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1 Hollis, Chris and Pennant, Mary and Cuenca, Jose and Glazebrook, Cris and Kendall, Tim and Whittington, Craig and Stockton, Sarah and Larsson, Linnéa and Bunton, Penny and Dobson, Suzanne and Groom, Madeleine J. and Hedderly, Tammy and Heyman, Isobel and Jackson, Georgina M. and Jackson, Stephen and Murphy, Tara and Rickards, Hugh and Robertson, Mary and Stern, Jeremy (2016) Clinical effectiveness and patient perspectives of different treatment strategies for tics in children and adolescents with Tourette syndrome: a systematic review and qualitative analysis. Health Technology Assessment, 20 (4). ISSN Access from the University of Nottingham repository: Copyright and reuse: The Nottingham eprints service makes this work by researchers of the University of Nottingham available open access under the following conditions. This article is made available under the University of Nottingham End User licence and may be reused according to the conditions of the licence. For more details see: A note on versions: The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher s version. Please see the repository url above for details on accessing the published version and note that access may require a subscription. For more information, please contact eprints@nottingham.ac.uk

2 Clinical effectiveness and patient perspectives of different treatment strategies for tics in children and adolescents with Tourette syndrome: a systematic review and qualitative analysis Chris Hollis, 1* Mary Pennant, 2 José Cuenca, 3 Cris Glazebrook, 1 Tim Kendall, 2 Craig Whittington, 2 Sarah Stockton, 2 Linnéa Larsson, 2 Penny Bunton, 4 Suzanne Dobson, 5 Madeleine Groom, 1 Tammy Hedderly, 6 Isobel Heyman, 7 Georgina M Jackson, 1 Stephen Jackson, 8 Tara Murphy, 9 Hugh Rickards, 10 Mary Robertson 11 and Jeremy Stern 5 1 Division of Psychiatry and Applied Psychology, The Institute of Mental Health, University of Nottingham, Developmental Psychiatry, Queen s Medical Centre, Nottingham, UK 2 National Collaborating Centre for Mental Health, Royal College of Psychiatrists, London, UK 3 Institute of Mental Health, University of Nottingham Innovation Park, University of Nottingham, Nottingham, UK 4 School of Psychological Sciences, University of Manchester, Manchester, UK 5 Tourettes Action, The Meads Business Centre, Farnborough, Hampshire, UK 6 Paediatric Neurology Department, Kings College Hospital NHS Foundation Trust, London, UK 7 Department of Child and Adolescent Mental Health, Great Ormond Street Hospital for Children, London, UK 8 School of Psychology, University of Nottingham, Nottingham, UK 9 Institute of Neurology, University College London, London, UK 10 National Centre for Mental Health, Birmingham, UK 11 Department of Neurology, St George s University Hospitals NHS Foundation Trust, London, UK *Corresponding author Declared competing interests of authors: Madeleine Groom reports grants from Shire Pharmaceuticals and personal fees from Janssen Pharmaceuticals outside the submitted work.

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4 Published XXXX 2015 DOI: /hta19XXX This report should be referenced as follows: Hollis C, Pennant M, Cuenca J, Glazebrook C, Kendall T, Whittington C, et al. Clinical effectiveness and patient perspectives of different treatment strategies for tics in children and adolescents with Tourette syndrome: a systematic review and qualitative analysis. Health Technol Assess 2015;19(X). Health Technology Assessment is indexed and abstracted in Index Medicus/MEDLINE, Excerpta Medica/EMBASE, Science Citation Index Expanded (SciSearch ) and Current Contents / Clinical Medicine.

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6 Health Technology Assessment HTA/HTA TAR ISSN (Print) ISSN (Online) Impact factor: Health Technology Assessment is indexed in MEDLINE, CINAHL, EMBASE, The Cochrane Library and the ISI Science Citation Index. This journal is a member of and subscribes to the principles of the Committee on Publication Ethics (COPE) ( Editorial contact: nihredit@southampton.ac.uk The full HTA archive is freely available to view online at Print-on-demand copies can be purchased from the report pages of the NIHR Journals Library website: Criteria for inclusion in the Health Technology Assessment journal Reports are published in Health Technology Assessment (HTA) if (1) they have resulted from work for the HTA programme, and (2) they are of a sufficiently high scientific quality as assessed by the reviewers and editors. Reviews in Health Technology Assessment are termed systematic when the account of the search appraisal and synthesis methods (to minimise biases and random errors) would, in theory, permit the replication of the review by others. HTA programme The HTA programme, part of the National Institute for Health Research (NIHR), was set up in It produces high-quality research information on the effectiveness, costs and broader impact of health technologies for those who use, manage and provide care in the NHS. Health technologies are broadly defined as all interventions used to promote health, prevent and treat disease, and improve rehabilitation and long-term care. The journal is indexed in NHS Evidence via its abstracts included in MEDLINE and its Technology Assessment Reports inform National Institute for Health and Care Excellence (NICE) guidance. HTA research is also an important source of evidence for National Screening Committee (NSC) policy decisions. For more information about the HTA programme please visit the website: This report The research reported in this issue of the journal was funded by the HTA programme as project number 10/142/01. The contractual start date was in June The draft report began editorial review in August 2013 and was accepted for publication in August The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors report and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report. This report presents independent research funded by the National Institute for Health Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, NETSCC, the HTA programme or the Department of Health. Queen s Printer and Controller of HMSO This work was produced by Hollis et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. Published by the NIHR Journals Library ( produced by Prepress Projects Ltd, Perth, Scotland (

7 Editor-in-Chief of Health Technology Assessment and NIHR Journals Library Professor Tom Walley Director, NIHR Evaluation, Trials and Studies and Director of the HTA Programme, UK NIHR Journals Library Editors Professor Ken Stein Chair of HTA Editorial Board and Professor of Public Health, University of Exeter Medical School, UK Professor Andree Le May Chair of NIHR Journals Library Editorial Group (EME, HS&DR, PGfAR, PHR journals) Dr Martin Ashton-Key Consultant in Public Health Medicine/Consultant Advisor, NETSCC, UK Professor Matthias Beck Chair in Public Sector Management and Subject Leader (Management Group), Queen s University Management School, Queen s University Belfast, UK Professor Aileen Clarke Professor of Public Health and Health Services Research, Warwick Medical School, University of Warwick, UK Dr Tessa Crilly Director, Crystal Blue Consulting Ltd, UK Dr Peter Davidson Director of NETSCC, HTA, UK Ms Tara Lamont Scientific Advisor, NETSCC, UK Professor Elaine McColl Director, Newcastle Clinical Trials Unit, Institute of Health and Society, Newcastle University, UK Professor William McGuire Professor of Child Health, Hull York Medical School, University of York, UK Professor Geoffrey Meads Professor of Health Sciences Research, Health and Wellbeing Research and Development Group, University of Winchester, UK Professor John Norrie Health Services Research Unit, University of Aberdeen, UK Professor John Powell Consultant Clinical Adviser, National Institute for Health and Care Excellence (NICE), UK Professor James Raftery Professor of Health Technology Assessment, Wessex Institute, Faculty of Medicine, University of Southampton, UK Dr Rob Riemsma Reviews Manager, Kleijnen Systematic Reviews Ltd, UK Professor Helen Roberts Professor of Child Health Research, UCL Institute of Child Health, UK Professor Helen Snooks Professor of Health Services Research, Institute of Life Science, College of Medicine, Swansea University, UK Professor Jim Thornton Professor of Obstetrics and Gynaecology, Faculty of Medicine and Health Sciences, University of Nottingham, UK Please visit the website for a list of members of the NIHR Journals Library Board: Editorial contact: nihredit@southampton.ac.uk NIHR Journals Library

8 DOI: /hta19XXX HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. X Abstract Clinical effectiveness and patient perspectives of different treatment strategies for tics in children and adolescents with Tourette syndrome: a systematic review and qualitative analysis Chris Hollis, 1* Mary Pennant, 2 José Cuenca, 3 Cris Glazebrook, 1 Tim Kendall, 2 Craig Whittington, 2 Sarah Stockton, 2 Linnéa Larsson, 2 Penny Bunton, 4 Suzanne Dobson, 5 Madeleine Groom, 1 Tammy Hedderly, 6 Isobel Heyman, 7 Georgina M Jackson, 1 Stephen Jackson, 8 Tara Murphy, 9 Hugh Rickards, 10 Mary Robertson 11 and Jeremy Stern 5 1 Division of Psychiatry and Applied Psychology, The Institute of Mental Health, University of Nottingham, Developmental Psychiatry, Queen s Medical Centre, Nottingham, UK 2 National Collaborating Centre for Mental Health, Royal College of Psychiatrists, London, UK 3 Institute of Mental Health, University of Nottingham Innovation Park, University of Nottingham, Nottingham, UK 4 School of Psychological Sciences, University of Manchester, Manchester, UK 5 Tourettes Action, The Meads Business Centre, Farnborough, Hampshire, UK 6 Paediatric Neurology Department, Kings College Hospital NHS Foundation Trust, London, UK 7 Department of Child and Adolescent Mental Health, Great Ormond Street Hospital for Children, London, UK 8 School of Psychology, University of Nottingham, Nottingham, UK 9 Institute of Neurology, University College London, London, UK 10 National Centre for Mental Health, Birmingham, UK 11 Department of Neurology, St George s University Hospitals NHS Foundation Trust, London, UK *Corresponding author Chris.Hollis@nottingham.ac.uk Background: Tourette syndrome (TS) is a neurodevelopmental condition characterised by chronic motor and vocal tics affecting up to 1% of school-age children and young people and is associated with significant distress and psychosocial impairment. Objective: To conduct a systematic review of the benefits and risks of pharmacological, behavioural and physical interventions for tics in children and young people with TS (part 1) and to explore the experience of treatment and services from the perspective of young people with TS and their parents (part 2). Data Sources: For the systematic reviews (parts 1 and 2), mainstream bibliographic databases, the Cochrane Library, education, social care and grey literature databases were searched using subject headings and text words for tic* and Tourette* from database inception to January Queen s Printer and Controller of HMSO This work was produced by Hollis et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. vii

9 ABSTRACT Review/research methods: For part 1, randomised controlled and controlled before-and-after studies of pharmacological, behavioural or physical interventions in children or young people (aged < 18 years) with TS or chronic tic disorder were included. Mixed studies and studies in adults were considered as supporting evidence. Risk of bias associated with each study was evaluated using the Cochrane tool. When there was sufficient data, random-effects meta-analysis was used to synthesize the evidence and the quality of evidence for each outcome was assessed using the Grading of Recommendations Assessment, Development and Evaluation approach. For part 2, qualitative studies and survey literature conducted in populations of children/ young people with TS or their carers or in health professionals with experience of treating TS were included in the qualitative review. Results were synthesized narratively. In addition, a national parent/carer survey was conducted via the Tourettes Action website. Participants included parents of children and young people with TS aged under 18 years. Participants (young people with TS aged years) for the in-depth interviews were recruited via a national survey and specialist Tourettes clinics in the UK. Results: For part 1, 70 studies were included in the quantitative systematic review. The evidence suggested that for treating tics in children and young people with TS, antipsychotic drugs [standardised mean difference () 0.74, 95% confidence interval (CI) 1.08 to 0.41; n = 75] and noradrenergic agents [clonidine (Dixarit, Boehringer Ingelheim) and guanfacine: 0.72, 95% CI 1.03 to 0.40; n = 164] are effective in the short term. There was little difference among antipsychotics in terms of benefits, but adverse effect profiles do differ. Habit reversal training (HRT)/comprehensive behavioural intervention for tics (CBIT) was also shown to be effective ( 0.64, 95% CI 0.99 to 0.29; n = 133). For part 2, 295 parents/carers of children and young people with TS contributed useable survey data. Forty young people with TS participated in in-depth interviews. Four studies were in the qualitative review. Key themes were difficulties in accessing specialist care and behavioural interventions, delay in diagnosis, importance of anxiety and emotional symptoms, lack of provision of information to schools and inadequate information regarding medication and adverse effects. Limitations: The number and quality of clinical is low and this downgrades the strength of the evidence and conclusions. Conclusions: Antipsychotics, noradrenergic agents and HRT/CBIT are effective in reducing tics in children and young people with TS. The balance of benefits and harms favours the most commonly used medications: risperidone (Risperdal, Janssen), clonidine and aripiprazole (Abilify, Otsuka). Larger and better-conducted addressing important clinical uncertainties are required. Further research is needed into widening access to behavioural interventions through use of technology including mobile applications ( apps ) and video consultation. Study registration: This study is registered as PROSPERO CRD Funding: The National Institute for Health Research Health Technology Assessment programme. viii NIHR Journals Library

10 DOI: /hta19XXX HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. X Contents List of tables List of figures Glossary List of abbreviations Plain English summary Scientific summary xiii xvii xxxi xxxiii xxxv xxxvii Chapter 1 Introduction 1 Clinical features 1 Epidemiology and prevalence 1 Comorbidities and coexisting psychopathologies 2 The Tourette syndrome phenotype 4 Lifespan prognosis 4 Aetiological theories 5 Cognitive functioning in Tourette syndrome 6 Neurobiology and neuroimaging 7 Treatment interventions 7 Organisation of services and referral pathways for Tourette syndrome in the UK 8 Overall aims and objectives of report 10 Chapter 2 Part 1: systematic review of interventions for tics in children and adolescents with Tourette syndrome 11 Methods 11 Review questions 11 Pharmacological interventions 11 Behavioural interventions 11 Physical interventions 12 Study selection 12 Search strategies 12 Screening 12 Inclusion/exclusion criteria 12 Data abstraction 13 Quality assessment 13 Data analysis 15 Tourette expert group 15 Pharmacological interventions 16 Introduction 16 Antipsychotic drugs 16 Noradrenergic agents 69 Stimulant drugs 94 Anticonvulsant drugs 103 Monoamine oxidase B inhibitors 112 Dopamine receptor agonists 114 Queen s Printer and Controller of HMSO This work was produced by Hollis et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. ix

11 CONTENTS 5HT 3 -receptor antagonists/antiemetic and gastroprokinetic agents 120 Gamma-aminobutyric acid B receptor agonists/skeletal muscle relaxants 127 Tricyclic antidepressants 128 Selective serotonin reuptake inhibitors 133 Nicotinic acetylcholine receptor antagonists 139 Transdermal nicotine 140 Omega-3 fatty acids 147 Head-to-head comparisons between different classes of drugs 153 Overall conclusions from pharmacological intervention 166 Behavioural interventions 167 Introduction 167 Included studies 168 Habit reversal training/comprehensive behavioural intervention for tics 169 Relaxation training 190 Anger control training 191 Parent training 196 Overall conclusions from behavioural intervention 198 Physical interventions 199 Introduction 199 Included studies 200 Deep brain stimulation 201 Repetitive transcranial magnetic stimulation 202 Intravenous immunoglobulin versus placebo 204 Botulinum toxin compared with placebo 208 Acupuncture and Chinese herbs 210 Overall conclusions from physical intervention 216 Paediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection 216 Introduction 216 Included studies 217 Intravenous immunoglobulin and plasma exchange versus placebo 217 Penicillin versus placebo 223 Penicillin compared with azithromycin 228 Summary of Paediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection 230 Overall conclusions from Paediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infection 230 Chapter 3 Qualitative Study of Experiences of Services and Treatments 231 Systematic review of qualitative studies 231 Methods 231 Results 232 Evidence summary 233 Online survey of parents of children with Tourette syndrome and other tic disorders 235 In-depth qualitative interviews with young people with Tourette syndrome 247 Qualitative evidence summary 257 Discussion 259 Conclusion 262 Overall discussion 262 Key findings 262 Implications of findings for practice and research 265 Overall conclusions 266 x NIHR Journals Library

12 DOI: /hta19XXX HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. X Recommendations for further research 266 Why is this important? 266 Why is this important? 267 Why is this important? 268 Why is this important? 268 Why is this important? 268 Why is this important? 269 Why is this important? 269 Why is this important? 269 Acknowledgements 271 References 275 Appendix 1 Search strategies 291 Appendix 2 Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram 313 Appendix 3 Study characteristics 315 Appendix 4 Grading of Recommendations Assessment, Development and Evaluation profile tables 357 Appendix 5 Sensitivity analyses 429 Appendix 6 Excluded studies 433 Appendix 7 Qualitative study of Experiences of Services and Treatment interviewee identifying codes and characteristics 441 Appendix 8 Qualitative study of Experiences of Services and Treatment interview schedule 445 Appendix 9 Demographic characteristics 449 Queen s Printer and Controller of HMSO This work was produced by Hollis et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xi

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14 DOI: /hta19XXX HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. X List of tables TABLE 1 Factors that decrease quality of evidence 14 TABLE 2 Other treatments (alternative/complementary) for tics as reported by parents and carers 242 TABLE 3 Medication and behavioural interventions for tics 243 TABLE 4 Adverse effects of medication as described by parents and carers 244 TABLE 5 Parental ranking of desired outcomes of treatment for tics 245 TABLE 6 Desired outcomes of treatment for tics as reported by parents and carers 246 TABLE 7 Psychoeducation and other treatments by main intervention received (medication and/or behavioural) 247 TABLE 8 Summary characteristics of young people who participated in the interviews 249 TABLE 9 Study characteristics for of pharmacological interventions 316 TABLE 10 Study characteristics for of behavioural therapy 341 TABLE 11 Study characteristics for of physical interventions 347 TABLE 12 Study characteristics for of PANDAS studies 352 TABLE 13 Study characteristics of qualitative studies/surveys 354 TABLE 14 Haloperidol vs. placebo 358 TABLE 15 Pimozide vs. placebo 360 TABLE 16 Risperidone vs. placebo 362 TABLE 17 Ziprasidone vs. placebo 364 TABLE 18 Risperidone vs. pimozide 365 TABLE 19 Haloperidol vs. pimozide 366 TABLE 20 Aripiprazole vs. other antipsychotics 368 TABLE 21 Olanzapine vs. haloperidol 370 TABLE 22 Antipsychotics vs. placebo 371 TABLE 23 Clonidine vs. placebo 372 Queen s Printer and Controller of HMSO This work was produced by Hollis et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xiii

15 LIST OF TABLES TABLE 24 Guanfacine vs. placebo 374 TABLE 25 Clonidine patch vs. placebo patch 375 TABLE 26 Noradrenergic agents vs. placebo 376 TABLE 27 Fluoxetine vs. placebo 377 TABLE 28 Desipramine vs. placebo 378 TABLE 29 Metoclopramide vs. placebo 380 TABLE 30 Ondansetron vs. placebo 382 TABLE 31 Levetiracetam vs. placebo 383 TABLE 32 Topiramate vs. placebo 384 TABLE 33 Methylphenidate vs. placebo 385 TABLE 34 Dexmethylphenidate vs. placebo 388 TABLE 35 All stimulants vs. placebo 389 TABLE 36 Pergolide vs. placebo 390 TABLE 37 Pramipexole vs. placebo 393 TABLE 38 Atomoxetine vs. placebo 395 TABLE 39 Selegiline vs. placebo 397 TABLE 40 Mecamylamine vs. placebo 398 TABLE 41 Baclofen vs. placebo 399 TABLE 42 Nicotine patch vs. placebo 400 TABLE 43 Omega-3 fatty acids vs. placebo 403 TABLE 44 Risperidone vs. clonidine 404 TABLE 45 Fluvoxamine vs. sulpiride 405 TABLE 46 Levetiracetam vs. clonidine 406 TABLE 47 Clonidine vs. desipramine 407 TABLE 48 Clonidine patch vs. haloperidol 407 TABLE 49 Habit reversal training/cbit vs. SP 408 TABLE 50 Videoconference CBIT vs. face-to-face CBIT 412 xiv NIHR Journals Library

16 DOI: /hta19XXX HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. X TABLE 51 Negative practice vs. HRT 413 TABLE 52 Exposure and response prevention vs. HRT 414 TABLE 53 Relaxation training vs. minimal therapy 415 TABLE 54 Anger control training vs. treatment as usual 416 TABLE 55 Parent training vs. treatment as usual 417 TABLE 56 Intravenous immunoglobulin vs. i.v. saline 418 TABLE 57 Botulinum toxin vs. i.v. saline 419 TABLE 58 Acupuncture and Chinese herbs vs. haloperidol and artane 422 TABLE 59 Intravenous immunoglobulin vs. i.v. saline 423 TABLE 60 Plasma exchange vs. i.v. saline 425 TABLE 61 Penicillin vs. placebo 426 TABLE 62 Penicillin vs. azithromycin 428 TABLE 63 Demographic characteristics of parents and carers completing survey 449 TABLE 64 Demographic and clinical characteristics of young people as reported by parents and carers 450 Queen s Printer and Controller of HMSO This work was produced by Hollis et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xv

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18 DOI: /hta19XXX HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. X List of figures FIGURE 1 Current service provision and referral pathways in the UK for TS 9 FIGURE 2 Standardised post-treatment total tic scores for haloperidol compared with placebo in the child and mixed studies 21 FIGURE 3 Standardised motor tic scores for haloperidol compared with placebo in the child and mixed studies 21 FIGURE 4 Standardised post-treatment vocal tic score for haloperidol compared with placebo in the child and mixed studies 22 FIGURE 5 Standardised post-treatment TS global score for haloperidol compared with placebo in the child study 22 FIGURE 6 Standardised post-treatment C-GAS score for haloperidol compared with placebo in the child study 23 FIGURE 7 Standardised post-treatment CGI-Severity score for haloperidol compared with placebo in the child study 23 FIGURE 8 Standardised post-treatment CGI score for haloperidol compared with placebo in the mixed study 24 FIGURE 9 Standardised post-treatment ESRS score for haloperidol compared with placebo in first phase of the child study 24 FIGURE 10 Standardised post-treatment AIMS score for haloperidol compared with placebo in the child study 26 FIGURE 11 Standardised CGI adverse effects score assessed by physicians and patients in the mixed study for haloperidol compared with placebo 26 FIGURE 12 Standardised post-treatment total tic scores for pimozide compared with placebo in the child and mixed studies 27 FIGURE 13 Standardised post-treatment motor tic scores for pimozide compared with placebo in the child and mixed studies 28 FIGURE 14 Standardised post-treatment vocal tic score for pimozide compared with placebo in the child and mixed studies 29 FIGURE 15 Standardised post-treatment TS global score for pimozide compared with placebo in children 29 FIGURE 16 Standardised post-treatment C-GAS score for pimozide compared with placebo in the child study 30 FIGURE 17 Standardised post-treatment CGI-Severity score for children following treatment with pimozide compared with placebo in the child study 30 Queen s Printer and Controller of HMSO This work was produced by Hollis et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xvii

19 LIST OF FIGURES FIGURE 18 Standardised CGI-Severity score for patients undergoing treatment with pimozide compared with placebo in the mixed study 32 FIGURE 19 Standardised post-treatment ESRS score for pimozide compared with placebo in first phase of the child study 32 FIGURE 20 Standardised post-treatment AIMS score for pimozide compared with placebo in the child study 33 FIGURE 21 Standardised CGI adverse effects scale for pimozide compared with placebo assessed by physicians and patients in the mixed study 33 FIGURE 22 Standardised change in total tic scores for risperidone compared with placebo in the child and mixed study 34 FIGURE 23 Proportion of children CGI much or very much improved for risperidone compared with placebo in children (RR of not being much or very much improved) 34 FIGURE 24 Standardised change in CGI-Severity score for risperidone compared with placebo in the mixed study 36 FIGURE 25 Adverse events reported in the child and mixed studies of risperidone compared with placebo 37 FIGURE 26 Adverse events with more than five events reported in only the mixed study of risperidone compared with placebo 39 FIGURE 27 Standardised ESRS scores for risperidone compared with placebo in the mixed study 40 FIGURE 28 Standardised post-treatment YGTSS total tic score for ziprasidone compared with placebo 41 FIGURE 29 Standardised post-treatment YGTSS global score for ziprasidone compared with placebo 41 FIGURE 30 Standardised change in CGI-Severity score for ziprasidone compared with placebo 41 FIGURE 31 Number of patients experiencing adverse events for ziprasidone compared with placebo 43 FIGURE 32 Change in body weight for ziprasidone compared with placebo 43 FIGURE 33 Standardised tic scores for treatment with risperidone compared with pimozide in the child and mixed studies 44 FIGURE 34 Standardised impairment scores for treatment with pimozide compared with risperidone in the child and mixed studies 44 FIGURE 35 Standardised change from baseline Hamilton Rating Scale for Anxiety total score for risperidone compared with pimozide in the mixed study 45 xviii NIHR Journals Library

20 DOI: /hta19XXX HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. X FIGURE 36 Standardised CGI scores for treatment with risperidone compared with pimozide in the child and mixed studies 45 FIGURE 37 Weight gain (kg) following treatment with risperidone compared with pimozide in the child and mixed studies 46 FIGURE 38 Standardised post-treatment ESRS score for risperidone compared with pimozide in the child study 46 FIGURE 39 Standardised post-treatment Side Effects Checklist score for risperidone compared with pimozide in the child study 48 FIGURE 40 Proportion of patients with EPS-like symptoms, insomnia and injuries for risperidone compared with pimozide in the mixed study 48 FIGURE 41 Standardised tic scores for haloperidol compared with pimozide in the child and mixed studies 49 FIGURE 42 Standardised post-treatment motor tic scores for haloperidol compared with pimozide in the child and mixed studies 49 FIGURE 43 Standardised post-treatment vocal tic scores for haloperidol compared with pimozide in the child and mixed studies 50 FIGURE 44 Standardised post-treatment C-GAS score for haloperidol compared with placebo in the child study 50 FIGURE 45 Standardised post-treatment CGI-Severity score for haloperidol compared with pimozide in children 51 FIGURE 46 Standardised post-treatment CGI score for haloperidol compared with pimozide in mixed parallel study 51 FIGURE 47 Standardised post-treatment ESRS score for haloperidol compared with pimozide in the child study 52 FIGURE 48 Standardised post-treatment AIMS score for haloperidol compared with pimozide in the child study 52 FIGURE 49 Proportion of children with treatment-limiting side effects for haloperidol compared with pimozide in the child study 52 FIGURE 50 Proportion of patients experiencing tiredness on more than one study day for haloperidol compared with pimozide in the mixed study 54 FIGURE 51 Standardised CGI adverse effects scale for haloperidol compared with pimozide assessed by physicians and patients in the mixed study 54 FIGURE 52 Standardised change in global/tic score for aripiprazole compared with other antipsychotics 55 FIGURE 53 Standardised change in motor tic score for aripiprazole compared with other antipsychotics 55 Queen s Printer and Controller of HMSO This work was produced by Hollis et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xix

21 LIST OF FIGURES FIGURE 54 Standardised change in vocal tic score for aripiprazole compared with other antipsychotics 56 FIGURE 55 Standardised change in impairment score for aripiprazole compared with tiapride 56 FIGURE 56 Proportion of patients much or very much improved for aripiprazole compared with another antipsychotic 57 FIGURE 57 Proportion of children experiencing different adverse events for aripiprazole compared with another antipsychotic 59 FIGURE 58 Standardised total tic score for olanzapine compared with haloperidol 61 FIGURE 59 Standardised change in CGI-Severity score for olanzapine compared with haloperidol 61 FIGURE 60 Standardised STESS side effects score for olanzapine compared with haloperidol 61 FIGURE 61 Standardised post-treatment tic score for antipsychotics compared with placebo in studies of children 62 FIGURE 62 Standardised post-treatment total tic score for antipsychotics compared with placebo in the child and mixed studies 63 FIGURE 63 Standardised post-treatment motor tic score for antipsychotics compared with placebo in the child and mixed studies 64 FIGURE 64 Standardised post-treatment vocal tic score for antipsychotics compared with placebo in the child and mixed studies 65 FIGURE 65 Standardised post-treatment global TS score for antipsychotics compared with placebo in child studies 67 FIGURE 66 Standardised post-treatment CGI-Severity score for antipsychotics compared with placebo in child studies 68 FIGURE 67 Standardised motor tic scores for clonidine compared with placebo in predominantly child studies 73 FIGURE 68 Standardised vocal tic scores for clonidine compared with placebo in predominantly child studies 73 FIGURE 69 Standardised impairment scores for clonidine compared with placebo in predominantly child studies 74 FIGURE 70 Standardised change in global TS score for clonidine compared with placebo in predominantly child studies 74 FIGURE 71 Proportion of children improving on the CGI scale as rated by parents, teachers and investigators for clonidine compared with placebo 75 xx NIHR Journals Library

22 DOI: /hta19XXX HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. X FIGURE 72 Standardised change in CGI-TS score for clonidine compared with placebo 75 FIGURE 73 Proportion of children with side-effects for clonidine compared with placebo 77 FIGURE 74 Proportion of patients experiencing side effects for clonidine compared with placebo 78 FIGURE 75 Proportion of participants experiencing moderate-to-severe sedation for clonidine compared with placebo 79 FIGURE 76 Standardised change in YGTSS total tic score for guanfacine compared with placebo 79 FIGURE 77 Standardised change in YGTSS motor tic scale for guanfacine compared with placebo 79 FIGURE 78 Standardised change in YGTSS vocal tic scale for guanfacine compared with placebo in the child study 80 FIGURE 79 Standardised change in YGTSS impairment scale for guanfacine compared with placebo 80 FIGURE 80 Standardised change in YGTSS global scale for guanfacine compared with placebo 80 FIGURE 81 Standardised tic scores for clonidine patch compared with placebo for child and mixed studies 82 FIGURE 82 Standardised post-treatment TSSL scores for clonidine patch compared with placebo in the mixed study 83 FIGURE 83 Proportion of patients with adverse events for clonidine patch compared with placebo patch 84 FIGURE 84 Standardised change in YGTSS total tic score for children with TS or CTD or with TS alone following treatment with atomoxetine compared with placebo 86 FIGURE 85 Proportion of children with TS or CTD showing a 25% or more reduction in YGTSS total tic score for atomoxetine compared with placebo (RR of not having a 25% or more reduction) 86 FIGURE 86 Standardised change in YGTSS motor tic score for children with TS or CTD or with TS alone for atomoxetine compared with placebo 87 FIGURE 87 Standardised change in YGTSS vocal tic score for children with TS or CTD or with TS alone for atomoxetine compared with placebo 87 FIGURE 88 Standardised change in CGI score for children with TS or CTD or with TS alone for atomoxetine compared with placebo 88 Queen s Printer and Controller of HMSO This work was produced by Hollis et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xxi

23 LIST OF FIGURES FIGURE 89 Proportion of children experiencing adverse events for atomoxetine compared with placebo 89 FIGURE 90 Standardised total tic/global scores for noradrenergic agents compared with placebo 91 FIGURE 91 Standardised impairment scores for noradrenergic agents compared with placebo 93 FIGURE 92 Standardised motor tic score for stimulant drugs compared with control in children with ADHD and tics 96 FIGURE 93 Standardised vocal tic score for stimulant drugs compared with control in children with ADHD and tics 97 FIGURE 94 Standardised YGTSS impairment score for stimulant drugs compared with a control in children with ADHD and tics 98 FIGURE 95 Standardised YGTSS global score for stimulant drugs compared with a control in children with ADHD and tics 100 FIGURE 96 Standardised teacher and parent-rated SSEC mood index score for immediate release methylphenidate compared with placebo in children with ADHD and tics 100 FIGURE 97 Proportion of children much or very much improved on the CGI for methylphenidate compared with placebo in children with ADHD and tics (RRs of not being much or very much improved) 101 FIGURE 98 Proportion of patients experiencing moderate or severe sedation for methylphenidate compared with placebo 102 FIGURE 99 Stimulant Side Effects Checklist Somatic Index for immediate release methylphenidate compared with placebo in children with ADHD and tics 102 FIGURE 100 Post-treatment cardiovascular and weight measurements for immediate release methylphenidate compared with placebo in children with ADHD and tics 104 FIGURE 101 Standardised YGTSS total tic score for anticonvulsants compared with placebo 106 FIGURE 102 Standardised change from baseline YGTSS motor tic score for topiramate compared with placebo 106 FIGURE 103 Standardised change from baseline YGTSS vocal tic score for topiramate compared with placebo 107 FIGURE 104 Standardised YGTSS global score for anticonvulsants compared with placebo 107 FIGURE 105 Standardised MASC score for levetiracetam compared with placebo 109 xxii NIHR Journals Library

24 DOI: /hta19XXX HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. X FIGURE 106 Standardised CDI score for levetiracetam compared with placebo 109 FIGURE 107 Standardised CGI score for levetiracetam compared with placebo 110 FIGURE 108 Proportion of patients experiencing more than one adverse event for topiramate compared with placebo 110 FIGURE 109 Proportion of patients experiencing adverse events for topiramate compared with placebo 111 FIGURE 110 Standardised YGTSS motor and vocal tic score for children treated with selegiline compared with placebo 113 FIGURE 111 Standardised YGTSS impairment and global score for children treated with selegiline compared with placebo 113 FIGURE 112 Standardised change from baseline total tic score for dopamine agonists compared with placebo 116 FIGURE 113 Standardised global tic score for dopamine agonists compared with placebo 116 FIGURE 114 Standardised change from baseline YGTSS impairment score for pergolide compared with placebo 117 FIGURE 115 Standardised change from baseline in CDI-S score for pramipexole compared with placebo 117 FIGURE 116 Standardised change from baseline in MASC score for pramipexole compared with placebo 117 FIGURE 117 Standardised change from baseline/post-treatment CGI-Severity score for pergolide compared with placebo 118 FIGURE 118 Proportion of children with improved and unchanged CGI-Severity scores for pramipexole compared with placebo 118 FIGURE 119 Proportion of patients with adverse events in studies of dopamine agonists compared with placebo 119 FIGURE 120 Standardised STESS side effect score for pergolide compared with placebo 119 FIGURE 121 Proportion of patients experiencing various adverse events for pergolide compared with placebo 121 FIGURE 122 Change from baseline in ECG parameters for pergolide compared with placebo 122 FIGURE 123 Standardised change from baseline YGTSS total tic score for children treated with antiemetic or gastroprokinetic agents compared with placebo 124 Queen s Printer and Controller of HMSO This work was produced by Hollis et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xxiii

25 LIST OF FIGURES FIGURE 124 Standardised change from baseline YGTSS motor tic score for children treated with an antiemetic or gastroprokinetic agent compared with placebo 124 FIGURE 125 Standardised change from baseline YGTSS vocal tic score for children treated with an antiemetic or gastroprokinetic agent compared with placebo 125 FIGURE 126 Standardised change from baseline in CGI-Severity score for children treated with an antiemetic or gastroprokinetic agent compared with placebo 125 FIGURE 127 Proportion of patients experiencing adverse events for metoclopramide compared with placebo 126 FIGURE 128 Weight gain for children for metoclopramide compared with placebo 126 FIGURE 129 Standardised YGTSS total tic score for baclofen compared with placebo 129 FIGURE 130 Standardised YGTSS total impairment score for baclofen compared with placebo 129 FIGURE 131 Standardised YGTSS global score for baclofen compared with placebo 130 FIGURE 132 Standardised CGI-Severity score for baclofen compared with placebo 130 FIGURE 133 Proportion of children with 30% reductions in YGTSS total, motor and vocal tic scores for desipramine compared with placebo (RRs are the relative risk of not having a 30% reduction) 132 FIGURE 134 Standardised change in YGTSS global scale score for desipramine compared with placebo 132 FIGURE 135 Proportion of children with 30% reductions in YGTSS global score for desipramine compared with placebo (RRs are the relative risk of not having a 30% reduction) 134 FIGURE 136 Proportion of children much or very much improved in the CGI-I scale for desipramine compared with placebo (the RR presented here is the RR of not being much or very much improved) 134 FIGURE 137 Proportion of children with adverse events for desipramine compared with placebo 135 FIGURE 138 Proportion of children with adverse events occurring in more than two participants for desipramine compared with placebo 135 FIGURE 139 Standardised tic scores for fluoxetine compared with placebo in predominantly child studies 137 FIGURE 140 Adverse events experienced by more than two patients for fluoxetine compared with placebo 138 xxiv NIHR Journals Library

26 DOI: /hta19XXX HEALTH TECHNOLOGY ASSESSMENT 2015 VOL. 19 NO. X FIGURE 141 Proportion of children experiencing adverse events for events where occurred greater than twice as often in the mecamylamine compared with the placebo group 141 FIGURE 142 Proportion of children experiencing 90/60 BP for mecamylamine compared with placebo 143 FIGURE 143 Heart rate after one week of treatment for mecamylamine compared with placebo 143 FIGURE 144 Standardised motor tic score for transdermal nicotine compared with placebo 145 FIGURE 145 Standardised vocal tic score for transdermal nicotine compared with placebo 145 FIGURE 146 Standardised impairment/social problems score for transdermal nicotine compared with placebo 145 FIGURE 147 Standardised change from baseline in YGTSS global score for transdermal nicotine compared with placebo 146 FIGURE 148 Standardised Conners Parent Rating Scale Anxiousness/shyness and Emotional liability scores for transdermal nicotine compared with placebo 146 FIGURE 149 Standardised clinician and parent-rated global improvement scale ratings for nicotine compared with placebo 148 FIGURE 150 Adverse events occurring in 30% of participants for nicotine compared with placebo 149 FIGURE 151 Standardised change from baseline YGTSS total tic score for children treated with omega-3 fatty acids compared with placebo 151 FIGURE 152 Proportion of children treated with 30% reductions in YGTSS total tic score for omega-3 fatty acids compared with placebo (RR is relative risk of not having a 30% reduction) 151 FIGURE 153 Standardised change from baseline YGTSS impairment score for children treated with omega-3 fatty acids compared with placebo 151 FIGURE 154 Standardised change from baseline YGTSS global score for children treated with omega-3 fatty acids compared with placebo 152 FIGURE 155 Proportion of children with 30% reductions in YGTSS impairment score for omega-3 fatty acids compared with placebo (RR is relative risk of not having a 30% reduction) 152 FIGURE 156 Proportion of children with 30% reductions in YGTSS global score for omega-3 fatty acids compared with placebo (RR is relative risk of not having a 30% reduction) 152 Queen s Printer and Controller of HMSO This work was produced by Hollis et al. under the terms of a commissioning contract issued by the Secretary of State for Health. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. xxv