Abstract
In 2011, the European Society for the Study of Tourette Syndrome (ESSTS) published the first European guidelines for Tourette Syndrome (TS). We now present an update of the part on pharmacological treatment, based on a review of new literature with special attention to other evidence-based guidelines, meta-analyses, and randomized double-blinded studies. Moreover, our revision took into consideration results of a recent survey on treatment preferences conducted among ESSTS experts. The first preference should be given to psychoeducation and to behavioral approaches, as it strengthens the patients’ self-regulatory control and thus his/her autonomy. Because behavioral approaches are not effective, available, or feasible in all patients, in a substantial number of patients pharmacological treatment is indicated, alone or in combination with behavioral therapy. The largest amount of evidence supports the use of dopamine blocking agents, preferably aripiprazole because of a more favorable profile of adverse events than first- and second-generation antipsychotics. Other agents that can be considered include tiapride, risperidone, and especially in case of co-existing attention deficit hyperactivity disorder (ADHD), clonidine and guanfacine. This view is supported by the results of our survey on medication preference among members of ESSTS, in which aripiprazole was indicated as the drug of first choice both in children and adults. In treatment resistant cases, treatment with agents with either a limited evidence base or risk of extrapyramidal adverse effects might be considered, including pimozide, haloperidol, topiramate, cannabis-based agents, and botulinum toxin injections. Overall, treatment of TS should be individualized, and decisions based on the patient’s needs and preferences, presence of co-existing conditions, latest scientific findings as well as on the physician’s preferences, experience, and local regulatory requirements.
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Introduction
The first European clinical guidelines for Tourette Syndrome (TSFootnote 1) were published in 2011 [1] by working groups of the European Society for the Study of Tourette Syndrome (ESSTS) and provided recommendations for the assessment and treatment of TS based on existing guidelines, meta-analyses, reviews, clinical trials, and case studies up to that point. The present guideline provides clinicians an update of recommendations for the pharmacological treatment of TS in Europe using evidence from clinical trials and clinical expertise.
In general, clinical guidelines rely on the combination of information from controlled clinical trials (including their shortcomings) and clinical (consensus-based) knowledge, given the lack of sufficiently comprehensive and detailed evidence. Regarding TS, the situation mentioned in our 2011 article with “…only a limited number of studies on pharmacological treatment options for TS met rigorous quality criteria…” still holds true. Especially head-to-head comparisons of different agents or their combination as well as optimal treatment duration and dosage have not been systematically investigated, hence calling for an approach supplemented by knowledge from clinical practice. Moreover, the effectiveness of pharmacological treatments in reducing tics varies between trials as a result of differences in methodology and patient characteristics. Furthermore, controlled studies in treatment resistant cases are lacking. It remains common practice to have to try various options until an effective reduction of tics is achieved [2].
Recently, a systematic review and guidelines of the American Academy of Neurology (AAN) for the treatment of TS have been published [3, 4]. The authors of the AAN guidelines used structured, evidence-based methodology as outlined in the 2011 edition of AAN's guideline development process manual. To formulate new European recommendations for the pharmacological treatment of TS, we complemented the English-language literature since 2011 and combined it with the results of a survey among ESSTS experts, who were asked about their pharmacological daily practice in children and adults with TS.
Methodology of selection of agents and literature search strategy
To select relevant agents, we combined agents with at least moderate or low evidence according to the guidelines of the AAN [3, 4] with those mentioned in our European survey. For these agents, we reviewed the English-language literature since 2011 in PubMed using the agent’s name in combination with “tics”, “tic disorder”, or “Tourette Syndrome”, including children, adolescents, and adults as search string. In addition, we checked the references since 2011 of other systematic reviews/meta-analyses [5,6,7,8,9], existing guidelines [3, 4, 10,11,12], non-systematic reviews on TS with statements about pharmacological treatment, i.e., dealing with various agents [13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38] or mentioning treatment in their title [39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64]. In addition, we had a look into the references of agent-specific reviews and meta-analyses of (in alphabetical order) aripiprazole [65,66,67,68,69,70,71,176]. 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 [183,184,185,186].
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].
Clinical recommendations for the pharmacological treatment of TS
Decisions about treatment of TS should be based on a thorough and broad diagnostic process (see Part I of this issue). Behavioral therapy approaches are recommended as first line treatment, based on assumed better tolerability of behavioral therapy, because behavioral approaches might strengthen the patients’ self-regulatory control [3, 188] (see Part V of this issue). However, these are not always locally accessible (a major factor in many countries) or feasible because of low introspective ability in young age or low IQ, or due to low motivation or ability to invest time and effort required for practicing in behavioral therapy. For individuals with clear impairments associated with their tics or with a preference for pharmacotherapy, after psychoeducation pharmacologic interventions may be considered alone or in addition to behavioral therapy. This concerns especially situations, where tics impair quality of life and cause subjective discomfort (e.g., pain or injury) or when tics result in sustained social problems (e.g., social isolation or bullying) or cause functional interference (e.g., impairment of academic achievements) [111]. In addition, pharmacological treatment acts faster, because prescription, dispensing, and intake of first dose are easier than planning and commencing behavioral therapy. Moreover, first treatment effects are often seen within a few days, while after behavioral therapy first beneficial effects in most cases cannot be observed until after a few weeks. Therefore, pharmacotherapy may be preferred in situations, where a rapid tic reduction is urgently required.
The waxing and waning course (including its time course) of the tics in each individual should be taken into account when deciding on starting therapy and when evaluating treatment effects.
Independently from the individual factors that result in the decision to start pharmacological treatment of tics it is important to inform patients and their parents about what can be achieved by this kind of treatment to avoid too high expectations. On average, a tic reduction of 50% can be expected. However, some patients report a reduction of 90%, while others feel no or only minimal improvement.
The decision to propose a treatment with a specific agent is an individual choice made by the clinician, in collaboration with the patient and family and depends on the patient’s needs, preferences, and priorities as well as on the physician’s preferences, experience, and local regulatory requirements.
During the last decades, several agents have been suggested and used as rational medication for the treatment of tics. Based on evidence from RCTs and on clinical experience aripiprazole, tiapride, and risperidone for TS as well as clonidine and guanfacine for TS and co-existing ADHD are the best established options, all on the basis of off-label use. In general, we recommend a “start low, go slow” drug up-titration, meaning that the therapy should be initiated with the lowest dose possible and gradually increased. It is important to bear in mind that the antipsychotic dosages normally used for the treatment of tics are considerably lower than those used to treat psychotic disorders.
Depending on its individual receptor binding profile, each agent bears the risk of specific adverse effects. Therefore, not only effectiveness but also potential adverse effects of each agent should be taken into consideration when deciding about the most suitable agent for a patient with TS. Most pharmacological treatments discussed in these guidelines have well known adverse effects, including weight gain, drug-induced movement disorders, elevated prolactin levels, sedation, and effects on heart rate, blood pressure, and electrocardiograms. Therefore, careful monitoring of adverse events is recommended (see Table 2). In case of treatment discontinuation, gradual tapering off antipsychotic medications is recommended to avoid withdrawal dyskinesias [3].
An important aspect when choosing an agent for a patient is also the presence of co-existing conditions. Often, the co-existence of ADHD or OCD, as well as mood, anxiety, or impulse control disorders may be more disturbing to the patient than the tics [167] and may thus have important implications for the choice of medication. Evidence for those choices is still limited, but this differentiation already presents an important step towards an individualized approach to medication in TS.
While the evidence-based practice recommendations of the AAN did not present a hierarchical recommendation what agent should be given first, the ESSTS survey indicates that aripiprazole is now the most commonly used agent for the pharmacological treatment of TS for both age groups (children and adolescents, adults). This may be the result of several factors, one being the unique pharmacological profile as a dopamine partial agonist [189], but also the availability of several RCTs with sufficient sample sizes that document a favorable benefit-risk ratio, predominantly being the result of its positive profile of adverse effects [69, 70, 72]. Positron emission tomography studies demonstrated that the clinical effect of an antipsychotic emerges when more than 65% of striatal dopamine D2 receptors are blocked, and EPSs become apparent when the receptor blockade exceeds 80% [190]. Thus, in the ideal antipsychotic therapy (antipsychotic efficacy without EPSs), about 70% of striatal dopamine D2 receptors are blocked. When tight antipsychotics bind 70% of D2 receptors, the remaining 30% are available for endogenous dopamine to bind. This means that dopaminergic transmission is reduced to 30%, and both tonic/phasic components are suppressed equally. In one study, aripiprazole was effective at a dose of up to 20 mg, where 10% or fewer D2 receptors were available for endogenous dopamine to bind; however, EPSs did not appear, because aripiprazole exerted a partial dopaminergic agonistic activity [191].
Tiapride, the second most commonly prescribed agent in children and adolescents with tics, especially in Germany, has a similar working mechanism as aripiprazole, showing a maximum of 80% of dopamine receptor occupation even in the presence of excess tiapride concentrations [145]. Interestingly, for two of the most commonly used agents according to the ESSTS survey there is evidence from pharmacodynamic studies explaining their low (aripiprazole) or very low (tiapride) potential for EPS compared to haloperidol [69, 70, 138, 145].
Another recommended antipsychotic agent, risperidone, actually has a good evidence base, but is associated with weight gain and metabolic adverse effects.
The European survey documented that noradrenergic agents are the third most given agents regarding both age groups together. Importantly, noradrenergic agents have a low effectiveness in patients with tics only, but this substantially increases in patients (particularly children and adolescents) with the combination of tics and ADHD, both for reducing tics and symptoms of ADHD [8, 90]. Therefore, we recommend noradrenergic agents as first line treatment of mild to moderate tics in patients with co-existing ADHD, but less in those without co-existing ADHD as there they have only minimal benefits. However, in some patients with mild tics only, noradrenergic agents may be more acceptable than antipsychotics, based on more favorable adverse effects.
In treatment resistant cases, treatment with agents with sometimes a still limited evidence base and less frequently prescribed by ESSTS experts might be considered. Reasonable choices include antipsychotics including haloperidol, pimozide, quetiapine, sulpiride, and amisulpiride as well as cannabis-based medicines, topiramate, and botulinum toxin injections.
Haloperidol is still relatively often used in adults with TS, but rarely mentioned by any ESSTS expert as treatment option for children and adolescents. Its declined use can be explained by its unfavorable adverse effect profile compared to other antipsychotics, even though haloperidol is the only officially licensed substance for TS and tics in Europe, and has a long tradition and established efficacy in the treatment of TS, with relatively low costs.
Current limitations and future directions
In the light of the limited existing evidence several questions remain unanswered: most importantly, the effectiveness of combinations of behavioral therapy with pharmacological treatment and of different agents needs further trials. Studies directly comparing different agents or combinations of agents in TS are rare, and there is currently only one study [192] available that compared pharmacological treatment with behavior therapy, yielding equal effects within a study period of 10 weeks. Moreover, the study periods of published trials on pharmacological treatment of TS were quite short, e.g., in view of the natural waxing and waning course of tics in TS. In addition, research should be conducted on treatment sequencing and decision-making and for whom particular sequences of treatment are most effective [3]. Another area in need of further evidence is the treatment of patients with co-existing conditions. Moreover, questions around how to deal with treatment refractoriness remain unanswered [193]. The risk of adverse events when using specific agents needs further exploration, e.g., sudden death due to QTc prolongation [116], hyperprolactinemia and its consequences [109], and weight gain [128]. In addition, the questions of optimal treatment duration, as well as long-term outcome after discontinuation of a pharmacological treatment of tics remain unanswered. These important points for the pharmacotherapy of TS are still open to discussion due to a non-existent or too small base of evidence and are important areas for future research. Unfortunately, the number of new agents that might be effective as treatment of TS is limited. Perhaps most promising are the Chinese herbal medicine products 5-ling granule and Ningdong granule, which were classified as compounds showing moderate confidence in evidence of treatment effects according to the AAN guidelines, based on well-powered RCTs conducted in China. However, these products are currently not available to clinicians on the European market. One final future step to improve pharmacological treatment of TS would be precision medicine as well as personalized medicine [194] by prior genetic testing or the use of other neurobiological markers [195]. This approach, however, is still an aspiration for neuropsychiatric disorders, such as TS.
Change history
29 November 2021
The original publication was revised due to update in article note.
Notes
We use the term TS in these guidelines, wherever information also applies to other forms of tic disorders. Only if there are substantial, well-known differences between TS and other forms of tic disorders we use TS or other terms, e.g. transient or chronic motor tic disorder.
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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.
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This article is part of the focused issue “Update of the European clinical guidelines for Tourette Syndrome and other tic disorders”.
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Roessner, V., Eichele, H., Stern, J.S. et al. European clinical guidelines for Tourette syndrome and other tic disorders—version 2.0. Part III: pharmacological treatment. Eur Child Adolesc Psychiatry 31, 425–441 (2022). https://doi.org/10.1007/s00787-021-01899-z
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DOI: https://doi.org/10.1007/s00787-021-01899-z