Review Article
No access
Published Online: 8 November 2024

Pharmacological Interventions for Attention-Deficit/Hyperactivity Disorder in Children and Adolescents with Tourette Disorder: A Systematic Review and Network Meta-Analysis

Publication: Journal of Child and Adolescent Psychopharmacology
Volume 34, Issue Number 9

Abstract

Objective: To evaluate the comparative efficacy of pharmacological interventions for children and adolescents with a dual diagnosis of persistent tic disorders or Tourette disorder and attention-deficit/hyperactivity disorder (TD + ADHD).
Methods: We searched CENTRAL, Embase, PubMed, PsycInfo, Web of Sciences, ClinicalTrials.gov, and WHO ICTRP up to September 2023 to identify double-blinded randomized controlled trials (RCTs) assessing pharmacological interventions for children and adolescents with TD + ADHD. Outcomes were change in ADHD symptoms (primary) and tics (secondary) severity. Standardized mean difference (SMD) was calculated and pooled in random-effects network meta-analysis. The Confidence in Network Meta-Analysis framework was adopted to determine certainty of evidence.
Results: We included 8 RCTs involving 575 participants. Network meta-analyses demonstrated that α2 agonists (SMD, 95% confidence interval [CI] ADHD: −0.72 [−1.13 to −0.31]; TD: −0.70 [−0.96 to −0.45]) and stimulants + α2 agonists (ADHD: −0.84 [−1.54 to −0.13]; TD: −0.60 [−1.04 to −0.17]) were more efficacious than placebo for ADHD symptoms and tics severity. Stimulants alone were more efficacious than placebo for ADHD symptoms severity only, but they did not worsen tics (ADHD: −0.54 [−1.05 to −0.03]; TD: −0.22 [−0.49 to 0.05]). There were no significant differences between any pairs of medications that were found efficacious against placebo for ADHD symptoms or tics severity. Certainty in the evidence varied from low to very low.
Conclusions: Stimulants are efficacious for ADHD symptoms severity and do not increase tics severity in TD + ADHD. α2 agonists are efficacious for both ADHD symptoms and tics severity in TD + ADHD. These findings should inform guidelines and help guide shared decision-making to choose a medication for children with TD + ADHD.

Get full access to this article

View all available purchase options and get full access to this article.

Disclaimer

The views expressed in this publication are those of the author(s) and not necessarily those of the NIHR, NHS, or the UK Department of Health and Social Care.

References

Allen AJ, Kurlan RM, Gilbert DL, et al. Atomoxetine treatment in children and adolescents with ADHD and comorbid tic disorders. Neurology 2005;65(12):1941–1949.
Balduzzi S, Rücker G, Schwarzer G. How to perform a meta-analysis with R: A practical tutorial. Evid Based Ment Health 2019;22(4):153–160.
Bloch MH, Leckman JF. Clinical course of Tourette syndrome. J Psychosom Res 2009;67(6):497–501.
Bloch MH, Panza KE, Landeros-Weisenberger A, et al. Meta-analysis: Treatment of attention-deficit/hyperactivity disorder in children with comorbid tic disorders. J Am Acad Child Adolesc Psychiatry 2009;48(9):884–893.
Bussing R, Fernandez M, Harwood M, et al. Parent and teacher SNAP-IV ratings of attention deficit hyperactivity disorder symptoms: Psychometric properties and normative ratings from a school district sample. Assessment 2008;15(3):317–328.
Castellanos FX, Giedd JN, Elia J, et al. Controlled stimulant treatment of ADHD and comorbid Tourette’s syndrome: Effects of stimulant and dose. J Am Acad Child Adolesc Psychiatry 1997;36(5):589–596.
Chaimani A, Salanti G. Using network meta-analysis to evaluate the existence of small-study effects in a network of interventions. Res Synth Methods 2012;3(2):161–176.
Chen Y, Ke Z, Ouyang Y, et al. Clonidine patch for Tourette syndrome with attention-deficit/hyperactivity disorder. Psychiatry Investig 2024;21(4):387–395.
Coghill D, Banaschewski T, Cortese S, et al. The management of ADHD in children and adolescents: Bringing evidence to the clinic: Perspective from the European ADHD Guidelines Group (EAGG). Eur Child Adolesc Psychiatry 2021;32(8):1337–1361.
Cohen SC, Leckman JF, Bloch MH. Clinical assessment of Tourette syndrome and tic disorders. Neurosci Biobehav Rev 2013;37(6):997–1007.
Conners CK, Sitarenios G, Parker JD, et al. Revision and restandardization of the Conners Teacher Rating Scale (CTRS-R): factor structure, reliability, and criterion validity. J Abnorm Child Psychol 1998a;26(4):279–291.
Conners CK, Sitarenios G, Parker JD, et al. The revised Conners’ Parent Rating Scale (CPRS-R): factor structure, reliability, and criterion validity. J Abnorm Child Psychol 1998b;26(4):257–268.
Correll CU, Cortese S, Croatto G, et al. Efficacy and acceptability of pharmacological, psychosocial, and brain stimulation interventions in children and adolescents with mental disorders: An umbrella review. World Psychiatry 2021;20(2):244–275.
Cortese S. Pharmacologic treatment of attention deficit-hyperactivity disorder. N Engl J Med 2020;383(11):1050–1056.
Cortese S, Adamo N, Del Giovane C, et al. Comparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: A systematic review and network meta-analysis. Lancet Psychiatry 2018;5(9):727–738.
Cortese S, Holtmann M, Banaschewski T, et al. European ADHD Guidelines Group. Practitioner review: Current best practice in the management of adverse events during treatment with ADHD medications in children and adolescents. J Child Psychol Psychiatry 2013;54(3):227–246.
DuPaul GJ, Power TJ, Anastopoulos AD, et al. ADHD Rating Scale-IV: Checklists, Norms, and Clinical Interpretation. New York, NY, USA: Guilford Press; 1998.
Eddy CM, Cavanna AE, Gulisano M, et al. Clinical correlates of quality of life in Tourette syndrome. Mov Disord 2011;26(4):735–738.
Farhat LC, Behling E, Landeros-Weisenberger A, et al. Comparative efficacy, tolerability, and acceptability of pharmacological interventions for the treatment of children, adolescents, and young adults with Tourette’s Disorder: A systematic review and network meta-analysis. Lancet Child Adolesc Health 2023;7(2):112–126.
Farhat LC, Bloch MH. Commentary: Identifying individualized predictions of response in ADHD pharmacotherapy—A commentary on Rodrigues et al. (2020). J Child Psychol Psychiatry 2021;62(6):701–703.
Farhat LC, Flores JM, Behling E, et al. The effects of stimulant dose and dosing strategy on treatment outcomes in attention-deficit/hyperactivity disorder in children and adolescents: A meta-analysis. Mol Psychiatry 2022;27(3):1562–1572.
Feigin A, Kurlan R, Mcdermott MP, et al. A controlled trial of Deprenyl in children with Tourette’s syndrome and attention deficit hyperactivity disorder. Neurology 1997 1996;46(4):965–968.
Gadow KD, Sverd J, Nolan EE, et al. Immediate-release methylphenidate for ADHD in children with comorbid chronic multiple tic disorder. J Am Acad Child Adolesc Psychiatry 2007;46(7):840–848.
Gorman DA, Thompson N, Plessen KJ, et al. Psychosocial outcome and psychiatric comorbidity in older adolescents with Tourette syndrome: Controlled study. Br J Psychiatry 2010;197(1):36–44.
Grados MA, Mathews CA, Tourette Syndrome Association International Consortium for Genetics. Latent class analysis of Gilles de la Tourette syndrome using comorbidities: Clinical and genetic implications. Biol Psychiatry 2008;64(3):219–225.
Hirschtritt ME, Lee PC, Pauls DL, et al. Tourette Syndrome Association International Consortium for Genetics. Lifetime prevalence, age of risk, and genetic relationships of comorbid psychiatric disorders in Tourette syndrome. JAMA Psychiatry 2015;72(4):325–333.
Hoekstra PJ, Steenhuis MP, Troost PW, et al. Relative contribution of attention-deficit hyperactivity disorder, obsessive-compulsive disorder, and tic severity to social and behavioral problems in tic disorders. J Dev Behav Pediatr 2004;25(4):272–279.
Hutton B, Salanti G, Caldwell DM, et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: Checklist and explanations. Ann Intern Med 2015;162(11):777–784.
Jaffe RJ, Coffey BJ. Pharmacologic treatment of comorbid attention-deficit/hyperactivity disorder and Tourette and tic disorders. Child Adolesc Psychiatr Clin N Am 2022;31(3):469–477.
Khalifa N, Von Knorring AL. Psychopathology in a Swedish population of school children with tic disorders. J Am Acad Child Adolesc Psychiatry 2006;45(11):1346–1353.
Krahn U, Binder H, König J. A graphical tool for locating inconsistency in network meta-analyses. BMC Med Res Methodol 2013;13:35.
Lebowitz ER, Motlagh MG, Katsovich L, et al. Tourette Syndrome Study Group. Tourette syndrome in youth with and without obsessive compulsive disorder and attention deficit hyperactivity disorder. Eur Child Adolesc Psychiatry 2012;21(8):451–457.
Leckman JF, King RA, Bloch MH. Clinical features of Tourette syndrome and tic disorders. J Obsessive Compuls Relat Disord 2014;3(4):372–379.
Leckman JF, Riddle MA, Hardin MT, et al. The Yale Global Tic Severity Scale: Initial testing of a clinician-rated scale of tic severity. J Am Acad Child Adolesc Psychiatry 1989;28(4):566–573.
Leucht S, Chaimani A, Cipriani A, et al. Network meta-analyses should be the highest level of evidence in treatment guidelines. Eur Arch Psychiatry Clin Neurosci 2016;266(6):477–480.
Man KKC, Häge A, Banaschewski T, et al. ADDUCE Consortium. Long-term safety of methylphenidate in children and adolescents with ADHD: 2-year outcomes of the Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) study. Lancet Psychiatry 2023;10(5):323–333.
Mcguire JF, Piacentini J, Brennan EA, et al. A meta-analysis of behavior therapy for Tourette Syndrome. J Psychiatr Res 2014;50:106–112.
Morand-Beaulieu S, Grot S, Lavoie J, et al. The puzzling question of inhibitory control in Tourette syndrome: A meta-analysis. Neurosci Biobehav Rev 2017;80:240–262.
National Institute for Health and Care Excellence. Attention deficit hyperactivity disorder: Diagnosis and management NICE guideline [NG87]. 2018. Available from: https://www.nice.org.uk/guidance/ng87
Nikolakopoulou A, Higgins JPT, Papakonstantinou T, et al. CINeMA: An approach for assessing confidence in the results of a network meta-analysis. PLoS Med 2020;17(4):E1003082.
Pringsheim T, Okun MS, Müller-Vahl K, et al. Practice guideline recommendations summary: Treatment of tics in people with Tourette syndrome and chronic tic disorders. Neurology 2019;92(19):896–906.
R Development Core Team. R: A Language and Environment for Statistical Computing. Vienna, Austria: R Foundation for Statistical Computing; 2010.
Rhodes KM, Turner RM, Higgins JP. Predictive distributions were developed for the extent of heterogeneity in meta-analyses of continuous outcome data. J Clin Epidemiol 2015;68(1):52–60.
Robertson MM, Eapen V, Singer HS, et al. Gilles de la Tourette syndrome. Nat Rev Dis Primers 2017;3:16097.
Roessner V, Eichele H, Stern JS, et al. European clinical guidelines for Tourette syndrome and other tic disorders-version 2.0. Part III: Pharmacological treatment. Eur Child Adolesc Psychiatry 2022;31(3):425–441.
Rücker G, Krahn U, König J, et al. netmeta: Network Meta-Analysis using Frequentist Methods. R package version 1.5-0. 2021.
Rücker G, Schwarzer G. Ranking treatments in frequentist network meta-analysis works without resampling methods. BMC Med Res Methodol 2015;15:58.
Salanti G. Indirect and mixed-treatment comparison, network, or multiple-treatments meta-analysis: Many names, many benefits, many concerns for the next generation evidence synthesis tool. Res Synth Methods 2012;3(2):80–97.
Scahill L, Chappell PB, Kim YS, et al. A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder. Am J Psychiatry 2001;158(7):1067–1074.
Singer HS, Brown J, Quaskey S, et al. The treatment of attention-deficit hyperactivity disorder in Tourette’s syndrome: A double-blind placebo-controlled study with clonidine and desipramine. Pediatrics 1995;95(1):74–81.
Spencer T, Biederman J, Coffey B, et al. A double-blind comparison of desipramine and placebo in children and adolescents with chronic tic disorder and comorbid attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 2002;59(7):649–656.
Sterne JAC, Savović J, Page MJ, et al. RoB 2: A revised tool for assessing risk of bias in randomised trials. BMJ 2019;366:l4898.
Sukhodolsky DG, Scahill L, Zhang H, et al. Disruptive behavior in children with Tourette’s syndrome: Association with ADHD comorbidity, tic severity, and functional impairment. J Am Acad Child Adolesc Psychiatry 2003;42(1):98–105.
Sukhodolsky DG, Woods DW, Piacentini J, et al. Moderators and predictors of response to behavior therapy for tics in Tourette syndrome. Neuorology 2017;88(11):1029–1036.
Tourette’s Syndrome Study Group. Treatment of ADHD in children with tics: A randomized controlled trial. Neurology 2002;58:527–536.
Turner RM, Davey J, Clarke MJ, et al. Predicting the extent of heterogeneity in meta-analysis, using empirical data from the Cochrane Database of Systematic Reviews. Int J Epidemiol 2012;41(3):818–827.
Werry JS, Biederman J, Thisted R, et al. Resolved: Cardiac arrhythmias make desipramine an unacceptable choice in children. J Am Acad Child Adolesc Psychiatry 1995;34(9):1239–1248.

Information & Authors

Information

Published In

cover image Journal of Child and Adolescent Psychopharmacology
Journal of Child and Adolescent Psychopharmacology
Volume 34Issue Number 9November 2024
Pages: 373 - 382
PubMed: 39320340

History

Published online: 8 November 2024
Published in print: November 2024
Published ahead of print: 24 September 2024

Permissions

Request permissions for this article.

Topics

Authors

Affiliations

Department of Psychiatry, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, Brazil.
Emily Behling
Child Study Center, Yale University School of Medicine, New Haven, Connecticut, USA.
Angeli Landeros-Weisenberger
Child Study Center, Yale University School of Medicine, New Haven, Connecticut, USA.
Pedro Macul Ferreira de Barros
Department of Psychiatry, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, Brazil.
Guilherme V. Polanczyk
Department of Psychiatry, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, Brazil.
Samuele Cortese
Centre for Innovation in Mental Health-Developmental Lab, School of Psychology, University of Southampton, Southampton, UK.
Solent NHS Trust, Southampton, UK.
Clinical and Experimental Sciences (CNS and Psychiatry), Faculty of Medicine, University of Southampton, Southampton, UK.
Hassenfeld Children’s Hospital at NYU Langone, New York University Child Study Center, New York City, New York, USA.
DiMePRe-J-Department of Precision and Rigenerative Medicine-Jonic Area, University of Bari “Aldo Moro,” Bari, Italy.
Child Study Center, Yale University School of Medicine, New Haven, Connecticut, USA.
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.

Notes

Address correspondence to: Michael Bloch, MD, MS, Department of Psychiatry, Yale University School of Medicine, 230 South Frontage Rd., New Haven, CT 06519, USA [email protected]
Funding: There was no direct funding that was received for this project.

Authors’ Contributions

Conceptualization: L.C.F., S.C., G.V.P., and M.H.B.; Data curation: L.C.F., E.B., and M.F.B.; Methodology: L.C.F., E.B., M.F.B., A.L.-W., and M.H.B.; Formal analysis: L.C.F. Writing—original draft: L.C.F. and M.H.B.; Writing—review and editing: E.B., A.L.-W., M.F.B., S.C., and G.V.P.; Supervision: M.H.B.

Disclosures

S.C., NIHR Research Professor (NIHR303122), is funded by the NIHR for this research project. S.C. is also supported by NIHR grants NIHR203684, NIHR203035, NIHR130077, NIHR128472, RP-PG-0618-20003 and by grant 101095568-HORIZONHLTH-2022-DISEASE-07-03 from the European Research Executive Agency. S.C. has declared reimbursement for travel and accommodation expenses from the Association for Child and Adolescent Central Health (ACAMH) in relation to lectures delivered for ACAMH, the Canadian AADHD Alliance Resource, the British Association of Psychopharmacology, and from Healthcare Convention for educational activity on ADHD, and has received honoraria from Medice. G.V.P. has been a consultant, advisory board member, and/or speaker for Aché, Abbott, Apsen, Medice, Novo Nordisk, Pfizer, and Takeda. G.V.P. also receives royalties from Editora Manole. M.H.B. has received grant or research support from Therapix Biosciences, Emalex Biosciences, Janssen Pharmaceuticals, Biohaven Pharmaceuticals, NIH, Lesbian Health Fund, and the Yale Foundation for Lesbian and Gay Studies (FLAGS), and Patterson Foundation. He has also served on the advisory board/data monitoring and safety board of Therapix Biosciences. He also serves as associate editor of Journal of Child Psychology and Psychiatry and on the editorial board of Journal of Child and Adolescent Psychopharmacology. He has received royalties from Wolters Kluwer for Lewis’s Child and Adolescent Psychiatry: A Comprehensive Textbook, Fifth Edition. He has received moonlighting pay from the Veteran’s Administration. The other authors report no disclosures.

Metrics & Citations

Metrics

Citations

Export citation

Select the format you want to export the citations of this publication.

View Options

Access content

To read the fulltext, please use one of the options below to sign in or purchase access.

Society Access

If you are a member of a society that has access to this content please log in via your society website and then return to this publication.

Restore your content access

Enter your email address to restore your content access:

Note: This functionality works only for purchases done as a guest. If you already have an account, log in to access the content to which you are entitled.

View options

PDF/EPUB

View PDF/EPUB

Full Text

View Full Text

Figures

Tables

Media

Share

Share

Copy the content Link

Share on social media

Back to Top