Tourette syndrome (TS) is associated with dysregulated cortico-striatal-thalamo-cortical neural circuitry, of which the primary implicated neurotransmitters include dopamine, glutamate, and gamma-aminobutyric acid. Pharmacologic intervention for tics should be considered when tics are causing psychological, functional, or physical impairment, and behavioral treatment is either inaccessible or ineffective. Only 3 medications have Food and Drug Administration approval for TS, including 2 typical antipsychotics (pimozide and haloperidol) and 1 atypical antipsychotic (aripiprazole). As such, off-label pharmacologic interventions are frequently used. Though there is no hierarchical recommendation for medication in the treatment of TS, common first-line approaches often include alphaagonists, followed by atypical antipsychotics, followed by typical antipsychotics. Pharmacological treatment options utilizing novel mechanisms of action are emerging.
Key points
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The decision to start medication in an individual with Tourette syndrome (TS) is based on the impact of tics on quality of life (eg, if causing psychological distress, functional impairment, physical pain) as well as the presence and severity of co-occurring conditions.
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There are no pharmacologic hierarchal recommendations in the treatment of TS; however, alpha-agonists are generally considered first line, and antipsychotics second line due to the greater risk for serious adverse effects (eg, sedation, weight gain, metabolic changes, movement disorders), albeit greater potential benefit.
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The field lacks large, high-quality, randomized controlled trials examining medication options for the treatment of TS; therefore, recommendations are predominantly based on small randomized controlled trials, retrospective reviews, case reports, and expert opinions.
Introduction
Tourette syndrome (TS) is a childhood-onset neuropsychiatric disorder characterized by motor and vocal tics. Tics are sudden, brief, recurrent, nonrhythmic, stereotyped movements (motor tics) or sounds (vocal tics) that are “unvoluntary” (between voluntary and involuntary) and may be simple (eg, eye blinking) or complex (eg, coordinated movements of multiple muscles) in their intensity and presentation. Tics are often preceded by a premonitory urge, or sensory-type feeling in the body that is temporarily relieved by performing the tic.
The clinical course in TS typically involves an early age of tic onset (ie, 5 years) with peak severity between ages 10 and 14 years, frequently followed by tic symptom improvement in the later teen years. Tics typically initially present as simple, motor, affecting the head/neck area and then progress in a caudal-rostral pattern with increased tic complexity and additional vocal tics. There is a higher incidence of TS in males than females; however, female sex has more recently been associated with worse tic-related impairment and functional interference. Compared to male individuals, tics in female individuals likely have a later age of tic onset, and likely increase in complexity with age rather than remitting.
TS is thought to be caused by dysfunction of the frontocortical-striatal-thalamo-cortical (CSTC) neurocircuitry networks of the brain, specifically dysfunction of the dopamine system. CSTC circuitry is associated with habit formation, affect regulation, reward processing, and inhibitory control. Disruption in this network is thought to lead to disinhibition and dysregulation of motor control in individuals with TS. The neurotransmitters associated with CSTC circuitry are dopamine, glutamate, which is the primary excitatory neurotransmitter, gamma-aminobutyric acid (GABA), which is the primary inhibitory transmitter, and serotonin. Potential imbalances in noradrenergic, cholinergic, cannabinoid, and opioid systems have also been implicated in tic disorders. Despite the variety of associated neurotransmitters, medications that utilize dopamine modulation continue to demonstrate the greatest impact on tic reduction.
General pharmacologic tic treatment guidelines
The goal of pharmacologic treatment in tic disorders is not to completely eliminate tics, but instead to reduce the severity and frequency of tics so as to allow for improved adaptive functioning and quality of life. Additionally, while pharmacologic interventions in tic disorders are used to help alleviate tic symptoms, they are not believed to be curative. This study focuses on the role of pharmacologic interventions in tic management.
Pharmacotherapy provides an important role in TS management. Currently, there are only 3 Food and Drug Administration (FDA)-approved pharmacologic interventions for TS: aripiprazole, haloperidol, and pimozide. Additional recommended pharmacotherapy options for tics include multiple off-label medications. Pharmacotherapy treatment recommendations, including those espoused most recently by the European Clinical Guidelines and the American Academy of Neurology Clinical Guidelines, are primarily based on a combination of small, placebo-controlled, randomized control trials (RCTs), other non-placebo-controlled trials, case series and studies, and expert consensus opinions. The most commonly prescribed pharmacotherapeutics have consistently been dopamine-modulating agents and alpha-agonists. In recent years, newer pharmacologic treatment options utilizing a variety of mechanisms (eg, glutamatergic, endocannabinoid) have been trialed, though often with limited success. It is important to note that historically the majority of participants studied were young, white males, thus potentially limiting generalizability, and that there continues to be a dearth of studies examining the long-term outcomes of common tic pharmacologic treatments. The following table is a non-exhaustive list of tic-targeting pharamcologic treatment options ( Table 1 ).
| Medication | FDA Approved | Category | Typical Therapeutic Dose Range | Tic Severity Reduction Likelihood | Certainty of Evidence |
|---|---|---|---|---|---|
| Clonidine | No | Alpha-agonist | 0.1–0.4 mg div bid | Probable | Moderate |
| Guanfacine | No | Alpha-agonist | 1–6 mg daily | Possible | Low |
| Haloperidol | Yes | Typical antipsychotic | 1–6 mg daily | Probable | Moderate |
| Pimozide | Yes | Typical antipsychotic | 1–6 mg daily | Possible | Moderate |
| Fluphenazine | No | Typical antipsychotic | 1–4 mg twice a day | Probable | Low |
| Aripiprazole | Yes | Atypical antipsychotic | 2–10 mg daily | Probable | Moderate |
| Risperidone | No | Atypical antipsychotic | 0.5–2 mg twice a day | Probable | Moderate |
| Ziprasidone | No | Atypical antipsychotic | 20–60 mg total daily (twice daily dosing) | Probable | Low |
| Metoclopramide | No | Other antipsychotic | 5–40 mg daily | Probable | Low |
| Topiramate | No | Anticonvulsant | 25–75 mg twice a day | Probable | Low |
| Cannabis | No | Endocannabinoid | – | Possible | Low |
| Ecopipam | No | Dopamine 1 antagonist | 50–100 mg daily | Probable | Moderate |
| Traditional Chinese Medicine | No | – | – | Probable | Very low |
| Tetrabenazine | No | VMAT2 inhibitor | 12.5–25 mg three times a day | Possible | Very low |
| Deutetrabenazine | No | VMAT2 inhibitor | 18–36 mg daily | Possible | Very low |
First-generation (typical) antipsychotics
First-generation (typical) antipsychotics were the first medication class to demonstrate efficacy in reducing tics in TS, and there is substantial evidence supporting their use. Typical antipsychotics work through blockade of dopamine (specifically D2) receptors. Each typical antipsychotic has a unique profile involving modulation of additional neurotransmitter receptors (eg, 5-HT, histamine, dopamine D3 receptors), thus contributing to unique benefits and side effect profiles. Despite the supported efficacy of these agents (standardized mean difference [SMD] −0.65), they are rarely used as first-line treatment in TS. This is due to their significant and potentially serious short-term and long-term side effects. Typical antipsychotics are commonly associated with extrapyramidal side effects (EPS), which include dystonic reactions, acute dyskinesias, tardive dyskinesia, akathisia, and Parkinsonian symptoms. Other common side effects of typical antipsychotics include QTc-prolongation, sedation, weight gain, and hyperprolactinemia, which can lead to gynecomastia, galactorrhea, irregular menses, and sexual dysfunction. Additionally, high doses of typical antipsychotics can increase risk for neuroleptic malignant syndrome.
Haloperidol
Haloperidol is a high-potency typical antipsychotic. Studies have generally demonstrated efficacy, with early non-randomized, noncontrolled trials showing improvement in tic symptoms between 78% and 91%. The first double-blind, placebo-controlled RCT of 57 individuals comparing haloperidol (and pimozide) to placebo found both to be significantly better than placebo in reducing tic severity, with haloperidol slightly more effective. Since then, multiple additional RCTs and meta-analyses have demonstrated haloperidol’s superiority over placebo. However, one smaller double-blind, placebo-controlled, crossover RCT of 22 youth who used lower dose ranges (mean 3.5 mg/day) did not demonstrate superiority. The greater incidence of adverse effects (eg, EPS, depression, anxiety, somnolence) across studies in those treated with haloperidol limits its benefits in clinical practice. Though haloperidol has been associated with QTc prolongation, that adverse effect was not observed in a controlled trial in youth. Ultimately, American Academy of Neurology (AAN) guidelines concluded that haloperidol was “probably” more likely to reduce tic severity compared to placebo with moderate confidence in the evidence.
Pimozide
Studies evaluating efficacy of pimozide have consistently demonstrated superiority over placebo, , albeit with slightly less effectiveness than haloperidol. Pimozide has demonstrated superiority in 7 double-blind trials, 2 naturalistic studies, and 3 meta-analyses/reviews. At the end of a 12 week, multicenter, double-blind, parallel-group study of 50 patients treated with pimozide, 38% of patients had very mild or no symptoms per Yale Global Tic Severity Scale (YGTSS). The most common side effects were depression, fatigue, and somnolence. Compared to haloperidol and risperidone, pimozide caused less EPS than haloperidol and less weight gain than risperidone. When utilizing pimozide, in addition to also assessing for dyskinesias, it is important to monitor electrocardiogram (EKGs) as pimozide is especially associated with prolonged QTc. Additionally, pimozide is extensively metabolized by Cyp3A4 and Cyp2D6 and should not be combined with medications that are strong inhibitors of Cyp3A4 or Cyp2D6, such as fluoxetine, thereby potentially limiting pharmacologic options for common TS-related comorbidities.
Fluphenazine
Fluphenazine is a high-potency D2 receptor blocker that may have fewer side effects than comparable neuroleptics. There have been limited studies of fluphenazine in TS and no RCTs to date. One open-label study of 21 children and adults previously treated with haloperidol found equivalent or better tic control in 16 of the participants with fewer side effects. A more recent retrospective chart review also supported fluphenazine as safe and effective in TS, with fewer side effects than haloperidol and with 80% of patients reporting moderate to marked improvement in tics. Most common side effects included drowsiness (70%), EPS (8%–23%), and weight gain (31%).
Second-generation (atypical) antipsychotics
Similar to their older counterparts, second generation, or atypical antipsychotics work through blockade of D2 receptors, as well as through modulation of serotonergic 5-HT2 receptors. While atypical antipsychotics have decreased risk of EPS and other serious adverse effects (eg, prolonged QTc and neuroleptic malignant syndrome) compared to typical antipsychotics, the risk of metabolic side effects, particularly weight gain and risk of type 2 diabetes mellitus, can often be a deterrent to use and reason for discontinuation. Atypical antipsychotics are generally preferred to typical antipsychotics as an earlier treatment option for tics. If prescribing atypical antipsychotics for tics, it is important to monitor weight, lipids, and glucose levels.
Aripiprazole
Aripiprazole is an atypical antipsychotic with a unique mechanism as a partial dopamine agonist. Since 2012, there have been numerous trials and meta-analyses demonstrating aripiprazole’s efficacy in reducing tics, and as of 2014, aripiprazole is the latest pharmacologic intervention to receive FDA-approval for the treatment of TS. Since then, the popularity of aripiprazole for tic treatment has grown significantly, and it is generally perceived by clinicians and parents of patients alike as being the most helpful with the least troublesome side effect profile. , Aripiprazole’s effect on tics has been shown to be similar to haloperidol and tiapride (not available in the United States), though with less risk for EPS and QTc prolongation. In a large double-blind, placebo-controlled RCT assessing high-dose and low-dose aripiprazole in 133 youth, both high (10 mg/day if >50 kg) and low (5 mg/day <50 kg) doses demonstrated significant improvement on TTS compared to placebo (high dose −9.9 [confidence interval (CI) −13.8 to −5.9]; low dose −6.3 [CI −10.2 to −2.3]) and on the clinical global impression – Improvement scale (CGI-I) compared to placebo (high dose 74%, low dose 69% with much or very much improved compared to 38% in the placebo group). The most common side effects reported in both the low-dose and high-dose groups were sedation, somnolence, and fatigue. Doses greater than 10 mg tend to have greater side effects without significant gain in efficacy and are not generally recommended. Given aripiprazole’s partial agonism at serotonin receptors, while not common, it is important to watch for mood-related changes, including activation, agitation, and manic switching. Metabolic side effects are frequently reported, and although aripiprazole is generally associated with less weight gain compared to other atypical antipsychotics, children are more vulnerable to associated weight gain compared to their older counterparts. Ultimately, AAN guidelines concluded that aripiprazole was probably more likely than placebo to reduce tic severity with moderate confidence in the evidence.
Risperidone
Compared to other atypical antipsychotic medications, risperidone is a high-potency dopamine blocker. As such, risperidone’s side effects may be more similar to those associated with typical antipsychotics (ie, EPS), particularly at the higher dose range. Though risperidone is not currently FDA-approved for TS, it has been well documented as an effective treatment with studies demonstrating benefit on tics comparable to haloperidol, pimozide, aripiprazole, and tiapride. One 12 week double-blind, parallel-group study of 50 participants comparing risperidone to pimozide found greater improvements on the YGTSS-total tic score (TTS) score in the risperidone group (54% vs 38%) with fewer reported incidences of EPS. Additional randomized, double-blind, placebo-controlled trials have demonstrated risperidone as superior to placebo , as well as have multiple systematic reviews/meta-analyses over the last 10 years. However, discontinuation secondary to adverse effects is common. Frequent side effects include fatigue, high appetite, weight gain, sedation, EPS, and hyperprolactinemia. In a prospective longitudinal study in youth, 35% of children taking risperidone experienced some form of EPS. Risperidone was also associated with a mean increase in body weight of almost 3 kg over an 8 week trial. In a review by Pringsheim and colleagues, 41% of children treated with risperidone developed prolactin elevation. This may be particularly important in prepubertal youth as the clinical signs of hyperprolactinemia, such as amenorrhea or gynecomastia, may be less observable. Of note, the significance of elevated prolactin in the absence of clinical signs is an area of ongoing discussion, as historically prescribers have been advised against checking and even adjusting medication unless there are associated clinical signs of elevated prolactin. Ultimately, AAN guidelines concluded that risperidone is probably more likely than placebo to reduce tic severity with moderate confidence.
Olanzapine
Olanzapine is a lower potency atypical antipsychotic with high anticholinergic properties. It had historically been suggested that one requires high-potency atypical antipsychotics to effectively treat tics; however, a recent meta-analysis suggests this is not the case. A number of case-reports, open-label studies and non-placebo-controlled trials utilizing olanzapine have demonstrated benefit on tics with similar efficacy to other antipsychotics. , A double-blind, non-placebo RCT comparing haloperidol and olanzapine treatment showed that both haloperidol and olanzapine were effective in reducing tic severity, with fewer side effects, such as EPS or EKG changes observed in the olanzapine group. In small trials, the most commonly reported side effects were sedation, dry mouth, increased appetite, and weight gain (4–5 kg within 6–8 weeks).
Quetiapine
Similar to olanzapine, quetiapine is a low-potency atypical antipsychotic with high anticholinergic properties. To date, there have been no RCTs examining quetiapine in TS. Data from open-label trials, case studies and retrospective surveys have been mixed, though generally positive. One open-label trial of quetiapine demonstrated improvement in tic severity, with sedation being the most common side effect. Quetiapine is generally associated with greater weight gain and metabolic effects compared to some other antipsychotics, though less so than olanzapine. Some researchers have speculated that quetiapine requires higher doses to be effective, which may limit its tolerability.
Ziprasidone
Ziprasidone is a high-potency dopaminergic atypical antipsychotic that, unlike most other atypical antipsychotics, is not associated with significant weight gain. There have been 2 studies on ziprasidone in youth one double-blind placebo-controlled RCT and one open-label study. Both studies and subsequent reviews have reported a statistically significant benefit on tics. , , The most common side effect was somnolence, which was transient, and reported EPS side effects were not greater than in placebo (though only doses up to 40 mg were used). Similar to pimozide, ziprasidone is associated with prolonged QTc and, as such, requires EKG monitoring and very careful consideration regarding simultaneous utilization of other agents that may also prolong QTc.
Clozapine
Clozapine is a low-potency atypical antipsychotic with a unique mechanism of action that reduces risk of EPS side effects. Clozapine has not been shown to be effective in reducing tics and should not be utilized as a tic-reducing agent. At least one study found clozapine to worsen tic severity in some individuals, and it has been associated with the emergence of facial tics.
Other Atypical Antipsychotics
There have not been controlled studies assessing the impact of paliperidone on tics; however, 2 case studies with a total of 4 patients demonstrated its benefit. There have been no studies to date on iloperidone, asenapine, or lurasidone; though given their shared mechanism with other effective medications, one might expect benefit.
Alpha-2 adrenergic agonists (alpha-agonists)
Alpha-2-adrenergic agents (alpha-agonists) are often preferred first-line agents for treatment of TS due to their overall safe side effect profile. Alpha agonists act on presynaptic auto-receptors reducing norepinephrine levels. A 2013 meta-analysis found an overall effect for alpha-agonists (SMD = 0.31) over placebo on tics. Alpha-agonists are commonly used in treating attention-deficit/hyperactivity disorder (ADHD), and they are more effective in treating tics if there is co-occurring ADHD (SMD = 0.68) compared to if there is not (SMD = 0.15). Common side effects to assess for include sedation, dry mouth, headache, and irritability. Blood pressure and pulse should also be monitored at baseline and with dose adjustments due to the risk of hypotension and rebound hypertension upon medication withdrawal.
Clonidine
Clonidine, which comes in immediate-release, extended-release, and transdermal formulations, is commonly used as a first-line tic treatment. In multiple studies, clonidine demonstrated efficacy compared to placebo and generally had a favorable side effect profile, particularly compared to antipsychotic medications. , A randomized, non-blinded 4 week comparison study of haloperidol versus clonidine adhesive patch in 119 youth found significant effects of the clonidine patch with no significant side effects reported. A larger double-blind, placebo-controlled RCT of 437 Chinese youth found statistical improvement in tic severity in those treated with clonidine patch compared to control with no significant adverse effects. The 2019 AAN guidelines reported that clonidine was “probably” more likely to reduce tics compared to placebo with moderate confidence in the evidence.
Guanfacine
Guanfacine comes in immediate-release and extended-release formulations. Compared to clonidine, studies demonstrating the efficacy of guanfacine as a treatment for tics have been less clear. One placebo-controlled, double-blind RCT of youth with TS and ADHD found a significant decrease in tic severity in the guanfacine group compared to placebo (31% vs 0%), in addition to improvement in ADHD symptoms. However, in 2 other double-blinded, placebo-controlled RCTs, guanfacine failed to provide significant benefits over placebo. , Most common side effects include sedation, mid-sleep awakening, dry mouth, irritability, and constipation. , Although guanfacine is recommended in some guidelines, its evidence is limited, especially compared to clonidine. AAN guidelines concluded that guanfacine was “possibly” more likely to reduce tic severity compared to placebo, with low confidence in the evidence.
Gamma-aminobutyric acid modulating
Studies have explored the efficacy of GABA-modulating agents in the management of TS. GABA, the primary inhibitory neurotransmitter in the central nervous system, plays a crucial role in regulating motor function and has been implicated in the pathophysiology of TS.
Older studies have suggested the effectiveness of benzodiazepines, particularly clonazepam, for the reduction of tics with response rates reported as high as 53% to 71%. Another study showed clonazepam to be superior to clonidine in the reduction of tics. However, there are no randomized, placebo-controlled studies, and given that benzodiazepines have the potential for tolerance, dependence, and paradoxic reaction in youth, they should be used with caution, and for short durations of time.
Topiramate, a GABAergic (and glutamate-modulating) anticonvulsant medication, has shown some benefit in tic symptom reduction. In a study of 29 children and adults, topiramate 50 to 200 mg demonstrated a positive response compared to placebo on the TTS. A 2020 meta-analysis found topiramate to be more effective than control medications (risk ratio [RR]: 1.13) with fewer adverse events (RR: 0.54). Common side effects associated with topiramate can include cognitive and language difficulties, aggression, mood swings, nausea, and decreased appetite. Per AAN guidelines, topiramate was found to be “probably or possibly” better than placebo in tic treatment, and can be considered prior to neuroleptics in individuals whose tics don’t respond to alpha-agonists.
Baclofen, a GABA-B agonist used to treat spasticity, has been explored as a tic reduction agent. In an open-label study in a large cohort of youth with TS, 250 out of 264 children taking baclofen reported a reduction in tic severity. A subsequent small double-blind, placebo-controlled cross-over RCT involving 10 youth with TS had mixed results. The overall YGTSS score and CGI-I improved significantly in the active compared to inactive treatment period, though the TTS did not differ. As such, the authors speculated the beneficial effects of baclofen on TS were not specifically related to tic reduction.
Traditional Chinese medicine
Traditional Chinese medicine (TCM) has been used as a treatment for a variety of illnesses for thousands of years. TCM compounds specifically used for tics include 5-Ling granule, Ningdong granule, and Qufeng Zhidong. 5-Ling granule, a proprietary polyherbal product approved for tics in China, has demonstrated significant benefit in studies in China, though has not been formally studied in the United States. In the largest tic treatment study to date with 603 participants, Zheng and colleagues compared 5-Ling granule and tiapride to placebo for 8 weeks and found a significantly greater improvement in YGTSS and TTS in both the 5-Ling granule (74%) and tiapride (68%) groups compared to placebo (44%). Ningdong granule was also well tolerated with few adverse effects. An RCT examining the benefit of Ningdong granule versus haloperidol versus Ningdong granule and haloperidol demonstrated a benefit of Ningdong granule, with the Ningdong granule and haloperidol combination being most effective. The mechanism of action of each of the TCM in targeting tics likely involves dopamine system modulation and possible downregulation of inflammatory processes. A significant challenge in assessing the benefit of TCM agents in the United States is first ensuring the safety of the individual ingredients in these proprietary formulations.
Cannabis/endocannabinoids
The endocannabinoid system is believed to be involved in motor control, and high-density central cannabinoid (CB1) receptors are found in areas implicated in TS, specifically the basal ganglia. While there have been numerous case reports and noncontrolled trials attesting to the efficacy of cannabis on tics, there have only been a handful of RCTs with mixed results. A 6 week double-blind, placebo-controlled RCT of 24 patients found a significant difference in those treated with up to 10 mg/day of tetrahydrocannabinol (THC) compared to placebo with no serious adverse events. Another small double-blind, cross-over trial using a combination of THC and cannabidiol (CBD) versus placebo demonstrated benefit with a correlation between plasma THC levels and the primary outcome measure, TTS. CANNA-TICS, the largest TS cannabis study to date, examined the use of nabiximols (1:1 THC:CBD ratio) in a 13 week, multicenter, double-blind, placebo-controlled RCT. Though superiority in the active group compared to the placebo was not demonstrated for their primary outcome, there were positive trends in certain secondary outcomes, including other measures of tics, depression, and quality of life. Additionally, there appeared to be a subgroup benefit in those who are male, had co-occurring ADHD, and had higher tic severity at baseline. Interestingly, small trials where only CBD (and not THC) are used have been ineffective. As there appears to be a positive signal in a subset of patients, further studies that determine the type (THC, CBD) and ratio of cannabis are warranted. Both the European Society for the Study of Tourette Syndrome and the AAN guidelines recommend cannabis for the treatment of tics in otherwise treatment-resistant adults, prior to deep brain stimulation.
Vesicular monoamine transporter 2 inhibitors
Tetrabenazine is a vesicular monoamine transporter 2 (VMAT2) inhibitor whose mechanism leads to a reduction in presynaptic dopamine and norepinephrine release. Its primary use is in tardive dyskinesia and Huntington’s chorea, though it has also been trialed in TS in several open-label and retrospective studies. The studies of tetrabenazine in youth and adults were generally positive, though there were notable side effects, including almost 30% experiencing Parkinsonism and akathisia. Additionally, there were high rates of sedation, prolonged QTc, and depression in around 20%. As such, tetrabenazine should be used with caution and after other options have been exhausted.
More recently, deutetrabenazine was trialed in youth with tics. Deutetrabenazine differs from tetrabenazine in that its active metabolites have longer half-lives, there is less variation in its peak concentrations, and it is associated with a reduced side effect burden. In an open-label trial of deutetrabenazine, 76% of patients were either much or very improved on CGI-I, and compared to tetrabenazine, there was less EPS, no impact on QTc, and lower incidence of depression. However, a more recent double-blind, placebo-controlled RCT did not demonstrate superiority compared to placebo. Similarly, an open-label extension study of deutetrabenazine with a 2 week randomized withdrawal did not demonstrate a difference between the experimental or placebo group in TTS worsening.
Ecopipam
Ecopipam is a first-in-class dopamine 1 receptor antagonist, which is in contrast to other antipsychotics, which primarily are D2 receptor antagonists. Currently in a Phase 3b trial, earlier studies of ecopipam have demonstrated positive results on tic reduction. A 4 week placebo-controlled, crossover RCT of 40 youth with TS demonstrated a significant decrease in TTS in the active treatment group compared to placebo. Similarly, in a larger 12 week double-blind, placebo-controlled RCT, the TTS was significantly reduced in the ecopipam group compared to the control group. There were no reported weight gain, dyskinesias, adverse events, metabolic changes, or EKG changes in the ecopipam group. The most common side effects experienced in the ecopipam group were headache, insomnia, fatigue, and somnolence (40%).
Pharmacology for co-occurring conditions
Individuals with TS often have high rates of co-occurring psychiatric conditions, particularly ADHD and OCD, in addition to anxiety disorders, mood disorders, body-focused repetitive behavior disorders, autism spectrum symptoms, etc. In many cases, these co-occurring conditions may be more severe and impairing than the tics themselves. In a study that examined rates of pharmacologic intervention in 314 youth with TS and a variety of co-occurring conditions, only 36% in the tic-only group received pharmacologic treatment. In comparison, 78% of the TS+ ADHD group, 58% of the TS+ obsessive-compulsive disorder (OCD) group, and 88% of the TS + ADHD + OCD group received medication. Though tics were the primary reason for initiating pharmacotherapy in the TS and TS+ OCD group, ADHD was the primary reason for initiating when that comorbidity was present. When initiating pharmacotherapy in an individual with TS, choosing the optimal treatment intervention requires careful consideration of these co-morbidities. Despite the fact that many of the first-line tic medications target additional co-occurring non-tic symptoms (eg, alpha-agonist for ADHD, atypical antipsychotic for severe mood instability), individuals with TS frequently require polypharmacy to best address the combination of commonly co-occurring comorbidities. When combining medications, it is important to monitor the patient’s EKG for QTc prolongations, blood pressure, heart rate, and metabolic profile.
Tourette Syndrome and ADHD
The combination of ADHD and tics has been associated with worse quality of life, increased social difficulties, and worse ADHD impairment. Historically stimulants (the gold-standard treatment of ADHD) were avoided in individuals with TS as they were believed to cause or exacerbate tics. However, this has not been supported by literature. In fact, a recent large meta-analysis found no difference in tic onset or tic worsening in the group using stimulants versus placebo controls. Furthermore, stimulants are equally effective in treating ADHD in youth who have tics versus those who do not. Alpha-agonists are another well-studied, FDA-approved, effective treatment class for ADHD that can also treat tics. , , As such, alpha-agonists could be considered first in individuals with co-occurring ADHD and tics, particularly if the tics are more bothersome than the ADHD. (If the ADHD is more impairing, then the treater should still consider a stimulant first.) Notably, alpha-agonists are more effective in treating tics when there is co-occurring ADHD compared to when there is not. It is also common to utilize the combination of stimulants and alpha-agonists when treating youth with co-occurring TS and ADHD as the combination has been shown to be synergistic. In a large trial evaluating the impact of combinations of methylphenidate and clonidine on tics and ADHD, the combined group had the greatest reduction in both tic and ADHD symptoms and the fewest side effects. When selecting a stimulant intervention in individuals with co-occurring tics and ADHD, it is preferable to start with the methylphenidate-based agents compared to amphetamine-based agents, as methylphenidate formulations have a less potent mechanism of action and fewer side effects. Finally, a 2018 Cochrane review of children diagnosed with ADHD and a chronic tic disorder concluded that there was benefit on ADHD symptoms with methylphenidate, atomoxetine, and clonidine, and a benefit on tic symptoms with guanfacine, desipramine, methylphenidate, clonidine, and a combination of methylphenidate and clonidine.
Tourette Syndrome and OCD
The overlap between TS and OCD is well documented, with shared genetics and phenomenology. There is evidence that the presentation of TS and co-occurring OCD is more similar to TS than it is to OCD without co-occurring tics. , Selective serotonin reuptake inhibitor (SSRIs) are the gold-standard pharmacologic treatment of OCD and should always be used as the first-line medication independent of whether there are co-occurring tics. That said, it is of note that in studies of individuals with co-occurring OCD and tics, SSRIs alone are not always as effective in treating the OCD. , In cases where there is partial response to SSRIs in individuals with TS and co-occurring OCD, and OCD symptoms remain significantly impairing, utilizing atypical or typical antipsychotics may be a useful augmentation strategy. Aripiprazole, risperidone, and haloperidol have demonstrated the greatest benefit in individuals with refractory OCD and co-occurring tics. Interestingly, in adults whose OCD did not respond to serotonergic medication alone, if they had co-occurring tics, the number needed to treat (NNT) with antipsychotic augmentation was 2; if there were not co-occurring tics, the NNT was 6. Oftentimes, individuals with TS and OCD have symptoms at the interface of tics and compulsions, sometimes referred to as “Tourettic OCD.” When one suspects this to be the case, and the symptoms are not responding to OCD monotherapy, one should consider utilizing standard tic treatments in addition to OCD treatment, often a first-generation or second-generation antipsychotic, though one can also consider alpha-agonists. Finally, although SSRIs do not directly reduce tic symptoms, given that tics are known to exacerbate during periods of stress, SSRIs may have an indirect role in improving tics via reduction of the co-occurring OCD or other anxiety/mood comorbidities. , As such, ensuring that one is effectively treating co-occurring conditions is important in optimizing tic treatment.
Tourette Syndrome and Intermittent Explosive Episodes
Many individuals with TS have difficulty regulating impulse and reward-seeking behaviors, and up to 25% of youth with TS have intermittent explosive disorder (IED), characterized by severe anger outbursts, or “rage attacks,” where small triggers result in disproportionate dysregulated responses. , Rage attacks are frequently reported by parents as the most impairing symptom in their children with TS. When youth with TS and rage attacks had co-occurring ADHD, methylphenidate was found to be effective in treating oppositional behaviors and aggression, though this effect was only observed in the cohort with co-occurring oppositional defiant disorder. Atypical antipsychotics may be a useful approach for severe rage attacks/IED, with one study finding aripiprazole effective in reducing both tic severity and explosive outbursts. Similar results were found with olanzapine with a decrease in parent-reported rating scales of disruptive behavior. In youth with TS, ADHD, and behavioral dysregulation, alpha-agonists may also be considered, particularly as it has been suggested that guanfacine may be effective in reducing “behavioral problems;” though more potent medications may be needed.
Treatment algorithm
Treatment of TS requires a comprehensive and individualized approach. The first step should always be a thorough evaluation to assess tic severity and related impairment as well as the presence and severity of common co-occurring conditions such as OCD, ADHD, rage attacks, mood disorders, and autism spectrum disorder. Following this assessment, clinicians should prioritize treatment based on the most impairing symptoms, unless there is an active mood disorder, in which case that should always be treated first. If tics are the primary concern, first-line treatments should include alpha-agonists or atypical antipsychotics. If a co-occurring condition is more problematic, then treatment should focus on that disorder. It is important to consider potential medication side effect profiles, medication feasibility and availability, and patient preferences when developing a tailored and effective treatment plan.
Summary
TS is characterized by motor and vocal tics, and is often accompanied by various co-occurring psychiatric conditions. Understanding the complex nature of TS is crucial for effective management. The treatment of TS involves a nuanced approach without formal hierarchal medication recommendations, though aripiprazole is widely considered the most effective treatment with the least aversive side effect profile for impairing tics. Multiple treatment modalities are available, with the greatest evidence in support of atypical antipsychotics and alpha-agonists (specifically clonidine). VMAT2 inhibitors and treatments utilizing GABAergic and glutamatergic mechanisms have been trialed, though often with limited benefit on tics. Novel approaches to tic treatment, including a first-in-class D1 receptor antagonist, endocannabinoid modulators, and TCM agents, hold promise for the future. The choice in treatment should be tailored to the patient’s individual profile, considering factors such as medical and psychiatric comorbidities, pre-treatment body mass index/weight, family history, medication side effect profile, and medication availability. Regularly scheduled evaluations are essential to care, and if the patient remains stable over a period of 6 to 12 months, it may be reasonable to consider a trial off medication, particularly given the trend of tic improvement as one matures into adulthood.
Clinics care points
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Alpha-agonists, particularly clonidine, should be considered as a first-line treatment option for TS due to their generally well-tolerated side effect profile. Alpha-agonists are more effective in tic reduction when there is co-occurring ADHD.
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Antipsychotic medications are the most effective class of anti-tic medications. Despite no standardized hierarchy, aripiprazole is widely considered the preferred antipsychotic agent for TS given its risk/benefit ratio compared to other antipsychotics.
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When utilizing pharmacologic treatment in TS, one should start with low doses and gradually titrate up to minimize side effects. Doses of neuroleptics required for treating tics are generally lower than the doses required for treating mood or psychotic disorders. Clinical management should include regular monitoring of side effects, including monitoring weight, vital signs, glucose, lipid profile, QTc, and extrapyramidal symptoms.
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