Abstract 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.
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.
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.
Since DSM-IV criteria for attention-deficit/hyperactivity disorder (ADHD) require that some symptoms causing impairment must be present before 7 years of age, clinicians are faced with a diagnostic ...and treatment dilemma on how to proceed with late-onset ADHD patients. We aimed to compare the response to methylphenidate between a group of patients fulfilling all DSM-IV ADHD criteria (full ADHD diagnosis) and a group of patients fulfilling all DSM-IV criteria except the age-at-onset criterion (late-onset ADHD).
We evaluated 180 children and adolescents (4-17 years old) and 111 adults from our ADHD unit. All ADHD diagnoses were assessed using DSM-IV criteria. Methylphenidate was administered twice daily (8 a.m. and noon), but an extra dose was allowed between 5 and 6 p.m. for children and adolescents needing extra coverage in the evening. The minimum dose was 0.30 mg/kg/day. Response to treatment was assessed in methylphenidatenaive subjects using the Swanson, Nolan, and Pelham Scale-version IV (SNAP-IV) at baseline and after 1 month of treatment. Data were collected from January 2000 to January 2006.
In both samples, subjects with the full ADHD diagnosis did not have a better response to methylphenidate at doses around 0.5 mg/kg/day than the late-onset ADHD subjects. In fact, adults with late-onset ADHD had a better response to methylphenidate than adults with the full diagnosis, even after adjustment for confounders (baseline SNAP-IV total score and ADHD types) (children and adolescents: F = 0.865, p = .354; adults: F = 5.760, p = .018).
These results concur with recent literature questioning the validity of the DSM-IV age-at-onset criterion for the diagnosis of ADHD and suggest that clinicians should consider implementing methylphenidate treatment for subjects with late-onset ADHD.
Abstract 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 ( n 422) 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 (OR 4.2) and substance dependence (OR 6.5), 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.
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.
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.
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.
Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe ...(requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19.
We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 death to 7 discharged from hospital) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021.
Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 20%), sarilumab 200 mg (n=159 38%), or sarilumab 400 mg (n=173 42%). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days 95% CI 9·0 to 15·0) and sarilumab 200 mg (10·0 days 9·0 to 12·0; hazard ratio HR 1·03 95% CI 0·75 to 1·40; log-rank p=0·96) or sarilumab 400 mg (10·0 days 9·0 to 13·0; HR 1·14 95% CI 0·84 to 1·54; log-rank p=0·34), or in proportions of patients alive (77 92% of 84 patients in the placebo group; 143 90% of 159 patients in the sarilumab 200 mg group; difference -1·7 -9·3 to 5·8; p=0·63 vs placebo; and 159 92% of 173 patients in the sarilumab 400 mg group; difference 0·2 -6·9 to 7·4; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% 95% CI -7·7 to 25·5; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group.
This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19.
Sanofi and Regeneron Pharmaceuticals.
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