Transcriptomics and candidate gene/protein expression studies have indicated several biological p... more Transcriptomics and candidate gene/protein expression studies have indicated several biological processes modulated by methylphenidate (MPH), widely used in attention-deficit/hyperactivity disorder (ADHD) treatment. However, the lack of a differential proteomic profiling of MPH treatment limits the understanding of the most relevant mechanisms by which MPH exerts its pharmacological effects at the molecular level. Therefore, our aim is to investigate the MPH-induced proteomic alterations using an experimental design integrated with a pharmacogenomic analysis in a translational perspective. Proteomic analysis was performed using the cortices of Wistar-Kyoto rats, which were treated by gavage with MPH (2 mg/kg) or saline for two weeks (n = 6/group). After functional enrichment analysis of the differentially expressed proteins (DEP) in rats, the significant biological pathways were tested for association with MPH response in adults with ADHD (n = 189) using genome-wide data. Following ...
Although the identification of reliable predictors of methylphenidate response in adults with att... more Although the identification of reliable predictors of methylphenidate response in adults with attention-deficit/hyperactivity disorder (ADHD) is necessary to guide treatment decisions, very few data exist on this issue. Here, we assessed the predictors of clinical response to immediate-release methylphenidate hydrochloride (IR-MPH) in a naturalistic setting by analyzing the influence of demographic factors, severity, and a wide range of comorbid psychiatric disorders. Two hundred fifty adult patients with ADHD were evaluated and completed a short-term treatment with IR-MPH. Mental health diagnoses were based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria through the use of standard structured interviews. The Swanson, Nolan, and Pelham Rating Scale, version 4, adapted to adults was used to assess the severity of ADHD. In the linear regression model, only higher severity of ADHD was associated to a better IR-MPH response (b = 0.770; P G 0.001). Treatment of comorbidities in a subsample (n = 62) did not modify this pattern. Our findings suggest that in clinical settings, patients with more severe ADHD symptoms have a good response to treatment independently from the presence of mild or stabilized comorbidities and their treatments. For adults with ADHD, differently from other common psychiatric disorders such as depression and anxiety, higher severity is associated with better treatment response.
Conflict of interest: LAR was on the speakers' bureau and/or acted as consultant for Eli-Lilly, J... more Conflict of interest: LAR was on the speakers' bureau and/or acted as consultant for Eli-Lilly, Janssen-Cilag, Novartis and Shire in the last three years. He receives authorship royalties from Oxford Press and ArtMed. He also received travel awards (air tickets + hotel) for taking part of two child psychiatric meetings from Novartis and Janssen-Cilag in 2010. The ADHD and Juvenile Bipolar Disorder Outpatient 34 Programs chaired by him received unrestricted educational and research support from the following pharmaceutical companies in the last three years: Abbott, Eli-Lilly, Janssen-Cilag, Novartis, and Shire.
Objective: This study evaluated the hypothesis that methylphenidate immediate release (MPH-IR) tr... more Objective: This study evaluated the hypothesis that methylphenidate immediate release (MPH-IR) treatment would improve Default Mode Network (DMN) within-connectivity. Method: Resting-state functional connectivity of the main nodes of DMN was evaluated in a highly homogeneous sample of 18 drug-naive male adult participants with ADHD. Results: Comparing resting-state functional connectivity functional magnetic resonance imaging (R-fMRI) scans before and after MPH treatment focusing exclusively on within-DMN connectivity, we evidenced the strengthening of functional connectivity between two nodes of the DMN: posterior cingulate cortex (PCC) and left lateral parietal cortex (LLP). Conclusion: Our results contribute to the further understanding on how MPH affects functional connectivity within DMN of male adults with ADHD and corroborate the hypothesis of ADHD being a delayed neurodevelopmental disorder.
A considerable proportion of adults with attention-deficit/hyperactivity disorder (ADHD) do not r... more A considerable proportion of adults with attention-deficit/hyperactivity disorder (ADHD) do not respond to the treatment with methylphenidate. This scenario could be due to inherited interindividual differences that may alter pharmacologic treatment response. In this sense, in 2012 we conducted a systematic search on PUBMED-indexed literature for articles containing information about pharmacogenomics of ADHD in adults. Five studies were found on methylphenidate pharmacogenomics and the only significant association was reported by one particular study. However, this single association with the SLC6A3 gene was not replicated in two subsequent reports. In the present review, although we could not find additional pharmacogenomics studies, we discuss these up-to-date findings and suggest new approaches for this field. Additionally, using systeomic-oriented databases, we provide a broad picture of new possible candidate genes as well as potential gene–gene interactions to be investigated ...
Background: Previous studies have suggested that individuals with ADHD have high scores in novelt... more Background: Previous studies have suggested that individuals with ADHD have high scores in novelty seeking and harm avoidance. However, it is not known whether personality is associated with specific subtypes and dimensions of the disorder. The aim of this study is to test for associations between scores in the temperament and character inventory of C.R. Cloninger with adult ADHD subtypes and severity. Sampling and Methods: The diagnostic interviews of 296 adult ADHD patients followed the DSM-IV criteria. ADHD dimensions were evaluated with the SNAP-IV scores, and personality dimensions were assessed using the Temperament and Character Inventory. Results: The combined subtype (n = 168) was associated with higher scores in novelty seeking (p < 0.001) and lower scores in cooperativeness (p = 0.006) than the inattentive subtype (n = 128). Higher inattention scores were associated with decreased self-directedness (p < 0.001) and increased harm avoidance (p = 0.02), whereas higher ...
Most adults with attention-deficit/hyperactivity disorder (ADHD) are not recognized and remain un... more Most adults with attention-deficit/hyperactivity disorder (ADHD) are not recognized and remain untreated, although a large fraction of these individuals are diagnosed and treated for other comorbid mental disorders, such as major depressive disorder (MDD). The fact that MDD is one of the most commonly occurring mental disorders with high comorbidity with adult ADHD raises the question whether such comorbidity is associated with differences in the clinical picture of ADHD. Three hundred and twenty adult ADHD outpatients were evaluated. Diagnoses followed DSM-IV criteria. Interviews to evaluate ADHD and oppositional defiant disorder (ODD) were performed based on the Portuguese version of K-SADS-E. Psychiatric comorbidities were investigated using SCID-IV and MINI. Regression models were applied to test MDD association with clinical and demographic outcomes. Subjects presenting ADHD and MDD had a higher frequency of generalized anxiety disorder and social phobia and a lower frequency of substance dependence, grade repetition and school suspensions, when compared to subjects with ADHD without MDD. Furthermore, adults presenting ADHD and MDD reported higher demand for psychotherapy and pharmacological treatment prior to enrollment in the study when compared to ADHD subjects free of MDD. However, contrary to what could be expected based on these data, the presence of MDD was not associated with an earlier ADHD diagnosis. These results point to the need for research and medical education into an earlier and more efficient ADHD diagnosis in patients who search for mental health care.
Several lines of evidence suggest a relevant role for the dopamine transporter (DAT1) gene not on... more Several lines of evidence suggest a relevant role for the dopamine transporter (DAT1) gene not only as a susceptibility factor for attention-deficit hyperactivity disorder (ADHD), but also as a predictor of individual methylphenidate (MPH) response. Pharmacogenetic studies of MPH response in ADHD have mainly focused on the 40-bp variable number of tandem repeats (VNTR) in the 3&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; untranslated region (3&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-UTR) of DAT1. Most studies were performed in samples of children and conflicting findings were obtained. Only two studies have assessed 3&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-VNTR in samples of adults-one with positive and the other with negative findings. In the present study, we investigate three potentially relevant polymorphisms in DAT1 gene (-839 C &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; T; Int8 VNTR and 3&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-VNTR), and their possible role in therapeutic response to MPH treatment in a sample of 171 Brazilian adults with ADHD. The diagnostic procedures followed the DSM-IV criteria and the outcome measures were the scales Swanson, Nolan, and Pelham Rating scale version IV and the Clinical Global Impression-Severity Scale, applied at the beginning and after the 30th day of treatment. Drug response was assessed by both categorical and dimensional approaches. There was no effect of any DAT1 polymorphisms or haplotypes on MPH response. This is the second report demonstrating absence of differences in MPH response according to DAT1 genotypes in adults with ADHD. Although DAT protein is crucial for the effect of MPH, genetic variations in DAT1 gene probably do not have a significant clinical role in this sample of adults with ADHD.
Results from pharmacogenetic investigations of methylphenidate (MPH) response in patients with AD... more Results from pharmacogenetic investigations of methylphenidate (MPH) response in patients with ADHD are still inconsistent, especially among adults. This study investigates the role of genetic variants (SLC6A4, HTR1B, TPH2, DBH, DRD4, COMT, and SNAP25) in the response to MPH in a sample of 164 adults. Genes were chosen owing to previous evidence for an influence in ADHD susceptibility. No significant differences in allele or genotype frequencies between MPH responders and nonresponders were detected. In conclusion, our findings do not support an effect of these genes in the pharmacogenetics of MPH among adults with ADHD.
Objective: This study addresses if deficits in cognitive, attention, and inhibitory control perfo... more Objective: This study addresses if deficits in cognitive, attention, and inhibitory control performance in adults with ADHD are better explained by the disorder itself or by comorbid conditions. Method: Adult patients with ADHD (n = 352) and controls (n = 94) were evaluated in the ADHD program of a tertiary hospital. The diagnostic process for ADHD and comorbidities was based on Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) criteria. Stepwise regression analyses evaluated the effect of ADHD, demographics, and comorbidities on the scores from Wechsler Adult Intelligence Scale-Revised, Continuous Performance Test, and Stroop Color and Word Test.. Results: Patients with ADHD of both genders had worse performance on neuropsychological domains, even after adjustment for comorbidities. The presence of comorbid bipolar disorder and specific phobia are associated with more Stroop errors, whereas patients with generalized anxiety disorder present a longer execution ...
Since approximately 70% of adult patients with attention-deficit/hyperactivity disorder (ADHD) ha... more Since approximately 70% of adult patients with attention-deficit/hyperactivity disorder (ADHD) have at least one comorbid disorder, rating of impairment specifically attributable to ADHD is a hard task. Despite the evidence linking environmental adversities with negative outcomes in ADHD, life events measures have not been used to rate the disorder impairment. The present study tested for the first time the hypothesis that increased ADHD severity is associated with an increase in negative recent life events, independently of comorbidity status. The psychiatric diagnoses of 211 adult ADHD outpatients were based on DSM-IV criteria assessed through structured interviews (K-SADS-E for ADHD and ODD, MINI for ASPD and SCID-IV-R for other comorbidities). ADHD severity was evaluated with the Swanson, Nolan and Pelham rating scale (SNAP-IV) and recent life events with the Life Experience Survey. Higher SNAP-IV inattention and hyperactivity scores, female gender, lower socioeconomic status an...
Methylphenidate (MPH) is a first line option in the psychopharmacologic treatment of adults with ... more Methylphenidate (MPH) is a first line option in the psychopharmacologic treatment of adults with Attention-Deficit/Hyperactivity Disorder (ADHD). However, there is a considerable proportion of adult patients who do not respond to treatment with MPH or discontinue drug therapy. Since effects of genetic variants in the response to MPH treatment might explain these negative outcomes, we conducted an electronic systematic search of MEDLINE-indexed literature looking for articles containing information about pharmacogenetics of ADHD in adults published until January, 2012. The keywords used were 'ADHD', 'Attention-Deficit/ Hyperactivity Disorder' and 'gene' in combination with methylphenidate, amphetamine or atomoxetine. Only 5 pharmacogenetic studies on adult ADHD met inclusion criteria. The results evidenced that most findings obtained so far are negative, and all studies focused on MPH response. There is only one positive result, for a polymorphism at the dopamine transporter gene (DAT1) gene. The current state of the art in adult ADHD implies that pharmacogenetic tests are far from routine clinical practice. However, the integration of these studies with neuroimaging and neuropsychological tests may help to understand mechanisms of drug action and the pathophysiology of ADHD.
European Archives of Psychiatry and Clinical Neuroscience, 2006
The aim of the present study is to verify if gender modifies the clinical, adaptative and psychol... more The aim of the present study is to verify if gender modifies the clinical, adaptative and psychological outcomes of adult attention-deficit/hyperactivity disorder (ADHD) subtypes. We evaluated 219 clinically referred adult patients. The interviews followed the DSM-IV criteria,using the K-SADS-E for ADHD and oppositional defiant disorder and SCID-IV for comorbidities. Regression models were used to analyze gender and subtype main effects and interactions in psychiatric outcomes. In the initial sample, 117 patients (53.5%) were of the combined subtype, 88 (40%) were inattentives and 14 (6.5%) hyperactives. There were no significant interactions between gender and subtype in any variable assessed. Men and women did not differ in the relative frequency of each subtype. Patients of the combined subtype in both genders presented a higher severity and increased rates of conduct and ODD disorders than inattentives. The main effects of gender and subtype in this sample are similar to those previously reported in other countries, suggesting the cross-cultural equivalence of the phenotype. The absence of significant interactions between gender and subtype suggests that, at least in clinical-based samples, DSM-IV adult ADHD subtypes present cross-gender validity.
IntroductionAttention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD),... more IntroductionAttention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD) are frequently co-occurring disorders in children and adolescents. However, their clinical status among adults is still under discussion. This study analyzes how the current clinical presentation of adult ADHD might be influenced by a lifetime history of CD and ODD.MethodsWe compared three groups of patients: ADHD without history of CD/ODD (n= 178), ADHD + history of ODD (n= 184), and ADHD + history of CD (n= 96).ResultsA history of CD (and to a lower extent ODD) is associated with a more severe and externalizing profile.ConclusionPast CD and ODD entail a significant negative mental health impact on persistent ADHD, reinforcing the importance of actively assessing the developmental history of adult ADHD patients.
The frequent comorbidity between attention-deficit hyperactivity disorder (ADHD) and bipolar diso... more The frequent comorbidity between attention-deficit hyperactivity disorder (ADHD) and bipolar disorder (BD) represents a challenge for disentangling specific impairments of each disorder in adulthood. Their functional impairments seem to be mediated by executive function deficits. However, little is known about the extent to which each executive function deficit might be disorder specific or explained by the comorbidity. The aim of the present study was to determine if comorbid BD could account for a significant share of executive function deficits when measured by the Wisconsin Card Sorting Test (WCST) in adults with ADHD. Adult patients with ADHD and healthy subjects were evaluated in the ADHD outpatient Program at the Hospital de Clínicas de Porto Alegre. Psychiatric diagnoses were based on DSM-IV criteria. WCST scores were compared by multivariate analysis of covariance among three groups: ADHD with BD (n = 51), ADHD without BD (n = 278), and healthy subjects (n = 91). When compared to patients without BD and healthy subjects, patients with ADHD and comorbid BD showed lower scores in total correct answers (p = 0.003); higher scores in total errors (p = 0.004) and non-perseverative errors (p = 0.002); and completed fewer categories (p = 0.009). Patients with ADHD without BD did not differ from healthy subjects. WCST impairments among patients with ADHD seem to be to a large extent attributable to comorbid BD. Although other executive function deficits (e.g., in the inhibitory control domain) have been demonstrated to accompany ADHD, the present findings suggest that set-shifting deficits are strongly related to comorbid BD.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2008
is a consultant for Novartis and serves on their speaker's bureau. He also speaks for McNeil Pedi... more is a consultant for Novartis and serves on their speaker's bureau. He also speaks for McNeil Pediatrics and receives research support from McNeil Pediatrics, Eli-Lilly, Novartis and Pfizer. Dr Rohde was on the speakers' bureau and/or acted as consultant for Eli-Lilly, Janssen-Cilag, and Novartis in the last three years. Currently, his only industry related activity is take part of the advisory board for Eli Lilly & Company. The ADHD Outpatient Program receives research support from the following pharmaceutical companies: Bristol
Ao Bau, meu co-orientador, pelo esforço, dedicação e persistência. Ao Eugênio e Salgado, pela ide... more Ao Bau, meu co-orientador, pelo esforço, dedicação e persistência. Ao Eugênio e Salgado, pela idealização do projeto, pelo convite inicial e pela amizade.
Resumo Os autores preconizam o ensino de Farmacologia Médica voltado à realidade de prescrição em... more Resumo Os autores preconizam o ensino de Farmacologia Médica voltado à realidade de prescrição em nosso meio, relatando experiências pedagógicas fundamentadas na solução de problemas. Dentre elas, que incluem solução de casos clínico-farmacológicos simulados, seminários de análise crítica da literatura original em Farmacologia aplicada e aulas expositivas, salienta-se a atividade prática da disciplina: preenchimento de fichas de avaliação da prescrição medicamentosa de pacientes internados no hospital-escola. No presente trabalho descrevem-se a metodologia dessa atividade e os resultados obtidos.
Transcriptomics and candidate gene/protein expression studies have indicated several biological p... more Transcriptomics and candidate gene/protein expression studies have indicated several biological processes modulated by methylphenidate (MPH), widely used in attention-deficit/hyperactivity disorder (ADHD) treatment. However, the lack of a differential proteomic profiling of MPH treatment limits the understanding of the most relevant mechanisms by which MPH exerts its pharmacological effects at the molecular level. Therefore, our aim is to investigate the MPH-induced proteomic alterations using an experimental design integrated with a pharmacogenomic analysis in a translational perspective. Proteomic analysis was performed using the cortices of Wistar-Kyoto rats, which were treated by gavage with MPH (2 mg/kg) or saline for two weeks (n = 6/group). After functional enrichment analysis of the differentially expressed proteins (DEP) in rats, the significant biological pathways were tested for association with MPH response in adults with ADHD (n = 189) using genome-wide data. Following ...
Although the identification of reliable predictors of methylphenidate response in adults with att... more Although the identification of reliable predictors of methylphenidate response in adults with attention-deficit/hyperactivity disorder (ADHD) is necessary to guide treatment decisions, very few data exist on this issue. Here, we assessed the predictors of clinical response to immediate-release methylphenidate hydrochloride (IR-MPH) in a naturalistic setting by analyzing the influence of demographic factors, severity, and a wide range of comorbid psychiatric disorders. Two hundred fifty adult patients with ADHD were evaluated and completed a short-term treatment with IR-MPH. Mental health diagnoses were based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria through the use of standard structured interviews. The Swanson, Nolan, and Pelham Rating Scale, version 4, adapted to adults was used to assess the severity of ADHD. In the linear regression model, only higher severity of ADHD was associated to a better IR-MPH response (b = 0.770; P G 0.001). Treatment of comorbidities in a subsample (n = 62) did not modify this pattern. Our findings suggest that in clinical settings, patients with more severe ADHD symptoms have a good response to treatment independently from the presence of mild or stabilized comorbidities and their treatments. For adults with ADHD, differently from other common psychiatric disorders such as depression and anxiety, higher severity is associated with better treatment response.
Conflict of interest: LAR was on the speakers' bureau and/or acted as consultant for Eli-Lilly, J... more Conflict of interest: LAR was on the speakers' bureau and/or acted as consultant for Eli-Lilly, Janssen-Cilag, Novartis and Shire in the last three years. He receives authorship royalties from Oxford Press and ArtMed. He also received travel awards (air tickets + hotel) for taking part of two child psychiatric meetings from Novartis and Janssen-Cilag in 2010. The ADHD and Juvenile Bipolar Disorder Outpatient 34 Programs chaired by him received unrestricted educational and research support from the following pharmaceutical companies in the last three years: Abbott, Eli-Lilly, Janssen-Cilag, Novartis, and Shire.
Objective: This study evaluated the hypothesis that methylphenidate immediate release (MPH-IR) tr... more Objective: This study evaluated the hypothesis that methylphenidate immediate release (MPH-IR) treatment would improve Default Mode Network (DMN) within-connectivity. Method: Resting-state functional connectivity of the main nodes of DMN was evaluated in a highly homogeneous sample of 18 drug-naive male adult participants with ADHD. Results: Comparing resting-state functional connectivity functional magnetic resonance imaging (R-fMRI) scans before and after MPH treatment focusing exclusively on within-DMN connectivity, we evidenced the strengthening of functional connectivity between two nodes of the DMN: posterior cingulate cortex (PCC) and left lateral parietal cortex (LLP). Conclusion: Our results contribute to the further understanding on how MPH affects functional connectivity within DMN of male adults with ADHD and corroborate the hypothesis of ADHD being a delayed neurodevelopmental disorder.
A considerable proportion of adults with attention-deficit/hyperactivity disorder (ADHD) do not r... more A considerable proportion of adults with attention-deficit/hyperactivity disorder (ADHD) do not respond to the treatment with methylphenidate. This scenario could be due to inherited interindividual differences that may alter pharmacologic treatment response. In this sense, in 2012 we conducted a systematic search on PUBMED-indexed literature for articles containing information about pharmacogenomics of ADHD in adults. Five studies were found on methylphenidate pharmacogenomics and the only significant association was reported by one particular study. However, this single association with the SLC6A3 gene was not replicated in two subsequent reports. In the present review, although we could not find additional pharmacogenomics studies, we discuss these up-to-date findings and suggest new approaches for this field. Additionally, using systeomic-oriented databases, we provide a broad picture of new possible candidate genes as well as potential gene–gene interactions to be investigated ...
Background: Previous studies have suggested that individuals with ADHD have high scores in novelt... more Background: Previous studies have suggested that individuals with ADHD have high scores in novelty seeking and harm avoidance. However, it is not known whether personality is associated with specific subtypes and dimensions of the disorder. The aim of this study is to test for associations between scores in the temperament and character inventory of C.R. Cloninger with adult ADHD subtypes and severity. Sampling and Methods: The diagnostic interviews of 296 adult ADHD patients followed the DSM-IV criteria. ADHD dimensions were evaluated with the SNAP-IV scores, and personality dimensions were assessed using the Temperament and Character Inventory. Results: The combined subtype (n = 168) was associated with higher scores in novelty seeking (p < 0.001) and lower scores in cooperativeness (p = 0.006) than the inattentive subtype (n = 128). Higher inattention scores were associated with decreased self-directedness (p < 0.001) and increased harm avoidance (p = 0.02), whereas higher ...
Most adults with attention-deficit/hyperactivity disorder (ADHD) are not recognized and remain un... more Most adults with attention-deficit/hyperactivity disorder (ADHD) are not recognized and remain untreated, although a large fraction of these individuals are diagnosed and treated for other comorbid mental disorders, such as major depressive disorder (MDD). The fact that MDD is one of the most commonly occurring mental disorders with high comorbidity with adult ADHD raises the question whether such comorbidity is associated with differences in the clinical picture of ADHD. Three hundred and twenty adult ADHD outpatients were evaluated. Diagnoses followed DSM-IV criteria. Interviews to evaluate ADHD and oppositional defiant disorder (ODD) were performed based on the Portuguese version of K-SADS-E. Psychiatric comorbidities were investigated using SCID-IV and MINI. Regression models were applied to test MDD association with clinical and demographic outcomes. Subjects presenting ADHD and MDD had a higher frequency of generalized anxiety disorder and social phobia and a lower frequency of substance dependence, grade repetition and school suspensions, when compared to subjects with ADHD without MDD. Furthermore, adults presenting ADHD and MDD reported higher demand for psychotherapy and pharmacological treatment prior to enrollment in the study when compared to ADHD subjects free of MDD. However, contrary to what could be expected based on these data, the presence of MDD was not associated with an earlier ADHD diagnosis. These results point to the need for research and medical education into an earlier and more efficient ADHD diagnosis in patients who search for mental health care.
Several lines of evidence suggest a relevant role for the dopamine transporter (DAT1) gene not on... more Several lines of evidence suggest a relevant role for the dopamine transporter (DAT1) gene not only as a susceptibility factor for attention-deficit hyperactivity disorder (ADHD), but also as a predictor of individual methylphenidate (MPH) response. Pharmacogenetic studies of MPH response in ADHD have mainly focused on the 40-bp variable number of tandem repeats (VNTR) in the 3&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; untranslated region (3&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-UTR) of DAT1. Most studies were performed in samples of children and conflicting findings were obtained. Only two studies have assessed 3&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-VNTR in samples of adults-one with positive and the other with negative findings. In the present study, we investigate three potentially relevant polymorphisms in DAT1 gene (-839 C &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt; T; Int8 VNTR and 3&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;-VNTR), and their possible role in therapeutic response to MPH treatment in a sample of 171 Brazilian adults with ADHD. The diagnostic procedures followed the DSM-IV criteria and the outcome measures were the scales Swanson, Nolan, and Pelham Rating scale version IV and the Clinical Global Impression-Severity Scale, applied at the beginning and after the 30th day of treatment. Drug response was assessed by both categorical and dimensional approaches. There was no effect of any DAT1 polymorphisms or haplotypes on MPH response. This is the second report demonstrating absence of differences in MPH response according to DAT1 genotypes in adults with ADHD. Although DAT protein is crucial for the effect of MPH, genetic variations in DAT1 gene probably do not have a significant clinical role in this sample of adults with ADHD.
Results from pharmacogenetic investigations of methylphenidate (MPH) response in patients with AD... more Results from pharmacogenetic investigations of methylphenidate (MPH) response in patients with ADHD are still inconsistent, especially among adults. This study investigates the role of genetic variants (SLC6A4, HTR1B, TPH2, DBH, DRD4, COMT, and SNAP25) in the response to MPH in a sample of 164 adults. Genes were chosen owing to previous evidence for an influence in ADHD susceptibility. No significant differences in allele or genotype frequencies between MPH responders and nonresponders were detected. In conclusion, our findings do not support an effect of these genes in the pharmacogenetics of MPH among adults with ADHD.
Objective: This study addresses if deficits in cognitive, attention, and inhibitory control perfo... more Objective: This study addresses if deficits in cognitive, attention, and inhibitory control performance in adults with ADHD are better explained by the disorder itself or by comorbid conditions. Method: Adult patients with ADHD (n = 352) and controls (n = 94) were evaluated in the ADHD program of a tertiary hospital. The diagnostic process for ADHD and comorbidities was based on Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) criteria. Stepwise regression analyses evaluated the effect of ADHD, demographics, and comorbidities on the scores from Wechsler Adult Intelligence Scale-Revised, Continuous Performance Test, and Stroop Color and Word Test.. Results: Patients with ADHD of both genders had worse performance on neuropsychological domains, even after adjustment for comorbidities. The presence of comorbid bipolar disorder and specific phobia are associated with more Stroop errors, whereas patients with generalized anxiety disorder present a longer execution ...
Since approximately 70% of adult patients with attention-deficit/hyperactivity disorder (ADHD) ha... more Since approximately 70% of adult patients with attention-deficit/hyperactivity disorder (ADHD) have at least one comorbid disorder, rating of impairment specifically attributable to ADHD is a hard task. Despite the evidence linking environmental adversities with negative outcomes in ADHD, life events measures have not been used to rate the disorder impairment. The present study tested for the first time the hypothesis that increased ADHD severity is associated with an increase in negative recent life events, independently of comorbidity status. The psychiatric diagnoses of 211 adult ADHD outpatients were based on DSM-IV criteria assessed through structured interviews (K-SADS-E for ADHD and ODD, MINI for ASPD and SCID-IV-R for other comorbidities). ADHD severity was evaluated with the Swanson, Nolan and Pelham rating scale (SNAP-IV) and recent life events with the Life Experience Survey. Higher SNAP-IV inattention and hyperactivity scores, female gender, lower socioeconomic status an...
Methylphenidate (MPH) is a first line option in the psychopharmacologic treatment of adults with ... more Methylphenidate (MPH) is a first line option in the psychopharmacologic treatment of adults with Attention-Deficit/Hyperactivity Disorder (ADHD). However, there is a considerable proportion of adult patients who do not respond to treatment with MPH or discontinue drug therapy. Since effects of genetic variants in the response to MPH treatment might explain these negative outcomes, we conducted an electronic systematic search of MEDLINE-indexed literature looking for articles containing information about pharmacogenetics of ADHD in adults published until January, 2012. The keywords used were 'ADHD', 'Attention-Deficit/ Hyperactivity Disorder' and 'gene' in combination with methylphenidate, amphetamine or atomoxetine. Only 5 pharmacogenetic studies on adult ADHD met inclusion criteria. The results evidenced that most findings obtained so far are negative, and all studies focused on MPH response. There is only one positive result, for a polymorphism at the dopamine transporter gene (DAT1) gene. The current state of the art in adult ADHD implies that pharmacogenetic tests are far from routine clinical practice. However, the integration of these studies with neuroimaging and neuropsychological tests may help to understand mechanisms of drug action and the pathophysiology of ADHD.
European Archives of Psychiatry and Clinical Neuroscience, 2006
The aim of the present study is to verify if gender modifies the clinical, adaptative and psychol... more The aim of the present study is to verify if gender modifies the clinical, adaptative and psychological outcomes of adult attention-deficit/hyperactivity disorder (ADHD) subtypes. We evaluated 219 clinically referred adult patients. The interviews followed the DSM-IV criteria,using the K-SADS-E for ADHD and oppositional defiant disorder and SCID-IV for comorbidities. Regression models were used to analyze gender and subtype main effects and interactions in psychiatric outcomes. In the initial sample, 117 patients (53.5%) were of the combined subtype, 88 (40%) were inattentives and 14 (6.5%) hyperactives. There were no significant interactions between gender and subtype in any variable assessed. Men and women did not differ in the relative frequency of each subtype. Patients of the combined subtype in both genders presented a higher severity and increased rates of conduct and ODD disorders than inattentives. The main effects of gender and subtype in this sample are similar to those previously reported in other countries, suggesting the cross-cultural equivalence of the phenotype. The absence of significant interactions between gender and subtype suggests that, at least in clinical-based samples, DSM-IV adult ADHD subtypes present cross-gender validity.
IntroductionAttention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD),... more IntroductionAttention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD) are frequently co-occurring disorders in children and adolescents. However, their clinical status among adults is still under discussion. This study analyzes how the current clinical presentation of adult ADHD might be influenced by a lifetime history of CD and ODD.MethodsWe compared three groups of patients: ADHD without history of CD/ODD (n= 178), ADHD + history of ODD (n= 184), and ADHD + history of CD (n= 96).ResultsA history of CD (and to a lower extent ODD) is associated with a more severe and externalizing profile.ConclusionPast CD and ODD entail a significant negative mental health impact on persistent ADHD, reinforcing the importance of actively assessing the developmental history of adult ADHD patients.
The frequent comorbidity between attention-deficit hyperactivity disorder (ADHD) and bipolar diso... more The frequent comorbidity between attention-deficit hyperactivity disorder (ADHD) and bipolar disorder (BD) represents a challenge for disentangling specific impairments of each disorder in adulthood. Their functional impairments seem to be mediated by executive function deficits. However, little is known about the extent to which each executive function deficit might be disorder specific or explained by the comorbidity. The aim of the present study was to determine if comorbid BD could account for a significant share of executive function deficits when measured by the Wisconsin Card Sorting Test (WCST) in adults with ADHD. Adult patients with ADHD and healthy subjects were evaluated in the ADHD outpatient Program at the Hospital de Clínicas de Porto Alegre. Psychiatric diagnoses were based on DSM-IV criteria. WCST scores were compared by multivariate analysis of covariance among three groups: ADHD with BD (n = 51), ADHD without BD (n = 278), and healthy subjects (n = 91). When compared to patients without BD and healthy subjects, patients with ADHD and comorbid BD showed lower scores in total correct answers (p = 0.003); higher scores in total errors (p = 0.004) and non-perseverative errors (p = 0.002); and completed fewer categories (p = 0.009). Patients with ADHD without BD did not differ from healthy subjects. WCST impairments among patients with ADHD seem to be to a large extent attributable to comorbid BD. Although other executive function deficits (e.g., in the inhibitory control domain) have been demonstrated to accompany ADHD, the present findings suggest that set-shifting deficits are strongly related to comorbid BD.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2008
is a consultant for Novartis and serves on their speaker's bureau. He also speaks for McNeil Pedi... more is a consultant for Novartis and serves on their speaker's bureau. He also speaks for McNeil Pediatrics and receives research support from McNeil Pediatrics, Eli-Lilly, Novartis and Pfizer. Dr Rohde was on the speakers' bureau and/or acted as consultant for Eli-Lilly, Janssen-Cilag, and Novartis in the last three years. Currently, his only industry related activity is take part of the advisory board for Eli Lilly & Company. The ADHD Outpatient Program receives research support from the following pharmaceutical companies: Bristol
Ao Bau, meu co-orientador, pelo esforço, dedicação e persistência. Ao Eugênio e Salgado, pela ide... more Ao Bau, meu co-orientador, pelo esforço, dedicação e persistência. Ao Eugênio e Salgado, pela idealização do projeto, pelo convite inicial e pela amizade.
Resumo Os autores preconizam o ensino de Farmacologia Médica voltado à realidade de prescrição em... more Resumo Os autores preconizam o ensino de Farmacologia Médica voltado à realidade de prescrição em nosso meio, relatando experiências pedagógicas fundamentadas na solução de problemas. Dentre elas, que incluem solução de casos clínico-farmacológicos simulados, seminários de análise crítica da literatura original em Farmacologia aplicada e aulas expositivas, salienta-se a atividade prática da disciplina: preenchimento de fichas de avaliação da prescrição medicamentosa de pacientes internados no hospital-escola. No presente trabalho descrevem-se a metodologia dessa atividade e os resultados obtidos.
Uploads
Papers by Marcelo Victor