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A 14-month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal Treatment Study of Children with ADHD.

BACKGROUND: Previous studies have demonstrated the short-term efficacy of pharmacotherapy and behavior therapy for attention-deficit/hyperactivity disorder (ADHD), but no longer-term (i.e., >4 months) investigations have compared these 2 treatments or their combination. METHODS: A group of 579 children with ADHD Combined Type, aged 7 to 9.9 years, were assigned to 14 months of medication management (titration followed by monthly visits); intensive behavioral treatment (parent, school, and child components, with therapist involvement gradually reduced over time); the two combined; or standard community care (treatments by community providers). Outcomes were assessed in multiple domains before and during treatment and at treatment end point (with the combined treatment and medication management groups continuing medication at all assessment points). Data were analyzed through intent-to-treat random-effects regression procedures. RESULTS: All 4 groups showed sizable reductions in symptoms over time, with significant differences among them in degrees of change. For most ADHD symptoms, children in the combined treatment and medication management groups showed significantly greater improvement than those given intensive behavioral treatment and community care. Combined and medication management treatments did not differ significantly on any direct comparisons, but in several instances (oppositional/aggressive symptoms, internalizing symptoms, teacher-rated social skills, parent-child relations, and reading achievement) combined treatment proved superior to intensive behavioral treatment and/or community care while medication management did not. Study medication strategies were superior to community care treatments, despite the fact that two thirds of community-treated subjects received medication during the study period. CONCLUSIONS: For ADHD symptoms, our carefully crafted medication management was superior to behavioral treatment and to routine community care that included medication. Our combined treatment did not yield significantly greater benefits than medication management for core ADHD symptoms, but may have provided modest advantages for non-ADHD symptom and positive functioning outcomes.

Anxiety Disorders↗

ADHD as a risk factor for incident unprovoked seizures and epilepsy in children.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) occurs more frequently than expected in prevalent cohorts with epilepsy. The association has been attributed to the epilepsy or its treatment, although it is impossible to determine in previous studies which condition occurs first. OBJECTIVES: To conduct a population-based case-control study of all newly diagnosed unprovoked seizures among Icelandic children younger than 16 years to address the question of time order. DESIGN: Children with seizures were matched to the next 2 same-sex births from the population registry. The Diagnostic Interview Schedule for Children was used to make a DSM-IV diagnosis of ADHD in a standardized fashion among cases and controls aged 3 to 16 years. RESULTS: A history of ADHD was 2.5-fold more common among children with newly diagnosed seizures than among control subjects (95% confidence interval [CI], 1.1-5.5). The association was restricted to ADHD predominantly inattentive type (odds ratio [OR], 3.7; 95% CI, 1.1-12.8), not ADHD predominantly hyperactive-impulsive type (OR, 1.8; 95% CI, 0.6-5.7) or ADHD combined type (OR, 2.5; 95% CI, 0.3-18.3). Seizure type, etiology, sex, or seizure frequency at diagnosis (1 or >1) did not affect findings. CONCLUSION: Attention-deficit/hyperactivity disorder occurs more often than expected before unprovoked seizures, suggesting a common antecedent for both conditions.

Attention Deficit Disorder with Hyperactivity↗

No association between catechol-O-methyltransferase (COMT) gene polymorphism and attention deficit hyperactivity disorder (ADHD) in an Irish sample.

Pharmacological and biochemical studies have indicated that imbalances in dopaminergic transmission may contribute to the aetiology of attention deficit hyperactivity disorder (ADHD). The enzyme catechol-O-methyltransferase (COMT) plays a key role in the degradation of catecholamines such as dopamine, L-DOPA, adrenaline, and noradrenaline and therefore could be considered as a candidate locus for ADHD susceptibility. We hypothesised that a proportion of the genetic susceptibility to ADHD may be a consequence of dopamine depletion in the synapses due to high-level activity of the COMT gene (allele 1). Using the haplotype-based haplotype relative risk method and 94 affected children and their parents genotyped for COMT alleles, we found no significant differences in the frequency of the transmitted and nontransmitted alleles to ADHD cases from their parents. The absence of association between COMT alleles and ADHD indicated that this locus does not play a significant role or at least a role independent of other genes, in predisposing to ADHD in the Irish population.

Adolescent↗

QTL association analysis of the DRD4 exon 3 VNTR polymorphism in a population sample of children screened with a parent rating scale for ADHD symptoms.

Current developments in molecular genetics have led to a rapid increase in research aimed at the identification of genetic variation that influences complex human phenotypes. One phenotype that has aroused a great deal of interest is the behavioral trait hyperactivity and the related clinical disorder attention-deficit hyperactivity disorder (ADHD). The driving force behind the molecular genetic research in this area is the overwhelming evidence from quantitative genetic studies that show high heritablility (h(2) = 0.7-0.9) for the behaviors characterizing the diagnosis of ADHD, whether the disorder is viewed as a categorical entity or a continuous trait. To date, molecular studies have aimed at identifying susceptibility genes for ADHD, defined using operational diagnostic criteria, and have focused on variation within genes that regulate dopamine neurotransmission. Several studies report ADHD to be associated with the 7-repeat allele of a 48 bp repeat polymorphism (DRD4-7) in exon 3 of the dopamine D4 receptor gene (DRD4). In this study, we take a dimensional perspective of ADHD and examine the relationship of this DRD4 polymorphism in a sample of children selected from the general population on the basis of high and low scores on the five ADHD items of the Strengths and Difficulties Questionnaire (SDQ) as rated by their parents. We found a significant relationship between DRD4-7 and high-scoring individuals [chi-square = 8.63; P = 0.003; OR = 2.09 (95% CI 1.24 < OR < 3.54), F-statistic = 7.245; P = 0.008].

Adolescent↗

Gene for the serotonin transporter and ADHD: no association with two functional polymorphisms.

Evidence from both human and animal studies implicates the serotonergic system in the development of attention-deficit hyperactivity disorder (ADHD) including positive association studies for several key serotonergic genes. The serotonin transporter (HTT) regulates the availability of serotonin by reuptake of the neurotransmitter from the synaptic cleft. Several studies have reported an association of this gene to ADHD, specifically the long variant of a common insertion/deletion polymorphism located in the promoter of this gene that results in increased transcription and higher HTT expression. An additional study found no evidence for an association with this polymorphism. Recently, an A/G single nucleotide polymorphism (SNP) was found within the promoter polymorphism with functional studies indicating that the long variant containing the G allele at this site behaves like the short variant. This previously unidentified functional change may have confounded earlier association studies. We investigated the relationship of several variants to ADHD: the promoter polymorphisms, SNP in the 3' untranslated region (3'UTR) with a reported association to ADHD and a rare, non-synonymous coding SNP. These polymorphisms were genotyped in 209 ADHD families identified through an affected proband. We did not find evidence for an association of these polymorphisms, or haplotypes of these polymorphisms, to ADHD in this sample.

Adolescent↗

A family-based study of Indian subjects from Kolkata reveals allelic association of the serotonin transporter intron-2 (STin2) polymorphism and attention-deficit-hyperactivity disorder (ADHD).

Serotonin transporter (SLC6A4) polymorphisms are variously implicated in mediating susceptibility to attention-deficit-hyperactivity disorder (ADHD), a highly heritable and heterogeneous disorder with onset in childhood. Since there has been no survey in this regard from India, a sample of 56 ADHD cases and 174 healthy individuals from Kolkata were genotyped for the SLC6A4 promoter (5-HTTLPR) and intron-2 (STin2) polymorphisms. We report that the observed distribution of allele frequencies is consonant with that expected as per Hardy-Weinberg equilibrium proportions. Pair-wise combination of alleles comprising the 5-HTTLPR and STin2 polymorphic systems exhibit significant (chi(2) = 14.74, df = 1; P = 0.0001) linkage disequilibrium of low magnitude (D' = 0.269). The estimates of haplotype-based haplotype relative risk (HHRR) (chi(2) = 4.92, P = 0.027; RR = 1.47; 95% CI = 1.01-2.13) and transmission disequilibrium test (TDT) statistics (chi(2) = 7.00, P = 0.008; OR = 3.00; 95% CI = 1.53-5.90) using a family-based study design, indicate significant preferential transmission of the STin2.12 (A12) allele to ADHD cases. Maternal inheritance of the A12 allele is significant in terms of the HHRR (chi(2) = 6.53, P = 0.011; RR = 2.00; 95% CI = 1.08-3.72) and TDT (chi(2) = 8.07, P = 0.005; OR = 6.50; 95% CI = 1.76-23.98) suggesting a novel role for epigenetic mechanisms in the etiology of ADHD. Similar analyses yielded no evidence of association between the 5-HTTLPR polymorphism and ADHD. Studies including additional polymorphic markers, ADHD subjects and other ethnic groups are warranted to further substantiate the present findings.

Adult↗

Development of a statistical approach to classifying treatment response in individual children with ADHD.

The use of cognitive tests as measures of treatment response in individual children with ADHD has not been adequately evaluated or commonly applied by clinicians. This is most likely due to a lack of suitable assessment tasks as well as clinicians' limited awareness of the appropriate statistical techniques for analysing cognitive change in individuals. This study investigated the application of statistical decision rules to the cognitive and behavioural measures of individual children with ADHD in order to classify a significant, positive response to medication. The previously reported data of 14 children with ADHD (combined type; ADHD-CT) were re-analysed to investigate changes in function following a low- and high-dose of stimulant medication (2.5 mg and 7.5 mg dexamphetamine, respectively). The performances of 14 age-, gender- and IQ-matched controls was also analysed to provide an estimate of the false-positive classification rate. Overall, the decision rule yielded a high sensitivity and high specificity to treatment response. In the high-dose condition, 71% of children with ADHD demonstrated improvements in both cognitive and behavioural function. This study demonstrates an evidence-based approach to evaluating concurrent cognitive and behavioural improvement in individual children with ADHD following treatment with stimulant medication.

Attention Deficit Disorder with Hyperactivity↗

Treating adolescent girls and women with ADHD: gender-specific issues.

Attention deficit hyperactivity disorder (ADHD), commonly diagnosed in males, is often a "hidden disorder" in girls and women. This lack of recognition can be partially explained because the symptoms are less overt in females. In addition, coexisting disorders in females are often different from those seen in males who have ADHD. Higher rates of anxiety, mood, and substance disorders, as well as learning disabilities, often complicate the picture. Thus, clinicians are challenged with disentangling the symptoms of ADHD from symptoms of these coexisting conditions. In addition, fluctuating hormone levels may affect ADHD symptoms and treatment in females. Only with gender-sensitive diagnosis and treatment will the public health concern posed by the underdiagnosis of ADHD in females be addressed. This case report of a 23-year-old female illustrates the specific difficulties with the gender-sensitive aspects of the diagnosis and treatment of ADHD in females.

Adolescent↗

Attention, play, and social behavior in ADHD preschoolers.

We investigated attention, play and nonplay behavior in preschool children with attention deficit hyperactivity disorder (ADHD) and a matched control group of non-ADHD children. Forty 4- to 5-year-old children (20 ADHD and 20 matched control) participated. Across a 6-week-period, children's social and play interactions as well as nonplay behaviors were videotaped in the classroom. Videotape recordings were analyzed for the level of attention, cognitive play, and social participation. In addition, children's level of attention and cooperative behavior were observed during two group activities. Findings indicated that ADHD, relative to non-ADHD, children engaged in less overall play and greater functional or sensorimotor play. ADHD children also engaged in more transitional behavior, were less competent with peers, and were less attentive and cooperative during group activities.

Attention↗

Inattentive and noninattentive ADHD children: do they constitute a unitary group?

Teacher-rated ADHD and normal control children were administered a continuous performance test (CPT), and were then further subdivided based upon the presence or absence of objectively assessed attentional deficits. In addition, children were assessed using several measures of cognitive and behavioral functioning. Attentional deficits were significantly more prevalent among the ADHD group, but about half of the ADHD children showed no evidence of objectively assessed attentional dysfunction. Further group analyses indicated that ADHD children with objectively assessed attentional dysfunction appeared cognitively impaired, while ADHD children without objective evidence of attentional dysfunction had more conduct problems. CPT inattention was not related to the presence of cognitive impairments or conduct problems in the control group. These data must be considered preliminary because teacher ratings were the only source of diagnosis and a single measure of inattention was used. However, they suggest that two subtypes of ADHD children can be identified, one characterized by inattention and learning problems, and the other by conduct problems.

Achievement↗

Assessing methylphenidate preference in ADHD patients using a choice procedure.

RATIONALE: Methylphenidate (MPH) is widely used in the treatment of attention deficit hyperactivity disorder (ADHD) and is associated with positive clinical effects across a wide range of domains. Despite the clinical effectiveness of MPH, concern has arisen with respect to its abuse potential. OBJECTIVES: To assess MPH preference in adults diagnosed with ADHD using a choice procedure and to evaluate the relationship among drug preference, therapeutic efficacy, and abuse potential in a clinical sample. METHODS: Participants were ten volunteers (ages 18-22 years) with ADHD who were receiving MPH treatment. Preference was assessed using a double-blind choice procedure with four sampling sessions wherein subjects received either placebo or MPH and eight choice sessions when they chose either capsule or no capsules. RESULTS: Overall, MPH was chosen significantly more often than placebo (chi2=52.5; P<0.001) and participants were equally separated into groups of those who chose MPH reliably (MPH choosers) and those who did not (MPH non-choosers). MPH decreased ADHD symptoms and resulted in lower ratings of stimulant effects among MPH choosers. MPH choosers also reported higher levels of baseline ADHD symptoms. CONCLUSIONS: Despite higher preference of MPH than placebo in this clinical sample, other measures of abuse potential were not elevated, and MPH choosers were more symptomatic than non-choosers. As such, MPH preference in ADHD populations likely reflects therapeutic efficacy rather than abuse potential. Future work should examine MPH choice in diagnosed and non-diagnosed populations to further explore the role of clinical efficacy in the preference of this stimulant drug.

Adolescent↗

Prevalence of attention deficit-/hyperactivity disorder (ADHD) and comorbid disorders in young male prison inmates.

OBJECTIVE: This study was performed to evaluate the prevalence of ADHD as well as comorbid conditions among young male prison inmates. METHOD: We investigated 129 prison inmates (mean age+/-SE: 19.2+/-2.0 years) and 54 healthy male control subjects (mean age+/-SE: 22.2+/-3.12 years) for the presence of adult ADHD using the Wender Utah Rating Scale (WURS), the Eysenck Impulsivity Questionnaire (EIQ), the diagnostic criteria for ADHD according to DSM-IV and ICD-10-research criteria and the Utah criteria for adult ADHD. In order to determine comorbid personality disorders we applied the International Personality Disorder Examination (IPDE). Externalization (ED) and Internalization Disorders (ID) were evaluated by means of the Achenbach Scales. Alcoholism (ALC) was examined via the Alcohol Use Disorder Test (AUDIT) and substance use disorder (SUD) has been investigated with the Structured Clinical Interview for DSM-IV (SCID). RESULTS: The overall prevalence of ADHD according to DSM-IV was 45%. The prevalence of disturbance of activity and attention (DAA) and hyperkinetic conduct disorder (HCD) via the ICD-10 research criteria was 21.7%. Sole DAA without any comorbid condition could be detected in one case. The most common diagnostic combinations were DAA/HCD and SUD/ALC (89% of all DAA/HCD cases). CONCLUSION: The prevalence of DAA/HCD or ADHD in young adult prison inmates is significantly elevated when compared to nondelinquent controls. Generally the population of young adult male prison inmates exhibits a considerable psychiatric morbidity. Of the total sample, 64% suffered from at least 2 disorders. Only 8.5% had no psychiatric diagnoses. This indicates the urgent need for more psychiatric expertise in young offender facilities.

Adolescent↗

Oculomotor inhibition in children with and without attention-deficit hyperactivity disorder (ADHD).

The aim of the present study was to distinguish between a general deficit in oculomotor control and a deficit restricted to inhibitory functions in children with attention deficit hyperactivity disorder (ADHD). In addition, we were interested in differentiating between a general inhibition deficit and deficient subfunctions of inhibition. We used a prosaccade task to measure general oculomotor abilities in 22 children with ADHD and in age- and gender-matched healthy controls. A fixation, an antisaccade and a countermanding saccade task were used to measure specific aspects of oculomotor inhibition. Two major results were obtained: First, our prosaccade task suggests similar saccadic response preparation and saccadic accuracy in the ADHD compared to the control children. Secondly, the fixation and the countermanding saccade task indicate deficits on measures of oculomotor inhibition in the ADHD group. While patients were specifically impaired in stopping an already initiated response or in suppressing exploratory saccades in a novel situation, inhibition of a prepotent response was not deficient. Our data thus indicate an underlying impairment in cognitive inhibition in ADHD that has been associated with prefrontal lobe functions. More specifically, as the anterior cingulate gyrus has been associated with the countermanding saccade task and group differences were most pronounced in this paradigm our data are in line with imaging data stressing the importance of this cortical structure in the pathophysiology of ADHD.

Adolescent↗

Neuronal network models of ADHD -- lateralization with respect to interhemispheric connectivity reconsidered.

BACKGROUND: Recent research on structural and functional anatomy related to ADHD has concentrated on fronto-striatocerebellar circuits. These findings and resultant neurobiological models of ADHD may explain some of the disturbances. On the other hand, there is some evidence that the restricted look at anterior-posterior anomalies might neglect the important additional information of lateralization problems related to hemispheric connectivity. OBJECTIVE: Hence, the role of lateralization in the pathophysiology of ADHD should be reconsidered. METHOD: After a short review of imaging studies in ADHD the special role of the corpus callosum (including the influence of its anomalies on general brain development, lateralization and functioning) is outlined and the first case of total agenesis of corpus callosum in a child with ADHD is presented and discussed within this context. CONCLUSIONS: In view of the remaining inconsistencies concerning structural and functional brain anomalies in ADHD, attention should be paid not only to anterior- posterior but also to left-right aspects of functional and structural brain anomalies. This should include disturbances probably related to anomalies of the corpus callosum, especially in regard to co-existing problems like dyslexia and developmental coordination disorder.

Agenesis of Corpus Callosum↗

Non-stimulant medications in the treatment of ADHD.

BACKGROUND: Stimulants are the first-line medication in the psychopharmacological treatment of attention-deficit hyperactivity disorder (ADHD). However, 10 to 30% of all children and adults with ADHD either do not respond to or do not tolerate treatment with stimulants. OBJECTIVE: To describe alternative treatment approaches with various non-stimulant agents, especially atomoxetine. METHOD: General review of empirically based literature concerning efficacy and safety of the substances. RESULTS: A large and still increasing body of data supports the usefulness of atomoxetine, a once daily dosing, and new selective noradrenalin reuptake inhibitor, with few side effects. Atomoxetine has been licensed in the US for use in ADHD across the lifespan, and is currently under consideration in Europe. Other non-stimulant substances, such as tricyclic antidepressants (TCAs) and alpha-2-adrenergic agonists, which are used to treat ADHD, are also reviewed. TCAs have been well studied and shown to be efficacious in the treatment of ADHD, but are limited by side effects. The number of studies documenting the efficacy of alpha-2-adrenergic agonists is still limited. Some experimental studies support a potential role of cholinergic drugs such as acetylcholinesterase inhibitors (tacrine, donepezil) as well as novel nicotinic analogues (ABT-418). CONCLUSION: Non-stimulant agents have been shown to be effective in treatment of ADHD. Especially, atomoxetine seems promising and newline drugs are in development.

Antidepressive Agents, Tricyclic↗

The Family Strain Index (FSI). Reliability, validity, and factor structure of a brief questionnaire for families of children with ADHD.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) in children affects every member of the family. Practical tools are needed to assess the effects of ADHD on families to better understand and address the level of stress, strain and burden that families experience. OBJECTIVE: To provide the preliminary reliability, validity and factor structure of the Family Strain Index (FSI), a 6-item parent-report questionnaire. METHODS: The FSI was completed by 1,477 parents of children with ADHD (aged 6-18 years) at the baseline visit of the ADORE study in 10 European countries (data missing for one patient). RESULTS: The FSI taps into an overall experience of worry and interruptions of activities in families of children with ADHD, as a single factor was identified with excellent internal consistency (alpha=0.87). Despite its brevity, almost no ceiling (worst score) or floor (best score) effects were observed for families of these highly symptomatic children. This score distribution and the 5-point response options suggest that the FSI will be responsive to changes in the experience of family strain associated with children's ADHD treatment. CONCLUSION: The ease of completion and coherence of the underlying construct indicates that the FSI may be a practical clinical tool for monitoring changes in family strain associated with children's ADHD treatment.

Adolescent↗

Toward mapping daily challenges of living with ADHD: maternal and child perspectives using electronic diaries.

Attention-deficit/hyperactivity disorder (ADHD) has an impact on the family as well as the affected child. This study developed and tested an electronic diary for mapping the challenges of everyday family life in a sample of children with ADHD being treated with pharmacotherapy. Across 7 days, mothers and children (27 ADHD; 25 non-ADHD) independently reported their moods, behaviors, and social contexts every 30 min during nonschool hours. Symptomatic behaviors and negative moods were elevated in the ADHD group, combined with maternal perceptions of lower parenting effectiveness and quality of life. Differences in the contexts of maternal anger were salient, with mothers in the ADHD group more often angry when with their children and comparison mothers more often angry when not. Although mothers' diaries were more informative, children's diaries also distinguished the two groups, especially during mornings and weekends. The need for family-wide interventions, the utility of child self-reports, and the promise of electronic diaries are discussed.

Activities of Daily Living↗

Hot and cool aspects of cognitive control in children with ADHD: decision-making and inhibition.

This study investigated hot and cool aspects of cognitive control in children with Attention Deficit Hyperactivity Disorder (ADHD). The study aimed to: (1) replicate the postulated response inhibition deficit of children with ADHD; (2) explore whether children with ADHD choose disadvantageously in a decision-making task and to explore the mechanisms underlying the expected response pattern; and (3) study whether performance on a combination of hot and cool executive control measures has predictive value for an ADHD diagnosis. The sample consisted of 20 children with ADHD and 22 normal developing children (NC, 8 to 12 years) matched on age, FSIQ, and gender. Two paradigms have been applied: (1) the stop signal paradigm, and (2) the adapted children's version of the IOWA Gambling task. There were no group differences for both paradigms. Both groups chose in a reward-oriented manner and seemed to develop the ability to take future consequences into account in making decisions. Moreover, feedback resulted in direct behavioral changes. Children with ADHD did not have a specific response inhibition deficit or a decision-making deficit.

Attention Deficit Disorder with Hyperactivity↗