Tic Reduction With Risperidone Versus Pimozide in a Randomized, Double-Blind, Crossover Trial

Tic Reduction With Risperidone Versus Pimozide in a Randomized, Double-Blind, Crossover Trial DONALD L. GILBERT, M.D., J. ROBERT BATTERSON, M.D., GOPALAN SETHURAMAN, PH.D., FLOYD R. SALLEE, M.D., PH.D.

AND

ABSTRACT Objective: To compare the tic suppression, electrocardiogram (ECG) changes, weight gain, and side effect profiles of pimozide versus risperidone in children and adolescents with tic disorders. Method: This was a randomized, doubleblind, crossover (evaluable patient analysis) study. Nineteen children aged 7 to 17 years with Tourette’s or chronic motor tic disorder were randomized to 4 weeks of treatment with pimozide or risperidone, followed by the alternate treatment after a 2-week placebo washout. The primary efficacy outcome measure was change in tic severity assessed by the Yale Global Tic Severity Scale (YGTSS). ECG results, weight gain, and side effects were also compared. Results: Compared to pimozide treatment, risperidone treatment was associated with significantly lower tic severity scores (YGTSS: baseline 43.3 ± 17.5, pimozide 34.2 ± 14.2, risperidone 25.2 ± 13.6; p = .05). Weight gain during the 4-week treatment periods was greater for risperidone (mean 1.9 kg) than pimozide (1.0 kg). No patient suffered a serious adverse event, but 6 of 19 subjects failed to complete the protocol. Neither medication was associated with ECG changes. Conclusions: In this study, risperidone appeared superior to pimozide for tic suppression but was associated with greater weight gain. J. Am. Acad. Child Adolesc. Psychiatry, 2004;43(2):206–214. Key Words: risperidone, pimozide, Tourette’s disorder, children, electrocardiogram.

Tourette’s disorder is a neuropsychiatric disorder characterized by motor and phonic tics (American Psychiatric Association, 2000). Symptoms are often mild, but in some cases tics can be functionally or socially impairing or painful. In these cases, treatment with ticsuppressing medications may be helpful. Numerous prior studies support the efficacy of typical dopamine 2 (D2) receptor blocking agents such as haloperidol or pimozide for the treatment of moderate

Accepted September 16, 2003. From the Departments of Neurology (Dr. Gilbert) and Psychiatry (Drs. Sethuraman and Sallee), Cincinnati Children’s Hospital Medical Center; Division of Developmental and Behavioral Sciences, Children’s Mercy Hospital, Kansas City, KS (Dr. Batterson). This research was supported in part by TEVA pharmaceuticals and by NINDS K23 NS41920-01 (D.L.G.). The investigators gratefully acknowledge the time and efforts of the families who participated in this study, and the skilled assistance of study coordinators Sara Peters, Christine Kuess, and Allen Setmayer. Correspondence to Dr. Gilbert, Division of Neurology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039; e-mail: [email protected]. 0890-8567/04/4302–0206©2004 by the American Academy of Child and Adolescent Psychiatry. DOI: 10.1097/01.chi.0000100425.25002.94

206

to severe tics (Ross and Moldofsky, 1978; Sallee et al., 1997; Shapiro and Shapiro, 1984; Shapiro et al., 1989; Tourette Syndrome Study Group, 1999). However, side effects such as sedation, restlessness (akathisia), mood changes, extrapyramidal symptoms, and tardive dyskinesia (Bruun, 1988; Mizrahi et al., 1980; Riddle et al., 1987) cause problems in some patients. Discontinuation of haloperidol is common (Silva et al., 1996). Atypical antipsychotics are another option for tic suppression. Open-label (Bruun and Budman, 1996; Lombroso et al., 1995) and placebo-controlled studies (Dion et al., 2002; Scahill et al., 2003) have shown that risperidone reduces tics. One randomized controlled trial suggested that risperidone has equal efficacy to pimozide, with fewer “extrapyramidal-like adverse events” (Bruggeman et al., 2001). Another study suggested that risperidone was no better than the α2adrenergic agonist clonidine (Gaffney et al., 2002). However, risperidone, like typical neuroleptics, has also been implicated in cases of tardive dyskinesia (Hong et al., 1999; Kumar and Malone, 2000; Silberbauer, 1998; Spivak and Smart, 2000). In addition, electrocardiogram (ECG) changes (Glassman and Bigger, 2001) and weight gain merit close scrutiny. ECG

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 43:2, FEBRUARY 2004

PIMOZIDE VS. RISPERIDONE FOR TICS

changes have been reported with pimozide (Fulop et al., 1987), and sudden cardiac death has been reported in conjunction with macrolide antibiotic use and prolonged QT interval (Flockhart et al., 2000). In a randomized trial, weight gain in adolescents during 12 weeks of treatment averaged 4.5 kg with risperidone versus 2.7 kg with pimozide (Bruggeman et al., 2001). Similarly, in an open-label 12-week study, adolescents gained 3.9 kg while taking risperidone versus 1.1 kg while taking haloperidol (Ratzoni et al., 2002). Decisions about atypical agents versus typical neuroleptics for suppression of tics require additional evidence from well-designed studies. The purpose of this clinical trial was to compare, in youths with moderate or severe tics, the benefits and side effects of once-daily pimozide, a typical neuroleptic, to twice-daily risperidone, an atypical agent. METHOD Subjects This protocol was approved by the institutional review boards of Cincinnati Children’s Hospital Medical Center and the Division of Developmental and Behavioral Sciences, Children’s Mercy Hospital, Kansas City, Kansas. Informed consent was obtained from parents of children and adolescents and assent was obtained from adolescents, consistent with institutional policies. Eligible subjects aged 7 to 17 years were recruited through the Tourette’s disorder clinics at participating sites. All children underwent a medical history, general physical and neurological examination, and screening blood testing. Diagnoses of Tourette’s disorder and chronic motor tic disorder were made using DSM-IV-TR criteria as determined by the primary clinical investigators (F.R.S., D.L.G., J.R.B.) using all available clinical information. A Clinical Global Impression of tic severity score of at least 4 (at least moderate) after 2 weeks off all medications was required. DSM-IV criteria were used to evaluate for the presence of comorbid attention-deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). The presence of other axis 1 and II disorders was allowed, provided that the severity of those disorders did not require concurrent medication. Subjects with diagnoses of transient tic disorder, anorexia nervosa, pervasive developmental disorder, substance/alcohol abuse or dependence within the past year, or any psychotic disorder were excluded. Persons with serious or unstable medical illness (e.g., diabetes) or with abnormal ECG or laboratory findings, and sexually active females of childbearing potential not using an effective contraceptive method were also excluded.

executor and the study pharmacist, and then the randomization file was deleted from the statistician’s hard drive and back-up drive. All subjects received placebo for 2 weeks prior to the 2-week visit, at which time the baseline tic severity scores were obtained. Pimozide (1 mg), risperidone (0.5 mg), and placebo were prepared in the study pharmacy in capsules with identical appearance and similar taste. The study pharmacy maintained the randomization code. No events required breaking the code. Patients and physicians were blinded to treatment order throughout the study. Patients were evaluated by the investigator in clinic every 2 weeks and had phone contacts with the study coordinator on the offweeks. Both treatment arms involved 2 weeks of titration of active drug, followed by 2 weeks at a stable medication dose. Both treatments were given twice daily, but the A.M. dose of pimozide was a placebo capsule. The study drug was titrated up at the investigator’s discretion depending on benefit and any side effects. The initial pimozide treatment was placebo in the A.M. and 1 mg at bedtime. The dose could be titrated up weekly to a maximum of 4 mg at bedtime, which was then maintained for the final 2 weeks. The initial risperidone treatment was 0.5 mg in the A.M. and 0.5 mg at bedtime. The dose could be titrated up to a maximum of 2 mg in the A.M. and 2 mg at bedtime, which was then maintained for the final 2 weeks. Doses were increased if symptoms were not improved or were only minimally improved. Doses were held the same if adverse events occurred. Doses and dosing intervals were chosen based on prior published studies used in calculating the sample size for this study (Lombroso et al., 1995; Sallee et al., 1997). Placebo was given for 2 weeks between the active treatments. Efficacy Outcomes The primary outcome of interest was the tic severity at the end of treatment (end of week 6 or 12), measured using the Yale Global Tic Severity Scale (YGTSS) (Leckman et al., 1989). This score is the sum of separate subscales for motor and phonic tics, rated 0 to 5 for number, frequency, intensity, complexity, and interference, plus an overall impairment rating from 0 to 50. As secondary efficacy measures, the investigators performed the Clinical Global Impression-Severity (CGI-S) scale at baseline. The CGI-S is a scale where patients are graded as 0, not assessed; 1, normal; 2, borderline; 3, mild; 4, moderate; 5, marked; 6, severe; and 7, extreme. At the end of each active treatment period, subjects were rated using the Clinical Global Impression of Improvement scale, which rates improvement as 0, not assessed; 1, very much improved; 2, much improved; 3, minimally improved; 4, no change; 5, minimally worse; 6, much worse; and 7, very much worse. Parents also graded symptom severity with the Tic Symptom Self-Report (TSSR) (Cohen et al., 1985). Extrapyramidal Side Effect Assessments At each visit the investigators rated any abnormal (non-tic) involuntary movements using the Abnormal Involuntary Movement Scale and the Extrapyramidal Symptoms Rating Scale (Guy, 1976).

Study Protocol

Cardiovascular Effects

Eligible patients were consented, prescreened, and tapered off all medications prior to the screening visit at week 0, at which time a full screening visit was performed. Subjects were then randomized by cluster (block size = 8, by site) into sequence 1 (pimozide first, risperidone second) or 2 (risperidone first, pimozide second). The statistician generated the allocation schedule prior to the start of the study using a random number table. Allocation was e-mailed to the

Cardiovascular effects were monitored with vital signs and resting ECGs at baseline and at the end of each treatment period. At the end of each treatment period, the final daily drug doses (both A.M. and P.M.) were combined and administered together at clinic. The ECG was performed prior to dosing (at trough) and at peak drug level, 2 hours after dose administration. ECGs were assessed for mean changes from baseline in the QT and QTc intervals, PR

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 43:2, FEBRUARY 2004

207

GILBERT ET AL.

intervals, and QRS intervals. We were particularly interested in whether treatment prolonged the QTc to greater than 450 ms.

TABLE 1 Baseline Characteristics of the Study Patients Characteristic

Weight Gain Subjects were weighed on the same scale by the same study coordinator at each visit, with shoes removed. Weights used for comparison were those at baseline, end of placebo washout between treatments, and end of each active treatment arm. Thus the reported gain in weight is the change from the treatment onset to completion 4 weeks later. Adverse Events At follow-up visits, a review of systems and a physical examination were performed. Adverse events and side effects were recorded using the Modified Subjective Treatment Emergent Symptoms Scale (STESS) (Guy, 1976).

No. enrolled Cincinnati, n (%) Kansas City, n (%) n (%) completed Sex male, n (%) Race white, n (%) Race African American, n (%) Age (yr), mean ± SD Comorbid ADHD, n (%) Comorbid OCD, n (%)

Total 19 14 (74) 5 (26) 13 (68) 15 (79) 18 (95) 1 (5) 11 ± 2.5 7 (37) 2 (11)

Note: ADHD = attention-deficit/hyperactivity disorder; OCD = obsessive-compulsive disorder.

Sample Size Calculation Power calculations and sample size given are based on absence of carryover effect. To calculate power we used the effect size from an open-label study (Lombroso et al., 1995) for an estimate of percentage change in YGTSS for risperidone (30% reduction). We then compared this to an estimate of percentage change in YGTSS for pimozide (35%–65%) (Sallee et al., 1997). Thus a difference in percentage reduction between risperidone and pimozide may range from 5 to 35 points. For a difference in percentage change in YGTSS between pimozide and risperidone of 25 points, the effect size is 0.96. Thus, for a sample of size 24 (12 per sequence), we would have 90% power to detect this difference at the .05 level of significance. Statistical Analysis Data of the continuous type were analyzed as a two-period, two-treatment, two-sequence design with a test for carryover effects. The scores at weeks 6 and 12 in the pimozide and risperidone arms were compared. The total source of variation in the ANOVA table was split into carryover effects, direct treatment effects, period effects, between-subject error, and within-subject error. The test for direct treatment effects is valid only if the test for carryover effects is nonsignificant. The carryover effects were tested as a betweensubject source of variation against the between-subject error (Grizzle, 1965; Jones and Kenward, 1989). This is an exact test in which a p value of greater than .05 indicates no difference in carryover effects, which is necessary for the crossover analysis to be valid. For ECG data, the change (peak to trough) at weeks 6 and 12 were compared using the same analysis.

RESULTS Demographics

Nineteen subjects (16 with Tourette’s disorder, 3 with chronic tic disorder) enrolled, and 13 completed the study. Demographics are shown in Table 1. Prior medication use in these subjects was as follows: α2adrenergic agonists (11), typical neuroleptics (4), atypical antipsychotics (1), stimulants (3), baclofen (1), St. 208

John’s wort (1). Additional diagnoses included learning disorder (3), oppositional defiant disorder (2), and conduct disorder (1). Study Completion and Dropouts

The profile of study randomization, dropouts, and completion is shown in Figure 1. Two subjects dropped out during treatment period 1 (1 on risperidone, 1 on pimozide) and four subjects dropped out during treatment period 2 (1 on risperidone, 3 on pimozide). Two subjects taking risperidone (one each period) and one taking pimozide (period 2) asked to discontinue the study due to worsening tics. Two subjects taking pimozide (one each period) dropped out and would not return for follow-up. An investigator discontinued one subject taking pimozide (period 2) due to marijuana use. Tic Reduction Efficacy

Final dosages were 1 to 4 mg/day (mean 2.5 mg) in the risperidone treatment arm and 1 to 4 mg/day (mean 2.4 mg) in the pimozide treatment arm. There was a significantly lower (less severe) YGTSS score after risperidone (mean 25.2) versus after pimozide (mean 34.2) (F1,11 = 4.7; p = .05) (Table 2). The mean change in scores in individuals after 4 weeks of pimozide was a decrease of 16%, versus a 42% decrease with risperidone (F1,11 = 4.5; p = .06). Both groups had some worsening in tics during the placebo washout prior to crossover (Fig. 2). Secondary analyses of CGI in tics showed a trend favoring risperidone (mean 2, much improved) versus pimozide (mean 3, minimally improved), but this did

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 43:2, FEBRUARY 2004

PIMOZIDE VS. RISPERIDONE FOR TICS

Fig. 1 Profile of randomized trial.

not reach statistical significance. Similarly, on the TSSR, scores at the end of treatment showed a trend toward superiority of risperidone (mean 10.8) over pimozide (mean 16.9). Post hoc analyses of YGTSS subscales for tic severity and overall impairment favored risperidone, but the difference did not reach significance. Adverse Events

Adverse events monitored both by spontaneous report and formal ascertainment using STESS showed no differences between the treatment arms (Table 2). One subject had an elective tonsillectomy during risperidone treatment, resulting in a short postponement of the week 6 visit. The enlarged tonsils were judged not to be related to treatment, and the patient completed

the study. Mild adverse events included increased appetite, dizziness, sedation, headaches, and chest pain. The frequencies were not different by treatment. Weight Gain

Weight gain occurred in both treatment arms. The weights at the end of treatment compared to baseline were not significantly different by treatment. The weights at the end of treatment for each drug include period 1 subjects whose weight reflects only the period 1 treatment and period 2 subjects whose total weight gain may include period 1 weight gain not lost during the placebo washout. Thus it appears that 8 weeks of pimozide or risperidone treatment, with 2 weeks off medicine in the middle, is associated with a weight gain of approximately 1.8 to 2.5 kg. Using treatment onset

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 43:2, FEBRUARY 2004

209

GILBERT ET AL.

TABLE 2 Treatment Efficacy and Side Effects Tic assessments YGTSS (total) mean ± SD YGTSS (Tic Subtotal), mean ± SD YGTSS (Overall Impairment), mean ± SD CGITics (Severity), mean ± SD CGITics (Improvement), mean ± SD TSSR, mean ± SD Side effects ESRS, mean ± SD Side Effect Checklist, mean ± SD Weight in kg, mean ± SD Mean treatment-period weight increase, kg

Baseline

Pimozide

Risperidone

p

43.3 ± 17.5 21.4 ± 7.2 21.9 ± 12.8 4.2 ± 0.9

34.2 ± 14.2 18.4 ± 6.6 15.8 ± 9.5

25.2 ± 13.6 15.2 ± 7.5 10 ± 7.9

.05 .18 .06

21.7 ± 16.2

3.1 ± 1.4 16.9 ± 11.6

2.1 ± 1.1 10.8 ± 9.4

.12 .06

0.1 ± 0.3 7.2 ± 4.2 54.9 ± 21.5 —

0.2 ± 0.6 8.2 ± 6.6 56.7 ± 21.6 1.0

0.2 ± 0.6 9.5 ± 6.0 57.4 ± 22.4 1.9

.89 .74 .21 —

Note: Results at baseline and after 4-week treatment with either risperidone or pimozide. YGTSS = Yale Global Tic Severity Scale; TSSR = Tic Symptom Self-Report; CGI = Clinical Global Impression (see text); ESRS = Extrapyramidal Symptoms Rating Scale.

weights separately as baselines, mean weight gain was 1.0 kg with pimozide and 1.9 kg with risperidone. Cardiovascular Effects

There were no significant differences between treatments in changes in ECG parameters (Table 3). In particular, increases in QTc were minimal and did not approach 450 ms. DISCUSSION

In this double-blind, crossover study, risperidone appeared to be superior to pimozide in suppressing tics in

children and adolescents with Tourette’s disorder. Both pimozide and risperidone were associated with a reduction in symptoms in a 4-week period, as measured by a standard assessment, the YGTSS. This scale is widely used in drug trials as a measure of symptom severity. The mean 42%, 18-point decrease on this scale during treatment with risperidone is a clinically meaningful benefit. Although the TSSR and CGI improvement scores were not significantly different by treatment, the direction and magnitude of the improvement favored risperidone over pimozide, consistent with the change in YGTSS. The TSSR and CGI scales are briefer and may be less sensitive to drug treatment effects. While the crossover design yielded sufficient precision in estimating effect sizes to detect a significant difference between treatments, interpretation of these results should still be cautious due to the small sample size. Patients experienced clinically significant weight gain during both treatments. The weight gain with risperidone appeared to be greater (mean 1.9 kg over 4 weeks versus 1.0 kg with pimozide), but this was not statistically significant in the crossover analysis. There were no clinically significant ECG changes or extrapyramidal symptoms. Clinical Implications

Fig. 2 Crossover study, Yale Global Tic Severity Scale (YGTSS) scores. Schema: Weeks 0–2: Both groups on placebo. Weeks 2–6: Group 1 (circles) on pimozide, group 2 (squares) on risperidone. Weeks 6–8: Crossover, washout—both groups on placebo. Weeks 8–12: Group 1 (circles) on risperidone, group 2 (squares) on pimozide. Symptom severity as measured by YGTSS was significantly less with risperidone versus pimozide (F1,11 = 4.7; p = .05).

210

This study corroborates the results of previous openlabel and controlled studies that have shown benefit in tic suppression with the atypical agent risperidone. An open-label study of seven children and adolescents showed that risperidone at dosages of 1.0 to 2.5 mg/day was associated with reduction in the YGTSS of 26% to 66% (Lombroso et al., 1995). Another open-

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 43:2, FEBRUARY 2004

PIMOZIDE VS. RISPERIDONE FOR TICS

TABLE 3 Treatment-Associated Changes in ECG Parameters Pimozide ECG Parameters PR interval QRS width QT interval QTc interval

Risperidone

Predose

Postdose

Change

Predose

Postdose

Change

p

148.8 ± 21.2 87.7 ± 8.8 368.5 ± 29.8 409.3 ± 16.4

146.3 ± 18.0 89.2 ± 10.5 374.9 ± 23.9 412.2 ± 15.7

−2.6 ± 8.4 1.5 ± 5.8 6.5 ± 16.4 2.8 ± 14.6

149.3 ± 20.2 87.5 ± 8.8 365.7 ± 24.9 409.2 ± 14.8

144.5 ± 19.1 87.1 ± 11.4 358.5 ± 27.0 417.2 ± 20.8

−4.8 ± 9.0 −0.5 ± 5.8 −7.2 ± 16.3 8.1 ± 14.6

.44 .19 .10 .43

Note: Changes in electrocardiogram (ECG) parameters before and after maximum study dose of risperidone and pimozide. All results are in milliseconds.

label study, involving 38 Tourette’s disorder patients aged 8 to 53 years who had previously responded poorly to either haloperidol or clonidine, found that doses of risperidone of 0.5 to 9.0 mg were associated with a change in YGTSS of +4.9 to −40.9 points, with a mean improvement of 22% (Bruun and Budman, 1996). That study also had a high dropout rate (22%), which appeared to be due to intolerable side effects. A double-blind, placebo-controlled, randomized trial in 48 adolescents and adults showed a mean 35% reduction in the Tourette’s Syndrome Severity Score (TSSS) with 1 to 6 mg daily of risperidone, compared to a 15% reduction with placebo (p = .05) (Dion et al., 2002). Three of 24 patients (12.5%) in the risperidone group dropped out, compared to 1 of 24 in the placebo group, but the incidence of fatigue (57%) and somnolence (35%) was significantly higher with risperidone. Another placebo-controlled study in 34 children and adults showed a mean 32% reduction in tic severity (YGTSS tic score) with a mean daily risperidone dose of 2.5 mg versus a 7% reduction with placebo (Scahill et al., 2003). Active comparator studies have also shown that risperidone reduces tics. A double-blind, parallel design study in 50 patients aged 11 to 50 showed a 56% reduction in the TSSS with 0.5 to 6 mg/day of risperidone, statistically equivalent to a 53% reduction with 1 to 6 mg/day of pimozide (Bruggeman et al., 2001). A shortcoming of that study was the use of a less sensitive rating scale for differentiating tic reduction between active agents. The primary endpoint in our study, the YGTSS, assesses tic characteristics and impairment in much greater detail. This, in combination with the crossover design of our study, may have allowed us to detect differences between agents despite the smaller sample size. Also similar to our study, dropouts were common: five patients (20%) taking risperidone and four (16%) taking pimozide. The main adverse events

were sedation and depression. Weight gain was greater with risperidone (Bruggeman et al., 2001). Although the authors concluded that risperidone might become the first-line drug in patients with Tourette’s disorder, α2-adrenergic agonists such as clonidine may be safer as first-line agents (Gilbert and Singer, 2001). A randomized controlled clinical trial comparing clonidine to risperidone showed no difference (Gaffney et al., 2002). In that study of 21 subjects aged 7 to 17, a mean daily dose of 1.5 mg risperidone was associated with a 21% reduction in tic severity rated with the YGTSS, compared to a 26% reduction with a mean daily dose of 0.175 mg clonidine. The low doses of risperidone used may explain the lesser efficacy compared to other studies. Also consistent with prior studies, we documented significant weight gain with both treatments. Given the rising incidence of obesity in children and adolescents and the associated health consequences (Ogden et al., 2002), use of either risperidone or pimozide for tic suppression should be restricted to patients with significant functional impairment or pain related to tics, refractory to safer agents. It is prudent for clinicians using either of these medications to monitor patients over time for unhealthy increases in Body Mass Index. There are at present no accepted recommendations for testing patients to identify risk for significant weight gain. Future, larger studies may consider assessing risk factors. Limitations

Limitations of this study include small sample size, related to compliance and recruitment issues. The compliance rate with this protocol was suboptimal, with 32% of subjects dropping out. Three of six dropouts were due to poor efficacy in the current treatment arm, but two of those these dropped out during their second treatment. One subject who dropped out in period 2

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 43:2, FEBRUARY 2004

211

GILBERT ET AL.

had experienced significant benefit during period 1. After several days of insufficient benefit on the second treatment, the parent insisted on discontinuing the study to restart the first medication. One subject lost to follow-up refused to return despite being offered flexible visiting times and a taxicab front-door pickup. Co-occurring diagnoses may also have contributed, as the three subjects with symptoms of either oppositional defiant disorder or conduct disorder failed to comply. Thus side effects, comorbid diagnoses, and efficacy may have contributed to the high dropout rate. As the total number of dropouts was just six, further inferences based on clinical characteristics would not likely be justified. Recruitment for this study was slower than we predicted, for several reasons. First, although families approached for this study appeared to like the idea of comparing two efficacious medications, the placebo washout periods, particularly during the school year, resulted in some families choosing not to participate. In addition, many subjects with moderate or severe tics also have moderate or severe ADHD, anxiety, or OCD. The exclusion of use of other psychotropic drugs made participation in this study inappropriate for those patients, which lowered the prevalence of these comorbid diagnoses relative to our total clinic population. Finally, because both treatments were already on the market, many of our more severely affected patients were already taking one of these medications with good benefit or an intolerable side effect and therefore were not interested in participating. This was initially a singlesite study (Cincinnati), but the other site was added later to increase sample size. At study completion, there were incomplete blocks at both sites, resulting in an unbalanced allocation to treatment order. However, since this was a crossover study, meaning comparison between treatment effects was within-subject, this should only have affected results if there were carryover effects. In this study, the test for differential carryover effects between treatments was nonsignificant. As a result of these difficulties with recruitment and compliance, the sample size was smaller than we had anticipated. Although our controlled clinical trial did not detect significant differences in side effects in children and adolescents taking risperidone or pimozide at up to 4 mg/day, the small sample size means the power to detect rare or uncommon side effects was low. Because all published studies of typical neuroleptics or atypical agents for tic suppression are fairly small, estimates of risk are imprecise. We recommend that cli212

nicians monitor closely all patients taking these medications. Additional limitations of this study relate specifically to the crossover design. The 2 × 2 crossover design is a popular method for clinical trials in Tourette’s disorder (Feigin et al., 1996; Gilbert et al., 2000; Goetz et al., 1987; Marras et al., 2001; Peterson et al., 1998; Sallee et al., 1996; Scahill et al., 1997; Singer et al., 2001) but has certain statistical limitations (Jones and Kenward, 1989). The popularity of this study design in Tourette’s disorder studies may be due to the high power achieved with a small sample size. This occurs because comparisons are estimated using differences obtained from the within-subject measurements. One of the main difficulties of this design relates to the carryover effect, the possibility that the effect of a treatment in one period might still be present at the start of the following period. Figure 2 suggests that for tic severity, this problem did not occur in this study. For a 2 × 2 crossover study to be valid, there can be no carryover effect that differs between the groups randomly assigned to treatment order A-B and B-A. So, to analyze the results, one first determines whether the null hypothesis, that the carryover effects are equal, is rejected. We could not reject the null hypothesis of equal carryover effects for all measured outcomes, and thus we were able to analyze differences from both treatment periods. However, dropout data cannot be analyzed as part of the two-period design. Failure to analyze dropouts may have biased our results. With regard to the estimate of efficacy, one patient taking risperidone dropped out due to insufficient efficacy. The loss of data in this single subject could mean that we have slightly overestimated the treatment effect of risperidone. Two subjects discontinued during period 2, one taking each treatment, because of insufficient efficacy, but efficacy had been satisfactory during period 1. Thus the effect of the loss of these two subjects should cancel out and likely would not bias the comparison. An additional study design-related limitation is that because there was no placebo group for comparison, it is possible that benefit in both groups was related to enrollment at a period of relatively higher tic severity, followed by a natural waning of symptoms. We believe that this concern is not valid for our study for several reasons. First, we had a 2-week placebo wash-in period before assessing baseline tic severity. Some or all of natural waning could have occurred during this phase without affecting baseline scores and therefore would

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 43:2, FEBRUARY 2004

PIMOZIDE VS. RISPERIDONE FOR TICS

not result in an overestimate of treatment effects. Second, as seen in Figure 2, symptoms worsened during the crossover back to near baseline levels, suggesting that the subjects in this study may have enrolled at a time of relatively stable tic severity, and that the treatment effects we measured are valid estimates. Although Tourette’s disorder symptoms wax and wane, removal of effective treatment would be a more plausible explanation of worsening symptoms during the two placebo periods. A final limitation of this study and other controlled clinical trials in Tourette’s disorder relates to generalizability of findings to patients with the most severe tics or comorbid ADHD or OCD. Such patients are appropriately reluctant to participate in studies involving placebo or excluding other psychotropic medications. The underrepresentation of such patients in welldesigned clinical trials may mean that the effect sizes observed will be different in severely affected patients taking polytherapy. In summary, the results of this study add to a growing body of well-designed, though small, clinical trials that support the idea that the atypical agent risperidone, as well as other atypical dopamine-blocking agents (Sallee et al., 2000), are effective in the treatment of Tourette syndrome. However, the weight gain and high dropout rates in this and other studies indicate an unfavorable ratio of efficacy to side effects of both typical neuroleptics and atypical agents as monotherapy for some patients. REFERENCES American Psychiatric Association (2000), Diagnostic and Statistical Manual of Mental Disorders, 4th edition-TR (DSM-IV-TR). Washington, DC: American Psychiatric Association Bruggeman R, Buitelaar JK, Gericke GS, Hawkridge SM, Temlett JA (2001), Risperidone versus pimozide in Tourette’s disorder: a comparative double-blind parallel-group study. J Clin Psychiatry 62:50–56 Bruun RD (1988), Subtle and underrecognized side effects of neuroleptic treatment in children with Tourette’s disorder. Am J Psychiatry 145:621–624 Bruun RD, Budman CL (1996), Risperidone as a treatment for Tourette’s syndrome. J Clin Psychiatry 57:29–31 Cohen DJ, Leckman JF, Shaywitz BA (1985), The Tourette syndrome and other tics. In: The Clinical Guide to Child Psychiatry. New York: Free Press Dion Y, Annable L, Sandor P, Chouinard G (2002), Risperidone in the treatment of Tourette syndrome: a double-blind, placebo-controlled trial. J Clin Psychopharmacol 22:31–39 Feigin A, Kurlan R, McDermott MP et al. (1996), A controlled trial of deprenyl in children with Tourette’s syndrome and attention deficit hyperactivity disorder. Neurology 46:965–968 Flockhart DA, Drici MD, Kerbusch T et al. (2000), Studies on the mechanism of a fatal clarithromycin–pimozide interaction in a patient with Tourette syndrome. J Clin Psychopharmacol 20:317–324 Fulop G, Phillips RA, Shapiro AK, Gomes JA, Shapiro E, Nordlie JW (1987), ECG changes during haloperidol and pimozide treatment of Tourette’s disorder. Am J Psychiatry 144:673–675

Gaffney GR, Perry PJ, Lund BC, Bever-Stille KA, Arndt S, Kuperman S (2002), Risperidone versus clonidine in the treatment of children and adolescents with Tourette’s syndrome. J Am Acad Child Adolesc Psychiatry 41:330–336 Gilbert DL, Sethuraman G, Sine L, Peters S, Sallee FR (2000), Tourette syndrome improvement with pergolide in a randomized, double-blind, crossover trial. Neurology 54:1310–1315 Gilbert D, Singer HS (2001), Commentary: “Risperidone was as effective as pimozide for Tourette’s disorder.” Evid Based Ment Health 4:75 Glassman AH, Bigger JT Jr (2001), Antipsychotic drugs: prolonged QTc interval, torsades de pointes, and sudden death. Am J Psychiatry 158:1774–1782 Goetz CG, Tanner CM, Wilson RS, Carroll VS, Como PG, Shannon KM (1987), Clonidine and Gilles de la Tourette’s syndrome: double-blind study using objective rating methods. Ann Neurol 21:307–310 Grizzle JE (1965), The two period change-over design and its use in clinical trials. Biometrics 21:467–480 Guy W (1976), ECDEU Assessment Manual for Psychopharmacology (publication ADM76-338). Rockville, MD: US Department of Health, Education, and Welfare, pp 217–222 Hong KS, Cheong SS, Woo JM, Kim E (1999), Risperidone-induced tardive dyskinesia (letter). Am J Psychiatry 156:1290 Jones B, Kenward M (1989), The 2 × 2 cross-over trial with continuous data. In: Design and Analysis of Cross-Over Trials, 1st ed. London: Chapman and Hall, pp 16–88 Kumar S, Malone DM (2000), Risperidone implicated in the onset of tardive dyskinesia in a young woman. Postgrad Med J 76:316–317 Leckman JF, Riddle MA, Hardin MT et al. (1989), The Yale Global Tic Severity Scale: initial testing of a clinician-rated scale of tic severity. J Am Acad Child Adolesc Psychiatry 28:566–573 Lombroso PJ, Scahill L, King RA et al. (1995), Risperidone treatment of children and adolescents with chronic tic disorders: a preliminary report. J Am Acad Child Adolesc Psychiatry 34:1147–1152 Marras C, Andrews D, Sime E, Lang AE (2001), Botulinum toxin for simple motor tics: a randomized, double-blind, controlled clinical trial. Neurology 56:605–610 Mizrahi EM, Holtzman D, Tharp B (1980), Haloperidol-induced tardive dyskinesia in a child with Gilles de la Tourette’s disease. Arch Neurol 37:780 Ogden CL, Flegal KM, Carroll MD, Johnson CL (2002), Prevalence and trends in overweight among US children and adolescents, 1999–2000. JAMA 288:1728–1732 Peterson BS, Zhang H, Anderson GM, Leckman JF (1998), A doubleblind, placebo-controlled, crossover trial of an antiandrogen in the treatment of Tourette’s syndrome. J Clin Psychopharmacol 18:324–331 Ratzoni G, Gothelf D, Brand-Gothelf A et al. (2002), Weight gain associated with olanzapine and risperidone in adolescent patients: a comparative prospective study. J Am Acad Child Adolesc Psychiatry 41:337–343 Riddle MA, Hardin MT, Towbin KE, Leckman JF, Cohen DJ (1987), Tardive dyskinesia following haloperidol treatment in Tourette’s syndrome (letter). Arch Gen Psychiatry 44:98–99 Ross MS, Moldofsky H (1978), A comparison of pimozide and haloperidol in the treatment of Gilles de la Tourette’s syndrome. Am J Psychiatry 135:585–587 Sallee FR, Kurlan R, Goetz CG et al. (2000), Ziprasidone treatment of children and adolescents with Tourette’s syndrome: a pilot study. J Am Acad Child Adolesc Psychiatry 39:292–299 Sallee FR, Nesbitt L, Jackson C, Sine L, Sethuraman G (1997), Relative efficacy of haloperidol and pimozide in children and adolescents with Tourette’s disorder. Am J Psychiatry 154:1057–1062 Sallee FR, Richman H, Beach K, Sethuraman G, Nesbitt L (1996), Platelet serotonin transporter in children and adolescents with obsessivecompulsive disorder or Tourette’s syndrome. J Am Acad Child Adolesc Psychiatry 35:1647–1656 Scahill L, Leckman JF, Schultz RT, Katsovich L, Peterson BS (2003), A placebo-controlled trial of risperidone in Tourette syndrome. Neurology 60:1130–1135 Scahill L, Riddle MA, King RA et al. (1997), Fluoxetine has no marked effect on tic symptoms in patients with Tourette’s syndrome: a doubleblind placebo-controlled study. J Child Adolesc Psychopharmacol 7:75–85 Shapiro AK, Shapiro E (1984), Controlled study of pimozide vs. placebo in Tourette’s syndrome. J Am Acad Child Psychiatry 23:161–173

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 43:2, FEBRUARY 2004

213

GILBERT ET AL.

Shapiro E, Shapiro AK, Fulop G et al. (1989), Controlled study of haloperidol, pimozide and placebo for the treatment of Gilles de la Tourette’s syndrome. Arch Gen Psychiatry 46:722–730 Silberbauer C (1998), Risperidone-induced tardive dyskinesia. Pharmacopsychiatry 31:68–69 Silva RR, Muñoz DM, Daniel W, Barickman J, Friedhoff AJ (1996), Causes of haloperidol discontinuation in patients with Tourette’s disorder: management and alternatives. J Clin Psychiatry 57:129–135

214

Singer HS, Wendlandt J, Krieger M, Giuliano J (2001), Baclofen treatment in Tourette syndrome: a double-blind, placebo-controlled, crossover trial. Neurology 56:599–604 Spivak M, Smart M (2000), Tardive dyskinesia from low-dose risperidone (letter). Can J Psychiatry 45:202 Tourette Syndrome Study Group (1999), Short-term versus longer-term pimozide therapy in Tourette’s syndrome: a preliminary study. Neurology 52:874–877

J. AM. ACAD. CHILD ADOLESC. PSYCHIATRY, 43:2, FEBRUARY 2004