Chris Hollis

Nonpharmacological interventions for ADHD: systematic review and meta-analyses of randomized controlled trials of dietary and psychological treatments

OBJECTIVE Nonpharmacological treatments are available for attention deficit hyperactivity disorder (ADHD), although their efficacy remains uncertain. The authors undertook meta-analyses of the efficacy of dietary (restricted elimination diets, artificial food color exclusions, and free fatty acid supplementation) and psychological (cognitive training, neurofeedback, and behavioral interventions) ADHD treatments. METHOD Using a common systematic search and a rigorous coding and data extraction strategy across domains, the authors searched electronic databases to identify published randomized controlled trials that involved individuals who were diagnosed with ADHD (or who met a validated cutoff on a recognized rating scale) and that included an ADHD outcome. RESULTS Fifty-four of the 2,904 nonduplicate screened records were included in the analyses. Two different analyses were performed. When the outcome measure was based on ADHD assessments by raters closest to the therapeutic setting, all dietary (standardized mean differences=0.21-0.48) and psychological (standardized mean differences=0.40-0.64) treatments produced statistically significant effects. However, when the best probably blinded assessment was employed, effects remained significant for free fatty acid supplementation (standardized mean difference=0.16) and artificial food color exclusion (standardized mean difference=0.42) but were substantially attenuated to nonsignificant levels for other treatments. CONCLUSIONS Free fatty acid supplementation produced small but significant reductions in ADHD symptoms even with probably blinded assessments, although the clinical significance of these effects remains to be determined. Artificial food color exclusion produced larger effects but often in individuals selected for food sensitivities. Better evidence for efficacy from blinded assessments is required for behavioral interventions, neurofeedback, cognitive training, and restricted elimination diets before they can be supported as treatments for core ADHD symptoms.

European guidelines on managing adverse effects of medication for ADHD

The safety of ADHD medications is not fully known. Concerns have arisen about both a lack of contemporary-standard information about medications first licensed several decades ago, and signals of possible harm arising from more recently developed medications. These relate to both relatively minor adverse effects and extremely serious issues such as sudden cardiac death and suicidality. A guidelines group of the European Network for Hyperkinetic Disorders (EUNETHYDIS) has therefore reviewed the literature, recruited renowned clinical subspecialists and consulted as a group to examine these concerns. Some of the effects examined appeared to be minimal in impact or difficult to distinguish from risk to untreated populations. However, several areas require further study to allow a more precise understanding of these risks.

The quality of life of children with attention deficit/ hyperactivity disorder: a systematic review

Quality of life (QoL) describes an individual’s subjective perception of their position in life as evidenced by their physical, psychological, and social functioning. QoL has become an increasingly important measure of outcome in child mental health clinical work and research. Here we provide a systematic review of QoL studies in children and young people with attention deficit hyperactivity disorder (ADHD) and address three main questions. (1) What is the impact of ADHD on QoL? (2) What are the relationships between ADHD symptoms, functional impairment and the mediators and moderators of QoL in ADHD? (3) Does the treatment of ADHD impact on QoL? Databases were systematically searched to identify research studies describing QoL in ADHD. Thirty six relevant articles were identified. Robust negative effects on QoL are reported by the parents of children with ADHD across a broad range of psycho-social, achievement and self evaluation domains. Children with ADHD rate their own QoL less negatively than their parents and do not always seeing themselves as functioning less well than healthy controls. ADHD has a comparable overall impact on QoL compared to other mental health conditions and severe physical disorders. Increased symptom level and impairment predicts poorer QoL. The presence of comorbid conditions or psychosocial stressors helps explain these effects. There is emerging evidence that QoL improves with effective treatment. In conclusion, ADHD seriously compromises QoL especially when seen from a parents’ perspective. QoL outcomes should be included as a matter of course in future treatment studies.

Autism spectrum disorders in extremely preterm children.

OBJECTIVES To investigate the prevalence, correlates, and antecedents of autism spectrum disorders (ASD) in extremely preterm children. STUDY DESIGN We conducted a prospective study of all births <26 weeks gestation in the United Kingdom and Ireland in 1995. Of 307 survivors at 11 years, 219 (71%) were assessed and compared with 153 term-born classmates. Parents completed the Social Communication Questionnaire (SCQ) to assess autism spectrum symptoms, and ASD were diagnosed by using a psychiatric evaluation. An IQ test and clinical evaluation were also administered. Longitudinal outcome data were available for extremely preterm children. RESULTS Extremely preterm children had significantly higher SCQ scores than classmates (mean difference, 4.6 points; 95% CI, 3.4-5.8). Sixteen extremely preterm children (8%) were assigned an ASD diagnosis, compared with none of the classmates. By hospital discharge, male sex, lower gestation, vaginal breech delivery, abnormal cerebral ultrasound scanning results, and not having had breast milk were independently associated with autism spectrum symptoms. By 6 years, independent associates were cognitive impairment, inattention and peer problems, withdrawn behavior at 2.5 years, and not having had breast milk. CONCLUSIONS Extremely preterm children are at increased risk for autism spectrum symptoms and ASD in middle childhood. These symptoms and disorders were associated with neurocognitive outcomes, suggesting that ASD may result from abnormal brain development in this population.

Association of the dopamine transporter (DAT1) 10/10-repeat genotype with ADHD symptoms and response inhibition in a general population sample.

Association between attention-deficit hyperactivity disorder (ADHD) and the 10-repeat allele of the dopamine transporter gene (DAT1) has been reported in independent clinical samples using a categorical clinical definition of ADHD. The present study adopts a quantitative trait loci (QTL) approach to examine the association between DAT1 and a continuous measure of ADHD behaviours in a general-population sample, as well as to explore whether there is an independent association between DAT1 and performance on neuropsychological tests of attention, response inhibition, and working memory. From an epidemiological sample of 872 boys aged 6–11 years, we recruited 58 boys scoring above the 90th percentile for teacher reported ADHD symptoms (SWAN ADHD scale) and 68 boys scoring below 10th percentile for genotyping and neuropsychological testing. A significant association was found between the DAT1 homozygous 10/10-repeat genotype and high-scoring boys (χ2square=4.6, P<0.03; odds ratio=2.4, 95% CI 1.1–5.0). Using hierarchical linear regression, a significant independent association was found between the DAT1 10/10-repeat genotype and measures of selective attention and response inhibition after adjusting for age, IQ, and ADHD symptoms. There was no association between DAT1 and any component of working memory. Furthermore, performance on tasks of selective attention although associated with DAT1 was not associated with SWAN ADHD high scores after controlling for age and IQ. In contrast, impairment on tasks that tapped sustained attention and the central executive component of working memory were found in high-scoring boys after adjusting for age and IQ. The results suggest that DAT1 is a QTL for continuously distributed ADHD behaviours in the general population and the cognitive endophenotype of response inhibition.

IQ and non-clinical psychotic symptoms in 12-year-olds: results from the ALSPAC birth cohort

Background Non-clinical psychotic symptoms appear common in children, but it is possible that a proportion of reported symptoms result from misinterpretation. There is a well-established association between pre-morbid low IQ score and schizophrenia. Psychosis-like symptoms in children may also be a risk factor for psychotic disorder but their relationship with IQ is unclear. Aims To investigate the prevalence, nature and frequency of psychosis-like symptoms in 12-year-old children and study their relationship with IQ. Method Longitudinal study using the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. A total of 6455 children completed screening questions for 12 psychotic symptoms followed by a semi-structured clinical assessment. IQ was assessed at 8 years of age using the Wechsler Intelligence Scale for Children (3rd UK edition). Results The 6-month period prevalence for one or more symptoms was 13.7% (95% CI 12.8–14.5). After adjustment for confounding variables, there was a non-linear association between IQ score and psychosis-like symptoms, such that only those with below average IQ score had an increased risk of reporting such symptoms. Conclusions Non-clinical psychotic symptoms occur in a significant proportion of 12-year-olds. Symptoms are associated with low IQ and also less strongly with a high IQ score. The pattern of association with IQ differs from that observed in schizophrenia.

Task-Related Default Mode Network Modulation and Inhibitory Control in ADHD: Effects of Motivation and Methylphenidate.

BACKGROUND Deficits characteristic of attention deficit/hyperactivity disorder (ADHD), including poor attention and inhibitory control, are at least partially alleviated by factors that increase engagement of attention, suggesting a hypodopaminergic reward deficit. Lapses of attention are associated with attenuated deactivation of the default mode network (DMN), a distributed brain system normally deactivated during tasks requiring attention to the external world. Task-related DMN deactivation has been shown to be attenuated in ADHD relative to controls. We hypothesised that motivational incentives to balance speed against restraint would increase task engagement during an inhibitory control task, enhancing DMN deactivation in ADHD. We also hypothesised that methylphenidate, an indirect dopamine agonist, would tend to normalise abnormal patterns of DMN deactivation. METHOD We obtained functional magnetic resonance images from 18 methylphenidate-responsive children with ADHD (DSM-IV combined subtype) and 18 pairwise-matched typically developing children aged 9-15 years while they performed a paced Go/No-go task. We manipulated motivational incentive to balance response speed against inhibitory control, and tested children with ADHD both on and off methylphenidate. RESULTS When children with ADHD were off-methylphenidate and task incentive was low, event-related DMN deactivation was significantly attenuated compared to controls, but the two groups did not differ under high motivational incentives. The modulation of DMN deactivation by incentive in the children with ADHD, off-methylphenidate, was statistically significant, and significantly greater than in typically developing children. When children with ADHD were on-methylphenidate, motivational modulation of event-related DMN deactivation was abolished, and no attenuation relative to their typically developing peers was apparent in either motivational condition. CONCLUSIONS During an inhibitory control task, children with ADHD exhibit a raised motivational threshold at which task-relevant stimuli become sufficiently salient to deactivate the DMN. Treatment with methylphenidate normalises this threshold, rendering their pattern of task-related DMN deactivation indistinguishable from that of typically developing children.

Attention-deficit hyperactivity disorder: treatment discontinuation in adolescents and young adults

BACKGROUND Symptoms of attention-deficit hyperactivity disorder (ADHD) are known to persist into adulthood in the majority of cases. AIMS To determine the prevalence of methylphenidate, dexamfetamine and atomoxetine prescribing and treatment discontinuation in adolescents and young adults. METHOD A descriptive cohort study using the UK General Practice Research Database included patients aged 15-21 years from 1999 to 2006 with a prescription for a study drug. RESULTS Prevalence of prescribing averaged across all ages increased 6.23-fold over the study period. Overall, prevalence decreased with age: in 2006, prevalence in males dropped 95% from 12.77 per 1000 in 15-year-olds to 0.64 per 1000 in 21-year-olds. A longitudinal analysis of a cohort of 44 patients aged 15 years in 1999 demonstrated that no patient received treatment after the age of 21 years. CONCLUSIONS The prevalence of prescribing by general practitioners to patients with ADHD drops significantly from age 15 to age 21 years. The fall in prescribing is greater than the reported age-related decrease in symptoms, raising the possibility that treatment is prematurely discontinued in some young adults in whom symptoms persist.

Cessation of attention deficit hyperactivity disorder drugs in the young (CADDY)--a pharmacoepidemiological and qualitative study.

OBJECTIVES To estimate the prevalence of attention deficit hyperactivity disorder (ADHD) pharmacological treatment, and its demographic and clinical details, and to estimate the proportion of patients in the target group who stopped ADHD treatment and investigate possible factors for continuation or cessation of treatment. DESIGN A pharmacoepidemiological study using an automated database and a qualititative study using patient interviews. Part 1 was a pharmacoepidemiological study that provided accurate data on use and cessation of ADHD drugs. Part 2 was an in-depth interview study to investigate the reasons, processes and outcomes of treatment cessation. SETTING Part 1: primary care using the General Practice Research Database (GPRD). Part 2: secondary and tertiary care paediatric clinics, child and adolescent mental health and adult mental health clinics in London, Nottingham, Dundee and Liverpool. PARTICIPANTS Part 1: patients were 15-21 years old during the study period (1 January 2001 and 31 December 2004), had at least one prescription for methylphenidate, dexamfetamine or atomoxetine and had at least 1 year of research-standard data available in the GPRD. Part 2: patients fulfilled Part 1 criteria, had a diagnosis of ADHD as detected by a predefined algorithm and had been treated with methylphenidate, dexamfetamine or atomoxetine for at least 1 year. Child and adolescent psychiatrists, adult psychiatrists and paediatricians involved in the treatment of young people with ADHD were also interviewed as part of the study. RESULTS Part 1: prevalence of prescribing averaged across all ages increased eightfold, from 0.26 per 1000 patients in 1999 to 2.07 per 1000 patients in 2006. The increase in prevalence in the younger patients was less evident in the older patients. Prevalence in 15-year-old males receiving a study drug prescription increased from 1.32 per 1000 patients in 1999 to 8.31 per 1000 patients in 2006, whereas the prevalence in 21-year-olds rose from 0 per 1000 patients in 1999 to 0.43 per 1000 patients in 2006. Survival analysis showed that the rate of treatment cessation largely exceeded the estimated rate of persistence of ADHD. The reduction in prescribing was most noticeable between 16 and 17 years of age. Kaplan-Meier analysis showed that approximately 18% of patients restarted treatment if they had stopped treatment after the age of 15. Patients who restarted treatment were more likely to restart within the first year following treatment cessation. Part 2: the Child Health and Illness Profile (CHIP) was chosen as the quality of life questionnaire for the Part 2 study because the CHIP-CE scale has been validated in children with ADHD in the UK. Because of the age range of participants, the adolescent version (CHIP-AE) was administered to patients after interview. Of the 15, a total of nine patients finished the questionnaire. Interviews showed that although some young people felt able to cope after stopping medication, others felt the need to restart to control symptoms. Some patients had difficulty re-engaging with services and clinicians recognised the lack of services for young adults. Patients continuing on treatment considered cessation as an option for the future, but were concerned about the process of stopping and its impact on behaviour. CONCLUSIONS Part 1 study demonstrated that the prevalence of prescribing by GPs to patients with ADHD dropped significantly from age 15 to 21. The fall in prescribing was greater than the reported age-related decrease in symptoms, raising the possibility that treatment is prematurely discontinued in some young adults where ADHD symptoms persist. Part 2 of the study identified that some young adults had difficulty in obtaining treatment after discharge from paediatric services. Future work should include randomised placebo-controlled trials into long-term treatment with stimulants, particularly methylphenidate.OBJECTIVE(S) To investigate the clinical and cost-effectiveness of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for the treatment of adults with pulmonary arterial hypertension (PAH) within their licensed indications. DATA SOURCES Major electronic databases (including the Cochrane Library, MEDLINE and EMBASE) were searched up to February 2007. Further data were obtained from dossiers submitted to NICE by the manufacturers of the technologies. REVIEW METHODS The systematic clinical and economic reviews were conducted according to accepted procedures. Model-based economic evaluations of the cost-effectiveness of the technologies from the perspective of the UK NHS and personal social services were carried out. RESULTS In total, 20 randomised controlled trials (RCTs) were included in this assessment, mostly of 12-18 weeks duration and comparing one of the technologies added to supportive treatment with supportive treatment alone. Four published economic evaluations were identified. None produced results generalisable to the NHS. There was no consensus in the industry submissions on the most appropriate model structure for the technology assessment. Improvement in 6-minute walk distance (6MWD) was seen with intravenous epoprostenol in primary pulmonary hypertension (PPH) patients with mixed functional class (FC) (mainly III and IV, licensed indication) compared with supportive care (58 metres; 95% CI 6-110). For bosentan compared with supportive care, the pooled result for improvement in 6MWD for FCIII patients with mixed PAH (licensed indication) was 59 metres (95% CI 20-99). For inhaled iloprost, sitaxentan and sildenafil no stratified data for improvement in 6MWD were available. The odds ratio (OR) for FC deterioration at 12 weeks was 0.40 (95% CI 0.13-1.20) for intravenous epoprostenol compared with supportive care. The corresponding values for inhaled iloprost (FCIII PPH patients; licensed indication), bosentan, sitaxentan (FCIII patients with mixed PAH; licensed indication) and sildenafil (FCIII patients with mixed PAH; licensed indication) were 0.29 (95% CI 0.07-1.18), 0.21 (95% CI 0.03-1.76), 0.18 (95% CI 0.02-1.64) and [Commercial-in-confidence information has been removed] respectively. The incremental cost-effectiveness ratios (ICERs) for the technologies plus supportive care compared with supportive care alone, determined by independent economic evaluation, were 277,000 pounds/quality-adjusted life-year (QALY) for FCIII and 343,000 pounds/QALY for FCIV patients for epoprostenol, 101,000 pounds/QALY for iloprost, 27,000 pounds/QALY for bosentan and 25,000 pounds/QALY for sitaxentan. For the most part sildenafil plus supportive care was more effective and less costly than supportive care alone and therefore dominated supportive care. In the case of epoprostenol the ICERs were sensitive to the price of epoprostenol and for bosentan and sitaxentan the ICERs were sensitive to running the model over a shorter time horizon and with a lower cost of epoprostenol. Two RCTs directly compared the technologies against each other with no significant differences observed between the technologies. Combinations of technologies were investigated in four RCTs, with some showing conflicting results. CONCLUSION(S) All five technologies when added to supportive treatment and used at licensed dose(s) were more effective than supportive treatment alone in RCTs that included patients of mixed FC and types of PAH. Current evidence does not allow adequate comparisons between the technologies nor for the use of combinations of the technologies. Independent economic evaluation suggests that bosentan, sitaxentan and sildenafil may be cost-effective by standard thresholds and that iloprost and epoprostenol may not. If confirmed, the use of the most cost-effective treatment would result in a reduction in costs for the NHS. Long-term, double-blind RCTs of sufficient sample size that directly compare bosentan, sitaxentan and sildenafil, and evaluate outcomes including survival, quality of life, maintenance on treatment and impact on the use of resources for NHS and personal social services are needed.

Enhanced cognitive control in young people with Tourette's syndrome.

Tourettes syndrome (TS) is a neurodevelopmental disorder characterized by the presence of chronic vocal and motor tics. Tics are sudden, highly stereotyped, movements that can be simple or complex in appearance. Since patients with TS have difficulties preventing unwanted movements, one might expect that their ability to voluntarily control goal-directed movements would be similarly poor. Indeed, it has been suggested that TS sufferers are impaired at inhibiting reflexively triggered movements and in rapidly selecting or switching between different motor sets. This idea is consistent with current views on the neurological basis of TS that posit a dysfunction of the neural circuits linking the frontal lobes and the striatum. These circuits are known to be involved in the voluntary control of action. By using an oculomotor switching task, we show for the first time that young people with TS exhibit paradoxically greater levels of cognitive control over their movements than their age-matched controls. This finding is consistent with an increased need to monitor and control movements and may indicate a subcortical locus for the triggering of tics. It also suggests that the constant need to suppress tics could have resulted in an enhancement of the executive processes involved in inhibitory control.