Tourette s syndrome (TS) is a common neuropsychiatric

JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Volume 26, Number 5, 2016 ª Mary Ann Liebert, Inc. Pp. 442 448 DOI: 10.1089/cap.2015.0104 The Effectiveness of Aripiprazole for Tics, Social Adjustment, and Parental Stress in Children and Adolescents with Tourette s Disorder Liang-Jen Wang, MD, MPH, 1 Wen-Jiun Chou, MD, MS, 1 Miao-Chun Chou, MD, 1 and Susan Shur-Fen Gau, MD, PhD 2 Abstract Objective: Tourette s syndrome (TS) frequently results in a negative impact on multiple functional domains. This prospective open-label study investigated the potential effectiveness of aripiprazole for tics, social adjustment, and parental stress in children and adolescents with TS. Methods: Study participants consisted of 26 patients (mean age 10.4 3.0 years; 22 boys and 4 girls) who were prescribed aripiprazole, with each dose ranging from 2.5 to 15 mg/day. At baseline and 2, 4, and 8 weeks from baseline, tic symptoms, social adjustment, and parenting stress were assessed using the Yale Global Tic Severity Scale (YGTSS), the Social Adjustment Inventory for Children and Adolescents (SAICA), and the Parenting Stress Index (PSI). Aripiprazole could be optionally titrated from 2.5 to 30 mg/day at each visit. Results: Of the 26 patients at the initial visit, 22 (84.6%) completed the study. The mean dose of aripiprazole at the endpoint was 8.0 4.0 mg/day. During the 8-week aripiprazole treatment period, motor tics, phonic tics, and impairment on the YGTSS all showed significant improvement. Home behaviors on the SAICA and child domain on the PSI also showed significant improvement. Patients phonic tics, but not motor tics, showed a positive correlation with their school function and peer relationships. The child domain on the PSI was positively correlated with motor tics, phonic tics, and impairment, as measured by the YGTSS. Conclusions: An 8-week aripiprazole treatment program for children and adolescents with TS was beneficial to their tic symptoms, behaviors at home, and caregivers stress with regard to fulfilling parenting roles. A long-term placebocontrolled trial with larger samples is warranted to confirm the effectiveness of aripiprazole for social adjustment and parental stress. Introduction Tourette s syndrome (TS) is a common neuropsychiatric disorder characterized by chronic involuntary motor and one or more vocal tics lasting longer than a year (Shprecher et al. 2014). A meta-analysis reported that the prevalence of TS in children was 0.77%, with a male-to-female ratio of *4:1 (Knight et al. 2012). The age at onset of TS is typically between 4 and 6 years and symptoms become increasingly severe between the ages of 10 and 12 years (Bloch and Leckman 2009). The symptoms of TS usually wax and wane and potentially lessen in late adolescence and early adulthood (Hallett 2015). Tic symptoms frequently result in a negative impact on multiple functional domains across a patient s life span, including social adjustment (Eddy and Cavanna 2013), peer relationships (Zinner et al. 2012), family function (Ohm 2006), academic performance (Abwender et al. 1996), and occupational achievement (Wei 2011). In addition to its influence on the children themselves, TS is known to have a negative impact on parents as well (Lee et al. 2007). Recent studies indicated that parenting stress is greater in caregivers of children with TS compared with those of children with typical development (Robinson et al. 2013; Stewart et al. 2015). Therefore, to have a comprehensive picture of TS, researchers should ideally use multidimensional outcome approaches (Waldon et al. 2013). An abundance of literature supports the idea that the pathophysiology of TS involves an abnormality in the central dopaminergic system (Leckman et al. 2010; Shprecher et al. 2014). Dopamine antagonists, also referred to as antipsychotic drugs, play a crucial role in pharmacotherapy for TS (Hartmann and Worbe 2013; Roessner et al. 2013). Aripiprazole is a quinolinone derivative antipsychotic 1 Department of Child and Adolescent Psychiatry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan. 2 Department of Psychiatry, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan. 442

ARIPIPRAZOLE FOR YOUTHS WITH TOURETTE S DISORDER 443 with the unique properties of partial agonism at D2 and 5-HT1A and antagonism at 5-HT2A receptors (McGavin and Goa 2002). Compared with other antipsychotic drugs, aripiprazole is expected to have a favorable adverse effects profile and to have the capability of normalizing dopaminergic transmission (Ghanizadeh 2012). A growing body of case series and open-label studies have claimed that aripiprazole is an effective treatment option for children and adolescents with chronic tic disorders or TS (Yoo et al. 2006, 2007, 2011; Seo et al. 2008; Lyon et al. 2009; Murphy et al. 2009; Cui et al. 2010; Wenzel et al. 2012). A randomized, double-blind placebocontrolled study demonstrated the efficacy and tolerability of aripiprazole for youths with TS in a 10-week treatment trial (Yoo et al. 2013). It remains unclear, however, whether aripiprazole has a secondary impact on patients social and family dysfunctions, along with the improvements in tic symptoms. The aim of this study then was to investigate the potential effectiveness of aripiprazole for tic symptoms, social adjustment, and parental stress in children and adolescents with TS. Methods Study population The research protocol was approved by the Institutional Review Board at Chang Gung Hospital in Taiwan. Eligible patients with a diagnosis of TS in the outpatient department of child psychiatry at Kaohsiung Chang Gung Memorial Hospital in Taiwan were recruited for this study. The inclusion criteria were (a) clinical diagnosis of TS based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV-TR) (American Psychiatric Association 2000); (b) age between 7 and 20 years; (c) symptoms of TS causing significant distress or impairment, as determined by patients, their caregivers, and the principal investigator; (d) drugnaïve for antipsychotic treatment; and (e) a signed and dated informed consent form provided before entry into the study. Patients were excluded if they (a) had a history of comorbid autistic spectrum disorders, intellectual disability, psychosis, or other major neuropsychiatric disorders as judged by the investigator; (b) had previously received treatment with any antipsychotic; (c) were pregnant or lactating women or women of childbearing potential who were not practicing a reliable form of birth control; (d) had any clinically significant abnormal physical or laboratory examination at baseline screening; and (e) required additional behavioral or family therapy other than medication treatment. Measurements The Chinese version of the Schedule for Affective Disorder and Schizophrenia for School-Age Children, epidemiologic version (K- SADS-E), is a semistructured diagnostic interview designed to assess current and past episodes of psychopathology in children and adolescents according to DSM-III-R and DSM-IV criteria (Kaufman et al. 1997). The K-SADS-E is administered by interviewing the parent(s) and the child and finally compiling summary ratings from all sources of information. The validity and reliability of the Chinese version of K-SADS-E have been established in Taiwan (Gau and Soong 1999). The Yale Global Tic Severity Scale (YGTSS) is a clinician-rated semistructured interview designed to measure tic severity over the previous week (Leckman et al. 1989). Tic severity is determined based on an evaluation of number, frequency, intensity, complexity, and interference. Each item is rated on a six-point Likert scale (0 5). The YGTSS consists of three distinct factors: motor tics (0 25), phonic tics (0 25), and total tic score (sum of motor tics and phonic tics). In addition, the impairment scale (0 50) evaluates the global level of functional impairment arising from tics (Leckman et al. 1989; Storch et al. 2007). A higher score represents a greater severity of tic symptoms. The YGTSS is a widely used scale, and psychometric evidence supports its reliability and validity (McGuire et al. 2013). The Social Adjustment Inventory for Children and Adolescents (SAICA), a 77-item scale, is designed for parental reporting about their children s four domains of social functioning: school function, spare time function, peer relationships, and home behaviors. (John et al. 1987). A higher mean score (items rated on a four-point Likert scale) indicates poorer social functioning. The Chinese version of the SAICA has been reported to have satisfactory levels of reliability and concurrent validity (Gau 2007). The Parenting Stress Index (PSI) is a 120-item questionnaire (items rated on a 5-point Likert scale) that is used to evaluate parenting stress based on the interrelationship between the child s and the parents characteristics (Loyd and Abidin 1985). The PSI is completed by the children s parents and consists of two major domains (parent domain and child domain). The parent domain scale contains 54 items and is made up of seven subscales. The child domain scale contains 47 items and has six subscales. Higher scores indicate a greater level of parenting stress (Chan 1994). The Chinese version of the PSI had been reported to be a reliable assessment tool in clinical practice to identify parenting stress requiring intervention (Yeh et al. 2001). Study procedure This was a prospective, open-label single-arm study to evaluate the efficacy and safety of aripiprazole in treating patients with TS. Twenty-six eligible patients who had a clinical DSM-IV-TR diagnosis of TS were recruited. After providing informed consent, patients and their caregivers received the Chinese K-SADS-E interview to confirm the diagnosis of TS and to rule out other major neuropsychiatric comorbidities. At baseline (week 0), the demographic characteristics, medical history, physical examination, vital signs, and body mass index (BMI) were determined and recorded. Patients and their caregivers were interviewed by a senior child psychiatrist to complete the ratings of the YGTSS and the SAICA. A caregiver of each patient was asked to fill out the PSI. Subsequently, the patients were initially prescribed oral aripiprazole with doses ranging between 2.5 and 15 mg daily based on the severity of their clinical symptoms, age, height, and body weight. The second, third, and fourth assessments were performed at weeks 2, 4, and 8 after treatment with aripiprazole was begun. Aripiprazole was allowed to be titrated optionally from 2.5 to 30 mg/ day at each visit; however, all dose adjustments had to be made with the approval of the investigator and concomitant medications were prohibited. The amount of returned drug determined drug compliance. The assessment procedures administered at week 0 were repeated at each visit. The caregivers were asked to fill out the PSI, and ratings for the YGTSS and the SAICA were conducted by the same rater as at week 0. In addition, vital signs, physical examination, and BMI were recorded at each visit. Statistical analyses Data were analyzed using the Statistical Package for the Social Sciences for Windows (version 16.0; SPSS, Inc., Chicago, IL).

444 WANG ET AL. Variables are presented as either mean standard deviation (SD) or frequency. All statistical tests are two-tailed, and differences were considered significant at p < 0.05. Data analysis was based on the intention-to-treat (ITT) principal. The ITT population is defined as all qualified patients who take at least one dose of study medication and have at least one available postbaseline efficacy evaluation. Of the 26 participants in this study, two dropped out without any posttreatment assessment and were excluded from the analyses. Missing data of the remaining 24 patients were accounted for by using the method of last observation carried forward. For outcome variables of interest, repeated-measures analysis of variance was performed to examine the effects of the aripiprazole treatment, followed by a post hoc least significant difference test. Generalized estimating equations were further utilized to account for potential correlations between patients tics symptoms, patients social function, and stress of their parents during the 8-week treatment period. The SAICA scores and PSI scores were set as dependent variables, and the YGTSS scores were set as independent variables. Results Twenty-six patients (22 boys and 4 girls, mean age: 10.4 3.0 years) participated in this study. Of these, 10 (38.5%) had comorbidities of attention-deficit/hyperactivity disorder (ADHD) and 1 (3.8%) had obsessive-compulsive disorder (OCD). Of the 26 patients enrolled in this study, 24, 22, and 22 remained in the study at weeks 2, 4, and 8, respectively. The reasons for premature discontinuation were adverse events associated with aripiprazole (n = 2), withdrawal of consent (n = 1), and lost to follow-up (n = 1). The data of the ITT population (20 boys and 4 girls, mean age: 9.9 2.1 years) were used in further analyses. The prescribed dose of aripiprazole at the endpoint ranged from 5 to 15 mg/day (8.0 4.0 mg/day). Table 1 shows the changes in tic symptoms as well as social and family functions during the 8-week treatment period with aripiprazole. During the 8 weeks, significant improvements were found across all dimensions of the YGTSS, including motor tics (F = 72.74, p < 0.001), phonic tics (F = 52.91, p < 0.001), total tic score (F = 92.21, p < 0.001), and the impairment scale (F = 62.32, p < 0.001). The mean scores for motor tics, phonic tics, and the impairment scale showed 57.7%, 69.9%, and 75.4% reductions from week 0 to week 8, respectively. On the SAICA, home behaviors significantly improved over the 8 weeks (F = 5.17, p = 0.003). Other domains on the SAICA, including school function (F = 2.21, p = 0.095), spare time function (F = 1.82, p = 0.151), and peer relationships (F = 0.19, p = 0.906), were not significantly changed. On the PSI, significant improvement was observed in the child domain (F = 3.41, p = 0.024), but not in the parent domain (F = 0.06, p = 0.981). Table 2 presents a summary of the correlations between each domain of the YGTSS, SAICA, and PSI during the 8-week aripiprazole treatment period. The motor tic scores on the YGTSS were positively correlated with the child Domain scores on the PSI (b = 1.11, p = 0.021). The phonic tic scores on the YGTSS were positively correlated with school function (b = 1.94, p = 0.022) and peer relationships on the SAICA (b = 3.33, p = 0.030) and child domain scores on the PSI (b = 1.17, p < 0.001). The impairment scores on the YGTSS were positively correlated with school function on the SAICA (b = 3.46, p = 0.030) and child domain scores on the PSI (b = 1.42, p < 0.001). Table 3 shows the changes in height, weight, BMI, and vital signs during aripiprazole treatment. During the 8-week study period, changes in body weight (1.9 kg increase, F = 9.80, p < 0.001), BMI (0.9 kg/m 2 increase, F = 7.61, p < 0.001), and pulse rate (8.3 beats/min increase, F = 4.24, p = 0.008) were all significant. Height (F = 2.28, p = 0.087), systolic blood pressure (F = 0.19, p = 0.904), and diastolic blood pressure (F = 0.05, p = 0.985) were not significantly changed. Discussion Results of this prospective open-label study suggested that youths treated with aripiprazole for two or more weeks showed a reduction in both motor and phonic tics and in overall impairment. These findings were generally comparable with previous studies, which investigated a similar research topic (Yoo et al. 2006, 2007, 2011; Seo et al. 2008; Lyon et al. 2009; Cui et al. 2010; Wenzel Table 1. Changes in Tic Symptoms and Social Function of Patients with Tourette s Syndrome, and Parenting Stress of Patients Caregivers During the 8-Week Aripiprazole Treatment Period Visit 1 (baseline) Visit 2 (week 2) Visit 3 (week 4) Visit 4 (week 8) Statistics a Mean SD Mean SD Mean SD Mean SD F p Post hoc test YGTSS Motor Tics 19.6 5.5 9.6 5.4 7.8 4.9 7.4 4.4 72.74 <0.001*** V1>V2>V3&V4 Phonic Tics 15.9 5.6 6.7 6.0 4.6 5.6 4.1 5.1 52.91 <0.001*** V1>V2>V3&V4 Total Tic Score 35.5 7.9 16.3 8.9 12.4 7.4 11.5 6.7 92.21 <0.001*** V1>V2>V3&V4 Impairment 32.7 10.2 14.6 11.0 10.0 8.6 6.5 6.5 62.32 <0.001*** V1>V2>V3>V4 SAICA School Function 5.5 3.0 4.7 2.2 4.6 2.4 4.5 1.7 2.21 0.095 Spare Time Function 18.9 8.9 16.6 9.2 15.2 9.5 15.9 8.6 1.82 0.151 V1>V3&V4 Peer Relationships 1.4 1.5 1.2 1.3 1.3 1.2 1.2 1.9 0.19 0.906 Home Behaviors 1.8 1.8 1.6 1.6 1.2 1.4 0.5 1.3 5.17 0.003** V1&V2&V3>V4 Parenting Stress Index Parent Domain 133.1 24.2 132.4 21.9 131.5 20.6 132.7 20.9 0.06 0.981 Child Domain 111.3 13.6 109.1 15.8 105.5 15.4 101.8 14.7 3.41 0.024* V1&V2>V4 a Statistical analyses used repeated-measure analysis of variance, followed by a post hoc least significant difference test. *p < 0.05; **p < 0.01; ***p < 0.001. SAICA, Social Adjustment Inventory for Children and Adolescents; SD, standard deviation; YGTSS, Yale Global Tic Severity Scale.

ARIPIPRAZOLE FOR YOUTHS WITH TOURETTE S DISORDER 445 Table 2. Relationships Between Patients Tic Symptoms and Social Function, and Parenting Stress of Patients Caregivers During the 8-Week Aripiprazole Treatment Period Motor Tics Phonic Tics Impairment b (95%CI) p b (95%CI) p b (95%CI) p SAICA School Function 1.65 (0.96 2.87) 0.072 1.94 (1.10 3.43) 0.022* 3.46 (1.13 10.65) 0.030* Spare Time Function 0.98 (0.84 1.15) 0.801 1.13 (0.99 1.29) 0.082 1.06 (0.86 1.31) 0.560 Peer Relationships 1.55 (0.43 5.61) 0.504 3.33 (1.12 9.85) 0.030* 6.57 (0.67 64.56) 0.106 Home Behaviors 0.71 (0.27 1.91) 0.501 1.60 (0.42 6.11) 0.494 4.84 (0.60 38.89) 0.138 Parenting Stress Index Parent Domain 1.03 (0.98 1.09) 0.216 1.05 (0.98 1.11) 0.179 1.09 (0.94 1.26) 0.244 Child Domain 1.11 (1.02 1.21) 0.021* 1.17 (1.09 1.27) <0.001*** 1.42 (1.19 1.71) <0.001*** Tic symptoms were assessed by the Yale Global Tic Severity Scale (YGTSS); SAICA, Social Adjustment Inventory for Children and Adolescents. Statistical analyses used generalized estimating equation models. *p < 0.05; ***p < 0.001. 95%CI, 95% confidence interval. et al. 2012). In the randomized, double-blind placebo-controlled study reported by Yoo et al. (2013), a significant difference in tic symptoms was observed between the aripiprazole-treated group and the placebo group from the second week and lasted to the endpoint (10th week). Taken together, these findings suggest that aripiprazole may exert its effects on improving tic symptoms within 2 weeks. With regard to the dosage of aripiprazole, previous studies reported that the dose for effectively treating children and adolescents with TS ranged from 5 to 45 mg/day (Wenzel et al. 2012). The flexible dosing regimen in our study suggested that a final mean dose of aripiprazole was 8.0 mg/day. In terms of social adjustment, scores for home behaviors on the SAICA significantly improved, but those for school function, spare time function, and peer relationships did not. Home behaviors represent the ability to interact affectionately with parents and siblings and the ability to follow rules/chores at home ( John et al. 1987). The findings in this study indicated that such ability potentially improved during aripiprazole treatment; however, changes in home behaviors were not directly correlated with changes in tic symptoms during follow-up. Aripiprazole is not only an effective treatment for tic symptoms but it is also beneficial for cooccurring internalizing and externalizing behavioral problems among patients with TS (Budman et al. 2008; Masi et al. 2012). We suppose that changes in home behaviors might therefore be attributed to the amelioration of externalizing behavioral problems related to aripiprazole, but not necessarily to improvements in tic symptoms. In addition, some cross-sectional studies have revealed that tic symptom severity was irrespective of social, behavioral, or emotional functioning among children with TS (Carter et al. 2000; Chang et al. 2008). Ohm (2006) suggested that medication treatment was capable of helping students achieve the goal of feeling more comfortable with peers and in the classroom. In the current follow-up study, we found that school function and peer relationships, although not changed significantly with aripiprazole treatment, were associated with tic symptoms. It is noteworthy that phonic tics showed a positive correlation with school function and peer relationships, but motor tics did not. Altman et al. (2009) reported a similar finding. Compared with motor tics, vocal tics interfered more easily with other people and had a greater negative impact on social functioning. We found that the child domain on the PSI significantly improved during the 8-week aripiprazole treatment period. In addition, child domain, but not parent domain, was consistently correlated with all dimensions of tic symptoms. High scores in the child domain are associated with children who display qualities that make it difficult for parents to fulfill their parenting roles (Loyd and Abidin 1985). On the other hand, high scores in the parent domain represent caregivers own stress, including Table 3. Dosage of Aripiprazole and Safety Data During the 8-Week Aripiprazole Treatment Period Statistics a Visit 1 (baseline) Visit 2 (week 2) Visit 3 (week 4) Visit 4 (week 8) Mean SD Mean SD Mean SD Mean SD F p Post hoc test Dosage (mg/day) 7.9 2.5 9.4 3.4 9.4 3.7 2.77 0.073 Height (cm) 140.5 14.6 140.7 14.5 140.8 14.4 140.8 14.5 2.28 0.087 V1<V4 Weight (kg) 36.8 11.7 37.2 11.5 37.8 11.7 38.7 12.3 9.80 <0.001*** V1&V2<V3<V4 BMI (kg/m 2 ) 18.2 3.8 18.4 3.6 18.7 3.7 19.1 3.9 7.61 <0.001*** V1&V2&V3<V4 Vital signs SBP (mmhg) 102.7 12.7 102.5 12.0 104.4 13.9 103.1 14.4 0.19 0.904 DBP (mmhg) 62.7 8.5 63.0 9.5 62.3 9.5 62.9 9.2 0.05 0.985 Pulse (beats/min) 75.8 12.4 83.4 11.9 84.9 13.7 84.1 14.6 4.24 0.008** V1<V2&V3&V4 a Statistical analyses used repeated-measure analysis of variance, followed by a post hoc least significant difference test. **p < 0.01; ***p < 0.001. BMI, body mass index; DBP, diastolic blood pressure; SBP, systolic blood pressure.

446 WANG ET AL. feelings of depression, isolation, incompetence, and being unsupported by their spouse. Previous studies have indicated that caregivers of children with TS experienced a high level of parenting stress (Robinson et al. 2013; Stewart et al. 2015). Caregivers may be frustrated in dealing with children s tic symptoms and worried about stigmatization or censure from others who do not understand this disease (Lee et al. 2007). We speculate that although the parent domain of parenting stress was unchanged during treatment, caregivers might benefit in terms of coping with their children s needs and improving parent child communications. Along with the improvement in tic symptoms of patients with TS, their caregivers may perceive a higher level of empowerment to fulfill their parenting roles. With regard to its safety profile, aripiprazole treatment is generally considered to be a safe and tolerable regimen for children and adolescents (Kirino 2012). Convincing evidence had indicated that children and adolescents undergoing antipsychotic treatment are at risk for adverse metabolic effects (Maayan and Correll 2011). Among the various antipsychotic drugs, aripiprazole seems to carry the least risk of weight gain and metabolic syndrome (Ben Amor 2012; Almandil et al. 2013); however, we found that body weight (1.8 kg increase) and BMI (0.8 kg/m 2 increase) became significantly elevated during the 8-week study period. Yoo et al. (2013) reported findings similar to ours. They found that body weight and BMI substantially increased in their aripiprazole-treated group during the 10-week study, but not in the placebo group. Furthermore, although blood pressure did not change in our study population, an increasing heart rate was observed at weeks 2, 4, and 8. In contrast, previous studies reported that heart rate was unchanged among youths during aripiprazole administration (Lyon et al. 2009; Gulisano et al. 2011; Cavanna et al. 2012). The underlying reasons for the discrepancy in findings with regard to heart rate between studies warrant further clarification. We suggest that clinicians still need to pay attention to potential changes in metabolic profiles and heart rate when prescribing aripiprazole for youths. This study has several limitations. First, this was an open-label nonrandomized study and lacked a comparison group. Thus, the treatment outcomes were possibly inflated by placebo effects, rating bias, or reporting bias. Whether the improved social adjustment and parenting stress were specifically derived from aripiprazole administration is uncertain. For example, patients caregivers might have received emotional support and gained adequate parenting skills through contact with a child psychiatrist. Such factors might also cause an amelioration of parenting stress. Therefore, a randomized controlled trial is warranted to clarify this. Second, the sample size in our study was small and this reduced its statistical power. Third, this study lacked information from patients teachers or peers. The measure of social adjustment (SAICA) relied solely on the reports by patients caregivers. Compared with teachers, caregivers have fewer opportunities to directly observe patients performance in school. The impairment scale on the YGTSS is a subjective rating of functional impairment arising from tics. Previous pharmacological trials (Lyon et al. 2009; Cui et al. 2010) focused on total tic score and used a more objective rating of tic severity (e.g., the Global Severity Score). Fourth, some crucial factors associated with social and family function such as adverse events in life and socioeconomic status were not identified in this study. In addition, some patients had comorbid conditions of ADHD or OCD and these psychiatric diseases may have had an additional negative impact on patients social and family dysfunctions than TS. Relationships between tic symptoms, social function, and family function are complex. Whether changes in social function and parenting stress were moderated by this factor remains unknown. Finally, the duration of aripiprazole therapy in this study was short. We cannot ensure that the effects of aripiprazole would persist over a longer follow-up period. Conclusions Results of this study suggested that an 8-week aripiprazole treatment period was effective in improving tic symptoms in children and adolescents with TS. Aripiprazole treatment was also beneficial for patients behaviors at home as well in reducing parental stress with regard to fulfilling their roles. Caregivers stress with regard to the child domain was positively correlated with TS symptoms during the 8-week follow-up period. Since concern has been growing about the functional impairments in patients with TS, a long-term placebo-controlled trial with larger sample sizes is warranted to confirm the beneficial effects of aripiprazole on social adjustment and parental stress. Clinical Significance Aripiprazole was effective in improving tic symptoms in children and adolescents with TS over an 8-week treatment period. In addition, aripiprazole provided secondary benefits in patients social behaviors and family dysfunctions, along with improvement in tic symptoms. Acknowledgments The authors thank Professor Wei-Tsun Soong for granting the use of the Chinese version of the K-SADS and Professor Shur-Fen Gau for granting the use of the Chinese version of the SAICA and for statistical consultation. This study was sponsored by Otsuka Taiwan Ltd. The study design, data analysis, and manuscript preparation were overseen by the authors of this study. Disclosures No competing financial interests exist. 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