AbstractBackgroundAttention-deficit/hyperactivity Disorder Research Articles

A cost-effectiveness analysis of lisdexamfetamine dimesylate in the treatment of adults with attention-deficit/hyperactivity disorder in the UK

BackgroundAttention-deficit/hyperactivity disorder (ADHD) is a chronic neurobehavioral disorder in children that may persist into adulthood. Lisdexamfetamine dimesylate (LDX) is approved in many countries for ADHD treatment in children, adolescents, and adults.ObjectivesEstimate the cost-effectiveness of LDX as a first- or second-line treatment for adults with ADHD from the United Kingdom (UK) National Health Service (NHS) perspective compared with methylphenidate extended release (MPH-ER) and atomoxetine (ATX).MethodsA 1-year decision-analytic model was developed. Health outcomes included response, non-response and inability to tolerate. Efficacy data were obtained from a mixed-treatment comparison (MTC). Response was a score of 1 or 2 on the Clinical Global Impression–Improvement scale. Tolerability was assessed by discontinuation rates due to adverse events. Utilities were identified via a systematic literature review. Health care resource use estimates were obtained via a survey of clinicians. Daily drug costs were estimated from mean doses reported in the trials used in the MTC. One-way and probabilistic sensitivity analyses (PSAs) were performed.ResultsLDX dominated MPH-ER and ATX; reducing mean per-patient annual cost by £5 and £200, and increasing mean quality-adjusted life years (QALYs) by 0.005 and 0.009, respectively. In the PSA, the probability of cost-effectiveness for LDX vs. MPH-ER and ATX at a threshold of £20,000 per QALY was 61% and 80%, respectively.ConclusionsFrom the perspective of the UK NHS, LDX is likely to provide a cost-effective treatment for adults with ADHD. This conclusion may be drawn with more certainty in comparison with ATX than with MPH-ER.

Comparative treatment patterns, healthcare resource utilization and costs of atomoxetine and long-acting methylphenidate among children and adolescents with attention-deficit/hyperactivity disorder in Germany

BackgroundAttention-deficit/hyperactivity disorder (ADHD) imposes a substantial burden on patients and their families.ObjectiveA retrospective, propensity score-matched cohort study compared treatment patterns, healthcare resource utilization (HRU) and costs among children/adolescents with ADHD aged 6–17 years at treatment initiation (index) in Germany who received atomoxetine (ATX) or long-acting methylphenidate (LA-MPH) monotherapy.MethodsPatients received at least one prescription for their index medication (ATX/LA-MPH) during 2006–2010; the first prescription marked the index date. ATX- and LA-MPH-indexed cohorts were matched 1:1 (n = 737); a patient subset was identified that had not received ADHD-indicated medications in 12 months prior to index (novel initiators: ATX, n = 486; LA-MPH, n = 488). Treatment patterns were evaluated among novel initiators, and HRU and costs among the matched cohorts in the 12 months after index.ResultsNo significant differences in baseline characteristics were found between the novel initiator patient subsets. ATX-indexed novel initiators had significantly longer persistence to index medication [mean (standard deviation; SD) days: 222.0 (133.9) vs 203.2 (135.0), P = 0.029) but higher switching rates (8.8 vs 5.5 %, P = 0.045) than LA-MPH-indexed novel initiators. The total ATX-indexed cohort required more prescriptions [any medication; mean (SD): 20.9 (11.5) vs 15.7 (9.0), P < 0.001] and outpatient visits [mean (SD): 10.1 (6.3) vs 8.3 (5.3), P < 0.001], and incurred significantly higher total median healthcare costs (€1144 vs €541, P < 0.001) versus matched LA-MPH patients.ConclusionsThese real-world data indicate that, among children/adolescents with ADHD in Germany, ATX-indexed patients may require more prescriptions and physician visits, and incur higher total healthcare costs, than matched LA-MPH patients.

Attention deficit/hyperactivity disorders with co-existing substance use disorder is characterized by early antisocial behaviour and poor cognitive skills

BackgroundAttention Deficit/Hyperactivity Disorder (ADHD) is associated with an increased risk of co-existing substance abuse. The Swedish legislation on compulsory healthcare can be applied to persons with severe substance abuse who can be treated involuntarily during a period of six months. This context enables a reliable clinical assessment of ADHD in individuals with severe substance use disorder (SUD).MethodsIn the context of compulsory care for individuals with severe SUD, male patients were assessed for ADHD, co-morbid psychiatric symptoms, psychosocial background, treatment history, and cognition. The data from the ADHD/SUD group (n = 60) was compared with data from (1) a group of individuals with severe substance abuse without known ADHD (SUD group, n = 120), as well as (2) a group with ADHD from an outpatient psychiatric clinic (ADHD/Psych group, n = 107).ResultsCompared to the general SUD group in compulsory care, the ADHD/SUD group had already been significantly more often in compulsory care during childhood or adolescence, as well as imprisoned more often as adults. The most common preferred abused substance in the ADHD/SUD group was stimulant drugs, while alcohol and benzodiazepine abuse was more usual in the general SUD group. Compared to the ADHD/Psych group, the ADHD/SUD group reported more ADHD symptoms during childhood and performed poorer on all tests of general intellectual ability and executive functions.ConclusionsThe clinical characteristics of the ADHD/SUD group differed from those of both the SUD group and the ADHD/Psych group in several respects, indicating that ADHD in combination with SUD is a particularly disabling condition. The combination of severe substance abuse, poor general cognitive ability, severe psychosocial problems, including indications of antisocial behaviour, and other co-existing psychiatric conditions should be considered in treatment planning for adults with ADHD and SUD.

BAIAP2 exhibits association to childhood ADHD especially predominantly inattentive subtype in Chinese Han subjects

BackgroundAttention-deficit/hyperactivity disorder (ADHD) is a common chronic neurodevelopmental disorder with a high heritability. Much evidence of hemisphere asymmetry has been found for ADHD probands from behavioral level, electrophysiological level and brain morphology. One previous research has reported possible association between BAIAP2, which is asymmetrically expressed in the two cerebral hemispheres, with ADHD in European population. The present study aimed to investigate the association between BAIAP2 and ADHD in Chinese Han subjects.MethodsA total of 1,397 ADHD trios comprised of one ADHD proband and their parents were included for family-based association tests. Independent 569 ADHD cases and 957 normal controls were included for case-control studies. Diagnosis was performed according to the DSM-IV criteria. Nine single nucleotide polymorphisms (SNPs) of BAIAP2 were chosen and performed genotyping for both family-based and case-control association studies.ResultsTransmission disequilibrium tests (TDTs) for family-based association studies showed significant association between the CA haplotype comprised by rs3934492 and rs9901648 with predominantly inattentive type (ADHD-I). For case-control study, chi-square tests provided evidence for the contribution of SNP rs4969239, rs3934492 and rs4969385 to ADHD and its two clinical subtypes, ADHD-I and ADHD-C. However, only the associations for ADHD and ADHD-I retained significant after corrections for multiplicity or logistic regression analyses adjusting the potential confounding effect of gender and age.ConclusionsThese above results indicated the possible involvement of BAIAP2 in the etiology of ADHD, especially ADHD-I.

Long-term effects of stimulants on neurocognitive performance of Taiwanese children with attention-deficit/hyperactivity disorder

BackgroundAttention-deficit/hyperactivity disorder (ADHD) is a common behavioral and neurocognitive disorder in school-age children. Methylphenidate (MPH) is the most frequently prescribed CNS stimulant for ADHD. The aim of this study is to evaluate the changes in intelligence quotient and domains of neurocognitive function after long-term MPH treatment of Taiwanese children with ADHD.MethodsThe Wechsler Intelligence Scale (WISC-III) was administrated twice at an interval of at least one year for all 171 subjects (6–12 years) and 47 age- and gender-matched children without ADHD. The ADHD-Rating scale and Clinical Global Impression-Severity (CGI-S) were also used at the time of enrolment, and at 6 months and one year later.ResultsTaiwanese children with ADHD had lower Verbal IQ (VIQ) and Full IQ (FIQ) and performed poorly on several subtests of the WISC-III, including Similarities, Vocabulary, and Coding, compared to healthy children without ADHD. After one year of MPH treatment, significant decrements in all scores of the ADHD-Rating scale and CGI-S and increments in several domains of the WISC-III, including FIQ, VIQ, PIQ, Perceptual Organization Index (POI), Picture Completion, Picture Arrangement, Object Assembly, and Digit Span were observed. When the ADHD children under MPH treatment were subdivided into two age groups (6–8 years and 9–12 years), significantly better performance in some subtests and subscales of the WISC-III (such as Similarities, Comprehension, and Object assembly) was found in the 6–8 years age group.ConclusionsLong-term MPH treatment may improve the neurocognitive profiles of the ADHD children, as seen in their performance in several subtests and in the IQ scores on the WISC-III. And this improvement had no correlation with the decrement of ADHD symptoms. Starting stimulant treatment at as young an age as possible is advised due to the greater benefits in the 6–8 years age group, as seen in this study. More research in this area is also needed to confirm these results.

Comparison of child self-reports and parent proxy-reports on quality of life of children with attention deficit hyperactivity disorder

BackgroundAttention deficit hyperactivity disorder (ADHD) is a neurobiological condition that affects 3%–7% of the pediatric population and significantly compromises the quality of life (QoL) of these individuals. The aim of the current study was to compare child self-reports and parent proxy reports on the QoL of children with ADHD.MethodsForty-five children with ADHD, combined type, aged 8–12 years without comorbidities, were compared with 43 typically developing children. PedsQL™ 4.0 (Pediatric QoL Inventory™) Generic Core Scales (physical, emotional, social, and school functioning) were completed by families and children self-reporting their health-related QoL.ResultsChildren with ADHD reported themselves significantly lowered their PedsQL™ scores on all dimensions in comparison to typically developing children. Statistically significant differences were observed in social functioning (p = 0.010), school functioning (p <0.001), psychosocial health (p <0.001), and total score (p = 0.002). The physical functioning and emotional functioning dimensions did not differ significantly between groups, with p = 0.841 and p = 0.070, respectively. Parents of children with ADHD also reported lower PedsQL™ scores, with statistically significant differences in all dimensions. The relationship between child self-reports and parent proxy reports indicated that there is greater agreement among children with ADHD, except for the school functioning.ConclusionsThis suggests that children with the disorder and their parents have a perception of the functional limitations the disorder brings. It is therefore important to undertake studies to verify the QoL in children with ADHD that aim to provide and measure the scope of the well-being of these children.

Prevalence of obesity and overweight among Chinese children with attention deficit hyperactivity disorder: a survey in Zhejiang Province, China

BackgroundAttention Deficit Hyperactivity Disorder (ADHD) is often comorbid with psychiatric and developmental disorders. This study aimed to investigate the prevalence of obesity and overweight among Chinese children with ADHD, and to explore which subtypes of the disorder may specifically be associated with obesity/overweight.MethodsChildren meeting the DSM-IV criteria for ADHD were enrolled in the study. Weight, weight z-score, height, height z-score, BMI, and BMI z-score were used to evaluate growth status. Obesity and overweight were determined using the National Growth Reference for Chinese Children and Adolescents. Relations between the prevalence of obesity/overweight and different ADHD subtypes and pubertal development were analyzed.ResultsA total of 158 children with ADHD (mean age: 9.2 years) were recruited for the study. The prevalences of obesity, overweight, and combined obesity/overweight were 12.0%, 17.1%, and 29.1%, respectively, which were significantly higher than in the general Chinese population (2.1%, 4.5%, and 6.6%, respectively). Multivariable analysis showed that the children with the combined subtype of ADHD and the onset of puberty were at a higher risk of becoming obese or overweight.ConclusionsThe prevalence of obesity in Chinese children with ADHD is higher than that of the general population. Children with the ADHD combined subtype who were at the onset of puberty were more likely to be overweight or obese.

Cognitive behaviour therapy in medication-treated adults with ADHD and persistent Symptoms: A randomized controlled trial

BackgroundAttention deficit hyperactivity disorder (ADHD) in adulthood is not fully treated by psychopharmacological treatment alone. The main aim of the current study was to evaluate a newly developed cognitive behaviour therapy (CBT) based group programme, the Reasoning and Rehabilitation for ADHD Youths and Adults (R&R2ADHD), using a randomized controlled trial.Methods54 adults with ADHD already receiving psychopharmacological treatment were randomly allocated to an experimental (CBT/MED) treatment condition (n = 27) and a 'treatment as usual' (TAU/MED) control condition (n = 27) that did not receive the CBT intervention. The outcome measures were obtained before treatment (baseline), after treatment and at three month follow-up and included ADHD symptoms and impairments rated by independent assessors, self-reported current ADHD symptoms, and comorbid problems.ResultsThe findings suggested medium to large treatment effects for ADHD symptoms, which increased further at three month follow-up. Additionally, comorbid problems also improved at follow-up with large effect sizes.ConclusionsThe findings give support for the effectiveness of R&R2ADHD in reducing ADHD symptoms and comorbid problems, an improving functions associated with impairment. The implications are that the benefits of R&R2ADHD are multifaceted and that combined psychopharmacological and CBT based treatments may add to and improve pharmacological interventions.Trial registrationACTRN12611000533998 (http://www.ANZCTR.org.au/ACTRN12611000533998.aspx)

Cross-fostering does not alter the neurochemistry or behavior of spontaneously hypertensive rats

BackgroundAttention-deficit/hyperactivity disorder (ADHD) is a highly heritable developmental disorder resulting from complex gene-gene and gene-environment interactions. The most widely used animal model, the spontaneously hypertensive rat (SHR), displays the major symptoms of ADHD (deficits in attention, impulsivity and hyperactivity) and has a disturbance in the noradrenergic system when compared to control Wistar-Kyoto rats (WKY). The aim of the present study was to determine whether the ADHD-like characteristics of SHR were purely genetically determined or dependent on the gene-environment interaction provided by the SHR dam.MethodsSHR/NCrl (Charles River, USA), WKY/NCrl (Charles River, USA) and Sprague Dawley rats (SD/Hsd, Harlan, UK) were bred at the University of Cape Town. Rat pups were cross-fostered on postnatal day 2 (PND 2). Control rats remained with their birth mothers to serve as a reference for their particular strain phenotype. Behavior in the open-field and the elevated-plus maze was assessed between PND 29 and 33. Two days later, rats were decapitated and glutamate-stimulated release of [3H]norepinephrine was determined in prefrontal cortex and hippocampal slices.ResultsThere was no significant effect of "strain of dam" but there was a significant effect of "pup strain" on all parameters investigated. SHR pups travelled a greater distance in the open field, spent a longer period of time in the inner zone and entered the inner zone of the open-field more frequently than SD or WKY. SD were more active than WKY in the open-field. WKY took longer to enter the inner zone than SHR or SD. In the elevated-plus maze, SHR spent less time in the closed arms, more time in the open arms and entered the open arms more frequently than SD or WKY. There was no difference between WKY and SD behavior in the elevated-plus maze. SHR released significantly more [3H]norepinephrine in response to glutamate than SD or WKY in both hippocampus and prefrontal cortex while SD prefrontal cortex released more [3H]norepinephrine than WKY. SHR were resilient, cross-fostering did not reduce their ADHD-like behavior or change their neurochemistry. Cross-fostering of SD pups onto SHR or WKY dams increased their exploratory behavior without altering their anxiety-like behavior.ConclusionThe ADHD-like behavior of SHR and their neurochemistry is genetically determined and not dependent on nurturing by SHR dams. The similarity between WKY and SD supports the continued use of WKY as a control for SHR and suggests that SD may be a useful additional reference strain for SHR. The fact that SD behaved similarly to WKY in the elevated-plus maze argues against the use of WKY as a model for anxiety-like disorders.

Dopamine transporter 3'UTR VNTR genotype is a marker of performance on executive function tasks in children with ADHD

BackgroundAttention-Deficit/Hyperactivity Disorder (ADHD) is a heterogeneous disorder from both clinical and pathogenic viewpoints. Executive function deficits are considered among the most important pathogenic pathways leading to ADHD and may index part of the heterogeneity in this disorder.MethodsTo investigate the relationship between the dopamine transporter gene (SLC6A3) 3'-UTR VNTR genotypes and executive function in children with ADHD, 196 children diagnosed with ADHD were sequentially recruited, genotyped, and tested using a battery of three neuropsychological tests aimed at assessing the different aspects of executive functioning.ResultsTaking into account a correction for multiple comparisons, the main finding of this study is a significant genotype effect on performances on the Tower of London (F = 6.902, p = 0.009) and on the Wechsler Intelligence Scale for Children, Third Edition (WISC-III) Freedom From Distractibility Index (F = 7.125, p = 0.008), as well as strong trends on Self Ordered Pointing Task error scores (F = 4,996 p = 0.026) and WISC-III Digit Span performance (F = 6.28, p = 0.023). Children with the 9/10 genotype exhibited, on average, a poorer performance on all four measures compared to children with the 10/10 genotype. No effect of genotype on Wisconsin Card Sorting Test measures of performance was detected.ConclusionResults are compatible with the view that SLC6A3 genotype may modulate components of executive function performance in children with ADHD.

MEG event-related desynchronization and synchronization deficits during basic somatosensory processing in individuals with ADHD

BackgroundAttention-Deficit/Hyperactivity Disorder (ADHD) is a prevalent, complex disorder which is characterized by symptoms of inattention, hyperactivity, and impulsivity. Convergent evidence from neurobiological studies of ADHD identifies dysfunction in fronto-striatal-cerebellar circuitry as the source of behavioural deficits. Recent studies have shown that regions governing basic sensory processing, such as the somatosensory cortex, show abnormalities in those with ADHD suggesting that these processes may also be compromised.MethodsWe used event-related magnetoencephalography (MEG) to examine patterns of cortical rhythms in the primary (SI) and secondary (SII) somatosensory cortices in response to median nerve stimulation, in 9 adults with ADHD and 10 healthy controls. Stimuli were brief (0.2 ms) non-painful electrical pulses presented to the median nerve in two counterbalanced conditions: unpredictable and predictable stimulus presentation. We measured changes in strength, synchronicity, and frequency of cortical rhythms.ResultsHealthy comparison group showed strong event-related desynchrony and synchrony in SI and SII. By contrast, those with ADHD showed significantly weaker event-related desynchrony and event-related synchrony in the alpha (8–12 Hz) and beta (15–30 Hz) bands, respectively. This was most striking during random presentation of median nerve stimulation. Adults with ADHD showed significantly shorter duration of beta rebound in both SI and SII except for when the onset of the stimulus event could be predicted. In this case, the rhythmicity of SI (but not SII) in the ADHD group did not differ from that of controls.ConclusionOur findings suggest that somatosensory processing is altered in individuals with ADHD. MEG constitutes a promising approach to profiling patterns of neural activity during the processing of sensory input (e.g., detection of a tactile stimulus, stimulus predictability) and facilitating our understanding of how basic sensory processing may underlie and/or be influenced by more complex neural networks involved in higher order processing.

Effects of an open-label pilot study with high-dose EPA/DHA concentrates on plasma phospholipids and behavior in children with attention deficit hyperactivity disorder

BackgroundAttention deficit hyperactivity disorder (ADHD) is the most common neurological condition in children. This pilot study evaluated the effects of high-dose eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) supplementation on the isolated plasma phospholipids and behavior in children with ADHD (primarily inattentive subtype and combined subtype).MethodsNine children were initially supplemented with 16.2 g EPA/DHA concentrates per day. The dosage was adjusted dependent on the ratio of arachidonic acid (AA) to EPA in the isolated plasma phospholipids at four weeks to reach a level normally found in the Japanese population.ResultsAt the end of the eight-week study, supplementation resulted in significant increases in EPA and DHA, as well as a significant reduction in the AA:EPA ratio (20.78 ± 5.26 to 5.95 ± 7.35, p < 0.01). A psychiatrist (blind to supplement compliance or dosage modifications) reported significant improvements in behavior (inattention, hyperactivity, oppositional/defiant behavior, and conduct disorder). There was also a significant correlation between the reduction in the AA:EPA ratio and global severity of illness scores.ConclusionThe findings of this small pilot study suggest supplementation with high-dose EPA/DHA concentrates may improve behavior in children with ADHD.

A QTL on rat chromosome 7 modulates prepulse inhibition, a neuro-behavioral trait of ADHD, in a Lewis x SHR intercross

BackgroundAttention deficit hyperactivity disorder (ADHD) is a complex neuropsychiatric disorder with a substantial genetic component. The Spontaneously Hypertensive Rats (SHR), considered as a good animal model of ADHD, also show less anxiety-like behaviors than Lewis (LEW) rats. The use of these inbred rat strains led us to the mapping of two quantitative trait loci (QTL), named Ofil1 (on chromosome 4) and Ofil2 (on chromosome 7), related to locomotion in the central and aversive area of an open field. Herein, we examined whether LEW and SHR rats differ in the acoustic startle reflex, a test used to study the neurobiology of anxiety, and in the prepulse inhibition of the startle response, which is known to be impaired in ADHD patients. The effect of the two aforementioned loci on these behavioral responses was also studied.MethodsFor this latter purpose, rats deriving from an F2 intercross between the LEW and SHR strains were selected according to their genotype at markers flanking the QTLs and bred to obtain lines of rats homozygous LEW/LEW or SHR/SHR for each of the two loci, thus generating 4 genotypic combinations.ResultsThe SHR rats displayed decreased startle and prepulse inhibition levels when compared to LEW rats. Ofil2 affected prepulse inhibition in female rats only.ConclusionThe results suggest that the LEW and SHR strains are appropriate for studying mechanisms of sensorimotor gating and indicate that the locus Ofil2 on rat chromosome 7 contain genes controlling prepulse inhibition, a neuro-behavioral trait of ADHD.

Neurogenetic interactions and aberrant behavioral co-morbidity of attention deficit hyperactivity disorder (ADHD): dispelling myths

BackgroundAttention Deficit Hyperactivity Disorder, commonly referred to as ADHD, is a common, complex, predominately genetic but highly treatable disorder, which in its more severe form has such a profound effect on brain function that every aspect of the life of an affected individual may be permanently compromised. Despite the broad base of scientific investigation over the past 50 years supporting this statement, there are still many misconceptions about ADHD. These include believing the disorder does not exist, that all children have symptoms of ADHD, that if it does exist it is grossly over-diagnosed and over-treated, and that the treatment is dangerous and leads to a propensity to drug addiction. Since most misconceptions contain elements of truth, where does the reality lie?ResultsWe have reviewed the literature to evaluate some of the claims and counter-claims. The evidence suggests that ADHD is primarily a polygenic disorder involving at least 50 genes, including those encoding enzymes of neurotransmitter metabolism, neurotransmitter transporters and receptors. Because of its polygenic nature, ADHD is often accompanied by other behavioral abnormalities. It is present in adults as well as children, but in itself it does not necessarily impair function in adult life; associated disorders, however, may do so. A range of treatment options is reviewed and the mechanisms responsible for the efficacy of standard drug treatments are considered.ConclusionThe genes so far implicated in ADHD account for only part of the total picture. Identification of the remaining genes and characterization of their interactions is likely to establish ADHD firmly as a biological disorder and to lead to better methods of diagnosis and treatment.

No evidence for the association of DRD4 with ADHD in a Taiwanese population within-family study

BackgroundAttention Deficit Hyperactivity Disorder (ADHD) is a prevalent and highly heritable childhood disorder. The dopamine D4 receptor (DRD4) gene has shown a genetic association with ADHD in Caucasian populations with meta-analysis indicating a small but significant effect across datasets. It remains uncertain whether this association can be generalised to non-Caucasian ethnic groups. Here we investigate two markers within the DRD4 gene in a Taiwanese population, the exon 3 variable number tandem repeat (VNTR) and a 5' 120 base-pair duplication.MethodsWithin-family transmission disequilibrium tests of association of the 5' 120 base-pair duplication, and exon 3 VNTR in a Taiwanese population.ResultsNo evidence of association of ADHD with either polymorphism in this population was observed.ConclusionThe DRD4 gene markers investigated were not found to be associated with ADHD in this Taiwanese sample. Further work in Taiwanese and other Asian populations will therefore be required to establish whether the reports of association of DRD4 genetic variants in Caucasian samples can be generalised to Asian populations.