EVIDENCE-BASED CHILD HEALTH: A COCHRANE REVIEW JOURNAL Evid.-Based Child Health 7: 1231–1234 (2012) Published online in Wiley Online Library (http://www.evidence-basedchildhealth.com). DOI: 10.1002/ebch.1862
Commentary Commentaries on ‘Pharmacological treatment for Attention Deficit Hyperactivity Disorder (ADHD) in children with comorbid tic disorders’ These are commentaries on a Cochrane review, published in this issue of EBCH, first published as: Pringsheim T, Steeves T. Cochrane Database of Systematic Reviews 2011, Issue 4. Art. No.: CD007990. DOI: 10.1002/ 14651858.CD007990.pub2 Further information for this Cochrane review is available in this issue of EBCH in the accompanying Summary article.
Commentary by Michael H. Bloch Pringsheim and Steeves conducted a systematic review of the pharmacological treatment of attention-deficit hyperactivity disorder (ADHD) in children with comorbid tics (1). The authors synthesized the results of eight randomized, placebo-controlled trials in this population. Their work yields two important findings: 1. There is no evidence from randomized, controlled clinical trials that therapeutic doses of psychostimulant medication worsen pre-existing tics. 2. Alpha-2 agonist medications, such as clonidine and guanfacine, appear comparably effective to psychostimulant medications in treating ADHD symptoms in children with tics. Despite some minor methodological differences, this work largely confirms the results of a similar systematic review and meta-analysis in this area (2). These findings have important implications for both clinical care and public policy regarding the treatment of children with ADHD and comorbid tic disorders.
Implications for public policy The Food and Drug Administration (FDA) currently requires the package inserts of most psychostimulant medications in the US to list the presence of a tic disorder or a family history of Tourette syndrome as a contraindication to their use. This warning was issued based on a large collection of case reports and case series. These case reports associated the emergence of de novo tics and exacerbation of existing tic symptoms with methylphenidate, dextroamphetamine and pemoline. However, the association between psychostimulants and tics may be a result of confounding. Approximately 20% of children with ADHD develop a chronic tic disorder, and the symptoms of ADHD typically precede the onset of tic symptoms by several years (3). Therefore, a Copyright 2012 John Wiley & Sons, Ltd.
significant proportion of children diagnosed initially with ADHD will eventually develop tics regardless of treatment. Supporting this observation, there were several case reports, around the same time period, linking medications that are not psychostimulants (alpha-2 agonists) to tic exacerbation (4,5). Alpha-2 agonists are currently recommended by the Tourette Syndrome Association Medical Advisory Board as the first-line pharmacological treatment for tics (6). The data supporting the FDA warning appears even thinner in light of the trial data synthesized by Pringsheim and Steeves, which suggest that there is no exacerbation of tics with methylphenidate use; in fact, there is a trend towards improvement in tics (effect size = 0.28, p = 0.07) (2). The FDA warning also has a significant effect on physician behaviour. Many doctors in the US are hesitant to prescribe psychostimulants to children with tics or who have a positive family history of tics. They know that a large proportion of these children will subsequently develop tics (regardless of whether the medication is actually responsible) and the doctors may be held responsible and possibly sued for prescribing a contraindicated medication. This contraindication therefore likely leads to many children with tics being sub-optimally treated for their ADHD. Untreated ADHD has significant implications for both individuals and society. When ADHD is present in children with tics, the ADHD typically causes greater impairment in academic performance and social relationships than do the tics themselves. Childhood ADHD is also associated with an increased risk of substance use and car accidents, as well as higher rates of incarceration and unemployment. In light of the data from this review, it would be prudent for the FDA to remove the contraindication for the use of psychostimulants in children with comorbid tics (or family history of Tourette syndrome). Instead, it may be more appropriate to list tics as a possible side effect. After all, none of this trial-based data can rule
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out the possibility that psychostimulants may worsen tics in a small number of individual cases.
Implications for clinicians Pringsheim and Steeves synthesize data from several clinical trials that suggest alpha-2 agonist medication, and probably atomoxetine (a selective norepinephrine reuptake inhibitor), may be as effective as psychostimulant medication in the treatment of ADHD in subjects with comorbid tics (1). For most individuals with ADHD and tics, alpha-2 agonist medications are a preferable first-line treatment compared with psychostimulants as they can significantly reduce symptoms for both conditions (2) However, as suggested in the Tourette syndrome Study Group trial, the combination of an alpha-2 agonist and methylphenidate was superior to either treatment alone in children with ADHD and tics. (7). Furthermore, the combination of these medications is usually quite well tolerated. Troublesome side effects of psychostimulants (insomnia and anxiety) are often counteracted by the side effects of alpha-2 agonists (sedation and fatigue). Despite the current FDA warning, a psychostimulant medication could be considered the initial drug of choice when rapid symptom relief is needed in a child with ADHD and tics because improvements with psychostimulants can be seen in days, whereas improvements with alpha-2 agonists usually take weeks. For instance, a methylphenidate derivative would be advisable, based on current data, in a child with severe ADHD and minimal tics who was in need of rapid improvement of ADHD symptoms at school (i.e. at risk of expulsion from school for disruptive and impulsive behaviour).
Conclusion Pringsheim and Steeves systematically reviewed eight randomized controlled trials involving the pharmacological treatment of ADHD in children with comorbid tics (1). Existing trial literature shows that, in the vast majority of cases of children with ADHD and comorbid tics, psychostimulants improve ADHD symptoms with no evidence suggesting that they worsen tics. As new evidence emerges from randomized, placebocontrolled trials, it is likely that the association inferred from case report level data was likely subject to confounding. The FDA should reconsider its current listing of tics, or a family history of Tourette syndrome, as a contraindication to the use of these medications in treating ADHD. Furthermore, clinicians should not be afraid to consider utilizing psychostimulants in children with tics and persistent ADHD symptoms, especially when other available pharmacological and behavioural treatments for ADHD have been ineffective.
Acknowledgements The author acknowledges the National Institute of Mental Health support of the Yale Child Study Center Research Copyright 2012 John Wiley & Sons, Ltd.
Commentaries
Training Program (MHB), the National Institutes of Health 1K23MH091240 (MHB), the APIRE/Eli Lilly Psychiatric Research Fellowship (MHB), the AACAP/Eli Lilly Junior Investigator Award (MHB), the Trichotillomania Learning Center (MHB), NARSAD (MHB), and UL1 RR024139 from the National Center for Research Resources, a component of the National Institutes of Health, and NIH roadmap for Medical Research (MHB).
Declaration of interest The author has no conflicts of interest to disclose.
Michael H. Bloch* Child Study Center and Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA Correspondence to: Michael H. Bloch, MD, MS, Child Study Center, Yale University School of Medicine, PO Box 2070900, New Haven, CT 06520, USA E-mail: [email protected] Keywords: attention-deficit hyperactivity disorder, methylphenidate,, psychostimulant medication, tic disorders
References 1. Pringsheim T, Steeves T. Pharmacological treatment for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders. Cochrane Database Syst Rev 2011; Issue (4): Art. No.: CD007990. 2. Bloch MH, Panza KE, Landeros-Weisenberger A, Leckman JF. Meta-analysis: treatment of attention-deficit/hyperactivity disorder in children with comorbid tic disorders. J Am Acad Child Adolesc Psychiatry 2009; 48: 884–893. 3. Leckman JF. Tourette’s syndrome. Lancet 2002; 360: 1577–1586. 4. Huk SG. Transient exacerbation of tics in treatment of Tourette’s syndrome with clonidine. J Am Acad Child Adolesc Psychiatry 1989; 28: 583–586. 5. Kessler AR. Clonidine treatment increases tics in patients with Tourette syndrome: case report. J Child Neurol 2001; 16: 380–381. 6. Scahill L, Erenberg G, Berlin CM, Jr., Budman C, Coffey BJ, et al. Contemporary assessment and pharmacotherapy of Tourette syndrome. NeuroRx 2006; 3: 192–206. 7. Tourette’s Syndrome Study Group. Treatment of ADHD in children with tics: a randomized controlled trial. Neurology 2002; 58: 527–536.
Commentary by Daniel A. Gorman and Elia Abi-Jaoude The management of attention deficit hyperactivity disorder (ADHD) in patients with comorbid tics is a common clinical challenge. Tourette syndrome and other chronic tic disorders are present in 2% of children (1), and approximately half who present clinically also meet criteria for ADHD (2). While many of these youngsters have mild to moderate tics that they can ignore or tolerate without treatment, ADHD and other comorbid conditions often require intervention because of the considerable distress and functional impairment they cause (3). The presence of tics, however, adds a level of complexity to the management of ADHD, in part because of a longstanding concern Evid.-Based Child Health 7: 1231–1234 (2012) DOI: 10.1002/ebch.1862
Commentaries: Pharmacological treatment for ADHD in children with comorbid tics
that stimulants – the most established pharmacological intervention for ADHD – may exacerbate tics. This concern stems largely from decades old case reports, leading to product monograph warnings that stimulants are contraindicated in individuals with a personal or family history of Tourette syndrome. In addition, the notion that stimulants exacerbate tics has theoretical plausibility given that they increase dopaminergic and noradrenergic transmission, whereas the main tic suppressing medications, antipsychotics and alpha-2 agonists, have opposite effects. In the last 15 years, however, more rigorous studies have reported that stimulants generally do not exacerbate tics. Consequently, the use of stimulants in individuals with tics appears to have increased, at least among specialists, and one set of recent guidelines considers stimulants as first-line medication for ADHD in children with tics as well as those without (4). On the other hand, physicians continue to report that some of their patients experience stimulant-induced tic exacerbation, and even investigators whose findings do not support this phenomenon will add the caveat that stimulants may worsen tics in vulnerable individuals (5,6). Evidence is also mounting in support of non-stimulant medications for ADHD, including the alpha-2 agonists clonidine and guanfacine (7), which are used to treat tics as well (8). Given all these factors, the management of ADHD in the presence of tics remains a source of considerable confusion and debate, making the review by Pringsheim and Steeves both important and timely. The authors limit their review to double-blind, randomized controlled trials. Only eight studies qualified for review, most were small, and all were of short duration. Each study included a placebo group and three had multiple active treatment groups. In total, seven agents were investigated: methylphenidate (three studies); clonidine and desipramine (two studies each); and dextroamphetamine, guanfacine, atomoxetine and deprenyl (one study each). All studies of stimulants and alpha-2 agonists used short-acting formulations. Meta-analysis was precluded by clinical heterogeneity and issues related to unit of analysis. Funnel plots could not be created to assess for publication bias, as the number of studies for each medication was too small. Two studies showed evidence of selective reporting, and all four trials with a cross-over design failed to report paired data for analysis. Two questions are at the heart of the Pringsheim and Steeves’ review: (1) Are medications for ADHD efficacious in children with a comorbid tic disorder? (2) Do they exacerbate tics? Regarding the first question, the authors report that all agents studied, except deprenyl, improved ADHD symptoms. Furthermore, the Tourette’s Syndrome Study Group (TSSG) 2002 found that the combination of methylphenidate and clonidine was superior to either agent alone (9). While the most evidence exists for methylphenidate, the results suggest that it may be less efficacious in patients with a tic disorder compared to those without. Copyright 2012 John Wiley & Sons, Ltd.
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The TSSG 2002 reported that methylphenidate alone had similar efficacy as clonidine alone for ADHD symptoms (9), and Gadow 2007 reported that effect sizes for ADHD outcomes with methylphenidate were generally in the medium range (6). In contrast, studies of these agents in patients without tics have typically found large effect sizes for methylphenidate (10) as opposed to medium effect sizes for clonidine (11). As Pringsheim and Steeves propose, the moderate response to methylphenidate in TSSG 2002 and Gadow 2007 could be due to the relatively low doses of methylphenidate used; however, the third methylphenidate study included in the review did not find evidence of greater benefit with higher doses (12). Another possible explanation is that ADHD associated with tics is neurobiologically distinct from ADHD without tics. Indeed, the question of whether tic-related ADHD is ‘true’ ADHD is a matter of controversy (13). A third possibility is that residual inattentive and behavioural symptoms that do not improve with methylphenidate are related not to ADHD, but to other factors such as distraction caused by tics or the effort to suppress them, or the effects of obsessive-compulsive disorder, learning disorders or other comorbid conditions. Herein lies a crucial point for clinicians: even though ADHD is commonly comorbid with tic disorders, other potential causes of poor attention and misbehaviour must be carefully assessed before ADHD medication is started or increased. On the question of whether ADHD medications exacerbate tics, most studies, including ones involving stimulants, did not find evidence for this on average. In fact, some studies found that tics improved with ADHD treatment. Nevertheless, several results signal that stimulants can lead to a dose-related increase in tics for certain patients. In Castellanos 1997, one study cohort experienced tic exacerbation with moderate to high doses of dextroamphetamine ( ≥ 12.5 mg twice/day) (12). The same cohort also had worse tics with a high dose of methylphenidate (20–25 mg twice/day), though not, oddly enough, with an even higher dose (35–45 mg twice/day). Gadow 2007 found a dose-related increase in simple motor tics on a measure where tics were counted over two minutes, but not on other measures of tic severity (6). Finally, TSSG 2002 reported that tics limited dose increases in 35% of subjects treated with methylphenidate alone, about twice as many as in each of the other treatment groups (9). Given these findings and the fact that few studies (none of which qualified for review) have investigated long-term effects on tics (5,14–16), caution is still warranted when considering stimulants for patients with tic disorders, especially at higher doses. A secondary objective of Pringsheim and Steeves’ review was to assess adverse effects of ADHD medications besides tic exacerbation in children with tic disorders. Although not all studies evaluated these adverse effects adequately, the review’s findings are consistent with what is generally known about the agents Evid.-Based Child Health 7: 1231–1234 (2012) DOI: 10.1002/ebch.1862
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investigated: initial insomnia, appetite suppression, stomach upset, headache, dizziness, and increases in heart rate and blood pressure with stimulants; appetite suppression, weight loss, nausea, and increased heart rate with atomoxetine; sedation in close to half of subjects taking clonidine and guanfacine; appetite suppression and increases in heart rate and blood pressure with desipramine. These and other adverse effects (17) are essential considerations for clinicians and families contemplating pharmacological intervention for ADHD. Overall, Pringsheim and Steeves’ thorough review highlights the limited evidence base regarding the pharmacological treatment of ADHD in the presence of tics. This paucity of research is striking given that approximately 20% of children with ADHD also have a tic disorder (18), and hundreds of randomized controlled trials have been conducted for stimulants (19) and dozens more for non-stimulants (7,20–22) in children with uncomplicated ADHD. Clearly, more studies are needed to inform the management of the considerable minority of ADHD patients with comorbid tics. In particular, future efforts should investigate the longterm effects, including adverse effects, of ADHD medications in children with tic disorders, as is being done in children without tics (23,24). Moreover, researchers should not only include measures of ADHD and tic severity but also assess other important outcomes such as psychosocial functioning and quality of life.
Declaration of interest The authors have no conflicts of interest to disclose.
Daniel A. Gorman1,2 * and Elia Abi-Jaoude1,3 1 Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada 2 Department of Psychiatry, The Hospital for Sick Children, Toronto, Ontario, Canada 3 Department of Psychiatry, University Health Network, Toronto, Ontario, Canada
Correspondence to: Daniel A. Gorman, The Hospital for Sick Children, Department of Psychiatry, 555 University Avenue, Toronto, ON M5G 1X8, Canada E-mail: [email protected] Keywords: tics, Tourette syndrome, attention-deficit hyperactivity disorder, stimulants, alpha-2 agonists, adverse effects
References 1. Khalifa N, von Knorring AL. Tourette syndrome and other tic disorders in a total population of children: clinical assessment and background. Acta Paediatr 2005; 94: 1608–1614. 2. Freeman RD. Tic disorders and ADHD: answers from a worldwide clinical dataset on Tourette syndrome. Eur Child Adolesc Psychiatry 2007; 16(Suppl 1): 15–23. 3. Gorman DA, Thompson N, Plessen KJ, Robertson MM, Leckman JF, Peterson BS. Psychosocial outcome and psychiatric comorbidity in older adolescents with Tourette syndrome: controlled study. Br J Psychiatry 2010; 197: 36–44. Copyright 2012 John Wiley & Sons, Ltd.
Commentaries
4. Pliszka SR, Crismon ML, Hughes CW, Conners CK, Emslie GJ, Jensen PS, et al. The Texas Children’s Medication Algorithm Project: revision of the algorithm for pharmacotherapy of attentiondeficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2006; 45: 642–657. 5. Gadow KD, Sverd J, Sprafkin J, Nolan EE, Grossman S. Longterm methylphenidate therapy in children with comorbid attentiondeficit hyperactivity disorder and chronic multiple tic disorder. Arch Gen Psychiatry 1999; 56: 330–336. 6. Gadow KD, Sverd J, Nolan EE, Sprafkin J, Schneider J. Immediate-release methylphenidate for ADHD in children with comorbid chronic multiple tic disorder. J Am Acad Child Adolesc Psychiatry 2007; 46: 840–848. 7. Sallee FR. The role of alpha2-adrenergic agonists in attentiondeficit/hyperactivity disorder. Postgrad Med 2010; 122: 78–87. 8. Singer HS. Treatment of tics and tourette syndrome. Curr Treat Options Neurol 2010; 12: 539–561. 9. Tourette’s Syndrome Study Group. Treatment of ADHD in children with tics: a randomized controlled trial. Neurology 2002; 58: 527–536. 10. Greenhill LL, Pliszka S, Dulcan MK, Bernet W, Arnold V, Beitchman J, et al. Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults. J Am Acad Child Adolesc Psychiatry 2002; 41(2 Suppl): 26S–49S. 11. Connor DF, Fletcher KE, Swanson JM. A meta-analysis of clonidine for symptoms of attention-deficit hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 1999; 38: 1551–1559. 12. Castellanos FX, Giedd JN, Elia J, Marsh WL, Ritchie GF, Hamburger SD, 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: 589–596. 13. Gadow KD, Nolan EE, Sverd J, Sprafkin J, Schneider J. Methylphenidate in children with oppositional defiant disorder and both comorbid chronic multiple tic disorder and ADHD. J Child Neurol 2008; 23: 981–990. 14. Law SF, Schachar RJ. Do typical clinical doses of methylphenidate cause tics in children treated for attention-deficit hyperactivity disorder? J Am Acad Child Adolesc Psychiatry 1999; 38: 944–951. 15. Nolan EE, Gadow KD, Sprafkin J. Stimulant medication withdrawal during long-term therapy in children with comorbid attention-deficit hyperactivity disorder and chronic multiple tic disorder. Pediatrics 1999; 103(4 Pt 1): 730–737. 16. Palumbo D, Spencer T, Lynch J, Co-Chien H, Faraone SV. Emergence of tics in children with ADHD: impact of once-daily OROS methylphenidate therapy. J Child Adolesc Psychopharmacol 2004; 14: 185–194. 17. Aagaard L, Hansen EH. The occurrence of adverse drug reactions reported for attention deficit hyperactivity disorder (ADHD) medications in the pediatric population: a qualitative review of empirical studies. Neuropsychiatr Dis Treat 2011; 7: 729–744. 18. Rothenberger A, Roessner V, Banaschewski T, Leckman JF. Coexistence of tic disorders and attention-deficit/hyperactivity disorder-recent advances in understanding and treatment. Eur Child Adolesc Psychiatry 2007; 16(Suppl 1): 1–4. 19. Pliszka SR. Pharmacologic treatment of attention-deficit/ hyperactivity disorder: efficacy, safety and mechanisms of action. Neuropsychol Rev 2007; 17: 61–72. 20. Geller B, Reising D, Leonard HL, Riddle MA, Walsh BT. Critical review of tricyclic antidepressant use in children and adolescents. J Am Acad Child Adolesc Psychiatry 1999; 38: 513–516. 21. Lindsay SE, Gudelsky GA, Heaton PC. Use of modafinil for the treatment of attention deficit/hyperactivity disorder. Ann Pharmacother 2006; 40: 1829–1833. 22. Vaughan B, Fegert J, Kratochvil CJ. Update on atomoxetine in the treatment of attention-deficit/hyperactivity disorder. Expert Opin Pharmacother 2009; 10: 669–676. 23. Poulton A. Long-term outcomes of stimulant medication in attention-deficit hyperactivity disorder. Expert Rev Neurother 2006; 6: 551–561. 24. Molina BS, Hinshaw SP, Swanson JM, Arnold LE, Vitiello B, Jensen PS, et al. The MTA at 8 years: prospective follow-up of children treated for combined-type ADHD in a multisite study. J Am Acad Child Adolesc Psychiatry 2009; 48: 484–500. Evid.-Based Child Health 7: 1231–1234 (2012) DOI: 10.1002/ebch.1862
Commentary Commentaries on ‘Pharmacological treatment for Attention Deficit Hyperactivity Disorder (ADHD) in children with comorbid tic disorders’ These are commentaries on a Cochrane review, published in this issue of EBCH, first published as: Pringsheim T, Steeves T. Cochrane Database of Systematic Reviews 2011, Issue 4. Art. No.: CD007990. DOI: 10.1002/ 14651858.CD007990.pub2 Further information for this Cochrane review is available in this issue of EBCH in the accompanying Summary article.
Commentary by Michael H. Bloch Pringsheim and Steeves conducted a systematic review of the pharmacological treatment of attention-deficit hyperactivity disorder (ADHD) in children with comorbid tics (1). The authors synthesized the results of eight randomized, placebo-controlled trials in this population. Their work yields two important findings: 1. There is no evidence from randomized, controlled clinical trials that therapeutic doses of psychostimulant medication worsen pre-existing tics. 2. Alpha-2 agonist medications, such as clonidine and guanfacine, appear comparably effective to psychostimulant medications in treating ADHD symptoms in children with tics. Despite some minor methodological differences, this work largely confirms the results of a similar systematic review and meta-analysis in this area (2). These findings have important implications for both clinical care and public policy regarding the treatment of children with ADHD and comorbid tic disorders.
Implications for public policy The Food and Drug Administration (FDA) currently requires the package inserts of most psychostimulant medications in the US to list the presence of a tic disorder or a family history of Tourette syndrome as a contraindication to their use. This warning was issued based on a large collection of case reports and case series. These case reports associated the emergence of de novo tics and exacerbation of existing tic symptoms with methylphenidate, dextroamphetamine and pemoline. However, the association between psychostimulants and tics may be a result of confounding. Approximately 20% of children with ADHD develop a chronic tic disorder, and the symptoms of ADHD typically precede the onset of tic symptoms by several years (3). Therefore, a Copyright 2012 John Wiley & Sons, Ltd.
significant proportion of children diagnosed initially with ADHD will eventually develop tics regardless of treatment. Supporting this observation, there were several case reports, around the same time period, linking medications that are not psychostimulants (alpha-2 agonists) to tic exacerbation (4,5). Alpha-2 agonists are currently recommended by the Tourette Syndrome Association Medical Advisory Board as the first-line pharmacological treatment for tics (6). The data supporting the FDA warning appears even thinner in light of the trial data synthesized by Pringsheim and Steeves, which suggest that there is no exacerbation of tics with methylphenidate use; in fact, there is a trend towards improvement in tics (effect size = 0.28, p = 0.07) (2). The FDA warning also has a significant effect on physician behaviour. Many doctors in the US are hesitant to prescribe psychostimulants to children with tics or who have a positive family history of tics. They know that a large proportion of these children will subsequently develop tics (regardless of whether the medication is actually responsible) and the doctors may be held responsible and possibly sued for prescribing a contraindicated medication. This contraindication therefore likely leads to many children with tics being sub-optimally treated for their ADHD. Untreated ADHD has significant implications for both individuals and society. When ADHD is present in children with tics, the ADHD typically causes greater impairment in academic performance and social relationships than do the tics themselves. Childhood ADHD is also associated with an increased risk of substance use and car accidents, as well as higher rates of incarceration and unemployment. In light of the data from this review, it would be prudent for the FDA to remove the contraindication for the use of psychostimulants in children with comorbid tics (or family history of Tourette syndrome). Instead, it may be more appropriate to list tics as a possible side effect. After all, none of this trial-based data can rule
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out the possibility that psychostimulants may worsen tics in a small number of individual cases.
Implications for clinicians Pringsheim and Steeves synthesize data from several clinical trials that suggest alpha-2 agonist medication, and probably atomoxetine (a selective norepinephrine reuptake inhibitor), may be as effective as psychostimulant medication in the treatment of ADHD in subjects with comorbid tics (1). For most individuals with ADHD and tics, alpha-2 agonist medications are a preferable first-line treatment compared with psychostimulants as they can significantly reduce symptoms for both conditions (2) However, as suggested in the Tourette syndrome Study Group trial, the combination of an alpha-2 agonist and methylphenidate was superior to either treatment alone in children with ADHD and tics. (7). Furthermore, the combination of these medications is usually quite well tolerated. Troublesome side effects of psychostimulants (insomnia and anxiety) are often counteracted by the side effects of alpha-2 agonists (sedation and fatigue). Despite the current FDA warning, a psychostimulant medication could be considered the initial drug of choice when rapid symptom relief is needed in a child with ADHD and tics because improvements with psychostimulants can be seen in days, whereas improvements with alpha-2 agonists usually take weeks. For instance, a methylphenidate derivative would be advisable, based on current data, in a child with severe ADHD and minimal tics who was in need of rapid improvement of ADHD symptoms at school (i.e. at risk of expulsion from school for disruptive and impulsive behaviour).
Conclusion Pringsheim and Steeves systematically reviewed eight randomized controlled trials involving the pharmacological treatment of ADHD in children with comorbid tics (1). Existing trial literature shows that, in the vast majority of cases of children with ADHD and comorbid tics, psychostimulants improve ADHD symptoms with no evidence suggesting that they worsen tics. As new evidence emerges from randomized, placebocontrolled trials, it is likely that the association inferred from case report level data was likely subject to confounding. The FDA should reconsider its current listing of tics, or a family history of Tourette syndrome, as a contraindication to the use of these medications in treating ADHD. Furthermore, clinicians should not be afraid to consider utilizing psychostimulants in children with tics and persistent ADHD symptoms, especially when other available pharmacological and behavioural treatments for ADHD have been ineffective.
Acknowledgements The author acknowledges the National Institute of Mental Health support of the Yale Child Study Center Research Copyright 2012 John Wiley & Sons, Ltd.
Commentaries
Training Program (MHB), the National Institutes of Health 1K23MH091240 (MHB), the APIRE/Eli Lilly Psychiatric Research Fellowship (MHB), the AACAP/Eli Lilly Junior Investigator Award (MHB), the Trichotillomania Learning Center (MHB), NARSAD (MHB), and UL1 RR024139 from the National Center for Research Resources, a component of the National Institutes of Health, and NIH roadmap for Medical Research (MHB).
Declaration of interest The author has no conflicts of interest to disclose.
Michael H. Bloch* Child Study Center and Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA Correspondence to: Michael H. Bloch, MD, MS, Child Study Center, Yale University School of Medicine, PO Box 2070900, New Haven, CT 06520, USA E-mail: [email protected] Keywords: attention-deficit hyperactivity disorder, methylphenidate,, psychostimulant medication, tic disorders
References 1. Pringsheim T, Steeves T. Pharmacological treatment for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders. Cochrane Database Syst Rev 2011; Issue (4): Art. No.: CD007990. 2. Bloch MH, Panza KE, Landeros-Weisenberger A, Leckman JF. Meta-analysis: treatment of attention-deficit/hyperactivity disorder in children with comorbid tic disorders. J Am Acad Child Adolesc Psychiatry 2009; 48: 884–893. 3. Leckman JF. Tourette’s syndrome. Lancet 2002; 360: 1577–1586. 4. Huk SG. Transient exacerbation of tics in treatment of Tourette’s syndrome with clonidine. J Am Acad Child Adolesc Psychiatry 1989; 28: 583–586. 5. Kessler AR. Clonidine treatment increases tics in patients with Tourette syndrome: case report. J Child Neurol 2001; 16: 380–381. 6. Scahill L, Erenberg G, Berlin CM, Jr., Budman C, Coffey BJ, et al. Contemporary assessment and pharmacotherapy of Tourette syndrome. NeuroRx 2006; 3: 192–206. 7. Tourette’s Syndrome Study Group. Treatment of ADHD in children with tics: a randomized controlled trial. Neurology 2002; 58: 527–536.
Commentary by Daniel A. Gorman and Elia Abi-Jaoude The management of attention deficit hyperactivity disorder (ADHD) in patients with comorbid tics is a common clinical challenge. Tourette syndrome and other chronic tic disorders are present in 2% of children (1), and approximately half who present clinically also meet criteria for ADHD (2). While many of these youngsters have mild to moderate tics that they can ignore or tolerate without treatment, ADHD and other comorbid conditions often require intervention because of the considerable distress and functional impairment they cause (3). The presence of tics, however, adds a level of complexity to the management of ADHD, in part because of a longstanding concern Evid.-Based Child Health 7: 1231–1234 (2012) DOI: 10.1002/ebch.1862
Commentaries: Pharmacological treatment for ADHD in children with comorbid tics
that stimulants – the most established pharmacological intervention for ADHD – may exacerbate tics. This concern stems largely from decades old case reports, leading to product monograph warnings that stimulants are contraindicated in individuals with a personal or family history of Tourette syndrome. In addition, the notion that stimulants exacerbate tics has theoretical plausibility given that they increase dopaminergic and noradrenergic transmission, whereas the main tic suppressing medications, antipsychotics and alpha-2 agonists, have opposite effects. In the last 15 years, however, more rigorous studies have reported that stimulants generally do not exacerbate tics. Consequently, the use of stimulants in individuals with tics appears to have increased, at least among specialists, and one set of recent guidelines considers stimulants as first-line medication for ADHD in children with tics as well as those without (4). On the other hand, physicians continue to report that some of their patients experience stimulant-induced tic exacerbation, and even investigators whose findings do not support this phenomenon will add the caveat that stimulants may worsen tics in vulnerable individuals (5,6). Evidence is also mounting in support of non-stimulant medications for ADHD, including the alpha-2 agonists clonidine and guanfacine (7), which are used to treat tics as well (8). Given all these factors, the management of ADHD in the presence of tics remains a source of considerable confusion and debate, making the review by Pringsheim and Steeves both important and timely. The authors limit their review to double-blind, randomized controlled trials. Only eight studies qualified for review, most were small, and all were of short duration. Each study included a placebo group and three had multiple active treatment groups. In total, seven agents were investigated: methylphenidate (three studies); clonidine and desipramine (two studies each); and dextroamphetamine, guanfacine, atomoxetine and deprenyl (one study each). All studies of stimulants and alpha-2 agonists used short-acting formulations. Meta-analysis was precluded by clinical heterogeneity and issues related to unit of analysis. Funnel plots could not be created to assess for publication bias, as the number of studies for each medication was too small. Two studies showed evidence of selective reporting, and all four trials with a cross-over design failed to report paired data for analysis. Two questions are at the heart of the Pringsheim and Steeves’ review: (1) Are medications for ADHD efficacious in children with a comorbid tic disorder? (2) Do they exacerbate tics? Regarding the first question, the authors report that all agents studied, except deprenyl, improved ADHD symptoms. Furthermore, the Tourette’s Syndrome Study Group (TSSG) 2002 found that the combination of methylphenidate and clonidine was superior to either agent alone (9). While the most evidence exists for methylphenidate, the results suggest that it may be less efficacious in patients with a tic disorder compared to those without. Copyright 2012 John Wiley & Sons, Ltd.
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The TSSG 2002 reported that methylphenidate alone had similar efficacy as clonidine alone for ADHD symptoms (9), and Gadow 2007 reported that effect sizes for ADHD outcomes with methylphenidate were generally in the medium range (6). In contrast, studies of these agents in patients without tics have typically found large effect sizes for methylphenidate (10) as opposed to medium effect sizes for clonidine (11). As Pringsheim and Steeves propose, the moderate response to methylphenidate in TSSG 2002 and Gadow 2007 could be due to the relatively low doses of methylphenidate used; however, the third methylphenidate study included in the review did not find evidence of greater benefit with higher doses (12). Another possible explanation is that ADHD associated with tics is neurobiologically distinct from ADHD without tics. Indeed, the question of whether tic-related ADHD is ‘true’ ADHD is a matter of controversy (13). A third possibility is that residual inattentive and behavioural symptoms that do not improve with methylphenidate are related not to ADHD, but to other factors such as distraction caused by tics or the effort to suppress them, or the effects of obsessive-compulsive disorder, learning disorders or other comorbid conditions. Herein lies a crucial point for clinicians: even though ADHD is commonly comorbid with tic disorders, other potential causes of poor attention and misbehaviour must be carefully assessed before ADHD medication is started or increased. On the question of whether ADHD medications exacerbate tics, most studies, including ones involving stimulants, did not find evidence for this on average. In fact, some studies found that tics improved with ADHD treatment. Nevertheless, several results signal that stimulants can lead to a dose-related increase in tics for certain patients. In Castellanos 1997, one study cohort experienced tic exacerbation with moderate to high doses of dextroamphetamine ( ≥ 12.5 mg twice/day) (12). The same cohort also had worse tics with a high dose of methylphenidate (20–25 mg twice/day), though not, oddly enough, with an even higher dose (35–45 mg twice/day). Gadow 2007 found a dose-related increase in simple motor tics on a measure where tics were counted over two minutes, but not on other measures of tic severity (6). Finally, TSSG 2002 reported that tics limited dose increases in 35% of subjects treated with methylphenidate alone, about twice as many as in each of the other treatment groups (9). Given these findings and the fact that few studies (none of which qualified for review) have investigated long-term effects on tics (5,14–16), caution is still warranted when considering stimulants for patients with tic disorders, especially at higher doses. A secondary objective of Pringsheim and Steeves’ review was to assess adverse effects of ADHD medications besides tic exacerbation in children with tic disorders. Although not all studies evaluated these adverse effects adequately, the review’s findings are consistent with what is generally known about the agents Evid.-Based Child Health 7: 1231–1234 (2012) DOI: 10.1002/ebch.1862
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investigated: initial insomnia, appetite suppression, stomach upset, headache, dizziness, and increases in heart rate and blood pressure with stimulants; appetite suppression, weight loss, nausea, and increased heart rate with atomoxetine; sedation in close to half of subjects taking clonidine and guanfacine; appetite suppression and increases in heart rate and blood pressure with desipramine. These and other adverse effects (17) are essential considerations for clinicians and families contemplating pharmacological intervention for ADHD. Overall, Pringsheim and Steeves’ thorough review highlights the limited evidence base regarding the pharmacological treatment of ADHD in the presence of tics. This paucity of research is striking given that approximately 20% of children with ADHD also have a tic disorder (18), and hundreds of randomized controlled trials have been conducted for stimulants (19) and dozens more for non-stimulants (7,20–22) in children with uncomplicated ADHD. Clearly, more studies are needed to inform the management of the considerable minority of ADHD patients with comorbid tics. In particular, future efforts should investigate the longterm effects, including adverse effects, of ADHD medications in children with tic disorders, as is being done in children without tics (23,24). Moreover, researchers should not only include measures of ADHD and tic severity but also assess other important outcomes such as psychosocial functioning and quality of life.
Declaration of interest The authors have no conflicts of interest to disclose.
Daniel A. Gorman1,2 * and Elia Abi-Jaoude1,3 1 Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada 2 Department of Psychiatry, The Hospital for Sick Children, Toronto, Ontario, Canada 3 Department of Psychiatry, University Health Network, Toronto, Ontario, Canada
Correspondence to: Daniel A. Gorman, The Hospital for Sick Children, Department of Psychiatry, 555 University Avenue, Toronto, ON M5G 1X8, Canada E-mail: [email protected] Keywords: tics, Tourette syndrome, attention-deficit hyperactivity disorder, stimulants, alpha-2 agonists, adverse effects
References 1. Khalifa N, von Knorring AL. Tourette syndrome and other tic disorders in a total population of children: clinical assessment and background. Acta Paediatr 2005; 94: 1608–1614. 2. Freeman RD. Tic disorders and ADHD: answers from a worldwide clinical dataset on Tourette syndrome. Eur Child Adolesc Psychiatry 2007; 16(Suppl 1): 15–23. 3. Gorman DA, Thompson N, Plessen KJ, Robertson MM, Leckman JF, Peterson BS. Psychosocial outcome and psychiatric comorbidity in older adolescents with Tourette syndrome: controlled study. Br J Psychiatry 2010; 197: 36–44. Copyright 2012 John Wiley & Sons, Ltd.
Commentaries
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