Original Authors: Paul Perry, Ph.D, BCPP, Gary Gaffney,
M.D.
Latest Revisers: Paul Perry, Ph.D, BCPP, Gary Gaffney,
M.D.
Creation Date: 1996
Peer Review Status: Internally Peer Reviewed
TIC DISORDERS (TOURETTE'S SYNDROME)
Diagnostically tic disorders are subdivided into simple tic disorder characterized by a single vocal or motor tic; chronic tic disorder which presents with various vocal or motor tics; and Tourette's Syndrome (TS) which is distinguished by both vocal and motor tics. Simple tics are benign and rarely require pharmacologic intervention. However, this is not the case for either chronic tic disorder or TS. They can present with a severe neuropsychiatric syndrome during childhood and have a lifelong duration. More specifically, TS is characterized by involuntary, repetitive, phonic and motor tics occurring with different patterns of frequency and intensity over one year or more. The motor tics most commonly involve the head, but could involve the torso and limbs. Coprolalia, or uncontrolled shouting of obscenities, is the phonic tic in 30% of cases. The tics must last one year or more for a diagnosis of TS. Symptoms are greatly reduced during sleep, can often be voluntarily controlled for short periods of time, and wax and wane over weeks to months. Severity of symptoms varies between patients, and only children and adults whose relationships, performance, and self-esteem are impaired require medical treatment. TS is often accompanied by attention deficit disorder, obsessive compulsive disorder, pathological impulsivity, motor hyperactivity, learning disabilities, and nonspecific behavioral abnormalities. Lifetime prevalence is estimated to be between 0.04% to 0.4%.
A chronic tic disorder or TS that causes a patient significant dysfunction often benefits from pharmacotherapy. The most common approach to treatment is the use of low dose neuroleptics (haloperidol, pimozide, and risperidone) because of their effectiveness in reducing tics. Besides the neuroleptics, clonidine and nicotine have been studied in controlled trials to assess their efficacy in the treatment of TS. Additionally, there are positive case reports suggesting clonazepam, beta-blockers, TCAs, and calcium-channel blockers are of potential utility in the treatment of TS. However, we are only considering the controlled efficacy drug trials in the treatment of TS (Shapiro et al 1989).
Neuroleptics - Efficacy
Dopamine blocking agents have been used extensively in the treatment of TS. The effectiveness of neuroleptics in TS is primarily a function of their ability to reduce tics. Haloperidol has become the treatment of choice for patients with TS, and it is effective in about 70% of cases (McConville et al, 1992). The FDA approved haloperidol for the treatment of adults with TS in 1969 and children (<12) yo) in 1978. Haloperidol is a butyrophenone neuroleptic that binds to DA receptors preferentially D2 rather than D1, and has little for the alpha-2 adrenergic receptor. Doses range from 2 to 15 mg/day. Pimozide, another neuroleptic, has a reported mechanism of action of selectively binding to central dopamine receptors, preferentially D2 receptors (Shapiro et al, 1989). The FDA has approved pimozide only for the treatment of patients with severe TS refractory to standard treatment because of ECG abnormalities which may increase the risk for fatal arrhythmias. A baseline ECG is required before treatment and periodically during treatment. The studies presented below show that ECG abnormalities are no more severe with pimozide than haloperidol, and do not reach the abnormal range, but caution still must be exercised when using this drug.
Shapiro et al (1989) contrasted the effectiveness of haloperidol, pimozide, and placebo using a double-blind 6-week parallel design evaluation of all three treatments followed by a 6-week crossover design evaluation of the two neuroleptics in the treatment of TS (DSM-III).. In the parallel design 20 patients received pimozide (11±7 mg/d, or 0.18±0.12 mg/kg/d or < or = 20 mg/d), 18 received haloperidol (5±3 mg/d, 0.08±0.05 mg/kg/d or < or = 10 mg/d), and 19 were assigned to placebo. Fifty five of the 57 patients entered the crossover portion of the study. Response was measured on various scales by the physician and the patient, as well as a judge who evaluated videotapes of patients under various conditions. Haloperidol was judged slightly more effective than pimozide while both neuroleptics were more effective than placebo. In the parallel design portion of the study, haloperidol reduced motor tics from 32 to 21 tics/min while phonic tics were decreased from 2.7 to 0.7 tics/min. Pimozide produced similar results reducing the motor tics from 32 to 17 tics/min while phonic tics were decreased from 2.7 to 1.7 tics/min.. Adverse effects were higher with both drugs than placebo, but not significantly different between the drugs. Akinesia, depression, cognitive dulling, loss of motivation, increased appetite, and weight gain were the most common ADRs observed. No clinically significant changes in ECG were noted with either drug. A prolonged QTc interval was seen with pimozide, but it did not extend into the abnormal range.
Sandor et al (1990) conducted a long-term (1-15 years) follow-up study of 33 TS patients comparing haloperidol (2-15 mg/d, 5.5±4 mg/d), pimozide (2-18 mg/d, 9±6 mg/d) or no drugs. They found that relief of symptoms was similar from both drugs. Seventy percent of the pimozide group and 78% of the haloperidol group reported moderate to marked improvement in symptoms as assessed by a subjective self report. The subjective Tourette's Syndrome Global Scale (TSGS) found the neuroleptic treatments equally effective and more effective than no treatment. Of the two drugs, pimozide appeared to be better tolerated as inferred by the higher discontinuation rate in the haloperidol group. Haloperidol caused more acute dystonias and akathisia than pimozide, but both were equal in the rate of other adverse effects, most notably stiffness, drowsiness, dizziness, dry mouth, and endocrine problems. No increased incidence of ECG abnormalities occurred in the pimozide group despite the warnings in the literature.
Three open trials of TS treatment with risperidone have been conducted (van der Linden et al 1994, Lombroso et al 1995, Bruun and Budman 1996). However, only one study was able to discontinue all concomitant medication prior to the start of the risperidone treatment. van der Linden et al (1994) treated 11 TS patients (10 male, 19-52 yo) with risperidone 2-6 mg/d for 4 weeks. Nine patients completed the trial. A rater-scored visual analogue scale demonstrated that the severity of the symptoms decreased from a baseline of 71 to 20 after 4 weeks of treatment. The CGI scale item that rated clinical improvement also suggested that significant improvement occurred with risperidone treatment.
ADRs. The use of neuroleptics in TS patients is accompanied by the concern of neuroleptic-tardive dyskinesia. This may not be as great as concern as one might think. Wolf and Wagner (1993) reported that the prevalence rates for TD in adolescents and children ranged from 1 to 4.8% which is considerably less than the 20% rate observed in adults. In TS, this observation may be related to the small neuroleptic doses required to produce a beneficial effect on motor and phonic ticks.
Nicotine - Efficacy
Nicotine has been shown to potentiate the cataleptic effects of haloperidol in animals nearly tenfold. Thus it was reasoned by McConville et al (1992) that nicotine might have a similar adjunctive effect in neuroleptic responsive neurological disorders such as TS that are characterized by excessive motor activity. They evaluated the effects of nicotine gum on 19 aged between 8-46 years. Ten of the patients were haloperidol (1-10 mg/d) refractory patients who had been symptomatic for 24 to 300 months The other nine were previously unmedicated TS patients who had been symptomatic for only 2-6 months. (The TS diagnosis requires symptoms to be present for a year.) With each patient serving as their own control, the effects of nicotine gum 2 mg (n=5), nicotine gum plus haloperidol (n=10), and placebo gum (n=4) were evaluated. Based on the results of a two hour videotape consisting of a 30 minute baseline, 30 minutes of chewing, 60 minutes after chewing the frequency and severity of the tics were quantitated. Patients on haloperidol had significant reductions in tic severity and frequency while chewing the gum and for the 60 minutes thereafter. The patients only chewing nicotine gum decreased tic frequency during chewing and for 30 minutes thereafter. Placebo gum had no effect. Thus it was concluded that nicotine gum markedly potentiated the haloperidol effects in treating TS. The treatment may be clinically useful as a prn adjunctive agent to haloperidol in stressful public situations when the patient requires immediate relief of the tics.
Dursun et al (1994) conducted an open trial in 5 TS patients using transdermal nicotine patches. Only 1 of the 5 TS patients was haloperidol-free during the trial. Their results showed that two 10 mg patches applied over 48 hours reduced tics of non-smoking TS patients with no reported ADRs for up to 4 weeks by 50% but at 16 weeks the effect was no longer significant.
Methylphenidate - Efficacy
Using a double-blind crossover design Gadow et al (1992) administered methylphenidate 0.2, 0.6 and 1.0 mg/kg/d and placebo for two weeks each to 11 boys (6-12 yo) diagnosed with the concomitant DSM-III-R diagnoses of ADHD and either chronic motor tic disorder or TS. MPD as expected reduced the ADHD behavior of hyperactivity and disruptive behavior in the classroom and physical aggression in the lunchroom and playground. Overall, motor tics neither improved nor worsened on MPD. Although not significant, the lowest rate of motor tics occurred at 0.6 mg/kg/d. One boy had an exacerbation of his tics while on MPD. Interestingly, vocal tics actually were significantly decreased on the MPD 0.6 and 1.0 mg/kg/d doses. The importance of this study is that it suggests stimulants such as MPD are not contraindicated in the treatment of ADHD in TS patients. The older literature has suggested that stimulants will worsen tics in TS patients.
Fluoxetine - Efficacy
Kurlan et al (1993) evaluated the effectiveness of the SSRI, fluoxetine, in the treatment of obsessions and compulsions in TS patients. The purpose of this study was to determine if the SSRI could decrease obsessions and compulsion and not to determine if fluoxetine could decrease tic frequency. Six of the 11 subjects were allowed to take either haloperidol or clonidine during the four month trial. Eleven male TS (DSM-III-R) patients (10-18 yo) were randomized to either a 4 month course of fluoxetine 20-40 mg/d or placebo. OCD symptoms were not ameliorated by the fluoxetine. Unsurprisingly, neither the motor nor the phonic tics improved with fluoxetine treatment. However, there was a trend toward improvement in tic severity, attention, and social functioning thereby suggesting the highly likely possibility of a type II error. The authors noted that in clinical practice their TS patients with the most severe obsessions and compulsions have responded. ADRs were characterized as "minimal" with complaints of hypomanic behavior, irritability, fatigue and agitation.
The fluoxetine ADRs may be a somewhat more serious problem. Riddle (1990/1991) described his ADR experience with 24 children and adolescents with diagnoses of OCD (17), TS (4), MDD (2), and trichotillomania (1) who were treated with fluoxetine 20-40 mg/d. Twelve (50%) of the patients experienced behavioral ADRs that included: motor restless (45%), sleep disturbance (45%), social disinhibition (25%) and subjective sensation of excitation (13%). Halving or discontinuation of the fluoxetine resulted in resolution of the ADRs. This reaction is similar to that occurring in panic disorder patients whose antidepressant dose is titrated upward too quickly. The "jitteriness syndrome" or "hypersensitivity" reaction was described by Pohl et al (1988). Forty-nine of 158 patients (30 %) with panic disorder developed this reaction in one retrospective study. Symptoms included jitteriness, shakiness, increased anxiety, and insomnia. Though TCA doses were most often started at ten mg/d symptoms still occurred. It appears with initial doses and tolerance develops over seven to ten days (Pohl et al 1988). However, if tolerance does not develop within this time period, it is unlikely to occur. Desipramine was reported to be more likely to produce this adverse effect than imipramine, based on retrospective data (Pohl et al 1988). Thus the clinician should expect that minors will experience the same behavioral ADRs as adults when treated with SSRIs such as fluoxetine or TCAs such as desipramine.
Alpha2 agonists - Efficacy
Clonidine has been scrutinized in a controlled trial as a potentially useful agent for the treatment of TS. Goetz et al (1987) conducted a 6 month, placebo controlled, double-blind, crossover study that evaluated the efficacy of clonidine in the treatment of TS. Thirty patients (23 males, and 7 females) TS (DSM-III) 8-62 years old (mean = 19 years old) completed the 6 months cross over study. The dose was titrated over a 6-week period to either 7.5 or 15 mcg/kg/d. A one week washout period was allowed between treatments. Nineteen patients were neuroleptic-free while 11 required either haloperidol, fluphenazine or trifluoperazine. The patients showed no significant improvement in motor tic distribution, frequency, or severity in patients on clonidine. It did not matter if the patients were or were not receiving neuroleptics. Comparisons were also made between bid. and tid. clonidine dosing, and low (7.5 mcg/kg/d) and high (15 mcg/kg/d) doses. Again no significant difference was found between either treatment group. Despite these discouraging findings, 43% of patients felt that they improved overall during treatment with clonidine, and 53% elected to stay on the drug after completion of the study, including some patients who did not subjectively or objectively improve but merely wanted to remain off neuroleptics.
Leckman et al (1991) hypothesized that the tics result from excessive firing of NE stimulated adrenergic CNS neurons. Theoretically clonidine can decrease the firing rate of and release of norepinephrine from central neurons, and indirect modulation of the firing of dopamine neurons due to its a2 adrenergic receptor agonist activity. Forty TS (DSM-III) patients completed a 12-week double-blind trial of clonidine (n=21) versus placebo (n=19). The patients ranged in age from 7 to 48 years (mean = 16 years) and had been symptomatic for 2 to 12 years. Clonidine was titrated over a two week period to a final dose that ranged from 3.2-5.7 mcg/kg/d (mean = 4.4 mcg/kg/d). The clonidine treated patients improved 26% over baseline compared to 11% improvement on placebo as determined by the TSGS. The total motor tic score showed the greatest improvement while on clonidine. Common side effects included sedation and fatigue reported in 90% of patients. Other ADRs included dry mouth, dizziness, and irritability. Vital signs were unchanged over the 12 weeks. No patient dropped out because of ADRs.
An important observation regarding the treatment of tic disorders in patients with ADHD has been reported by Steingard et al (1993). They investigated the effect of clonidine in the treatment of ADHD with and without comorbid tic disorders. Clonidine has been suggested as an alternative pharmacotherapy for patients comorbid for both ADHD and tic disorders. To examine the efficacy of clonidine in this population of children, the use of clonidine in the treatment of children with ADHD with and without comorbid tic disorders was examined in a retrospective chart review of 54 children over a 4-year period. Treatment was administered openly to these patients and response was assessed using clinical global improvement measures. Overall, clonidine treatment resulted in improvement in 72% (39/54) of all of the ADHD subjects and 75% (18/24) of the subjects who had tic disorder as well as ADHD. Thus 96% (23/24) of the ADHD plus tic disorder subjects responded to clonidine while only 53% (16/30) of the ADHD only responded. This report lead to speculation that clonidine was the drug of choice in the treatment of ADHD subjects with concomitant tic disorders. Open trial data with guanfacine also suggested that this might be the case. Chappel et al (1996) treated 8 patients with ADHD and TS diagnoses with guanfacine 0.75-3.0 mg/d for 4-20 weeks. Other medication was washed out for a period of 1 month prior to the start of therapy. Subjectively, the parents noted no improvement of the ADHD symptoms according to the scores on the Connor's Parent Rating Scale. However, the objective scores derived from the Continuous Performance Test demonstrated overall improvement in attention and decreased impulsivity. As with clonidine, the improvement in the tics was not as robust as typically observed with neuroleptics. Motor tics improved 8%, objectively and 40%, subjectively while vocal tics improved 21% according to the objective ratings and 38% according to the subjective ratings. Thus guanfacine appeared to be a reasonable alternative treatment in the children comorbid with ADHD and TS. However, the hope that alpha2 agonists would be the drugs of choice for patients with comorbid tic disorders and ADHD were dealt a severe blow by a controlled trial that found that the TCA, desipramine, was actually more effective than clonidine in this patient population. Singer et al (1995) using a crossover design 37 TS/ADHD (7-13 yo) received 6 week trials of clonidine 50 mcg po qid, desipramine 50 mg po qid, and placebo. Desipramine was more effective than clonidine and placebo in the treatment of the ADHD and tics while neither drug was effective in the treatment of the obsessions and compulsions.
Calcium Channel Blockers - Efficacy
The literature has various case reports of calcium channel blockers (CCBs) being effective in patients with TS (Berg 1985, Goldstein 1984, Walsh et al 1986). Verapamil and nifedipine appear to be effective, but diltiazem does not. CCBs are known to have CNS activity. A possible mechanism is reduced calcium influx to the presynaptic neuron which results in decreased release of transmitters. All patients described in the case reports had been treated with a neuroleptic and/or clonidine except for one patient who was drug naive. Two of the 5 cases showed a favorable response in 30 minutes, all patients continued to take the drug, and the response lasted to the time of the report in all cases, up to 9 months. No bothersome side effects have been reported with the exception of one woman who discontinued nifedipine due to flushing and tachycardia. Diltiazem was initiated with no response, and 2 weeks later she requested to be restarted on nifedipine. Despite the age of these case reports, no subsequent trials of CCBs available in the United States can be found in the literature.
Summary
The controlled drug trials in the treatment of TS are presented in Table 1. Haloperidol and pimozide are effective in 70% of patients. However, because a more conservative approach of reserving it for severe or refractory cases because of its risk of EPS ADRs may be desired, risperidone might be a useful alternative neuroleptic. However, controlled trials are still not completed. Pimozide appears to have a lower EPS risk compared to haloperidol, and it may worthwhile to utilized this neuroleptic if EPS is a problem. However, it should be remembered that many patients respond to haloperidol doses (1-2 mg/d) that are low enough such that EPS is not problem. The use of nicotine on a prn basis to potentate the action of haloperidol during stressful periods could allow for the use of lower doses which may reduce the occurrence of the EPS ADRs. The value of the SSRIs to treat the obsessions and compulsions associated with TS remains to be resolved. Clinically they appear effective despite the finding in a small controlled trial that they were not. Patients with TS appear to be responsive to alpha2 agonists, although not nearly to the extent of the neuroleptics. Clonidine or guanfacine potentially may be the drug of choice in patient with concomitant ADHD and tic disorders. The paucity of clonidine-induced ADRs is impressive, especially when one considers the number of patients who desired to remain treated by it without response merely to remain off neuroleptics. The CCBs represent a promising new class of drugs as judged by early reports of their use. Although more research needs to be conducted in this area, a trial of verapamil or nifedipine could be considered in a refractory patient or one unwilling to take other drugs because their side effect profile.
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Table 1. Controlled pharmacotherapy studies in Tourette's syndrome. |
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|
Study |
Dose |
Population |
Results |
|
Shapiro et al 1989 |
HLP 0.08 mg/kg/d (18), |
57 TS (DSM-III) |
HLP sl > PMZ > PLB |
|
McConville et al 1989 |
10 HLP 1-10 mg/d & tx-refractory |
19 TS (DSM-III) 8-46 yo |
HLP patients: |
|
Sandor et al 1990 |
HLP 5.5±4 mg/d, PMZ 9±6 mg/d, no drugs 1-15 yr f-up |
33 TS 9-50 yo |
Moderate-marked relief: HLP 78%, PMZ 70% |
|
Gadow et al 1992 |
MPD 0.2. 0.6, and 1.0 mg/kg/d vs placebo x 2 wk each |
ADHD + TS or chronic motor tics n = 11 males 6-12 yo |
MPD decreased vocal tics at 0.6 and 1.0 mg/kg/dose but not 0.2 motor tics not improved but best response was to the 0.6 mg/kg/d dose |
|
Kurlan et al 1993 |
FLX 20-40 mg/d vs placebo x 4 months |
OCD (17) |
FLX = placebo |
|
Goetz et al (1987) |
CLD 7.5-15 mcg/kg/d vs placebo |
TS |
19/30 required neuroleptics no effect on tics |
|
Leckman et al (1991) |
CLD 3.2-5.7 mcg/kg/d vs placebo |
TS |
motor tics improved the most vs placebo, 26% vs 11% |
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