CHAPTER FIFTEEN

Emerging Treatment Strategies in Tourette Syndrome: What’s in the Pipeline? Cristiano Termine*,1, Claudia Selvini*, Giorgio Rossi*, Umberto Balottin†

*Child Neuropsychiatry Unit, Department of Experimental Medicine, University of Insubria, Varese, Italy † Department of Child Neurology and Psychiatry, IRCCS “C. Mondino” Foundation, University of Pavia, Pavia, Italy 1 Corresponding author: e-mail address: [email protected]

Contents 1. Introduction 2. Potential and Emerging Pharmacological Treatments 2.1 Newest atypical antipsychotic agents 2.2 GABA modulator agents 2.3 Selective norepinephrine reuptake inhibitors 2.4 S5aR and other neuroactive agents 2.5 Currently ongoing trials 3. Potential and Emerging Nonpharmacological Treatments 3.1 Electroconvulsive therapy 3.2 Repetitive TMS 4. Conclusion References

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Abstract Tourette syndrome (TS) is a neurodevelopmental disorder characterized by multiple motor/phonic tics and a wide spectrum of behavioral problems (e.g., complex tic-like symptoms, attention deficit hyperactivity disorder, and obsessive-compulsive disorder). TS can be a challenging condition even for the specialists, because of the complexity of the clinical picture and the potential adverse effects of the most commonly prescribed medications. Expert opinions and consensus guidelines on the assessment and treatment of tic disorders have recently been published in Europe and Canada. All pharmacological treatment options are mere symptomatic treatments that alleviate, but do not cure, the tics. We still lack evidence of their effects on the natural longterm course and on the prognosis of TS and how these treatments may influence the natural course of brain development. The most commonly prescribed drugs are dopamine antagonists, such as typical (e.g., haloperidol, pimozide) and atypical neuroleptics (e.g., risperidone, aripiprazole), International Review of Neurobiology, Volume 112 ISSN 0074-7742 http://dx.doi.org/10.1016/B978-0-12-411546-0.00015-9

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2013 Elsevier Inc. All rights reserved.

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and a-2-adrenoreceptor agonists (e.g., clonidine). However, several studies have investigated the efficacy and tolerability of alternative pharmacological agents that may be efficacious, including the newest atypical antipsychotic agents (e.g., paliperidone, sertindole), tetrabenazine, drugs that modulate acetylcholine (e.g., nicotine) and GABA (e.g., baclofen, levetiracetam), tetrahydrocannabinol, botulinum toxin injections, anticonvulsant drugs (e.g., topiramate, carbamazepine), naloxone, lithium, norepinephrine, steroid 5a reductase, and other neuroactive agents (buspirone, metoclopramide, phytostigmine, and spiradoline mesylate). As regards nonpharmacological interventions, some of the more recent treatments that have been studied include electroconvulsive therapy and repetitive transcranial magnetic stimulation. This review focuses primarily on the efficacy and safety of these emerging treatment strategies in TS.

1. INTRODUCTION Tourette syndrome (TS) is a chronic childhood-onset neurodevelopmental disorder characterized by multiple motor and one or more phonic tics, which do not have to be present simultaneously (American Psychiatric Association, 2000). Recently, Robertson, Eapen, and Cavanna (2009) showed that tic disorders are far from rare and TS may be seen in up to 1% of youngsters aged 5–18, with a male:female ratio of 3:1. Tics can be simple or complex; they may be temporarily suppressed and are preceded by premonitory urges (Kwak, Dat Vuong, & Jankovic, 2003). Around 90% of these patients exhibit comorbid conditions, the most common of which are obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD), as well as mood disorders (e.g., depression or anxiety), impulse control disorders (e.g., explosive outburst or conduct disorder), sleep disturbances, and personality disorders. Complex tic-related symptoms may also be present, including coprophenomena (such as coprolalia: the uttering of obscene language), echophenomena (copying behaviors), paliphenomena (repetitive behaviors), self-injurious behaviors, and nonobscene socially inappropriate symptoms (Cavanna, Servo, Monaco, & Robertson, 2009). Self-injurious behaviors may be integral to TS as they are sometimes present even in mild cases (Robertson & Stern, 2000), and control of these symptoms is clearly of great importance for maintaining physical health. The presence of these comorbidities can be associated with social difficulties and can have a greater impact on health-related quality of life (HR-QoL) than the tic severity (Muller-Vahl et al., 2010). Therefore, the treatment of tics and tic-related symptoms in TS is vital for maintaining patients’ current QoL and could even have an impact on their future well-being (Eddy et al., 2011).

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Many children with Tourette’s disorder improve through adolescence. However, about 20% of adults with GTS retain socially disabling tics throughout life and also experience severe symptoms and considerable disability (Bloch et al., 2006; Rindner, 2007). This often leads to a decreased self-reported QoL, because emergence of unwelcome motor and vocal tics in social situations may lead not only to embarrassment, but also to decreased self-consciousness, social isolation, thoughts of persecution, physical pain, and limited working capability. TS can be a challenging condition even for the specialists, because of the complexity of the clinical picture encompassing motor and behavioral symptoms (i.e., neurology and psychiatry), and the potential adverse effects of some of the most commonly prescribed medications. The treatment of TS is complicated by the range of symptoms associated with this condition and by the variability across individual symptom profiles. In relation to efficacy, studies clearly indicate that no pharmacological agent has yet been identified that will reliably ameliorate tics in all sufferers. Psychoeducation in TS includes information about long- and short-term variability of tics, their natural course, and possible coexisting problems, and aims to improve symptom tolerance and support stress reduction. Nonpharmacologic and/or pharmacologic interventions should be considered in addition to psychoeducation for persons with a clear impairment associated with tics, either at first referral or later, if the symptoms worsen over time. Expert opinions and consensus guidelines on the assessment and treatment (both pharmacological and nonpharmacological) of tic disorders have recently been published in both Europe and Canada (Pringsheim et al., 2012; Roessner et al., 2011). However, it is difficult to give guidelines with regard to indications for pharmacological treatment of TS because persons with TS have a high interindividual variability of symptoms, because of the temporal fluctuations of tics, and because coexisting conditions may interfere with the effects of tic treatment. A trial-and-error approach is likely to be necessary in order to identify the most appropriate combinations of treatments for patients with a more complex array of symptoms, such as those exhibiting features of OCD and ADHD. In such complex cases, there are clear safety issues pertaining to drug interactions and contraindications, in addition to concerns related to the use of medication in children (Eddy et al., 2011). Moreover, subjective impairment does not necessarily equate with objective tic severity: some individuals with relatively severe tics experience only mild impairment, while in other cases, mild tics may be associated with significant suffering (Scahill et al., 2006).

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All pharmacological treatment options are mere symptomatic treatments that alleviate, but do not cure, the tics (Gilbert, 2006). The most commonly prescribed drugs are dopamine antagonists, such as typical (e.g., haloperidol, pimozide) and atypical neuroleptics (e.g., risperidone, aripiprazole), and a-2-adrenoreceptor agonists (e.g., clonidine). The results of a Europeanbased survey, promoted by the European Society for the Study of Tourette Syndrome (ESSTS), showed that clinicians currently prescribe the atypical antipsychotic risperidone, followed by clonidine, aripiprazole, pimozide, sulpiride, tiapride, and haloperidol, as first-choice medications for tics. Particularly, aripiprazole, risperidone, and sulpiride are the three preferred antitic agents for adults, while risperidone, clonidine, and aripiprazole are the preferred medications for children with TS. However, it should be emphasized that this is not the general consensus within a wider perspective: the Canadian guidelines (Pringsheim et al., 2012) made strong recommendations for the use of the a-2-adrenoreceptor agonists clonidine and guanfacine in children with TS. These authors made weak recommendations for other agents such as pimozide, haloperidol, risperidone, aripiprazole, quetiapine, ziprasidone, botulinum toxin injections, and tetrabenazine, primarily because of the high rates of adverse reactions accompanying these medications. Other factors responsible for the variability of drug prescriptions among clinicians are the different availability of anti-tic medications across different countries, as well as differences in clinicians’ perception of the tolerability profile of atypical antipsychotics (especially with regard to tardive dyskinesia) and the therapeutic potential of tetrabenazine. The unfortunate paucity of class I and class II evidence trials, especially for tetrabenazine and the newer antipsychotics, prevents the formulation of clinically relevant evidence-based guidelines. However, we believe that the considerable efforts and fruitful dialogues that have taken place in the last years have resulted in what will be retrospectively looked at as an important “paradigm shift.” Recommendations on the pharmacological management of TS are no longer dictated exclusively by the authority of single eminent opinion leaders; rather, they rely on a wider consensus of experts from different backgrounds (Pringsheim et al., 2012; Roessner et al., 2011). In addition to informing clinical practice, experts’ consensus should direct future efforts in devising multicenter trials of selected pharmacological agents in order to build a solid level of evidence for the most promising treatment options for TS. In the last years, several studies investigated the efficacy and tolerability of alternative pharmacological agents, including the newest atypical

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antipsychotic agents (e.g., paliperidone, sertindole), tetrabenazine, drugs, which modulate acetylcholine (e.g., nicotine) and g-aminobutyric acid ([GABA]; e.g., baclofen and levetiracetam [LEV]), tetrahydrocannabinol, botulinum toxin injections, anticonvulsant drugs (e.g., topiramate, carbamazepine), naloxone, lithium, norepinephrine, steroid 5a reductase (S5aR), and other neuroactive agents (buspirone, metoclopramide, physostigmine, and spiradoline mesylate). About nonpharmacological treatments, some of the more recent treatments that have been studied include electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (TMS). This review focuses primarily on the efficacy and safety of these emerging treatment strategies in TS (see Table 15.1 for a summary).

2. POTENTIAL AND EMERGING PHARMACOLOGICAL TREATMENTS 2.1. Newest atypical antipsychotic agents Several drug trials, neurophysiological and imaging studies, and analyses of human samples (e.g., cerebrospinal fluid, blood, urine, postmortem brain tissue) led to numerous hypotheses on neurochemical abnormalities in TS (Harris & Singer, 2006) including imbalances in noradrenergic, glutamatergic, serotoninergic, opioid, cholinergic, and GABAergic systems (Swain, Scahill, Lombroso, King, & Leckman, 2007). The most common and generally accepted hypothesis, though, relates to dopaminergic dysfunction (Albin & Mink, 2006; Bloch, State, & Pittenger, 2011). For instance, abnormalities of dopamine transporter binding capacity (Cheon et al., 2004; Serra-Mestres et al., 2004; Singer, Hahn, & Moran, 1991; Yeh et al., 2006, 2007) and increases in cortical (Minzer, Lee, Hong, & Singer, 2004; Yoon et al., 2007) and striatal (Wong et al., 1997) dopamine receptors have been reported. Hence, the main rationale of pharmacological treatment in TS is the use of drugs that modulate the dopaminergic system, above all through blockage of postsynaptic D2 receptors. However, there is little doubt that, in addition to the dopaminergic system, other neurotransmitter systems, for example, serotonergic pathways (Mu¨ller-Vahl et al., 2005; Steeves et al., 2010), play an important role in the pathophysiology of TS and comorbid disorders. This notwithstanding, antipsychotic drugs achieve the most reliable and fastest treatment response compared to other medications and, therefore, they are the mainstay of any pharmacological treatment for tics. Controlled clinical trials have documented the efficacy of several “typical” antipsychotics such as haloperidol, pimozide, sulpiride,

Table 15.1 Summary table of revised intervention trials Pediatric and/or N Dose Study Design pts adult

Primary outcome

Interpretation

Other information

Gradual but significant improvement in tic frequency, severity, and CGI

Effective

6/15 ¼ ADHD 9/15 ¼ OCD/OCB

Ropinirole Open-label study

15

Pediatric Start dose ¼ 0.5 mg/day and adult Max. dose ¼ 1 mg/day (fixed dose)

Randomized, double-blind, placebocontrolled clinical study

63

Pediatric Start dose ¼ 0.125 mg/day No evidence for superior Ineffective efficacy of pramipexole Max. dose ¼ 0.5 mg/day over placebo (flexible dose) Improvement on DuPaul ADHD Scale scores

Gonce and Open-label Barbeau (1977) study

7

Adult

Kaim (1983)

Retrospective study

1

Pediatric Fixed dose

Merikangas, Merikangas,

Randomized, single-blind, active

19

Adult

Anca, Giladi, and Korczyn (2004) Pramipexole Kurlan et al. (2012)

22/63 ¼ ADHD

Clonazepam Range, 4–6 mg/day

Range, 1–6 mg/day

71% ¼ Improved

Effective

Improvement in tics and Effective abnormal vocalization 68% ¼ Improved

Superior to haloperidol in 17%

1/7 ¼ Started neuroleptic drug simultaneously

Kopp, and Hanin (1985)

comparator, crossover study

Equivalent to haloperidol in 33% Inferior to haloperidol in 50%

Jankovic and Retrospective, 112 Pediatric Rohaidy (1987) open-label, and adult crossover study Drtilkova, Balaotikova, Lemanova, and Zak (1994)

Randomized, active comparator study

20

Retrospective, 7 Steingard, Goldberg, Lee, open-label, crossover study and DeMaso (1994)

Effective Patients with mild symptoms improved with clonazepam or clonidine

Pediatric

32% ¼ OCD 36% ¼ ADHD

Superior to clonidine

Pediatric

Clonazepam þ clonidine decreased tic frequency and severity

Effective

Tics under control

Effective

100% ¼ ADHD

Topiramate Abuzzahab and Case report Brown (2001)

2

Adult

Range, 50–200 mg/day

Continued

Table 15.1 Summary table of revised intervention trials—cont'd Pediatric N and/or Study Design pts adult Dose

Primary outcome

Interpretation

Jankovic, JimenezShahed, and Brown (2010)

Randomized, double-blind, placebocontrolled study

29

Pediatric 118 mg and adult

Improvement on YGTSS Effective by 14.29 points in Total Tic Score

Kuo and JimenezShahed (2010)

Retrospective study

41

Pediatric and adult

75.6% ¼ Moderate to marked improvement

60

Pediatric Range, 1–2 g/day

Effective Led to a mean 20% reduction in tics 43/60 ¼ Improvement in behavior and school performance

Prospective, 70 open-label, 4-year followup study

Pediatric Range, 1–2 g/day

49/70 ¼ Tic improvement 70% Improvement in behavior and school performance

Effective

Levetiracetam Prospective, Awaad, open-label Michon, and Minarik (2005) study

Awaad (2007)

Effective

Other information

Smith-Hicks, Bridges, Paynter, and Singer (2007)

Randomized, 22 double-blind, placebocontrolled, crossover study

Pediatric Range, 750–3000 mg/day Slight reduction in tics No improvement in ADHD or OCD

Oulis et al. (2008)

Case report

Adult

Hedderick, Morris, and Singer (2009)

Randomized, 12 double-blind crossover study

1

Max. dose, 2 g/day

Noneffective

Improvement on YGTSS Effective scores

Pediatric Range, 250–1750 mg/day No improvement in tics, Noneffective ADHD, or OCD and adult (max. 50 mg/kg/day) Effective 15% Worsened 26% Showed no changes 59% Showed improvement in tics Significant improvement in tics and ADHDassociated subgroup

Prospective, Fernandezopen-label Jaen, study FernandezMayoralas, Munoz-Jareno, and CallejaPerez (2009)

29

Pediatric 30–40 mg/kg/day (max. 2 g/day)

Awaad (1999)

24

Effective Pediatric Range, 500–1250 mg/day 9/12 Improved in the treatment group and 1/12 in the placebo group Significant improvement in tics

Randomized, double-blind, placebocontrolled study

Combination with clonidine

100% ¼ ADHD

Comorbidities ¼ epilepsy and headache

Continued

Table 15.1 Summary table of revised intervention trials—cont'd Pediatric N and/or Study Design pts adult Dose

Primary outcome

Interpretation

Other information

Baclofen 264 Pediatric Start dose ¼ 10 mg/day Max. dose ¼ 80 mg/day

Awaad (1999)

Open-label study

Singer, Wendlandt, Krieger, and Giuliano (2001)

Randomized, 10 double-blind, placebocontrolled, crossover study

Pediatric Start dose ¼ 15 mg/day Max. dose ¼ 60 mg/day

Randomized, 15 double-blind, placebocontrolled, crossover study

Adult

Effective 250/264 ¼ Significant decrease in the severity of motor (p < 0.02) and vocal (p < 0.02) tics on YGTSS within 1–2 weeks Mean change in CGI score: 0.9 Mean change in total YGTSS score: 14.7 Reduction in the impairment score rather than a decrease in tics

Effective

Naloxone van Wattum, Chappell, Zelterman, Scahill, and Leckman (2000)

30 and 300 mg/kg at 3-day Low dose of 30 mg caused Effective intervals (randomized dose) a significant decrease of 14% in tics, while a high dose caused a significant increase of 31% in tics

Comorbidities ¼ ADHD, ADD

Naltrexone 100% ¼ SIB

Herman et al. (1987)

Open label

3

Pediatric 0.5, 1.0, 1.5, and 2.0 mg/kg

Total SIB was reduced significantly

Effective on SIB

Kurlan et al. (1991)

Randomized, double-blind, active comparator/ placebocontrolled study

10

Adult

Significant improvement in tics on TSSL (p < 0.04) Improvement in performance on Trail Making B test (p < 0.08)

Effective and superior to propoxyphene on attention ability

Allen et al. (2005)

Randomized, double-blind, placebocontrolled, parallel group study

148 Pediatric 0.5–1.5 mg/kg/day

Significant reduction in Effective tic severity on the YGTSS total score (p ¼ 0.063) and on the ADHD Rating Scale total score (p < 0.001)

100% ¼ ADHD

Gilbert et al. (2007)

Open-label study

11

Decreasing short interval Effective cortical inhibition (SICI) correlated with improving ADHD

100% ¼ ADHD

50 mg/day

Atomoxetine

Pediatric Start dose ¼ 0.8–1.0 mg/kg/day Max. dose ¼ 1.0–1.5 mg/kg/day (fixed titration)

Continued

Table 15.1 Summary table of revised intervention trials—cont'd Pediatric N and/or Study Design pts adult Dose

Spencer et al. (2008)

Primary outcome

Interpretation

Other information

Randomized, double-blind, placebocontrolled, parallel group study

117 Pediatric Range, 0.5–1.5 mg/kg/day Significant improvement Effective on ADHD symptom measures and significant reduction in tic severity

100% ¼ ADHD

Randomized, double-blind, placebocontrolled, parallel assignment study

33

Pediatric 6000 mg/day

Beneficial in reduction of tic-related impairment in some children and adolescents

60

Pediatric Range, 50–200 mg/day

v-3 Fatty acids Gabbay et al. (2012)

Currently ongoing trials Riluzole

Randomized, double-blind, placebocontrolled, parallel assignment study

No significantly higher response rates or lower mean scores on the YGTSS-Tic

Ineffective

D-Serine

Randomized, double-blind, placebocontrolled, parallel assignment study

60

Pediatric 30 mg/kg/day

Ecopipam

Open-label study

18

Adult

N-acetylcysteine Randomized, double-blind, placebocontrolled, parallel assignment study

40

Pediatric 1200–2400 mg/day

Pramipexole

63

Pediatric 0.125–0.5 mg/day

Randomized, double-blind, placebocontrolled, parallel assignment, flexible dose study

50 or 100 mg/day

Continued

Table 15.1 Summary table of revised intervention trials—cont'd Pediatric and/or N Dose Study Design pts adult

Primary outcome

Interpretation

Other information

Electroconvulsive therapy Case report

1

Adult

8 Sessions

Effective Tics in full remission, objective improvement in depression, but patient withdrawn and socially disconnected

Comorbidities ¼ major depressive episode Cotherapy ¼ clomipramine and haloperidol

Trivedi, Case report Mendelowitz, and Fink (2003)

1

Adult

Six bilateral ECT en bloc

Full resolution of tics

Full resolution of both the catatonic and TS-like symptoms

Strassnig, Riedel, and Mu¨ller (2004)

Case report

1

Adult

Acute ¼ 3 times/week Maintenance ¼ 1 time/ month

Marked improvement in Effective tic severity and frequency; OCD absent

Comorbidity ¼ OCD

Karadenizli, Dilbaz, and Bayam (2005)

Case report

1

Adult

7 Sessions

2 Years of remission

Comorbidities ¼ SIB and psychotic features Cotherapy ¼ carbamazepine

Rapoport, Feder, and Sandor (1998)

Effective

Effective

Morais et al. (2007)

Case report

1

Adult

Dhossche, Reti, Shettar, and Wachtel (2010)

Case report

2

Adult

Dehning, Case report Feddersen, Mehrkens, and Mu¨ller (2011)

1

Adult

Nonrelapse on tic, First month ¼ 2 sessions/ depression, or anxiety week Second month ¼ 1 session/ symptoms 7 days Third month ¼ 1 session/ 10 days Fourth to sixth months ¼ 1 session/15 days Seventh to eighth months ¼ 1 session/month

Effective

Cotherapy ¼ olanzapine, sulpiride, citalopram, and clonidine

Effective

50% ¼ Autism 100% ¼ SIB

5-Year-long remission

Effective

No significant improvement in symptoms

Ineffective

Repetitive transcranial magnetic stimulation Munchau et al. Single-blind, 12 (2002) placebocontrolled, crossover repetitive study

Adult

1 Hz (1200 pulses/day)

7/12 ¼ OCD

Continued

Table 15.1 Summary table of revised intervention trials—cont'd Pediatric and/or N Dose Study Design pts adult

Primary outcome

Chae et al. (2004)

Randomized, 8 blinded, crossover study

Adult

1 or 15 Hz

Significant improvement Effective in tics

Mantovani et al. (2006)

Open-label study

10

Adult

1 Hz (1200 pulses/day)

Clinically significant improvement ¼ 67% reduction in tic severity

Mantovani et al. (2007)

Case report

2

Pediatric 1 Hz (1200 pulses/day) and adult

2

Adult

Mrakic-Sposta et al. (2008)

2 mA

Interpretation

Effective

Effective Improvement in tics Normalized of the hemispheric asymmetry in motor cortex excitability Improvement in depression and anxiety Less remarkable reduction in OCD

Other information

2/10 ¼ TS þ OCD 3/10 ¼ TS pure 5/10 ¼ Only OCD 8/10 ¼ MDD Presence of cotherapy 100% ¼ OCD, ADHD, MDD

Kwon et al. (2011)

Open-label cohort study

10

Pediatric 1 Hz (1200 stimuli/day)

Effective No side effects and no worsening of ADHD, depressive, or anxiety symptoms Significant improvement in tics

Wu, Shahana, Huddleston, Lewis, and Gilbert (2012)

Open-label, controlled study

40

Pediatric 50 Hz

Safe and well tolerated

Le, Liu, Sun, Hu, and Xiao (2013)

Open-label study

25

Pediatric 1 Hz

Significant reduction in tics and ADHD symptoms

16/40 ¼ TS 24/40 ¼ Healthy controls

Effective

CGI, Clinical Global Impression Scale; ADHD, attention deficit/hyperactivity disorder; OCD, obsessive-compulsive disorder; OCB, obsessive-compulsive behaviors; YGTSS, Yale Global Tics Severity Scale; ADD, attention deficit disorder; SIB, self-injurious behaviors; MDD, major depressive disorder.

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fluphenazine, and tiapride for tics (Kastrup, Schlotter, Plewnia, & Bartels, 2005). However, the common adverse effects of these medications, including sedation, weight gain, hyperprolactinaemia, extrapyramidal symptoms, and electrocardiographic QT prolongation, can all contribute to reducing patients’ HR-QoL (Pae et al., 2009). This is the reason why many authors recommend the use of atypical antipsychotics as a first-line treatment rather than typical antipsychotics (Eddy et al., 2011; Roessner et al., 2011; Singer, 2010). Risperidone is the most investigated atypical antipsychotic agent for the treatment of TS. In comparison to haloperidol and pimozide, risperidone was as effective in reducing tics and showed less frequent and less severe adverse reactions (Bruun & Budman, 1996; Diantoniis, Henry, Partridge, & Soucar, 1996; Lombroso et al., 1995; Shulman, Singer, & Weiner, 1995). Furthermore, compared to clonidine, risperidone was more effective in patients with TS and comorbid obsessive-compulsive symptoms, while both were equally effective in the treatment of pure tics (Gaffney et al., 2002). Because of these positive outcomes, several experts have made this agent their first choice (Eddy et al., 2011; Roessner et al., 2011). Unfortunately, the benefits of atypical antipsychotics are still limited by some troublesome adverse effects. These include both psychiatric adverse effects such as dysphoria, social phobia, and anxiety, and nonpsychiatric adverse effects such as extrapyramidal symptoms, acute dystonic reactions, akathisia, hyperprolactinaemia, sedation, and weight gain (Cavanna et al., 2009), which can potentially lead to reduced compliance and drug discontinuation. Moreover, neuroleptic malignant syndrome is another severe iatrogenic complication of treatment with antipsychotic medication in adults and in adolescents. Since the development of atypical antipsychotics, a number of new therapeutic options have become available, and the newest atypical antipsychotic agents could be potential treatment options for tics and the comorbid symptoms associated with TS. 2.1.1 Paliperidone Paliperidone (9-hydroxy-risperidone) is an atypical antipsychotic medication that provides controlled delivery of the major active metabolite of risperidone (Marder et al., 2007; Peuskens, 1995). It is available in an oral extended-release (ER) formulation. Paliperidone ER was approved for treating schizophrenia in 2006, and in 2009, it became the first atypical antipsychotic licensed for treating schizoaffective disorder (Wang et al., 2012). The short-term efficacy, safety, and tolerability of paliperidone ER in

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patients with schizophrenia were demonstrated in three pivotal 6-week, randomized, double-blind, placebo-controlled studies in patients with acute schizophrenia. Paliperidone ER was effective and well tolerated, producing clinically meaningful improvements in personal and social functioning compared to placebo (Davidson et al., 2007; Kane et al., 2007; Marder et al., 2007). Nevertheless, concerns about the propensity of paliperidone to produce metabolic syndrome remain, given that risperidone commonly produces metabolic syndrome at frequencies ranging from 9% to 24% (Saddichha, Ameen, & Akhtar, 2008). Moreover, its long-term use in children and adolescents may increase waist circumference, serum lipid, insulin level, and the Homeostasis Model Assessment Insulin Resistance index (Calarge, Acion, Kuperman, Tansey, & Schlechte, 2009). Also, its rate of extrapyramidal side effects was considerably higher than that of a placebo at doses larger than 9 mg/day. The risks for orthostatic hypotension, prolongation of the corrected QT interval (QTc), and hyperprolactinaemia are also causing concern (Wang, Ree, Huang, Hsiao, & Chen, 2013). The limited evidence suggests that paliperidone ER can potentially be superior to quetiapine and risperidone. However, few direct head-to-head comparisons between paliperidone ER and other antipsychotics have been conducted to confirm these results. The distinctive pharmacological characteristics of paliperidone ER, including smooth fluctuations in plasma drug concentrations, predominantly renal excretion, low risk of causing hepatic impairment, and low drug–drug interaction, might provide important clinical advantages compared to risperidone. However, there is still no evidence regarding its use in patients with TS. 2.1.2 Sertindole Sertindole is an antipsychotic compound with a high affinity for dopamine D2, serotonin 5-HT2A, 5-HT2C, and a1-adrenergic receptors, which has been reintroduced in the market after extended re-evaluation of its safety and risk–benefit profile. Sertindole is generally well tolerated, but is associated with a dose-related QTc interval prolongation (þ22 ms). Risk factors for drug-induced arrhythmia, such as cardiac diseases, congenital long QT syndrome, and prolongated QTc at baseline, and drug interactions should be considered before prescribing sertindole. To minimize cardiovascular risk, regular electrocardiographic recording is required. Sertindole can be an important second-line option for the treatment of schizophrenia in patients intolerant to at least another antipsychotic agent, and potentially could be

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effective in suppressing tics. Up to now, there is no evidence-based information available on this agent in the treatment of TS. 2.1.3 Ropinirole Ropinirole is a nonergolinic dopamine agonist, approved by the Food and Drug Administration of the United States for the treatment of Parkinson’s disease and restless legs syndrome. It can also reduce the side effects caused by selective serotonin reuptake inhibitors (SSRIs), including parkinsonism, and sexual dysfunction. Ropinirole acts as a D2, D3, and D4 dopamine receptor agonist, with the highest affinity for D2. It is weakly active at the 5-HT2- and a2 receptors, and is said to have virtually no affinity for the 5-HT1, benzodiazepine, GABA, muscarinic, a1, and b adrenoreceptors. Side effects include nausea, dizziness, hallucinations, orthostatic hypotension, and sudden diurnal sleep attacks. Unusual side effects specific to D3 agonism can include hypersexuality and compulsive gambling, even in patients without a prior history of these behaviors. There is limited evidence for the use of ropinirole in the treatment of patients with TS. Anca et al. (2004) examined the effects of treatment with ropinirole in 15 subjects with TS over a period of 8 weeks. All patients in this open-label study took ropinirole at doses of 0.25–0.5 mg bid. Most of them showed an improvement in their tics during treatment. However, further (placebo-controlled) studies are necessary to replicate these results. 2.1.4 Pramipexole Pramipexole is a dopamine agonist that could theoretically normalize the suspected central dopamine hyperactivity in TS. A multicenter randomized, placebo-controlled, double-blind clinical trial tested pramipexole given for 6 weeks to 63 children and adolescents with TS (Kurlan et al., 2012). There were no significant differences in the adjusted mean change in the Total Tic Score of the Yale Global Tic Severity Scale (YGTSS) between patients treated with pramipexole (7.16) and those who received the placebo drug (7.17). There were no significant treatment effects on change from baseline in the Global Severity Score of the YGTSS, and on parent- and investigator-scored Clinical Global Impression of Improvement. In patients with comorbid ADHD, an improvement in DuPaul ADHD Scale scores was observed in those receiving pramipexole compared to those receiving placebo. The authors concluded that there was no evidence that pramipexole had efficacy in suppressing tics, but that it might decrease comorbid ADHD symptoms.

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2.2. GABA modulator agents Dysfunction of the GABAergic system in TS may conceivably underlie the symptoms of motor disinhibition presenting as tics and associated behavioral symptoms, such as those of ADHD and OCD. Lerner et al. (2012) found a decreased binding of GABA(A) receptors in TS patients bilaterally in the ventral striatum, globus pallidus, thalamus, amygdala, and right insula. In addition, the GABA-A receptor binding was increased in the bilateral substantia nigra, left periaqueductal gray, right posterior cingulate cortex, and bilateral cerebellum. These results are consistent with the longstanding hypothesis that circuits involving the basal ganglia and thalamus are disinhibited in TS. In addition, the abnormalities in GABA(A) receptor binding in the insula and cerebellum appear particularly noteworthy, based on recent evidence implicating these structures in the generation of tics. It has been hypothesized that, in TS, a decrease in striatal GABAergic projections would cause an insufficient inhibition of excitatory thalamocortical neurons, with the ultimate result being increased glutamatergic cortical excitation and the appearance of tics (Swain et al., 2007). Moreover, studies with TMS have shown that the cortical silent period (i.e., the period of decreased excitability following stimulation) is significantly shortened and the intracortical inhibition is defective in TS patients compared to controls (Ziemann, Paulus, & Rothenberger, 1997). This reduction of intracortical excitability is also frequently seen in children with ADHD in comorbidity with a tic disorder. Because motor cortex lesions are unlikely in TS patients, abnormal intracortical inhibition must be the consequence of a dysfunction of the subcortical input. The authors suggested that reduced activity in inhibitory systems could be one of the factors leading to a reduced suppression of involuntarily triggered movements. If these alterations of the GABAergic system play a role in the pathophysiology of TS, then GABAergic drugs might be expected to improve tics. Thus, drugs such as clonazepam, baclofen, and topiramate have been evaluated in the treatment of tics, with varying results. 2.2.1 Benzodiazepines Some reports suggest that tics may be reduced through the administration of benzodiazepines. Benzodiazepines have good efficacy in the short term, but their use is likely limited by their potential for tolerance and addiction, and their troublesome side effects such as sedation, somnolence, fatigue, confusion, dizziness, drowsiness, hyperactivity, and ataxia (Eddy et al., 2011).

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Medication may cause a paradoxical change in behavior, with increased aggression, hyperexcitability, and irritability (Singer, 2010). Clonazepam is a benzodiazepine that acts as a GABA(A) receptor agonist and an a-2-adrenergic receptor agonist, and upregulates 5-HT1 serotonin receptor binding sites. There are no placebo-controlled trials to date, but small, openlabel trials have shown some benefit over tic control (Dion & Chouinard, 1987). Goetz (1992) reported an improvement in tic symptoms in 71% of patients with TS treated with clonazepam. Of note, improvements have been found to be superior to clonidine in a subsequent study (Drtilkova et al., 1994). However, other studies have reported modest effectiveness (Gonce & Barbeau, 1977; Steingard et al., 1994). Benzodiazepines should always be prescribed with caution, because of the associated changes in tolerance and the potential for addiction. Despite the common side effects of drowsiness, irritability, fatigue, and paradoxical aggression, benzodiazepines may prove useful in selected cases for shortterm relief, and are probably best reserved for patients with significant comorbid anxiety. 2.2.2 Topiramate Topiramate, a fructopyranose derivative, is a GABAergic drug, primarily used as an anticonvulsant, that has been used in recent years to treat tics. It has advantages over antipsychotic drugs in that it carries no risk of tardive dyskinesia or other movement disorders. In a double-blind, placebocontrolled study by Jankovic et al. (2010), the treatment of tics with topiramate in 20 patients with TS demonstrated superiority to placebo, without any difference between the two groups in terms of adverse effects. This study extended a previous observation, based on which topiramate was suggested to be safe and effective for use in moderate to severe TS (Jankovic et al., 2010). Kuo and Jimenez-Shahed (2010), in a retrospective chart review, showed that topiramate can be used for tics in TS with at least moderate efficacy; typical adverse effects included cognitive/language problems (24.4%, n ¼ 10/41) and aggression or mood swings (9.8%, n ¼ 4/41). However, randomized controlled trials are needed. 2.2.3 Levetiracetam LEV is a broad-spectrum antiepileptic agent that has been used effectively for a variety of seizure types in adults and children, and for different psychiatric disorders (Farooq et al., 2009; Ulloa, Towfigh, & Safdieh, 2009). LEV does not have a direct effect on GABA receptor-mediated responses. A brain-specific binding site for LEV was demonstrated for the first time

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in the brain tissue of rats (Noyer, Gillard, Matagne, He´nichart, & Wu¨lfert, 1995); no specific binding was observed in peripheral tissues. It has been suggested that LEV binds to SV2a, a synaptic vesicle protein found in neurons, and exerts an atypical GABAergic effect by enhancing chloride ion influx at the GABA(A) receptor complex (Lynch et al., 2004). In vitro findings reveal that LEV behaves as a modulator of GABA(A) and glycine receptors, suppressing the inhibitory effect of other negative modulators such as b-carbolines and zinc. LEV inhibits the ability of zinc and b-carbolines to interrupt chloride influx, an effect that enhances chloride ion influx at the GABA(A) receptor complex (Poulain & Margineanu, 2002; Rigo et al., 2002). Several open-label clinical trials have suggested that LEV may be a useful treatment for tics and may have a prolonged beneficial effect (Awaad et al., 2005; Fernandez-Jaen et al., 2009). In a study by Awaad et al. (2005) in 60 children with TS, LEV led to a mean 20% reduction in tics, and improvement on both the YGTSS and CGI measures; 43 patients also improved in behavior and performance in school. Moreover, in a 4-year follow-up study, 49 of 70 patients exhibited improvement after treatment with LEV, which was found to be safe and well tolerated (Awaad, 2007). A highly significant effect was also reported in a case report by Oulis et al. (2008). Recently, Martı´nez-Granero, Garcı´a-Pe´rez, and Montan˜es (2010) reviewed the available clinical trials with LEV, concluding in favor of its potential benefits in alleviating tics and neuropsychiatric disorders. However, two randomized, double-blind, crossover studies involving LEV have provided conflicting evidence with regard to efficacy. Smith-Hicks et al. (2007) administered LEV and placebo for 4 weeks in a crossover study, with a washout period in between the two phases of 2 weeks. Children were aged 8–16 years and had moderately severe tics. Mild reductions in tics were observed for both LEV and placebo, but without different between interventions. Another study (Hedderick et al., 2009) showed that the change in mean total tics score for 10 patients aged 8–27 years who were treated with LEV went from 22.7 to 23.6. Despite initial reports of efficacy, double-blind, randomized trials failed to demonstrate significant improvements in tic severity during treatment with LEV (Roessner et al., 2011). In summary, the established safety profile of LEV makes this drug a treatment alternative in case of intolerance to currently used drugs. The low risk of drug interactions with LEV might be another consideration for patients who require the concurrent use of other medications for the treatment of comorbid conditions. New controlled studies with larger population sizes and over longer durations are necessary to assess the real efficacy of LEV in patients with TS.

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2.2.4 Baclofen The GABA-derivative baclofen has also been investigated as a possible treatment for tics (Scahill et al., 2006). Baclofen is a GABA(B) receptor agonist used in the treatment of spasticity. Its binding reduces the release of the excitatory neurotransmitters glutamine and aspartate. One open-label study evaluated baclofen in a small number of patients and demonstrated no benefit (Shapiro, 1988), while a second study reported a beneficial effect in 95% of children (Awaad, 1999). In a small double-blind, placebo-controlled crossover study, baclofen (20 mg three times daily) showed a statistically significant improvement in the overall impairment score but no reduction in motor or vocal tics (Singer et al., 2001). However, the authors noted that the improvement seemed to be related to decreases in impairment scores rather than in tics per se. No major side effects were reported. 2.2.5 Naloxone Although SSRIs represent the first-line pharmacotherapy for OCD and atypical antipsychotic drugs blocking 5-HT2A receptors are often used in add-on augmentation treatment strategies for this condition, opiate drugs have also shown efficacy in treatment-refractory OCD in comorbidity with a tic disorder. Kurlan et al. (1991) investigated the effect of drugs acting on the endogenous opioid system. They studied 10 adults with TS who received propoxyphene hydrochloride (260 mg/day), naltrexone hydrochloride (50 mg/day), and placebo in a double-blinded, randomized clinical trial. A significant decrease in tics was observed after treatment with naltrexone, compared to placebo. These findings indicate that pharmacological manipulation of the endogenous opioid system does influence symptoms of TS. Other authors replicated these earlier findings and showed that naloxone had opposite effects on tics at different dosages. Low doses led to a significant decrease in tics, whereas high doses caused a significant increase in tics. Therefore, activity at opioid receptors appears to influence the expression of TS, and the difference in response to naloxone in TS subjects may be based on a dose-response effect (van Wattum et al., 2000). Recently, Rojas-Corrales, Gibert-Rahola, and Mico (2007) explored whether 5-HT2A-related behavior is affected by atypical opiate drugs. In this study, a head-twitch response was induced in mice by the administration of either 5-hydroxytryptophan (5-HTP) or a 5-HT2A/C agonist. Dose-effect curves of atypical opiate drugs (tramadol, methadone, and levorphanol), morphine, and other psychoactive drugs (fluvoxamine, desipramine, nefazodone, and clozapine) were performed. Opioid mechanisms

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were investigated by the administration of naloxone. They found that combined 5-HT and opioid properties result in a greater efficacy in antagonizing 5-HT2A-related behavior. These results provide behavioral evidence to support the convergent effects of the 5-HT and opioid systems in discrete brain areas, offering the potential for therapeutic advances in the management of refractory stereotypies and compulsive behaviors.

2.3. Selective norepinephrine reuptake inhibitors SSRIs (atomoxetine) and stimulants (methylphenidate) could be used for the treatment of TS and comorbid ADHD (Rizzo, Gulisano, Calı`, & Curatolo, 2013). Atomoxetine is a nonstimulant drug used to treat ADHD (Perwien et al., 2006) that acts as a presynaptic blocker of noradrenalin reuptake (Swanson et al., 2006). A post hoc analysis of a double-blind, placebocontrolled study showed that atomoxetine was effective in treating both tics and ADHD symptoms; nausea, and a decreased appetite and decreased body weight were reported as the most common adverse effects (Allen et al., 2005). Rippel et al. (2006) evaluated 110 TS patients with and without ADHD for the association of the norepinephrine transporter gene (SLC6A2) with two single nucleotide polymorphisms, a T182C single nucleotide polymorphism located in the 50 flanking promoter region and a silent mutation (G1287A) occurring in exon 9. No association was identified between either of the two polymorphisms and TS/ADHD. In a small subset, SLC6A2 polymorphisms did not predict the therapeutic response to atomoxetine. Further research on other polymorphisms of the same gene using larger sample sizes are indicated in the pursuit of biomarkers for therapeutic responders.

2.4. S5aR and other neuroactive agents The enzyme S5aR catalyzes the conversion of D4-3-ketosteroid precursors— such as testosterone, progesterone, and androstenedione—into their 5areduced metabolites. Although the current nomenclature assigns five enzymes to the S5aR family, only types 1 and 2 appear to play an important role in steroidogenesis, mediating an overlapping set of reactions, albeit with distinct chemical characteristics and anatomical distribution. The discovery that the 5a-reduced metabolite of testosterone, 5a-dihydrotestosterone, is the most potent androgen and stimulates prostatic growth led to the development of S5aR inhibitors with a high efficacy and tolerability. Two of these agents, finasteride and dutasteride, have received official approval for the treatment

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of benign prostatic hyperplasia and are being tested for the prevention of prostate cancer. Over the last decade, converging lines of evidence have highlighted the role of 5a-reduced steroids and their precursors in brain neurotransmission and behavioral regulation. Some authors have recently investigated the role of S5aR in neuropsychiatric disorders and found that S5aR inhibitors may elicit therapeutic effects in a number of disorders associated with dopaminergic hyperreactivity, including psychotic disorders, TS, and impulse control disorders (Paba et al., 2011).

2.5. Currently ongoing trials In the last years, the scientific community has emphasized the critical need for the testing and development of new pharmacotherapy for tic suppression in TS. There are some ongoing trials on different medications (see ClinicalTrials.gov). In a pilot study, some authors investigated the safety, tolerability, and efficacy of two medications that modulate glutamate neurotransmission: riluzole and D-serine. The rationale of this research is that glutamate is an essential component of the pathways implicated in TS and an extensive modulator of dopamine, the major neurotransmitter associated with tics. Riluzole is a drug commonly used to treat amyotrophic lateral sclerosis. It preferentially blocks the TTX-sensitive sodium channel, reduces the influx of calcium ions, and indirectly prevents the stimulation of glutamate receptors (glutamate antagonist) (Song, Huang, Nagata, Yeh, & Narahashi, 1997). However, the action of riluzole on glutamate receptors has been controversial, as no binding of the molecule has been shown on any known receptor (Wokke, 1996). D-Serine, synthesized in the brain by serine racemase from L-serine, serves as both a neurotransmitter and a gliotransmitter by coactivating N-methyl-D-aspartate receptors (NMDAr), making them able to open if they bind glutamate. D-Serine is a potent agonist at the glycine site of the NMDA-type glutamate receptor. It is a more potent agonist at the glycine site on the NMDAr than glycine itself (Mothet et al., 2000). Both riluzole and D-serine have been proposed as treatments for tics and obsessive-compulsive behaviors. On the basis of changes in brain neurotransmitters, in particular dopamine, being critically involved in TS, some authors are now focusing their attention on Ecopipam, a selective antagonist of the D1-type receptors. This is a synthetic benzazepine derivative drug that acts as a selective dopamine D1/D5 receptor antagonist, with little affinity for either dopamine D2-like or

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5-HT2 receptors (Chipkin et al., 1988). It has sedative, antipsychotic, and anorectic effects, and was researched for human use although never approved for medical prescription, mainly because of side effects such as depression and anxiety (Astrup et al., 2007; Hou & Schumacher, 2001). Moreover, two studies are assessing the safety and efficacy of two medications indicated for treating Parkinson’s disease, pramipexole (a dopamine agonist of the nonergoline class) and pergolide (an ergoline-based dopamine receptor agonist), in young TS patients. Other pharmacological treatments under examination include new a-2-agonist medications and Nacetylcysteine (NAC), a natural supplement that acts as an antioxidant and glutamate-modulating agent. NAC has been used safely for decades and the only side effect commonly seen is nausea. NAC has recently been demonstrated to be effective in a double-blind, placebo-controlled trial in adults with trichotillomania (Grant, Odlaug, & Kim, 2009). In other trials, NAC showed some efficacy in diverse psychiatric conditions such as bipolar depression, schizophrenia, and cocaine dependence. Recently, some investigators conducted a trial to determine if NAC is an effective treatment for tics.

3. POTENTIAL AND EMERGING NONPHARMACOLOGICAL TREATMENTS Emerging areas of research in TS concern brain morphometry and immature and anomalous patterns of functional connectivity of various brain regions. Longitudinal studies of the trajectories of brain growth are currently under way to discover how the structure of the brain may change over time. Longitudinal functional magnetic resonance imaging studies are also needed to determine how the regional connectivity may change depending on the course and outcome of the disorder (Leckman, 2012). Besides the surgical techniques involving deep brain stimulation (DBS) (Mu¨ller-Vahl, 2013), recent studies included ECT and repetitive TMS.

3.1. Electroconvulsive therapy ECT is most often applied to treat depressive disorders. However, few case reports have documented the technique’s potential effectiveness in treating TS (Eddy et al., 2011). Six single case reports to date (Dhossche et al., 2010; Karadenizli et al., 2005; Rapoport et al., 1998; Strassnig et al., 2004; Trivedi et al., 2003) have reported beneficial effects, despite these patients having

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had quite a complex clinical presentation with several comorbidities (depression: n ¼ 2; catatonia: n ¼ 2; OCD: n ¼ 1; self-injurious behavior: n ¼ 1). ECT could have a less specific therapeutic effect in TS by altering stress levels, or could indirectly reduce dopamine levels by increasing serotonin (Bloch, 2008). However, it remains to be seen whether this approach can be effective in ameliorating tics in pure TS. In addition, no data is available to support the usefulness of this approach in adolescents and it is unlikely to be appropriate for use in children. Recently, Dehning et al. (2011) documented the first 5-year long-term ECT with full remission from severe TS. The limitations of this approach also include side effects such as short-term memory problems and the benefits may not be durable. Until better controlled studies are conducted, this approach might probably be restricted to cases with comorbid severe depression.

3.2. Repetitive TMS A few preliminary studies investigating the therapeutic effectiveness of repetitive transcranial magnetic stimulation (rTMS) have reported a favorable outcomes in TS patients (Mantovani et al., 2007, 2006). Mantovani et al. (2006) showed that rTMS over the supplementary motor area (SMA) on both hemispheres led to an average of 67% reduction in tic severity or complete symptom remission. Treatment also resulted in reduced scores on scales assessing depression and OCSs and the therapeutic effects were present even after 3 months. A recent open-label 12-week pilot study that assessed the efficacy of rTMS in young TS patients (mean age 11.2  2.0 years) showed an improvement in tic symptoms without side effects or worsening of ADHD, and without depressive or anxiety symptoms. Low-frequency rTMS over the SMA appears to be effective in children with TS (Kwon et al., 2011). Other authors showed that a single session of TBS in children appears to be safe and well tolerated (Wu et al., 2012). Moreover, Le et al. (2013) found that 1 Hz rTMS of the SMA can improve clinical symptoms in children with TS for at least 6 months. However, several studies of rTMS, using stimulation frequencies ranging between 1 and 15 Hz and targeting premotor and motor areas, showed only minimal success in suppressing tics. Munchau et al. (2002), in a single-blind, placebo-controlled crossover repetitive trial involving 12 patients who received 1 Hz rTMS over the motor and premotor cortex, reported no significant improvement in tics, obsessions, or compulsions.

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Echophenomena are common in patients with TS. The SMA has been shown to be overactive before the onset of tics in these patients, and it is possible that this area might also play a key role in the generation of echopraxia. Finis et al. (2012) evaluated whether echophenomena can also be evoked in healthy controls by modifying the neural activity of this cortical region. They modulated the activity of the SMA in 30 healthy controls by rTMS, using both 5 Hz (which can temporarily increase neural activity) and 1 Hz (which disrupts or reduces cortical activity) frequencies of stimulation. Their results showed an increase in echophenomena following a 5 Hz stimulation, but no effect following a 1 Hz stimulation. This finding implies that the SMA is a relay mediating echophenomena. Further controlled studies are needed to determine the effectiveness of rTMS, especially for treating more severe tics. The advantages of this technique include fewer and milder side effects (e.g., headache) than in other approaches such as DBS or ECT, and no anesthesia is involved. Drawbacks include the likelihood of a purely ephemeral benefit and the fact that this approach requires multiple treatment sessions (Bloch, 2008).

4. CONCLUSION The breadth of the phenomenological spectrum of TS and the variability of presentation across patients are common challenges for the effective treatment of this condition (Eddy et al., 2011). Alternative strategies are now becoming available for refractory TS patients, but the concept of treatment refractoriness has not been sufficiently well characterized to date (Porta et al., 2011). Two sets of guidelines have been published critically evaluating the available evidence and expressing the views of the TS experts in Europe (Roessner et al., 2011) and Canada (Pringsheim et al., 2012). Few doubleblind, controlled trials specifically focusing on the efficacy and tolerability of medications are available (e.g., the use of more recently developed and promising pharmacological options, such as aripiprazole, is based almost entirely on case series and open-label studies). The patchy evidence for rational pharmacotherapy in TS is reflected in the off-label status of a number of agents that are routinely used to treat patients with TS, both in pediatric and adult settings. Multicenter collaborative pharmacological trials of both existing and new pharmacological agents are needed. Severe intractable cases might need a referral to specialist centers to consider the possibility of using DBS, ECT, or rTMS.

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