Antipsychotic agents

Positive effects for D2 dopamine receptor blockers have been reported in the treatment of tics since 40 years (in average a marked decrease of tics in about 70% of cases [237]). Particularly, the blockade of striatal D2 dopamine receptors is thought to lead to reduction of tics. However, a high blockade of the receptors correlates also with the rate of unfavorable adverse reactions, such as extrapyramidal symptoms (EPS) or tardive dyskinesia (TD) [27].

Typical antipsychotics For a long time, placebo-controlled treatment studies in TS have been conducted only to prove the efficacy of the typical antipsychotics, haloperidol and pimozide. In an early randomized, double-blind, placebo-controlled crossover study, both pimozide and haloperidol significantly decreased tic frequency in nine patients with TS [206]. The results of a subsequent randomized, double-blind, placebo-controlled study of the treatment of 57 patients with TS confirmed that both haloperidol and pimozide were more effective than placebo, but haloperidol was slightly more effective than pimozide. Adverse reactions occurred more frequently with haloperidol versus placebo, but the frequency was not significantly different for haloperidol as compared with pimozide [236]. The dosages used in this study ranged from 2 to 20 mg/day for haloperidol and from 2 to 48 mg/day for pimozide. The effect of the medicine with a strong blockade of D2 dopamine receptors reduced tics in up to 80% of the cases [236]. However, in daily clinical practice, lower doses such as 1–4 mg/day for haloperidol and 2–8 mg/day for pimozide are typically used nowadays to treat TS [128, 191, 224].

In a double-blind, 24-week, placebo-controlled, randomized, double-crossover study of more commonly used doses of haloperidol (mean of 3.5 mg/day) and pimozide (mean of 3.4 mg/day) conducted with 22 subjects, aged 7–16 years, pimozide was significantly more effective than placebo in reducing tics, whereas haloperidol failed to have a significant effect. Moreover, haloperidol exhibited a threefold higher frequency of serious adverse reactions and significantly greater extrapyramidal symptoms relative to pimozide [214]. In contrast to several other studies, haloperidol was not superior to placebo, possibly due to the limited study power.

Furthermore, a long-term naturalistic follow-up study (1–15 years) of 33 TS patients treated with pimozide (2–18 mg) or haloperidol (2–15 mg) suggested benefits of pimozide over haloperidol; both drugs produced comparable relief of symptoms at follow-up; significantly, more patients on haloperidol (8 of 17) as compared with those on pimozide (1 of 13) discontinued treatment [218]. In addition, haloperidol produced significantly more acute dyskinesia/dystonia than pimozide.

A third typical antipsychotic, fluphenazine, has been used particularly in the United States for many years to treat TS, though it has merely been studied systematically. In an open-label study that included both children and adults, fluphenazine was effective at doses ranging from 2 to 15 mg/day in 17 of 21 patients [91]. In a naturalistic follow-up of 41 patients, treatment with fluphenazine for at least 1 year was safe and effective [240]. A small controlled study of fluphenazine, trifluoperazine, and haloperidol found similar reduction of tics. However, fluphenazine was better tolerated [25]; haloperidol was associated with more sedation and extrapyramidal adverse reactions.

The high frequency of drowsiness and extrapyramidal-motoric adverse reactions (dystonia, akathisia, pseudo-Parkinsonism, probably due to the strong dopaminergic blockade in the nigrostriatal pathways) limits the use of the typical antipsychotics foremost in higher doses. It has also been reported that akathisia due to antipsychotic agents may worsen the tic symptoms [280]. Moreover, several case reports raised concerns about the risk of treatment with typical antipsychotics to induce tardive dyskinesia [93, 192, 241]. Although, it is difficult to confidently quantify the rates of tardive dyskinesia owing to the limited long-term data available, the risk of this potentially debilitating and treatment-persistent adverse reaction ought to be considered in the choice of treatment [284]. This is important with greater certainty as atypical antipsychotics have shown a significantly lower risk of tardive dyskinesia [155].

Other adverse reactions, e.g., the onset of anxiety [29, 138, 154] or hyperprolactinemia with its adverse reactions, such as gynecomastia, galactorrhea, irregular menses, and sexual dysfunction [205] are more common adverse reactions than tardive dyskinesia. Additionally, during long-term medication with haloperidol, the increased appetite may result in significant weight gain [114].

Benzamides The benzamides (tiapride, sulpiride, and amisulpride) are further selective D2 dopamine receptor antagonists but in contrast to the typical antipsychotics with low (sulpiride) or as good as no (tiapride) antipsychotic action.

In addition to tiapride binding to the supersensitive D2 dopamine receptors in the ventral striatum and parts of the limbic system (Locus coeruleus), a blockade of some serotonergic receptors (5HT3, 5HT4) is assumed. Since the 1970s, there have been reports about successful treatment of TS with tiapride [61, 124, 139, 145, 183]. Several placebo-controlled studies on small sample sizes followed [43, 74]. Only one randomized, double-blind, placebo-controlled crossover study has been published with tiapride (involving 17 children), indicating a significant reduction of tic symptomatology [68]. The main adverse reactions were drowsiness, moderate transient hyperprolactinemia, and weight gain (the maximum was 10 kg during 18 months in two children). Such massive weight gain is rather the exception than the rule, because the mean weight gain was 2–4 kg [151] with the dosage range of 100–900 mg/day. Tiapride had no adverse reactions on children’s cognitive performance. Neither neurophysiological parameters such as the EEG frequency analysis and sensory-evoked potentials were affected by tiapride nor were the neurosecretory, hypothalamic-hypophyseal regulation of the sex hormones, thyroid stimulating hormone, growth hormone, or thyroid hormone impaired. This rather advantageous profile of short- and long-term adverse reactions with doses effectively reducing tics has been proven in rats too [23, 227].

Since 1970 [291], the positive effects on tics have also been reported regularly for the benzamide sulpiride [199]. It is a highly selective D2-dopamine receptor antagonist associated with less extrapyramidal and vegetative adverse reactions than haloperidol [156]. An ongoing discussion focuses on whether that medication possibly has a specific binding in mesolimbic and mesocortical systems. In addition to its mild antipsychotic potency, it has some antidepressant effect in low doses (in particular 50–200 mg daily) as well as a stimulating and anxiolytic effect [176]. In an open-label retrospective review in which 63 out of 114 patients (55%) suffering from TS had been treated with sulpiride [197], worthwhile beneficial effects occurred in 37 patients (59%). In a 14-week, randomized, double-blind, placebo-controlled crossover study trial of fluvoxamine (a specific 5HT reuptake inhibitor) versus sulpiride followed by single-blind combined therapy (4 weeks) in 11 subjects with coexisting obsessive–compulsive disorder and TS [85], sulpiride monotherapy reduced tics and non-significantly improved obsessive–compulsive symptoms. Fluvoxamine, either alone or combined with sulpiride, non-significantly ameliorated tics and reduced obsessive–compulsive symptoms. Just recently in an open-label study with 189 children and adolescents with an average age of 8 years (range 3–15 years), 6 weeks’ treatment with sulpiride improved motor as well as vocal tics. The most commonly encountered adverse reaction was sedation (reported by 16.4%) [100]. Furthermore, in patients suffering from OCD without tics, sulpiride has proven its efficacy [14, 270]. In one case of treating TS with the combination of sulpiride and imipramine, the tics increased [69]. This might be attributed most likely to the reported effects of increase of serotonin associated with increase of tics.

The main adverse reactions of sulpiride treatment are sustained sedation or drowsiness (up to 25%) and, less frequently, depression, despite its antidepressant, drive-normalizing, and mood-brightening potential [197]. Patients have also complained about restlessness and sleep disturbances [209]. Another important problem with sulpiride is a strong stimulation of prolactin-secretion causing galactorrhea/amenorrhea and a commonly observed increased appetite leading to weight gain [12, 105, 281]. Other adverse reactions occur less frequently (hypotension, rarely long-QT syndrome, dry mouth, sweating, nausea, activation or sedation, insomnia, allergic rash, or pruritus). There has only been one case report about tardive dyskinesia in an adult treated with sulpiride for tics (Eapen, Katona et al. 1993).

Successful treatment of TS disorder with amisulpride has been published only in case reports [75, 272].

Atypical antipsychotics Atypical antipsychotics are effective in the treatment of TS too. The best evidence is available for risperidone. We will herein review all atypical antipsychotics in the order of their date of FDA approval for non-TS disorders.

Clozapine, a dibenzodiazepine with 5-HT2A, 5-HT2C, 5-HT3, and weaker D1 antagonist properties, and the first FDA-approved atypical antipsychotic agent (FDA approval: 1990), has not been found to be helpful in the treatment of TS in several case reports which also documented the serious adverse reactions associated with this agent [35]. On the contrary, it is reported that clozapine exacerbates tics [13] and induces stuttering, facial tics, and myoclonic seizures [15].

The atypical antipsychotic agent best studied for the treatment of TS is risperidone (FDA approval: 1993) with a high affinity for dopamine D2- and 5-HT2-receptors. However, in several case reports and open-label studies including small groups of patients, risperidone showed similar efficacy across different ages as haloperidol and pimozide did with less frequent and less severe adverse reactions [30, 58, 86, 122, 140, 198, 219, 238, 261, 275]. The efficacy of risperidone has been confirmed in two randomized, double-blind, placebo-controlled trials involving 26 children and 8 adults with an age range 6–62 years [226], and 48 adolescents and adults between 14 and 49 years, [60], respectively, with mean daily doses of about 2.5 mg (range 1–6 mg/day). Gaffney et al. subsequently [83] compared 8 weeks’ treatment effects of risperidone with clonidine in 21 subjects with TS aged 7 to 17 years in a randomized, double-blind study. Risperidone and clonidine appeared equally effective in the treatment of tics; however, in the cases with comorbid obsessive–compulsive symptoms, risperidone was superior. The most common adverse reaction seen with both treatments was mild-to-moderate sedation, which subsequently resolved with continued administration of the medication or with a dose reduction. No clinically significant extrapyramidal symptoms were observed.

Furthermore, in a 12-week, randomized, double blind, parallel group study, both risperidone (26 patients were treated with a mean daily dose of 3.8 mg) and pimozide (24 patients were treated with a mean daily dose of 2.9 mg) reduced tics, anxiety, and depressive mood [28], whereas obsessive–compulsive symptoms improved only in the risperidone group. The latter finding is in line with the superior efficacy of risperidone for coexisting obsessive–compulsive symptoms in TS in the study of Gaffney et al. [83] as well as in an earlier case report [86]. Although the severity of extrapyramidal adverse reactions was low in both the groups, fewer patients in the risperidone group reported extrapyramidal adverse reactions (n = 4) as compared with the pimozide group (n = 8). Depression, fatigue, and somnolence were reported as the most prominent adverse reactions in both treatment groups. This is in line with a retrospective study carried out on 58 adult and adolescent TS patients who were treated with risperidone; 17 patients (29.3%) developed a major depressive disorder, including 1 patient who later committed suicide, and 13 patients (22.4%) became dysphoric while taking risperidone [143]. In a randomized, double blind, crossover study of 19 TS children (ages, 7–17 years), who underwent a 4-week treatment with pimozide or risperidone, followed by the alternative treatment after a 2-week placebo washout, risperidone was more effective than pimozide in reducing tics, in contrast to Bruggeman et al.’s report [28], which suggested that risperidone and pimozide were equally efficacious in the treatment of TS.28 Risperidone, however, was associated with more weight gain during the 4-week treatment periods. No serious adverse reactions were reported [88].

Risperidone also appears to be effective in treating aggressive behavior in patients with TS. In a retrospective chart review of 28 children and adolescents (one female) aged 5–18 years with TS and aggression problems, 22 (78.5%) showed both decreased aggression scores and tic reduction when treated with a mean daily dose of 2 mg risperidone [219]. This is in accordance with the potential of risperidone to manage pediatric aggression in other disorders [177]. Moreover, positive effects of risperidone not only on tics but also on sleep disturbances have been reported in the case of a 12-year-old boy with no previous psychopharmacological treatment [7].

Finally, in line with the other agents, the problem of causality between treatment and the natural course of tic symptomatology has also been mentioned for risperidone leading to one report about induction of tics by risperidone [72].

Several case reports [17, 18, 117, 141] and open-label studies [33, 126, 148, 262] have suggested efficacy of olanzapine (FDA approval: 1996) in the treatment of TS in adolescents and adults during the last 10–15 years. In four patients with severe TS (aged 19–40 years), a 52-week, double blind, crossover study with olanzapine (5 and 10 mg daily) versus low-dose pimozide (2 and 4 mg daily) was performed [171]. The reduction in tic severity was highly significant with 10 mg olanzapine versus baseline and versus 2 mg pimozide, and was significant for 5 mg olanzapine versus 4 mg pimozide. Only moderate sedation was reported by one patient during olanzapine treatment, whereas three patients complained of minor motor adverse reactions and sedation during pimozide treatment. All patients opted for olanzapine treatment at the end of the study. Compared to other antipsychotics, olanzapine has a greater activity at serotonin 5-HT₂ receptors than at D2 dopamine receptors. This may explain the lack of extrapyramidal effects. Additionally, olanzapine does not appear to block dopamine within the tubero-infundibular tract, explaining the lower incidence of hyperprolactinemia than with typical antipsychotic agents or risperidone. Nevertheless, the most widely reported adverse reactions were drowsiness/sedation and increased appetite frequently followed by weight gain [148]. In this context also metabolic adverse reactions (glucose and lipid metabolism) arise [184], although there seems to be no correlation between weight gain and metabolic disturbances [153].

Quetiapine (FDA approval: 1997) with its greater affinity for 5-HT2 receptors than for dopamine D2 receptors has shown its efficacy in reducing tics in two children with TS [179, 181, 182]. In an open-label trial with 12 subjects with a mean age of 11.4 ±2.4 years quetiapine reduced tics significantly [159]. Three subjects complained of sedation in the first week of treatment, but in the 8 weeks under investigation patients did not experience extrapyramidal adverse reactions and no statistically significant weight gain. Contrarily, in a retrospective study with longer observation period and higher dosage (175.0 SD 116.8 mg/day) of quetiapine the only noteworthy adverse reaction was weight increase. Quetiapine reduced tics also significantly in an open label study of 12 patients aged 8–18 years with TS [48]. Routine laboratory parameters and serum prolactin level were all normal and did not change throughout treatment.

Although there has been great hope for ziprasidone (FDA approval: 2001) as a potent treatment option in TS without the problem of weight gain [6], only one randomized, double blind, placebo-controlled study in 28 children and adolescents (7–17 years) [212] and one open open-label study in 24 children and adolescents (7–16 years) so far has proved this expectation [211, 213]. A mean daily dose of 28.2 mg ziprasidone reduced tics more effectively than placebo. Mild transient somnolence was the most common adverse reaction of low-dose exposure (5–20 mg/day), consistent with what is seen in clinical practice. This may be caused by enhanced 5-HT2C antagonistic activity of ziprasidone at low doses [260]. No patient experienced extrapyramidal symptoms, akathisia, or tardive dyskinesia, although administration of a single, low dose of ziprasidone may not be reflective of either higher doses or long-term risk in a naturalistic treatment setting [213]. In addition, there was no weight gain and changes of the analyzed laboratory parameters except of prolactin. Although QT prolongation has been discussed prominently in ziprasidone, a single dose of ziprasidone to treat TS was well tolerated without clinically significant effects on electrocardiograms collected around the time of maximum serum concentration [213] and even in higher doses no elevated risk of QT prolongation has been reported compared to other antipsychotics [266].

In addition to ziprasidone also aripiprazole (FDA approval: 2002) induced no weight gain during an 8-week, open-label trial with a flexible dosing strategy of aripiprazole in 72 children and adolescents with TS aged 6–18 years [49]. In a 10 week open-label, flexible-dose study with eleven subjects (10 males) with TS (age 9–19 years) who had not responded to or had not tolerated previous tic medication, effects of aripiprazole were promising [142], albeit with some weight gain in five patients. Finally, in an open-label, flexible-dose study including sixteen children (15 males) aged 8–17 years there was a mean increase of 2.3 kg after a 6-week trial with aripiprazole [167]. It provides a high affinity at dopamine D2 receptors but acts in contrast to other atypical antipsychotics as a partial agonist. Under treatment of clinical useful doses (10–30 mg/day) aripiprazole exhibits D2-receptor binding of 80–100% [96]. However, while binding at the active state of D2-receptors, aripiprazole shows 30% agonistic activity compared to dopamine [34]. Aripiprazole also acts as a partial agonist at 5-HT1A receptors and as a potent antagonist at 5-HT2A receptors [113]. This profile raised the hope that aripiprazole might be superior to previous pharmacological treatment options even in refractory cases. Excellent efficacy in the treatment of tics has been reported in a total of 201 cases, at least 31 of them adults [31, 47, 49, 52, 55, 63, 76, 103, 106, 118, 119, 142, 158, 166, 167, 173, 265, 288, 289]. A randomized, double blind, placebo-controlled study is, however, still lacking. Nevertheless, this drug should be considered because of its promising perspective based on actual clinical experiences. Even in “refractory” TS, aripiprazole has shown about 75% reduction of severe coprolalia in a 28-year-old man [16] as well as good efficacy in treating TS and coexisting OCD in an adult female [283]. Accordingly, Budman et al. [32] found in their retrospective, observational study of 37 children and adolescents with TS who were refractory to previous treatment that aripiprazole still reduced tics as well as explosive outbursts in these patients. Aripiprazole was tolerated reasonably well, although 8/37 (22%) children discontinued treatment; most common adverse reactions included weight gain, akathisia, and sedation at a mean daily dose of 12.3 (SD 7.50) mg in the 29 subjects who completed the study. In a 12-week, open-label trial with flexible dosing strategy aripiprazole revealed a good tic reduction in 15 participants, aged 7–19 years. Nausea and sedation were the most commonly reported adverse reactions that ameliorated in all participants within 2 weeks, with the exception of 1 participant who had continuously complained of sedation, but did not stop taking the drug [232]. The mean weight gain during this study was negligible.

For the newest atypical antipsychotic paliperidone (FDA approval: 2006) as well as for sertindole (not approved by the FDA for use in the USA) no data on the treatment of tics have been published.

Noradrenergic agents

In general, noradrenergic agents (clonidine, guanfacine, and atomoxetine) are mostly used in children and adolescents with a combination of attention-deficit/hyperactivity disorder (ADHD) and mild tics given their efficacy in treating ADHD symptoms in addition to tics [11]. Their tic-suppressing effects seem to be generally smaller, however, than those of antipsychotic agents.

Despite the frequent use of the α-2 adrenergic agonist clonidine for nearly three decades in the treatment of TS, controlled studies with clonidine are few in number. It is used more commonly in America than in Europe [195]. Case reports of clonidine’s efficacy in treating TS appeared in the early 1980s [150] and open-label trial evidence has been contradictory [45, 46, 234, 248]. A single-blind, placebo-controlled trial demonstrated a significant improvement in 6 out of 13 patients [133]. A randomized, placebo-controlled trial on 47 patients (7–48 years old) suffering from TS showed that treatment with clonidine reduced tic severity and frequency better than placebo [134], whereas another randomized, placebo-controlled study in 30 children and adults with TS found no difference [92]. A randomized, double blind, placebo-controlled study of desipramine and clonidine for the treatment of ADHD in TS revealed that clonidine did not alter tic severity in 34 children aged 7–13 years [247]. However, in the largest well-designed, randomized trial on orally administered clonidine, which included a placebo group, clonidine reduced tics significantly [271].

A transdermal clonidine preparation is also available and has been tested for the first time in nine patients in a placebo-controlled crossover trial. Although no objective improvement was recorded, most subjects felt they had improved [84]. A recent randomized, double blind, placebo-controlled multicentre trial using a clonidine adhesive patch revealed in the randomly assigned clonidine group (n = 326) a significant improvement of TS in 68.85% compared to 46.85% in the clinical control group (n = 111) [62]. Accordingly, clonidine transdermal patch treatment was effective in 53 out of 65 children with TS [116].

Adverse reactions of clonidine include sedation, dry mouth, headache, irritability, and midsleep awakening [62]. Blood pressure and pulse should be measured at baseline and monitored during dose adjustment. Specific guidelines for blood pressure monitoring during follow-up have not been established but regular monitoring of pulse and blood pressure changes, and symptoms suggestive of cardiovascular problems (e.g., exercise intolerance, dizziness, syncope) is recommended [53]. Baseline and follow-up electrocardiograms have been recommended in some practice guidelines [64], but not in others [53]. Although blood pressure is generally not a problem with clonidine, patients and families should be educated about the possibility of rebound hypertension, tics, and anxiety with abrupt discontinuation [19]. Although many authors report that the adverse reactions tend to be mild and transient, this view is not fully supported by others [89, 99, 137] especially when moderate to severe tics require higher dosage.

Guanfacine, another α-2 adrenergic agonist, has modest efficacy in reducing tics and in improving attention in children and adolescents. An open-label study of guanfacine in 10 children with TS [40] and in 25 medication-free children (23 males and 2 females) [24] with TS + ADHD aged 7–16 years revealed a significant decrease in tic severity and improvement in attention. In addition, a case report had described a 6-year-old boy with TS treated successfully with guanfacine [77]. These open label observations were confirmed by a randomized placebo-controlled double-blind trial in 34 children with TS + ADHD with a mean age of 10.4 years [223]. In contrast, in another double blind, placebo-controlled study on 24 children with TS aged 6–16 years guanfacine was not superior to placebo [50]. In summary, whether guanfacine would be effective for the treatment of moderate to severe tics remains unanswered [225]. In addition, the suggestion that guanfacine is a better tolerated alternative to clonidine remains unclear without a direct comparison study [217].

The most common adverse reactions of guanfacine are somnolence, headache, fatigue, sedation, dizziness, irritability, upper abdominal pain, and nausea. Somnolence, sedation, and fatigue adverse reactions emerge within the first 2 weeks of dosing and generally remit [210]. There is a concern that guanfacine has a propensity to induce mania in children with a personal or family history of bipolar disorder [102] as well as syncopal episodes probably due to drug-induced hypotension or bradycardia [123]. Guanfacine approved to treat hypertension in several European countries has been withdrawn from the market in several European countries probably due to lack of financial success.

The selective noradrenaline reuptake inhibitor atomoxetine had already been shown to be effective in randomized, placebo-controlled trials for treating ADHD in children [41]. Also in the treatment of ADHD with coexisting tics its efficacy was tested in a large, industry-sponsored multicenter study in 148 children [5]. Atomoxetine reduced both tics and ADHD symptoms in the study’s subgroup suffering from ADHD + TS [256]. Significant increases of mean pulse rate and rates of treatment-emergent nausea, decreased appetite, and decreased body weight were observed during medication with atomexetine. Concerns were raised, however, that children with severe ADHD or tics might have been unlikely to be enrolled in the study [87] which had a fairly high dropout rate in both treated (34%) and untreated (26%) groups during the double-blind portion of the trial. Moreover, case studies describe patients experiencing manifestation, recurrences, or exacerbation of tics following treatment with atomoxetine [136, 178, 180, 230].

Alternatives

Tetrabenazine, a vesicular monoamine transporter type 2 inhibitor, depletes presynaptic dopamine and serotonin stores and blocks postsynaptic dopamine receptors. In view of the hypothesized supersensitivity of dopaminergic receptors thought to be responsible for the tics in TS [231], tetrabenazine might be an alternative to antipsychotic treatment. Its divergent mechanism of action might result in different efficacy and adverse reactions profiles than the treatment with antipsychotics [109]. In some clinical studies on hyperkinetic movement disorders, including patients or samples with TS, tetrabenazine has shown its potential to ameliorate tics [108, 109, 111, 112, 174, 268, 278]. Results of two retrospective chart reviews enrolling only patients with TS (n = 77; mean age about 15 years; [120] and [188]) showed that 18–24 months’ treatment with tetrabenazine resulted in a moderate to marked improvement in functioning and TS-related symptoms in over 80% of patients. Adverse reactions included drowsiness/fatigue (36.4%), nausea (10.4%), depression (9.1%), insomnia (7.8%), and akathisia/parkinsonism (6.5%), but these symptoms improved with reduction in dosage [120]. Weight gain was less pronounced in doses of comparable efficacy than under treatment with antipsychotics and most patients who switched from an antipsychotic drug to tetrabenazine subsequently lost weight [170]. There were no reports of tardive dystonia or serious adverse reactions. In contrast there is a report about two patients with TS who developed tardive dystonia after treatment with antipsychotic agents. The dystonic movements persisted after the offending drugs were stopped and improved with tetrabenazine [252]. In summary, these findings encourage to conduct further studies.

Findings from preclinical studies in animals have suggested that nicotine might potentiate the effect of antipsychotic agents used to treat TS. Indeed, in 2 case reports negative effects of smoking cessation on TS have been reported [57, 59]. In initial open-label studies, chewing nicotine gum in addition to treatment with antipsychotics reduced tics in frequency and severity and improved concentration and attention [146, 216]. Similar effects were observed in a subsequent controlled trial involving nicotine gum plus haloperidol. Only in the group chewing the nicotine gum, tic frequency was reduced, while placebo gum alone had no effect on tic symptoms [147]. However, the short duration of effects as well as the bitter taste and gastrointestinal adverse reactions limit the compliance. Similar findings have been reported for application of transdermal nicotine patches to potentiate haloperidol in TS [242, 243]. In 11 poor-responders to antipsychotic treatment of TS, transdermal nicotine patches delivering 7 mg of nicotine in 24 h reduced tics 47% in frequency and 34% in severity [244]. In two of these patients tic reduction lasted even after removal of the transdermal nicotine patches. This result was in line with similar reports on tic reduction longer than 4 weeks after 48 h of nicotine administration by a transdermal patch [66, 67]. Correspondingly, retrospective case studies also found that application of a single transdermal nicotine patch delivering about 7 mg nicotine in 24 h resulted in a significant tic reduction for a mean of 10 days [239, 243]. The participants complained, however, about nausea and occasional headache and sedation. In the first randomized, double-blind study 70 patients with TS were treated with either transdermal nicotine (7 mg/24 h) or placebo patches in addition to their individual optimal dose of haloperidol [245]. In the patients who completed all 19 days of nicotine (n = 27) or placebo (n = 29), improvement of emotional and behavioral symptoms but also adverse reactions such as nausea and vomiting were more frequent under nicotine treatment. A subsequent randomized, double blind, placebo-controlled trial examined the acute (4 h) and sustained (2 weeks) effects of a single dose of transdermal nicotine on clinical (i.e., tics), attentional (continuous performance task, event-related potential, patient and parental reports), and behavioral symptoms in 23 children and adolescents with TS receiving treatment with antipsychotic agents. In the 14 evaluable patients with complete primary efficacy data, nicotine (compared to placebo) failed to alter symptoms at 4 h but counteracted ERP-P300 signs of diminished attention seen 2 weeks following placebo treatment. Secondary efficacy measures, including patient self-reports and parental ratings, found nicotine to reduce complex tics and improve behaviors related to inattention [104]. One study investigated neurophysiological mechanisms possibly underlying nicotine treatment of TS by using transcranial magnetic stimulation (TMS). A single dose of nicotine in 10 non-smoking and non-treated adults with TS reduced tic severity as assessed by blind video scoring in the majority of patients. In addition, nicotine abolished the reduced inhibition in patients compared to controls [172].

Tetrahydrocannabinol (THC) has been suggested to be effective and safe in the treatment of tics [162–164] without influence on neuropsychological performance [161]. This knowledge is based on a randomized, double blind, placebo-controlled study in which 24 adult patients with TS were treated over a 6-week period with up to 10 mg THC/day. No serious adverse reaction occurred and the reported mild adverse reactions were dizziness, tiredness, and dry mouth. Hasan et al. [98] reported about a 15-year-old boy with treatment refractory TS plus ADHD leading to severe physical and psychosocial impairment. For the first time after several years of unsuccessful medication even with a combination of different agents, the administration of THC improved tics considerably without adverse reactions, allowing parallel stimulant treatment of coexisting ADHD. Along with the THC treatment, TMS measured cortical inhibition was increased.

In addition to the use of pharmacological treatment options with systemic effects, there is increasing evidence for the efficacy of botulinum toxin injections to treat persistent well-localized (non-complex) motor and, sometimes, vocal tics by temporarily weakening the associated muscles. Initially, botulinum toxin injection was used for selected severe cases [3, 107, 125, 229]. Other case reports and case series followed also including children after the age of 8 years [4, 131, 215, 257, 273, 279]. In 35 of 186 patients, botulinum toxin injections were effectively controlling motor tics [8]. The effect on vocal tics was minimal. Adverse reactions included temporary soreness and mild muscle weakness. In 30 patients with vocal tics assessment after 15 days and then 4 times over a 12-month period botulinum toxin injection improved vocal tics in 93% of patients, with 50% being tic-free [187]. Mean response time was 5.8 days and mean duration of response was 102 days. Quality of life improved and premonitory experiences dropped from 53 to 20%. Hypophonia was the only adverse reaction of note (80% of patients). Just recently, the positive short-term and long-term (up to 10 years) treatment effects of botulinum toxin injections every 3 months on simple motor tics of 15 patients (mean age 43 years; range 18–84) could be shown [190]. Marras et al. [144] concluded from their randomized, double blind, controlled clinical trial that the treated tic frequency as well as the urge associated with the treated tic were reduced by botulinum toxin injection. Still, the patients’ subjective perception was that overall this treatment did not improve their condition. This is perhaps due to the fact that only selected subset of tics could be treated in each patient.

The dopamine autoagonist talipexole with putative preferential activity on presynaptic dopamine receptors was investigated one time in a randomized, double blind, placebo-controlled study [90]. In 13 adult men with TS, talipexole was poorly tolerated because of clinically significant sedation and dizziness. Tics did not improve at tolerable doses. These findings suggest that talipexole has no role in the regular management of tic disorders.

Clonazepam, a benzodiazepine which acts primarily on the GABAergic system, has a long history in the treatment of TS with dosages up to 6 mg/day [89]. Although there have been no placebo-controlled trials in TS, open-label studies have been carried out in adults [94, 274] and adolescents with TS [115, 264]. In a single-blind comparison with clonidine in 20 children, clonazepam was superior in suppressing tics [61]. In a single-blind clinical study of 20 patients with TS, those with high red blood cell-to-plasma choline ratios responded better to clonazepam than to haloperidol [152]. As with all benzodiazepines, tolerance and adverse reactions including sedation, short-term memory problems, ataxia, and paradoxic disinhibition often limit the use of clonazepam [89]. There are no data on other benzodiazepines except a case report about the therapeutic effect of low-dosage diazepam on facial tics in children [78].

The GABA B receptor agonist baclofen, which is used for the treatment of spasticity, has been examined in an open-label study in a large cohort of children with TS [8]. 250 of 264 patients on baclofen treatment experienced a significant decrease in the severity of tics. A small randomized, double blind, placebo-controlled study of baclofen in 10 children was inconclusive because there was a reduction in overall impairment but no changes in tic frequency or severity [251]. The results of these studies provide only modest support for the use of baclofen in TS. Common adverse reactions were sedation and drowsiness.

Other GABAergic drugs including the anticonvulsant levetiracetam have shown tic reduction in open studies on TS [9, 71]. Adverse reactions, however, as well as the finding that levetiracetam did not change the mean total YGTSS and Clinical Global Impression score in a small randomized, double blind, crossover study (n = 10) [99] as well as in a randomized, double blind, placebo-controlled, crossover trial in 22 children with TS (mean age 12.2 years) [253] question its usefulness in the treatment of TS.

Topiramate reduced tics in a small randomized, double-blind study on 20 patients of a broad age range (7–65 years) compared to placebo [110]. This is in line with a chart review on 41 patients with TS [127] as well as a previous report on two patients with TS who were successfully treated with topiramate while previous medications were tapered and discontinued during the first 2 weeks of treatment [1].

Lithium has been used successfully to reduce tics in five of ten children and adolescents [121], a 22-year-old male [277], and three adolescents suffering from TS who had been initially treated with haloperidol [70]. Failure has also been described, though [26], and firmer evidence is lacking.

Several case reports [81, 220–222] and a randomized, double-blind, placebo-controlled study involving 10 adults with TS suggest that tic reduction may be achieved with naloxone [129], an opioid receptor antagonist. Some studies indicated that difference in response to naloxone in TS subjects may be based on a dose–response effect [38, 276].

Some attention has also been given to the use of treatments that include a modulation of the body’s autoimmune-response. In children fulfilling criteria for pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS; a subgroup of children with OCD and/or tic disorder that experience symptom exacerbations following streptococcal infections), plasma exchange and intravenous immunoglobulin (IVIG) were both effective in lessening of symptoms [185, 293], although benefits through IVIG could not be confirmed in unselected patients with a tic disorder [101]. In a small prospective study, antibiotic prophylaxis with penicillin or azithromycin administered for 12 months in children fulfilling PANDAS criteria was associated with significant decreases in neuropsychiatric exacerbations [254]. A case study of a patient with TS reported benefits of treatment with celecoxib, a COX-2 inhibitor [165].

Finally, a wide range of further neuroactive agents have been examined non-systematically with divergent results concerning their efficacy in the treatment of TS. For example buspirone [65], carbamazepine [168, 292], metoclopramide [2, 169], physostigmine [258, 259], and spiradoline mesylate [39] have received some attention. A comprehensive overview of other case reports and non-blinded trials can be found elsewhere [195].

Treatment of tics in the context of comorbidities

Children and adolescents with TS are frequently affected by coexisting psychiatric conditions [79], which may be regarded the rule rather than the exception. In clinical samples of TS about half of the cases also meet criteria for ADHD and vice versa, TS is present in about 20% of children with ADHD [208, 228]. This co-occurrence of TS and ADHD is in most cases associated with a higher psychopathological, social, and academic impairment resulting from the negative impact of ADHD [10, 95, 200–202]. Besides, patients with TS also suffer more frequently from obsessive–compulsive symptoms or disorder (about 50%). Especially the need to achieve a ‘‘just right’’ feeling in TS has to be seen as an indicator for a continuum between TS and OCD [203].

Coexisting disorders cause often more clinical impairment and may be more responsive to treatment than the tics themselves [19]. It is therefore crucial to select an appropriate treatment goal (tics or coexisting conditions), when deciding on treatment options. Treatment of tics and coexisting conditions should be prioritized according to the impairment caused by each problem (for a decision tree see Fig. 1). Thus, in many cases not the tics, but coexisting problems require treatment e.g. ADHD or OCD. Clinicians should thus avoid to start two medications simultaneously, for instance one for tics and one for ADHD symptoms. Primary treatment of a coexisting condition, such as ADHD may reduce stress and improve attentional resources, and sometimes reduce tics by enhancing the individual’s ability of tic suppression.

Fig. 1 Decision tree for the treatment of tic disorders including Tourette syndrome. Indications for treatment are given in “Tics cause subjective discomfort (e.g. pain or injury)”, “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)” and “Tics cause functional interference (e.g. impairment of academic achievements)”. Solid arrow next level of evaluation/treatment, dashed-dotted arrow monitoring after successful treatment, dashed arrow alternating between two treatment options. Note: patient preference (after psychoeducation) and availability of therapists have to be considered in the choice of treatment. DBS deep brain stimulation, THC Tetrahydrocannabinol

---

Treatment algorithms of coexisting conditions in the context of TS are similar to treatment of these conditions without the presence of TS. Well-designed controlled clinical trials have not indicated a deterioration of tics in persons treated with stimulants [21] nor induction of first tics by stimulant treatment even in children at risk [175, 204].

Long-term treatment with methylphenidate (MPH) is not associated with increases in tic severity. In a two year prospective, open label study in which effects of MPH treatment were evaluated in 34 prepubertal children with ADHD and with chronic multiple tic disorder, the authors found no evidence that motor or vocal tics changed in frequency or severity during the MPH maintenance therapy, whereas initial behavioral improvements were maintained [82]. In a subsequent blinded placebo-controlled discontinuation trial in 19 children with ADHD and with chronic tic disorder who had received psychostimulants for a minimum of one year, tics did not change in their frequency or severity of motor or vocal tics during the maintenance dose of stimulant medication compared with the placebo condition. Treatment with the maintenance dose was, however, associated with behavioral improvement in ADHD symptoms, indicating continued efficacy. These studies prove that neither treatment nor discontinuation of treatment with MPH in patients with tics lead to an exacerbation of tics. Thus, abrupt withdrawal of stimulant medication in children receiving long-term maintenance therapy does not appear to result in worsening of tic frequency or severity.

Higher doses of stimulants, in the range of 45 mg b.i.d. of MPH and 22.5 mg b.i.d. of dexamphetamine, however, may still lead to (reversible) tic exacerbations [36]. Thus, in general, stimulants may be safely used in children with TS and ADHD, when using doses based on the typical clinical titration procedure [21]. Other treatment options for ADHD in the context of TS include clonidine [271], atomoxetine [5, 256], and desipramine [255].

Coexisting OCD in patients with TS may be less responsive to serotonin reuptake inhibitor monotherapy compared to OCD in patients without tics [149]. Co-administration of an antipsychotic agent may be helpful [20, 56].