Ziprasidone Treatment of Children and Adolescents With Tourette's Syndrome: A Pilot Study

Ziprasidone Treatment of Children and Adolescents With Tourette's Syndrome: A Pilot Study FLOYD R. SALLEE, M.D., ROGER KURLAN, M.D., CHRISTOPHER G. GOETZ, M.D., HARVEY SINGER, M.D., LAWRENCE SCAHILL, PH.D., GORDON LAW, PH.D., VALERIE M. DITTMAN, R.N., AND PHILLIP B. CHAPPELL, M.D.

ABSTRACT Objective: To evaluate the efficacy and tolerability of ziprasidone in children and adolescents with Tourette's syndrome and chronic tic disorders. Method: Twenty-eight patients aged 7 to 17 years were randomly assigned to ziprasidone or placebo for 56 days. Ziprasidone was initiated at a dose of 5 mg/day and flexibly titrated to a maximum of 40 mg/day. Results: Ziprasidone was significantly more effective than placebo in reducing the Global Severity (p

=.016) and Total Tic (p =.008)

scores on the Yale Global Tic Severity Scale. Compared with placebo, ziprasidone significantly reduced tic frequencies as determined by blind videotape tic counts (p

= .039). The mean (±SD) daily dose of ziprasidone during the last 4 weeks of

the trial was 28.2 ± 9.6 mg. Mild transient somnolence was the most common adverse event. No clinically significant effects were observed on specific ratings of extrapyramidal symptoms, akathisia, or tardive dyskinesia. Conclusions: In this limited sample, ziprasidone (5-40 mg/day) appears to be effective and well tolerated in the treatment of Tourette's syndrome. Ziprasidone may be associated with a lower risk of extrapyramidal side effects in children. However, additional studies are necessary to evaluate more fully its safety and efficacy in children with tic disorders. J. Am. Acad. Child Ado/esc. Psychiatry,

2000,39(3):292-299. KeyWords: ziprasidone, Tourette's syndrome, tics, antipsychotic agents.

Tourette's syndrome (TS), or Tourette's disorder as it is referred to in DSM-IV(American PsychiatricAssociation, 1994), is a complex neuropsychiatric disorder characterized by involuntary motor and phonic tics. Tic symptoms usually first occur in childhood and may persist for life. Typically, the disorder follows a fluctuating course in which the severity and frequency of symptoms change over time (American Psychiatric Association, 1994). Comorbid conditions, including obsessive-compulsive disorder (OCD), attention-deficit hyperactivity disorder, Accepted August 26, 1999. Dr. Sallee isProftssor ofPsychiatry and Pediatrics, Children's Hospital Medical Center, Cincinnati; Dr. Kurianis Proftssor ofNeurology, University ofRochester School of Medicine and Dentistry, Rochester, NY; Dr. Goetz is Proftssor of Neurology, Rush University/Rush Presbyterian-Saint Luke's Medical Center, Chicago; Dr. Singer is Haller Proftssor of Pediatric Neurologic Diseases, Johns Hopkins University School of Medicine, Baltimore; Dr. Scahill is Assistant Proftssor ofNursingand Child Psychiatry and Dr. Chappell isAssistant Clinical Proftssor of ChildPsychiatry, Yale ChildStudy Center, New Haven, CT;Dr. Law, Ms. Dittman, and Dr. Chappell are with Pfizer CentralResearch, Groton, CT This study wassponsored by Pfizer CentralResearch, Groton, CT Reprintrequests to Dr. Chappell, Pfizer CentralResearch, Eastern PointRoad, Groton, CT 06340. 0890-8567/00/3903-0292©2000 by the American Academy of Child and Adolescent Psychiatry.

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learning disabilities, and disruptive behavior are common (Coffeyet al., 1997; Walkup et aI., 1995). Chronic motor or vocal tic disorder (CTD) is similar to TS, but either motor or vocal tics, but not both, are present (American Psychiatric Association, 1994). The precise etiology of TS is uncertain, but it probably has a neurochemical basis and a genetic component (Sadovnick and KurIan, 1997). Central monoaminergic pathways encompassing the basal ganglia and regions of the frontal cortex have been implicated in the psychopathology ofTS (Leckman et aI., 1991b; Singer, 1997). Roles for dopamine and serotonin are suggested further by the efficacy of dopamine receptor antagonists in suppressing tic symptoms, the efficacy of selective serotonin reuptake inhibitors in the treatment of related conditions such as OCD, and preliminary findings which suggest that antipsychotic agents with both dopamine- and serotoninreceptor antagonistic activities may be effective therapies for TS (Chappell et al., 1997). Traditional antipsychotics are the mainstay of pharmacological treatment for TS, and haloperidol remains the most frequently prescribed medication for the disorder (Chappell et aI., 1997). Although a large proportion of

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ZIPRASIDONE IN TOURETTE'S SYNDROME

patients with TS benefit from haloperidol, many experience adverse effects, including sedation, extrapyramidal $1Plptoms,akathisia, and weight gain. Despite being rare, mrdive dyskinesia is a serious drawback of haloperidol (Silva et al., 1996). Pimozide is also effective in the treatlXlent of TS and, at equivalent doses, may be superior to haloperidol for controlling the symptoms of the disorder in children and adolescents (Sallee et al., 1997). This traditional antipsychotic may be less liable than haloperidol to cause dystonia, but otherwise it has a similar tolerability profile. Clonidine is another widely used drug for the treatment ofTS, but its efficacyin the disorder remains to be established (Goetz, 1992; Leckman et al., 1991a). Recent preliminary data suggest that another U 2 agonist, guanfacine, may be beneficial in the treatment of symptoms of attention-deficit hyperactivity disorder in children with TS while being less sedating than clonidine (Chappell et al., 1995). Several potential new therapeutic options for TS have emerged in recent years, and the recently developed atypical antipsychotics appear to show particular promise (Chappell et al., 1997). Despite having distinct pharmacological profiles, these newer anti psychotics are all characterized by having a relatively greater affinity for 5-HT2 receptors than for D 2 receptors and a low liability to cause extrapyramidal symptoms compared with traditional antipsychotic agents (Gerlach and Peacock, 1995). Preliminary results from short-term, open-label studies and anecdotal reports in both children and adults suggest that one of these newer antipsychotic agents, risperidone, may be a promising alternative to traditional antipsychotics for some patients with TS (Bruun and Budman, 1996; Lombroso et al., 1995; Van der Linden et al., 1994). A recent case report described partial control of tic symptoms using olanzapine (Bhadrinath, 1998). However, another antipsychotic agent combining 5-HT2 and D 2 receptor antagonistic properties, clozapine, does not appear to confer therapeutic benefit in TS (Caine et al., 1979). Nevertheless, cautious optimism is warranted and other recently developed antipsychotic agents merit investigation as potential treatments forTS and related CTD. Ziprasidone is a novel antipsychotic that has been shown to be effective at doses of 80 to 160 mg/day in the treatment of schizophrenia in adults (Daniel et al., 1999; Goff et al., 1998). It has high affinity for the human 5HTlA receptor (K, = 0.4 nmollL) and the human D 2 receptor (K, = 5 nmol/L), comparable with that of risperidone (Zorn et al., 1999). Behavioral and second-messenger

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studies have shown that ziprasidone is an antagonist at 5HT lA and D 2 receptors (Seeger et al., 1995; Zorn et al., 1999). The delicate balance of serotonin and dopamine in the cortico-striatal-thalamo-cortical circuitry has relevance for both TS (Leckman et al., 1991b) and OCD (Rapoport et al., 1992). Modification of dopaminergic hypertransmission in TS by blockade of D 2 directly and 5-HT2 indirectly would provide for both tic and OCD symptom control. As well as having a high 5-HTlA/D2 affinity ratio, ziprasidone possesses additional pharmacodynamic attributes that may differentiate it from other antipsychotic agents and may have therapeutic implications. It has been shown in vitro to have high affinity for human 5-HT IA and 5HT 2C receptors (Zorn et al., 1999). Ziprasidone is an antagonist at 5-HT2C receptors but an agonist at 5-HT IA receptors (Seeger et al., 1995; Zorn et al., 1999). Ziprasidone also moderately inhibits in vitro synaptosomal serotonin and norepinephrine reuptake (Seeger et al., 1995). Ziprasidone has only moderate affinity for human adrenergic U I and histaminergic HI receptors, and negligible affinity for the muscarinic M I receptor.This pharmacological profile suggests that ziprasidone may be effective in the treatment ofTS and related tic disorders and may be better tolerated than existing therapies for these conditions. This double-blind, placebo-controlled trial was conducted to provide preliminary data on the efficacy and tolerability of ziprasidone in children and adolescents with TS or CTD. METHOD Patients The patients were boys and girls, aged 7 to 17 years, with a DSMIV (American PsychiatricAssociation, 1994) diagnosis ofTS or CTD. Patients were required to have tic symptoms that, in the clinical judgment of the investigator, were severe enough to warrant treatment with medication, At screening, all patients were healthy and had normal laboratory tests; no subject had a history of neuroleptic malignant syndrome or known hypersensitivity to antipsychotic agents, At screening, all patients had been free of psychotropic medications for at least 4 weeks (8 weeks in the case of antipsychotics and Huoxerinc). None of the female patients were pregnant or breast-feeding. Patients were excluded if they had a secondary tic disorder or if they met the DSM-1V(American Psychiatric Association, 1994) criteria for major depression, pervasive developmental disorder, autism, mental retardation, anorexia/bulimia, substance abuse, or any psychotic disorder. The rationale for excluding patients with mental retardation and anorexia/bulimia is that such patients are not representative of TS patients in general and may respond differently to medications compared with TS patients without such comorbid conditions. The study was reviewed and approved by the appropriate institutional review boards at each site. Before any study-related procedure

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was performed, written informed consent was signed by the parentls) or legal guardian(s) of all subjects. In addition, written informed assent was provided by all adolescent subjects (aged 13-17 years).

Study Design This was a 56-day, double-blind, placebo-controlled, randomized, multicenter, flexible dose-escalating, parallel-group trial. Because no prior information was available on the effects of ziprasidone in children, a gradual dose adjustment schedule was adopted to minimize risk of adverse events. Treatment was administered orally, twice daily, with food, except for days 1 to 3, when the patients received a single dose of either 5 mg of ziprasidone or placebo. Thereafter, on days 4 to 28 the dose of ziprasidone was adjusted as tolerated to a maximum total daily dosage of 40 mg (20 mg twice daily). The dose was then kept constant, if clinically possible, for the duration of the study.

Efficacy Assessments The primary efficacyassessments were the changes from baseline to last visit in the Global Severiry and Total Tic scores of the YaleGlobal Tic Severiry Scale (YGTSS) (Leckman et al., 1989) and the Clinical Global Impression Severiry Scale for TS (CGI-TS) (Leckman et al., 1988). The YGTSS is a valid and reliable instrument which provides both a Global Severiry score and separate ratings of tic severiry and overall impairment; it is widely used as a primary outcome measure in clinical trials ofTS (Kompoliti and Goetz, 1997; Leckman et al., 1988, 1991a). Assessments were made at weeks 0, 2, 4, 6, 7, and 8 and at a follow-up visit at study exit. Formal interrater reliability checks were not performed. However, each investigator had extensive experience with the primary rating instruments and all had participated together in previous multisite trials (Tourette Syndrome Study Group, 1999). The secondary efficacyassessments included the change from baseline to last visit on the Goetz Videotape Rating Scale (i.e., total score and 5-minute videotape tic counts) (Goetz et al., 1987) and the Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) (Scahill et al., 1997). For the Goetz Videotape Rating Scale, the patients were Videotapedunder standardized conditions for 5 minutes at baseline and week 8. The baseline and week 8 videotapes were copied and presented in a random order for scoring.Tapes were scored for the anatomic distribution, intensity, and frequency of tic symptoms. The tic count included the total number of motor and phonic tics in the 5-minute videotape interval.

Safety and Tolerability Assessments All adverse events volunteered and observed during the study or within 6 days of the last day of treatment were recorded using the standard terminology of the U.S. FDA COSTART adverse event coding dictionary (U.S. Food and Drug Administration, 1993). In addition, specificassessments of movement disorders were undertaken. These were performed at screening, baseline,weeks2, 4, 6, 8, and at study exit or early discontinuation using the Simpson-Angus rating scale (sum of items 1-10) (Simpson and Angus, 1970) and Barnes Akathisia Scale (BAS) (Braude et al., 1983). (The head rotation item from the modified Simpson-Angus rating scale was substituted for the original item 7 [head dropping].) The Abnormal Involuntary Movements Scale (AIMS) (National Institute of Mental Health, 1976) was performed at screening, at baseline, at week 8, and at study exit or early discontinuation. A categorical rating of the level of sedation (0-3 scale: absent, mild, moderate, severe) was performed at screening, at baseline, and at weeks 1 through 8 or on discontinuation.

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Clinical laboratory tests and serum prolactin levels were measured at screening and before administration of the morning dose of study drug at weeks 1, 4, 8 or on early discontinuation. Vital signs, including blood pressure (sitting and standing) and pulse rate, were assessed at screening, at baseline,and at weeks 1 through 8 or on discontinuation. Body weight measurements were obtained at screening, baseline, week 4, and week 8. A 12-lead electrocardiogram (ECG) was obtained at screening and at weeks 4 and 8 or on discontinuation. Physical examination and oral temperature measurement were performed at screening and study exit or discontinuation.

Statistical Analysis The statistical analysis used for all efficacy variables was an intentto-treat analysis with the last observation being carried forward. All patients with a baseline assessment and at least one postbaseline assessment were included in the analysis (n = 27; 16 in the ziprasidone group and 11 in the placebo group). Mean baseline-to-endpoint changes for the primary efficacy variables and Goetz Videotape Rating Scale were compared between the treatment groups. Estimates of treatment effects were based on leastsquares means derived from an analysis of covariance model, with the baseline value as the covariate and with fixed terms for study centers and treatment. Comparisons between treatments were estimated using least-squares means from a type III sum of squares analysis of PROC GLM of SAS®. The p values were derived from a Student t test. Statistical tests were 2-sided and were considered significant if p :0; .05. No adjustments to significance levelswere made. Descriptive statisticswere used to compare the CY-BOCS, SimpsonAngus, BAS,AIMS, and sedation scores, as well baseline demographic and illness characteristics, the incidence of adverse events, body weights, serum prolactin concentrations, and laboratory abnormalities. Several subjects had baseline CY-BOCS scores of zero. Therefore, only data from subjects who were judged as having mild or greater obsessive-compulsive symptoms at baseline were included in the analysis of this endpoint (n = 5 per treatment group).

RESULTS

Demographics

A total of 29 patients were screened and 28 were randomly assigned to double-blind treatment (Table 1). All but one patient had a primary diagnosis of TS: one patient in the ziprasidone group had a primary diagnosis of CTD. The mean ages, body weights, times since diagnosis, and gender distribution were similar in the 2 treatment groups (Table 1). Subjects in the 2 treatment groups were not specifically age- and sex-matched. A total of 8 subjects in the placebo group and 12 in the ziprasidone group had secondary diagnoses (Table 2). A total of 24 patients completed the study. One subject in the ziprasidone group discontinued on day 30 of the study because of an adverse event (sedation); 2 subjects in the placebo group discontinued (on days 42 and 44) because of insufficient clinical response, and another placebo subject withdrew consent after 8 days of treat-

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TABLE 1

TABLE 2

Baseline Demographic and Illness Characreristics

Secondary Diagnoses

Placebo (n = 12) No. of patients (boys/girls) Mean age, years (range) Mean weight, kg (range) Boys Girls Tourette's syndrome No. of patients with diagnosis Mean time since first diagnosis, years (range) Chronic motor or vocal tic disorder No. of patients with diagnosis Mean time since first diagnosis, years

Ziprasidone in = 16)

8/4 11.8 (8-16)

14/2 11.3 (7-14)

44.0 (25-71) 44.0 (35-58)

47.1 (27-96) 51.1 (35-68)

12

15

4.5

(2-6)

4.1

No. of subjects with secondary diagnoses Conduct disorder Learning disability Obsessive-compulsive disorder Oppositional defiant disorder Attention-deficit hyperactivity disorder

Placebo

Ziprasidone

8

4

12 1 1 6

1

3

6

9

o 1

gressively from 7.6 ± 0.6 mg/day to 32.1 ± 8.5 mg/day. The mean daily dose of ziprasidone remained relatively constant throughout the remainder of the study and was 28.2 ± 9.6 mg/day (0.64 ± 0.24 mg/kg per day) from week 5 to week 8. In patients with higher body weight, the daily dose was higher on average (lesslikely to be reduced due to sedation) than in patients with lower body weight.

(0-9)

o 5.4

ment. All 28 patients randomly assigned to doubleblind treatment were analyzed for adverse events, but the patient on placebo who withdrew consent contributed no postbaseline efficacy or laboratory data and was therefore excluded from the efficacy analyses. StudyTherapy

The median durations of treatment in the ziprasidone and placebo groups were 57.5 days (range 30-64 days) and 56.5 days (range 8-62 days), respectively. Over weeks 1 to 4, the mean daily dose of ziprasidone increased pro-

Efficacy

The mean scores for all 3 primary efficacy variables at last visit decreased in both treatment groups from baseline over the 8-week treatment period, with the greatest decreases occurring at week 8. At last visit, the mean change from baseline in the YGTSS Global Severity score in the ziprasidone group was significantly greater than that in the placebo group (39.0% versus 16.2%, p = .016) (Table 3). Similarly, the mean change from baseline to last visit in the YGTSS Total Tic score in the ziprasidone

TABLE 3 Mean (SD) for Primary Efficacy Variables Placebo Baseline

Last Visit a

No. of subjects YGTSS Global Severity score

11 46.9 (17.7)

11 39.3 (21.3)

No. of subjects YGTSS Total Tic score

11 24.6 (9.6)

11 22.9 (10.8)

No. of subjects CGI-TS

11 4.5 (1.0)

11 3.8 (1.4)

Ziprasidone Change [%]

-7.6 (10.6) [16.2]

-1.7 (5.0) [6.9]

-0.7 (0.9) [15.6]

Baseline

Last Visit a

16 46.9 (13.8)

16 28.6 (17.3)

16 24.7 (6.8)

16 16.1 (7.4)

16 4.6 (0.9)

16 3.2 (1.1)

Change [%]

p Value b

-18.3 (9.9) [39.0]

.016

-8.6 (6.7) [34.8]

.008

-1.4 (1.0) [30.4]

.107

Note: YGTSS = Yale Global Tic Severity Scale; CGI-TS = Clinical Global Impression Severity Scale for Tourette's Syndrome. Intent-to-treat, last observation carried forward. b Ziprasidone versus placebo, change from baseline.

a

J.

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group was significantly greater than that in the placebo group (34.8% versus 6.9%, p = .008) (Table 3 and Fig. 1). However, although the mean change from baseline to last visit in the CGI-TS score in the ziprasidone group was greater than that in the placebo group (30.4% versus 15.6%), the difference was not statisticallysignificant (p = .107) (Table 3). Ziprasidone treatment was also associated with improvements in the secondary efficacy variables. The mean change from baseline to last observation in the total number of motor and phonic tics counted on the 5minute Goetz Videotape Rating Scale for the ziprasidone group was significantly greater than the placebo group (49.8% versus 3.5%, p = .039) (Table 4). Similarly, the mean change from baseline in the total score from the Goetz Videotape Rating Scale (i.e., sum of anatomic distribution, intensity, and tic frequency scores) was significantly greater in the ziprasidone group than in the placebo group (54.0% versus 0.92%, p = .043) (Table 4). In the subjects with mild or greater obsessive-compulsive symptoms at baseline (n = 5 per group), there was a 4.5% increase from baseline to week 8 for the placebo group compared with a 26.5% decrease for the ziprasidone group (Table 4).

Tolerability Of the 28 patients analyzed, 23 (82.1 %) experienced a treatment-emergent adverse event during double-blind treatment or within 6 days of the last day of treatment: all 16 patients 000%) in the ziprasidone group and 7 (58.3%) of the 12 patients in the placebo group. The majority of treatment-emergent adverse events were mild or moderate. One case each of somnolence and akathisia, both occurring in the ziprasidone group, were considered to be severe but did not necessitate discontinuation of treatment. The patient who experienced severe somnolence first did so on day 35 while receiving a dose of 40 mg of ziprasidone per day. The dose of ziprasidone was reduced over days 36 to 42, and by days 51 to 56 the severity of the somnolence had decreased to moderate. After completion of the study, the somnolence resolved. The patient who developed akathisia first did so on day 43 of the study after receiving the maximum dose of ziprasidone (40 mg/day) for 3 weeks. The dose of ziprasidone was reduced from 40 mg/ day to 30 mg/ day over days 44 to 45, and the akathisia subsequently resolved without any further dose reduction. The patient did not require any concomitant medication for this adverse event. Only 1 (6.3%) of the 16 subjects in the ziprasi-

40.,-----------------------------35

30

e 25

8

til

CJ

i= ~ 20

~

til

~

~ 15

10

5

0+--...1..-Baseline

Week 4

Week 8

Fig. 1 Mean (SD) Yale Global Tic Severity Scale (YGTSS) Total Tic score at baseline, week 4, and week 8 (0 placebo; • = ziprasidone).

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=

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TABLE 4 Mean (SO) Scores for Secondary Efficacy Variables Placebo

Io, of subjects ;oetzVideotape Rating-total score

lo, of subjects .Joerz Videotape Raring-total no. of tics/5 min

No. of subjects CY-BOCSC-total score

Baseline

Lasr Visit a

11 43.7 (35.8)

11 43.3 (36.8)

11 54.5 (39.5)

11 52.5 (39.5)

5 13.2 (9.0)

5 13.8 (8.6)

Ziprasidone Change [%]

-0.5 (33.2) [-0.92]

-1.9 (37.0) [-3.5]

+0.6 (2.9) [+4.5]

Baseline

Last Visit a

15 60.4 (41.5)

15 27.8 (25.4)

15 69.5 (43.8)

15 34.9 (28.0)

5 19.6 (2.6)

5 14.4 (5.9)

Change [%]

pValue b

-32.6 (33.4) [54.0]

.043

-34.5 (35.1) [-49.8]

.039

-5.2 (5.4) [-26.5]

NO

Note: CY-BOCS

= Children's Yale-Brown Obsessive Compulsive Scale; NO = not determined. For the Goetz Videotape Ratings, all recordings were acquired on day 57, except one patient's recordings were acquired on day 43; the obsessive-compulsive disorder scores from CY-BOCS are week 8 values. b Ziprasidone versus placebo, change from baseline. C Sum of items 1 through 5, 6A, and 7 through 10 from CY-BOCS. a

done group discontinued because of an adverse event (mild sedation). The most common adverse event was transient mild sedation. Mean sedation scores showed a modest increase up to week 6, when the mean weekly dose of ziprasidone was maximal, and declined slighdy in weeks 7 and 8. The placebo group sedation score was 1.0 at baseline and varied from 1.1 to 1.3 over weeks 1 to 8. Sedation scores in the ziprasidone group were 1.2 at baseline and 1.1, 1,3, 1.3, 1.6, 1.3, 1.8, 1.6, and 1.4 at weeks 1 to 8, respectively. Eleven (69%) of the 16 patients in the ziprasidone group and 5 (45%) of the 11 patients in the placebo group had an increase in sedation score above baseline values on at least one visit during the 8-week treatment period (X2 = 1.44, P = .21). In general, the sedation resolved after ziprasidone dose reduction. No clinically significant effects were observed in specific assessments of movement disorders. Mean SimpsonAngus, BAS, and AIMS scores in the ziprasidone group at week 8 were similar to those in the placebo group (data not shown). The mean (±SO) change in body weight from baseline to week 8 in the ziprasidone group (+0.7 ± 1.5 kg) was similar to that in the placebo group (+0.8 ± 2.3 kg). Physical examination revealed no significant changes from baseline for any patient, except mild gynecomastia in one

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boy in the ziprasidone group. Five boys in the ziprasidone group experienced increasesin serum prolactin concentrations greater than 1.1 times the upper limit of normal during the study. However, these elevations were transient, and serum prolactin concentrations returned to normal by the end of the study (mean ± SO prolactin concentration: 5.7 ± 1.6 ng/mL in the placebo group versus 5.7 ± 2.8 ng/mL in the ziprasidone group). The highest prolactin concentration recorded (51 ng/mL) occurred in the boy with the highest baseline value (21 ng/mL). There was no discernible pattern of laboratory test abnormalities. No clinicallysignificant differences between the treatment groups were observed in assessmentsof vital signs, and there were no clinically significant changes in pulse rate, standing or sitting blood pressure, or ECG parameters. DISCUSSION

The results of this initial pilot study suggest that ziprasidone may be an effective anti-tic agent in children with TS or CTO. Ziprasidone produced clinically and statistically significant improvement in tic symptoms as judged by clinician-rated global standardized ratings (YGTSS) and on quantitative videotape tic counts obtained under double-blind conditions.

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In the dose range evaluated in this study (5-40 mg/day), ziprasidonewas generallywell tolerated and most adverseeffects were mild and transient. The most common dose-limiting adverse effect was sedation, which usually resolved with decreases in dose. Although at the maximum dose one subject developed akathisia (which resolved after a dose reduction), there were no acute dystonic reactions or parkinsonian symptoms in any subject. Thus, in this limited sample, ziprasidone also appeared to be associated with a low risk of extrapyramidal effects. However, definitive assessment of whether children and adolescents may be more prone to sedation or extrapyramidal symptoms with ziprasidone will require larger-scale studies. Study Limitations

Although this was a placebo-controlled, blinded, and randomized study, the sample size was comparatively small and the findings regarding both efficacy and safety will need to be replicated in future larger-scale studies. Another limitation of this study is that assessment of treatment effects on comorbid behavioral conditions was limited to obsessive-compulsive symptoms. Children with TS suffer from a wide range of comorbid difficulties, which may have greater impact than tic frequency and severityon a child'sdevelopment and functioning (Walkup, 1999; Walkup et al., 1995). In the present study, the CGITS ratings were included to provide a global assessmentof overall function, including the impact of comorbid problems. Although ziprasidone was associated with a 30.4% decrease in CGI-TS scores compared with a 15.6% decreasein the placebo group, this differencefailedto achieve statistical significance (p = .107), probably because of the small sample size. In future studies the impact of treatment with ziprasidone on the full range of comorbid difficulties in children with TS should be evaluated, using both clinician ratings and outcome measures specifically derived from the patient and family. Clinical Implications

In this study ziprasidone appeared to have a moderate anti-tic effect, as measured by a mean decrease of 35% in the YGTSS tic subscale score and a 49.8% decrease in tic frequencies estimated by videotape tic counts. This appears to be somewhat less than what may be achieved with the traditional neuroleptics pimozide and haloperidol, albeit at greater risk of intolerable side effects. For example, in a recent study by Sallee et al. (1997), which compared the relative efficacy of equivalent doses of

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haloperidol and pimozide in a placebo-controlled crossover study of 22 adolescents with TS, pimozide caused a 54% mean decrease from baseline in tic severity subscale scores and haloperidol caused a 43% decrease. No controlled studies have been published to date on the effects of other atypical antipsychotics in TS; thus it is difficult to make meaningful comparisons of ziprasidone with agents such as risperidone, olanzapine, and quetiapine. Open-label studies of risperidone in children and adults with TS have suggested mean response rates ranging from 22% to 46% decreases in tic severity (Bruun and Budman, 1996; Lombroso et al., 1995; Van der Linden et al., 1994). Ziprasidone may offer improved toleration relative to both typical and other atypical neuroleptics. A promising observation from this study was that ziprasidone did not appear to be associated with any appreciable weight gain. Weight gain has been a significant and difficult issue in adults treated with atypical neuroleptics (Wirshing et al., 1999). As these agents have found increasing use in children and adolescents, it has become apparent that pediatric patients are also vulnerable to substantial weight gain with these compounds. In the open-label study of risperidone in children with TS conducted by Lombroso et al. (1995), all 7 subjects had weight gains, ranging from 8 to 14 pounds. In a recent caseseriesof olanzapine treatment in 5 preadolescent children with various diagnoses, 3 of the children experienced substantial weight gains (of 9, 10, and 16 pounds) (Krishnamoorthyand King, 1998). Studies in adult patients with schizophrenia have shown that ziprasidone does not appear to be associated with significant weight gain (Daniel et aI., 1999). Should future studies confirm that ziprasidone does not cause weight gain in children and adolescents, that could have important implications for the clinical management of children with severe tic disorders. Also of potential importance was the finding that ziprasidone caused only transient increases in prolactin concentration. By contrast, risperidone can be associated with sustained hyperprolactinemia and there have been numerous case reports of gynecomastia, galactorrhea, and amenorrhea in patients treated with this medication (Bruun and Budman, 1996). One 14-year-old boy in the ziprasidone group developed mild gynecomastia. However, he had no elevation in prolactin levelsand this physical finding was attributed to physiological gynecomastia of adolescence, which occurs in up to 39% of adolescent boys (Frantz and Wilson, 1985).

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ZIPRASIDONE IN TOURETTE'S SYNDROME

Another intriguing observation was that in those subjects judged to have clinically significant OCD at baseline, ziprasidone was associated with a 26% mean decrease from baseline YBOCS scores, compared with a 4.5% increase in YBOCS scores in the placebo group. Although the sample size (n = 5 subjects per group) is tOO small to permit firm conclusions, future studies should examine the potential effectiveness of ziprasidone as an antiobsessional agent both in patients with primary OCD and in patients with combined TS and OCD. It will be of great interest to determine whether ziprasidone is an effective monotherapy for both tic and obsessive-compulsive symptoms. In conclusion, the results of this pilot study suggest that ziprasidone may be an effective anti-tic medication that appears to be well tolerated in children and adolescents with TS and CTD. These preliminary results should be confirmed in future larger-scale studies, designed to assess more fully the safety of ziprasidone and its effects on both tics and the full range of cornorbid behavioral problems associated with TS.

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