JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Volume 20, Number 4, 2010 Mary Ann Liebert, Inc. Pp.

. 291298 DOI: 10.1089/cap.2009.0125

Effectiveness and Tolerability of Aripiprazole in Children and Adolescents with Tourettes Disorder: A Pilot Study in China
1 1 1 Yong-hua Cui, M.D., Yi Zheng, M.D., Yun-ping Yang, M.D., Jing Liu, M.D.,2 and Jun Li, Ph.D.3

Abstract

Objective: The primary aim of the study was to evaluate the effectiveness and tolerability of aripiprazole on motor and vocal tics in children and adolescents with Tourettes disorder (TD). The secondary aim was to assess the response of TD-associated behaviors to aripiprazole exposure. Methods: This was an 8-week, open-label trial with exible dosing strategy of aripiprazole in children and adolescaents with TD. A total of 72 patients, aged 618 years, participated in the 8-week trial. The Yale Global Tic Severity Scale (YGTSS), the Clinical Global ImpressionsTics (CGITics), and the Child Behavior Checklist (CBCL) were compared at the baseline, weeks 2 and 4, and end point. The side effects of aripiprazole, electrocardiogram (ECG), and body mass index (BMI) were evaluated. Results: Over the 8-week trial, aripiprazole administration was associated with a signicant decrease in total tic severity as measured by the YGTSS (50.3% reduction by week 8). The mean scores of motor tic in the YGTSS were 17.42 4.83, 12.93 3.76, 8.39 3.70, and 6.75 3.95 at baseline, weeks 2 and 4, and end point. A signicant decrease in the scores was observed in week 2 compared to the baseline, and the scores continued to decrease for the remainder of the study period (degrees of freedom [df ] 3, F 96.02, p 0.000). The mean phonic tic scores were 12.71 4.60, 8.53 3.26, 6.10 2.50, and 3.63 2.20 at baseline, weeks 2 and 4, and end point, respectively. A signicant change was observed during week 2 compared to the baseline, and this change continued for the rest of the study period (df 3, F 95.16, p 0.000). Signicant improvement was also observed according to the CGITics severity. The mean CGITics severity score was 4.77 1.69 at baseline and decreased to 2.20 1.39 at end point (t 10.70, p 0.000). A signicant reduction of behavior symptoms was noticed according to the CBCL and its subscales between baseline and end point. The majority of subjects tolerated aripiprazole well. The extrapyramidal symptoms (EPS) during this study were negligible. In all 21 (29.2%) of the 72 participants complained of nausea and 19 (26.4%) of them reported sedation. There was no signicant difference of BMI between the two phases (df 64, t 0.94, p 0.352). There were no signicant changes in laboratory results. ECG monitoring revealed no signicant impact on cardiac conduction by aripiprazol. Conclusion: In this preminary open-label trial, aripiprazole showed effectiveness in treating tic symptoms without causing signicant weight gain or other serious side effects. Aripiprazole could be an option for TD cases that do not respond to conventional therapies. Further controlled, double-blind studies are warranted.

Introduction

ncreasing awareness of the clinical complexity of Tourettes disorder (TD) and associated features have led to the recognition of the high frequency of associated co-morbid psychopathology. The majority of clinically referred individuals with TD also meet criteria for one or more co-morbid psychiatric disorders, including attention-decit/hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), oppositional deant disor1 2

der (ODD), conduct disorder, rage episodes, aggression, and other emotional disorders, which are often more debilitating than the tics themselves, and these individuals may experience signicant social and behavioral difculties (McCracken 1999; Kadesjo et al. 2000; Freeman et al. 2000; Stephens et al. 2004, Chao et al. 2009). Although the relationship between TD and associated co-morbid psychiatric disorders has been difcult to untangle, behavioral and emotional symptoms are leading causes of dysfunction and disability in clinically referred samples (Coffey et al. 2000a).

Beijing Anding Hospital, Capital Medical University, Beijing, China. Sixth Hospital, Beijing University, Beijing, China. 3 Beijing Normal University, Beijing, China. This study is an investigator-initiated study supported by grant funding (Capital Medical Science Development Fund) from the Beijing city health administration (to the rst author).

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292 The exact causes of TD are not yet well established (Leckman 2002). No clear single neurotransmitter system has so far been clearly identied (Rickards 2009). However, dopamine release was greater in patients with TD than in controls. Abnormal motor coordination caused by the phasic dysfunction of dopamine transmission may produce tics (Singer et al. 2002; Nikolaus et al. 2009). Currently, the only medications formally approved for use in TD are haloperidol and pimozide (Thompson 2007). However, signicant side effects, including extrapyramidal symptoms (EPS) such as acute dystonic reactions, Parkinsonism, akathisia, and tardive dyskinesia (Shapiro et al. 1973), have limited their longterm efcacy and safety prompted the development of the novel atypical neuroleptics. Aripiprazole is an atypical antipsychotic drug that is proposed to have a unique mechanism of action (Bowles and Levin 2003; Shapiro et al. 2003). The U.S. Food and Drug Administration (FDA) approved indications for aripiprazole in adolescents ages 1317 with schizophrenia and bipolar disorder. There are only limited data on the effects or side effects of aripiprazole in children and adolescents with TD. Few studies have investigated the effect of aripiprazole in children and adolescents with TD, and the sample sizes of these studies were all very small. A 12-week, open-label trial with a exible dosing strategy of aripiprazole was performed with 15 children and adolescents with TD or chronic tic disorders aged 719 years. This study demonstrated that a relatively low dose of aripiprazole could be used to control tic symptoms effectively in children and adolescents with TD and chronic tic disorders without causing signicant weight gain (Seo et al. 2008). Another retrospective, observational study suggested that aripiprazole could improve the explosive outbursts symptoms of children and adolescents with TD and aripiprazole was tolerated reasonably well (Budman et al. 2008). But a case reported an acute dystonic episode in a patient with TD treated with the partial dopamine agonist aripiprazole (Fountoulakis et al. 2006). The preliminary evidence suggested that aripiprazoles benet-versus-risk prole merits should be further explored for use in TD. Our hypotheses were that aripiprazole might be effective in treating tic symptoms without causing serious side effects and aripiprazole could be as an interesting option for TD cases that did not respond to conventional therapies. The aim of the study was to explore the use and tolerability of aripiprazole as a treatment for tics and co-morbid symptoms in youths with TD. This was a rst study of aripiprazole on TD in China. Methods Subjects The subjects were recruited from outpatient units in three hospitals in China over a period of 7 months from November, 2008, to July, 2009. All subjects were Chinese and of Han nationality. The study protocol was approved by Institutional Review Boards (IRBs) in three sites. Written informed consent and assent were obtained. All subjects were required to meet the following inclusion criteria: (1) Between the ages of 6 and 18 years; (2) Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) (American Psychiatric Association 1994) diagnosis of TD; (3) minimum body weight of greater than or equal to 25 kg; (4) outpatient status and not believed to require inpatient hospitalization during the course of the study; (5) minimum Clinical Global ImpressionsSeverity (CGI-S) score of moderately ill or greater severity (rating of 4); (6) normal screening medical history and

CUI ET AL. physical examination; and (7) patient and parent/guardian must provide written informed consent (or assent). Subjects were excluded from participation in the study if they had one or more of the following exclusion criteria: (1) Intelligence quotient (IQ) score below 70 by Wechsler Intelligence Scale for Children, 3rd edition (WISC-III) (potential participants with a low IQ were excluded from this study because they were not expected to be able to describe their symptoms or the side effects of the medication appropriately); (2) prior adequate treatment with aripiprazole; (3) hypersensitivity to aripiprazole; (4) need for co-morbid psychotropic medication during the study period or required concurrent medication that effects tics; (5) current use of psychostimulants, mood stabilizers, or anticonvulsants; (6) presence of signicant co-morbid medical illness; (7) history of seizure disorder; (8) history of substance or alcohol abuse or dependence within 6 months of screening; (9) pregnancy, lactation, or positive pregnancy test; (10) absence of acceptable contraceptive method for sexually active females; (11) detection of pregnancy during the study, which would have led to withdrawal from the study; and (12) concurrent behavioral treatment for tic symptoms during the 6-week treatment period. Study design and measurements This study was an 8-week, open-label exible dose design in outpatients with TD receiving monotherapy with aripiprazole. All subjects had a 7- to 14-day screening period. The tics and co-morbid symptoms of each participant at baseline were evaluated by appointed psychiatrists Severity of tic symptoms during the previous week was evaluated using the Yale Global Tic Severity Scale (YGTSS) (Leckman et al. 1989). The YGTSS is a semistructured interview designed to elicit information concerning the specic character and anatomical distribution of tics. It has robust psychometric properties as a measure of change in tic severity and has been used in a number of studies internationally (Storch et al. 2005; Storch et al. 2007). The interview began with systemic assessment of current tic symptoms (both motor and phonic tic symptoms) that the clinician rated as present or absent over the past week. This was followed by assessing the most severe tic symptoms by the patients themselves. Motor and phonic tic symptoms were rated according to number, frequency, intensity, complexity, and interference on a 6-point ordinal scale. Patients Current Total Tic score and Total Most Severe Tic score ranged from mild to severe (0 absent, 15 for severity). The YGTSS was evaluated at baseline, weeks 2 and 4, and end point through face-toface interviews with each participant. Tic severity was also assessed using the Clinical Global ImpressionsTics (CGITics) (Zhang 1998). The CGI consists of 07 points. It is used to evaluate the severity of clinical symptoms and measure change in them over the course of the study. It has robust psychometric properties as a measure of change in clinical symptoms and has been used in a number of studies internationally (Zhang 1998). Operational denition of CGITics severity was as follows: (1) Normal or no tics at all; (2) borderline, tics may or may not be present; (3) mild, observable motor and/or vocal tics that may or may not be noticed, would not call attention to the individual, and are associated with no distress or impairment; (4) moderate, observable motor and/or vocal tics that would always be noticed, would call attention to the individual, and may be associated with some distress or impairment; (5) marked, exaggerated motor and/or vocal tics that are disruptive, would always call attention to the individual, and are always associated with signi-

ARIPIPRAZOLE IN TOURETTES DISORDER cant distress or impairment; and (6) severe, extremely exaggerated motor and/or vocal tics that are disruptive, would always call attention to the individual, and are associated with injury or inability to carry out daily functions. The scale was evaluated at baseline, weeks 2 and 4, and end point through face-to-face interviews with each participant. Staff for conducting clinician ratings all received extensive training by the responsible author in the primary outcome measures, and satisfactory interrater reliability was documented. Interrater reliability of YGTSS and CGITics in this study was assessed with the Pearson correlation test. Interrater reliability of YGTSS in this study was 0.87 and that of CGITics was 0.89. To maximize interrater reliability between sites, the number of raters at each site was minimized; they were all provided with identical instructions for administering YGTSS and CGITics, and efforts were to be made to ensure that the same rater administered the scales for a given patient. Those raters who failed to achieve the requisite level of interrater reliability were not allowed to rate subjects in the trial. The co-morbid symptoms of each participant were evaluated with the Child Behavior Checklist (CBCL). The CBCL is a widely used parent-reported questionnaire designed to assess the behavioral problems and social competence of children 418 years of age, which was revised by Achenbach and was used after being translated into Chinese (Su et al. 1998). The CBCLChinese (CBCL-C) consists of 20 items that assess social competence and 118 items concerning behavioral and emotional problems. The questionnaires were scored using eight measures: Withdrawal, somatic complaints, anxiety and depression, social problems, cognitive problems, attention problems, delinquent behavior, and aggressive behavior. They were grouped into two broad band scores: Internalization behavior problem score, consisting of withdrawal, somatic complaints, anxiety and depression, and externalization behavior problem score, consisting of delinquent and aggressive behaviors. Standardized T scores with a mean of 50 (standard deviation [SD] 10) were provided for each subscale. A T score greater than 60 indicated a borderline clinical range. The higher the score, the more severe the childs behavioral and psychological problems (Yang et al. 2000). The scale was evaluated at baseline and end point. All subjects had a complete review of their current health status, which included a careful medical history. Vital signs, including blood pressure and pulse rate, were assessed at screening, baseline, weeks 2 and 4, and end point. Meanwhile, laboratory tests were conducted and included routine hematology, prolactin, clinical chemistry, and routine urinalysis. In addition, an ECG was done to rule out any preexisting cardiac conditions. The side effects of aripiprazole were evaluated using an adverse events chart made by this study team. The chart was developed to evaluate extrapyramidal symptoms, gastrointestinal symptoms, neuromuscular symptoms, sedation, or other cognitive symptoms. Height, weight, and body mass index (BMI) of each participant were checked at baseline and end point, and the BMI of each participant was compared between the two phases. Dosing schedule Aripiprazole was initiated at doses of 1.252.5 mg daily in prepubertal children and at 2.55 mg in adolescents, and exibly titrated every 57 days as tolerated and clinically indicated. Treatment duration was 8 weeks (with dosing generally titrated to therapeutic range within about 4 weeks). Data analyses

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Analysis of variance (ANOVA) was performed to evaluate the quantitative change in the scores pertaining to motor tic, phonic tic, total tic, global impairment, and global severity in the YGTSS at baseline, weeks 2 and 4, and end point. The same statistical method was also used for CGITics. Change in the CBCL was analyzed using a paired t-test. Adverse effects were evaluated by descriptive statistics. In addition, weight and prolactin were examined as primary side effects and were compared from baseline to week 8, using paired t-tests and a one-sample t-test based on percent change from baseline values. The last observation carried forward (LOCF) was used as the end point for a participant. All statistical analyses were performed using the SPSS statistical package, version 15.0. All statistical tests were two-sided at the 5% level of signicance. Results A total of 72 subjects were enrolled (age range 618; 10.23 2.47 years; 55 males, 17 females). A total of 25 participants ve to their tic symptoms, whereas 47 had a history of were drug na using neuroleptics; 31 took low doses of neuroleptics (e.g., less than 200 mg/day of tiapride or 1 mg/day of haloperidol or 1.5 mg/day of risperidone); 16 took moderate-to-high doses of neuroleptics (200400 mg/day of tiapride or 14.5 mg/day of haloperidol or 1.53.5 mg/day of risperidone) (Table 1). Seven of 72 subjects (9.7%) discontinued aripiprazole before 8 weeks. Of those 7 subjects, 5 were adolescents and 2 were prepubertal children. Four of the 7 dropouts discontinued at the end of 4 weeks because of no signicant reduction of symptoms. Two dropouts withdrew from the study at the end of 4 weeks because of continuous sedation, and another participant dropped out because of skin hypersensitivity at the end of 2 weeks, a symptom that disappeared 2 days after stopping the drug. In the cases of early withdrawal, data were obtained using the LOCF method. All 72 subjects provided data over 2 weeks of the study, and these were used for analyses. There were no differences in outcomes stratied by site. The initial dosage of aripiprazole was 1.252.5 mg daily in prepubertal children and at 2.55 mg in adolescents, and exibly titrated every 57 days as tolerated and clinically indicated. The mean daily dosages of aripiprazole were 4.88 0.63 mg, 7.33 2.06 mg during weeks 2 and 4, and the nal dose of aripiprazole was 8.17 2.41 mg or 0.19 mg/kg (range from 0.1 to 0.60 mg/kg).

Table 1. Demographics and Prior History of Treatment n (%) Total of subjects Males Females Mean age (SD) Never used medications Ever used medications Tiapride (<200mg/d) Risperidone (<1.5mg/d) Haloperidol (<1mg/d) Tiapride (200400mg/d) Risperidone (1.53.5mg/d) Haloperidol (14.5mg/d) 72 55 17 10.23 25 47 13 9 9 7 3 6 (100%) (76.4%) (23.6%) (2.47) (34.7%) (65.3%) (18.1%) (12.5%) (12.5%) (9.7%) (4.2%) (8.3%)

294 Primary outcome measure: Effectiveness of aripiprazole of tic symptoms A signicant reduction of symptoms was noticed in three subscales, except global impairment of the YGTSS between baseline and week 2; this reduction continued for the remainder of the study period. A signicant reduction of symptoms was noticed in the subscale of global impairment of the YGTSS between baseline and week 3, and this reduction also continued for the remainder of the study period (Table 2). The mean scores of motor tic in the YGTSS were 17.42 4.83, 12.93 3.76, 8.39 3.70, and 6.75 3.95 at baseline, weeks 2 and 4, and end point. A signicant decrease in the scores was observed in week 2 compared to the baseline, and the scores continued to decrease for the remainder of the study period (df 3, F 96.02, p 0.000). The mean phonic tic scores were 12.71 4.60, 8.53 3.26, 6.10 2.50, 3.63 2.20 at baseline, weeks 2 and 4, and end point, respectively. A signicant change was observed during week 2 compared to the baseline, and this change continued for the rest of the study period, as was the case in the motor tic scores (df 3, F 95.16, p 0.000). Total tic scores were 30.13 7.08, 21.46 4.30, 14.49 4.75, 10.38 4.32 at baseline, weeks 2 and 4, and end point. A signicant change in global impairment score was observed during week 2 compared to the baseline, and the change was continued for the entire remaining period (df 3, F 187.58, p 0.000). The means of the global impairment scores were 29.58 13.58, 27.60 9.82, 17.67 7.18, and 8.08 4.23 at baseline, weeks 2 and 4, and end point, respectively. Signicant improvement in the global impairment score in comparison to the baseline score was observed from week 4, and the improvement continued for the rest of the study period (df 3, F 74.83, p 0.000). The mean global severity scores were 59.72 16.55, 46.46 10.32, 32.17 8.01, and 18.46 5.429 at baseline, weeks 2 and 4, and end point. A signicant change from the baseline score was demonstrated during week 2 and continued thereafter (df 3, F 180.38, p 0.000). The degree of symptom reduction was 18% to 100% in the motor tic symptoms and 4% to 100% in the phonic tic symptoms. The degree of mean decrease of YGTSS Total Tic score was 50.3%. The degree of mean decrease of YGTSS Global impairment was 56.5%. Meanwhile, 2 participants developed a new symptom of a motor tic and another participant experienced aggravation of a phonic tic symptom. Signicant improvement was observed according to the CGITics severity. The mean CGITics severity score was 4.77 1.69 at baseline and decreased to 2.20 1.39 at end point (t 10.70, p 0.000). Secondary outcome measure-1: Effectiveness of aripiprazole on behavior symptoms The CBCL results were returned by caregivers of 72 participants (response rate 100%). Most forms were completed by mothers

CUI ET AL. (73%), followed by fathers (16%) and others (11%; e.g., step parents, grandparents). A signicant reduction of behavior symptoms was noticed according to the CBCL and its subscales between baseline and end point. The t-test for equality of means was used to determine signicance of the differences between the mean CBCL T-scores of baseline and end point (Table 3). The differences between the mean T-scores were signicant with regard to the following scales: Somatic complaints ( p < 0.05), Anxious/ Depressed ( p < 0.01), Thought problems ( p < 0.01), Attention problems ( p < 0.05), Aggressive behavior ( p < 0.05), Externalizing ( p < 0.01), Internalizing ( p < 0.01), as well as the total problems scales ( p < 0.01). Secondary outcome measure-2: Short-term safety of aripiprazole in children and adolescents The majority of subjects tolerated aripiprazole well. The EPS during this study were negligible. Nausea and sedation were the most commonly reported side effects. In all, 21 (29.2%) of the 72 participants complained of nausea and 19 (26.4%) of them reported sedation. Both side effects ameliorated in all participants within 2 weeks, with the exception of 2 participants who had continuously complained of sedation and withdrew from the study at the end of 4 weeks for continuous sedation. Paired t-tests of preand week-8 nonfasting laboratory results and BMIs showed several statistically signicant changes from baseline (Table 4), but none was deemed clinically signicant (all values within normal ranges). No signicant changes in albumin (ALB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (Cre), blood urea nitrogen (Bun), or prolactin (PRL) were observed (Table 4). There were also no signicant changes in fasting glucose, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides concentrations, routine hematology, or routine urinalysis observed. ECG monitoring did show signicant impact on cardiac conduction. Thirteen of 72 subjects had QTc interval increases (mean increase 9.1 4.4 milliseconds). However, these increases were considered nonsignicant, because readings <440 are considered to be normal in children (Moss 1993). The mean QTc interval at baseline was 401.8 16.9 and, at the end of week 8, was 399.8 12.4. There was no signicant difference between the two phases (Table 4). Paired t-test analysis of the results at initial and nal visits showed that none of the changes in measurements was clinically signicant (all within laboratory normal ranges). Uncorrected p values are represented. Discussion We found 11 articles regarding the use of aripiprazole in tic disorders. Six were open-label studies that looked at the use of aripiprazole in TD (Yoo et al., 2006; Miranda et al. 2007 Lyon

Table 2. Change of Scores of the YGTSS and Its Subscales (n 72) Baseline (mean SD) 2 weeks (mean SD) 4 weeks (mean SD) 8 weeks (mean SD) df Motor tic scores Phonic tic scores Total tic scores Global impairment scores Global severity scores
a

F 41.86 45.53 86.73 44.43 98.87

p value 0.000 0.000 0.000 0.000 0.000

17.42 4.83 12.71 4.60 30.13 7.08 29.58 13.58 59.72 16.55

13.74 5.00 9.19 3.52a 22.93 5.40a 27.60 9.82 50.53 11.06a

10.32 4.96 8.00 3.34 18.32 6.03 20.20 6.71a 38.52 9.61

9.25 4.18 5.74 2.45 14.98 4.57 12.86 4.83 27.85 6.23

3 3 3 3 3

less than 0.001 (comparison with baseline). Abbreviations: YGTSS Yale Global Tic Severity Scale; SD standard deviation.

ARIPIPRAZOLE IN TOURETTES DISORDER Table 3. Comparison of the Mean Scores of CBCL (T-Scores) Between Baseline and End Point (n 72) CBCL scores Total Externalizing Internalizing Withdrawn Somatic complaints Anxious/ Depressed Social problems Thought problems Attention problems Delinquent behavior Aggressive behavior Baseline End point p (mean SD) (mean SD) T-test value 56.36 8.54 52.14 6.33 56.28 8.44 57.40 8.07 54.66 7.76 57.97 8.06 54.18 7.63 56.31 8.35 57.82 9.11 52.91 10.97 55.09 10.15 49.46 8.39 48.38 7.92 52.14 9.48 56.16 8.14 53.94 7.60 54.82 9.29 52.88 9.68 52.16 9.22 55.08 8.65 51.74 8.72 51.88 7.43 4.93 2.81 3.07 1.81 2.14 3.13 0.92 3.24 2.26 1.04 2.06 0.000 0.007 0.003 0.075 0.037 0.003 0.363 0.002 0.027 0.301 0.043

295 use of aripriprazole to treat children and adolescents with TD in China. In our open-label, acute treatment trial of children and adolescents with moderate-to-severe TD, aripiprazole administration was associated with noticeable improvement on dimensional measures across a variety of symptomatic areas, including reduced total tic frequency, intensity, interference, impairment, and severity and decreased behavior problems. The magnitude and signicance of effect of aripiprazole on measures of tic severity was in line with an array of other similar reports. Aripiprazole was associated with a statistically signicant decrease in the YGTSS Total Tic score of 50.3%. Yoo et al. (2007) reported that there was a 52.8% reduction in the mean YGTSS Total Tic scores after a mean of 9.8 4.8 mg/day of aripiprazole for 8 weeks. Seo et al. (2008) reported that the degree of symptom reduction according to YGTSS was 5064.8% with a mean end point dosage of 8.17 4.06 mg. Another 12-week case series of 6 children and adolescents with TD and OCD, mean decrease of YGTSS was 56% with a mean dose of 11.7 mg of aripiprazole (Murphy et al. 2005). It seems that there was a greater magnitude of effect of aripiprazole than for most other medications used in treating tics in childhood, such as those reported for olanzapine (30%; McCracken et al. 2008), ziprasidone (35%; Sallee et al. 2000), risperidone (2142%; Gaffney et al. 2002; Scahill et al. 2003; Gilbert et al. 2004), and pimozide (21%; Gilbert et al. 2004). The difference was notable, but it needs further exploration. Taken together with the signicant drop in YGTSS Impairment ratings, the data (56.5%) from this study suggest that the overall clinical benet for tic control per se is meaningful. The mean CGITics severity score was 4.77 1.69 at baseline and decreased to 2.20 1.39 at end point (t 10.698, p 0.000). The signicant improvement observed according to CGITics severity also conrmed this nding. An important aim of this study was to evaluate the possible broader effectiveness of aripiprazole on commonly co-occurring behavior symptoms in TD. A signicant reduction of behavior symptoms was noticed according to the CBCL and its subscales between baseline and end point in this study. This nding expanded on the observations (Stigler et al. 2004; ValicentiMcDermott et al. 2006; Owen et al. 2008a; Owen et al. 2008b; Stigler et al. 2009; Bastiaens et al. 2009) that rating of behavioral problems decreased with aripiprazole treatment. Given that behavior problems in TD often form the primary source of impairment and stress, we believe aripiprazoles benecial effects are clinically important. The effectiveness of aripiprazole on behavior symptoms in TD may have contributed to the improvement of impairment. With regard to dosing aripiprazole in TD and tic disorders, there are no clear guidelines (Greenaway et al. 2009). In our study, the initial dosage of aripiprazole was 1.252.5 mg daily in prepubertal children and at 2.55 mg in adolescents, and exibly titrated every 57 days as tolerated and clinically indicated. The nal mean daily dose of aripiprazole was 8.17 mg (range 2.5 17.5 mg). This dosage was consistent with the available reports (from 6.7 to 14.5 mg/day)(Murphy et al. 2005; Davies et al. 2006; Yoo et al. 2006; Miranda et al. 2007; Yoo et al. 2007; Seo et al. 2008; Budman et al. 2008; Findling et al. 2008b). A dose of 10 mg/ day appears to be a reasonable target dose for these conditions for many children and must adolescents. Given that younger children are more susceptible to the side effects of aripiprazole, they should be started at lower initial doses with a lower target dose (Greenaway et al. 2009).

Abbreviations: CBCL Child Behavior Checklist; SD standard deviation.

et al. 2009; Seo et al. 2008; Kawohl et al. 2009; Murphy et al. 2009). Outcomes in all six studies were measured by the YGTSS at baseline and end point. In all the six studies, signicant reductions in the YGTSS were noted in participants aged 719 years with doses ranging between 2.520 mg/day. In three of the six studies, signicant improvement was shown from CGI scales at end point. In addition to these open-label studies there was a pilot study (Yoo et al. 2006), three case series (Murphy et al. 2005; Davies et al. 2006; Duane 2006), and one retrospective study (Budman et al., 2008), all nding clinical improvement with reasonable tolerability with use of aripiprazole in the treatment of tic disorders. A small dose of aripiprazole was found to be effective in controlling tic symptoms in the above-mentioned studies investigating tic disorders. However, the sample size of these studies was relatively small, even including some case reports. Aripiprazole is relatively new, even in the adult population, and without the experience of time and the relative lack of excellent efcacy and safety data, there is not enough evidence to support its use in tic disorders. To the best of our knowledge, there have been not any data regarding the administration of aripiprazole to patients with tic disorders in China. So our study was a rst study investigating the

Table 4. Safety Report Comparison Between Initial and Final Visit (n 72) Inspection item ALB ALT AST Cre Bun PRL BMI QTc interval Initial value (mean SD) 44.36 11.10 20.38 8.13 21.92 10.02 57.61 28.03 3.64 1.58 11.49 4.00 20.71 9.80 401.78 16.85 Final value (mean SD) 41.53 11.74 24.72 10.38 24.26 9.68 53.97 29.49 3.68 1.77 11.25 4.69 21.57 8.11 399.75 12.41 T-test 2.04 3.48 2.48 2.08 0.51 0.70 0.94 0.87 p value 0.046 0.001 0.016 0.041 0.610 0.484 0.352 0.387

Abbreviations: SD Standard deviation; ALB albumin(g/L); ALT alanine aminotransferase (U/L); AST aspartate aminotransferase (U/L); Cre Creatinine(mmol/L); Bun blood urea nitrogen(mmol/L); PRL prolactin(ng/ml); BMI body mass index.

296 In this acute trial, aripiprazole was reasonably tolerated, as 65 of 72 (90.3%) of subjects were able to complete the protocol, and adverse events were generally mild to moderate in severity. Aripiprazole is associated with a relatively low risk of weight gain (Murphy et al. 2005; Haupt 2006; Correll et al. 2009; Reynolds et al. 2009). However, it resulted in rapid and robust weight gain in an animal model (Kalinichev et al. 2005). An open-label aripiprazole study in the treatment of youth with tic disorders ( Murphy et al. 2009) also reported that although aripiprazole was well tolerated increases in weight were found. Even though there was no signicant weight gain in this study, it is not conclusive. A relatively small dose of aripiprazole was administered, and some of the participants complained of nausea in the beginning of this study. These two factors may have affected the weight changes of the participants. An additional longterm study investigating the weight change associated with aripiprazole will be needed to conrm the effect of aripiprazole on weight. Furthermore, the other side effects such as nausea and sedation were transient, and not as serious as those observed in other trials of aripiprazole (Findling et al. 2003; Yoo et al. 2007; Seo et al. 2008; Robert et al. 2009). Nausea remitted in 2 weeks, and sedation remitted after changing aripiprazole from daytime to nighttime administration. Although none of the trials specically assessed changes in sleep parameters or use of concurrent hypnotic medications, it may be logical to administer this medication at bedtime to take advantage of its sedating effects (Greenaway et al. 2009). There have been a few case reports describing EPS, including one report of Parkinsonism (Lua et al. 2009) and another of acute dystonia (Singh et al. 2007). However Osorio et al. (2009) reported three cases of psychiatric geriatric patients who suffered from tardive dyskinesia that were resolved after switching treatment from haloperidol to aripiprazole. The EPS symptoms during this study were negligible, which may be due to a relatively small dose and a relatively slow titration of aripiprazole. Because a number of patients taking aripiprazole developed EPS, there is recommendation that patients be informed of the possibility of, and assessed routinely for these adverse effects (Greenaway et al. 2009). Aripiprazole has no warnings pertaining to cardiac functioning (Bristol-Myers Squibb Canada 2009) and may even decrease QTc intervals (Goodnick et al. 2002). No statistically signicant changes in ECG readings were found in this study. However, further research using a larger sample size and longer treatment period is clearly needed to draw rm conclusions. There were no clinically signicant laboratory abnormalities noted during aripiprazole exposure, including for prolactin; therefore, aripiprazole could be used when individuals are particularly susceptible to hyperprolactinemia induced by other agents. Finally, the impact of aripiprazole treatment on metabolic parameters such as weight, fasting glucose, and lipids does appear to be less than some of the other available atypical agents when used in children and adolescents (Greenaway et al. 2009). Although a small dose of aripiprazole was found to be effective in controlling tic symptoms and behavior symptoms, several limitations of this study must be taken into account. First, this study was an open-label trial, not placebo or another active drug controlled, and both the participants and their parents were not blinded. Second, the sample size was relatively small. Third, the co-morbid conditions were not considered enough to prole diagnostically. Fourth, the lack of statistical correction for multiple hypothesis testing was another limitation. All of these limitations mean that the

CUI ET AL. ndings of this study cannot be easily generalized to all the children and adolescents with TD. Conclusions In conclusion, this short-term study suggests that aripiprazole shows effectiveness in treating tic symptoms without causing signicant weight gain or other serious side effects. Aripiprazole could be an possible option for TD cases that do not respond to conventional therapies. Further controlled, double-blind studies need to be conducted with a larger sample size to evaluate the safety and efcacy of aripiprazole in treating TD. Disclosures The studys authors do not promote for any pharmaceutical companies, and there are no other conicts of interest. References
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CUI ET AL. Address correspondence to: Yi Zheng, M.D. Yun-ping Yang, M.D. Beijing Anding Hospital Capital Medical University XiCheng District Beijing, China, 100088 E-mail: yizheng@ccmu.edu.cn