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Pharmacological management of tics in patients with TS
Journal of Psychosomatic Research 55 (2003) 41 – 48
Review
Pharmacological management of tics in patients with TS Paul Sandor * Department of Psychiatry, Toronto Western Hospital, Edith-Cavell Wing, 399 Bathurst Street, Toronto, ON, Canada M5T 2S8
Abstract This articles reviews the evidence published in the English language literature concerning the pharmacological treatment of tics in patients with Tourette Syndrome. The focus is on the efficacy and
safety of the current treatments. A clinical approach to pharmacological management of Tourette Syndrome patients is outlined. D 2003 Elsevier Inc. All rights reserved.
Keywords: Tics; Tourette Syndrome; Dopamine receptor antagonists; Antipsychotics; Clonidine; Nicotine; Tetrabenazine; Marihuana; Botulinum toxin; Treatment
Introduction Tourette Syndrome (TS) is a childhood onset, neurodevelopmental disorder that manifests with multiple motor and phonic tics and affects between 1% and 3% of the general population [1]. The tics vary in frequency and anatomical distribution over time, and there is also wide interindividual variation in the severity of the disorder. In general, tics tend to be most pronounced between the ages of 10 and 13, with the majority of patients experiencing substantial decrease in symptom severity by the end of their teens [2]. It appears that only a minority of those affected by TS come to medical attention[3]. This may be partly because many cases are mild, and partly because of difficulties in obtaining well-informed, expert advice. Once diagnosis has been made, the question of appropriate treatment arises. In general, this is a result of cost –benefit analysis weighing the impact of untreated tics on psychological and social development and educational success versus the possible benefits as well as adverse effects of the various treatments. Ultimately, the treatment should only be considered when the benefits of such intervention distinctly outweigh the potential adverse effects. Because it is impossible to predict the degree of benefits or adverse effects for any given individual, often, a therapeutic trial of treatment is necessary before one can decide whether the treatment is worthwhile. Hence, any time new treatment is initiated, it
* Tel.: +1-416-603-5794; fax: +1-416-603-5292. E-mail address: [email protected] (P. Sandor). 0022-3999/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0022-3999(03)00060-6
is important to document and monitor the severity of target symptoms as well as to enquire systematically about potential adverse effects at regular intervals. Fluctuating course, the influence of psychosocial factors and suppressibility of symptoms complicate the evaluation of treatment response in TS patients. All of the pharmacological interventions available to date are strictly symptomatic and tend to be used on a long-term basis. The large number of agents, which have been used to treat tics attests to the fact that none of these are ideal, i.e., none offer complete symptomatic relief without adverse effects. Over the past 40 years, much has been learned about the pharmacotherapy of TS and the efficacy and safety of dopamine receptor antagonists and clonidine have been well established. Numerous medications are in use, despite weak or no evidence of efficacy. This paper will describe various pharmacological treatments for patients with TS, highlighting the ones with best empirical support.
Dopamine receptor antagonists Successful treatment of TS with haloperidol was reported 40 years ago [4,5] and ushered in the era of pharmacological treatment for TS. There are also many open-label studies and case series which suggest that many of the dopamine receptor antagonists can be useful in reducing the tic frequency and severity. These observations suggest that the blockade of dopamine type 2 receptors is central for the efficacy of this treatment, hence, the choices of the antipsychotic depends largely on adverse effect profile. Relatively low doses of dopamine receptor antagonists are
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P. Sandor / Journal of Psychosomatic Research 55 (2003) 41–48
sufficient to control tics in most patients with TS. This is consistent with the recent evidence that the equivalent of about 2 mg haloperidol/day achieves saturation of about 80% of the dopamine 2 receptors [6]. Clinical practice has gradually moved from the typical dopamine receptor antagonists, namely, haloperidol and pimozide to the atypical ones such as risperidone, sulpiride, olanzapine and, to some extent, quetiapine. The typical dose ranges for these agents are indicated in Table 1. Dopamine receptor antagonists significantly reduce tic frequency and severity in about 70% of the cases [7]. Surprisingly, by early 2000, there have been only five well-designed placebo-controlled studies of dopamine receptor antagonists efficacy as reviewed by Scahill et al. [8]. Four more controlled studies of antipsychotic medication treatment of tics have been published since then. Olanzapine versus pimozide [9], risperidone versus clonidine [10], risperidone versus pimozide [11] and risperidone versus placebo [12]. Pimozide was proposed as an alternative to haloperidol treatment for TS patients because of less frequent extrapyramidal adverse effects and comparable efficacy [13,14]. More recently, Sallee et al. [15] suggested that pimozide possesses superior efficacy when compared with haloperidol, however, in this study, haloperidol was no more effective than placebo, which conflicts with many of the earlier studies that found haloperidol to be an effective treatment. Pimozide has been shown to be effective in long-term follow-up of up to 15 years [16,17]. Both haloperidol and pimozide efficacy is limited by a propensity to extrapyramidal symptoms. Indeed, akathisia may sometimes aggravate tics [18]. Concerns have been expressed also about the risks of tardive dyskinesia, and there have been case reports of tardive dyskinesia in patients with TS [19 – 21]. Overall, risk of tardive dyskinesia appears to be relatively low in children and adolescents, ranging from 1% to 4.8% [22]. The onset of anxiety, which is clearly related to treatment with haloperidol and pimozide [23 – 25], is more common than tardive dyskinesia. The so-called ‘‘atypical dopamine receptor antagonists’’ offer fewer adverse effects and equal efficacy in the treatment of psychosis. For similar reasons, these agents have gradually displaced haloperidol and pimozide as the main-
stay in the treatment of tics. The evidence of risperidone efficacy is fairly extensive. The initial case reports were followed by encouraging open-label studies [26 –29] suggesting that risperidone efficacy was comparable to that of haloperidol and pimozide, while the adverse effects were less pronounced and less frequent. Gaffney et al. [30] reported on a randomized double-blind comparative trial of clonidine and risperidone which found, somewhat surprisingly, that both agents were equally efficacious in reducing the tic severity. In the double-blind placebocontrolled trial of risperidone in 48 patients with TS who were randomly assigned to either risperidone or placebo treatment [12] risperidone at a median dose of 2.5 mg/day (dose range of 1– 6 mg) was found to be significantly more effective than placebo. Sixty percent of the risperidonetreated group improved versus only 26.1% of the placebotreated group. Contrary to previous case reports [31], no increase in obsessive – compulsive symptoms was noted in the Dion study. The most common adverse effects of treatment with risperidone include sedation, increased appetite and weight, and increased prolactin levels. Although extrapyramidal symptoms may occur, these are much less frequent than with haloperidol or pimozide. Dysphoria and depression may occur in predisposed individual during treatment with risperidone [32]. Reports of olanzapine efficacy in the treatment of TS patients are beginning to emerge. These include case reports [33] and open-label studies [34,35]. All of these suggested that olanzapine has good efficacy and tolerability. There is also a small 52-week double-blind crossover study of olanzapine versus pimozide in four patients, which found that both olanzapine and pimozide reduced tics significantly [9]. Based on this limited experience, most frequent adverse effects include excessive sedation and increased appetite and weight. There are concerns that with long-term treatment, some patients gain weight [36] and may develop disturbances of glucose metabolism [37]. Significant disturbances in lipid metabolism may be present even in the absence of large weight gain [38], hence, regular monitoring is required. The association between antipsychotic treatment and weight gain has provoked considerable concern in recent years as the atypical antipsychotics gained wide acceptance. There is some suggestion that at least in patients with
Table 1 Antipsychotic medications used to treat tics in TS Generic name
Dose range (mg/day)
Fluphenazine Haloperidol Olanzapine Pimozide Quetiapine Risperidone
4.0 – 24.0 0.25 – 6.0 2.5 – 20.0 1.0 – 8.0 100.0 – 600.0 0.25 – 6.0
Sulpiride Ziprasidone
200.0 – 1000.0 5.0 – 40.0
Adverse effects
References
Sedation, irritability, dysphoria, dystonia, akathisia Sedation, dystonia, akathisia, weight gain, dysphoria, galactorhea, anxiety, tardive dyskinesia Weight gain, sedation, hyperlipidemia, glucose metabolism disturbances Akathisia, dystonia, weight gain, ECG changes, depression, anxiety, tardive dyskinesia Sedation, weight loss, weight gain, dizziness, dysphoria Sedation, dizziness, akathisia, dystonia, headache, depressed mood, obsessive – compulsive symptoms Sedation, akathisia, depression, weight gain, galactorhea Sedation, ECG changes
[110 – 112] [9,14,113 – 116] [9,35,40] [13,114,117 – 120] [44,121,122] [31,38,122 – 125] [62,126] [42]
P. Sandor / Journal of Psychosomatic Research 55 (2003) 41–48
schizophrenia, increased weight is associated with better treatment response [36]. It is unknown whether this association holds true in the treatment of tics, however, weight gain has been frequently a reason for discontinuation of treatment in TS patients, especially with olanzapine and risperidone. Although atypical antipsychotics have been associated with increased glucose levels and new onset diabetes [39], one has to be aware also of the possibility of asymptomatic hypoglycemia during treatment with olanzapine [40]. In view of the concerns about weight gain, there is hope that a novel agent ziprasidone may be an effective treatment for tics with minimal risk of inducing unacceptable weight gain [41]. Only one preliminary study in Tourette patients has been published to date [42], with encouraging results. Twenty-eight children and adolescents were randomly assigned to either ziprasidone or placebo and treated for 56 days. Ziprasidone at the mean dose of 28.2 mg was significantly more effective than placebo in reducing the tic frequency and severity. The treatment was well tolerated. The most common adverse effect was transient mild sedation. The change in weight was the same in ziprasidone as in the placebo group. There was a transient increased in serum prolactin and no other laboratory abnormalities. Although concerns have been raised about the risk of prolonged QT interval during treatment with ziprasidone, there is some evidence that the mean prolongation of the QT interval due to ziprasidone is comparable to that seen with risperidone and quetiapine and much smaller than that seen with thioridazine [43]. Nevertheless, it is prudent to obtain a baseline ECG before starting treatment with ziprasidone to detect any preexisting conduction defect that might contraindicate the use of this medication. Similarly, one should avoid combining ziprasidone with other medications that are known to prolong the QT interval, e.g., other typical and atypical antipsychotics and tricyclic antidepressants. Quetiapine is another agent with relatively low propensity to induce weight gain. To date, only case reports have appeared suggesting that quetiapine may be an effective treatment for tics. It appears that relatively high doses are required, on the order of 200 –500 mg/day [44,45].
Other treatments Nicotine and mecamylamine Evidence from animal studies suggests that nicotine can augment catalepsy induced by dopamine receptor antagonists [46,47]. Based on such considerations, open-label studies of nicotine augmentation of haloperidol treatment in patients with TS suggested a possible benefit with regard to tic frequency and severity. There are reports that nicotine administered in chewing gum [48] and as a transdermal patch [49] reduced tic frequency in some TS patients. This early literature, however, was based on case studies or short
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series of cases without adequate controls. Surprisingly, there have been case reports suggesting that single application of a transdermal nicotine patch for 24 h may have reduced tics for up to 4 weeks [50 – 52]. A recent paper by Silver et al. [49] is the best attempt to assess the efficacy of transdermal nicotine and haloperidol in treating patients with TS. This was a double-blind placebo-controlled study lasting 33 days, where 27 patients were treated with nicotine and 29 with a placebo patch in addition to haloperidol. There was a significant reduction in clinician-rated global improvement scale of TS in the nicotine group, however, it was not clearly demonstrated on the Yale Globe Tic Severity Scale Scores. It is of note that 23% of the patients in the nicotine group and 20% of the placebo group were withdrawn because of adverse effects or recurrence of symptoms. The most common adverse effects in the nicotine group were nausea and vomiting. These observations are tantalizing but await a replication from other centers. Moreover, it is unclear how frequently nicotine needs to be applied in order to be effective. Importantly, the balance of evidence would suggest that nicotine alone does not provide significant benefits. Similarly, a pure nicotinic receptor antagonist mecamylamine does not appear to be effective in reducing tics on its own [53], although it may be helpful in combination with dopamine receptor antagonists and/or clonidine [54]. Tetrabenazine The first report of using tetrabenazine to treat symptoms of TS appeared in 1974 [55]. Jankovic et al. [56,57] reported beneficial effects on the frequency and severity of tics based on uncontrolled series of cases. Tetrabenazine doses ranged from 25 to 150 mg/day. Tetrabenazine is not associated with a risk of tardive dyskinesia, however, it can occasionally cause extrapyramidal symptoms and depression. Prospective, well-designed studies are required to confirm tetrabenazine safety and efficacy in comparison with placebo and other agents. Marihuana (tetrahydrocannabinol) The putative beneficial effects of marijuana on tics have been reported as early as 1988 by Sandyk and Awerbuch [58] who observed a significant benefit in three patients. Despite such clinical lore, there has been only one very recent report of a randomized double-blind placebo-controlled crossover single dose trial of Delta-9-tetrahydrocannabinol in 12 adult TS patients [59]. There was improvement in tics on subjective rating and to a lesser extent on objective rating of motor and vocal tics. A companion paper from the same group found no untoward effects on a range of neuropsychological measures [60]. One must keep in mind, however, that this was a single-dose study and both efficacy and safety of this intervention must be assessed in longer-term studies to determine whether Delta-9-tetrahydrocannabinol has any therapeutic utility.
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Sulpiride Although not available in North America, sulpiride is a first-line treatment for TS in Britain and several European countries [61,62]. The efficacy seems similar to other antipsychotics. As with many other antipsychotics, the main ad-verse effects include drowsiness and occasionally depression.
randomized double-blind controlled clinical trial of botulinum toxin for simple motor tics and concluded that the treated tic frequency as well as the urge associated with the treated tic were reduced. However, 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. Clonidine
Anticonvulsants and benzodiazepines It has been suggested that nonspecific EEG abnormalities are more frequent in TS patients than in controls [63]. Several other studies found no significant differences on a variety of EEG measures [64 – 66]. There is no evidence that anticonvulsants can be helpful in the treatment of tics, while there are numerous reports of tics precipitated or aggravated with anticonvulsant treatment [67 –70]. Although case reports of beneficial effects of clonazepam and other benzodiazepines have appeared for the past 20 years [71 –73], no systematic study of the benefits of clonazepam has been reported either as a stand alone treatment, or as a treatment in combination with dopamine receptor antagonists. Nevertheless, clinical experience suggests that clonazepam can be helpful in selected cases of TS [73] and clonazepam continues to be mentioned in this role in reviews of pharmacological therapy of tics, e.g., Refs. [62,74 – 76]. Baclofen An interesting report by Awaad [77] compared the efficacy of baclofen and Botox injection in a large number of children with TS. Tics were evaluated by videotape recording and rated by blinded raters. Unfortunately, the subjects were not randomized to each treatment. Nevertheless, he found that 250/264 patients on baclofen treatment experienced a significant decrease in the severity of tics. Adverse effects included sedation and drowsiness. A recent small doubleblind 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 [78]. Botulinum toxin In addition to the use of pharmacological agents with systemic effects, there is growing evidence to support the use of local injections of botulinum toxin for the treatment of motor and, sometimes, vocal tics. Initially, botulinum toxin injection was used for selected severe cases [79 – 81]. Other case reports and case series followed [82 – 84]. In the above-mentioned report by Awaad [77], Botox injections were effectively controlling motor tics in 35/186 patients. The effect of Botox injections on vocal tics was minimal. Adverse effects included temporary soreness and mild muscle weakness. Marras et al. [85] published the first
Case reports of clonidine effectiveness in TS appeared in the early 1980s [86] and open-label trial evidence has been contradictory [87,88]. Single, blind, placebo-controlled trial of 13 patients demonstrated a significant improvement in 6 out of 13 patients [89]. A larger open-label trial was less positive [90]. The problems in management of tics with clonidine include the possibility of a paradoxical increase in tics [91] and marked increase in tics after stopping clonidine suddenly [92]. Placebo control trials showed that treatment with clonidine reduces tics severity and frequency [93], although another study by Goetz et al. [94] found no difference between clonidine and placebo. In the most recent, largest and well-designed trial, which included a placebo group, clonidine reduced tics significantly, while the only adverse effect was sedation [95]. The preponderance of evidence supports the use of clonidine as a potentially effective treatment for TS patients that may reduce mild to moderate tics and improve attention. In addition, clonidine tends to reduce anxiety and alleviate initial insomnia. The adverse effects tend to be mild and transient, most commonly daytime sedation and lightheaded feelings. Thus, clonidine is a useful first-line treatment for many children and adults with diagnosis of TS. Guanfacine Guanfacine has been suggested as a better-tolerated alternative to clonidine. The initial open-label study suggested that guanfacine treatment could have beneficial effects on both tics and attentional problems in patients with TS [96]. These initial impressions were confirmed by randomized placebo-controlled double-blind trial of an 8-week duration [97]. Without a direct comparison study, it is unclear whether guanfacine is indeed better tolerated than clonidine. There is a concern that guanfacine has a propensity to induce mania in children with personal or family history of bipolar disorder [98]. Dopaminergic agonists An experimental treatment emerged recently involving the use of dopaminergic agonists in treatment of symptoms of TS. The assumption is that the stimulation of the presynaptic dopamine receptors symptoms may lead to down-regulation of the dopamine release into the synaptic cleft, however, this may be too simple an explanation.
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Nevertheless, these observations suggest that instead of the simple model of excessive activity of dopamine system, we need to consider the concept of dopaminergic dysregulation explored in recent imaging studies [99,100]. Small studies with pergolide showed promising results [101,102]. These were confirmed in a randomized placebo-controlled trial studying 24 children and adolescents with TS, where pergolide treatment was significantly more effective in reducing tics severity compared to placebo [103]. The treatment was well tolerated. A very small, single, blind pilot study of levodopa with carbidopa pretreatment showed a significant reduction in tic severity on both subjective and objective measures [104]. Opioid receptor agonists and antagonists A few case reports drew attention to the possible involvement of the endogenous opioids in neurophysiology of TS [105,106]. Randomized double-blind placebo-controlled trial of propoxyphene and naltrexone in 10 adults with TS showed that naltrexone improved the tics, but only on a subjective measure of tic severity in contrast with placebo or propoxyphene. Similarly, naltrexone treatment was associated with a modest improvement on tests of attention, which was not present with placebo or propoxyphene [107]. The dose level of opiate receptor antagonists appears to be rather important because it has been demonstrated that low-dose naloxone infusion decreases the tics while high doses cause a significant increase in severity compared to the baseline [108]. In summary, only weak evidence supports a possible therapeutic effect on patients with TS, of agents that interact with the opioid system.
An approach to the management of tics An accurate diagnosis of TS accompanied by a systematic enquiry regarding the presence or absence of Attention Deficit Hyperactivity Disorder, Obsessive – Compulsive Disorder, behavioral disturbances such as rage and sleep disturbances is a necessary first step. The diagnostic process must be based on a careful history and direct observation. It is useful to create a hierarchy of symptoms according to their intrusiveness, i.e., to assess the impact of the various symptoms on the patient’s ability to function in various spheres, e.g., at home, at school or at work. This is not directly related to the severity of symptoms since patients vary as to their ability to tolerate a given degree of symptoms. Similarly, the people that the patient comes into contact will have widely differing tolerance for patients’ symptoms. The response of the environment is an important determinant of how disabling a given symptom may be. When planning the treatment, it is logical to address the most intrusive symptoms first. It is useful to document the severity of symptoms in a systematic manner, e.g., utilizing TSGSS to record the type,
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frequency and intensity of various tics because this will be important in evaluating the response to treatment. The decision whether to treat is based on evaluating whether and to what extent the target symptoms impair patient’s function at home, at school or at work. If it is clear that educational success, psychosocial adjustment or family relations suffer as a result of the symptoms, it is justifiable to consider pharmacological intervention. In this context, one must keep in mind that tics tend to fluctuate spontaneously as well as in response to external events, e.g., tics often tend to decrease during vacation time and increase a few days before return to school. It is important not to confuse such fluctuations with therapeutic response or therapeutic failure. When TS alone is present, the treatment is aimed to reduce the frequency and intensity of tics. Clonidine represents the first line of treatment because of favorable adverse effects profile. Moreover, it is likely, that in addition to reducing tics, it can also improve initial insomnia and reduce the symptoms of ADHD. To minimize the risk of sedation and lightheadedness, the dose should be increased gradually over a period of a couple of weeks, starting with 0.025 – 0.05 mg at bedtime and aiming at a total daily dose of 0.15 – 0.3 mg. Typically, one-third of the daily dose is given in the morning, and two-thirds in the evening to minimize daytime somnolence. The therapeutic response may not become apparent for 2 or 3 months. Hence, an adequate treatment trial should last about three months. The odds of treatment response are about 50%. If a trial of treatment with clonidine is unsuccessful, one may move to treatment with low doses of dopamine receptor antagonists listed in Table 1. Once again, the treatment should begin with a low dose that may be increased gradually. The frequency of dose change is guided by the elimination half-life of each drug, and, typically, a dose would be increased every 1 or 2 weeks. Therapeutic response may be expected in a matter of days once an effective dose has been reached. The most common adverse effects include sedation, increased appetite and extrapyramidal symptoms such as restlessness, tremor, and rigidity or dystonic reaction. The issue of potential weight gain is best addressed at the outset because preventing weight gain is easier than weight reduction. A healthy, balanced diet and sufficient exercise needs to be discussed with each patient since at the moment, there are no reliable predictors of who is at risk of significant weight gain. Two newer antipsychotics agents, quetiapine and ziprasidone, seem to have the lowest propensity for inducing weight gain, however, there is only preliminary evidence that these agents are effective in suppressing tics. Tetrabenazine represents a useful alternative for those patients who cannot tolerate antipsychotic treatment. Although controlled randomized trials are lacking, large series of cases would suggest that it is quite effective in reducing tics with a relatively low risk of inducing EPS.
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While it does not induce weight gain, there is a risk of depression in some individuals. If none of the above treatments are effective, a trial of treatment with a dopamine agonist is warranted, although there is only preliminary evidence of efficacy. Rage and aggressive behavior are present in about onethird of the clinical population of children with TS and as such represent a major management challenge. A psychosocial approach to management is described elsewhere in this issue (Greene et al.). It appears that risperidone [109] is rather effective in reducing the frequency and intensity of rage in this population. The subject is discussed in more depth elsewhere in this issue (Budman et al.). The management of comorbid conditions, namely, ADHD and OCD, are also covered elsewhere in this issue. (See articles by Dr. Kurlan and by Dr. Miguel.) The approach to treatment of tics in TS patients, described above is based on best available evidence. Despite a growing number of published clinical trials, much remains to be done, and the treatments that we offer continue to be palliative. Addressing the disorder more directly awaits further advances in our understanding of the basic mechanisms of TS.
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[58] Sandyk R, Awerbuch G. Marijuana and Tourette’s syndrome. J Clin Psychopharmacol 1988;8:444 – 5. [59] Muller-Vahl KR, Schneider U, Koblenz A, Jobges M, Kolbe H, Daldrup T, Emrich HM. Treatment of Tourette’s syndrome with Delta 9-tetrahydrocannabinol (THC): a randomized crossover trial. Pharmacopsychiatry 2002;35:57 – 61. [60] Muller-Vahl KR, Koblenz A, Jobges M, Kolbe H, Emrich HM, Schneider U. Influence of treatment of Tourette syndrome with delta9-tetrahydrocannabinol (delta9-THC) on neuropsychological performance. Pharmacopsychiatry 2001;34:19 – 24. [61] Robertson MM, Schnieden V, Lees AJ. Management of Gilles de la Tourette syndrome using sulpiride. Clin Neuropharmacol 1990;13: 229 – 35. [62] Robertson MM, Stern JS. Gilles de la Tourette syndrome: symptomatic treatment based on evidence. Eur Child Adolesc Psychiatry 2000;9(Suppl 1):I60 – 75. [63] Hyde TM, Emsellem HA, Randolph C, Rickler KC, Weinberger DR. Electroencephalographic abnormalities in monozygotic twins with Tourette’s syndrome. Br J Psychiatry 1994;164:811 – 7. [64] Drake ME, Hietter SA, Padamadan H, Bogner JE. Computerized EEG frequency analysis in Gilles de la Tourette syndrome. Clin Electroencephalogr 1991;22:250 – 3. [65] Neufeld MY, Berger Y, Chapman J, Korczyn AD. Routine and quantitative EEG analysis in Gilles de la Tourette’s syndrome. Neurology 1990;40:1837 – 9. [66] Syrigou-Papavasiliou A, Verma NP, LeWitt PA. Sensory evoked responses in Tourette syndrome. Clin Electroencephalogr 1988;19: 108 – 10. [67] Neglia JP, Glaze DG, Zion TE. Tics and vocalizations in children treated with carbamazepine. Pediatrics 1984;73:841 – 4. [68] Burd L, Kerbeshian J, Fisher W, Gascon G. Anticonvulsant medications: an iatrogenic cause of tic disorders. Can J Psychiatry 1986;31: 419 – 23. [69] Sotero de Menezes MA, Rho JM, Murphy P, Cheyette S. Lamotrigine-induced tic disorder: report of five pediatric cases. Epilepsia 2000;41:862 – 7. [70] Holtmann M, Korn-Merker E, Boenigk HE. Carbamazepine-induced combined phonic and motor tic in a boy with Down’s syndrome. Epileptic Disord 2000;2:39 – 40. [71] Kaim B. A case of Gilles de la Tourette’s syndrome treated with clonazepam. Brain Res Bull 1983;11:213 – 4. [72] Goetz CG. Clonidine and clonazepam in Tourette syndrome. Adv Neurol 1992;58:245 – 51. [73] Gonce M, Barbeau A. Seven cases of Gilles de la Tourette’s syndrome: partial relief with clonazepam: a pilot study. Can J Neurol Sci 1977;4:279 – 83. [74] Erenberg G. Pharmacologic therapy of tics in childhood. Pediatr Ann 1988;17:395 – 404. [75] Singer HS. The treatment of tics. Curr Neurol Neurosci Rep 2001; 1:195 – 202. [76] Peterson BS, Cohen DJ. The treatment of Tourette’s syndrome: multimodal, developmental intervention. J Clin Psychiatry 1998;59 (Suppl 1):62 – 72. [77] Awaad Y. Tics in Tourette syndrome: new treatment options. J Child Neurol 1999;14:316 – 9. [78] Singer HS, Wendlandt J, Krieger M, Giuliano J. Baclofen treatment in Tourette syndrome: a double-blind, placebo-controlled, crossover trial. Neurology 2001;56:599 – 604. [79] Adler CH, Zimmerman RS, Lyons MK, Simeone F, Brin MF. Perioperative use of botulinum toxin for movement disorder-induced cervical spine disease. Mov Disord 1996;11:79 – 81. [80] Scott BL, Jankovic J, Donovan DT. Botulinum toxin injection into vocal cord in the treatment of malignant coprolalia associated with Tourette’s syndrome. Mov Disord 1996;11:431 – 3. [81] Jankovic J. Botulinum toxin in the treatment of dystonic tics. Mov Disord 1994;9:347 – 9. [82] Salloway S, Stewart CF, Israeli L, Morales X, Rasmussen S, Blitzer
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A, Brin MF. Botulinum toxin for refractory vocal tics. Mov Disord 1996;11:746 – 8. [83] Trimble MR, Whurr R, Brookes G, Robertson MM. Vocal tics in Gilles de la Tourette syndrome treated with botulinum toxin injections. Mov Disord 1998;13:617 – 9. [84] Kwak CH, Hanna PA, Jankovic J. Botulinum toxin in the treatment of tics. Arch Neurol 2000;57:1190 – 3. [85] Marras C, Andrews D, Sime E, Lang AE. Botulinum toxin for simple motor tics: a randomized, double-blind, controlled clinical trial. Neurology 2001;56:605 – 10. [86] McKeith IG, Williams A, Nicol AR. Clonidine in Tourette syndrome. Lancet 1981;1:270 – 1. [87] Cohen DJ, Young JG, Nathanson JA, Shaywitz BA. Clonidine in Tourette’s syndrome. Lancet 1979;2:551 – 3. [88] Cohen DJ, Detlor J, Young JG, Shaywitz BA. Clonidine ameliorates Gilles de la Tourette syndrome. Arch Gen Psychiatry 1980;37:1350 – 7. [89] Leckman JF, Detlor J, Harcherik DF, Ort S, Shaywitz BA, Cohen DJ. Short- and long-term treatment of Tourette’s syndrome with clonidine: a clinical perspective. Neurology 1985;35:343 – 51. [90] Shapiro AK, Shapiro E, Eisenkraft GJ. Treatment of Gilles de la Tourette’s syndrome with clonidine and neuroleptics. Arch Gen Psychiatry 1983;40:1235 – 40. [91] Kessler AR. Clonidine treatment increases tics in patients with Tourette syndrome: case report. J Child Neurol 2001;16:380 – 1. [92] Leckman JF, Ort S, Caruso KA, Anderson GM, Riddle MA, Cohen DJ. Rebound phenomena in Tourette’s syndrome after abrupt withdrawal of clonidine. Behavioral, cardiovascular, and neurochemical effects. Arch Gen Psychiatry 1986;43:1168 – 76. [93] Leckman JF, Hardin MT, Riddle MA, Stevenson J, Ort SI, Cohen DJ. Clonidine treatment of Gilles de la Tourette’s syndrome. Arch Gen Psychiatry 1991;48:324 – 8. [94] Goetz CG, Tanner CM, Wilson RS, Carroll VS, Como PG, Shannon KM. Clonidine and Gilles de la Tourette’s syndrome: double-blind study using objective rating methods. Ann Neurol 1987;21:307 – 10. [95] Treatment of ADHD in children with tics: a randomized controlled trial. Neurology 2002;58:527 – 36. [96] Chappell PB, Riddle MA, Scahill L, Lynch KA, Schultz R, Arnsten A, Leckman JF, Cohen DJ. Guanfacine treatment of comorbid attention-deficit hyperactivity disorder and Tourette’s syndrome: preliminary clinical experience. J Am Acad Child Adolesc Psychiatry 1995; 34:1140 – 6. [97] Scahill L, Chappell PB, Kim YS, Schultz RT, Katsovich L, Shepherd E, Arnsten AF, Cohen DJ, Leckman JF. A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder. Am J Psychiatry 2001;158:1067 – 74. [98] Horrigan JP, Barnhill LJ. Guanfacine and secondary mania in children. J Affect Disord 1999;54:309 – 14. [99] George MS, Robertson MM, Costa DC, Ell PJ, Trimble MR, Pilowsky L, Verhoeff NP. Dopamine receptor availability in Tourette’s syndrome. Psychiatry Res 1994;55:193 – 203. [100] Malison RT, McDougle CJ, van Dyck CH, Scahill L, Baldwin RM, Seibyl JP, Price LH, Leckman JF, Innis RB. [123I]beta-CIT SPECT imaging of striatal dopamine transporter binding in Tourette’s disorder. Am J Psychiatry 1995;152:1359 – 61. [101] Lipinski JF, Sallee FR, Jackson C, Sethuraman G. Dopamine agonist treatment of Tourette disorder in children: results of an open-label trial of pergolide. Mov Disord 1997;12:402 – 7. [102] Griesemer DA. Pergolide in the management of Tourette syndrome. J Child Neurol 1997;12:402 – 3. [103] Gilbert DL, Sethuraman G, Sine L, Peters S, Sallee FR. Tourette’s syndrome improvement with pergolide in a randomized, doubleblind, crossover trial. Neurology 2000;54:1310 – 5. [104] Black KJ, Mink JW. Response to levodopa challenge in Tourette syndrome. Mov Disord 2000;15:1194 – 8.
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Review
Pharmacological management of tics in patients with TS Paul Sandor * Department of Psychiatry, Toronto Western Hospital, Edith-Cavell Wing, 399 Bathurst Street, Toronto, ON, Canada M5T 2S8
Abstract This articles reviews the evidence published in the English language literature concerning the pharmacological treatment of tics in patients with Tourette Syndrome. The focus is on the efficacy and
safety of the current treatments. A clinical approach to pharmacological management of Tourette Syndrome patients is outlined. D 2003 Elsevier Inc. All rights reserved.
Keywords: Tics; Tourette Syndrome; Dopamine receptor antagonists; Antipsychotics; Clonidine; Nicotine; Tetrabenazine; Marihuana; Botulinum toxin; Treatment
Introduction Tourette Syndrome (TS) is a childhood onset, neurodevelopmental disorder that manifests with multiple motor and phonic tics and affects between 1% and 3% of the general population [1]. The tics vary in frequency and anatomical distribution over time, and there is also wide interindividual variation in the severity of the disorder. In general, tics tend to be most pronounced between the ages of 10 and 13, with the majority of patients experiencing substantial decrease in symptom severity by the end of their teens [2]. It appears that only a minority of those affected by TS come to medical attention[3]. This may be partly because many cases are mild, and partly because of difficulties in obtaining well-informed, expert advice. Once diagnosis has been made, the question of appropriate treatment arises. In general, this is a result of cost –benefit analysis weighing the impact of untreated tics on psychological and social development and educational success versus the possible benefits as well as adverse effects of the various treatments. Ultimately, the treatment should only be considered when the benefits of such intervention distinctly outweigh the potential adverse effects. Because it is impossible to predict the degree of benefits or adverse effects for any given individual, often, a therapeutic trial of treatment is necessary before one can decide whether the treatment is worthwhile. Hence, any time new treatment is initiated, it
* Tel.: +1-416-603-5794; fax: +1-416-603-5292. E-mail address: [email protected] (P. Sandor). 0022-3999/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0022-3999(03)00060-6
is important to document and monitor the severity of target symptoms as well as to enquire systematically about potential adverse effects at regular intervals. Fluctuating course, the influence of psychosocial factors and suppressibility of symptoms complicate the evaluation of treatment response in TS patients. All of the pharmacological interventions available to date are strictly symptomatic and tend to be used on a long-term basis. The large number of agents, which have been used to treat tics attests to the fact that none of these are ideal, i.e., none offer complete symptomatic relief without adverse effects. Over the past 40 years, much has been learned about the pharmacotherapy of TS and the efficacy and safety of dopamine receptor antagonists and clonidine have been well established. Numerous medications are in use, despite weak or no evidence of efficacy. This paper will describe various pharmacological treatments for patients with TS, highlighting the ones with best empirical support.
Dopamine receptor antagonists Successful treatment of TS with haloperidol was reported 40 years ago [4,5] and ushered in the era of pharmacological treatment for TS. There are also many open-label studies and case series which suggest that many of the dopamine receptor antagonists can be useful in reducing the tic frequency and severity. These observations suggest that the blockade of dopamine type 2 receptors is central for the efficacy of this treatment, hence, the choices of the antipsychotic depends largely on adverse effect profile. Relatively low doses of dopamine receptor antagonists are
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sufficient to control tics in most patients with TS. This is consistent with the recent evidence that the equivalent of about 2 mg haloperidol/day achieves saturation of about 80% of the dopamine 2 receptors [6]. Clinical practice has gradually moved from the typical dopamine receptor antagonists, namely, haloperidol and pimozide to the atypical ones such as risperidone, sulpiride, olanzapine and, to some extent, quetiapine. The typical dose ranges for these agents are indicated in Table 1. Dopamine receptor antagonists significantly reduce tic frequency and severity in about 70% of the cases [7]. Surprisingly, by early 2000, there have been only five well-designed placebo-controlled studies of dopamine receptor antagonists efficacy as reviewed by Scahill et al. [8]. Four more controlled studies of antipsychotic medication treatment of tics have been published since then. Olanzapine versus pimozide [9], risperidone versus clonidine [10], risperidone versus pimozide [11] and risperidone versus placebo [12]. Pimozide was proposed as an alternative to haloperidol treatment for TS patients because of less frequent extrapyramidal adverse effects and comparable efficacy [13,14]. More recently, Sallee et al. [15] suggested that pimozide possesses superior efficacy when compared with haloperidol, however, in this study, haloperidol was no more effective than placebo, which conflicts with many of the earlier studies that found haloperidol to be an effective treatment. Pimozide has been shown to be effective in long-term follow-up of up to 15 years [16,17]. Both haloperidol and pimozide efficacy is limited by a propensity to extrapyramidal symptoms. Indeed, akathisia may sometimes aggravate tics [18]. Concerns have been expressed also about the risks of tardive dyskinesia, and there have been case reports of tardive dyskinesia in patients with TS [19 – 21]. Overall, risk of tardive dyskinesia appears to be relatively low in children and adolescents, ranging from 1% to 4.8% [22]. The onset of anxiety, which is clearly related to treatment with haloperidol and pimozide [23 – 25], is more common than tardive dyskinesia. The so-called ‘‘atypical dopamine receptor antagonists’’ offer fewer adverse effects and equal efficacy in the treatment of psychosis. For similar reasons, these agents have gradually displaced haloperidol and pimozide as the main-
stay in the treatment of tics. The evidence of risperidone efficacy is fairly extensive. The initial case reports were followed by encouraging open-label studies [26 –29] suggesting that risperidone efficacy was comparable to that of haloperidol and pimozide, while the adverse effects were less pronounced and less frequent. Gaffney et al. [30] reported on a randomized double-blind comparative trial of clonidine and risperidone which found, somewhat surprisingly, that both agents were equally efficacious in reducing the tic severity. In the double-blind placebocontrolled trial of risperidone in 48 patients with TS who were randomly assigned to either risperidone or placebo treatment [12] risperidone at a median dose of 2.5 mg/day (dose range of 1– 6 mg) was found to be significantly more effective than placebo. Sixty percent of the risperidonetreated group improved versus only 26.1% of the placebotreated group. Contrary to previous case reports [31], no increase in obsessive – compulsive symptoms was noted in the Dion study. The most common adverse effects of treatment with risperidone include sedation, increased appetite and weight, and increased prolactin levels. Although extrapyramidal symptoms may occur, these are much less frequent than with haloperidol or pimozide. Dysphoria and depression may occur in predisposed individual during treatment with risperidone [32]. Reports of olanzapine efficacy in the treatment of TS patients are beginning to emerge. These include case reports [33] and open-label studies [34,35]. All of these suggested that olanzapine has good efficacy and tolerability. There is also a small 52-week double-blind crossover study of olanzapine versus pimozide in four patients, which found that both olanzapine and pimozide reduced tics significantly [9]. Based on this limited experience, most frequent adverse effects include excessive sedation and increased appetite and weight. There are concerns that with long-term treatment, some patients gain weight [36] and may develop disturbances of glucose metabolism [37]. Significant disturbances in lipid metabolism may be present even in the absence of large weight gain [38], hence, regular monitoring is required. The association between antipsychotic treatment and weight gain has provoked considerable concern in recent years as the atypical antipsychotics gained wide acceptance. There is some suggestion that at least in patients with
Table 1 Antipsychotic medications used to treat tics in TS Generic name
Dose range (mg/day)
Fluphenazine Haloperidol Olanzapine Pimozide Quetiapine Risperidone
4.0 – 24.0 0.25 – 6.0 2.5 – 20.0 1.0 – 8.0 100.0 – 600.0 0.25 – 6.0
Sulpiride Ziprasidone
200.0 – 1000.0 5.0 – 40.0
Adverse effects
References
Sedation, irritability, dysphoria, dystonia, akathisia Sedation, dystonia, akathisia, weight gain, dysphoria, galactorhea, anxiety, tardive dyskinesia Weight gain, sedation, hyperlipidemia, glucose metabolism disturbances Akathisia, dystonia, weight gain, ECG changes, depression, anxiety, tardive dyskinesia Sedation, weight loss, weight gain, dizziness, dysphoria Sedation, dizziness, akathisia, dystonia, headache, depressed mood, obsessive – compulsive symptoms Sedation, akathisia, depression, weight gain, galactorhea Sedation, ECG changes
[110 – 112] [9,14,113 – 116] [9,35,40] [13,114,117 – 120] [44,121,122] [31,38,122 – 125] [62,126] [42]
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schizophrenia, increased weight is associated with better treatment response [36]. It is unknown whether this association holds true in the treatment of tics, however, weight gain has been frequently a reason for discontinuation of treatment in TS patients, especially with olanzapine and risperidone. Although atypical antipsychotics have been associated with increased glucose levels and new onset diabetes [39], one has to be aware also of the possibility of asymptomatic hypoglycemia during treatment with olanzapine [40]. In view of the concerns about weight gain, there is hope that a novel agent ziprasidone may be an effective treatment for tics with minimal risk of inducing unacceptable weight gain [41]. Only one preliminary study in Tourette patients has been published to date [42], with encouraging results. Twenty-eight children and adolescents were randomly assigned to either ziprasidone or placebo and treated for 56 days. Ziprasidone at the mean dose of 28.2 mg was significantly more effective than placebo in reducing the tic frequency and severity. The treatment was well tolerated. The most common adverse effect was transient mild sedation. The change in weight was the same in ziprasidone as in the placebo group. There was a transient increased in serum prolactin and no other laboratory abnormalities. Although concerns have been raised about the risk of prolonged QT interval during treatment with ziprasidone, there is some evidence that the mean prolongation of the QT interval due to ziprasidone is comparable to that seen with risperidone and quetiapine and much smaller than that seen with thioridazine [43]. Nevertheless, it is prudent to obtain a baseline ECG before starting treatment with ziprasidone to detect any preexisting conduction defect that might contraindicate the use of this medication. Similarly, one should avoid combining ziprasidone with other medications that are known to prolong the QT interval, e.g., other typical and atypical antipsychotics and tricyclic antidepressants. Quetiapine is another agent with relatively low propensity to induce weight gain. To date, only case reports have appeared suggesting that quetiapine may be an effective treatment for tics. It appears that relatively high doses are required, on the order of 200 –500 mg/day [44,45].
Other treatments Nicotine and mecamylamine Evidence from animal studies suggests that nicotine can augment catalepsy induced by dopamine receptor antagonists [46,47]. Based on such considerations, open-label studies of nicotine augmentation of haloperidol treatment in patients with TS suggested a possible benefit with regard to tic frequency and severity. There are reports that nicotine administered in chewing gum [48] and as a transdermal patch [49] reduced tic frequency in some TS patients. This early literature, however, was based on case studies or short
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series of cases without adequate controls. Surprisingly, there have been case reports suggesting that single application of a transdermal nicotine patch for 24 h may have reduced tics for up to 4 weeks [50 – 52]. A recent paper by Silver et al. [49] is the best attempt to assess the efficacy of transdermal nicotine and haloperidol in treating patients with TS. This was a double-blind placebo-controlled study lasting 33 days, where 27 patients were treated with nicotine and 29 with a placebo patch in addition to haloperidol. There was a significant reduction in clinician-rated global improvement scale of TS in the nicotine group, however, it was not clearly demonstrated on the Yale Globe Tic Severity Scale Scores. It is of note that 23% of the patients in the nicotine group and 20% of the placebo group were withdrawn because of adverse effects or recurrence of symptoms. The most common adverse effects in the nicotine group were nausea and vomiting. These observations are tantalizing but await a replication from other centers. Moreover, it is unclear how frequently nicotine needs to be applied in order to be effective. Importantly, the balance of evidence would suggest that nicotine alone does not provide significant benefits. Similarly, a pure nicotinic receptor antagonist mecamylamine does not appear to be effective in reducing tics on its own [53], although it may be helpful in combination with dopamine receptor antagonists and/or clonidine [54]. Tetrabenazine The first report of using tetrabenazine to treat symptoms of TS appeared in 1974 [55]. Jankovic et al. [56,57] reported beneficial effects on the frequency and severity of tics based on uncontrolled series of cases. Tetrabenazine doses ranged from 25 to 150 mg/day. Tetrabenazine is not associated with a risk of tardive dyskinesia, however, it can occasionally cause extrapyramidal symptoms and depression. Prospective, well-designed studies are required to confirm tetrabenazine safety and efficacy in comparison with placebo and other agents. Marihuana (tetrahydrocannabinol) The putative beneficial effects of marijuana on tics have been reported as early as 1988 by Sandyk and Awerbuch [58] who observed a significant benefit in three patients. Despite such clinical lore, there has been only one very recent report of a randomized double-blind placebo-controlled crossover single dose trial of Delta-9-tetrahydrocannabinol in 12 adult TS patients [59]. There was improvement in tics on subjective rating and to a lesser extent on objective rating of motor and vocal tics. A companion paper from the same group found no untoward effects on a range of neuropsychological measures [60]. One must keep in mind, however, that this was a single-dose study and both efficacy and safety of this intervention must be assessed in longer-term studies to determine whether Delta-9-tetrahydrocannabinol has any therapeutic utility.
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Sulpiride Although not available in North America, sulpiride is a first-line treatment for TS in Britain and several European countries [61,62]. The efficacy seems similar to other antipsychotics. As with many other antipsychotics, the main ad-verse effects include drowsiness and occasionally depression.
randomized double-blind controlled clinical trial of botulinum toxin for simple motor tics and concluded that the treated tic frequency as well as the urge associated with the treated tic were reduced. However, 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. Clonidine
Anticonvulsants and benzodiazepines It has been suggested that nonspecific EEG abnormalities are more frequent in TS patients than in controls [63]. Several other studies found no significant differences on a variety of EEG measures [64 – 66]. There is no evidence that anticonvulsants can be helpful in the treatment of tics, while there are numerous reports of tics precipitated or aggravated with anticonvulsant treatment [67 –70]. Although case reports of beneficial effects of clonazepam and other benzodiazepines have appeared for the past 20 years [71 –73], no systematic study of the benefits of clonazepam has been reported either as a stand alone treatment, or as a treatment in combination with dopamine receptor antagonists. Nevertheless, clinical experience suggests that clonazepam can be helpful in selected cases of TS [73] and clonazepam continues to be mentioned in this role in reviews of pharmacological therapy of tics, e.g., Refs. [62,74 – 76]. Baclofen An interesting report by Awaad [77] compared the efficacy of baclofen and Botox injection in a large number of children with TS. Tics were evaluated by videotape recording and rated by blinded raters. Unfortunately, the subjects were not randomized to each treatment. Nevertheless, he found that 250/264 patients on baclofen treatment experienced a significant decrease in the severity of tics. Adverse effects included sedation and drowsiness. A recent small doubleblind 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 [78]. Botulinum toxin In addition to the use of pharmacological agents with systemic effects, there is growing evidence to support the use of local injections of botulinum toxin for the treatment of motor and, sometimes, vocal tics. Initially, botulinum toxin injection was used for selected severe cases [79 – 81]. Other case reports and case series followed [82 – 84]. In the above-mentioned report by Awaad [77], Botox injections were effectively controlling motor tics in 35/186 patients. The effect of Botox injections on vocal tics was minimal. Adverse effects included temporary soreness and mild muscle weakness. Marras et al. [85] published the first
Case reports of clonidine effectiveness in TS appeared in the early 1980s [86] and open-label trial evidence has been contradictory [87,88]. Single, blind, placebo-controlled trial of 13 patients demonstrated a significant improvement in 6 out of 13 patients [89]. A larger open-label trial was less positive [90]. The problems in management of tics with clonidine include the possibility of a paradoxical increase in tics [91] and marked increase in tics after stopping clonidine suddenly [92]. Placebo control trials showed that treatment with clonidine reduces tics severity and frequency [93], although another study by Goetz et al. [94] found no difference between clonidine and placebo. In the most recent, largest and well-designed trial, which included a placebo group, clonidine reduced tics significantly, while the only adverse effect was sedation [95]. The preponderance of evidence supports the use of clonidine as a potentially effective treatment for TS patients that may reduce mild to moderate tics and improve attention. In addition, clonidine tends to reduce anxiety and alleviate initial insomnia. The adverse effects tend to be mild and transient, most commonly daytime sedation and lightheaded feelings. Thus, clonidine is a useful first-line treatment for many children and adults with diagnosis of TS. Guanfacine Guanfacine has been suggested as a better-tolerated alternative to clonidine. The initial open-label study suggested that guanfacine treatment could have beneficial effects on both tics and attentional problems in patients with TS [96]. These initial impressions were confirmed by randomized placebo-controlled double-blind trial of an 8-week duration [97]. Without a direct comparison study, it is unclear whether guanfacine is indeed better tolerated than clonidine. There is a concern that guanfacine has a propensity to induce mania in children with personal or family history of bipolar disorder [98]. Dopaminergic agonists An experimental treatment emerged recently involving the use of dopaminergic agonists in treatment of symptoms of TS. The assumption is that the stimulation of the presynaptic dopamine receptors symptoms may lead to down-regulation of the dopamine release into the synaptic cleft, however, this may be too simple an explanation.
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Nevertheless, these observations suggest that instead of the simple model of excessive activity of dopamine system, we need to consider the concept of dopaminergic dysregulation explored in recent imaging studies [99,100]. Small studies with pergolide showed promising results [101,102]. These were confirmed in a randomized placebo-controlled trial studying 24 children and adolescents with TS, where pergolide treatment was significantly more effective in reducing tics severity compared to placebo [103]. The treatment was well tolerated. A very small, single, blind pilot study of levodopa with carbidopa pretreatment showed a significant reduction in tic severity on both subjective and objective measures [104]. Opioid receptor agonists and antagonists A few case reports drew attention to the possible involvement of the endogenous opioids in neurophysiology of TS [105,106]. Randomized double-blind placebo-controlled trial of propoxyphene and naltrexone in 10 adults with TS showed that naltrexone improved the tics, but only on a subjective measure of tic severity in contrast with placebo or propoxyphene. Similarly, naltrexone treatment was associated with a modest improvement on tests of attention, which was not present with placebo or propoxyphene [107]. The dose level of opiate receptor antagonists appears to be rather important because it has been demonstrated that low-dose naloxone infusion decreases the tics while high doses cause a significant increase in severity compared to the baseline [108]. In summary, only weak evidence supports a possible therapeutic effect on patients with TS, of agents that interact with the opioid system.
An approach to the management of tics An accurate diagnosis of TS accompanied by a systematic enquiry regarding the presence or absence of Attention Deficit Hyperactivity Disorder, Obsessive – Compulsive Disorder, behavioral disturbances such as rage and sleep disturbances is a necessary first step. The diagnostic process must be based on a careful history and direct observation. It is useful to create a hierarchy of symptoms according to their intrusiveness, i.e., to assess the impact of the various symptoms on the patient’s ability to function in various spheres, e.g., at home, at school or at work. This is not directly related to the severity of symptoms since patients vary as to their ability to tolerate a given degree of symptoms. Similarly, the people that the patient comes into contact will have widely differing tolerance for patients’ symptoms. The response of the environment is an important determinant of how disabling a given symptom may be. When planning the treatment, it is logical to address the most intrusive symptoms first. It is useful to document the severity of symptoms in a systematic manner, e.g., utilizing TSGSS to record the type,
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frequency and intensity of various tics because this will be important in evaluating the response to treatment. The decision whether to treat is based on evaluating whether and to what extent the target symptoms impair patient’s function at home, at school or at work. If it is clear that educational success, psychosocial adjustment or family relations suffer as a result of the symptoms, it is justifiable to consider pharmacological intervention. In this context, one must keep in mind that tics tend to fluctuate spontaneously as well as in response to external events, e.g., tics often tend to decrease during vacation time and increase a few days before return to school. It is important not to confuse such fluctuations with therapeutic response or therapeutic failure. When TS alone is present, the treatment is aimed to reduce the frequency and intensity of tics. Clonidine represents the first line of treatment because of favorable adverse effects profile. Moreover, it is likely, that in addition to reducing tics, it can also improve initial insomnia and reduce the symptoms of ADHD. To minimize the risk of sedation and lightheadedness, the dose should be increased gradually over a period of a couple of weeks, starting with 0.025 – 0.05 mg at bedtime and aiming at a total daily dose of 0.15 – 0.3 mg. Typically, one-third of the daily dose is given in the morning, and two-thirds in the evening to minimize daytime somnolence. The therapeutic response may not become apparent for 2 or 3 months. Hence, an adequate treatment trial should last about three months. The odds of treatment response are about 50%. If a trial of treatment with clonidine is unsuccessful, one may move to treatment with low doses of dopamine receptor antagonists listed in Table 1. Once again, the treatment should begin with a low dose that may be increased gradually. The frequency of dose change is guided by the elimination half-life of each drug, and, typically, a dose would be increased every 1 or 2 weeks. Therapeutic response may be expected in a matter of days once an effective dose has been reached. The most common adverse effects include sedation, increased appetite and extrapyramidal symptoms such as restlessness, tremor, and rigidity or dystonic reaction. The issue of potential weight gain is best addressed at the outset because preventing weight gain is easier than weight reduction. A healthy, balanced diet and sufficient exercise needs to be discussed with each patient since at the moment, there are no reliable predictors of who is at risk of significant weight gain. Two newer antipsychotics agents, quetiapine and ziprasidone, seem to have the lowest propensity for inducing weight gain, however, there is only preliminary evidence that these agents are effective in suppressing tics. Tetrabenazine represents a useful alternative for those patients who cannot tolerate antipsychotic treatment. Although controlled randomized trials are lacking, large series of cases would suggest that it is quite effective in reducing tics with a relatively low risk of inducing EPS.
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While it does not induce weight gain, there is a risk of depression in some individuals. If none of the above treatments are effective, a trial of treatment with a dopamine agonist is warranted, although there is only preliminary evidence of efficacy. Rage and aggressive behavior are present in about onethird of the clinical population of children with TS and as such represent a major management challenge. A psychosocial approach to management is described elsewhere in this issue (Greene et al.). It appears that risperidone [109] is rather effective in reducing the frequency and intensity of rage in this population. The subject is discussed in more depth elsewhere in this issue (Budman et al.). The management of comorbid conditions, namely, ADHD and OCD, are also covered elsewhere in this issue. (See articles by Dr. Kurlan and by Dr. Miguel.) The approach to treatment of tics in TS patients, described above is based on best available evidence. Despite a growing number of published clinical trials, much remains to be done, and the treatments that we offer continue to be palliative. Addressing the disorder more directly awaits further advances in our understanding of the basic mechanisms of TS.
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