Feasibility trial of the dialectical behavior therapy skills training group as add-on treatment for adults with attention-deficit/hyperactivity disorder.

OBJECTIVE: Our aim was to explore the feasibility, and efficacy of a Dialectical Behavior Therapy Skill Training Group (DBT-ST) as an add-on treatment for adult attention-deficit/hyperactivity disorder (ADHD) in Latin America. METHOD: Adults with ADHD (n = 31) with stable medication treatment for ADHD and residual symptoms (ASRS > 20) were randomly assigned to DBT-ST (n = 16) or treatment as usual (TaU; n = 15) for 12 weeks. Feasibility was accessed by attendance and completion rates at 12 weeks. Efficacy outcomes were measured with the ASRS, and performed at 0, 6, 12, and 16 weeks. RESULTS: The DBT-ST protocol had 81.25% completion rate, with a mean attendance of 87.25% of the sessions. No significant interactions between group and time were detected for outcome measures. DISCUSSION: The DBT-ST was feasible as add-on treatment for adult patients with ADHD in Latin America. Replicating previous findings, DBT-ST has shown no significantly higher improvement in ADHD symptoms in comparison with TaU. Registered at the Clinical Trials database (NCT03326427).

Attention-deficit hyperactivity disorder in ancient Greece: The Obtuse Man of Theophrastus.

We present an ancient Greek description written by the philosopher Theophrastus in his classic book ' Characters' comparable with modern attention-deficit hyperactivity disorder. The arguments are based in one chapter of this book-The Obtuse Man-presenting features of a character closely resembling the modern description of attention-deficit hyperactivity disorder. In a free comparative exercise, we compared Theophrastus descriptions with modern Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) attention-deficit hyperactivity disorder symptoms. The sentences describing The Obtuse Man written by Theophrastus are similar to several symptoms of attention-deficit hyperactivity disorder and he would probably be currently diagnosed with this disorder as an adult. To our knowledge, this is the oldest description compatible with the current conception of attention-deficit hyperactivity disorder in adults in the Western literature. Differently than the moralistic view of ancient Greece regarding those symptoms, the medical attention-deficit hyperactivity disorder conception may be advantageous to patients since it might reduce prejudice and allow individuals to seek treatment.

Severity but not comorbidities predicts response to methylphenidate in adults with attention-deficit/hyperactivity disorder: results from a naturalistic study.

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 < 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.

Could comorbid bipolar disorder account for a significant share of executive function deficits in adults with attention-deficit hyperactivity disorder?

OBJECTIVE: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

Theophrastus's Anaisthetos Transdiagnostic Presentation: comment on Pehlivanidis and Papanikolaou (2022).

We were pleased to read Pehlivanidis and Papanikolaou's article1 and see that more colleagues are recognizing Theophrastus' text as the first description of Attention Deficit Hyperactivity Disorder (ADHD).2 We agree with the authors' perspective that Theophrastus' description may suggest the presence of more than one neurodevelopmental disorder. In fact, Theophrastus' description aligns with the shared clinical symptoms and underlying neurodevelopmental mechanisms of ADHD and Social Pragmatic Communication Disorder (SPCD). It is fascinating that a description from over 2000 years ago already presented prototypical individual transdiagnostic aspects that are compatible with a modern biological view of psychiatry. Indeed, it is not unexpected that heritable traits with clear biological underpinnings should have been perceived since the dawn of medicine. A significant leap forward in the development of this field came a few decades ago when Clements (1966)3 published a NIH-sponsored project entitled 'Minimal Brain Dysfunction in Children.' This seminal work prepared the terrain for the ongoing understanding of the grouping of signs, symptoms, and biological factors observed across various neurodevelopmental disorders. This grouping can be present in different spectrums, proportions, and nuances, including children and adults with some impairments that are not solely explained by their cognitive abilities. Thus, the characterization of 'The Obtuse Man' by Theophrastus could be considered a prototypical case of this more integrated and less fragmented view of what we call neurodevelopmental disorders.

Evaluation of the effectiveness of the FOCUS ADHD App in monitoring adults with attention-deficit/hyperactivity disorder.

BACKGROUND: The current investigation assessed a) the performance of the FOCUS ADHD mobile health application (App) in increasing pharmacological treatment adherence and improving patients' knowledge of attention-deficit/hyperactivity disorder (ADHD) and b) the impact of implementing a financial incentive for using the App (i.e., a discount on medication). METHODS: In a randomized, blind, parallel-group clinical trial, 73 adults diagnosed with ADHD were allocated into three groups for 3 months: a) Pharmacological treatment as usual (TAU); b) TAU and the App (App Group); and c) TAU and the App + a commercial discount on the purchase of medication prescribed for ADHD treatment (App + Discount Group). RESULTS: There was no significant difference in mean treatment adherence between groups, assessed as a medication possession ratio (MPR). However, the App + Discount Group exhibited greater medication intake registrations compared with the App Group during the initial phase of the trial. The financial discount also produced a 100% App adoption rate. App use did not increase ADHD knowledge, though knowledge scores were high at baseline. The usability and quality of the App were rated favorably. CONCLUSIONS: The FOCUS ADHD App achieved a high adoption rate and positive evaluations by users. Use of the App did not increase adherence to treatment as measured by MPR, but, for App users, the addition of a financial incentive to use the App produced an increase in treatment adherence in terms of medication intake registrations. The present results offer encouraging data for combining incentives with mobile digital health solutions to positively impact treatment adherence in ADHD.

No significant association between genetic variants in 7 candidate genes and response to methylphenidate treatment in adult patients with ADHD.

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.

The role of a lifetime history of oppositional defiant and conduct disorders in adults with ADHD: implications for clinical practice.

INTRODUCTION: Attention-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. METHODS: We 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). RESULTS: A history of CD (and to a lower extent ODD) is associated with a more severe and externalizing profile. CONCLUSION: Past 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.

Adrenergic α2A receptor gene is not associated with methylphenidate response in adults with ADHD.

Adrenergic α2A receptor gene (ADRA2A) is one of the most promising candidate genes for ADHD pharmacogenetics. Thus far, three studies have investigated the association between the ADRA2A -1291 C>G polymorphism and the therapeutic response to methylphenidate (MPH) in children with ADHD, all of them with positive results. The aim of this study is to investigate, for the first time, the association between three ADRA2A polymorphisms (-1291 C>G, -262 G>A, and 1780 C>T) and the response to MPH in adults with ADHD. The sample comprises 165 Brazilians of European descent evaluated in the adult ADHD outpatient clinic of the Hospital de Clínicas de Porto Alegre. The diagnostic procedures followed the DSM-IV criteria. Drug response was assessed by both categorical and dimensional approaches, through 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. We found no evidence of association between the three ADRA2A polymorphisms and the therapeutic response to MPH treatment. Our findings do not support a significant role for the ADRA2A gene in ADHD pharmacogenetics, at least among adult patients.

Response to methylphenidate is not influenced by DAT1 polymorphisms in a sample of Brazilian adult patients with ADHD.

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' untranslated region (3'-UTR) of DAT1. Most studies were performed in samples of children and conflicting findings were obtained. Only two studies have assessed 3'-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 > T; Int8 VNTR and 3'-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.

Inattention and hyperactivity dimensions of ADHD are associated with different personality profiles.

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 hyperactivity/impulsivity scores correlated positively with novelty seeking (p<0.001) and persistence (p=0.03). CONCLUSIONS: These findings suggest that personality dimensions are strongly correlated with ADHD subtypes and severity dimensions, pointing to the need for studies evaluating the mechanisms behind this association.

Integrative proteomics and pharmacogenomics analysis of methylphenidate treatment response.

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 MPH treatment in rats, 98 DEPs were found (P < 0.05 and FC < -1.0 or > 1.0). The functional enrichment analysis of the DEPs revealed 18 significant biological pathways (gene-sets) modulated by MPH, including some with recognized biological plausibility, such as those related to synaptic transmission. The pharmacogenomic analysis in the clinical sample evaluating these pathways revealed nominal associations for gene-sets related to neurotransmitter release and GABA transmission. Our results, which integrate proteomics and pharmacogenomics, revealed putative molecular effects of MPH on several biological processes, including oxidative stress, cellular respiration, and metabolism, and extended the results involving synaptic transmission pathways to a clinical sample. These findings shed light on the molecular signatures of MPH effects and possible biological sources of treatment response variability.

The impact of individual and methodological factors in the variability of response to methylphenidate in ADHD pharmacogenetic studies from four different continents.

Several studies have evaluated the association between individual polymorphisms and response to methylphenidate (MPH) in subjects with attention-deficit/hyperactivity disorder (ADHD). There are few replication studies for each polymorphism of interest and results are sometimes inconsistent in this field. Although data collection from multiple international sites would allow large sample sizes, this approach has been criticized for introducing sampling variability due to differences in ethnicity and methodology between studies. To examine these issues, we aggregated nine pharmacogenetic studies from four different continents and conducted a two stage analysis: (a) we evaluated the role of methodological aspects in the variability of ADHD symptom improvement between studies using meta-regression analysis; (b) we assessed the role of individual characteristics of the subjects in the variability of ADHD symptoms improvement using multivariate regression analysis in the same data sets. At the study level, from five evaluated factors, only the design of the study (open studies vs. randomized controlled trials) was significantly associated with heterogeneity of results (P = 0.001). At the individual level, age (P < 0.001), comorbid oppositional defiant disorder (P < 0.001), and pre-treatment scores (P < 0.001) were associated with change of ADHD scores with treatment in the final multivariate model. Our results suggest that joint analyses of pharmacogenetic studies are feasible and promising, since fixed variables, such as the site where the study was conducted, were not related to results. Nevertheless, stratified analyses according to the design of the study must be preferentially conducted and the role of individual factors such as demographic data and comorbid profile as confounders should be assessed.

The role of comorbid major depressive disorder in the clinical presentation of adult ADHD.

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.

Should we keep on? Looking into pharmacogenomics of ADHD in adulthood from a different perspective.

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 in pharmacogenomics of persistent ADHD.

Pharmacogenetics of response to methylphenidate in adult patients with Attention-Deficit/Hyperactivity Disorder (ADHD): a systematic review.

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.

Cognitive deficits in adults with ADHD go beyond comorbidity effects.

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 time in Stroop. CONCLUSION: Neuropsychological deficits in adults with ADHD go beyond comorbidity. Specific comorbid disorders may influence the neuropsychological functioning in adults with ADHD.

Does age of onset of impairment impact on neuropsychological and personality features of adult ADHD?

The consideration of age of onset of impairment as part of the ADHD diagnosis is controversial and has been a revisited issue with the emergence of the new classifications in Psychiatry. The aim of this study is to compare patients with early and late onset of ADHD impairment in terms of neuropsychological and personality characteristics. Adult patients with ADHD (n = 415) were evaluated in the ADHD outpatient program at Hospital de Clínicas de Porto Alegre, Brazil. The diagnostic process for ADHD and comorbidities was based on DSM-IV criteria. The comparison between the two ages of onset groups (before 7; n = 209 or from 7 to 12 years; n = 206) was performed with ANOVA, followed by Stepwise forward regression analyses to restrict the number of comparisons and access the possible effect of multiple confounders. Patients with early onset ADHD present higher scores in novelty seeking in both analyses (respectively P = 0.016 and P = 0.002), but similar cognitive and attention features as compared with the late onset group. These data add to previous evidence that despite a more externalizing profile of early onset ADHD, the overall performance is similar reinforcing the need for awareness and inclusion of the late onset group in DSM-V diagnostic criteria.

Smoking and ADHD: an evaluation of self medication and behavioral disinhibition models based on comorbidity and personality patterns.

OBJECTIVE: The prevalence of smoking is significantly increased among adults with Attention-Deficit/Hyperactivity Disorder (ADHD), and this association has a significant impact in both disorders, ascribed to either self-medication or behavioral disinhibition hypotheses. However, little is known about clinical variables associated with cigarette smoking among patients with ADHD. The present study evaluates comorbidity, demographic and personality profiles of patients with ADHD in relation to smoking status. METHODS: Patients (n422) were evaluated in the adult ADHD outpatient clinic of Hospital de Clínicas de Porto Alegre. Diagnoses were based on DSM-IV criteria and interviews were performed with Portuguese version of K-SADS-E for ADHD and Oppositional-Defiant Disorder. Axis I psychiatric comorbidities were evaluated with the SCID-I and smoking behavior with Fagerström Test for Nicotine Dependence (FTND). Personality was evaluated with Cloninger's Temperament and Character Inventory (TCI). RESULTS: The presence of smoking was strongly associated with externalizing characteristics as antisocial personality disorder (OR4.2) and substance dependence (OR6.5), but not with internalizing disorders. Moreover, smoking was associated with higher novelty seeking and lower harm avoidance scores. CONCLUSIONS: Smoking initiation among patients with ADHD is consistent with a behavioral disinhibition profile beyond the possible role of self-medication in smoking persistence. Smoking in these patients is strongly associated with externalizing comorbid disorders.