Invited review

Pharmacological treatment of tic disorders and Tourette Syndrome

Veit Roessner
a,
*
, Katja Schoenefeld
a
, Judith Buse
a
, Stephan Bender
a
, Stefan Ehrlich
a
,
Alexander Mnchau
b
a
Department of Child and Adolescent Psychiatry, University of Technology Dresden, Fetscherstrasse 74, 01307 Dresden, Germany
b
Department of Neurology, University Medical Centre Hamburg-Eppendorf (UKE) Hamburg, Martinistrae 52, 20246 Hamburg, Germany
a r t i c l e i n f o
Article history:
Received 27 February 2012
Received in revised form
11 May 2012
Accepted 28 May 2012
Keywords:
Tics
Tic disorders
Tourette Syndrome
Pharmacologic
Pharmacotherapy
Treatment
a b s t r a c t
The present review gives an overview of current pharmacological treatment options of tic disorders and
Tourette Syndrome (TS). After a short summary on phenomenology, clinical course and comorbid
conditions we review indications for pharmacological treatment in detail. Unfortunately, standardized
and large enough drug trials in TS patients fullling evidence based medicine standards are still scarce.
Treatment decisions are often guided by individual needs and personal experience of treating clinicians.
The present recommendations for pharmacological tic treatment are therefore based on both scientic
evidence and expert opinion. As rst-line treatment of tics risperidone (best evidence level for atypical
antipsychotics) or tiapride (largest clinical experience in Europe and low rate of adverse reactions) are
recommended. Aripiprazole (still limited but promising data with low risk for adverse reactions) and
pimozide (best evidence of the typical antipsychotics) are agents of second choice.
In TS patients with comorbid attention decit hyperactivity disorder (ADHD) atomoxetine, stimulants
or clonidine should be considered, or, if tics are severe, a combination of stimulants and risperidone.
When mild to moderate tics are associated with obsessiveecompulsive symptoms, depression or anxiety
sulpiride monotherapy can be helpful. In more severe cases the combination of risperidone and
a selective serotonin reuptake inhibitor should be given.
In summary, further studies, particularly randomized, double-blind, placebo-controlled trials including
larger and/or more homogenous patient groups over longer periods are urgently needed to enhance the
scientic basis for drug treatment in tic disorders.
This article is part of the Special Issue entitled Neurodevelopmental Disorders.
2012 Elsevier Ltd. All rights reserved.
1. Introduction
Tics are sudden, rapid, non-rhythmically recurrent, mainly
involuntary movements (motor tics) and/or sounds (vocal/phonic
tics). Single tics are indistinguishable from spontaneous move-
ments but occur misplaced in context and time (Paszek et al., 2010).
They are typically preceded by premonitory sensations including an
urge to move. Onset age is between four and eight years in most
cases. In addition to large inter-individual variations tic frequency,
severity, localization, complexity etc also vary intra-individually
over time. Commonly they are exacerbated by emotional tension,
stress, anxiety, and fatigue. Concerning the longer-term course
there is a risk for chronication (dened as the presence of tics for
more than a year) in a considerable proportion of affected children.
On the hand, tics improve or remit independently of treatment in
late adolescence or early adulthood in most patients (Schlander
et al., 2011). Therefore, in the majority of patients with chronic
tics psychoeducation and reassurance of patients and their families
followed by a watch and wait strategy is often sufcient. Patient
education and counseling foster acceptance of tics, reduce stress
and prevent stigmatization (Verdellen et al., 2011).
Tourette Syndrome (TS)
1
is a chronic tic disorder characterized
by at least one phonic and several motor tics present for more than
one year with onset before the age of 18. All tic disorders are more
common in boys (male/female ratio of about 4:1). The prevalence of
tic disorders varies between 10 and 15% for transient tics, about
3e4% for chronic motor or chronic vocal/phonic tics to 1% for TS
(Robertson, 2008).
For the expert it is usually straightforward to diagnose TS
because the diagnosis is quite categorical e tics yes or no (Paszek
* Corresponding author. Tel.: 49 351 458 2244; fax: 49 351 458 5754.
E-mail address: veit.roessner@uniklinikum-dresden.de (V. Roessner).
1
The term Tourette Syndrome (TS) is used to cover all tic disorders unless
otherwise stated.
Contents lists available at SciVerse ScienceDirect
Neuropharmacology
j ournal homepage: www. el sevi er. com/ l ocat e/ neuropharm
0028-3908/$ e see front matter 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.neuropharm.2012.05.043
Neuropharmacology 68 (2013) 143e149
et al., 2010). For detailed clinical assessment of tic disorders and
their comorbidities there are guidelines for both children and
adults (see Cath et al., 2011).
Most TS patients also suffer from comorbid conditions such as
attention decit hyperactivity disorder (ADHD),
obsessiveecompulsive disorder or depression (Roessner et al.,
2007; Wanderer et al., 2012). These comorbidities are often more
bothersome than having tics. Tics and associated problems can
have a signicant impact on patients daily functioning across many
domains. Therefore, to tailor treatment adequately it is essential to
take possible coexisting conditions into account (Greimel et al.,
2011).
Unfortunately, until now clinical course and prognosis of tics
cannot be predicted at a given point in time so that treatment
decisions have to be individualized. In addition, there is still no
evidence that pharmacological treatment has a positive effect onthe
clinical course. Generally, compared to behavioral treatment
options, pharmacotherapy is more effective and acts faster.
However, so far there are no studies directly comparing the efcacy
of pharmacological and behavioral treatment (Roessner et al., 2011).
2. Indications and general rules for pharmacological
treatment
As pointed out above, many affected children, adolescents and
adults do not seek and/or do not require pharmacological treat-
ment because their tics are mild to moderate, transient and do not
impair social functioning. When persisting tics impact on quality of
life, social and academic functioning and lifetime activities phar-
macological treatment should be considered either at rst referral
or later in the course, particularly in the following scenarios
(Roessner et al., 2011).
2.1. Tics cause sustained social problems (e.g. social isolation or
bullying)
Tics cause social impairment in some but not all affected
persons and sometimes only for some days. Hence, it is important
to assess the extent of social problems in some detail. Particularly,
persistent complex motor tics and loud vocal/phonic tics can cause
problems including social isolation, bullying or stigmatization.
Noisy tics can disrupt classes and distract others. However, friction
and conicts, social sanctions and isolation are more often caused
by coexisting conditions, particularly ADHD, than by tics (Debes
et al., 2009). Often, but not always, counseling and education of
patients, peers, and teachers reduce tension and stigma and
increase acceptance to such an extent that medical treatment is no
longer needed.
2.2. Tics cause emotional problems (e.g. reactive depressive
symptoms)
Up to 20e30% of TS patients have a major depressive disorder
(Snijders et al., 2006). Subclinical depressive and/or anxious
symptoms, low self esteem and/or social withdrawal, driven by
social sanctions, are even more common. Such problems may arise
solely because of tics, comorbid disorders or both (Zinner et al.,
2012).
2.3. Tics cause subjective discomfort (e.g. pain or injury)
Pain in TS can be musculoskeletal due to repetitive non-
physiological movements, e.g. neck extension, arm stretching, or,
in rare cases, caused by self inicted injuries (Krauss and Jankovic,
1996). Some patients produce pain deliberately because this
relieves tics (Riley and Lang, 1989). Tic suppression can lead to
increasing inner tension, discomfort and ultimately pain. Some
patients report that their tics cause or aggravate headaches (Kwak
et al., 2003). To reduce the risk of further injuries and minimize the
use of analgetic medication, pharmacological tic reduction should
be considered.
2.4. Tics impair performance (e.g. academic achievements)
Bouts of tics can delay homework. They can also interfere with
falling asleep or disrupt sleep leading to hypoarousal during the day
(Gilbert, 2006). Frequent phonic tics can impair speech and hence
communication. Additionally, tics can impair academic achieve-
ments e.g. by loosing the line because of frequent eye rolling tics.
Also, many children with TS try to suppress their tics in the class-
room. This may lead to inattention correlating negatively with
academic performance (Kurlan et al., 2001).
It should be borne in mind that any psychopharmacological
treatment can reduce but not cure tics which should be commu-
nicated with the patient and their families to prevent disappoint-
ment and frustration fueled by unrealistic expectations. Medication
can reduces tic symptoms by 25%e50%. Over-medication driven
by the belief that higher dosages will necessarily be more
effective can cause signicant adverse reactions, particularly
sedation, apathy or weight gain. The aim of pharmacological
treatment is to ameliorate tics and improve psychosocial
functioning with as few adverse reactions as possible.
3. Pharmacological treatment e rationale options and
adverse reactions
Genetic studies have not detected unequivocal disturbances in
certain metabolic pathways in TS patients. Drug trials, imaging
studies and analyses of human samples (e.g. cerebrospinal uid,
blood, urine, post-mortem brain tissue) led to several hypotheses
on neurochemical abnormalities in TS (Harris and Singer, 2006)
including imbalances in noradrenergic, glutamatergic, serotonin-
ergic, opioid, cholinergic, and Gamma-aminobutyric acid (GABA)-
ergic systems (Swain et al., 2007). The most common and generally
accepted hypothesis though relates to dopaminergic dysfunction. It
is based on neurophysiological and -imaging studies, some
randomized controlled trials (RCT) and broad clinical experience
with dopamine blocking agents (Bloch et al., 2011). For instance,
abnormalities of dopamine transporter binding capacity (Cheon
et al., 2004; Serra-Mestres et al., 2004; Singer et al., 1991; Yeh
et al., 2006, 2007) and increases of cortical (Minzer et al., 2004;
Yoon et al., 2007) and striatal (Wong et al., 1997) dopamine
receptors have been reported. Hence, the main rationale of phar-
macological treatment in TS is the use of drugs which modulate the
dopaminergic system, above all through blockage of post-synaptic
D2-receptors. However, there is little doubt that in addition to the
dopaminergic system other neurotransmitter systems, e.g. seroto-
nergic pathways (Muller-Vahl et al., 2005; Steeves et al., 2010), also
play an important role in the pathophysiology of TS and comorbid
disorders.
This notwithstanding, antidopaminergic, i.e. antipsychotic
drugs, achieve the most reliable and fastest treatment response
compared to other medication and are therefore the mainstay of
any pharmacological treatment. In most cases, they are associated
with acceptable adverse reactions including drowsiness (particu-
larly occurring in the dosing phase) and increased appetite result-
ing in weight gain. However, the latter can be a long-term problem.
In a minority of patients, excessive sedation, mental slowing and
considerable cognitive impairment occur. Further possible adverse
reactions are extrapyramidal symptoms, in particular parkinsonism
V. Roessner et al. / Neuropharmacology 68 (2013) 143e149 144
and mild akathisia. Tardive dyskinesia is extremely unusual in TS
(Muller-Vahl and Krueger, 2011). Hyperprolactinemia is relatively
common and can be associated with amenorrhea, galactorrhea and
gynecomastia. It is reversible, after dose reduction or cessation of
treatment. The risk of neuroleptic malignant syndrome also exists
in TS, but is very low (Robertson and Stern, 2000).
The risk and spectrum of adverse reactions of antipsychotics in
TS has only rarely been studied systematically. Most information
about adverse reactions derived for antipsychotic treatment studies
in patients with schizophrenia. However, compared to schizo-
phrenia, mean dosages are lower and treatment duration shorter in
TS. Also, as pointed out above, some adverse reactions like tardive
dyskinesias are typical and bothersome in schizophrenia but are
very rare or non-existent inTS. Therefore, the antipsychotic adverse
reaction prole in patients with schizophrenia cannot be extrapo-
lated to the TS population.
In the group of typical antipsychotic drugs, pimozide (Sallee
et al., 1997) and uphenazine (Borison et al., 1983) may be
equally effective as haloperidol but have fewer adverse reactions. In
TS patients, untoward effects after intake of atypical antipsychotics
are quite similar to those induced by typical antipsychotics
(Roessner et al., 2011).
The use of benzamides is associated with fewer and less severe
adverse reactions compared to other antipsychotics. Extrapyra-
midal adverse reactions are very uncommon. For instance, tiapride
is well tolerated. Of note, it has been recommended for the treat-
ment of tardive dyskinesia (Dose and Lange, 2000).
The alpha-2-adrenoreceptor agonists clonidine or guanfacine
are further alternatives with a low risk of adverse reactions but
more promising efcacy in cases of TS and comorbid ADHD than in
pure TS (Weisman et al., in press). Sedation and hypotension often
limit higher dosages sometimes necessary for sufcient tic control.
Compared to clonidine, guanfacine has longer lasting effects so that
fewer dosages per day are required. Also, sedation and hypotension
are less of a problem. Because of possible rebound hypertension
associated with abrupt discontinuation of this medication it is
advisable to regularly monitor blood pressure (Jankovic and Kurlan,
2011). This notwithstanding, the recently published Canadian
guidelines made strong recommendations for both alpha-2-
adrenoreceptor agonists clonidine and guanfacine (children only).
These authors made weak recommendations for other agents like
pimozide, haloperidol, risperidone, aripiprazole, quetiapine,
ziprasidone, botulinum toxin injections and tetrabenazine,
primarily because of high rates of adverse reactions accompanied
with these medications (Pringsheim et al., 2012).
4. Pharmacological treatment e the choices
4.1. Cochrane reviews
The most recent Cochrane review analyzed all randomized,
controlled, double-blind studies were the effect of atypical anti-
psychotics was compared with placebo (Pierce and Rickards, in
press). There were only three studies fullling these criteria e
two where risperidone and one where ziprasidone was tested. In
one trial risperidone was unambiguously more effective than
placebo (although the 95% condence intervals were large). In the
other two trials, however, there were no signicant differences
between risperidone/ziprasidone and placebo. Adverse effects of
risperidone included weight gain and extrapyramidal symptoms.
The Cochrane reviewof Pringsheimand Marras (2009) included six
randomized controlled trials on pimozide in TS. In total, 162 people
were included with an age-range of 7e53 years. Pimozide was
compared with risperidone (two trials), haloperidol (one trial),
haloperidol and placebo (two trials), and placebo (one trial). The
two studies that compared pimozide and risperidone reported no
signicant differences in terms of tic reduction or adverse reac-
tions. In contrast to haloperidol, pimozide had fewer adverse
reactions but was also slightly less effective. Additionally, the
studies revealed that pimozide was more effective than placebo.
Curtis et al. (2009) examined the effectiveness of Delta 9-
tetrahydrocannabinol (Delta 9-THC) in treating TS. They included
28 TS patients (age ranged from 18 to 68 years) from one double-
blind, parallel group trial and one double-blind, crossover trial in
their Cochrane review. They reported positive effects on tic severity
and tic frequency but these were small and only present in selected
outcome measures of tic severity. Taken together, these Cochrane
reviews highlight that the evidence for the usefulness and safety of
the drugs studied is small and variable and does not allow rm
recommendations.
4.2. Selected agents
In the following section, the most relevant substances to treat
tics in clinical practice are reviewed. A comprehensive review of
studies on the pharmacological treatment of TS including a number
of drugs not mentioned here has recently been published on behalf
of the European Society for the Study of Tourette Syndrome (ESSTS)
(Roessner et al., 2011). For an overview see Table 1.
4.2.1. Noradrenergic agents
Clonidine and guanfacine are a-2-adrenergic agonists. Both are
used more commonly in Anglo-American countries as rst line
treatment for mild to moderate tics (Singer, 2010). The notion that
guanfacine might be better-tolerated than clonidine is not undis-
puted because there is no study directly comparing these drugs
(Sandor, 2003).
The most common adverse reactions are fatigue, sedation,
dizziness, drowsiness, depression, headache, irritability, confusion,
hypotension, constipation and dry mouth (Du et al., 2008). Some
authors report that adverse effects are mild and self-limited
whereas others have a more critical view on this (Goetz, 1992;
Hedderick et al., 2009; Lichter and Jackson, 1996).
Because there are only few clinical studies assessing the effects
of guanfacine with heterogeneous patient samples the role of
guanfacine in the treatment of tics remains somewhat unclear
(Scahill et al., 2006). The initial dose of guanfacine is 0.5 mg at
bedtime. Every 5e7 days the dose should be increased by 0.5 mg, to
a maximum dose of 4 mg/day either in a once daily or twice-a-day
regime. It is important to note that guanfacine is not on the market
in many European countries.
Surprisingly, although clonidine has been used for at least
three decades the number of controlled studies of clonidine in TS
is also low. One small, single-blind and randomized study
(subjects aged 7e17 years) of Gaffney et al. (2002) showed similar
effectiveness of clonidine and risperidone. However, there is little
doubt that clonidine and guanfacine have smaller tic-suppressing
potency than antipsychotic drugs (Robertson, 2000). Further-
more, a-2-adrenergic agonists are mostly used in patients with
tics and ADHD. A recent meta-analysis of Weisman et al. (in press)
conrmed this assertion because tic reduction was present in
children with comorbid ADHD but not those without. Clonidine
should be started gradually with an initial dose of 0.05 mg,
preferentially at bedtime to avoid day time fatigue, sedation,
dizziness and drowsiness. However, in view of the short half-life
of about 6 h, a twice-a-day regimen or even more daily dosages
are often needed. The maximum dose should not exceed
0.3e0.4 mg/day.
The selective noradrenergic reuptake inhibitor atomoxetine is
used successfully to treat ADHD (Cheng et al., 2007). In the study of
V. Roessner et al. / Neuropharmacology 68 (2013) 143e149 145
Spencer et al. (2008) atomoxetine reduced both ADHD symptoms
and tics in children (7e17 years old) with ADHD TS. In viewof its
different mode of action it is not surprising that patients with
ADHD who do not respond to stimulants may respond to
atomoxetine. Adverse reactions of atomoxetine include reduced
appetite, nausea and vomiting and insomnia.
The optimal therapeutic dosages for ADHD treatment lies
between 0.5 and 1.2 mg/kg body weight, but there is no TS-specic
dosage information.
4.2.2. Benzamides
The two benzamide agents, tiapride and sulpiride, are commonly
used in Europe (Roessner et al., 2011). For tiapride there are reports
on successful treatment of TS (Drtlkov, 1996; Klepel et al., 1988;
Mathe et al., 1978; Pasquier and Pouplard, 1977) and a few placebo-
controlled studies comprising small samples (Chouza et al., 1982;
Forner-Valero et al., 1986). There is only one randomized, double-
blind, placebo-controlled crossover study in 17 children (Eggers
et al., 1988). The authors found a signicant reduction in tic
symptoms under tiapride treatment. The main adverse reactions
are weight gain, drowsiness as well as moderate transient hyper-
prolactinemia. Tiapride has no inuence on childrens cognitive
performance and neurophysiological parameters. Also, it does not
inuence the neurosecretory, hypothalamic-hypophyseal regula-
tion of sex hormones, thyroid stimulating hormone, growth
hormone or thyroid hormone. This, together with its favorable
benet-to-risk ratio, is the basis of recommendations for tiapride as
rst line treatment of TS in Europe.
The daily dose of tiapride ranges between 100 and 900 mg; the
maximum dose should not exceed 2e10 mg/kg body weight; in
higher doses a division into several daily doses can be helpful.
Positive effects on tics were also reported for sulpiride
(Robertson and Stern, 2000). Sulpiride has antidepressive and
mood stabilizing potential (Mauri et al., 2008), and can have posi-
tive effects on obsessiveecompulsive symptoms with or without
tics (Sevincok et al., 2000).
Most common adverse reactions are drowsiness, sedation,
restlessness, sleep disturbances and depression (Robertson et al.,
1990; Ruther et al., 1999). Further adverse reactions, such as dry
mouth, nausea, activation or sedation, insomnia, allergic rash and
sweating, are infrequent. Patients (pre-menopausal women) also
reported on increased appetite leading to weight gain (Baptista
et al., 1997); galactorrhea/amenorrhea caused by a strong stimu-
lation of Prolactin-secretion by sulpiride can also occur.
The initial dose of sulpiride is 50e100 mg/day (2 mg/kg body
weight); the maximum dose should not exceed 2e10 mg/kg body
weight (if necessary intake in three daily doses).
4.2.3. Typical antipsychotics
Data on the effectiveness and rate and severity of adverse
reactions of haloperidol and pimozide are variable. These were the
rst typical neuroleptics shown to be effective in placebo-
controlled trials in TS.
A double-blind, 24-week, placebo-controlled, randomized,
double-crossover study of haloperidol with a mean dose of 3.5 mg/
day and pimozide with a mean dose of 3.4 mg/day in 22 children
and adolescents (age range between of 7e16 years) found that
haloperidol did not have any signicant effect on tics (Sallee et al.,
1997). On the other hand, pimozide was signicantly more effective
than placebo to reduce tics. In comparison to pimozide, haloperidol
produced a threefold higher frequency of serious adverse reactions
and signicantly greater extrapyramidal symptoms.
Adverse reactions of haloperidol and pimozide include extrapy-
ramidal symptoms, particularly dystonia, akathisia, and parkin-
sonism, and hyperprolactinemia with all its consequences
(galactorrhea, gynecomastia, irregular menses and sexual
Table 1
Most common and important medication for pharmacologic treatment of Tourette Syndrome and other chronic tic disorders (see Roessner et al., 2011).
Medication Indication Start dosage (mg) Therapeutic
range (mg)
Frequent adverse reactions Physical examinations e at start and at control Level of
evidence
Alpha-adrenergic agonists
Clonidine ADHD/TS 0.05 0.1e0.3 Orthostatic hypotension,
sedation, sleepiness
Bloodpressure, ECG A
Guanfacin ADHD/TS 0.5e1.0 1.0e4.0 Orthostatic hypotension,
sedation, sleepiness
Bloodpressure, ECG A
Typical neuroleptics
Haloperidol TS 0.25e0.5 0.25e15.0 EPS, sedation, increased appetite Bloodcount, ECG, weight, transaminases,
neurologic status, prolactine
A
Pimozide TS 0.5e1.0 1.0e6.0 EPS, sedation, increased appetite Bloodcount, ECG, weight, transaminases,
neurologic status, prolactine
A
Atypical neuroleptics
Aripirazole TS 2.50 2.5e30 Sedation, akathisia, EPS, headache,
increased appetite (less than other
neuroleptics), orthostatic hypotension
Bloodcount, bloodpressure, weight, ECG,
transaminases, bloodsugar
C
Olanzapine TS/OCB 2.5e5.0 2.5e20.0 Sedation, increased appetite, akathisia Bloodcount, bloodpressure, ECG, weight,
electrolytes, transaminases, prolactine,
bloodlipids-and sugar
B
Quetapine TS 100e150 100e600 Sedation, increased appetite, agitation,
orthostatic hypotension
Bloodcount, bloodpressure, ECG, weight,
electrolytes, transaminases, prolactine,
bloodlipids-and sugar
C
Risperidone TS/DBD 0.25 0.25e6.0 EPS, sedation, increased appetite,
orthostatic hypotension
Bloodcount, bloodpressure, ECG, weight,
electrolytes, transaminases, prolactine,
bloodlipids-and sugar
A
Ziprasidone TS 5.0e10.0 5.0e10.0 EPS, sedation Bloodcount, ECG, weight, transaminases,
prolactine
A
Benzamides
Sulpiride TS/OCB 50e100 (2 mg/kg) 2e10 mg/kg Problems with sleep, agitation,
increased appetite
Bloodcount, ECG, weight, transaminases,
prolactine, electrolytes
B
Tiapride TS 50e100 (2 mg/kg) 2e10 mg/kg Sedation, increased appetite Bloodcount, ECG, weight, transaminases,
prolactine, electrolytes
B
DBD (disruptive behavior disorder), OCB (obsessiveecompulsive behavior), TS (Tourette Syndrome), EPS (extrapyramidal symptoms). Evidence level: A (>2 controlled
randomized trials), B (1 controlled, randomized trial), C (case studies, open trials).
V. Roessner et al. / Neuropharmacology 68 (2013) 143e149 146
dysfunction). Additionally, drowsiness, increased appetite and
anxiety were observed. Given the variable effectiveness, large spec-
trum and relatively high frequency of adverse reactions the use of
typical antipsychotics, particularly in higher doses, should generally
be avoided.
When used the daily doses for haloperidol and pimozide are low
e 1e4 mg/day for haloperidol and 2e8 mg/day for pimozide. The
maximum dose of 5 mg/day for haloperidol and 10 mg/day for
pimozide should not be exceeded.
4.2.4. Atypical antipsychotics
Risperidone is the best examined antipsychotic agent for the
treatment of TS. In comparison to haloperidol and pimozide, ris-
peridone was similarly effective in reducing tics. However, risper-
idone showed less frequent and less severe adverse reactions
(Bruun and Budman, 1996; Diantoniis et al., 1996; Lombroso et al.,
1995; Shulman et al., 1995). Furthermore, compared to clonidine,
risperidone was more effective in patients with TS and comorbid
obsessiveecompulsive symptoms whereas both were equally
effective in the treatment of pure tics (subjects aged 7e17 years)
(Gaffney et al., 2002).
Commonadverse effects include metabolic adverse reactions (e.g.
hyperglycemia and dyslipidemia), fatigue and somnolence, mild to
moderate sedation, hypotension, hyperprolactinemia and weight
gain. In addition, extrapyramidal symptoms were reported but only
rarely. Because of these positive outcomes several experts made this
agent their rst choice (Eddy et al., 2011; Roessner et al., 2011).
The typical mean daily dose of risperidone is 2.5 mg with
a range between 1 and 6 mg/day in a twice-a-day regimen.
Concerning treatment of TS with ziprasidone the base of
evidence is low. Just two studies proved the effectiveness of
ziprasidone in reducing tics (children and adolescents aged 7e16 or
17 years) (Sallee et al., 2000, 2003). Adverse effects are usually mild
and include transient somnolence and sedation as well as
hyperprolactinemia.
The daily dose uctuates between 5 and 40 mg (intake in
divided doses) according to literature information.
In clinical studies, quetiapine reduced tics signicantly (Copur
et al., 2007; Mukaddes and Abali, 2003) (Corpur et al.: patients
aged 8e18 years; Mukaddes and Abali: subjects with a mean age of
11.4 2.4).
Quetiapine should be started with 25e50 mg/day and then
gradually be increased up to 600 mg/day divided in two doses.
Information on adverse reactions is limited. It appears that they are
milder than those of other atypical antipsychotics agents.
Aripiprazole has become a potentially attractive alternative.
Apart from its high antagonistic afnity to the dopamine D2
receptors, aripiprazole also acts as a partial agonist which sets it
apart from other atypical antipsychotics. Good to excellent effec-
tiveness has not only been reported in patients with uncomplicated
tics but also in refractory cases of TS. However, as yet no random-
ized, double-blind, placebo-controlled study has been carried out.
Adverse reactions, such as weight gain, nausea, akathisia and
sedation, were commonly reported but generally aripiprazole was
tolerated reasonably well.
Aripiprazole should be started with 2e2.5 mg/day and then be
increased to a maximum dose of 30 mg/day.
Taken together, many papers with treatment recommendations
mainly advise the use of atypical antipsychotics as rst-line treat-
ment rather than typical antipsychotics (Eddy et al., 2011; Roessner
et al., 2011; Singer, 2010).
4.2.5. Alternatives
Especially US authors mention tetrabenazine in their reviews on
TS (Jankovic and Kurlan, 2011; Kurlan, 2010). Tetrabenazine acts as
a vesicular monoamine-transporter-type 2-inhibitor; presynaptic
dopamine and serotonin stores are depleted and post-synaptic
dopamine receptors are blocked. Hence, tetrabenazine could be an
alternative for antipsychotic drugs.
Some clinical studies on hyperkinetic movement disorders,
including TS patients suggest that tetrabenazine can be useful to
treat tics (Jankovic et al., 1984; Jankovic and Beach, 1997; Paleacu
et al., 2004). However, scientic evidence that this drug is effec-
tive for tic treatment is low (Muller-Vahl and Roessner, 2011).
The adverse reactions of tetrabenazine are dose related and
include depression, akathisia, drowsiness and fatigue as well as
nausea and parkinsonism. Contrary to antipsychotic drugs, weight
gain is uncommon.
In clinical practice 50e150 mg/day in three divided doses are
typically used to treat TS. Higher doses than 200 mg/day should be
avoided.
Tetrahydrocannabinol (THC) has been shown to be effective and
safe in smaller clinical trials (subjects were adults) (Muller-Vahl
et al., 1999, 2002, 2003). Adverse reactions, particularly tiredness,
dizziness and dry mouth were mild. Patients were treated with
doses up to 10 mg/day. TCH might be a good alternative when
combined treatment of TS and comorbid ADHD with stimulants is
required.
In contrast to the previous agents, botulinum toxin injections
have no systemic effect. Botulinum toxin injections temporarily
block neuromuscular transmission and can be very helpful to treat
bothersome or painful focal motor tics, particularly those affecting
neck muscles. Adverse reactions during the treatment with botu-
linum toxin are muscle weakness, increase of premonitory urges or
spread of tics and urges from injected muscles to neighboring body
segments. In addition to a number of promising case reports and
case series (Kwak et al., 2000; patients aged 8e69 years) there is
only one randomized, double-blind controlled clinical trial
(subjects with mean age 31.5; range 15e55 years) (Marras et al.,
2001). These authors found that botulinum toxin injections into
single muscles to treat few motor tics signicantly reduced tic
frequency and premonitory urges. Overall benet for patients was
limited though. On the other hand, individualized treatment of
different muscles using larger botulinum toxin dosages over longer
periods has been shown to be quite effective in an uncontrolled
observational study (Kwak et al., 2000).
It is estimated that botulinum toxin treatment is a suitable
option in about 10e15% of TS patients requiring medical inter-
vention, sometimes as an add-on treatment (Simpson et al., 2008).
5. TS specic problems in assessing treatment effectiveness
Tics in TS wax and wane, over minutes, hours, weeks, months,
and years. Because of these intraindividual uctuations of
frequency, intensity, location and complexity, longer observation
periods are necessary to reasonably assess the effectiveness of
treatment in TS (see Fig. 1) (Roessner et al., 2011).
In addition to the notion of a naturally waxing and waning
course environmental and/or psychosocial factors can have
a modulating inuence on TS independently of pharmacological
treatment. For instance periods of stress, excitement, anxiety, anger
or fatigue can exacerbate tics; periods of concentration or active
engagement can reduce them. This has to be considered, particu-
larly in situations of rating tic severity in the setting of a clinical
trial. In this context the general problemof reliable measurement of
tic severity also has to be considered.
Other confounding factors potentially inuencing effects of
pharmacological treatment are comorbid conditions in TS patients.
Accordingly, the most appropriate drug has to be selected. For
instance, as pointed out above, Weisman et al. (in press) showed
V. Roessner et al. / Neuropharmacology 68 (2013) 143e149 147
that in patients with TS ADHD the a-2-adrenergic agonists
clonidine and guanfacine were much more effective in reducing tic
symptoms than in TS patients without ADHD.
6. Conclusions
Taken together, scientic evidence on pharmacological treat-
ment options of TS is still limited. Only few studies meet rigorous
quality criteria, in terms of their design and methodology. Above all,
the naturally waxing and waning course of tics, the inuence of
environmental factors including stress and the still unresolved
question of measurement of tic severity complicate treatment
studies in TS.
On the basis of available evidence from clinical trials and expert
opinion risperidone and tiapride can be recommended as rst line
treatments if other interventions, such as psychoeducation and
behavioral treatment are not sufcient or not available. Pimozide
(best evidence of the typical antipsychotics) and aripiprazole (very
promising, but fewdata and clinical experiences) can be considered
as second line treatment. In the presence of comorbid ADHD
clonidine, atomoxetine (milder cases) or the combination of ris-
peridone plus stimulants (more severe cases) is recommended.
Sulpiride might be effective in cases with mild to moderate tics
accompanied by obsessiveecompulsive, depressive or anxious
symptoms. For more severe cases the combination of risperidone
and a selective serotonin reuptake inhibitor has to be considered. It
is important to note that apart fromhaloperidol all drugs are use off
label in TS. However, until now there are no studies on poly-
pharmacy in TS.
For high-quality evidence on pharmacological treatment in TS,
future studies should include longer observation periods, larger
groups, a more standardized methodological approach, placebo as
control condition and a double blind design.
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