NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE Centre for Clinical Practice

Transcription

1 NATIONAL INSTITUTE FOR HEALTH AND CLINICAL EXCELLENCE Centre for Clinical Practice Review consultation document Review of Clinical Guideline (CG72) Attention Deficit Hyperactivity Disorder 1. Background information Guideline issue date: year review: 2011 National Collaborating Centre: Mental Health 2. Consideration of the evidence Literature search Through an assessment of abstracts from a high-level randomised control trial (RCT) search, new evidence was identified related to the following clinical areas within the guideline: The experience of treatment and care for ADHD The organisation of care for ADHD Psychological interventions and parent training Interventions for children with ADHD in educational settings Dietary interventions Pharmacological treatment Combining and comparing psychological and pharmacological interventions 30 Aug 12 Sept 2011 (9am) 1 of 105

2 Through this stage of the process, a sufficient number of studies relevant to the above clinical areas were identified from the high level RCT search to allow an assessment for a proposed review decision and are summarised in Table 1 below. From initial intelligence gathering, qualitative feedback from other NICE departments, the views expressed by the Guideline Development Group, as well as the high-level RCT search, an additional focused literature search was also conducted for the following clinical area: Diagnosis of ADHD The results of the focused search are summarised in Table 2 below. All references identified through the high-level RCT search, initial intelligence gathering and the focused searches can be viewed in Appendix Aug 12 Sept 2011 (9am) 2 of 105

3 Table 1: Summary of articles from the high level RCT search Clinical area 1: Diagnosis of ADHD Clinical question Summary of evidence Relevance to guideline recommendations Diagnostic clinical questions in the guideline: Q: Is there a consistent pattern of signs and symptoms demarcating ADHD from other disorders? Is this pattern associated with clinically meaningful impairment? Is this pattern of signs and symptoms the same in children than in adults? Through an assessment of the abstracts from the high-level RCT search, 23 studies relevant to the diagnostic clinical questions covered in the guideline were identified. Children and adolescents (19 studies) Objective measures A case-control study was identified which aimed to test the validity and reliability of a computerised continuous function (CPF) test for assessment of ADHD. 1 The results of the study indicated that the CPF test could differentiate between children with and without ADHD. A study conducted in Child and Adolescent Mental Health Services (CAMHS) in England assessed the accuracy of a No new evidence was identified which would invalidate current guideline recommendation(s). 30 Aug 12 Sept 2011 (9am) 3 of 105

4 Can the clinical features two stage process for the detection of hyperkinetic and impairments of disorders. 2 The process involved screening using the ADHD be distinguished Strengths and Difficulties Questionnaire and the DAWBA as from another diagnosis? a valid and reliable standard. The study concluded that identification of children with hyperkinetic disorders within the Q: Does ADHD have a included CAMHS appeared to be consistent with that of a characteristic course? validated, standardised assessment. One study was identified which described the Restricted Q: Is there any evidence of: Academic Situation Scale (RASS) to assess behaviour in Heritability of ADHD from children with ADHD. 3 family and genetic One study was identified which demonstrated cross-grade studies? instability of clinically elevated teacher ratings. 4 Neurobiological The psychometric properties of the Life Participation Scale underpinning of ADHD? for ADHD-Child Version (LPS-C) was evaluated in one study. 5 The results of the study indicated that the LPS-C had Q: is the neurobiological internal consistency in addition to convergent, divergent and evidence linked to core discriminant validity. signs/symptoms? 30 Aug 12 Sept 2011 (9am) 4 of 105

5 Other diagnostic measures Q: Is there evidence of the One study was identified which examined the neurobiological social context (environmental, bases of attentional alerting deficits in children with ADHD familial [not including genetics] using functional magnetic resonance imaging (fmri). 6 The and/or educational factors) results demonstrated that children with ADHD had deficits in influencing ADHD? alerting functions relating to abnormal activities in frontal and parietal regions subserving top-down attention control Q: What is the most reliable processes. way of diagnosing the three Identification of mild cognitive impairment using novel webenabled computerised tests was evaluated in children with sub-types of ADHD plus Hyperkinetic Disorder? ADHD. 7 The results of the pilot study indicated that Should the diagnosis be computerised tests may be useful for measuring cognitive given by specialists function in ADHD although additional confirmatory studies only? are required. What is the minimum A case-control study was identified which evaluated the role required assessment for of neuropschologic tests in the diagnosis of ADHD in a diagnosis to be given? children. 8 The study concluded that neuropsychological tests Should sub-typing be as diagnostic tools for ADHD should be used with caution 30 Aug 12 Sept 2011 (9am) 5 of 105

6 based on cross-sectional assessment of symptoms only (e.g. last 6 months) or also consider sub-type at onset? Is the diagnostic approach different in adults compared to children? although they may hold promise for identifying core cognitive deficits. Heritability of ADHD One study was identified which carried out a familial risk analysis of first degree relatives for ADHD and psychoactive substance use disorder (PSUD). 9 The results of the study indicated that the patterns of familial risk analysis suggested that ADHD and PSUF are independently transmitted in adolescent females. Q: What are the criteria that trigger the use of this guideline (i.e. which children, young people and adults should be included in this guideline and which should not)? Signs and symptoms One case-control study was identified which aimed to demonstrate a correlation between social skills and ADHD among adolescents with intellectual disabilities (ID). 10 The results indicated that ADHD strongly increased the impairment of social skills, while behavioural disorders were less damaging in ID performance. In addition, the authors 30 Aug 12 Sept 2011 (9am) 6 of 105

7 Relevant section of guideline concluded that the Wechsler Intelligence Scale for Children Diagnosis of ADHD (WISC) and the Developmental Behaviour Checklist (DBC) could be used to enable better assessment of comorbidity in Recommendations adolescents with ID Academic performance in students with ADHD was compared with controls in a case-control study. 11 The results of the study indicated that students with ADHD had poorer academic performance even in the absence of comorbid learning disorders and parental educational level. A visual Go/Nogo task was assessed in children with ADHD (combined and inattentive subtype) and age-matched controls. 12 The results of the study indicated a response inhibition deficit in children with either of the ADHD subtypes tested. Developmental processes among children with ADHD and a control group was assessed in one study. 13 The results of the study indicated that children with ADHD exhibit more difficulty in negotiating important developmental tasks. 30 Aug 12 Sept 2011 (9am) 7 of 105

8 A case-control study was identified which aimed to determine the underlying nature of hyperactivity in children with ADHD concluding that children with ADHD have a deficient ability to inhibit activity to low levels. 14 One study described the clinical presentation of preschool children diagnosed with moderate to severe ADHD. 15 The results of the study indicated that most participants experienced comorbid disorders. In addition, ADHE severity correlated with more internalising difficulties and lower functioning. A case-control study was identified which investigated recognition and understanding of emotional expressions in boys with ADHD. 16 Boys with ADHD demonstrated impairments in recognition and emotion tasks. A case-control study was identified which indicated that children with ADHD have executive function alteration as determined by screening Aug 12 Sept 2011 (9am) 8 of 105

9 Characteristic course of disease One study was identified which examined the effect of sex on the course and psychiatric correlates of ADHD from childhood into adolescence. 18 The results of the study indicated there is no evidence sex moderated the effect of age on ADHD symptoms although patterns of psychiatric comorbidity were conditional on sex. Issues with diagnosis One study was identified which indicated that ADHD was over diagnosed in 64 children and adolescents treated in a community setting. 19 Adults (four studies) Objective measures A case-control study was identified which evaluated the psychometric properties of the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-QSF) in adults with 30 Aug 12 Sept 2011 (9am) 9 of 105

10 ADHD. 20 The results of the study supported the validity of the Q-LES-QSF as a measure of QoL in adults with ADHD. One study was identified which aimed to validate the Adult ADHD Investigator Symptom Rating Scale (AISRS). 21 The AISRS had high internal consistency and good convergent and discriminant validities. Questionnaires A case-control study concluded that behavioural questionnaires cannot be used interchangeably with neuropsychological testing for the assessment of executive function deficits in adults with ADHD. 22 Signs and symptoms One study was identified which aimed to determine what types of life impairments are most affected by continued ADHD symptoms in adults. 23 The study concluded that work and interpersonal impairments appeared to be more likely to 30 Aug 12 Sept 2011 (9am) 10 of 105

11 be related to life impairment and were associated with ADHD severity. Summary In summary, the identified studies evaluated objective measures and other diagnostic measures for assessment of ADHD, heritability, signs and symptoms, characteristic course of disease and issues with diagnosis. The majority of identified studies had been conducted in children and adolescents as opposed to adults. Variability between the identified studies in terms of the diagnostic measures assessed was apparent. Through the in-house review process the update of the Diagnostic and Statistical Manual of Mental Disorders (to version DSM-5) was identified. However, this is currently undergoing field testing and is not expected to be published until May As such, there is insufficient consistent new evidence to update the 30 Aug 12 Sept 2011 (9am) 11 of 105

12 current guideline recommendations: A diagnosis of ADHD should not be made solely on the basis of rating scale or observational data. However rating scales such as the Conners rating scales and the Strengths and Difficulties questionnaire are valuable adjuncts, and observations (for example, at school) are useful when there is doubt about symptoms. For a diagnosis of ADHD, symptoms of hyperactivity/impulsivity and/or inattention should meet the diagnostic criteria in DSM-IV or ICD-10 (hyperkinetic disorder); be associated with at least moderate psychological, social and/or educational or occupational impairment based on interview and/or direct observation in multiple settings, and be pervasive, occurring in two or more important settings including social, familial, educational and/or occupational settings. ADHD should be considered in all age groups, with symptom criteria adjusted for age-appropriate changes in behaviour. 30 Aug 12 Sept 2011 (9am) 12 of 105

13 In determining the clinical significance of impairment resulting from the symptoms of ADHD in children and young people, their views should be taken into account wherever possible. Clinical area 2: The organisation of care for ADHD Clinical question Summary of evidence Relevance to guideline recommendations Q: Does the organisation of care for ADHD produce harm/benefits on the desired outcomes? Relevant section of guideline The organisation of care for ADHD Recommendations Through an assessment of abstracts from the high-level RCT search, two studies relevant to the clinical question were identified. One cluster RCT assessed the effect of electronic health record (EHR) decision support on physician management and documentation of care for children with ADHD. 24 The results of the study indicated that children at the intervention sites were more likely to have had a visit during the study period in which their ADHD was assessed. In addition, improved documentation of symptoms, treatment effectiveness and treatment of adverse effects was observed at intervention sites. No new evidence was identified which would invalidate current guideline recommendation(s). 30 Aug 12 Sept 2011 (9am) 13 of 105

14 A second RCT was identified which evaluated whether the adoption of a collaborative consultation service model improved patient outcomes. 25 The collaborative consultative service involved promoting the use of titration trials and periodic monitoring during medication maintenance. The results of the study indicated that the collaborative consultative service increased the use of evidencebased practices by paediatricians although no difference in children s ADHD symptoms was observed between the intervention and control group. Summary In summary, the identified new evidence does not contradict the current guideline recommendations which suggest that mental health trusts should form multidisciplinary specialist ADHD teams and/or clinics which should have expertise in the diagnosis and management of ADHD. Clinical area 3: Psychological interventions and parent training Clinical question Summary of evidence Relevance to guideline 30 Aug 12 Sept 2011 (9am) 14 of 105

15 Q: For people with ADHD, do psychological interventions or other approaches produce harm/benefits on the desired outcomes? Relevant section of guideline Psychological interventions and parent training Recommendations Through an assessment of abstracts from the high-level RCT search, 35 studies relevant to the clinical question were identified. Parent training (12 studies) A Cochrane systematic review protocol was identified with the aim of determining whether parent-training interventions are effective in reducing ADHD symptoms. 26 One RCT assigned mothers of children with ADHD to a waitlist control group, a traditional behavioural parent training programme or an enhanced behavioural parent training programme. 27 A beneficial effect of participating in the parent training programmes was observed although treatment gains were not maintained. In one RCT parents of children with ADHD reported on a daily basis how successful they were in managing their child s behaviour and the attributions for success and recommendations No new evidence was identified which would invalidate current guideline recommendation(s). 30 Aug 12 Sept 2011 (9am) 15 of 105

16 failure. 28 One RCT was identified which compared a standard behavioural parent training programme with a Coaching Our Acting-Out Children: heightening essential skills programme (COACHES) in fathers of children with ADHD. 29 Improvements in both groups posttreatment on measures of child behaviour were observed. The efficacy of the Incredible Years Basic parent training programme for families with children with ADHD was assessed in an RCT. 30 Compared with a waitlist control group the intervention group was associated with significantly lower levels of parent-reported inattention and hyperactive/impulsive difficulties. One small scale RCT compared Parent-Child Interaction Therapy (PCIT) with waitlist control in families of preschool children with ADHD. 31 The PCIT was found to be an efficacious intervention. 30 Aug 12 Sept 2011 (9am) 16 of 105

17 One RCT reported the results of an intervention that trained parents to be friendship coaches for their children with ADHD. 32 Some beneficial effects of this intervention were observed. A protocol for a trial on social skills training and parental training in improving children s ADHD symptoms and social interactions was identified. 33 The efficacy of the revised new forest parenting programme (NFPP) compared with treatment as usual in treating ADHD in preschool children was assessed in a small scale RCT. 34 The results indicated that the NFPP had an effect on ADHD symptoms. One RCT was identified which evaluated the effectiveness of behavioural parent training (BPT) as an adjunct to routine clinical care (RCC) compared with RCC alone. 35 Improvements were observed in both groups. Specifically BPT+RCC led to a decrease in behavioural and internalising 30 Aug 12 Sept 2011 (9am) 17 of 105

18 problems although no differences between groups were observed for ADHD symptoms. A follow-up of the above RCT concluded that BPT+RCC is more useful in children with no or single-type comorbidity. 36 An RCT was identified which evaluated a combined parent and child programme intervention in children with ADHD. 37 Some beneficial effects of the intervention were observed. Homeopathy and complementary medicine (five studies) A Cochrane systematic review was identified which assessed the efficacy and safety of homeopathy as a treatment for ADHD. 38 The results of the review indicated that the forms of homeopathy evaluated to date do not suggest significant treatment effects for ADHD. A second Cochrane systematic review assessed the effectiveness of meditation therapies for ADHD but was unable to conclude about the effectiveness of this intervention due to the poor quality of included studies. 39 In addition, the efficacy and safety of acupuncture as a 30 Aug 12 Sept 2011 (9am) 18 of 105

19 treatment for ADHD in children and adolescents was assessed in a Cochrane systematic review however no studies met the inclusion criteria for the review. 40 A protocol for an RCT was identified which will evaluate the effectiveness of the Neuro Emotional Technique (NET) versus a control group and a sham NET group in children with ADHD. 41 A systematic review assessed the effect of chiropractic care on children with ADHD concluding that there is insufficient evidence to evaluate the efficacy of this intervention in this population. 42 Neurofeedback (three studies) The clinical efficacy of neurofeedback versus computerised attention skills training as a control in children with ADHD was evaluated in an RCT. 43 For parent and teacher ratings, improvements in the neurofeedback group were superior to those in the control group. 30 Aug 12 Sept 2011 (9am) 19 of 105

20 A six-month follow-up study of the above RCT was identified. 44 Improvements in the neurofeedback group at follow-up were superior to those of the control group. An additional RCT was identified which compared neurofeedback training with computerised attention skills training in children with ADHD. 45 The aim of this study was to further understand the neuronal mechanisms of neurofeedback training. Behavioural training (three studies) One RCT evaluated the efficacy of a dialectal behavioural therapy-based method compared with a discussion group in adults with ADHD. 46 A beneficial reduction in ADHD symptoms was observed in the skills training group. Electro-acupuncture with behaviour therapy on preschool children with ADHD was assessed in an RCT. 47 Compared with a control group which received sham electro- 30 Aug 12 Sept 2011 (9am) 20 of 105

21 acupuncture and behaviour therapy, the intervention demonstrated a positive effect in reducing ADHD symptoms. One RCT evaluated a HeartMath self-regulation skills and coherence training programme in children with ADHD. 48 Improvements in various aspects of cognitive functioning were observed. Cognitive behavioural therapy (two studies) One RCT was identified which compared cognitive behavioural therapy (CBT) with relaxation and education support in adults with ADHD. 49 The results of the study indicated that lower posttreatment scores on both the Clinical Global Impression scale and the ADHD rating scale were observed in the CBT group. In addition, self-reported symptoms were also significantly improved for CBT. An RCT evaluated the efficacy of a 12-week manualised meta-cognitive therapy group intervention compared with supportive therapy in adults with ADHD. 50 Improvement in 30 Aug 12 Sept 2011 (9am) 21 of 105

22 dimensional and categorical estimates of severity of ADHD symptoms was observed in the meta-cognitive therapy group compared with supportive therapy. School-based interventions (three studies) One RCT was identified which conducted a school-based randomised interventional trial to determine whether intervention-induced reductions in ADHD symptoms reduced future tobacco use. 51 The intervention was a classroombased intervention called the Good Behaviour Game. The results of the study indicated that interventions which target ADHD symptoms may protect children from early-onset smoking. A small-scale RCT evaluated the efficacy of an after-school treatment programme compared with a community comparison for adolescents with ADHD. 52 Small beneficial effects were observed for behavioural and academic outcomes. 30 Aug 12 Sept 2011 (9am) 22 of 105

23 The Child Life and Attention Skills Program was evaluated in one RCT. 53 This was a behavioural psychosocial treatment for children with ADHD integrated across home and school. The results of the study indicated that children randomised to the intervention group had significantly fewer inattention symptoms and significantly improved social and organisational skills compared with the control group. Other interventions (seven studies) A small scale RCT was identified which evaluated the use of binaural auditory beat stimulation in reducing symptoms of ADHD. 54 The results of the study indicated that symptoms of inattention were not significantly reduced in the intervention group. A systematic review assessed the effect of psychoeducation programmes on clinical outcomes in children and adolescents with ADHD. 55 Positive outcomes measured as improvement on a number of different variables including 30 Aug 12 Sept 2011 (9am) 23 of 105

24 parent and child satisfaction were observed. A protocol for an RCT was identified which aims to determine the efficacy of a behavioural sleep programme in treating sleep problems experienced by children with ADHD. 56 An RCT evaluating the efficacy of the First Step to Success intervention for adolescents with ADHD was identified. 57 The programme had a beneficial effect for some aspects including disruptive behaviour symptoms and social functioning but intervention effects on the home-based assessments of problem behaviours were not significant. A Cochrane systematic review protocol was identified with the aim of assessing the beneficial and harmful effects of social skills training in children and adolescents with ADHD. 33 The effect of environments on attention in children with ADHD was assessed in a controlled trial. 58 The results of the study indicated that children with ADHD concentrated better after a walk in the park compared with a walk in town or a 30 Aug 12 Sept 2011 (9am) 24 of 105

25 neighbourhood walk. The impact of a physical therapy intervention in improving motor function in children with ADHD and developmental coordination disorder was evaluated in a small scale RCT. 59 The intervention had a beneficial impact on the motor performance in this population. Summary In general, the identified new evidence supports the current guideline recommendations which state that parent-training and education programmes are recommended in the management of children with ADHD. The results of the studies relating to CBT in adults with ADHD already treated with medication are supportive of the current guideline recommendation which suggests that for adults with ADHD stabilised on medication but with persisting functional impairment associated with the disorder, or where there has been 30 Aug 12 Sept 2011 (9am) 25 of 105

26 no response to drug treatment, a course of either group or individual CBT to address the person s functional impairment should be considered. Group therapy is recommended as the first-line psychological treatment because it is the most cost effective. No studies were identified which examined the use of CBT in children with ADHD. In terms of behavioural training and school-based behavioural interventions, new evidence was identified which indicated a beneficial effect of the training programmes evaluated. However, the studies compared different behavioural training interventions where the content is likely to differ and focused on different age groups (preschool children, school children and adults with ADHD). As such, there is insufficient new evidence in this area to update the guideline recommendations on psychological interventions and parent training. Three RCTs were identified focusing on neurofeedback for control 30 Aug 12 Sept 2011 (9am) 26 of 105

27 of ADHD symptoms, which is a new intervention not currently recommended by the guideline. However, feedback from the GDG indicated that this treatment is fairly experimental at the moment and currently has restricted use in the UK. Therefore, it may be pertinent to await further evidence, particularly on the benefits, harms and cost-effectiveness of this treatment, before an update is commissioned. This area will be factored into the future reviews of this guideline. There is currently insufficient evidence relating to homeopathy, meditation therapies and acupuncture as treatments for ADHD to make a conclusion about the effectiveness of these interventions. Lastly, in terms of other interventions, the identified evidence incorporated different psychological interventions (including physical therapy, psychoeducation and binaural auditory beat stimulation) making it difficult to compare the different trials. As such, insufficient evidence was identified to update the guideline recommendations 30 Aug 12 Sept 2011 (9am) 27 of 105

28 on psychological interventions and parent training. Clinical area 4: Interventions for children with ADHD in educational settings Clinical question Summary of evidence Relevance to guideline recommendations Q: For people with ADHD do educational interventions produce harm/benefits on the desired outcomes? Relevant section of guideline Interventions for children with ADHD in educational settings Recommendations Through an assessment of abstracts from the high-level RCT search, one study relevant to the clinical question was identified. School-based screening for ADHD (One study) A further RCT assessed the impact of early school-based screening and educational interventions on longer-term outcomes in children with ADHD. 60 This was a populationbased 5-year follow-up study conducted in schools in England. None of the interventions were associated with improved outcomes. No new evidence was identified which would invalidate current guideline recommendation(s). Summary In terms of school-based screening for ADHD, no new evidence 30 Aug 12 Sept 2011 (9am) 28 of 105

29 was identified which would invalidate the current guideline recommendation which states that universal screening for ADHD should not be undertaken in nursery, primary and secondary schools. No evidence was identified which evaluated the effect of teacher training on children with ADHD. Clinical area 5: Dietary interventions Clinical question Summary of evidence Relevance to guideline recommendations Q: For people with ADHD do dietary interventions produce Through an assessment of abstracts from the high-level RCT search, 12 studies relevant to the clinical question were identified. Potential new evidence identified relating to the harm/benefits on the desired use of polyunsaturated Elimination diets (three studies) outcomes? fatty acids for treatment Relevant section of guideline Dietary interventions Recommendations One small RCT of 27 children assessed the efficacy of an elimination diet in reducing symptoms of ADHD. 61 The number of clinical responders in the intervention group was greater than that in the control group. An additional small scale RCT focusing on elimination diets investigated their effects on physical and sleep complaints in of ADHD symptoms whereby some symptom control, typically in a subgroup of study participants, has been reported in some 30 Aug 12 Sept 2011 (9am) 29 of 105

30 27 children with ADHD. 62 The results indicated that the number of physical and sleep complaints were significantly lower in the diet group compared with control. A third RCT was identified which aimed to investigate whether there is a connection between diet and behaviour in children with ADHD. 63 The authors concluded that a strictly supervised restricted elimination diet may be a valuable instrument to assess whether ADHD is induced by food. studies. Nutritional supplementation (two studies) One RCT examined the effects of zinc supplementation in American children with ADHD. 64 Children with ADHD were randomly assigned to zinc supplementation or placebo for 13 weeks followed by five weeks with added d-amphetamine. The results indicated that clinical outcomes were equivocal. Iron supplementation in treating ADHD in children was evaluated in a RCT. 65 The authors concluded that iron supplementation should be investigated as a potential 30 Aug 12 Sept 2011 (9am) 30 of 105

31 intervention for children with low iron levels and ADHD. Fatty acids (seven studies) A small RCT assessed the efficacy of n-3 polyunsaturated fatty acid (PUFA) supplementation versus sunflower oil as a placebo in children with ADHD. 66 The n-3 PUFA was well tolerated whilst a subgroup of children achieved symptom control. A placebo-controlled RCT evaluated the efficacy of n-3 PUFA supplementation (eicosapentaenoic acid) in children with ADHD. 67 An improvement in symptoms following the 15-week PUFA treatment was observed in two ADHD subgroups (oppositional and less hyperactive/impulsive children). A placebo-controlled one-way crossover RCT assessed omega 3 and 6 PUFAs supplementation in children and adolescents with ADHD. 68 The results of the study indicated that the majority of study participants did not respond to PUFA treatment although a subgroup experienced a 25% 30 Aug 12 Sept 2011 (9am) 31 of 105

32 reduction in ADHD symptoms. A placebo-controlled RCT was identified which examined the effect of fatty acid supplementation in children with ADHD. 69 No significant differences in any treatment effects were observed between the two groups. One RCT including 132 children with ADHD were randomised to PUFAs alone, PUFAs plus micronutrients or placebo. 70 Positive treatment effects were observed for both PUFA groups although no additional effects were found with the micronutrients. A similar RCT examined the effect of PUFA and micronutrient supplementation on cognition in children with ADHD. 71 After 15 weeks improvements in a test of the ability to switch and control attention was observed in the PUFA group compared to placebo. No significant improvement in other cognitive measures was observed. A Cochrane systematic review protocol was identified which aims to compare the effectiveness of PUFA in treating ADHD in children and adolescents Aug 12 Sept 2011 (9am) 32 of 105

33 Summary In summary, new literature was identified focusing on the use of elimination diets in reducing symptoms of ADHD. However, these were small scale RCTs in which the type of elimination diet used was not described in the abstract of the study. As such, no conclusive new evidence was identified which would invalidate the current guideline recommendation which states that elimination of artificial colouring and additives from the diet is not recommended as a generally applicable treatment for children and young people with ADHD. In terms of dietary fatty acid, new evidence was identified relating to the use of PUFAs for treatment of ADHD symptoms. The majority of the studies identified reported some symptom control typically in a subgroup of study participants. As such, the identified new evidence may have the potential to change the direction of the current guideline recommendation which states that dietary fatty acid 30 Aug 12 Sept 2011 (9am) 33 of 105

34 supplementation is not recommended for the treatment of ADHD in children and young people. However, heterogeneity across the identified studies was evident relating to the participants (some studies included children whilst others also included adolescents) and comparators (one study compared two fatty acids, one study used vitamin C as a placebo whilst the other studies compared fatty acids with placebo). Taking study heterogeneity into account and that this is a small area of the guideline, this new evidence may not be significant enough to warrant updating the guideline at this point. Clinical area 6: Pharmacological treatment Clinical question Summary of evidence Relevance to guideline recommendations Q: For people with ADHD does drug treatment produce harm/benefits on the desired outcomes? Relevant section of guideline Through the high level RCT search 156 studies relevant to the clinical question were identified. It should be noted that the clinical studies identified used a large number of different instruments to measure key outcomes, core symptoms, and/or quality of life making comparisons across the different trials difficult. In addition, the duration of studies differed considerably whilst few direct head- No new evidence was identified which would invalidate current guideline recommendation(s). 30 Aug 12 Sept 2011 (9am) 34 of 105

35 Pharmacological interventions to-head comparisons of active drugs were identified. Recommendations General systematic reviews (10 studies) Efficacy of pharmacological treatments Three systematic reviews and a meta-analysis indicated a generally beneficial effect of pharmacological treatment for ADHD. 73,74,75,76 One systematic review was identified which aimed to determine whether sex and age has an effect on pharmacological treatment of ADHD. 77 The review concluded that pharmacological therapy for ADHD has efficacy for both sexes and across all ages. A pharmacoepidemiological study was identified which investigated the prevalence of pharmacological treatment for ADHD in the UK. 78 The results of the study indicated that there has been an increase in GP prescribing for ADHD from 1999 to 2006 although some young adults have difficulty in obtaining treatment for ADHD after discharge from paediatric 30 Aug 12 Sept 2011 (9am) 35 of 105

36 services. Methylphenidate The efficacy of methylphenidate and amphetamine formulations in treating ADHD in children and adolescents was assessed in a meta-analysis. 79 The results of the metaanalysis indicated that amphetamine products may be slightly more efficacious compared with methylphenidate. The harms and benefits of pharmacological treatment for ADHD in adults were assessed in a systematic review and meta-analysis. 80 The review concluded that current evidence supports the use of immediate release methylphenidate in adults with ADHD. Atomoxetine A meta-analysis was identified which examined aggression/hostility-related events among children and adults treated with atomoxetine for ADHD. 81 Aggression/hostility- 30 Aug 12 Sept 2011 (9am) 36 of 105

37 related events occurred more often in paediatric patients treated with atomoxetine compared with placebo. Adverse events A study was identified which analysed data from 49 RCTs which concluded that psychosis or mania is a potential adverse reaction to drug treatment for ADHD in children. 82 NIMH Collaborative Multisite Multimodal Treatment Study of Children with ADHD (MTA) study follow up A prospective follow-up of the MTA study was identified which aimed to determine long-term effects 6-8 years after initial enrolment of participants. 83 The study concluded that the type or intensity of 14 months of treatment for ADHD in children does not predict functioning 6-8 years later. Children and adolescents (88 studies) 30 Aug 12 Sept 2011 (9am) 37 of 105

38 Methylphenidate (41 studies) Methylphenidate versus placebo Five RCTs were identified which evaluated the effect of the methylphenidate-osmotic release oral system (OROS) in children and adolescents with ADHD. 84,85,86,87,88 A beneficial effect of OROS methylphenidate was observed. 18 RCTs were identified which assessed the efficacy and safety of methylphenidate in children and adolescents with ADHD. 89,90,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106 In general, a beneficial effect of methylphenidate treatment on some measured outcomes (including functional outcomes, working memory, word accuracy, reaction time variability and motor function) was observed. A post-hoc analysis of an RCT was identified which aimed to determine whether pretreatment clinical and social characteristics influenced the response to methylphenidate in children with ADHD. 107 The results of the study indicated that children with three or more comorbid disorders did not 30 Aug 12 Sept 2011 (9am) 38 of 105

39 respond to methylphenidate treatment. A crossover trial was identified which evaluated sex differences in response to methylphenidate among children with ADHD. 108 Females had a superior response at 1.5 hours after the first dose although they had an inferior response to medication, compared with males, at the 12-hour time point. A double-blind placebo controlled RCT evaluated low dose and high dose methylphenidate in children with inattentive or combined type ADHD. 109 The study describes implications for medication titration practices in children with ADHD. A double-blind within subject RCT was identified which compared methylphenidate treatment with placebo on food consumption in children with ADHD. 110 The results of the study indicated that food consumption decreased as a function of methylphenidate dose. A double-blind placebo controlled two-week medication trial of methylphenidate in children with ADHD and comorbid 30 Aug 12 Sept 2011 (9am) 39 of 105

40 disorders was identified. 111 The study concluded that the type of comorbid disorder may have an impact on response to methylphenidate. Methylphenidate versus atomoxetine A double-blind RCT was identified where children and adolescents with ADHD were randomised to osmotically released methylphenidate, atomoxetine or placebo. 112 A switch from methylphenidate to atomoxetine after six weeks occurred under double-blind conditions. The response rates for both treatments were greater than placebo with osmotically released methylphenidate superior to atomoxetine. Multilayer-release methylphenidate versus immediate-release methylphenidate Three RCTs were identified which compared multilayerrelease and immediate-release methylphenidate in children 30 Aug 12 Sept 2011 (9am) 40 of 105

41 with ADHD. 113,114,115 The results of one study indicated that multilayer-release methylphenidate was maintained throughout the school day. 113 The other two studies measured improvements in the outcomes tested for both treatments. 114,115 Dexmethylphenidate versus placebo Three RCTs evaluated the efficacy of dexmethylphenidate extended release (ER) in children with ADHD indicating a beneficial effect over placebo on the measured outcomes. 116,117,118 A double-blind crossover RCT was identified which compared the efficacy and safety of extended-release dexmethylphenidate with extended-release methylphenidate in children with ADHD. 119 The results of the study indicated that both treatments improved ADHD symptoms although extended-release methylphenidate retained a greater effect at the end of the 12 hour study period. 30 Aug 12 Sept 2011 (9am) 41 of 105

42 Methylphenidate versus amphetamine salts A small-scale RCT was identified which evaluated driving performance in adolescents with ADHD treated with methylphenidate, extended-release mixed amphetamine salts or placebo. 120 The results of the study indicated that neither drug treatment was associated with significant worsening of driving simulator performance relative to placebo although on-road driving errors were more common in those treated with extended-release mixed amphetamine salts compared with placebo. Methylphenidate versus amantadine A small-scale RCT was identified which evaluated the efficacy of amantadine in comparison with methylphenidate for treatment of children and adolescents with ADHD. 121 The results of the study indicated that no significant differences between the two groups were observed for Parent and 30 Aug 12 Sept 2011 (9am) 42 of 105

43 Teacher Rating Scale scores. Methylphenidate versus venlafaxine A small-scale RCT was identified which compared the efficacy of methylphenidate versus venlafaxine for ADHD in children and adolescents. 122 No significant differences in Parent and Teacher Rating Scale scores between the two groups were observed. Methylphenidate versus Ginko biloba An RCT was identified which evaluated the effect of methylphenidate versus Ginko biloba in children with ADHD. 123 The results of the study demonstrated that methylphenidate was more effective than Ginko biloba for treatment of ADHD in children. Cost-effectiveness evaluations An economic analysis was identified which evaluated the 30 Aug 12 Sept 2011 (9am) 43 of 105

44 cost-effectiveness of OROS methylphenidate in adolescents with ADHD. 124 The study concluded that OROS methylphenidate is a cost-effect treatment for adolescents with ADHD. Dexamphetamine (One study) Dexamphetamine versus placebo A Cochrane systematic review was identified which evaluated the effectiveness of amphetamine for treatment of ADHD in children or adults with or without intellectual disability. 125 One study was included in the review which indicated no significant difference between amphetamine and placebo for any ADHD measures. Atomoxetine (29 studies) Atomoxetine versus placebo 17 RCTs and a systematic review were identified which assessed the efficacy and safety of atomoxetine in children 30 Aug 12 Sept 2011 (9am) 44 of 105

45 and adolescents with ADHD. 126,127,128,129,130,131,132,133,134,135,136,137,138,139,140,141,142 In general, a beneficial effect of atomoxetine treatment on ADHD symptoms and other measured outcomes was observed. Adverse events were reported in some studies. A post-hoc meta-analysis aimed to determine the effect of comorbid ODD in ADHD on atomoxetine treatment. 143 Atomoxetine treatment significantly reduced ADHD symptoms in both ODD-comorbid and noncomorbid subjects. In addition, a study which conducted a post-hoc analysis of an RCT was identified which measured the effects of atomoxetine on high-risk behaviours and QoL in adolescents with ADHD. 144 The results of the study suggested that atomoxetine treatment improved self-reported high-risk behaviours and QoL in adolescents with ADHD. A small-scale placebo controlled RCT was identified which examined the effect of augmenting atomoxetine treatment with extended-release methylphenidate in children with 30 Aug 12 Sept 2011 (9am) 45 of 105

46 ADHD. 145 Atomoxetine treatment was found to be beneficial but addition of methylphenidate did not improve the response. The long-term safety and tolerability of atomoxetine treatment of ADHD in children and adolescents was evaluated in a pooled analysis of RCTs. 146 The results of the study indicated that less than 6% of patients exhibited aggressive/hostile behaviours. An RCT was identified which evaluated the utility of above standard doses of atomoxetine to treat ADHD in children and adolescents. 137 No advantage in increasing the dose of atomoxetine was observed. A Cochrane systematic review protocol was identified with the aim of evaluating the effectiveness of atomoxetine for the treatment of ADHD in people with intellectual disabilities. 147 Two atomoxetine titration dosing schedules (slow or fast titration) were evaluated in adolescents with ADHD. 148 The 30 Aug 12 Sept 2011 (9am) 46 of 105

47 results of the RCT indicated a greater improvement in ADHD symptoms with the higher dose tested. Atomoxetine versus methylphenidate A double-blind RCT was identified which compared oncedaily atomoxetine with twice-daily methylphenidate in children and adolescents with ADHD. 149 The results of the study indicated that atomoxetine was non-inferior to methylphenidate for the treatment of ADHD symptoms although more adverse events were observed in the atomoxetine group. Atomoxetine versus amphetamine salts Analysis of data from an RCT was undertaken to compare the efficacy of amphetamine salts with atomoxetine in children with ADHD. 150 Greater improvements were observed in the group receiving amphetamine salts compared with atomoxetine. 30 Aug 12 Sept 2011 (9am) 47 of 105

48 Cost-effectiveness evaluations Three studies were identified which examined the costeffectiveness of atomoxetine treatment in children with ADHD, one of which was conducted in the UK. 151,152,153 All identified studies indicated that atomoxetine is an effective alternative treatment which provides value-for-money in children with ADHD. Clonidine (four studies) Clonidine versus placebo The safety and tolerability of clonidine alone or in combination with methylphenidate in children with ADHD was assessed in three double-blind placebo controlled RCTs. 154,155,156 The results indicated that methylphenidate was most efficacious for treatment of ADHD. Adverse events were more common in the clonidine treated group. 30 Aug 12 Sept 2011 (9am) 48 of 105

49 Clonidine versus carbamazepine An RCT was identified which compared the efficacy of clonidine and carbamazepine in children with ADHD. 157 Compared to carbamazepine, clonidine improved symptoms of hyperactivity and impulsivity however no significant improvement in inattention symptoms was observed. Modafinil (three studies) Modafinil versus placebo A secondary analysis of three placebo controlled RCTs was carried out in one study to evaluate the efficacy of modafinil in children and adolescents with ADHD. 158 Modafinil improved ADHD symptoms and behaviours in children and adolescents with inattentive and combined subtypes of ADHD. The efficacy of modafinil for ADHD in children and adolescents was evaluated in a small-scale double-blind placebo controlled RCT. 159 After six weeks of treatment a 30 Aug 12 Sept 2011 (9am) 49 of 105

50 beneficial effect of modafinil over placebo was observed although decreased appetite occurred more frequently in the treatment group. Modafinil versus methyphenidate A double-blind RCT was identified which evaluated the efficacy of modafinil for ADHD in children and adolescents compared with methylphenidate. 160 Antidepressants (one study) Tricyclic antidepressants A Cochrane systematic review protocol was identified with the aim of assessing the efficacy of tricyclic antidepressants in reducing ADHD symptoms among children and adolescents. 161 Atypical antipsychotics (three studies) Risperidone versus placebo 30 Aug 12 Sept 2011 (9am) 50 of 105

51 A double-blind placebo controlled RCT was identified which evaluated the effect of risperidone for treatment-resistant aggression in children with ADHD. 162 Risperidone was moderately effective when used in combination with psychostimulants for treatment-resistant aggression in children with ADHD. A Cochrane systematic review was identified which evaluated the effectiveness of risperidone for treatment of ADHD in children or adults with or without intellectual disability. 163 No studies met the inclusion criteria for the review. Divalproex versus placebo The efficacy of divalproex in reducing aggressive behaviour in children with ADHD was assessed in a small-scale doubleblind placebo controlled RCT. 164 The results of the study indicated that more children in the intervention group had remission of aggressive symptoms. 30 Aug 12 Sept 2011 (9am) 51 of 105

52 Other treatments (six studies) Acetyl-L-carnitine versus placebo One placebo controlled RCT was identified which reported the results of a preliminary trial of acetyl-l-carnitine (a metabolite involved in energy metabolism) in children with ADHD. 165 The results of the study indicated no effect on the population studied. Buspirone versus methylphenidate A small-scale double-blind RCT was identified which compared buspirone with methylphenidate for treatment of ADHD in children. 166 No significant differences were observed between the two treatments on the total scores measured by the parent and teacher ADHD rating scale although methylphenidate had a beneficial effect over buspirone in reducing symptoms of inattention. 30 Aug 12 Sept 2011 (9am) 52 of 105

53 Aripiprazole versus placebo A small-scale double-blind placebo controlled RCT was identified which evaluated aripiprazole for treatment of children and adolescents with bipolar disorder comorbid with ADHD. 167 No significant treatment effect on ADHD symptoms were observed. Melatonin versus placebo A double-blind placebo controlled RCT was identified which assessed the effect of melatonin treatment in children with ADHD and insomnia. 168 Study outcomes included sleep, behaviour, cognition and QoL. The results of the study indicated that total sleep time increased but no effect on behaviour, cognition or QoL was observed. Mixed amphetamine salts versus placebo An RCT was identified which examined whether pairing a placebo with stimulant medication (mixed amphetamine 30 Aug 12 Sept 2011 (9am) 53 of 105

54 salts) produces a response which enables children with ADHD to take lower doses of stimulant medication. 169 Hypericum perforatum (St John s Wort) versus placebo A small-scale double-blind placebo controlled RCT was identified which evaluated the efficacy of Hypericum perforatum for the treatment of ADHD symptoms in children and adolescents. 170 No difference in change of ADHD symptoms was observed between the two groups. No RCTs were identified which evaluated the efficacy and safety of bupropion in children and adolescents with ADHD. Summary On the whole, the identified new evidence indicates that methylphenidate and atomoxetine in the treatment of children with ADHD generally have beneficial effects on ADHD symptoms and other outcomes measured. Study abstracts did not specify if the 30 Aug 12 Sept 2011 (9am) 54 of 105