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Neuroscience and Biobehavioral Reviews 37 (2013) 1157–1161

Contents lists available at SciVerse ScienceDirect

Neuroscience and Biobehavioral Reviews

jou rn al h om epage: www.elsev ier .com/ locate /neubiorev

eview

harmacological treatment of Gilles de la Tourette syndrome

ndreas Hartmanna,b,∗, Yulia Worbec

Centre de Référence National Maladie Rare: ‘Syndrome Gilles de la Tourette’, Département de Neurologie, Pôle des Maladies du Système Nerveux, FranceCentre de Recherche de l’Institut du Cerveau et de la Moelle Epinière, UPMC/INSERM UMR S975, CNRS UMR 7225, FranceBehavioural and Clinical Neuroscience Institute, Cambridge University, Cambridge, United Kingdom

r t i c l e i n f o

rticle history:eceived 20 July 2012eceived in revised form 10 October 2012ccepted 28 October 2012

a b s t r a c t

Pharmacological treatment is usually indicated in moderate to severe tics in psychosocial and/or func-tional impairment. Neuroleptics with D2 antagonistic activity remain the cornerstone of anti-tic therapy.Lack of randomized controlled clinical trials base therapeutic decisions mainly on clinical expertise andcommon sense. Recently, aripiprazole has emerged as the neuroleptic with the most advantageous effi-

eywords:illes de la Tourette syndromeicsreatmenteuroleptics

cacy/side effect ratio for treating tics. Yet, in non-responders to aripiprazole, many neuroleptic andnon-neuroleptic drugs, including botulinum toxin injections, are available and often successful. Apartfrom conducting methodologically sound trials (which includes sufficiently long observation periods),future efforts in the field should test the combination of cognitive-behavioral therapy with drugs or ofmulti-drug therapy as well as the development of biomarkers (endophenotypes) to monitor and evenpredict treatment response.

© 2012 Elsevier Ltd. All rights reserved.

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11572. Principles of treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11583. Pharmacologic approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11584. Neuroleptics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11585. Focus on aripiprazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11596. Non-neuroleptic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11597. Conclusions and further directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1160

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1160

. Introduction

In his initial description of ‘la maladie des tics’ in 1885,eorges Gilles de la Tourette assumed an organic etiology of

ics. Nonetheless, for the following 75 years, tics and Gilles dea Tourette syndrome (GTS) were considered from a predomi-antly psychodynamic viewpoint. Accordingly, “treatment” of tics

In 1959, however, the British psychiatrist Bockner treated twoticcing patients with chlorpromazine, a recently introduced neu-roleptic, one of them with success (Bockner, 1959). Two years later,the French psychiatrist Seignot treated one patient with severe GTSwith haloperidol: the results were remarkable (Seignot, 1961). Thisencouraging report and subsequent ones (Kushner, 1999) inspiredShapiro and Shapiro (1968), two American psychiatrists and pio-

as mainly performed by psychonanalysis and pharmacologicalherapy unavailable (see also Párraga et al., 2010, for other pre-euroleptic area treatment options).

∗ Corresponding author at: Centre de Référence National Maladie Rare: ‘Syndromeilles de la Tourette’, Département de Neurologie, Pôle des Maladies du Systèmeerveux, Groupe Hospitalier Pitié-Salpêtrière, 47 Boulevard de l’Hôpital, 75651 Parisedex 13, France. Tel.: +33 01 42 16 13 16; fax: +33 01 44 16 13 21.

E-mail address: andreas.hartmann@psl.aphp.fr (A. Hartmann).

149-7634/$ – see front matter © 2012 Elsevier Ltd. All rights reserved.ttp://dx.doi.org/10.1016/j.neubiorev.2012.10.014

neers in the field of GTS, to treat large series of patients withhaloperidol which thus became the drug of choice in the treatmentof tics.

More than 50 years later, we believe that neuroleptics still rep-resent the first choice of molecules for the treatment of tics. Manydetailed and excellent reviews are available on the pharmacothe-

rapy of tics and GTS (Scahill et al., 2006; Singer, 2010; Roessneret al., 2011; Huys et al., 2012). In the present review, we will usea more personal approach to highlight some controversies in thetreatment of tics, unmet needs and future directions.

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primarily based on the use of neuroleptics (dopamine receptorantagonists). Among ‘typical’ neuroleptics (which refers to theirpreferential affinity to D2 receptors), haloperidol and pimozide arethe most commonly used, with a slightly better side effect profile

Table 1Pharmacotherapy of tics – a selection.

Neuroleptics Empiricalsupport

Starting doses (mg) Therapeuticdoses (mg)

Haloperidol A 0.25–0.5 1–4Pimozide A 0.5–1.0 2–8Risperidone A 0.25–0.5 1–3Fluphenazine B 0.5–1.0 1.5–10Tiapride B 50–150 150–500Olanzapine C 2.5–5.0 2.5–12.5Sulpiride C 100–200 200–1000Aripiprazole C 2.5–5.0 5–15

OthersClonidine B 0.0025–0.05 0.1–0.3Guanfacine B 0.5–1.0 1–3Botulinum toxin B 30–300 U/injection

siteTetrabenazine C 12.5–25 25–150Baclofen C 10 40–60Nicotine patch C 7 7–21

Level of proof: Jobson KO, Potter WZ. International Psychopharmacology AlgorithimProject Report: introduction. Psychopharmacol. Bull. 1995;31:457–459:Category A = treatments with good supportive evidence for short-term safety andefficacy derived from at least two randomized placebo-controlled trials with posi-

158 A. Hartmann, Y. Worbe / Neuroscience an

. Principles of treatment

Treatment of tics depends as much on common sense and clin-cal experience than on controlled, randomized and double-blindrials that are much too scarce in GTS due to the rarity and theegrettable but somewhat understandable lack of interest from theharmaceutical industry in this condition. Although the prevalencef GTS has been estimated at 1% (Robertson, 2008), the crucialut unanswered question is how many of these potential patientseceive accurate diagnosis and if so, whether they require treat-ent beyond psychoeducation (see below).Even if available, controlled trials in GTS present many method-

logical pitfalls. The most common is duration of treatment which issually too short to accommodate the waxing and waning nature ofics, especially in children and adolescents (Roessner et al., 2011.).nother, more recent concern stems from the fact that apart from

ic reduction per se (usually evaluated with the Yale Global Ticeverity Scale – YGTSS), quality of life is a major variable to beaken into account in future studies evaluating treatment efficacynd for which an appropriate scale has recently become availableCavanna et al., 2008).

The first step in treating GTS patients is usually referred tos psychoeducation: counsel and instruct the patient, the fam-ly as well as school or work environment about the nature ofics, co-morbidities and overall prognosis. In a large number ofases, these simple measures, accompanied by regular follow-up,re remarkably effective and may prevent the need to introducepecific anti-tic therapy. Decision to treat is based on four criteria:

Tics cause sustained social problems for the patient (e.g. socialisolation or bullying).Tics cause social and emotional problems for the patient (e.g.reactive depressive symptoms).Tics cause functional interference.Tics cause subjective discomfort (e.g. pain or injury).

Whereas the first three criteria are relatively subjectivealthough a sharp decline in school performance or impeding lis-encing are clear warning signs that action should be taken), the lastriterion is rather objective, especially with regard to tic sequelae.or instance, certain violents neck can cause cervical myelopathieseading to tetraplegia (Dobbs and Berger, 2003) or cause strokehrough vertebral artery dissection (Van Meerbeeck et al., 2011;ehman et al., 2011). Also, automutilations (blindness through ocu-ar enucleation, lacerations, fractures, burns, etc.) can be extremelyevere and even life-threatening (Cheung et al., 2007).

Furthermore, it is essential to take into account co-morbiditiesobsessive–compulsive disorder – OCD, attention deficit withyperactivity disorder – ADHD, depression, anxiety, impulse con-rol disorder, autism spectrum disorders, learning disabilities),resent in more than 90% of GTS patients (Cavanna et al., 2009)nd to hierarchize the patients’ needs accordingly. Several studiesave shown that patients’ quality of life is often more com-romized by co-morbidities than by tics as such. Therefore, ifossible/available, a multidisciplinary (neurologists, psychiatrists,sychologists, neuropsychologists, social workers) evaluation andollow-up is recommended (Chang, 2007; Kepley and Conners,007; Woods et al., 2007). Although treatment of co-morbidities iseyond the scope of this article, two points deserve mention. First,ntidepressants are of extremely limited utility in children (Cohent al., 2008); therefore, in case of depression, access to psychother-py is crucial. Second, psychostimulants are not contraindicated in

TS: some cases may be aggravated but others improved due totress reduction (Bloch et al., 2009). Therefore, this class of drugshould not be shunned but used on a case-to-case basis after carefuleuropyschological workup, since there is considerable semiologic

ehavioral Reviews 37 (2013) 1157–1161

overlap between tics and ADHD. Last not least, the role of the fam-ily in tic reduction is of major importance (Ginsburg and NewmanKingery, 2007). In difficult situations, family therapy should be con-sidered.

3. Pharmacologic approaches

As discussed in previous articles of this special issue, many brainstructures and neurotransmitters are implicated in the genesis oftics. Unsurprisingly, pharmacological treatment of tics is mostlyempirical and dominated by case studies or series as well as openlabel trials; very few studies, as already mentioned, fulfill classA evidence criteria (Table 1). Also, even if based on rather solidevidence, treatment practices differ widely across countries andcontinents (to be discussed below).

Recent reviews have extensively listed all available evidenceon tic treatment, in particular the recently published ESSTS guide-lines (2011) and we refer to this publication for anyone seekingmethodolical details on case reports, case series and clinical trials.Interestingly, these guidelines have made apparent substantial dif-ferences in treatment recommendations between European und UScenters (Jankovic and Kurlan, 2011a, discussed in Müller-Vahl andRoessner, 2011; Jankovic and Kurlan, 2011b). Besides obvious dif-ferences related to differential availability of drugs, they also reflectdifferent stances on the risks and benefits of using certain classof drugs, especially neuroleptics. In this article, we have chose tohighlight our personal approach of treating tics in agreement withmany of our European colleagues. A special mention is made ofaripiprazole which appears to us as the most promising drug for tictreatment to emerge over the last decade.

4. Neuroleptics

Historically, as already mentioned, treatment of tics has been

tive results.Category B = treatments with fair supportive data as evidenced by at least one pos-itive placebo-controlled study.Category C = treatments with minimal supportive evidence such as open-label stud-ies and accumulated clinical experience.

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or the latter compared to the former but also slightly less effi-acy (Pringsheim and Marras, 2009). Common to both drugs as wells to most neuroleptics are sedation, weight gain and metabolicisturbances. Pimozide may prolong QT intervals and patientsherefore require ECG monitoring after introducing the drug. How-ver, extrapyramidal side effects (parkinsonian syndromes andardive dyskinesia) appear nowadays as much less a concern thanreviously thought. In fact, a retrospective recent case series of21 patients did not detect a single case of tardive dyskinesia inTS patients treated with a variety of neuroleptics, inclunding chil-ren and adolescents (n = 100 out of 521). The authors went so fars to question whether GTS ‘protects’ against neuroleptic-inducedardive dyskinesia (Müller-Vahl and Krueger, 2011). The authors’wn clinical experience are in accordance with this favorable sideffect profile of neuroleptics for treating tics. Reasons may includeower dosages and slower dose escalation in GTS than in the classicntipsychotic indications, where tardive dyskinesia appear to occurn up to 30% of cases (Correll and Schenk, 2008). More speculatively,TS patients, especially in younger age groups, may possess a formf cerebral plasticity rendering them more resistant to neuroleptic-nduced extrapyramidal side effects.

Nonetheless, in light of the fear of tardive dyskinesia, so-calledatypical’ neuroleptics have attracted great interest over the pastwo decades for treating tics. This class of molecules is char-cterized by a less potent blockade of D2 receptors as well as-HT2-A and 5-HT2-C receptors antagonism. Risperidone offers theest level of evidence in this group and is considered by manys first choice treatment for tics (Scahill et al., 2003). However,etabolic side effects (increases in glucose, lipids, prolactine) occur

requently and must be closely monitored. Also, depression riskue to anti-serotoninerc activity may be a concern, in addition toepression resulting from diminished dopaminergic transmissionommon to all neuroleptics. The benzamides (tiapride, sulpiride)re further selective D2 dopamine receptor antagonists but in con-rast to the typical neuroleptics with low (sulpiride) or as good as notiapride) antipsychotic action which appear to result in less or noxtrapyramidal side effects. Nonetheless, weight gain and sedationan occur and must be monitored (Roessner et al., 2011).

Finally, among the atypical neuroleptics, tetrabenazine (Portat al., 2008) deserves special mention. As a monoamine depletor,t offers the potential advantage of not inducing tardive dyskine-ia and is therefore especially favored in North America (Jankovicnd Kurlan, 2011a; Pringsheim et al., 2012). However, sedations a major issue as well as rare but sometimes severe depressiveeactions.

. Focus on aripiprazole

Aripiprazole is one of the most recently introduced neurolepticsnd offers a particular mode of action: apart from its D2 antagonis-ic activity, it is also a partial D2 and 5-HT1-A receptor agonist and

5-HT2-A antagonist (Croxtall, 2012). Over the past decade, it hasecome the favorite neuroleptic in many centers for treating ticsespite the lack of controlled studies and lack of approval for use

n children. However, many open label studies and case series areow available which underline the remarkable efficacy of aripipra-ole on tics while generally displaying a more favorable side effectrofile than most typical and atypical neuroleptics with regard toedation and weight gain (Davies et al., 2006; Seo et al., 2008; Lyont al., 2009; Murphy et al., 2009; Neuner et al., 2012; Wenzel et al.,012). Nonetheless, the risk of developing akathisia appears more

mportant than with other neuroleptics; this side effect, however,

an be potentially controlled with concomitant use of propanololNeuner et al., 2012). In the long run, many patients also underlineenefitial behavioral effects (‘pacifying’) of aripiprazole unrelatedo sedation (Budman et al., 2008).

ehavioral Reviews 37 (2013) 1157–1161 1159

Unfortunately, randomized controlled trials regarding the effi-cacy and safety of aripiprazole are lacking and unlikely to occuras the drug will fall into the public domain by 2014. How-ever, a one-weekly formulation of aripiprazole is currently beingtested in children and adolescents and adults (clinicaltrialsgov.NCT01418352 and NCT01418339) and to be completed in the sec-ond half of 2013.

6. Non-neuroleptic drugs

Another group of molecules used for more than two decadesin the treatment of tics are alpha2 receptor agonists, e.g. cloni-dine (Goetz et al., 1987) and guanfacine (Scahill et al., 2001).Both molecules have been evaluated in controlled clinical trialsand been shown efficient for the treatment of tics although theirefficacy is usually lower than for neuroleptics with comparablesedation (Swain et al., 2007); however, they appear to be helpfulin managing behavioral problems, especially ADHD (Posey et al.,2004).

Benzodiazepines, in particular clonazepam, are much less fre-quently used for treating tics (Gonce and Barbeau, 1977) sincetheir efficacy seems to be limited and indirect. The same rea-soning can be applied to antidepressants, especially selectiveserotonin reuptake inhibitors, which can be helpful in reducing OCDand/or anxiety and thus tics, but seem devoid of intrinsic anti-ticactivity. More recently, two antiepileptics, leviracetam and topira-mate, have been suggested as useful in the treatment of tics, butresults remain preliminary and sometimes conflicting (Abuzzahaband Brown, 2001; Hedderick et al., 2009; Jankovic et al., 2010).Other interesting leads include the cannabiod system (Müller-Vahl,2003), the GABAergic system (Singer et al., 2001) and nicotin-ergic transmission to enhance neuroleptic action (Silver et al.,2001).

Most recently and rather unexpectedly, histamine has comecenter stage as a potential pharmacologic target in the treat-ment of tics. Based on the missense mutations in the histidinedecarboxylase gene supposed to result in loss-of-function andtherefore reduced synthesis of histamine (Ercan-Sencicek et al.,2010; Fernandez et al., 2012), drugs that increase histaminergicneurotransmission may potentially be helpful in the treatmentof tics. Since this class of drugs is known foremost for its pro-awakening effects, in particular treatment of co-morbid ADHDappears as a plausible target for this class of drugs (Hartmann et al.,2012).

Finally, we insist on the potential benefits of botulinum toxinto treat isolated tics. Botulinum toxin allows a targeted and limitedintervention on localized and potentially dangerous tics, expeciallythose of the neck. Moreover, injections into the vocal cords canbe considered in the presence of important vocal tics (Porta et al.,2004). An interesting phenomenon is the observation that pre-monitory sensations sometimes diminish or even dispappear afterrepeated injections of botulinum toxin into the affected musclegroup (Kwak et al., 2000; Marras et al., 2001).

Table 1 recapitulates major pharmacological treatments for ticsavailable to date.

In practice, we propose an approach based on the recommenda-tions adapted from the “Tourette Practice Parameter Work Group”(Scahill et al., 2006):

1. Mild tics generally do not require treatment.

2. For moderate tics – if available – cognitive-behavioral ther-

apy (CBT) should be proposed. If a pharmacologic treatmentis the first option, aripiprazole is the molecule of choice(2.5–5 mg/day).

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. For isolated tics, botulinum toxin injections should be consid-ered.

. For severe tics, first increase ariprazole dose, then considerrisperidone, pimozide, haloperidol or any other neuroleptic.Next, consider tetrabenazine and anticonvulsants.

. Finally, in case of pharmaco-resistance, deep brain stimulationcan be considered.

. Conclusions and further directions

Future pharmacologic studies in GTS should target twouestions: (i) association of CBT with pharmacotherapy; (ii) com-ination pharmacotherapy using molecules with different modesf action. In both cases, treatment periods should not be less than

months. Also, we recommend to form, as far as possible, sub-roups with regard to age and co-morbidity. In addition, quality ofife as an indicator of treatment response and success should be

onitored. Finally, the advent of biomarkers, most likely the def-nition of endophenotypes, may prove very helpful to assess andven predict treatment response.

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