European clinical guidelines for Tourette syndrome and other tic disorders—version 2.0. Part III: pharmacological treatment

Agents from recently published AAN guidelines

The authors of the AAN guidelines included only systematic reviews and randomized controlled trials (RCTs) on the treatment of tics that included at least 20 participants. They concluded that there is “….moderate confidence that haloperidol, risperidone, aripiprazole, tiapride, clonidine, botulinum toxin injections, 5-ling granule, and Ningdong granule were probably more likely than placebo to reduce tics….”. Lower confidence was reported for pimozide, ziprasidone, metoclopramide, guanfacine, topiramate, and tetrahydrocannabinol (THC). Strong confidence was demonstrated only for behavioral approaches for tics (for detailed description of the behavioral approaches consult Part II of our guidelines).

Agents mentioned in the ESSTS survey

In the survey of the ESSTS Guidelines Group conducted in 2019, ESSTS experts’ prescription practices for the treatment of TS were gathered. They were asked which medication they would consider as first, second, third, and subsequent choices, provided absence of contra-indications for the available agents and absence of co-existing conditions. Contrary to our prior survey from 2011 [111], we also asked the experts to give their recommendations separately for children/adolescents and adults.

In general within the answers of 59 clinicians, choices in children/adolescents did not differ from those in adults and pointed to a high preference for aripiprazole in both age groups. The main difference between the age groups was that haloperidol was much more commonly considered in adults, while in children/adolescents tiapride was more often mentioned (for details consult, Table 1). When comparing the results of our ESSTS surveys performed in 2011 and in 2019, a clear shift over the last decade can be seen from risperidone, pimozide, and (ami)sulpiride in favor of aripiprazole (Fig. 1).

We also collected experts’ opinion on the reason for starting pharmacological treatment of TS. Fifty-nine clinicians treating patients with TS who were members of ESSTS (95% from Europe) regarded as most important reason that the “patient/parents requested medication”, followed by “behavior therapy had not been successful”, and finally “high severity of tics”. While 81% of clinicians would use pharmacotherapy as first-line to treat severe tics, in the case of moderate tics this was done only by 34%, and in the case of mild tics by 3% of clinicians (for detailed description of the survey’s results consult Part V of this issue).

Selection of agents to be discussed in detail

From the moderate confidence group in the AAN guidelines [3] all agents except 5-ling granule and Ningdong granule were commonly prescribed by ESSTS experts (see Table 1). From the lower confidence group only ziprasidone and metoclopramide were not prescribed by ESSTS experts. Vice versa, amisulpiride, tetrabenazine, quetiapine, sertraline, atomoxetine, and sulpiride were mentioned by ESSTS experts as prescribed agents but not in the list of agents with at least moderate or low evidence according to the AAN guidelines.

Dysfunction of transmitter systems as basis for psychopharmacological treatment

TS has been associated with a dysfunction of many neurotransmitter systems, especially the dopaminergic system [39, 112]. Based on findings from nuclear imaging studies, four hypotheses on dopamine dysfunction in TS have been postulated: (1) dopamine hyper-innervation within the striatum; (2) supersensitive postsynaptic striatal dopamine receptors; (3) presynaptic dopamine abnormality in dopa carboxylase; and (4) elevated intrasynaptic dopamine release as a result of an imbalance between tonic and phasic dopamine levels [112]. Besides a dysfunction in the dopaminergic system, imbalances in other neurotransmitter systems have been suggested including serotonergic, noradrenergic, glutamatergic, GABAergic, cholinergic, histaminergic, endocannabinoid, and opioid systems [34, 39]. These findings give some rationale to use substances other than dopamine blocking drugs particularly for the treatment of tics resistant to dopamine-modulating agents.

Dopamine-modulating agents

The first agents used in treating tics were first-generation antipsychotics approved by the Food and Drug Administration (FDA), e.g. haloperidol (in 1969) and pimozide (in 1984), whereas aripiprazole was approved in 2014. In European countries, only haloperidol has been licensed for TS [113]. Discrepancies concerning the licensing of the same agents in Europe and the US largely stem from differences in interests of pharmaceutical companies between the US and Europe. In general, adverse effects of dopamine receptor antagonists are broad, ranging from extrapyramidal adverse effects including acute dystonia, parkinsonism, and akathisia to metabolic adverse effects including weight gain, type 2 diabetes mellitus, lipid spectra abnormalities, blood pressure changes, fatigue, headache, body temperature dysregulation, hyperprolactinemia, and sexual dysfunction, increase of prolactin levels, and QTc-prolongation as well as ‘behavioral’ changes, such as concentration problems, apathy, anhedonia and sedation, aggression, anxiety, and agitation [114, 115]. The limited existing evidence does not allow to predict individual potential adverse effects preceding the start of treatment [116]. Regarding hyperprolactinemia, antipsychotics with tight D2-binding predictably lead to hyperprolactinemia (“prolactin-raising”), whereas antipsychotics with loose D2-binding and partial agonistic action (e.g., aripiprazole) are considered as “prolactin-sparing” [117]. While most experts recommend measurement of prolactin levels before and during treatment with antipsychotics, long-term effects of hyperprolactinemia on sexual, bone, and breast development without accompanying acute clinical symptoms are unknown. Accordingly, the question of whether switching to another antipsychotic only because of hyperprolactinemia (without any clinical symptoms) is still a matter of debate [109, 118].

First-, second-, and third-generation antipsychotic agents are all being used in TS. First generation antipsychotics show predominantly extrapyramidal adverse effects and sedation, while second-generation drugs have more metabolic adverse effects (i.e., weight gain, disturbed blood lipid spectra, a higher risk of diabetes, and other metabolic adverse effects [108, 119, 120]). Second- and third-generation antipsychotics are more widely used and have a mode of action that is distinct from first generation antipsychotics’ mode of action, by their binding to both dopamine and 5-HT2 receptors, i.e., their 5-HT2A receptor antagonism [51]. In line with this observation and despite the absence of regulatory approval for their use in TS for the majority of agents (with the exception of aripiprazole in the US), treatment recommendations favor the use of newer generation antipsychotics rather than first generation antipsychotics as first line treatment for tics, predominantly because of a more favorable tolerability with respect to extrapyramidal adverse effects [111, 115, 121]. In the following paragraphs we review the various antipsychotics that may be used as treatment of TS.

First-generation antipsychotics

Second- and third-generation antipsychotics

Benzamides

Noradrenergic agents

Noradrenergic agents such as clonidine and guanfacine are more commonly used in children and adolescents than in adults and mainly in those patients with a combination of ADHD and mild tics given their efficacy in treating ADHD symptoms in addition to tics.

Cannabis-based medicines

First reports of successful self-medication with the exocannabinoid cannabis date back to 1988 [157]. During the last years, more and more, mostly adult patients use cannabis as a self-medication and report beneficial effects [86, 158]. Indeed, there is an increasing number of case reports and small studies suggesting that cannabis-based medicines including cannabis flowers, cannabis extracts, and pure THC (dronabinol) might be effective in the treatment of tics and co-existing symptoms including ADHD. Since 2011, no new RCTs have been published. A recent meta-analysis on the two available small-scale RCTs (combined n = 41) demonstrated no significant benefit of THC compared to placebo as treatment of TS [159]. No serious adverse reactions were reported either, with only mild adverse reactions including dizziness, tiredness, and dry mouth [160, 161].

Botulinum toxin

In addition to the use of pharmacological agents with systemic effects, there is some evidence for the efficacy of botulinum toxin injections to treat persistent well-localized motor and, sometimes, vocal tics by temporarily weakening the associated muscles, through the inhibition of acetylcholine release from peripheral motor nerve terminals. In European practice this approach is limited to older adolescents and adults in patients with insufficient response to other treatments. According to the AAN guidelines on TS [3] botulinum toxin as local application is probably more likely than placebo to reduce tics. This judgement as well as several reviews after 2011 on botulinum toxin in TS [74–85] are based on the only published randomized crossover trial of botulinum toxin injection versus placebo for the treatment of simple motor tics from 2001 conducted in 20 adolescents and adults [162]. Adverse reactions associated with botulinum toxin may include temporary soreness and mild muscle weakness including hypophonia when used in the throat region to treat disturbing vocal tics [163].

Topiramate

Topiramate is a sulfamate modified fructose diacetonide with unknown mechanisms of action. There have been no new English-language RCTs, since a 12-week randomized controlled trial of topiramate versus placebo published in 2010 that showed superior effects of topiramate compared to placebo in 29 children and adults with TS [164]. However, the authors of a recent meta-analysis [96] summarizing a total of 15 studies from China involving 1070 participants aged 2–17 years concluded that topiramate is a promising medication with good efficacy and tolerability for children with TS compared to haloperidol and tiapride.

While generally well tolerated at low doses (25–150 mg/day) it may cause a variety of adverse effects, including cognitive and language problems, aggression or mood swings, paresthesia, nausea, sweating problems, and decreased appetite [165].

Attention-deficit/hyperactivity disorder (ADHD)

ADHD is prevalent in 30–50% of referred children with TS and is strongly associated with functional impairment [166, 167]. ADHD symptoms typically improve in adolescence [169], but some adults with TS may still need continued treatment for this co-existing disorder [170]. Several pharmacological trials have assessed medication for co-existing ADHD in TS. Across studies, therapeutic doses of methylphenidate, dextroamphetamine, clonidine, guanfacine, and atomoxetine reduce ADHD symptoms as well as tics in patients with TS, probably through allowing a better self-regulatory control [99]. The α-2 agonists clonidine and guanfacine are among the agents with the most favorable efficacy-versus-adverse events ratio but effect sizes vary [8, 9, 90]. While earlier studies described that stimulants exacerbated tics or even caused first tics in some individuals [171], more recent studies demonstrated that tics do not emerge or worsen under the treatment with short-acting [172, 173] or short- and long-acting stimulants [174]; however, a transient increase may occur. On the contrary, a mild reduction of tics may occur in the treatment with methylphenidate in children with tics plus ADHD [99]. In rare cases with a persistent increase of tics after introducing a stimulant, the use of atomoxetine may be a viable alternative, which may in general have a positive effect on tics via a reduction of ADHD symptoms [3, 103]. When treating with psychostimulants, some adverse events should be taken into consideration: sleeplessness, nervousness, headache, blood pressure raise, loss of appetite, weight loss, and gastro-intestinal complaints. According to an open-label study aripiprazole results in an effective reduction of tics, but affects ADHD symptoms only moderately [175].

Obsessive–compulsive disorder (OCD)

Obsessive–compulsive behaviors are very common in people with TS, presenting frequently sensory-motor phenomena, such as urges and just-right feelings that may overlap with tics. Diagnostic criteria for OCD are met in up to 50% of people with tics [105, 176]. Trial data for OCD treatment in children (POTS II) suggest that individuals with tics respond as well to selective serotonin reuptake inhibitors (SSRIs) as those without tics and respond equally well to cognitive behavioral interventions [177] in contrast to an earlier study indicating a less favorable response to sertraline [178]. In addition, for OCD co-existing with TS, behavioral therapy approaches are the first-line treatment [3]. Small observational studies suggest that individuals without sufficient treatment response to behavioral therapy alone may benefit from an added SSRI [105]. Some fixed-dose trials of SSRIs showed that in the treatment of OCD higher doses are significantly superior to lower ones; there is, however, an expected greater adverse effect burden with higher doses of SSRIs [179]. It is worth noting that SSRIs may not only reduce OCD symptoms but also alter overall affect, anxiety, and stress sensitivity, which may lead to better self-regulation and tic suppression. However, this has not been documented in an RCT.

In treatment resistant OCD in the context of TS, antipsychotic augmentation of treatment with SSRI using aripiprazole and risperidone may be considered [180]; the subgroup of patients with OCD and co-existing tics had a particularly beneficial response to treatment with antipsychotic augmentation in a meta-analysis [179]. However, it is important to keep in mind the limited evidence base and the need for drug safety monitoring, as pointed out in an observational study including children with tic-related OCD [180] as well as a meta-analysis including adults with OCD (without tics) [181].

Other co-existing psychiatric conditions

In addition to ADHD and OCD, people with TS are at risk of developing depression, anxiety disorders, oppositional defiant disorder, rage attacks, and mood disorders [176]. Co-existing mood disorders are more often seen in adolescents and adults than in children and in those with greater tic severity [3]. It is worth noting that there is an increased risk of suicidal ideation, suicide attempts, and suicide in people with TS, also when statistically controlling for other co-existing psychiatric conditions [182]. Unfortunately, there are no treatment studies to guide the clinician in treating these co-existing problems.

Guanfacine and clonidine can be effective in individuals with co-existing impulse control disorder [90]. Aripiprazole and risperidone are useful for co-existing irritability and aggressive behaviors [183–186].

Tics and stereotyped movements are frequent in Autism Spectrum Disorder, and a clear diagnostic distinction between them may be challenging to establish [28, 106]. Treatment with risperidone or fluoxetine may be considered in cases with stereotypies that are debilitating and involving harm and injury to self and others [187].

Conflict of interest

VR has received payment for consulting and writing activities from Lilly, Novartis, and Shire Pharmaceuticals, lecture honoraria from Lilly, Novartis, Shire Pharmaceuticals, and Medice Pharma, and support for research from Shire Pharmaceuticals and Novartis. He has carried out clinical trials in cooperation with the Novartis, Shire, Servier and Otsuka companies. KMV has received financial or material research support from the EU (FP7-HEALTH-2011 No. 278367, FP7-PEOPLE-2012-ITN No. 316978), the German Research Foundation (DFG: GZ MU 1527/3-1), the German Ministry of Education and Research (BMBF: 01KG1421), the National Institute of Mental Health (NIMH), the Tourette Gesellschaft Deutschland e.V., the Else-Kröner-Fresenius-Stiftung, and Abide Therapeutics, Almirall Hermal GmbH, GW pharmaceuticals, Lundbeck, Syneos Health, and Therapix Biosciences Ltd. She has received consultant's honoraria from Abide Therapeutics, Allmiral, Boehringer Ingelheim International GmbH, Bionorica Ethics GmbH, CannaMedical Pharma GmbH, Canopy Grouth, Columbia Care, CTC Communications Corp., Eurox Deutschland GmbH, Global Praxis Group Limited, IMC Germany, Lundbeck, Resalo Vertrieb GmbH, Sanity Group, STADAPHARM GmbH, Synendos Therapeutics AG, and Tilray. She is/was a consultant or advisory board member for Abide Therapeutics, The Academy of Medical Cannabis Limited, Alirio, Aphria Deutschland GmbH, CannaMedical Pharma GmbH, Bionorica Ethics GmbH, CannaXan GmbH, Canopy Growth, Columbia Care, CTC Communications Corp., IMC Germany, Leafly Deutschland GmbH, Lundbeck, Nuvelution TS Pharma Inc., Resalo Vertrieb GmbH, Sanity Group, Syqe Medical Ltd., Therapix Biosciences Ltd., Tilray, and Wayland Group. She has received speaker’s fees from Aphria Deutschland GmbH, Cogitando GmbH, Emalex, Eurox Deutschland GmbH, Ever pharma GmbH, PR Berater, Spectrum Therapeutics GmbH, Tilray, and Wayland Group. She has received royalties from Medizinisch Wissenschaftliche Verlagsgesellschaft Berlin, Elsevier, and Kohlhammer. She served as a Guest editor for Frontiers in Neurology on the research topic “The neurobiology and genetics of Gilles de la Tourette syndrome: new avenues through large-scale collaborative projects”, and is Associate editor for “Cannabis and Cannabinoid Research”, Editorial Board Member for “Medical Cannabis and Cannabinoids” and “MDPI-Reports”, and scientific board member for “Zeitschrift für Allgemeinmedizin”. CG is supported by VolkswagenStiftung (Freigeist Fellowship) and served ad hoc as advisory board for Lundbeck. AC is author of the book “Pharmacological Treatment of Tics”. Cambridge University Press, 2020. PJH has received a payment as member of an advisory board meeting of Shire Pharmaceuticals and has carried out a clinical trial in cooperation with Servier. All other authors declare that they have no conflict of interests.