Pharmacological Treatment of Tourette Disorder in Children

Abstract

Background:

Tourette disorder (TD) is a neurodevelopmental disorder characterized by childhood onset of tics lasting more than one year, with multiple motor tics and at least one phonic tic at some point during the course of the symptoms. Treatment of tics may include psychoeducation, non-pharmacologic treatment, or pharmacologic treatment. We review pharmacologic treatment here.

Methods:

We performed a literature review on pharmacologic treatments for TD.

Results:

There is no current evidence to suggest that medications impact the prognosis of tic disorders, so current clinical guidelines recommend reassurance of the patient and family and monitoring if there is no change in function or quality of life due to tics. If treatment is indicated, it must be chosen based on the needs of each individual patient. Comprehensive behavioral intervention for tics (CBIT) is considered first-line management for most individuals with bothersome tics, especially if they are mild to moderate in severity. Pharmacotherapy should be considered when tics are impairing daily functioning, causing social problems, accompanied by other neuropsychiatric symptoms, or when the patient is not likely to benefit from CBIT. Current recommended pharmacotherapy options include alpha-2 adrenergic agonists, dopamine modulators, GABAergic medications, dopamine depleters, and botulinum toxin injections. Additionally, there are other novel medications that are being studied in ongoing clinical trials.

Conclusions:

This review summarizes available pharmacotherapy options for TD in children. It provides an overview of new medications and offers guidance to physicians when selecting appropriate treatments. If medications are indicated for tic management, treatment should be chosen based on the needs of the individual patient.

Introduction

Tourette disorder (TD) is characterized by childhood onset of tics lasting more than one year, with multiple motor tics and at least one phonic tic at some point during the course of the symptoms (Association AP, 2013). The etiology is believed to be multifactorial, involving complex genetic and environmental factors (Georgitsi et al., 2016). The pathophysiology of tics is thought to be related to dysfunctional cortical–basal ganglia–thalamocortical circuits and their associated neurotransmitters (Singer, 2019; Augustine and Singer, 2018; Kumar et al., 2016; Freeman et al., 2000). The epidemiology of TD has been evaluated by several studies in the past with an estimated prevalence of 0.3%–1% worldwide (Knight et al., 2012). Studies have also shown that up to 20% of children in the United States have tics at some point during childhood (Knight et al., 2012; CDC, 2009).

TD is commonly accompanied by other neuropsychiatric disorders including attention-deficit/hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), anxiety, and disruptive behavioral disorder (Hirschtritt et al., 2015). Approximately 85% of individuals with TD have at least one associated condition (Hirschtritt et al., 2015). TD prognosis can be variable, but tic severity tends to peak just before puberty and declines after adolescence in the majority of affected individuals.

Current clinical guidelines recommend reassurance and education of the patient and family for mild cases, especially if there is no impact of tics on function or quality of life (Pringsheim et al., 2019a; 2019b). However, a treatment plan should be established if there is impairment of daily functioning, social or emotional problems due to tics, or coexisting impairing neuropsychiatric disorders. Behavioral interventions, such as comprehensive behavioral intervention for tics (CBIT), are effective and should be recommended as initial therapy for bothersome tics; pharmacologic treatment should be considered when behavioral therapy is ineffective, unavailable, or not applicable (McGuire et al., 2015). Identifying co-occurring neuropsychiatric disorders is crucial, as these conditions may contribute more significantly to the patient’s overall disability than the tics themselves. Addressing these co-occurring issues could potentially help alleviate the tics. Therefore, the treatment should be individualized based on the most prominent and disabling symptoms.

There are several options for pharmacologic treatment including alpha-2 adrenergic agonists, dopamine modulators, GABAergic medications, anticonvulsants, dopamine depleters, and botulinum toxin injection (Frey and Malaty, 2022). There are other novel medications that are being studied. Overall, greater emphasis should be placed on well-controlled clinical trials in patients with TD compared with open-label studies, as the latter are likely confounded by placebo (nocebo) effects (Wang et al., 2024).

This review summarizes available pharmacotherapy options for TD in children. It provides an overview of new medications and offers guidance to physicians when selecting appropriate treatments.

First-Line Medications

Alpha-2 adrenergic agonists

The most potent medications for tics are those that block dopamine D2 receptors, including typical and atypical antipsychotic medications. However, dopamine modulators are also associated with the most bothersome side effects and thus are not recommended as first-line medications. As a result, alpha-2 adrenergic agonists are preferred as first-line agents due to their better tolerability (Pringsheim et al., 2019a; 2019b).

Modulation of central noradrenergic systems with alpha-2 receptor agonists has been a mainstay of tic treatment for several decades (Essoe et al., 2019). The main alpha-2 agonists are clonidine and guanfacine. Their mechanisms of action are similar, but they differ in half-life and side effect frequency. They are generally well tolerated and are moderately effective for reducing tics. Based on this, alpha-2 agonists are recommended in current guidelines as first-line medications for tics (Pringsheim et al., 2012). Alpha-2 agonists are also effective for treating ADHD symptoms; therefore, they may be a preferred choice for treating patients with both tics and ADHD (Pringsheim et al., 2019a; 2019b). In addition, the effect size of alpha agonists on tics is larger in children with tics and comorbid ADHD compared with in children with tics and without ADHD (Pringsheim et al., 2019a; 2019b). A recent American Academy of Neurology (AAN) guideline concluded that clonidine is effective with moderate certainty of evidence, and guanfacine is effective with low certainty of evidence in reducing tic severity (Pringsheim et al., 2019a; 2019b; Roessner et al., 2011). Clonidine has been used for the management of TD for the past 30 years. Multiple randomized clinical trials have demonstrated its effectiveness in reducing tic severity with moderate confidence (Pringsheim et al., 2019a; 2019b). The most common side effects seen with clonidine include sedation, bradycardia, orthostatic hypotension, and dry mouth (Pringsheim et al., 2012). The dose is typically started at 0.05 mg/day and titrated up slowly with close monitoring of blood pressure and heart rate to a therapeutic range of 0.1–0.4 mg/day and divided 3–4 times per day for the immediate release form (Pringsheim et al., 2012). There is an extended-release form available, with similar therapeutic range of 0.1–0.4 mg/day. Clonidine transdermal patches are also effective and safe. The patch is dosed at 1 mg/week for patients weighing >20 and ≤40 kg, 1.5 mg/week for patients weighing >40 and ≤60 kg, and 2 mg/week for patients weighing >60 kg (Song et al., 2017).

Guanfacine is generally preferred over clonidine in practice due to its less sedating effect (Pringsheim et al., 2019a; 2019b; Ueda and Black, 2021; Osland et al., 2018). The dose is typically started at 0.5 mg/day and titrated to up to 4 mg/day, divided twice a day (Pringsheim et al., 2012). Guanfacine is available in an extended release form, and the dosing can be started at 1 mg and advanced by 1 mg every 2 weeks, generally up to 4 mg once daily. Although extended release guanfacine demonstrated improved tic severity on the Yale Global Tic Severity Scale (YGTSS) in a randomized double-blind study, the change was not statistically significant (Seideman and Seideman, 2020). The most common side effects of guanfacine include drowsiness, dry mouth, headache, irritability, bradycardia, and stomach ache (Pringsheim et al., 2019a; 2019b).

Second-Line Medications

Second-line medications include dopamine modulators, including typical and atypical antipsychotics and GABAergic medications. Atypical antipsychotics should be considered second line after the first-line treatment approaches (CBIT or alpha-2 agonists) are either ineffective or causing side effects. Despite the effectiveness of dopamine modulators, they may cause significant side effects that limit their use in clinical practice. Atypical antipsychotics should be tried prior to typical antipsychotics due to the more favorable side effect profile of atypical antipsychotics. GABAergic medications can be considered second line, but there is limited evidence for efficacy.

Dopamine modulators

Haloperidol, pimozide, and aripiprazole are currently the only medications approved by the U.S. Food and Drug Administration (FDA) to treat tics. Pimozide and haloperidol are typical antipsychotics that are both potent D2 receptor antagonists. Aripiprazole is an atypical antipsychotic with greater affinity for the 5-HT 2 receptor than the D2 receptor. It has fewer extrapyramidal side effects than typical antipsychotics and may be more effective at treating mood and disruptive behaviors. Atypical antipsychotic medications might be particularly preferred for patients with behavioral comorbidities such as anxiety and disruptive behaviors.

Typical antipsychotics

Haloperidol was the first medication approved by the FDA to be used in TD management in adult patients in 1969 and in children in 1978 (Shapiro et al., 1987). Haloperidol is effective in reducing tic severity with moderate confidence (Pringsheim et al., 2019a; 2019b). The most common side effects include elevated prolactin levels, extrapyramidal symptoms, or parkinsonism (Quezada and Coffman, 2018).

Pimozide, a diphenylbutylpiperidine derivative, is a D2 receptor antagonist. The most common side effects of pimozide include extrapyramidal symptoms, prolonged QT, and increased prolactin (Pringsheim et al., 2019a; 2019b).

Fluphenazine is a typical antipsychotic that blocks both D1 and D2 receptors (Budman, 2014). One retrospective study in 2014 showed that 80.5% of patients had moderate improvement in their tics with fluphenazine. The mean age was 15.8 years, and the patients were reviewed over 26 years (Wijemanne et al., 2014). The side effect profile of fluphenazine is similar to the other typical antipsychotics.

Atypical antipsychotics

Aripiprazole is an atypical antipsychotic that alters dopaminergic neurotransmission through both D2 partial agonist and antagonist activity. It has both serotonergic and dopaminergic effects. Aripiprazole has a lower risk of side effects and similar efficacy compared with other agents. Thus, it is recommended by the Canadian treatment guidelines as first line (Pringsheim et al., 2012; Budman, 2014; Yang et al., 2015; Yang et al., 2019). It has been proven to reduce tic severity with moderate confidence. The dose is typically started at 2.5 mg/day and titrated up to a therapeutic range of 2.5–30 mg/day (Roessner et al., 2022). The most common side effects of aripiprazole include weight gain, sedation, and somnolence (Pringsheim et al., 2019a; 2019b).

In contrast, risperidone is recommended as first-line therapy in the European guidelines (Roessner et al., 2011). It has been shown to be effective with moderate certainty of evidence (Pringsheim et al., 2019a; 2019b). The dose is typically started at 0.25 mg/day and titrated up to a therapeutic range of 0.25–3 mg/day (Roessner et al., 2022; Dion et al., 2002). The most common side effects include weight gain, extrapyramidal symptoms, fatigue, and somnolence (Pringsheim et al., 2019a; 2019b).

Other antipsychotics such as ziprasidone, olanzapine, and quetiapine are reported to be effective, but the evidence is weak. In a pilot study, 28 youth were randomized to ziprasidone or placebo, and the ziprasidone group had significantly improved tic severity (Sallee et al., 2000). However, ziprasidone has not been studied in an larger phase 3 efficacy trial. Thus, the use of these agents is limited but can be preferred when other medications are not effective or causing side effects (Pringsheim et al., 2019a; 2019b; Quezada and Coffman, 2018; Roessner et al., 2013).

Benzamides are D2-blocking agents that can be used in the management of TD, but benzamides are not used or available in the United States. These medications have fewer extrapyramidal side effects compared with other dopamine antagonist medications (Quezada and Coffman, 2018).

GABAergic medications

There have been multiple studies on medications that act on gamma-aminobutyric acid (GABA) receptors, and contrary results have been found. Examples include topiramate, clonazepam, and baclofen.

Topiramate has a wide range of mechanisms of action including blockade of voltage-dependent sodium channels and interaction with GABA receptors and blockade of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid and kainate receptors. Topiramate is shown to reduce tics compared with placebo with low certainty of evidence (Pringsheim et al., 2019a; 2019b). An effective dose range of 25–200 mg/day is usually used (Jankovic et al., 2010). The most common or concerning side effects are paresthesia, cognitive and language problems, weight loss, glaucoma, and renal stones (Pringsheim et al., 2019a; 2019b).

Baclofen is a GABA-B receptor agonist. It was reported to decrease the tic severity in one of the studies in 1999, but there are other studies showing mixed results. A double-blind, placebo-controlled trial showed that there was no difference in the YGTSS between baclofen and placebo. There was a reduction in total tic score, but this was primarily due to a reduction in the impairment score rather than a decrease in tics (Singer et al., 2001). There are insufficient data to determine whether it is effective in reducing tic severity comparing with placebo per AAN guidelines (Pringsheim et al., 2019a; 2019b; Awaad, 1999).

Clonazepam, the most commonly used benzodiazepine in TD, acts on GABA receptors. It has been reported as effective in the management of tics, but its use is limited due to intolerance of side effects, including sedation, ataxia, and short-term memory problems (Essoe et al., 2019; Roessner et al., 2011; Quezada and Coffman, 2018).

Other Medications

VMAT2 inhibitors

Vesicular monoamine transport-2 (VMAT-2) is a presynaptic protein that transports dopamine into synaptic vesicles. VMAT-2 inhibitors deplete the presynaptic dopamine (Ueda and Black, 2021).

Tetrabenazine was the first medication in this group shown to control tics in an open-label study of 10 patients with TD, published in 1984. Four of the patients had marked improvement in tics, and three of them had mild improvement. However, there have been no randomized placebo-controlled trials of tetrabenazine to assess efficacy (Jankovic et al., 1984; Kenney et al., 2007). Deutetrabenazine and valbenazine, also VMAT-2 inhibitors, have been studied more extensively in TD. In two randomized controlled trials of deutetrabenazine versus placebo in youth with TD, the primary endpoint was not reached (Coffey et al., 2021; Jankovic et al., 2021). In six trials evaluating valbenazine in youth with TD, the primary endpoint also was not reached (Farber et al., 2021). Both agents were considered safe and well tolerated.

Dopamine agonists

The role of dopamine in TD is controversial. The dopaminergic hypothesis suggests excessive synaptic dopamine or central dopamine receptor hypersensitivity leads to tics, but dopamine agonists may also suppress tics by normalizing dopamine hypersensitivity (Kurlan et al., 2012).

Dopamine agonists can also be considered as an option for the treatment of tics when other medications are ineffective, but there is insufficient evidence to support effectiveness (Feinberg and Carroll, 1979). Ropinirole and pramipexole have been used in TD, but the evidence for use is weak (Anca et al., 2004). In 2012, pramipexole was evaluated in a 6-week randomized, placebo-controlled trial of 63 children and adolescents with TD. Pramipexole was noted to be more effective than placebo in suppressing tics (Kurlan et al., 2012). Pergolide is another dopamine agonist previously suggested for the management of tics, but it was withdrawn from the market in the United States due to serious side effects (Singer, 2010).

Botulinum toxin injections

Botulinum toxin is a neurotoxic protein that prevents the release of the neurotransmitter acetylcholine from axon endings at the neuromuscular junction. It is FDA approved for the treatment of migraine, spasticity, and cervical dystonia in adult patients and blepharospasm in patients more than 12 years of age (Padda and Tadi, 2023).

There have been several studies and case reports demonstrating botulinum toxin effectiveness for tics. A meta-analysis of treatments for TD has demonstrated that onabotulinumtoxinA injections are probably more likely to reduce tic severity compared with placebo (Pringsheim et al., 2019a; 2019b). In practice, botulinum toxin injections are used mostly for focal tics, such as simple motor tics involving eye blinking and neck jerking. Side effects usually include weakness of the surrounding muscles.

Complementary alternative medicine and supplementation

There are several studies about complementary medicines and supplements that reported potential efficacy in reducing tics.

Ningdong granule (NDG) is a compound product thought to have reduced tics by regulating dopamine, serotonin, and GABA and modulating the D2 receptor pathway (Frey and Malaty, 2022; Quezada and Coffman, 2018). NDG (formulated by Zhao) was also reported in the AAN guidelines to reduce tic severity with a moderate level of evidence (Pringsheim et al., 2019a; 2019b).

A multicenter, double-blinded randomized, placebo-controlled trials of 603 patients with TD aged 5–18 years showed that 5-Ling granule (5-LGr) was comparable to tiapride, an atypical antipsychotic, in reducing tics with a better safety profile than tiapride (Zheng et al., 2016). Another product, Yi-Gan San has been studied in an ongoing placebo-controlled trial (NCT03564132). Choudongning capsule has shown potential promise in several double-blind, placebo-controlled studies (Wang et al., 2021).

Magnesium is another supplement known to be taken by the children with TD (Smith and Ludlow, 2023). In an open-label clinical trial, including children aged 7–14 years with TD, treated with magnesium and vitamin B (6), there was a statistically significant reduction in the YGTSS (García-López et al., 2008). However, there was no control group in this study, and further investigations with randomized clinical trials are necessary regarding the safety and effectiveness.

Another open-label clinical trial evaluated the effectiveness of both l-theanine and vitamin B6 in reducing tic severity and co-occurring disorders. Supplementation with both l-theanine and vitamin B6 was significantly effective in reducing tics when compared with the group who received only psychoeducation (Rizzo et al., 2022).

Potential Medications Under Investigation

There are several pharmacological compounds under investigation to treat TD.

Ecopipam has selective D1 receptor antagonism and has been studied in several recent clinical trials. In an open-label study, ecopipam was safe and effective in reducing tic severity (Gilbert et al., 2014). In another placebo-controlled clinical trial, 40 children with TD were included and randomized to either ecopipam or placebo for 30 days. Ecopipam reduced tics and was well tolerated (Gilbert et al., 2018). A phase IIb trial, and the corresponding open-label extension, the D1AMOND study, is completed, but the results are not available at the time of this publication (NCT04007991) (NCT04114539).

Cannabinoids are used by patients with TD, and there are clinical trials ongoing. Initially, patients self-reported tic improvement following the use of cannabinoids (Szejko et al., 2019). A recent Cochrane review demonstrated that there was not enough evidence to support whether or not cannabinoids are an effective treatment for TD (Curtis et al., 2009). The AAN guidelines report with low confidence that patients with tics receiving tetrahydrocannabinol are possibly more likely than those receiving placebo to have reduced tic severity (Pringsheim et al., 2019a; 2019b).

In a trial of THX-110, a combination drug of dronabinol and palmitoylethanolamide, subjects had significantly reduced tics compared with baseline within 1 week of starting treatment. Side effects were common but were generally managed by decreasing the dose, slowing the dosing titration, and/or shifting the dosing to nighttime (Bloch et al., 2021).

Finally, the inhibitor of the monoacylglycerol lipase and selective modulator of the endocannabinoid system Lu AG06466 did not meet the primary endpoint of tic reduction in phase 2/3 studies (Müller-Vahl et al., 2021).

Conclusions

TD is a lifelong neurological disorder and may have functional, emotional, and social effects on children. There are several management options, including pharmacologic treatments. Treatment should be based on the individual needs including degree of tic severity, presence or absence of co-occurring conditions, and the effect of symptoms on daily functioning.

Behavioral therapy is the first-line management recommended by the AAN with a high certainty of evidence. Pharmacotherapy is used when the behavioral therapy is ineffective, unavailable, or when co-occurring neuropsychiatric disorders require treatment. The medications in clinical use include alpha adrenergic agonists, dopamine modulators, and GABAergic medications.

The reviewed articles and studies demonstrated evidence supporting the use of various medications. The most potent medications for tics are those that block dopamine D2 receptors, including typical and atypical antipsychotic medications. However, dopamine modulators are associated with the most bothersome side effects and thus are not recommended as first-line medications. As a result, alpha-2 adrenergic agonists are preferred as first-line agents due to their better tolerability (Pringsheim et al., 2019a; 2019b). In general, first-line medications should be started at a low dose and gradually increased as needed. If tics do not respond, there is no other benefit to neuropsychiatric comorbidities or a patient develops side effects, a second-line medication should be started in its place.

When there are co-occurring neuropsychiatric disorders, the treatment should be tailored to the specific needs of each patient. Alpha-2 agonist medications are more preferable for patients with ADHD and tics. Atypical antipsychotic medications might be particularly preferred for patients with behavioral comorbidities such as anxiety and disruptive behaviors.

Several case reports and case series have reported potential benefit of combining various treatments. While there are no specific guidelines on when to use combination therapy, our clinical experience suggests considering it when monotherapy is limited by debilitating side effects or insufficient efficacy (George et al., 2023; Masi et al., 2013; Oulis et al., 2008; Kalian et al., 1993). The use of other mentioned therapies and complementary medications should be considered if there is no response to first-, second-, and third-line medications. Table 1 summarizes the medications recommended by their level of evidence and clinical practice. Further investigations are necessary to assess the efficacy of more novel medications.

Table 1.

Medications Recommended by Their Level of Evidence and Clinical Practice

	Medications	Mechanism of action	Major side effects	AAN level of evidence
First-line medications	Guanfacine	Alpha-2 adrenergic agonist	Drowsiness, dry mouth, bradycardia, orthostatic hypotension, headache, stomach ache	Low
First-line medications	Clonidine	Alpha-2 adrenergic agonist	Sedation, bradycardia, orthostatic hypotension, dry mouth	Moderate
Second-line medications	Atypical antipsychotics: Aripiprazole and risperidone	Partial D2 Agonist D2 antagonist	Weight gain, metabolic syndrome, sedation, somnolence, extra pyramidal symptoms	Moderate Moderate
	Typical antipsychotics: Haloperidol and pimozide	D2 antagonist	Extrapyramidal symptoms, weight gain, increased prolactin levels, QTc-prolongation, sedation	Moderate Low
	Topiramate	Multiple mechanisms	Paresthesia, cognitive and language problems, weight loss, glaucoma, renal stones	Low

AAN, American Academy of Neurology.

When discussing treatment of tics with families, it is important to reinforce that only symptomatic treatments exist, and there is no cure for tics. Additionally, the waxing and waning nature of tics should be considered.

Footnotes

Clinical Significance

TD is a common neurodevelopmental disorder that can result in impairing or painful tics. There are many options for treating impairing or painful tics, but treatment approaches must be weighed against potential side effects. This review provides an overview of treatments and a practical approach to medication selection in TD.

Authors’ Contributions

A.C.: Conceptualization, Methodology, Investigation, Writing-Original Draft; J.V.: Writing- Review and Editing, Supervision; J.W.M.: Conceptualization, Writing-Review and Editing, Supervision; P.M.: Writing-Reviewing and Editing, Supervision.

Disclosures

I certify that none of the authors have any relevant financial or nonfinancial relationships to disclose as defined in the point above.

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