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Meta-Analysis: Risk of Tics Associated With Psychostimulant Use in Randomized, Placebo-Controlled Trials

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Objective

Clinical practice currently restricts the use of psychostimulant medications in children with tics or a family history of tics for fear that tics will develop or worsen as a side effect of treatment. Our goal was to conduct a meta-analysis to examine the risk of new onset or worsening of tics as an adverse event of psychostimulants in randomized, placebo-controlled trials.

Method

We conducted a PubMed search to identify all double-blind, randomized, placebo-controlled trials examining the efficacy of psychostimulant medications in the treatment of children with attention-deficit/hyperactivity disorder (ADHD). We used a fixed effects meta-analysis with risk ratio of new onset or worsening tics in children treated with psychostimulants compared to placebo. We used stratified subgroup analysis and meta-regression to examine the effects of stimulant type, dose, duration of treatment, recorder of side effect data, trial design, and mean age of participants on the measured risk of tics.

Results

We identified 22 studies involving 2,385 children with ADHD for inclusion in our meta-analysis. New onset tics or worsening of tic symptoms were commonly reported in the psychostimulant (event rate = 5.7%, 95% CI = 3.7%−8.6%) and placebo groups (event rate = 6.5%, 95% CI = 4.4%−9.5%). The risk of new onset or worsening of tics associated with psychostimulant treatment was similar to that observed with placebo (risk ratio = 0.99, 95% CI = 0.78−1.27, z = −0.05, p = .962). Type of psychostimulant, dose, duration of treatment, recorder, and participant age did not affect risk of new onset or worsening of tics. Crossover studies were associated with a significantly greater measured risk of tics with psychostimulant use compared to parallel group trials.

Conclusion

Meta-analysis of controlled trials does not support an association between new onset or worsening of tics and psychostimulant use. Clinicians may want to consider rechallenging children who report new onset or worsening of tics with psychostimulant use, as these symptoms are much more likely to be coincidental rather than caused by psychostimulants.

Section snippets

Search Strategy for Identification of Studies

Two reviewers searched the electronic database of PubMed on August 18, 2013, for relevant studies using the search: (Attention deficit disorder with hyperactivity OR ADHD OR ADDH OR hyperactiv* OR hyperkin* OR “attention deficit*” OR “brain dysfunction”) AND (methylphenidate OR Ritalin OR Metadate OR Equasym OR Daytrana OR Concerta OR Dextroamphetamine OR amphetamine OR Adderall OR Vyvanse OR Dexedrine OR Dextrostat). The search used only randomized controlled trials. The references of

Included Trials

Figure 1 depicts the selection of trials for this meta-analysis. A total of 815 references were identified in PubMed. In all, 92 trials were eligible for inclusion. Of these 92 trials, 16 trials published data on tics as a side effect of psychostimulant medication. Authors of 6 additional trials responded to electronic mail requests with unpublished data regarding the risks of tics in psychostimulant trials. Therefore, a total of 22 trials, involving 2,385 participants, was included in our

Discussion

Meta-analysis demonstrated no statistically significant relationship between psychostimulant use and new onset or worsening of tics in children with ADHD. Specifically, the relative risk of new onset or worsening of tics was 0.99 (95% CI = 0.78–1.27), indicating no evidence of an association between psychostimulants and tics. Furthermore, we found no association between risk of new onset or worsening of tics and type of psychostimulant, dose, type or duration of treatment, recorder of side

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    This article is discussed in an editorial by Drs. Susan Friedland and John T. Walkup on page 706.

    Clinical guidance is available at the end of this article.

    This article can be used to obtain continuing medical education (CME) at www.jaacap.org.

    This article was reviewed under and accepted by deputy editor John T. Walkup, MD.

    Dr. Bloch served as the statistical expert for this research.

    The authors acknowledge the support of the National Institutes of Health (NIH) K23MH091240 (M.H.B.), R01HD070821 (J.F.L.), T32MH018268 (J.F.L.), the Tourette Syndrome Association, the Patterson Foundation, the Rembrandt Foundation, Grifols (formerly Talecris) (J.F.L.), UL1 RR024139 from the National Center for Research Resources, a component of NIH, and NIH roadmap for Medical Research (M.H.B.).

    Disclosure: Dr. Leckman has received grant or research support from the Tourette Syndrome Association. He has served on the scientific advisory boards of the National Organization for Rare Disorders (NORD) and the Brain and Behavior Research Foundation (formerly NARSAD). He has received royalties from John Wiley and Sons, McGraw Hill, and Oxford University Press. He has authored the Yale Global Tic Severity Scale (YGTSS) assessment tool. He has received donations to clinical and research programs by the Associates of the Yale Child Study Center. Dr. Bloch has received grant or research support from the National Institutes of Health K23 Award, the Trichotillomania Learning Center, the Tourette Syndrome Association, the Patterson Foundation, the National Alliance for Research on Schizophrenia and Depression (NARSAD), the Rembrandt Foundation, and the American Academy of Child and Adolescent Psychiatry Research Initiative Junior Investigator Award. Ms. Cohen, Ms. Mulqueen, Mr. Ferracioli-Oda, Mr. Stuckelman, and Ms. Coughlin report no biomedical financial interests or potential conflicts of interest.

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