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Pharmacological treatment of Gilles de la Tourette syndrome
Neuroscience and Biobehavioral Reviews 37 (2013) 1157–1161
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Review
Pharmacological treatment of Gilles de la Tourette syndrome Andreas Hartmann a,b,∗ , Yulia Worbe c a
Centre de Référence National Maladie Rare: ‘Syndrome Gilles de la Tourette’, Département de Neurologie, Pôle des Maladies du Système Nerveux, France Centre de Recherche de l’Institut du Cerveau et de la Moelle Epinière, UPMC/INSERM UMR S975, CNRS UMR 7225, France c Behavioural and Clinical Neuroscience Institute, Cambridge University, Cambridge, United Kingdom b
a r t i c l e
i n f o
Article history: Received 20 July 2012 Received in revised form 10 October 2012 Accepted 28 October 2012 Keywords: Gilles de la Tourette syndrome Tics Treatment Neuroleptics
a b s t r a c t Pharmacological treatment is usually indicated in moderate to severe tics in psychosocial and/or functional 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 and common sense. Recently, aripiprazole has emerged as the neuroleptic with the most advantageous efficacy/side effect ratio for treating tics. Yet, in non-responders to aripiprazole, many neuroleptic and non-neuroleptic drugs, including botulinum toxin injections, are available and often successful. Apart from 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 of multi-drug therapy as well as the development of biomarkers (endophenotypes) to monitor and even predict treatment response. © 2012 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5. 6. 7.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Principles of treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacologic approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neuroleptics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Focus on aripiprazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Non-neuroleptic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions and further directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction In his initial description of ‘la maladie des tics’ in 1885, Georges Gilles de la Tourette assumed an organic etiology of tics. Nonetheless, for the following 75 years, tics and Gilles de la Tourette syndrome (GTS) were considered from a predominantly psychodynamic viewpoint. Accordingly, “treatment” of tics was mainly performed by psychonanalysis and pharmacological therapy unavailable (see also Párraga et al., 2010, for other preneuroleptic area treatment options).
∗ Corresponding author at: Centre de Référence National Maladie Rare: ‘Syndrome Gilles de la Tourette’, Département de Neurologie, Pôle des Maladies du Système Nerveux, Groupe Hospitalier Pitié-Salpêtrière, 47 Boulevard de l’Hôpital, 75651 Paris Cedex 13, France. Tel.: +33 01 42 16 13 16; fax: +33 01 44 16 13 21. E-mail address: [email protected] (A. Hartmann). 0149-7634/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neubiorev.2012.10.014
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In 1959, however, the British psychiatrist Bockner treated two ticcing patients with chlorpromazine, a recently introduced neuroleptic, one of them with success (Bockner, 1959). Two years later, the French psychiatrist Seignot treated one patient with severe GTS with haloperidol: the results were remarkable (Seignot, 1961). This encouraging report and subsequent ones (Kushner, 1999) inspired Shapiro and Shapiro (1968), two American psychiatrists and pioneers in the field of GTS, to treat large series of patients with haloperidol which thus became the drug of choice in the treatment of tics. More than 50 years later, we believe that neuroleptics still represent the first choice of molecules for the treatment of tics. Many detailed and excellent reviews are available on the pharmacotherapy of tics and GTS (Scahill et al., 2006; Singer, 2010; Roessner et al., 2011; Huys et al., 2012). In the present review, we will use a more personal approach to highlight some controversies in the treatment of tics, unmet needs and future directions.
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2. Principles of treatment Treatment of tics depends as much on common sense and clinical experience than on controlled, randomized and double-blind trials that are much too scarce in GTS due to the rarity and the regrettable but somewhat understandable lack of interest from the pharmaceutical industry in this condition. Although the prevalence of GTS has been estimated at 1% (Robertson, 2008), the crucial but unanswered question is how many of these potential patients receive accurate diagnosis and if so, whether they require treatment beyond psychoeducation (see below). Even if available, controlled trials in GTS present many methodological pitfalls. The most common is duration of treatment which is usually too short to accommodate the waxing and waning nature of tics, especially in children and adolescents (Roessner et al., 2011.). Another, more recent concern stems from the fact that apart from tic reduction per se (usually evaluated with the Yale Global Tic Severity Scale – YGTSS), quality of life is a major variable to be taken into account in future studies evaluating treatment efficacy and for which an appropriate scale has recently become available (Cavanna et al., 2008). The first step in treating GTS patients is usually referred to as psychoeducation: counsel and instruct the patient, the family as well as school or work environment about the nature of tics, co-morbidities and overall prognosis. In a large number of cases, these simple measures, accompanied by regular follow-up, are remarkably effective and may prevent the need to introduce specific anti-tic therapy. Decision to treat is based on four criteria: • Tics cause sustained social problems for the patient (e.g. social isolation 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 subjective (although a sharp decline in school performance or impeding liscencing are clear warning signs that action should be taken), the last criterion is rather objective, especially with regard to tic sequelae. For instance, certain violents neck can cause cervical myelopathies leading to tetraplegia (Dobbs and Berger, 2003) or cause stroke through vertebral artery dissection (Van Meerbeeck et al., 2011; Lehman et al., 2011). Also, automutilations (blindness through ocular enucleation, lacerations, fractures, burns, etc.) can be extremely severe and even life-threatening (Cheung et al., 2007). Furthermore, it is essential to take into account co-morbidities (obsessive–compulsive disorder – OCD, attention deficit with hyperactivity disorder – ADHD, depression, anxiety, impulse control disorder, autism spectrum disorders, learning disabilities), present in more than 90% of GTS patients (Cavanna et al., 2009) and to hierarchize the patients’ needs accordingly. Several studies have shown that patients’ quality of life is often more compromized by co-morbidities than by tics as such. Therefore, if possible/available, a multidisciplinary (neurologists, psychiatrists, psychologists, neuropsychologists, social workers) evaluation and follow-up is recommended (Chang, 2007; Kepley and Conners, 2007; Woods et al., 2007). Although treatment of co-morbidities is beyond the scope of this article, two points deserve mention. First, antidepressants are of extremely limited utility in children (Cohen et al., 2008); therefore, in case of depression, access to psychotherapy is crucial. Second, psychostimulants are not contraindicated in GTS: some cases may be aggravated but others improved due to stress reduction (Bloch et al., 2009). Therefore, this class of drugs should not be shunned but used on a case-to-case basis after careful neuropyschological workup, since there is considerable semiologic
overlap between tics and ADHD. Last not least, the role of the family in tic reduction is of major importance (Ginsburg and Newman Kingery, 2007). In difficult situations, family therapy should be considered. 3. Pharmacologic approaches As discussed in previous articles of this special issue, many brain structures and neurotransmitters are implicated in the genesis of tics. Unsurprisingly, pharmacological treatment of tics is mostly empirical and dominated by case studies or series as well as open label trials; very few studies, as already mentioned, fulfill class A evidence criteria (Table 1). Also, even if based on rather solid evidence, treatment practices differ widely across countries and continents (to be discussed below). Recent reviews have extensively listed all available evidence on tic treatment, in particular the recently published ESSTS guidelines (2011) and we refer to this publication for anyone seeking methodolical details on case reports, case series and clinical trials. Interestingly, these guidelines have made apparent substantial differences in treatment recommendations between European und US centers (Jankovic and Kurlan, 2011a, discussed in Müller-Vahl and Roessner, 2011; Jankovic and Kurlan, 2011b). Besides obvious differences related to differential availability of drugs, they also reflect different stances on the risks and benefits of using certain class of drugs, especially neuroleptics. In this article, we have chose to highlight our personal approach of treating tics in agreement with many of our European colleagues. A special mention is made of aripiprazole which appears to us as the most promising drug for tic treatment to emerge over the last decade. 4. Neuroleptics Historically, as already mentioned, treatment of tics has been primarily based on the use of neuroleptics (dopamine receptor antagonists). Among ‘typical’ neuroleptics (which refers to their preferential affinity to D2 receptors), haloperidol and pimozide are the most commonly used, with a slightly better side effect profile Table 1 Pharmacotherapy of tics – a selection. Neuroleptics
Empirical support
Starting doses (mg)
Therapeutic doses (mg)
Haloperidol Pimozide Risperidone Fluphenazine Tiapride Olanzapine Sulpiride Aripiprazole
A A A B B C C C
0.25–0.5 0.5–1.0 0.25–0.5 0.5–1.0 50–150 2.5–5.0 100–200 2.5–5.0
1–4 2–8 1–3 1.5–10 150–500 2.5–12.5 200–1000 5–15
Others Clonidine Guanfacine Botulinum toxin
B B B
Tetrabenazine Baclofen Nicotine patch
C C C
0.0025–0.05 0.5–1.0 30–300 U/injection site 12.5–25 10 7
0.1–0.3 1–3
25–150 40–60 7–21
Level of proof: Jobson KO, Potter WZ. International Psychopharmacology Algorithim Project Report: introduction. Psychopharmacol. Bull. 1995;31:457–459: Category A = treatments with good supportive evidence for short-term safety and efficacy derived from at least two randomized placebo-controlled trials with positive results. Category B = treatments with fair supportive data as evidenced by at least one positive placebo-controlled study. Category C = treatments with minimal supportive evidence such as open-label studies and accumulated clinical experience.
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for the latter compared to the former but also slightly less efficacy (Pringsheim and Marras, 2009). Common to both drugs as well as to most neuroleptics are sedation, weight gain and metabolic disturbances. Pimozide may prolong QT intervals and patients therefore require ECG monitoring after introducing the drug. However, extrapyramidal side effects (parkinsonian syndromes and tardive dyskinesia) appear nowadays as much less a concern than previously thought. In fact, a retrospective recent case series of 521 patients did not detect a single case of tardive dyskinesia in GTS patients treated with a variety of neuroleptics, inclunding children and adolescents (n = 100 out of 521). The authors went so far as to question whether GTS ‘protects’ against neuroleptic-induced tardive dyskinesia (Müller-Vahl and Krueger, 2011). The authors’ own clinical experience are in accordance with this favorable side effect profile of neuroleptics for treating tics. Reasons may include lower dosages and slower dose escalation in GTS than in the classic antipsychotic indications, where tardive dyskinesia appear to occur in up to 30% of cases (Correll and Schenk, 2008). More speculatively, GTS patients, especially in younger age groups, may possess a form of cerebral plasticity rendering them more resistant to neurolepticinduced extrapyramidal side effects. Nonetheless, in light of the fear of tardive dyskinesia, so-called ‘atypical’ neuroleptics have attracted great interest over the past two decades for treating tics. This class of molecules is characterized by a less potent blockade of D2 receptors as well as 5-HT2-A and 5-HT2-C receptors antagonism. Risperidone offers the best level of evidence in this group and is considered by many as first choice treatment for tics (Scahill et al., 2003). However, metabolic side effects (increases in glucose, lipids, prolactine) occur frequently and must be closely monitored. Also, depression risk due to anti-serotoninerc activity may be a concern, in addition to depression resulting from diminished dopaminergic transmission common to all neuroleptics. The benzamides (tiapride, sulpiride) are further selective D2 dopamine receptor antagonists but in contrast to the typical neuroleptics with low (sulpiride) or as good as no (tiapride) antipsychotic action which appear to result in less or no extrapyramidal side effects. Nonetheless, weight gain and sedation can occur and must be monitored (Roessner et al., 2011). Finally, among the atypical neuroleptics, tetrabenazine (Porta et al., 2008) deserves special mention. As a monoamine depletor, it offers the potential advantage of not inducing tardive dyskinesia and is therefore especially favored in North America (Jankovic and Kurlan, 2011a; Pringsheim et al., 2012). However, sedation is a major issue as well as rare but sometimes severe depressive reactions. 5. Focus on aripiprazole Aripiprazole is one of the most recently introduced neuroleptics and offers a particular mode of action: apart from its D2 antagonistic activity, it is also a partial D2 and 5-HT1-A receptor agonist and a 5-HT2-A antagonist (Croxtall, 2012). Over the past decade, it has become the favorite neuroleptic in many centers for treating tics despite the lack of controlled studies and lack of approval for use in children. However, many open label studies and case series are now available which underline the remarkable efficacy of aripiprazole on tics while generally displaying a more favorable side effect profile than most typical and atypical neuroleptics with regard to sedation and weight gain (Davies et al., 2006; Seo et al., 2008; Lyon et al., 2009; Murphy et al., 2009; Neuner et al., 2012; Wenzel et al., 2012). Nonetheless, the risk of developing akathisia appears more important than with other neuroleptics; this side effect, however, can be potentially controlled with concomitant use of propanolol (Neuner et al., 2012). In the long run, many patients also underline benefitial behavioral effects (‘pacifying’) of aripiprazole unrelated to sedation (Budman et al., 2008).
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Unfortunately, randomized controlled trials regarding the efficacy and safety of aripiprazole are lacking and unlikely to occur as the drug will fall into the public domain by 2014. However, a one-weekly formulation of aripiprazole is currently being tested in children and adolescents and adults (clinicaltrialsgov. NCT01418352 and NCT01418339) and to be completed in the second half of 2013.
6. Non-neuroleptic drugs Another group of molecules used for more than two decades in the treatment of tics are alpha2 receptor agonists, e.g. clonidine (Goetz et al., 1987) and guanfacine (Scahill et al., 2001). Both molecules have been evaluated in controlled clinical trials and been shown efficient for the treatment of tics although their efficacy is usually lower than for neuroleptics with comparable sedation (Swain et al., 2007); however, they appear to be helpful in managing behavioral problems, especially ADHD (Posey et al., 2004). Benzodiazepines, in particular clonazepam, are much less frequently used for treating tics (Gonce and Barbeau, 1977) since their efficacy seems to be limited and indirect. The same reasoning can be applied to antidepressants, especially selective serotonin reuptake inhibitors, which can be helpful in reducing OCD and/or anxiety and thus tics, but seem devoid of intrinsic anti-tic activity. More recently, two antiepileptics, leviracetam and topiramate, have been suggested as useful in the treatment of tics, but results remain preliminary and sometimes conflicting (Abuzzahab and 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 nicotinergic transmission to enhance neuroleptic action (Silver et al., 2001). Most recently and rather unexpectedly, histamine has come center stage as a potential pharmacologic target in the treatment of tics. Based on the missense mutations in the histidine decarboxylase gene supposed to result in loss-of-function and therefore reduced synthesis of histamine (Ercan-Sencicek et al., 2010; Fernandez et al., 2012), drugs that increase histaminergic neurotransmission may potentially be helpful in the treatment of tics. Since this class of drugs is known foremost for its proawakening effects, in particular treatment of co-morbid ADHD appears as a plausible target for this class of drugs (Hartmann et al., 2012). Finally, we insist on the potential benefits of botulinum toxin to treat isolated tics. Botulinum toxin allows a targeted and limited intervention on localized and potentially dangerous tics, expecially those of the neck. Moreover, injections into the vocal cords can be considered in the presence of important vocal tics (Porta et al., 2004). An interesting phenomenon is the observation that premonitory sensations sometimes diminish or even dispappear after repeated injections of botulinum toxin into the affected muscle group (Kwak et al., 2000; Marras et al., 2001). Table 1 recapitulates major pharmacological treatments for tics available to date. In practice, we propose an approach based on the recommendations 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 therapy (CBT) should be proposed. If a pharmacologic treatment is the first option, aripiprazole is the molecule of choice (2.5–5 mg/day).
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3. For isolated tics, botulinum toxin injections should be considered. 4. For severe tics, first increase ariprazole dose, then consider risperidone, pimozide, haloperidol or any other neuroleptic. Next, consider tetrabenazine and anticonvulsants. 5. Finally, in case of pharmaco-resistance, deep brain stimulation can be considered. 7. Conclusions and further directions Future pharmacologic studies in GTS should target two questions: (i) association of CBT with pharmacotherapy; (ii) combination pharmacotherapy using molecules with different modes of action. In both cases, treatment periods should not be less than 3 months. Also, we recommend to form, as far as possible, subgroups with regard to age and co-morbidity. In addition, quality of life as an indicator of treatment response and success should be monitored. Finally, the advent of biomarkers, most likely the definition of endophenotypes, may prove very helpful to assess and even predict treatment response. References Abuzzahab, F.S., Brown, V.L., 2001. Control of Tourette’s syndrome with topiramate. American Journal of Psychiatry 158, 968. Bloch, M.H., Panza, K.E., Landeros-Weisenberger, A., Leckman, J.F., 2009. Metaanalysis: treatment of attention-deficit/hyperactivity disorder in children with comorbid tic disorders. Journal of the American Academy of Child and Adolescent Psychiatry 48, 884–893. Bockner, S., 1959. Gilles de la Tourette’s disease. Journal of Mental Science 105, 1078–1080. Budman, C., Coffey, B.J., Shechter, R., Schrock, M., Wieland, N., Spirgel, A., Simon, E., 2008. Aripiprazole in children and adolescents with Tourette disorder with and without explosive outbursts. Journal of Child and Adolescent Psychopharmacology 18, 509–515. Cavanna, A.E., Schrag, A., Morley, D., Orth, M., Robertson, M.M., Joyce, E., Critchley, H.D., Selai, C., 2008. The Gilles de la Tourette syndrome-quality of life scale (GTSQOL): development and validation. Neurology 71, 1410–1416. Cavanna, A.E., Servo, S., Monaco, F., Robertson, M.M., 2009. The behavioral spectrum of Gilles de la Tourette syndrome. Journal of Neuropsychiatry and Clinical Neurosciences 21, 13–23. Chang, S., 2007. Neurocognitive factors in Tourette syndrome. In: Woods, D.W., Piacentini, J.C., Walkup, J.T. (Eds.), Treating Tourette Syndrome and Tic Disorders. The Guilford Press, New York, pp. 85–112. Cheung, M.Y., Shahed, J., Jankovic, J., 2007. Malignant Tourette syndrome. Movement Disorders 22, 1743–1750. Cohen, D., Deniau, E., Maturana, A., Tanguy, M.L., Bodeau, N., Labelle, R., Breton, J.J., Guile, J.M., 2008. Are child and adolescent responses to placebo higher in major depression than in anxiety disorders? A systematic review of placebo-controlled trials. PLoS One 3, e2632. Correll, C.U., Schenk, E.M., 2008. Tardive dyskinesia and new antipsychotics. Current Opinion in Psychiatry 21, 151–156. Croxtall, J.D., 2012. Aripiprazole: a review of its use in the management of schizophrenia in adults. CNS Drugs 26, 155–183. Davies, L., Stern, J.S., Agrawal, N., Robertson, M.M., 2006. A case series of patients with Tourette’s syndrome in the United Kingdom treated with aripiprazole. Human Psychopharmacology 21, 447–453. Dobbs, M., Berger, J.R., 2003. Cervical myelopathy secondary to violent tics of Tourette’s syndrome. Neurology 60, 1862–1863. Ercan-Sencicek, A.G., Stillman, A.A., Ghosh, A.K., Bilguvar, K., O’Roak, B.J., Mason, C.E., Abbott, T., Gupta, A., King, R.A., Pauls, D.L., Tischfield, J.A., Heiman, G.A., Singer, H.S., Gilbert, D.L., Hoekstra, P.J., Morgan, T.M., Loring, E., Yasuno, K., Fernandez, T., Sanders, S., Louvi, A., Cho, J.H., Mane, S., Colangelo, C.M., Biederer, T., Lifton, R.P., Gunel, M., State, M.W., 2010. L-histidine decarboxylase and Tourette’s syndrome. New England Journal of Medicine 362, 1901–1908. Fernandez, T.V., Sanders, S.J., Yurkiewicz, I.R., Ercan-Sencicek, A.G., Kim, Y.S., Fishman, D.O., Raubeson, M.J., Song, Y., Yasuno, K., Ho, W.S., Bilguvar, K., Glessner, J., Chu, S.H., Leckman, J.F., King, R.A., Gilbert, D.L., Heiman, G.A., Tischfield, J.A., Hoekstra, P.J., Devlin, B., Hakonarson, H., Mane, S.M., Günel, M., State, M.W., 2012. Rare copy number variants in tourette syndrome disrupt genes in histaminergic pathways and overlap with autism. Biological Psychiatry 71, 392–402. Ginsburg, G.S., Newman Kingery, J., 2007. Management of familial issues in persons with Tourette syndrome. In: Woods, D.W., Piacentini, J.C., Walkup, J.T. (Eds.), Treating Tourette Syndrome and Tic Disorders. The Guilford Press, New York, pp. 225–241. Goetz, C.G., Tanner, C.M., Wilson, R.S., Carroll, V.S., Como, P.G., Shannon, K.M., 1987. Clonidine and Gilles de la Tourette’s syndrome: double-blind study using objective rating methods. Annals of Neurology 21, 307–310.
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Tourette’s syndrome and role of tetrabenazine: review and personal experience. Clinical Drug Investigation 28 (7), 443–459, Review. PubMed PMID: 18544005. Posey, D.J., Puntney, J.I., Sasher, T.M., Kem, D.L., McDougle, C.J., 2004. Guanfacine treatment of hyperactivity and inattention in pervasive developmental disorders: a retrospective analysis of 80 cases. Journal of Child and Adolescent Psychopharmacology 14, 233–241. Pringsheim, T., Marras, C., 2009. Pimozide for tics in Tourette’s syndrome. Cochrane Database of Systematic Reviews (April (2)), CD006996. Pringsheim, T., Doja, A., Gorman, D., McKinlay, D., Day, L., Billinghurst, L., Carroll, A., Dion, Y., Luscombe, S., Steeves, T., Sandor, P., 2012. Canadian guidelines for the evidence-based treatment of tic disorders: pharmacotherapy. Canadian Journal of Psychiatry 57, 133–143. Robertson, M.M., 2008. The prevalence and epidemiology of Gilles de la Tourette syndrome. Part 1: The epidemiological and prevalence studies. 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Contents lists available at SciVerse ScienceDirect
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Review
Pharmacological treatment of Gilles de la Tourette syndrome Andreas Hartmann a,b,∗ , Yulia Worbe c a
Centre de Référence National Maladie Rare: ‘Syndrome Gilles de la Tourette’, Département de Neurologie, Pôle des Maladies du Système Nerveux, France Centre de Recherche de l’Institut du Cerveau et de la Moelle Epinière, UPMC/INSERM UMR S975, CNRS UMR 7225, France c Behavioural and Clinical Neuroscience Institute, Cambridge University, Cambridge, United Kingdom b
a r t i c l e
i n f o
Article history: Received 20 July 2012 Received in revised form 10 October 2012 Accepted 28 October 2012 Keywords: Gilles de la Tourette syndrome Tics Treatment Neuroleptics
a b s t r a c t Pharmacological treatment is usually indicated in moderate to severe tics in psychosocial and/or functional 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 and common sense. Recently, aripiprazole has emerged as the neuroleptic with the most advantageous efficacy/side effect ratio for treating tics. Yet, in non-responders to aripiprazole, many neuroleptic and non-neuroleptic drugs, including botulinum toxin injections, are available and often successful. Apart from 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 of multi-drug therapy as well as the development of biomarkers (endophenotypes) to monitor and even predict treatment response. © 2012 Elsevier Ltd. All rights reserved.
Contents 1. 2. 3. 4. 5. 6. 7.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Principles of treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacologic approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Neuroleptics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Focus on aripiprazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Non-neuroleptic drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions and further directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction In his initial description of ‘la maladie des tics’ in 1885, Georges Gilles de la Tourette assumed an organic etiology of tics. Nonetheless, for the following 75 years, tics and Gilles de la Tourette syndrome (GTS) were considered from a predominantly psychodynamic viewpoint. Accordingly, “treatment” of tics was mainly performed by psychonanalysis and pharmacological therapy unavailable (see also Párraga et al., 2010, for other preneuroleptic area treatment options).
∗ Corresponding author at: Centre de Référence National Maladie Rare: ‘Syndrome Gilles de la Tourette’, Département de Neurologie, Pôle des Maladies du Système Nerveux, Groupe Hospitalier Pitié-Salpêtrière, 47 Boulevard de l’Hôpital, 75651 Paris Cedex 13, France. Tel.: +33 01 42 16 13 16; fax: +33 01 44 16 13 21. E-mail address: [email protected] (A. Hartmann). 0149-7634/$ – see front matter © 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.neubiorev.2012.10.014
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In 1959, however, the British psychiatrist Bockner treated two ticcing patients with chlorpromazine, a recently introduced neuroleptic, one of them with success (Bockner, 1959). Two years later, the French psychiatrist Seignot treated one patient with severe GTS with haloperidol: the results were remarkable (Seignot, 1961). This encouraging report and subsequent ones (Kushner, 1999) inspired Shapiro and Shapiro (1968), two American psychiatrists and pioneers in the field of GTS, to treat large series of patients with haloperidol which thus became the drug of choice in the treatment of tics. More than 50 years later, we believe that neuroleptics still represent the first choice of molecules for the treatment of tics. Many detailed and excellent reviews are available on the pharmacotherapy of tics and GTS (Scahill et al., 2006; Singer, 2010; Roessner et al., 2011; Huys et al., 2012). In the present review, we will use a more personal approach to highlight some controversies in the treatment of tics, unmet needs and future directions.
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2. Principles of treatment Treatment of tics depends as much on common sense and clinical experience than on controlled, randomized and double-blind trials that are much too scarce in GTS due to the rarity and the regrettable but somewhat understandable lack of interest from the pharmaceutical industry in this condition. Although the prevalence of GTS has been estimated at 1% (Robertson, 2008), the crucial but unanswered question is how many of these potential patients receive accurate diagnosis and if so, whether they require treatment beyond psychoeducation (see below). Even if available, controlled trials in GTS present many methodological pitfalls. The most common is duration of treatment which is usually too short to accommodate the waxing and waning nature of tics, especially in children and adolescents (Roessner et al., 2011.). Another, more recent concern stems from the fact that apart from tic reduction per se (usually evaluated with the Yale Global Tic Severity Scale – YGTSS), quality of life is a major variable to be taken into account in future studies evaluating treatment efficacy and for which an appropriate scale has recently become available (Cavanna et al., 2008). The first step in treating GTS patients is usually referred to as psychoeducation: counsel and instruct the patient, the family as well as school or work environment about the nature of tics, co-morbidities and overall prognosis. In a large number of cases, these simple measures, accompanied by regular follow-up, are remarkably effective and may prevent the need to introduce specific anti-tic therapy. Decision to treat is based on four criteria: • Tics cause sustained social problems for the patient (e.g. social isolation 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 subjective (although a sharp decline in school performance or impeding liscencing are clear warning signs that action should be taken), the last criterion is rather objective, especially with regard to tic sequelae. For instance, certain violents neck can cause cervical myelopathies leading to tetraplegia (Dobbs and Berger, 2003) or cause stroke through vertebral artery dissection (Van Meerbeeck et al., 2011; Lehman et al., 2011). Also, automutilations (blindness through ocular enucleation, lacerations, fractures, burns, etc.) can be extremely severe and even life-threatening (Cheung et al., 2007). Furthermore, it is essential to take into account co-morbidities (obsessive–compulsive disorder – OCD, attention deficit with hyperactivity disorder – ADHD, depression, anxiety, impulse control disorder, autism spectrum disorders, learning disabilities), present in more than 90% of GTS patients (Cavanna et al., 2009) and to hierarchize the patients’ needs accordingly. Several studies have shown that patients’ quality of life is often more compromized by co-morbidities than by tics as such. Therefore, if possible/available, a multidisciplinary (neurologists, psychiatrists, psychologists, neuropsychologists, social workers) evaluation and follow-up is recommended (Chang, 2007; Kepley and Conners, 2007; Woods et al., 2007). Although treatment of co-morbidities is beyond the scope of this article, two points deserve mention. First, antidepressants are of extremely limited utility in children (Cohen et al., 2008); therefore, in case of depression, access to psychotherapy is crucial. Second, psychostimulants are not contraindicated in GTS: some cases may be aggravated but others improved due to stress reduction (Bloch et al., 2009). Therefore, this class of drugs should not be shunned but used on a case-to-case basis after careful neuropyschological workup, since there is considerable semiologic
overlap between tics and ADHD. Last not least, the role of the family in tic reduction is of major importance (Ginsburg and Newman Kingery, 2007). In difficult situations, family therapy should be considered. 3. Pharmacologic approaches As discussed in previous articles of this special issue, many brain structures and neurotransmitters are implicated in the genesis of tics. Unsurprisingly, pharmacological treatment of tics is mostly empirical and dominated by case studies or series as well as open label trials; very few studies, as already mentioned, fulfill class A evidence criteria (Table 1). Also, even if based on rather solid evidence, treatment practices differ widely across countries and continents (to be discussed below). Recent reviews have extensively listed all available evidence on tic treatment, in particular the recently published ESSTS guidelines (2011) and we refer to this publication for anyone seeking methodolical details on case reports, case series and clinical trials. Interestingly, these guidelines have made apparent substantial differences in treatment recommendations between European und US centers (Jankovic and Kurlan, 2011a, discussed in Müller-Vahl and Roessner, 2011; Jankovic and Kurlan, 2011b). Besides obvious differences related to differential availability of drugs, they also reflect different stances on the risks and benefits of using certain class of drugs, especially neuroleptics. In this article, we have chose to highlight our personal approach of treating tics in agreement with many of our European colleagues. A special mention is made of aripiprazole which appears to us as the most promising drug for tic treatment to emerge over the last decade. 4. Neuroleptics Historically, as already mentioned, treatment of tics has been primarily based on the use of neuroleptics (dopamine receptor antagonists). Among ‘typical’ neuroleptics (which refers to their preferential affinity to D2 receptors), haloperidol and pimozide are the most commonly used, with a slightly better side effect profile Table 1 Pharmacotherapy of tics – a selection. Neuroleptics
Empirical support
Starting doses (mg)
Therapeutic doses (mg)
Haloperidol Pimozide Risperidone Fluphenazine Tiapride Olanzapine Sulpiride Aripiprazole
A A A B B C C C
0.25–0.5 0.5–1.0 0.25–0.5 0.5–1.0 50–150 2.5–5.0 100–200 2.5–5.0
1–4 2–8 1–3 1.5–10 150–500 2.5–12.5 200–1000 5–15
Others Clonidine Guanfacine Botulinum toxin
B B B
Tetrabenazine Baclofen Nicotine patch
C C C
0.0025–0.05 0.5–1.0 30–300 U/injection site 12.5–25 10 7
0.1–0.3 1–3
25–150 40–60 7–21
Level of proof: Jobson KO, Potter WZ. International Psychopharmacology Algorithim Project Report: introduction. Psychopharmacol. Bull. 1995;31:457–459: Category A = treatments with good supportive evidence for short-term safety and efficacy derived from at least two randomized placebo-controlled trials with positive results. Category B = treatments with fair supportive data as evidenced by at least one positive placebo-controlled study. Category C = treatments with minimal supportive evidence such as open-label studies and accumulated clinical experience.
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for the latter compared to the former but also slightly less efficacy (Pringsheim and Marras, 2009). Common to both drugs as well as to most neuroleptics are sedation, weight gain and metabolic disturbances. Pimozide may prolong QT intervals and patients therefore require ECG monitoring after introducing the drug. However, extrapyramidal side effects (parkinsonian syndromes and tardive dyskinesia) appear nowadays as much less a concern than previously thought. In fact, a retrospective recent case series of 521 patients did not detect a single case of tardive dyskinesia in GTS patients treated with a variety of neuroleptics, inclunding children and adolescents (n = 100 out of 521). The authors went so far as to question whether GTS ‘protects’ against neuroleptic-induced tardive dyskinesia (Müller-Vahl and Krueger, 2011). The authors’ own clinical experience are in accordance with this favorable side effect profile of neuroleptics for treating tics. Reasons may include lower dosages and slower dose escalation in GTS than in the classic antipsychotic indications, where tardive dyskinesia appear to occur in up to 30% of cases (Correll and Schenk, 2008). More speculatively, GTS patients, especially in younger age groups, may possess a form of cerebral plasticity rendering them more resistant to neurolepticinduced extrapyramidal side effects. Nonetheless, in light of the fear of tardive dyskinesia, so-called ‘atypical’ neuroleptics have attracted great interest over the past two decades for treating tics. This class of molecules is characterized by a less potent blockade of D2 receptors as well as 5-HT2-A and 5-HT2-C receptors antagonism. Risperidone offers the best level of evidence in this group and is considered by many as first choice treatment for tics (Scahill et al., 2003). However, metabolic side effects (increases in glucose, lipids, prolactine) occur frequently and must be closely monitored. Also, depression risk due to anti-serotoninerc activity may be a concern, in addition to depression resulting from diminished dopaminergic transmission common to all neuroleptics. The benzamides (tiapride, sulpiride) are further selective D2 dopamine receptor antagonists but in contrast to the typical neuroleptics with low (sulpiride) or as good as no (tiapride) antipsychotic action which appear to result in less or no extrapyramidal side effects. Nonetheless, weight gain and sedation can occur and must be monitored (Roessner et al., 2011). Finally, among the atypical neuroleptics, tetrabenazine (Porta et al., 2008) deserves special mention. As a monoamine depletor, it offers the potential advantage of not inducing tardive dyskinesia and is therefore especially favored in North America (Jankovic and Kurlan, 2011a; Pringsheim et al., 2012). However, sedation is a major issue as well as rare but sometimes severe depressive reactions. 5. Focus on aripiprazole Aripiprazole is one of the most recently introduced neuroleptics and offers a particular mode of action: apart from its D2 antagonistic activity, it is also a partial D2 and 5-HT1-A receptor agonist and a 5-HT2-A antagonist (Croxtall, 2012). Over the past decade, it has become the favorite neuroleptic in many centers for treating tics despite the lack of controlled studies and lack of approval for use in children. However, many open label studies and case series are now available which underline the remarkable efficacy of aripiprazole on tics while generally displaying a more favorable side effect profile than most typical and atypical neuroleptics with regard to sedation and weight gain (Davies et al., 2006; Seo et al., 2008; Lyon et al., 2009; Murphy et al., 2009; Neuner et al., 2012; Wenzel et al., 2012). Nonetheless, the risk of developing akathisia appears more important than with other neuroleptics; this side effect, however, can be potentially controlled with concomitant use of propanolol (Neuner et al., 2012). In the long run, many patients also underline benefitial behavioral effects (‘pacifying’) of aripiprazole unrelated to sedation (Budman et al., 2008).
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Unfortunately, randomized controlled trials regarding the efficacy and safety of aripiprazole are lacking and unlikely to occur as the drug will fall into the public domain by 2014. However, a one-weekly formulation of aripiprazole is currently being tested in children and adolescents and adults (clinicaltrialsgov. NCT01418352 and NCT01418339) and to be completed in the second half of 2013.
6. Non-neuroleptic drugs Another group of molecules used for more than two decades in the treatment of tics are alpha2 receptor agonists, e.g. clonidine (Goetz et al., 1987) and guanfacine (Scahill et al., 2001). Both molecules have been evaluated in controlled clinical trials and been shown efficient for the treatment of tics although their efficacy is usually lower than for neuroleptics with comparable sedation (Swain et al., 2007); however, they appear to be helpful in managing behavioral problems, especially ADHD (Posey et al., 2004). Benzodiazepines, in particular clonazepam, are much less frequently used for treating tics (Gonce and Barbeau, 1977) since their efficacy seems to be limited and indirect. The same reasoning can be applied to antidepressants, especially selective serotonin reuptake inhibitors, which can be helpful in reducing OCD and/or anxiety and thus tics, but seem devoid of intrinsic anti-tic activity. More recently, two antiepileptics, leviracetam and topiramate, have been suggested as useful in the treatment of tics, but results remain preliminary and sometimes conflicting (Abuzzahab and 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 nicotinergic transmission to enhance neuroleptic action (Silver et al., 2001). Most recently and rather unexpectedly, histamine has come center stage as a potential pharmacologic target in the treatment of tics. Based on the missense mutations in the histidine decarboxylase gene supposed to result in loss-of-function and therefore reduced synthesis of histamine (Ercan-Sencicek et al., 2010; Fernandez et al., 2012), drugs that increase histaminergic neurotransmission may potentially be helpful in the treatment of tics. Since this class of drugs is known foremost for its proawakening effects, in particular treatment of co-morbid ADHD appears as a plausible target for this class of drugs (Hartmann et al., 2012). Finally, we insist on the potential benefits of botulinum toxin to treat isolated tics. Botulinum toxin allows a targeted and limited intervention on localized and potentially dangerous tics, expecially those of the neck. Moreover, injections into the vocal cords can be considered in the presence of important vocal tics (Porta et al., 2004). An interesting phenomenon is the observation that premonitory sensations sometimes diminish or even dispappear after repeated injections of botulinum toxin into the affected muscle group (Kwak et al., 2000; Marras et al., 2001). Table 1 recapitulates major pharmacological treatments for tics available to date. In practice, we propose an approach based on the recommendations 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 therapy (CBT) should be proposed. If a pharmacologic treatment is the first option, aripiprazole is the molecule of choice (2.5–5 mg/day).
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