Do psychostimulants cause tics?

Background

Attention deficit hyperactivity disorder (ADHD) is the most common neurobehavioral disorder in the pediatric population. Its incidence ranges between 5% and 12% in developed countries.1,2 Children with ADHD typically have difficulties with hyperactivity, impulsivity and maintaining attention.3 Recommendations for the management of children and adolescents with ADHD vary depending on the patient’s age. Overall, management includes behavior therapy and pharmacotherapy including psychostimulants methylphenidate and amphetamine; non-stimulants, such as atomoxetine; alpha agonists, such as extended-release guanfacine and extended-release clonidine, and tricyclic antidepressants.4

ADHD commonly co-occurs with tic disorders.1,3 Up to 50% of children with tic disorders also have ADHD.3 The relationship between ADHD and tic disorders is thought to be attributed to abnormalities in noradrenergic and dopaminergic transmission within corticostriatal circuits causing failure of inhibition of intrusive thoughts, sensory inputs and motor responses.1,3 When ADHD and tic disorders are present in a child, the ADHD symptoms have a more prominent impact on the child’s social relationships and academic achievements in comparison to the tics.3 Additionally, the greatest predictor of psychosocial quality of life in the pediatric population with a tic disorder is the severity of ADHD symptoms. Conversely, the impact of tic disorders on ADHD symptoms is limited.3 For these reasons, treatment for ADHD is a greater priority than treatment for tics.

Historically, clinicians have been hesitant to use stimulants for the treatment of children with ADHD and tic disorders for fear of worsening tics. In animal studies, methylphenidate and dextroamphetamine have demonstrated dose-dependent tic-like movements.5-7 Additionally, in the 1970s and 1980s, there were several case reports and case series published about pediatric patients who either experienced worsening of tics or new onset tic disorders after the use of psychostimulants for ADHD.8-14 As a result of a case series in 1982, which included 15 children who developed tics after initiation of psychostimulants, the Food and Drug Administration (FDA) mandated that the labeling for psychostimulants list tics and/or family history of tic disorders as a contraindication or as a significant adverse reaction.3,9,15 Psychostimulants have a biological explanation for aggravating tics in that they can increase dopamine in the synaptic cleft whereas most medications used to treat tic disorders antagonize dopamine.15 However, when ADHD and tic disorders occur together, ADHD symptoms precede tic symptoms by 2 to 3 years.15 This makes it difficult to discern whether the tics are a result of psychostimulant initiation or if they were to occur regardless of pharmacotherapy taken by the child. Moreover, tic severity increases and decreases depending on stress, excitement, fatigue or anxiety in the child’s life.1,15 Recent literature has brought into question whether psychostimulants cause or worsen tics. The purpose of this FAQ is to provide a summary of that literature.

Literature review

In order to assess the risk associated with psychostimulant use and new onset or worsening of tics, Cohen et al completed a meta-analysis in 2015.15 The meta-analysis included 22 double blind, randomized, placebo-controlled trials involving 2,385 patients under the age of 18 with an ADHD or hyperkinetic disorder diagnosis. All trials compared methylphenidate or dextroamphetamine derivatives to placebo. The primary objective was the proportion of children reporting tics as a side effect of medication as reported by clinician, participant, parent or teacher. The authors also conducted secondary analyses evaluating the type of psychostimulant (methylphenidate and mix-amphetamine derivatives), medication duration of action (short-acting and long-acting), reporter of side effect data, trial design and patient age. There was no significant increase in the risk of new onset or worsening of tics when comparing psychostimulant to placebo (relative risk [RR]=0.99, 95% confidence interval [CI]=0.78 to 1.27, p=0.96). The event rate for reported new onset or worsening of tics was 5.7% in the psychostimulant arm (95% CI=3.7% to 8.6%) and 6.5% of children in the placebo arm (95% CI=4.4% to 9.5%). The secondary analyses found no significant difference between the 2 groups in new onset or worsening of tics when comparing methylphenidate and amphetamine derivatives, long-acting and short-acting psychostimulants, psychostimulant dose, duration of active treatment, recorder of side effect data, study design and patient age. The authors concluded that although new onset or worsening of tics in children with ADHD occurs when taking a psychostimulant or placebo, there is no association between psychostimulant use and tic onset or worsening. A major limitation of this meta-analysis is that not all of the trials included were designed to evaluate safety outcomes.

In 2018, Osland et al published a Cochrane review.3 This systematic review included 8 randomized, double-blind controlled trials involving 510 patients with both ADHD and chronic tic disorder. The primary outcomes were to assess ADHD and tic symptom severity measured by validated clinician, teacher, or parent-reported scales. The secondary outcome was to evaluate adverse effect incidence. Unfortunately, a meta-analysis was not completed due to heterogeneity and unit-of-analysis problems. Because the nature of this narrative is to evaluate stimulant association with new onset or worsening of tics, the studies included in the systematic review focusing on psychostimulants will be discussed further.

Methylphenidate

Osland et al included 3 trials that included children with ADHD and a tic disorder taking methylphenidate.3 The first was a parallel-group study which randomized children to groups including clonidine, flexible dose of methylphenidate, clonidine plus methylphenidate or placebo.16 The primary outcome was the change from baseline to week 16 in a behavioral rating scale used for diagnosing ADHD in children and adolescents, the ADHD Conners Abbreviated Symptom Questionnaire (ASQ) for Teachers. A main secondary outcome was the change in baseline in the Yale Global Tic Severity Scale (YGTSS), a clinician administered tic severity rating scale. The primary outcome was statistically significant for treatment effect in comparing pharmacotherapy to placebo. Improvement in YGTSS from baseline was statistically significant with methylphenidate alone and methylphenidate plus clonidine (11 points, 98.3% CI 2.1 to 19.8, p=0.003 for both groups). The methylphenidate only group reported the lowest rate of worsening tics (20%) compared to placebo (22%), while the clonidine only group’s event rate was 26%. However, tic worsening affected dose titrations more frequently in the methylphenidate only group (35%) than in the methylphenidate plus clonidine (15%), clonidine only (18%) or placebo (19%) groups.

The second study performed by Gadow et al in 2007 is a cross-over trial which randomized children to 3 groups receiving three varying doses of methylphenidate (0.1 mg/kg, 0.3 mg/kg, and 0.5 mg/kg) and placebo.17 The primary outcome was change in YGTSS score. Regarding ADHD symptoms, ASQ scores improved with all doses of methylphenidate, but a dose-dependent effect was found with 0.5 mg/kg showing superiority. No statistical differences were found between the 3 groups for the YGTSS score regarding mean total motor, total phonic, impairment, or global severity scores. However, teacher scores on the Global Tic Rating Scale showed improvement with tics in patients receiving any of the 3 doses of methylphenidate compared to placebo (p=0.002). The two-minute tic/habit count category of the scale illustrated an increase in simple motor tics in children in the 0.3 mg/kg and 0.5 mg/kg methylphenidate groups compared to placebo (p=0.009). Regarding side effects, somatic symptoms such as sleep and appetite problems, headache, stomach upset, and dizziness were reported at higher rates during methylphenidate treatment compared to placebo (p<0.001). Additionally, diastolic blood pressure and heart rate was higher during treatment with methylphenidate compared to placebo.

Lastly, Castellanos et al designed a cross-over trial which randomized 20 children to groups of methylphenidate, dextroamphetamine and placebo treatment for 3 weeks each.18 Authors found that in the first cohort of 10 patients during the second week of methylphenidate therapy, total tic severity was greater when compared to the third week of methylphenidate and placebo (p<0.01). In the other cohorts, there were no significant effects of methylphenidate on tic severity. Regarding side effects, transient weight loss due to appetite suppression was reported in three patients receiving methylphenidate, and initial insomnia was reported in two patients taking methylphenidate.

Dextroamphetamine

Osland and colleagues included 1 trial that evaluated dextroamphetamine. The Castellanos et al study previously mentioned included 3 dextroamphetamine dose titrations (7.5 mg, 15 mg, or 22.5 mg twice daily) given for 3 weeks.18 There was a significant increase in tic severity in the first cohort of 10 patients during the second (15 mg twice daily) and third (22.5 mg twice daily) week of therapy compared to placebo (p=0.03). The second cohort of 6 patients that used low to intermediate doses did not find an increase in tic severity while the third cohort of 4 patients that used higher doses found a trend toward an increase in tic severity, but this did not reach statistical significance. Adverse reactions reported in 4 children included transient weight loss and initial insomnia was reported in 10 children.

Despite the high heterogeneity between the 3 studies above, a meta-analysis of these same studies was conducted in 2009 by Bloch et al.19 Results of the methylphenidate studies revealed a trend toward improvement in tic symptoms in patients with ADHD and tic disorder (effect size [ES] = 0.28, 95% CI -0.03 to 0.58, p=.07). The only study of dextroamphetamine found that tic severity worsened with psychostimulant treatment (ES = -0.59, 95% CI -1.06 to -0.13, p=0.01) at doses of 15 mg and 22.5 mg twice daily. The lower dose range used 7.5 mg during the first week of titration demonstrated no change in tic severity and the majority of patients showed a decrease in tic severity. As expected, both psychostimulants decreased ADHD symptoms.

Conclusion

Psychostimulants have been thought to be associated with new onset or worsening of tics due to literature from the 1970s and 1980s showing a possible relationship between the two. The most recent published literature suggests that psychostimulants may not increase tic severity or cause tics. Additionally, the American Academy of Neurology practice guideline for the treatment of tics in people with Tourette syndrome and chronic tic disorders summary includes a recommendation stating methylphenidate is more effective than placebo at reducing tic severity and ADHD symptoms based on evidence-based conclusions from systematic reviews.20 The literature supporting and opposing the association between psychostimulants and the development or worsening or tics is low quality. The older evidence is derived from case reports and case series, while the newer data is from safety endpoints collected during trials that were not designed to study the association between psychostimulants and tic onset or severity. Because the evidence is conflicting, perhaps it is warranted for clinicians to reexamine the FDA’s recommendations and consider the potential risk of tic onset or worsening as a precaution, rather than a contraindication.

References

  1. Ogundele MO, Ayyash HF. Review of the evidence for the management of co-morbid Tic disorders in children and adolescents with attention deficit hyperactivity disorder. World J Clin Pediatr. 2018;7(1):36-42.
  2. Attention-Deficit / Hyperactivity Disorder (ADHD). Centers for Disease Control and Prevention. https://www.cdc.gov/ncbddd/adhd/index.html. Published 2019. Accessed July 25, 2019.
  3. Osland ST, Steeves TD, Pringsheim T. Pharmacological treatment for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders. Cochrane Database Syst Rev. 2018;6:CD007990.
  4. Wolraich M, Brown L, Brown RT, et al. ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2011;128(5):1007-1022.
  5. Costall B, Naylor RJ. The involvement of dopaminergic systems with the stereotyped behaviour patterns induced by methylphenidate. J Pharm Pharmacol. 1974;26:30-33.
  6. Pechnick R, Janowsky DS, Judd L. Differential effects of methylphenidate and amphetamine on stereotyped behavior in the rat. Psychopharmacology (Berlin). 1979;65:311-315.
  7. Randrup A, Munkvad I. Pharmacology and physiology of stereotyped behavior. J Psychiatry Res. 1974;11:1-10.
  8. Golden GS. Gilles de la Tourette's syndrome following methylphenidate administration. Dev Med Child Neurol. 1974;16(1):76-78.
  9. Lowe TL, Cohen DJ, Detlor J, Kremenitzer MW, Shaywitz BA. Stimulant medications precipitate Tourette's syndrome. JAMA. 1982;247(12):1729–1731.
  10. Golden GS. The effect of central nervous system stimulants on Tourette syndrome. Ann Neurol. 1977;2:69-70.
  11. Denckla MB, Bemporad JR, MacKay MC. Tics following methylphenidate administration. A report of 20 cases. JAMA. 1976;235:1349-1351.
  12. Sleator EK. Deleterious effects of drugs used for hyperactivity on patients with Gilles de la Tourette syndrome. Clin Pediatr. 1980;19:453-454.
  13. Pollack MA, Cohen NL, Friedhoff AJ. Gilles de la Tourette’s syndrome. Familial occurrence and precipitation by methylphenidate therapy. Arch Neurol. 1977;34:630-632.
  14. Bremness AB, Sverd J. Methylphenidate-induced Tourette syndrome: case report. Am J Psychiatry. 1979;136:1334-1335.
  15. Cohen SC, Mulqueen JM, Ferracioli-oda E, et al. Meta-analysis: Risk of tics associated with psychostimulant use in randomized, placebo-controlled trials. J Am Acad Child Adolesc Psychiatry. 2015;54(9):728-736.
  16. Tourette Syndrome Study Group. Treatment of ADHD in children with tics: a randomized controlled trial. Neurology. 2002;58:527-536.
  17. 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.
  18. 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;36:589-596.
  19. 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.
  20. 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.

Prepared by:
Joette Amundaray Miller, PharmD
PGY-2 Pediatric Pharmacy Resident
University of Illinois at Chicago College of Pharmacy

September 2019

The information presented is current as of July 8, 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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