RESUMO
OBJECTIVES: This systematic review sought to provide evidence for the effectiveness of common pharmacological interventions used for treating attention deficit hyperactivity disorder (ADHD) symptoms in the autism spectrum disorder (ASD) population, considering studies attempting to find safe and effective drugs. METHODS: We searched for randomized controlled trials describing the effectiveness and/or safety profile of pharmacological interventions for treating ASD and ADHD or ASD with ADHD symptoms using three bibliographic databases: PubMed, Cochrane Library, and Embase. We have chosen ADHD symptoms measured by any clinical scale as the primary outcome. As additional outcomes, we have used other symptoms of aberrant behavior measured by the aberrant behavior checklist, satisfaction with treatment, and peer satisfaction. RESULTS: Twenty-two publications met the inclusion criteria for the systematic review and eight for the meta-analysis. In our investigation, we found a few articles using clonidine, modafinil, and bupropion as interventions when compared to methylphenidate (MPH). Our meta-analysis showed that MPH had positive changes compared to placebo in symptoms such as hyperactivity, irritability, or inattention. However, no effect was found in stereotyped symptoms, and our data's quantitative analysis revealed a large effect of MPH-induced adverse effects on the dropout rate. On the other hand, atomoxetine initiation had positive effects when compared to placebo on symptoms of hyperactivity and inattention. We have found no effect of atomoxetine on stereotypes or irritability. Furthermore, atomoxetine did not influence side effects that caused dropouts from studies. CONCLUSION: Our results indicated that atomoxetine has a modest effect on hyperactivity and inattention symptoms, with a relatively benign profile of side effects. MPH appears to be effective in handling hyperactivity, inattention, and irritability symptoms. However, our results on atomoxetine revealed increased dropouts due to adverse effects when compared to MPH or placebo. Evidence for other substances such as guanfacine, clonidine, bupropion, or modafinil is either preliminary or nonexistent.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Espectro Autista , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Espectro Autista/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Clonidina/uso terapêutico , Metilfenidato/uso terapêutico , Resultado do TratamentoRESUMO
INTRODUCTION: There have been substantial increases in the use of Schedule II stimulants in the United States. Schedule II stimulants are the gold standard treatment for attention-deficit hyperactivity disorder (ADHD), but also carry the risk of addiction. Since the neurocognitive deficits seen in ADHD resemble those of chronic cannabis use, and the rise in stimulant use is incompletely understood, this study sought to determine if recreational cannabis (RC) legalization increased distribution rates of Schedule II stimulants. METHODS: The distribution of amphetamine, lisdexamfetamine, and methylphenidate were extracted from the ARCOS database of the Drug Enforcement Administration. The three-year population-corrected slopes of distribution before and after RC sales were evaluated. RESULTS: Total stimulant distribution rates were significantly higher in states with RC sales after (p=0.049), but not before (p=0.221), program implementation compared to states without RC. Significant effects of time (p<0.001) and RC sales status (p=0.045) were observed, while time x RC sales status interaction effects were not significant (p=0.406). DISCUSSION: RC legalization did not contribute to a more pronounced rise in Schedule II stimulant distribution in states. Future studies could explore the impact of illicit cannabis use on stimulant rates and the impact of cannabis sales on distribution rates of non-stimulant ADHD pharmacotherapies and ADHD diagnoses.
Assuntos
Estimulantes do Sistema Nervoso Central , Humanos , Estados Unidos/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Cannabis , Metilfenidato/uso terapêutico , Anfetamina , Legislação de MedicamentosRESUMO
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.
Assuntos
Estimulantes do Sistema Nervoso Central , Dinaminas , Metabolismo Energético , Metilfenidato , Dinâmica Mitocondrial , Estresse Oxidativo , Córtex Pré-Frontal , Ratos Wistar , Animais , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Metilfenidato/farmacologia , Masculino , Dinâmica Mitocondrial/efeitos dos fármacos , Feminino , Estimulantes do Sistema Nervoso Central/farmacologia , Metabolismo Energético/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Dinaminas/metabolismo , Ratos , Caracteres Sexuais , Trifosfato de Adenosina/metabolismo , GTP Fosfo-Hidrolases/metabolismo , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas Mitocondriais , Ubiquitina-Proteína LigasesRESUMO
CASE: DL is an 8-year-old Mexican boy with a posterior atrial septal defect and partial anomalous pulmonary venous return of the right lower pulmonary vein with resultant right heart dilation with normal right ventricular systolic and diastolic function and no arrhythmias. Surgical repair was deferred, and DL's condition was being medically managed with furosemide 0.5 mg/kg BID and spironolactone 0.5 mg/kg BID.DL presents for developmental assessment due to poor performance in school following a lifting of COVID-19 pandemic restrictions and return to in-person classes. He has been attending full-time classes for 3 months without improvements in math, reading, and writing skills. Current attentional concerns at school include an inability to complete tasks without getting distracted by minimal stimuli and highly impulsive behavior.At the first assessment, DL was performing below grade expectations (e.g., reading by syllable without text comprehension, demonstrating preoperational addition and subtraction skills, inability to take dictation)-all of which was viewed as negatively impacted by attentional deficits. DL met DSM-5 criteria for ADHD, predominantly inattentive type. He was started on 10-mg immediate-release methylphenidate PO at 8 am with breakfast and a second dose of 10-mg immediate-release methylphenidate PO 4 hours after the first dose.After a month, at the first follow-up consultation, improvement in attention span, impulsivity, and school performance were observed, including reading skills and math proficiency. However, DL's mother raised concerns about circumoral cyanosis and acrocyanosis in the fingers of both hands after playing outside. These signs were not previously observed. During physical examination at the same visit, heart rate, blood pressure, and oximetry were within baseline ranges and his cardiac examination was unchanged. DL's dosage of methylphenidate was lowered to 10-mg immediate-release methylphenidate PO QD in the mornings with breakfast (8 am).DL did not return to clinic for another 2 months, having discontinued the medication after 2 months of treatment given financial limitations. His mother reported that DL's exertional circumoral cyanosis and acrocyanosis resolved while he was off medication. However, she observed an increase in inattentive symptoms and impulsivity and decline in his academic skills. She asked if our team was able continue the treatment despite the drug side effects, since she believed the benefits outweighed the disadvantages.Given these concerns, the team requested an updated cardiology assessment. The Cardiologist recommended discontinuation of methylphenidate and recommended follow-up with cardiothoracic surgery for reassessment of the surgical timeline.Given the limited treatment options in Mexico, what would you do next as the treating developmental-behavioral clinician ?
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Cardiopatias Congênitas , Humanos , Masculino , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Criança , Cardiopatias Congênitas/tratamento farmacológico , México , COVID-19 , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Metilfenidato/farmacologia , Metilfenidato/administração & dosagemRESUMO
Importance: Stimulants (methylphenidate and amphetamines) are often prescribed at unlicensed doses for adults with attention-deficit/hyperactivity disorder (ADHD). Whether dose escalation beyond US Food and Drug Administration recommendations is associated with positive risk benefits is unclear. Objective: To investigate the impact, based on averages, of stimulant doses on treatment outcomes in adults with ADHD and to determine, based on averages, whether unlicensed doses are associated with positive risk benefits compared with licensed doses. Data Sources: Twelve databases, including published (PubMed, Cochrane Library, Embase, Web of Sciences) and unpublished (ClinicalTrials.gov) literature, up to February 22, 2023, without language restrictions. Study Selection: Two researchers independently screened records to identify double-blinded randomized clinical trials of stimulants against placebo in adults (18 years and older) with ADHD. Data Extraction and Synthesis: Aggregate data were extracted and synthesized in random-effects dose-response meta-analyses and network meta-analyses. Main Outcome Measures: Change in ADHD symptoms and discontinuations due to adverse events. Results: A total of 47 randomized clinical trials (7714 participants; mean age, 35 (SD, 11) years; 4204 male [56%]) were included. For methylphenidate, dose-response curves indicated additional reductions of symptoms with increments in doses, but the gains were progressively smaller and accompanied by continued additional risk of adverse events dropouts. Network meta-analyses showed that unlicensed doses were associated with greater reductions of symptoms compared with licensed doses (standardized mean difference [SMD], -0.23; 95% CI, -0.44 to -0.02; very low certainty of evidence), but the additional gain was small and accompanied by increased risk of adverse event dropouts (odds ratio, 2.02; 95% CI, 1.19-3.43; moderate certainty of evidence). For amphetamines, the dose-response curve approached a plateau and increments in doses did not indicate additional reductions of symptoms, but there were continued increments in the risk of adverse event dropouts. Network meta-analysis did not identify differences between unlicensed and licensed doses for reductions of symptoms (SMD, -0.08; 95% CI, -0.24 to 0.08; very low certainty of evidence). Conclusions and Relevance: Based on group averages, unlicensed doses of stimulants may not have positive risk benefits compared with licensed doses for adults with ADHD. In general, practitioners should consider unlicensed doses cautiously. Practitioners may trial unlicensed doses if needed and tolerated but should be aware that there may not be large gains in the response to the medication with those further increments in dose. However, the findings are averages and will not generalize to every patient.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Estimulantes do Sistema Nervoso Central , Metilfenidato , Adulto , Masculino , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/efeitos adversos , Metilfenidato/uso terapêutico , Anfetaminas/uso terapêutico , Resultado do TratamentoRESUMO
Methylphenidate (MPD), known as Ritalin, is a psychostimulant used to treat children, adults, and the elderly. MPD exerts its effects through increasing concentrations of dopamine (DA), norepinephrine (NE), and serotonin (5-HT) in the synaptic cleft. Concomitant behavioral and neuronal recording from the ventral tegmental area (VTA), locus coeruleus (LC), and from the dorsal raphe (DR) nucleus, which are the sources of DA, NE, and 5-HT to the mesocorticolimbic circuit, were investigated following acute and repetitive (chronic) saline, 0.6, 2.5, or 10.0 mg/kg MPD. Animals received daily saline or MPD administration on experimental days 1 to 6 (ED1-6), followed by a 3-day washout period and MPD rechallenge on ED10. Each chronic MPD dose elicits behavioral sensitization in some animals while inducing behavioral tolerance in others. The uniqueness of this study is in the evaluation of neuronal activity based on the behavioral response to chronic MPD. Neuronal excitation was observed mainly in brain areas of animals exhibiting behavioral sensitization, while neuronal attenuation following chronic MPD was observed in animals expressing behavioral tolerance. Different ratios of excitatory/inhibitory neuronal responses were obtained from the VTA, LC, or DR following chronic MPD. Thus, each brain area responds differently to each MPD dose used, suggesting that DA, NE, and 5-HT in the VTA, LC, and DR exert different effects.
Assuntos
Metilfenidato , Humanos , Criança , Ratos , Animais , Idoso , Metilfenidato/farmacologia , Serotonina/farmacologia , Área Tegmentar Ventral , Dopamina/farmacologia , Núcleo Dorsal da Rafe , Locus Cerúleo , Norepinefrina/farmacologia , Ratos Sprague-DawleyRESUMO
OBJECTIVE: The aim of this study was to analyze the effect of the pharmacological treatment on the sleep patterns of children with attention deficit hyperactivity disorder (ADHD). DATA SOURCE: A high-sensitivity electronic search was performed in the following databases: Cochrane Library, MEDLINE via PubMed, LILACS via the Regional Health Portal (BVS), Embase, Scopus, CINAHL, and Web of Science, as recommended by the Cochrane Handbook, and which has undergone peer review according to the PRESS Guide. DATA SYNTHESIS: The studies contemplated the use of the drugs atomoxetine, guanfacine, methylphenidate, dasotraline, L-theanine, and lisdexamfetamine. They showed efficiency in reducing the symptoms of ADHD, although all, except atomoxetine, affected sleep quality, such as by reducing total rapid eye movement (REM), non-REM phase, slow-wave sleep time, and longer sleep-onset latency. CONCLUSIONS: The drugs used in the treatment of ADHD seem to have negative repercussions on the sleep quality of children, with the drug atomoxetine showing lesser effects on this variable.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Estimulantes do Sistema Nervoso Central , Metilfenidato , Criança , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Cloridrato de Atomoxetina/uso terapêutico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Metilfenidato/uso terapêutico , SonoRESUMO
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.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Estimulantes do Sistema Nervoso Central , Metilfenidato , Animais , Ratos , Masculino , Metilfenidato/farmacologia , Metilfenidato/uso terapêutico , Motivação , Ratos Wistar , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/uso terapêutico , Recompensa , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológicoRESUMO
O consumo de psicoestimulantes tem crescido exponencialmente, sobretudo entre estudantes de medicina, na busca por aumentar o rendimento acadêmico. Atualmente, a extensa carga horária de aulas e estudos, exigências de produtividade e altos níveis de estresse podem desencadear o uso. Objetivo: Analisar o uso de psicoestimulantes por estudantes do curso de Medicina de um Centro Universitário privado em Minas Gerais. Métodos: Foi realizado um estudo descritivo, quantitativo, com delineamento transversal entre os discentes do 1° ao 5° ano do curso de Medicina no 2° semestre de 2021. Os participantes responderam ao questionário semi-estruturado elaborado pelos autores. Os dados obtidos foram tabulados no software Statistical Product and Service Solutions. Resultados: Dos 244 entrevistados, cerca de 57.4% faziam uso de algum psicoestimulante. Houve maior uso entre os estudantes do 2° ano e as principais substâncias utilizadas foram: cafeína (85%), energético (65%) e metilfenidato (60%). A melhora na concentração (97%) foi o efeito mais percebido pelos usuários, seguido de redução do sono (83%) e melhora de raciocínio (80%). Muitos consideraram que os estimulantes cerebrais têm o potencial de melhorar o rendimento acadêmico, mas pode reduzir a qualidade do sono e consequentemente torná-los susceptíveis a outras enfermidades. Conclusão: É notável que existe uso abusivo de estimulantes cerebrais, sendo fundamental o trabalho em conjunto entre instituição de ensino e familiares, em prol da prevenção e do controle de danos causados por esse hábito
The consumption of psychostimulants has grown exponentially, especially among medical students, in the quest to increase academic performance. Currently, the extensive workload of classes and studies, productivity demands and high levels of stress can trigger use. Objective: To analyze the use of psychostimulants by medical students at a private University Center in Minas Gerais. Methods: A descriptive, quantitative, cross-sectional study was carried out among students from the 1st to the 5th year of the medicine course in the 2nd semester of 2021. The participants answered the semi-structured questionnaire prepared by the authors. The data obtained were tabulated in the Statistical Product and Service Solutions software. Results: Of the 244 respondents, about 57.4% used some psychostimulant. There was greater use among 2nd year students and the main substances used were: caffeine (85%), energy drink (65%) and methylphenidate (60%). Improved concentration (97%) was the effect most perceived by users, followed by reduced sleep (83%) and improved thinking (80%). Many considered that brain stimulants have the potential to improve academic performance, but can reduce sleep quality and consequently make them susceptible to other illnesses. Conclusion: It is notable that there is abusive use of brain stimulants, and it is essential to work together between educational institutions and family members in order to prevent and control the damage caused by this habit
Assuntos
Humanos , Masculino , Feminino , Adulto , Adulto Jovem , Estudantes de Medicina , Desempenho Acadêmico , Estimulantes do Sistema Nervoso Central/efeitos adversos , Atenção/efeitos dos fármacos , Cafeína/efeitos adversos , Consumo de Bebidas Alcoólicas , Paullinia/efeitos adversos , Bebidas Energéticas/efeitos adversos , Anfetaminas/efeitos adversos , Metilfenidato/efeitos adversosRESUMO
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.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Criança , Oxidantes , Metilfenidato , Plasticidade Neuronal , Antioxidantes , Metanálise , Dissertação AcadêmicaRESUMO
BACKGROUND: Attention deficit hyperactivity disorder (ADHD) has a prevalence of 5.3% among children and adolescents. It is characterized by attention deficit, hyperactivity, and impulsivity. OBJECTIVE: We aimed to conduct a survey involving pediatric neurologists in the management of ADHD and compare the results with the current literature and guidelines. DESIGN AND SETTING: Descriptive analytical study of a virtual environment, was used Test of equality of proportions for comparison between two groups of pediatric neurologists (working as specialists for > 6 versus ≤ 6 years), with a significance level of P = 0.05. METHODS: This cross-sectional study used a virtual questionnaire covering the steps in the diagnosis and treatment of children with ADHD. The inclusion criteria were professionals who had completed their residency/specialization in pediatric neurology and clinical neurologists working in pediatric neurology. RESULTS: Among the 548 electronic invitations sent, 128 were considered valid. For all participants, the diagnosis was clinically based on the disease classification manuals. Combination treatment promotes improvement of symptoms (96.9%). Among psychostimulants, short-acting methylphenidate was the most commonly prescribed medication (85.2%). Headache was the most common side effect (77.3%). Altogether, 73.4% of the participants requested laboratory tests, 71.1% requested an electrocardiogram, and 42.2% requested an electroencephalogram. Pediatric neurologists working as specialists for ≤ 6 years had more frequent referrals to psycho-pedagogists for diagnosis (P = 0.03). CONCLUSIONS: The participants complied with clinical guidelines, emphasizing the relevance of diagnostic manuals and treatment guidelines for an eminently clinical situation and enabling uniformity in quality treatment.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Estimulantes do Sistema Nervoso Central , Metilfenidato , Criança , Adolescente , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estudos Transversais , Neurologistas , Brasil , Metilfenidato/efeitos adversos , Estimulantes do Sistema Nervoso Central/uso terapêutico , AtitudeRESUMO
Introducción: el consumo de estimulantes de tipo anfetamínico (ETA) y sus derivados está cada vez más presente en los estudiantes universitarios y, en particular, en los programas de medicina. El objetivo principal de este estudio fue revisar la literatura sobre el uso de ETA y sus derivados en estudiantes de medicina latinoamericanos. Materiales y método: se realizó una revisión de la literatura disponible, utilizando las bases de datos PubMed, SciELO y LILACS. Se encontraron un total de 1.054 artículos, de los cuales 17 fueron seleccionados para esta revisión. Resultados: la revisión muestra, en general, una mayor frecuencia de uso de ETA en estudiantes de medicina de América Latina en comparación con la población general y estudiantes de otras carreras universitarias. También existe una tendencia a un mayor uso en hombres, de mayor nivel socioeconómico y en cursos posteriores del programa. La razón más informada para usar ETA fue aumentar el rendimiento académico. Como factor protector se destacaron los deportes, el tiempo en familia y la profesión de alguna creencia religiosa. De los artículos seleccionados, no se encontraron estudios sobre las consecuencias a largo plazo del uso de ETA en estudiantes de medicina. Discusión: en resumen, los estudiantes de medicina latinoamericanos tienen un alto consumo de ETA, por lo que es evidente la necesidad de nuevos estudios para mejorar la precisión estadística, determinar factores de riesgo específicos, estudiar las consecuencias a largo plazo y establecer políticas de prevención y tratamiento.
Introduction: the consumption of amphetamine-type stimulants (ATS) and their derivatives are increasingly present in university students and in particular in medical programs. The main objective of this study was to review the literature on the use of ATS and their derivatives in Latin American medical students. Materials and method: a review of the literature available was performed, using PubMed, SciELO, and LILACS databases. A total of 1054 articles were found, of which 17 were selected for this review. Results: the review generally shows a higher frequency of use of ATS in medical students of Latin America compared to the general population and students from other university degrees. There is also a tendency of a higher use in men, from higher socioeconomic status, and in later courses of the program. The most reported reason for using ATS was to increase the academic performance. As a protective factor, sports, family time and professing some religious belief stood out. Of the selected articles, no studies were found on the long-term consequences of the use of ATS in medical students. Discussion: in summary, Latin American medical students have a high consumption of ATS, and therefore there is an evident need for new studies to improve statistical precision, to determine specific risk factors, to study long-term consequences, and to stablish prevention policies and treatment.
Assuntos
Humanos , Estudantes de Medicina , Transtornos Relacionados ao Uso de Anfetaminas/epidemiologia , Anfetaminas/administração & dosagem , Desempenho Acadêmico , Estimulantes do Sistema Nervoso Central/administração & dosagem , América Latina , Metilfenidato/administração & dosagemRESUMO
Attention Deficit Hyperactivity Disorder is a neurodevelopmental disorder with three presentations: inattentive, hyperactive/impulsive and combined. These may represent an independent disease entity. Therefore, the therapeutic approach must be focused on their neurobiological, psychological and social characteristics. To date, there is no comprehensive analysis of the efficacy of different treatments for each presentation of ADHD and each stage of development. This is as narrative overview of scientific papers that summarize the most recent findings and identify the most effective pharmacological and psychosocial treatments by ADHD presentation and age range. Evidence suggests that methylphenidate is the safest and most effective drug for the clinical management of children, adolescents and adults. Atomoxetine is effective in preschoolers and maintains similar efficacy to methylphenidate in adults, whereas guanfacine has proven to be an effective monotherapy for adults and is a worthy adjuvant for the management of cognitive symptoms. The psychosocial treatments with the best results in preschoolers are behavioral interventions that include training of primary caregivers. In adolescents, the combination of cognitive and cognitive-behavioral therapies has shown the best results, whereas cognitive-behavioral interventions are the most effective in adults. Pharmacological and psychosocial treatments must be adjusted to the ADHD presentation and its neurocognitive characteristics through the patient's development.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Estimulantes do Sistema Nervoso Central , Metilfenidato , Adolescente , Adulto , Cloridrato de Atomoxetina/uso terapêutico , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Estimulantes do Sistema Nervoso Central/uso terapêutico , Criança , Guanfacina/uso terapêutico , Humanos , Metilfenidato/uso terapêuticoRESUMO
BACKGROUND: There is insufficient evidence to support treatment recommendations for preschool children aged 3-5 years with attention-deficit hyperactivity disorder (ADHD). We aimed to investigate the efficacy and safety of methylphenidate and behavioural parent training in reducing the frequency and severity of symptoms and improving global functioning in preschool children with ADHD. METHODS: We did an 8-week, randomised, double-blind, placebo-controlled and sham behavioural parent training-controlled clinical trial (the MAPPA Study) in children aged 3-5 years with moderate-to-severe ADHD. The trial was conducted at the Institute of Psychiatry, Hospital das Clinicas, University of São Paulo Medical School, São Paulo, Brazil. Participants were randomly assigned (1:1:1) to receive immediate-release methylphenidate plus educational intervention (sham behavioural parent training), placebo medication plus behavioural parent training, or placebo medication plus educational intervention. Randomisation was done by an independent research manager by use of a permuted block randomisation procedure. Parents, teachers, study staff, and evaluators remained masked to group allocation. Methylphenidate and placebo were titrated to a maximum dose of 1·25 mg/kg per day administered orally twice daily, and behavioural parent training and the educational intervention were delivered weekly through 90 min sessions with both the child and parent, conducted by two psychologists or learning therapists. The primary outcomes were parents' and teachers' composite scores of the Swanson, Nolan, and Pelham-IV scale (SNAP-IV-P/T), the Clinical Global Impressions Severity (CGI-S) scale, and the Children's Global Assessment Scale (CGAS). This trial is registered with ClinicalTrials.gov, NCT02807870, and is now complete. All participants were invited to participate in an open observational follow-up, which is ongoing. FINDINGS: Between Aug 21, 2016, and Oct 21, 2019, 153 children were randomly assigned to receive methylphenidate plus the educational intervention (n=51), placebo plus behavioural parent training (n=51), or placebo plus the educational intervention (n=51). Nine (6%) children discontinued treatment. All participants were included in the intention-to-treat analysis. Children in the methylphenidate plus educational intervention group showed greater reductions in the SNAP-IV-P/T (endpoint mean difference -3·93 [95% CI -7·14 to -0·73], p=0·049; effect size -0·55 [95% CI -0·99 to -0·10]) and CGI-S scores (endpoint mean difference -0·49 [-0·82 to -0·17], p=0·0088; effect size -0·70 [-1·16 to -0·24]) and a greater increase in CGAS scores (endpoint mean difference 5·25 [95% CI 2·09 to 8·40], p=0·0036; effect size 0·80 [95% CI 0·32 to 1·28]) than children in the placebo plus educational intervention group. Children in the placebo plus behavioural parent training group did not have significantly different SNAP-IV-P/T scores (endpoint mean difference -3·18 [95% CI -6·38 to 0·02], p=0·077; effect size -0·44 [95% CI -0·89 to 0·003]) or CGI-S scores (endpoint mean difference -0·35 [-0·68 to -0·03], p=0·052; effect size -0·50 [-0·96 to -0·04]) compared to children in the placebo plus educational intervention group, but they had a greater increase in CGAS scores compared to the placebo plus educational intervention group (endpoint mean difference 3·69 [0·53 to 6·85], p=0·033; effect size 0·56 [0·08 to 1·04]). Children in the methylphenidate plus educational intervention versus placebo plus behavioural parent training group did not have statistically or clinically significant differences in primary outcomes. Children in the methylphenidate plus educational intervention group had more mild adverse events than the other two groups, and there were no between-group differences for moderate or severe adverse events. INTERPRETATION: Methylphenidate was effective in reducing ADHD symptoms and improving functionality, and behavioural parent training was effective in improving functionality for preschool children with ADHD after 8 weeks of treatment. FUNDING: São Paulo Research Foundation and Brazilian National Council for Scientific and Technological Development.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Estimulantes do Sistema Nervoso Central , Metilfenidato , Pré-Escolar , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Brasil , Estimulantes do Sistema Nervoso Central/uso terapêutico , Estimulantes do Sistema Nervoso Central/efeitos adversos , Metilfenidato/uso terapêutico , Metilfenidato/efeitos adversos , Nucleotidiltransferases/uso terapêutico , Pais/educaçãoRESUMO
BACKGROUND: Methylphenidate hydrochloride (MPH) is a psychostimulant widely used in the treatment of attention-deficit hyperactive disorder (ADHD), as well as a performance enhancer, for at least 60 years. Despite the notable effectiveness as a psychostimulant, ADHD is a chronic disorder and has a two-third chance of accompanying the individual throughout life. Long-term use of MPH has been associated not only with an increase in the development of neurodegenerative diseases, but it also causes side effects on male fertility in experimental animals. OBJECTIVES: To investigate whether methylphenidate poses a risk to sperm DNA structure and to the quality of embryos conceived after treatment during adolescence in rats. MATERIALS AND METHODS: Wistar rats at 38 days of age were treated either with 5 mg/kg body weight of MPH, in a single daily dose for 30 days, via gavage or with distilled water-only protocol. Levels of oxidative stress in testicular and epididymal tissues were evaluated. Sperm chromatin quality and acrosome integrity was assessed under flow cytometry. From 107 days of age, animals were mated with untreated females. The effects of the paternal contribution at two different embryo development moments-cleavage stage (2.5 days post coitum) and late gestation (20 days post coitum) -were analyzed. RESULTS: MPH caused high levels of sperm DNA damage, which was reflected in 40% of decrease in early embryo quality and a lower number of live pups at 20 dpc. DISCUSSION: The high level of fragmentation seen in the embryos sired from the MPH group is consistent with the poor chromatin structure of the sperm and does not seem to be a result of oxidative stress in the reproductive tissues. CONCLUSIONS: The results presented here suggest that the subchronic use of MPH during male prepubertal phase may cause long-term subfertility and compromise embryo survival.
Assuntos
Estimulantes do Sistema Nervoso Central , Infertilidade , Metilfenidato , Animais , Estimulantes do Sistema Nervoso Central/toxicidade , Cromatina , Feminino , Masculino , Metilfenidato/toxicidade , Gravidez , Ratos , Ratos Wistar , Sêmen , Espermatozoides , ÁguaRESUMO
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.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Metilfenidato , Animais , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Modelos Animais de Doenças , Feminino , Hipocampo/metabolismo , Metilfenidato/farmacologia , Camundongos , Plasticidade Neuronal , Nicotina/metabolismo , Nicotina/farmacologia , Gravidez , Receptores de AMPA/metabolismoRESUMO
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.
Assuntos
Estimulantes do Sistema Nervoso Central , Metilfenidato , Estimulantes do Sistema Nervoso Central/análise , Cromatografia Líquida/métodos , Humanos , Metilfenidato/análogos & derivados , Espectrometria de Massas em Tandem/métodosRESUMO
Early life exposure to sex hormones affects several brain areas involved in regulating locomotor and motivation behaviors. Our group has shown that neonatal exposure to testosterone propionate (TP) or estradiol valerate (EV) affected the brain dopamine (DA) system in adulthood. Here, we studied the long-lasting effects of neonatal exposure to sex hormones on behavioral and neurochemical responses to amphetamine (AMPH) and methylphenidate (MPD). Our results show that AMPH-induced locomotor activity was higher in female than male control rats. The conditioned place preference (CPP) to AMPH was only observed in EV male rats. In EV female rats, AMPH did not increase locomotor activity, but MPD-induced CPP was observed in control, EV and TP female rats. Using in vivo brain microdialysis, we observed that AMPH-induced extracellular DA levels were lower in nucleus accumbens (NAcc) of EV and TP female rats than control rats. In addition, MPD did not increase NAcc extracellular DA levels in EV rats. Using in vivo fast-scan cyclic voltammetry in striatum, MPD-induced DA reuptake was higher in EV than control rats. In summary, our results show that early life exposure to sex hormones modulates mesolimbic and nigrostriatal DA neurons producing opposite neurochemical effects induced by psychostimulant drugs in NAcc or striatum.
Assuntos
Estimulantes do Sistema Nervoso Central , Metilfenidato , Transtornos Relacionados ao Uso de Substâncias , Propionato de Testosterona , Anfetamina/farmacologia , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Dopamina/farmacologia , Estradiol/farmacologia , Feminino , Masculino , Metilfenidato/farmacologia , Atividade Motora , Núcleo Accumbens , RatosRESUMO
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.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Estimulantes do Sistema Nervoso Central , Metilfenidato , Animais , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Homeostase , Inflamação/metabolismo , Metilfenidato/efeitos adversos , Mitocôndrias/metabolismo , OxirreduçãoRESUMO
Clinical guidelines currently recommend practitioners titrate stimulant medications, i.e., methylphenidate (MPH) and amphetamines (AMP), to the dose that maximizes symptom control without eliciting intolerable adverse events (AEs) when treating attention-deficit/hyperactivity disorder (ADHD) in school-aged children/adolescents. However, robust evidence-base regarding the effects of doses and dosing strategies of stimulants on clinical outcomes in the treatment of children/adolescents with ADHD is currently lacking and stimulants are often underdosed in clinical practice. To address this gap and provide rigorous evidence-base in relation to the dose and dosing strategy of stimulants, we conducted the largest systematic review and dose-response meta-analysis examining change in ADHD symptoms (efficacy), and treatment discontinuations due to AEs (tolerability) and any reason (acceptability). We conducted one-stage random-effects dose-response meta-analyses examining MPH and AMP separately, stratifying trials based on fixed-dose and flexible-dose design. Daily doses of stimulants were converted to MPH- and AMP-equivalent doses by adjusting for different pharmacokinetics across formulations. We also conducted pairwise meta-analyses to provide indirect comparisons between flexible-dose versus fixed-dose trials. Our study included 65 RCTs involving 7 877 children/adolescents. Meta-analyses of fixed-dose trials for both MPH and AMP demonstrated increased efficacy and increased likelihood of discontinuation due to AEs with increasing doses of stimulants. The incremental benefits of stimulants in terms of efficacy decreased beyond 30 mg of MPH or 20 mg of AMP in fixed-dosed trials. In contrast, meta-analyses of flexible-dose trials for both MPH and AMP demonstrated increased efficacy and reduced likelihood of discontinuations for any reason with increasing stimulant doses. The incremental benefits of stimulants in terms of efficacy remained constant across the FDA-licensed dose range for MPH and AMP in flexible-dose trials. Our results suggest that flexible titration as needed, i.e., considering the presence of ADHD symptoms, and tolerated, i.e., considering the presence of dose-limiting AEs, to higher doses of stimulants is associated with both improved efficacy and acceptability because practitioners can increase/reduce doses based on control of ADHD symptoms/dose-limiting AEs. Although fixed-dose trials that are required by the FDA are valuable to characterize dose-dependency, they may underestimate the true potential benefit of trialing dose-increases of stimulants in clinical practice by not allowing dose adjustment based on response and tolerability. Additional research is required to investigate potential long-term effects of using high doses of stimulants in clinical practice.