom mature spines; the latter effect was also reversed by MPH.

Development of analytical method for the determination of methylphenidate, the analog ethylphenidate and their metabolite ritalinic acid in oral fluid samples by micro-QuEChERS and liquid chromatography-tandem mass spectrometry.

The aim of this study was to develop a quantitative method for the analysis of methylphenidate, the analog ethylphenidate and their metabolite ritalinic acid in oral fluid, using micro-QuEChERS extraction and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Oral fluid samples were collected with Quantisal™ device, extracted by micro-QuEChERS technique and analyzed by LC-MS/MS. The developed method met the validation criteria of Academy Standards Board (ASB) Standard Practices for Method Validation in Forensic Toxicology (Standard 036, 2019) with limits of detection and quantification of 0.5 ng/mL and calibration curve from 0.5 to 50 ng/mL. Within-run imprecision was greater than 18.7% while between-run imprecision was greater than 17.0 % for all analytes. Bias did not vary more than 7.7 %. No evidence of carryover was found. Stability studies presented satisfactory results for 24 h on autosampler (10 °C), after 3 cycles of freeze/thaw, 7 days on freezer (-20 °C) and until 7 days on refrigerator (4 °C) for methylphenidate. The validated method was further successfully applied to the analysis of 5 authentic oral fluid samples collected from volunteers at parties and music festivals from different cities in Brazil. Four samples had positive results for methylphenidate and ritalinic acid, and only one sample was positive for methylphenidate. Ethylphenidate was not detected in the samples. The method showed acceptable analytical performance and is environmentally friendly, requiring reduced use of solvents and reagents, with potential to be applied to clinical and forensic analyses.

Evidence of methylphenidate effect on mitochondria, redox homeostasis, and inflammatory aspects: Insights from animal studies.

Methylphenidate (MPH) is a central nervous system (CNS) stimulant known for its effectiveness in the treatment of Attention Deficit Hyperactivity Disorder (ADHD), a neuropsychiatric condition that has a high incidence in childhood and affects behavior and cognition. However, the increase in its use among individuals who do not present all the diagnostic criteria for ADHD has become a serious public health problem since the neurological and psychiatric consequences of this unrestricted use are not widely known. In addition, since childhood is a critical period for the maturation of the CNS, the high prescription of MPH for preschool children also raises several concerns. This review brings new perspectives on how MPH (in different doses, routes of administration and ages) affects the CNS, focusing on animal studies that evaluated changes in mitochondrial (bioenergetics), redox balance and apoptosis, as well as inflammatory parameters. MPH alters brain energy homeostasis, increasing glucose consumption and impairing the activity of enzymes in the Krebs cycle and electron transport chain, as well as ATP levels and Na+,K+-ATPase activity. MPH induces oxidative stress, increasing the levels of reactive oxygen and nitrogen species and altering enzymatic and non-enzymatic antioxidant defenses, which, consequently, is related to damage to proteins, lipids, and DNA. Among the harmful effects of MPH, studies also demonstrate its ability to induce inflammation as well as alter the apoptosis pathway. It is important to highlight that age, treatment time, administration route, and dose are factors that can influence MPH effects. However, young animals seem to be more susceptible to damage caused by MPH. It is possible that changes in mitochondrial function and markers of status oxidative, apoptosis and inflammation may be exerting important mechanisms associated with MPH toxicity and, therefore, the unrestricted use of this drug can cause brain damage.

Development and validation of a LC-PDA method for methylphenidate analysis in sewage.

Methylphenidate (MPH) is an important emerging pollutant found in effluents and wastewater. Thus, we aimed to develop and validate a method for detection and quantitation of MPH residues in sewage through high performance liquid chromatography coupled with photodiode array detector (LC-PDA). Here we describe a selective, accurate, precise, and valid method for determination of MPH in sewage with a total running time of 10 min, with limits of detection and quantification of 0.27 and 0.92 µg/mL, respectively. MPH retention peak was observed at 5 min. The method was applied to MPH analysis in a sewage sample pretreated with solid phase extraction, obtaining a result of 2.8 µg/L of MPH. Thus, the developed method can be considered feasible to be applied to MPH residual contamination analysis in sewage using a widely available apparatus.

"Real-world" effectiveness of methylphenidate in improving the academic achievement of Attention-Deficit Hyperactivity Disorder diagnosed students-A systematic review.

WHAT IS KNOWN AND OBJECTIVE: Attention-deficit hyperactivity disorder (ADHD) symptoms usually impairs academic achievement and can trigger the onset of medication. Methylphenidate is a drug widely prescribed to treat ADHD. However, systematic reviews of randomized clinical trials suggest that it does not lead to great improvements in academic performance. Thus, we aimed to evaluate the evidence on the "real-world" effectiveness of methylphenidate in improving the academic achievement of ADHD students. METHODS: We conducted a systematic review of observational studies retrieved from five electronic databases, besides a manual search and search in grey literature. Studies evaluating treatment with methylphenidate compared to no treatment or other pharmacological/non-pharmacological alternatives used in ADHD were included. The risk of bias of the selected studies was assessed using adapted versions of the Newcastle-Ottawa Scale. RESULTS AND DISCUSSION: Nine studies (from ten reports) were included in the review: four cohorts, two before-and-after designs and three cross-sectional studies. They involved 12,269 children and adolescents aged 6-18 years. The doses of methylphenidate ranged from 10 to 72 mg/day, and the duration of the treatment from 2.6 months to 4.25 years. Five of these studies concluded that methylphenidate improves academic performance. However, three of the four lowest-bias risk studies concluded that the drug is ineffective. Five studies assessed the long-term use of methylphenidate, and four of them concluded that it does not result in better outcomes in the school setting. Most included studies had considerable limitations and significant heterogeneity regarding methodological design and academic performance measurement criteria. WHAT IS NEW AND CONCLUSION: Although some studies indicate that the short-term use of methylphenidate may improve outcomes in the school environment, the available evidence does not support the establishment of adequate conclusions about the real benefits of methylphenidate in the academic improvement of ADHD students.

Uso não prescrito de metilfenidato e desempenho acadêmico de estudantes de medicina / Non-prescribed use of methylphenidate and academic performance of medical students / El uso no prescrito de metilfenidato y el rendimiento académico de estudiantes de medicina

O metilfenidato é um fármaco indicado no tratamento do transtorno de déficit de atenção e hiperatividade (TDAH) e da narcolepsia. Atua no sistema nervoso central inibindo a recaptação de dopamina e noradrenalina, o que provoca um efeito psicoestimulante. Estudos anteriores demonstraram um aumento no consumo da droga por indivíduos saudáveis que buscam aprimoramento cognitivo. O objetivo deste estudo foi investigar a relação entre o uso não prescrito de metilfenidato e o desempenho acadêmico de estudantes de medicina de uma universidade do sul de Santa Catarina. Trata-se de uma pesquisa descritiva de caráter quantitativo. Participaram da pesquisa 243 acadêmicos do segundo ao oitavo semestre do curso de medicina; os dados foram coletados por meio de um questionário e analisados com ajuda do software SPSS versão 21.0. A prevalência de uso não prescrito do metilfenidato foi de 2,9%, enquanto 17,3% dos pesquisados afirmaram já ter utilizado o medicamento alguma vez na vida. As motivações para consumo mais citadas foram melhorar o desempenho cognitivo (10%) e ficar acordado por mais tempo (4,1%), e a forma de obtenção mais comum foi por meio de amigos (56,5%). O psicoestimulante não apresentou efeitos de aprimoramento cognitivo, uma vez que participantes que nunca utilizaram o fármaco apresentaram um desempenho acadêmico superior (8,80) se comparados àqueles que usam (7,92) ou já usaram (8,01). Os resultados corroboram a hipótese de efeito relacionado a sensações de bem-estar em pessoas saudáveis, o que torna preocupante a injustificada exposição aos efeitos adversos da droga. Ressalta-se a necessidade de ações que visem à promoção de saúde mental aos universitários.(AU)

Methylphenidate is a drug indicated for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It acts on the central nervous system by inhibiting dopamine and norepinephrine reuptake, causing a psychostimulant effect. Previous studies have shown an increase in drug use by healthy individuals seeking cognitive enhancement. This study aimed to investigate the relationship between non-prescribed methylphenidate use and academic performance of medical students of a university in southern Santa Catarina. It is quantitative descriptive study. A total of 243 students from the second to the eighth semester of the medicine school participated in the research; data were collected by using a questionnaire and analyzed with the software SPSS Version 21.0. The prevalence of non-prescribed methylphenidate use was 2.9% and 17.3% of respondents said they had used the drug once in their lifetime. The most cited motivations for consumption were improving cognitive performance (10%) and staying awake longer (4.1%), with the most common way of obtention being through friends (56.5%). The psychostimulant had no cognitive enhancement effects since participants who never used the drug had a higher academic performance (8.80) compared with those who use (7.92) or have used it (8.01). The results corroborate the hypothesis of an effect related to feelings of well-being in healthy people, thus making the unjustified exposure to the adverse effects of the drug concerning. We emphasize the need for actions aimed at promoting mental health to university students.(AU)

El metilfenidato es un medicamento indicado para el tratamiento del trastorno por déficit de atención e hiperactividad (TDAH) y de la narcolepsia. Actúa sobre el sistema nervioso central al inhibir la reabsorción de dopamina y norepinefrina, causando un efecto psicoestimulante. Estudios anteriores han demostrado un aumento del consumo de este medicamento por personas sanas que buscan una mejora cognitiva. El objetivo de este estudio fue investigar la relación entre el uso no prescrito de metilfenidato y el rendimiento académico de los estudiantes de medicina de una universidad en el sur de Santa Catarina (Brasil). Se trató de una investigación cuantitativa descriptiva. Participaron en la investigación 243 estudiantes del segundo al octavo semestre del curso de medicina; los datos se recolectaron mediante un cuestionario y se analizaron con la ayuda del software SPSS, versión 21.0. La prevalencia del uso no prescrito de metilfenidato fue del 2,9%, y el 17,3% de los encuestados dijeron que habían usado el medicamento en algún momento de sus vidas. Las motivaciones de consumo más citadas fueron: mejorar el rendimiento cognitivo (10%) y permanecer despierto por más tiempo (4,1%), y la forma más común de obtenerlo fue con los amigos (56,5%). El psicoestimulante no tuvo ningún efecto de mejora cognitiva, ya que los participantes que nunca lo usaron tuvieron un rendimiento académico superior (8,80) en comparación con aquellos que lo usan (7,92) o lo han usado (8,01). Los resultados corroboraron la hipótesis de un efecto relacionado con los sentimientos de bienestar en personas sanas, lo que provoca una exposición injustificada a los efectos adversos de este fármaco. Se enfatiza la necesidad de acciones dirigidas a promover la salud mental de los estudiantes universitarios.(AU)

We need to talk about the use of methylphenidate by medical students - review of the literature / Precisamos falar sobre uso de Metilfenidato por estudantes de medicina - revisão da literatura

Abstract: Introduction: Studies methylphenidate (MPH) has been used by medical students to increase their mental activity and improve the performance required during undergraduate school, generating concern regarding the risks to their physical and mental health. This scenario indicates the need for specifically aimed measures in medical schools. Objective: To review the literature about the use of MPH without medical indication amongst medical students. Method: A thorough review of the literature published in English, Spanish, and Portuguese, between 2013 and 2019, based on data made available by Pubmed and Scielo, utilizing keywords in the three above languages, along the four stages of the selection process. Results and Discussion: Altogether, 224 articles were found, of which 25 were selected after reading, dealing with the use of MPH or 'cognition enhancer' by undergraduate medical students without a doctor's prescription. The research indicated significant variability in the frequency of consumption, related to the investigated pattern of use, use with or without indication, before or after entering University and country where the study was carried out. The most frequent justification for the use without medical indication was to attain improvement in academic performance. A lack of research with a fair appraisal of the cognition, behavioral and psychic risks involved, among them addiction and the approach of the topic in medical schools, was noted. Conclusion: The high rates of usage of MPH by medical students aiming at cognitive enhancement strengthens the importance of preventative actions in medical schools. The strategies must consider information concerning the risks of use (of MPH) without medical indication; non-pharmacological interventions for performance improvement; sleep hygiene measures organization for adequate study activities; broad discussions about ethical aspects and curricular structure.

Resumo: Introdução: Estudos mostram que o metilfenidato (MPH) tem sido utilizado por estudantes de medicina para aumentar sua atividade mental e melhorar o desempenho exigido durante a graduação, gerando preocupações quanto aos riscos à sua saúde física e mental. Esse cenário indica a necessidade de medidas especificamente direcionadas nas escolas médicas. Objetivo: Revisar a literatura sobre o uso de MPH sem indicação médica entre estudantes de medicina. Método: Revisão minuciosa da literatura publicada em inglês, espanhol e português, entre 2013 e 2019, com base em dados disponibilizados pelo PUBMED e SCIELO, utilizando palavras-chave nos três idiomas acima, ao longo das quatro etapas do processo de seleção. Resultados e Discussão: Ao todo, foram encontrados 224 artigos, dos quais 25 foram selecionados após leitura, tratando do uso de MPH ou 'potencializador da cognição' por graduandos de medicina sem prescrição médica. A pesquisa indicou variabilidade significativa na frequência de consumo, relacionada ao padrão de uso investigado, uso com ou sem indicação, antes ou após a entrada na Universidade e país onde o estudo foi realizado. A justificativa mais frequente para o uso sem indicação médica foi a de obter melhora no desempenho acadêmico. Notou-se a carência de pesquisas com uma avaliação adequada dos riscos cognitivos, comportamentais e psíquicos envolvidos, entre eles o risco de adição e a abordagem do tópico nas escolas médicas. Conclusão: As altas taxas de uso do MPH por estudantes de medicina visando o aprimoramento cognitivo reforça a importância de ações preventivas nas escolas médicas. As estratégias devem considerar informações sobre os riscos do uso (do MPH) sem indicação médica; intervenções não farmacológicas para melhoria do desempenho cognitivo; medidas de higiene do sono; organização para atividades de estudo adequadas; amplas discussões sobre aspectos éticos e estrutura curricular.

Percepções e uso do metilfenidato entre universitários da área da Saúde em Ceilândia, DF, Brasil / Perceptions and use of methylphenidate among health students in Ceilândia, DF, Brazil / Percepciones y uso del metilfenidato entre universitarios del área de la salud en Ceilândia, Distrito Federal - DF, Brasil

As percepções e o uso de metilfenidato entre universitários foram investigados em estudo descritivo realizado em duas etapas. A primeira, quantitativa, foi realizada por meio do preenchimento de um questionário semiestruturado on-line. Para a segunda etapa, qualitativa, foi realizado um grupo focal. Dos 337 participantes da primeira etapa, 14,5% relataram usar o metilfenidato. Entre os usuários, a prevalência de uso sem prescrição foi maior para o sexo masculino (65,3%), após ingresso na faculdade (57,1%), e 61,2% relataram eventos adversos. O principal motivo de uso foi o doping intelectual (65,3%). Já na etapa qualitativa, além de reforçar os achados anteriores, foram identificados tópicos temáticos como a pressão externa exercida por familiares, sociedade e a rotina universitária. Esses achados apontam para a necessidade de medidas de apoio e orientação aos universitários e de reformulação do processo ensino-aprendizagem.(AU)

This descriptive study investigated the use and perceptions of methylphenidate among university students. The study was conducted in two stages. In the first stage (quantitative), the students completed an online semi-structured questionnaire. The second stage (qualitative) consisted of focus group discussions. Of the 337 participants in the first stage, 14.5% reported using methylphenidate. The prevalence of methylphenidate use without a prescription was greater among men (65.3%) and after starting university (57.1%); 61.2% of the students reported adverse events. The main reason for using the drug was intellectual doping (65.3%). In the qualitative stage, which reinforced the findings of the quantitative stage, we identified themes such as external pressure from family, society and university routine. The findings underline the need to provide student support and advice and reformulate the teaching and learning process.(AU)

Se investigaron las percepciones y el uso del metilfenidato entre universitarios, en un estudio descriptivo realizado en dos etapas. La primera, cuantitativa, se realizó por medio del llenado de un cuestionario semiestructurado online. Para la segunda etapa, cualitativa, se realizó un grupo focal. De los 337 participantes de la primera etapa, el 14,5% relató que usaba metilfenidato. Entre los usuarios, la prevalencia de uso sin prescripción fue mayor para el sexo masculino (65,3%), después del ingreso en la facultad (57,1%) y el 61,2% relataron eventos adversos. El principal motivo de uso fue el dopping intelectual (65,3%). En la etapa cualitativa, además de reforzar los hallazgos anteriores, se identificaron tópicos temáticos tales como la presión externa ejercida por los familiares, la sociedad y la rutina universitaria. Esos hallazgos señalan la necesidad de medidas de apoyo y orientación a los universitarios y de reformulación del proceso enseñanza-aprendizaje.(AU)

A review of Cochrane reviews on pharmacological treatment for attention deficit hyperactivity disorder / Revisão de revisões Cochrane sobre o tratamento farmacológico para transtorno do déficit de atenção e hiperatividade

ABSTRACT. Attention deficit hyperactivity disorder (ADHD) is one of the most frequent childhood psychiatric problems. Objective: The objective of this study was to identify, synthesize the results, and critically evaluate all Cochrane systematic reviews (SRs) on the pharmacological interventions for children and adolescents (up to age 18) diagnosed with ADHD. Methods: The search was performed in the Cochrane Database of Systematic Reviews (via Wiley) in July 2020. Results: The search strategy resulted in four SRs of high methodological quality, analyzing 51 randomized clinical trials (9,013 participants). Compared to placebo, treatment with tricyclic antidepressants (TCAs) (desipramine), amphetamine, and methylphenidate showed improvement in symptoms such as difficulty concentrating, impulsivity, and hyperactivity in the short term (up to 6 months). There was an increase in the occurrence of adverse events, such as reduced appetite, difficulty sleeping, and abdominal pain. Insufficient evidence was found to support the effects of supplementation with polyunsaturated fatty acids. Conclusions: The use of TCAs, amphetamine, and methylphenidate in children and adolescents with ADHD seems to present positive effects and higher rates of minor adverse events when compared to placebo.

RESUMO. Déficit de atenção e hiperatividade (TDAH) é uma das mais frequentes condições psiquiátricas da infância. Objetivo: O objetivo deste artigo foi identificar, sintetizar os resultados e avaliar criticamente todas as revisões sistemáticas (RS) da Cochrane sobre as intervenções farmacológicas para crianças e adolescentes (até 18 anos de idade) diagnosticados com transtorno do déficit de atenção com hiperatividade. Métodos: A pesquisa foi realizada na base de dados Cochrane de Revisões Sistemáticas — CDSR (via Wiley) em julho de 2020. Resultados: A estratégia de busca resultou em quatro RS de alta qualidade metodológica, que analisavam 51 ensaios clínicos randomizados (9.013 participantes). Comparado ao placebo, o tratamento com antidepressivos tricíclicos (desipramina), anfetamina e metilfenidato apresentou melhora nos sintomas, como dificuldade de concentração, impulsividade e hiperatividade no curto prazo (até seis meses). Houve aumento na ocorr≖ncia de eventos adversos, como redução do apetite, dificuldade para dormir e dor abdominal. Foram encontradas evid≖ncias insuficientes para apoiar os efeitos da suplementação com ácidos graxos poli-insaturados. Conclusões: Com base nos resultados de revisões sistemáticas Cochrane, o uso de antidepressivos tricíclicos, anfetamina e metilfenidato em crianças e adolescentes com TDAH parece apresentar efeitos positivos e taxas mais elevadas de eventos adversos menores quando comparado ao placebo. Dado o alto risco de viés nos estudos primários incluídos nessas RS, ainda são necessários novos ensaios clínicos randomizados com rigor metodológico para apoiar esses achados.

Uso não prescrito de metilfenidato por estudantes de uma universidade brasileira: fatores associados, conhecimentos, motivações e percepções / Non-prescribed use of methylphenidate by students of a Brazilian university: associated factors, knowledge, motivations and perceptions

Resumo Introdução O metilfenidato, utilizado especialmente para tratar o Transtorno do Déficit de Atenção e Hiperatividade tem conquistado universitários que buscam melhorar o desempenho cognitivo. Objetivo Investigar conhecimentos, motivações, percepções e perfil de uso não prescrito desse medicamento por estudantes de uma Universidade Federal de Minas Gerais. Método Aplicação de questionário estruturado a 696 estudantes de Bioquímica, Enfermagem, Farmácia e Medicina, e análise descritiva e dos fatores associados ao uso, por meio de modelos de regressão logística. Resultados: Dos participantes, 96,7% afirmaram conhecer o medicamento e desses, 4,3% o utilizam/utilizavam por motivos não prescritos. O principal motivo de uso era o melhoramento cognitivo, e a universidade foi o principal local de início de uso. A maior parte dos usuários percebeu aumento na concentração e 50% relatou ocorrência de efeitos indesejados. Houve maior chance de uso não prescrito entre homens, maiores de 21 anos, envolvidos em atividades extracurriculares e menor chance de uso entre estudantes de Enfermagem. Conclusão A análise de diferentes aspectos relacionados com o uso não prescrito do metilfenidato propicia um melhor entendimento das situações vivenciadas entre universitários e aponta os riscos à saúde relacionados à busca por melhores desempenhos acadêmicos e estratégias para lidar com sobrecarga de atividades.

Abstract Background Methylphenidate, especially used to treat Attention Deficit Hyperactivity Disorder, has conquered over university students who seek to improve cognitive performance. Objective To investigate knowledge, motivations, perceptions, and profile of non-prescribed use of this drug by students of a Federal University of Minas Gerais. Method A structured questionnaire was applied to 696 students of Biochemistry, Nursing, Pharmacy, and Medicine, and descriptive analysis and associated factors, using logistic regression models. Results Of the participants, 96.7% said they knew the medicine and of these, 4.3% use it/used it for reasons not prescribed. The main reason for using it was the cognitive improvement and the university was the main place of use. Most users noticed an increased concentration and 50% reported the occurrence of unwanted effects. There was a greater chance of non-prescribed use among men, over 21 years old, involved in extracurricular activities, and less chance of use among nursing students. Conclusion Analysis of different aspects related to the non-prescribed use of Methylphenidate provides a better understanding of the situations experienced by university students and points to health risks related to the search for better academic performance and strategies for dealing with activity overload.

The influence of early exposure to methylphenidate on addiction-related behaviors in mice.

Methylphenidate (MET) has a putative cognitive enhancer effect that has led adolescents and young adults to increase and indiscriminate its use aiming to ameliorate their productivity. However, the impacts of MET on addiction-related behaviors, emotional levels, and cognition are still not fully understood. To investigate the influence of chronic treatment with MET during adolescence on addiction-like behaviors, memory, and anxiety in adult mice. Thirty-day-old female mice received i.p. 10 mg/kg MET or Veh injections for 10 consecutive days. Forty days after the treatment (mice were 70-days-old), animals were submitted to the behavioral evaluation under the effects of MET, which included: MET-induced conditioned place preference (CPP), behavioral sensitization, and plus-maze discriminative avoidance task. Pre-exposure to MET during adolescence promoted an early expression of CPP and also facilitated the development of MET-induced behavioral sensitization during adulthood. These addictive-like behaviors were accompanied by anxiogenic effects of MET but not by any memory-enhancing effect. We demonstrated that exposure to MET during adolescence can increase the vulnerability to addiction-like behaviors and anxiety during adulthood. Our results reinforce the necessity of a more efficient system to control MET indiscriminate use, thus avoiding its potential tardive addictive effects.

Methylphenidate decreases the EEG mu power in the right primary motor cortex in healthy adults during motor imagery and execution.

This study investigated the effects of dopaminergic drugs on the EEG mu power during motor imagery, action observation, and execution. This is a double-blind, crossover study with a sample of 15 healthy adults under placebo vs. methylphenidate vs. risperidone conditions during motor imagery, action observation, and execution tasks. The participants had drug dosage adjustment based on body weight/dose (mg/kg). We also analyzed the mu band power by electroencephalography during the study steps. The main result is the interaction between the condition and task factors for the C3 and C4 electrodes, with decreasing EEG mu power in the methylphenidate when compared to risperidone (p ≤ 0.0083). Our results can indicate that the methylphenidate decreases the neurophysiological activity in the central cortical regions during the perceptual experience of tasks with or without body movement.

A review of Cochrane reviews on pharmacological treatment for attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder (ADHD) is one of the most frequent childhood psychiatric problems. Objective: The objective of this study was to identify, synthesize the results, and critically evaluate all Cochrane systematic reviews (SRs) on the pharmacological interventions for children and adolescents (up to age 18) diagnosed with ADHD. Methods: The search was performed in the Cochrane Database of Systematic Reviews (via Wiley) in July 2020. Results: The search strategy resulted in four SRs of high methodological quality, analyzing 51 randomized clinical trials (9,013 participants). Compared to placebo, treatment with tricyclic antidepressants (TCAs) (desipramine), amphetamine, and methylphenidate showed improvement in symptoms such as difficulty concentrating, impulsivity, and hyperactivity in the short term (up to 6 months). There was an increase in the occurrence of adverse events, such as reduced appetite, difficulty sleeping, and abdominal pain. Insufficient evidence was found to support the effects of supplementation with polyunsaturated fatty acids. Conclusions: The use of TCAs, amphetamine, and methylphenidate in children and adolescents with ADHD seems to present positive effects and higher rates of minor adverse events when compared to placebo.

Déficit de atenção e hiperatividade (TDAH) é uma das mais frequentes condições psiquiátricas da infância. Objetivo: O objetivo deste artigo foi identificar, sintetizar os resultados e avaliar criticamente todas as revisões sistemáticas (RS) da Cochrane sobre as intervenções farmacológicas para crianças e adolescentes (até 18 anos de idade) diagnosticados com transtorno do déficit de atenção com hiperatividade. Métodos: A pesquisa foi realizada na base de dados Cochrane de Revisões Sistemáticas ­ CDSR (via Wiley) em julho de 2020. Resultados: A estratégia de busca resultou em quatro RS de alta qualidade metodológica, que analisavam 51 ensaios clínicos randomizados (9.013 participantes). Comparado ao placebo, o tratamento com antidepressivos tricíclicos (desipramina), anfetamina e metilfenidato apresentou melhora nos sintomas, como dificuldade de concentração, impulsividade e hiperatividade no curto prazo (até seis meses). Houve aumento na ocorr≖ncia de eventos adversos, como redução do apetite, dificuldade para dormir e dor abdominal. Foram encontradas evid≖ncias insuficientes para apoiar os efeitos da suplementação com ácidos graxos poli-insaturados. Conclusões: Com base nos resultados de revisões sistemáticas Cochrane, o uso de antidepressivos tricíclicos, anfetamina e metilfenidato em crianças e adolescentes com TDAH parece apresentar efeitos positivos e taxas mais elevadas de eventos adversos menores quando comparado ao placebo. Dado o alto risco de viés nos estudos primários incluídos nessas RS, ainda são necessários novos ensaios clínicos randomizados com rigor metodológico para apoiar esses achados.