Aripiprazole for Tourette’s syndrome: a systematic review and meta-analysis

Wei Zheng1,2, Xian-Bin Li1,2, Ying-Qiang Xiang1,2*, Bao-Liang Zhong3, Helen F. K. Chiu3, Gabor S. Ungvari4,5,Chee H. Ng6, Grace K. I. Lok7 and Yu-Tao Xiang8*1Beijing Anding Hospital, Capital Medical University, Beijing, China2China National Clinical Research Center for Psychiatric Disorders, China3Department of Psychiatry, Chinese University of Hong Kong, Hong Kong, SAR, China4The University of Notre Dame Australia/Marian Centre, Perth, Australia5School of Psychiatry and Clinical Neurosciences, University of Western Australia, Perth, Australia6Department of Psychiatry, University of Melbourne, Melbourne, Victoria, Australia7Kiang Wu Nursing College of Macau, Macao, SRA, China8Unit of Psychiatry, Faculty of Health Sciences, University of Macau, Macao, SAR, China

Objective To review the efficacy and safety of aripiprazole (ARI) for Tourette’s syndrome (TS).Methods This review included randomized controlled trials (RCTs) of children and adolescents (6–18 years) with TS comparing ARImonotherapy with another monotherapies in relation to clinical improvement and adverse events.Results Six RCTs with a total of 528 subjects (ARI treatment group: n = 253; control group: n = 275) met the inclusion criteria. These in-cluded two RCTs (n = 255) that compared ARI monotherapy with tiapride (TIA). Tic symptoms control assessed by Yale Global Tic SeverityScale (Standard Mean Difference (SMD) =�0.38 (Confidence Interval (CI) =�1.32 to 0.56); I2 = 90%, P = 0.42) revealed no significant dif-ferences between the two groups. Extrapyramidal symptoms were significantly different when ARI (1.5%) was compared with haloperidol(HAL) (43.5%). No significant group differences were found in the rates of nausea/vomiting, dizziness, and dry mouth between ARI andTIA (RR=0.57 to 1.00 (95%CI = 0.14–4.20); I2 = 0% to 69%, P = 0.35 to 1.00).Conclusion This review found that ARI has similar efficacy to TIA and HAL for TS, while extrapyramidal symptoms were significantlyless with ARI than with HAL. ARI can be considered as an alternative treatment option for TS. Copyright © 2015 John Wiley & Sons, Ltd.

key words—aripiprazole; Tourette’s syndrome; children; RCT

INTRODUCTION

Tourette’s syndrome (TS), characterized by a combina-tion of multiple motor tics and one or more phonic ticsduring a period of more than 1year, is a childhood-onset neurodevelopmental disorder which may affectup to 1% of pediatric population (Robertson et al.,2009). TS is frequently co-morbid with other disordersincluding attention-deficit/hyperactivity disorder(ADHD), obsessive–compulsive disorder (OCD), andoppositional defiant disorder (ODD) (Grados andMathews, 2008; Lyon et al., 2009; Cui et al., 2010;Gulisano et al., 2011).

Although the pathophysiology of TS is not fully un-derstood, it has been hypothesized that dopamine re-lease is greater in TS than in controls (Nikolaus et al.,2009; Rickards, 2009; Cui et al., 2010). Medicationsrecommended for TS include haloperidol (HAL),pimozide (PIM) and other antipsychotics (Egolf andCoffey, 2014; Thompson, 2007). However, the use ofthese agents is limited by their significant adverse drugreactions (ADRs) such as extrapyramidal symptoms(EPS), which has led to increased use of second gener-ation antipsychotic medications (Shapiro et al., 1973;Lyon et al., 2009; Cui et al., 2010; Yang et al., 2013).Aripiprazole (ARI), a partial agonist at dopaminergic

receptors (Yoo et al., 2006), has been approved for thetreatment of schizophrenia (Charpeaud et al., 2014;Khanna et al., 2014) and bipolar disorder (Brownet al., 2013; Kirino, 2014). ARI is emerging as apromising alternative treatment for TS (Greenawayand Elbe, 2009), as shown by case reports

*Correspondence to: Dr. Y.-Q. Xiang, Beijing Anding Hospital, AnkangHutong, Xicheng District, Beijing (100088), China; E-mail:xyingq_1976@163.com; or Dr. Y.-T. Xiang, 3/F, Building E12, Facultyof Health Sciences, University of Macau, Avenida da Universidade, Taipa,Macau SAR, China. Tel: +853-8822-4223; Fax: +853-2288-2314; E-mail:xyutly@gmail.com

Received 6 January 2015Accepted 2 July 2015Copyright © 2015 John Wiley & Sons, Ltd.

human psychopharmacologyHum. Psychopharmacol Clin Exp (2015)Published online in Wiley Online Library(wileyonlinelibrary.com) DOI: 10.1002/hup.2498

(Fountoulakis et al., 2006; Ben Djebara et al., 2008;Ikenouchi-Sugita et al., 2009), case series (Murphyet al., 2005; Kawohl et al., 2009; Wenzel et al.,2012), and several open-label trials (Yoo et al., 2006;Lyon et al., 2009; Cui et al., 2010) which indicated thatARI might be both effective and well tolerated in TS.However, results from RCTs (Liu et al., 2011; Wanget al., 2013) comparing efficacy of ARI with approvedtreatment for TS have been mixed.Efficacy and safety data, and systematic reviews for

the use of ARI in TS are still few and far between.Thus, a comprehensive review and meta-analysis toassess the efficacy and safety of the ARI for TS wasconducted which included recent RCTs (Wang et al.,2013) published in Chinese language that are notwidely known to the international readership.

METHOD

The protocol used for reviewing ARI for TS has beenpublished online (http://www.crd.york.ac.uk/pros-pero/). The registration number of this protocol isCRD42014012899 at the Preferred Reporting Itemsfor Systematic Reviews and Meta-Analyses(PRISMA). PRISMA provides evidence-based mini-mum set of items for reporting systematic reviewsand meta-analyses.

Types of studies included in the analysis

All RCTs comparing ARI monotherapy with placeboor any drug monotherapy used in TS were included.Case series, non-randomized studies, animal trials,and reviews were excluded.

Participants

Children and adolescents (6–11 and adolescents12–18years, respectively) (Yoo et al., 2013) with aclinical diagnosis of TS were included. Diagnosiswas established according to the following classifica-tions: (i) DSM-IV (Diagnostic and Statistical Manualof Mental Disorders, 4th edition) (Yoo et al., 2013);(ii) ICD-10 (International Classification of Diseases,10th edition) (Sartorius et al., 1995); and (iii) CCMD-3 (Chinese Mental Disorder Classification andDiagnosis, standard 3th edition) (Chinese Society ofPsychiatry, 2001).

Types of interventions

All published RCTs that probed ARI monotherapy forTS were included. Comparisons included (i) ARImonotherapy versus placebo; (ii) ARI monotherapyversus any drug monotherapy (tiapride (TIA), HAL,risperidone).

Types of outcome measures

Clinical outcomes based on intent to treat (ITT) analy-sis were recorded. The primary outcome measure wasthe change in total psychopathology assessed withstandardized rating scales, such as the Yale GlobalTic Severity Scale (YGTSS), or the Clinical GlobalImpression Scale (CGI-S). Key secondary outcomewas adverse events assessed by the Treatment Emer-gent Symptom Scale (TESS) (Table 1).

Study selection

PubMed, PsycINFO, Embase, and Cochrane Librarydatabases and the Cochrane Controlled Trials Registerof ARI for TS were searched as well as Chinese data-bases of CBM, CNKI, VIP, and Wanfang. The searchincluded all human studies published between January2000 and August 2014, supplemented by hand searchof academic dissertation and conference proceedings,and several key literature sources. Furthermore, bibli-ographies of pertinent RCTs and review of studies thatwere omitted in the initial electronic search weresearched manually (Varadhan et al., 2012).The following search terms were used: (Tourette Syn-

drome OR Combined Vocal and Multiple Motor TicDisorder OR Gilles de la Tourette Syndrome OR Gillesde la Tourette’s Disease OR Multiple Motor and VocalTic Disorder, Combined OR Gilles De La Tourette’sSyndrome OR Tourette’s Disease OR Tourette DisorderOR Tourette’s Disease OR Tourette’s Disorder ORTourettes Disorder OR Tourette’s Syndrome OR Syn-drome, Tourette’s ORTourette’s SyndromeORChronicMotor and Vocal Tic Disorder OR Combined MultipleMotor and Vocal Tic Disorder OR Tic Disorder, Com-bined Vocal and Multiple Motor) AND (AripiprazoleOR Abilify) AND (randomized controlled trial OR con-trolled clinical trial OR randomized OR placebo ORdrug therapy OR randomly OR trial OR groups).

Table 1. Definition of outcome measures

Outcome measure

Improvement in ticssymptoms

Measurements: Change of the Yale Global TicSeverity Scale total score with aripiprazolecompared with placebo or approved treatmentin four RTCs.

Adverse events Measurements: Treatment Emergent SymptomScale evaluated adverse events in four RTCsincluding extrapyramidal symptoms, nausea/vomiting, drowsiness, headache, dizziness,decreased or increased appetite, nasopharyngitis,sedation, weakness/lassitude, akathisia, drymouth, prolonged QT on electrocardiogram, liverfunction test abnormalities, insomnia, upperrespiratory tract infection, weight gain, and anxiety.

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Copyright © 2015 John Wiley & Sons, Ltd. Hum. Psychopharmacol Clin Exp (2015).DOI: 10.1002/hup

Data extraction

Two of the authors (WZ and X-BL) independentlyconducted the literature search and extracted the data.Any disagreement was resolved by consensus. Datawere extracted into simple standard forms. Datapresented only in graphs and figures were extractedwhenever possible, but included only if the twoauthors independently came to the same conclusion.Authors were contacted directly to obtain missinginformation or clarification. In case of multicenterstudies, data were extracted separately for each center(Higgins and Green, 2008).

Assessment of risk of bias

The method of random sequence generation (selectionbias), allocation concealment (selection bias), blindingof participants and raters (performance bias), blindingof outcome assessment (detection bias), incompleteoutcome data (attrition bias), selective reporting(reporting bias), and other bias was used to assess themethodological quality of RCTs.

Statistical methods

The meta-analysis was conducted using CochraneRevMan 5.1 software. For continuous data, standardizedmean differences (SMDs)±95% confidence intervals(CIs), for dichotomous data risk ratio (RR)±95% CIswere calculated. When RRs were significant, thenumber-needed-to-treat (NNT) or number-needed-to-harm was calculated as the inverse of the risk difference(RD). The I2 method to assess statistical heterogeneitywas used. A random effect model was employed, whenI2>50% (Higgins et al., 2003). Otherwise, a fixed ef-fects model was used. Publication bias was examinedwith funnel plots and the Egger’s test (Egger et al.,1997). All analyses were 2 tailed, with alpha set at 0.05.

RESULTS

Results of the search

The original search yielded 331 electronic records, ofwhich 159 articles were in English and 172 in Chinese.Of the 331 studies, six studies (Liang et al., 2010;Gulisano et al., 2011; Liu et al., 2011; Rizzo et al.,2012;Wang et al., 2013; Yoo et al., 2013) met inclusioncriteria (N=528, ARI treatment group: n=253; controlgroup: n=275). Only two RCTs (Liu et al., 2011; Wanget al., 2013) (ARI vs. TIA) which had relevant dataabout clinical efficacy were included in meta-analysis,while two RCTs (Gulisano et al., 2011; Rizzo et al.,2012) (ARI vs. PIM) which lacked relevant data, oneRCT (Yoo et al., 2013) of ARI versus placebo and one

RCT (Liang et al., 2010) of ARI versus HAL, were ex-cluded from meta-analysis (Figure 1).

The characteristics of studies

The six studies included 528 participants; 414 weremale (78.4%). Sample sizes in each study ranged from50 to 200 (median 78; Table 2). In two studies, ARImonotherapy was compared with TIA monotherapy(n=260, 49.2%). Two studies where ARI monother-apy was compared with PIM monotherapy (n=125,23.7%), were excluded from meta-analysis becauselack of information about clinical efficacy. ARI mono-therapy was compared with placebo in one study(n=61, 11.5%) and with HAL monotherapy in another(n=82, 15.5%). The mean trial duration was 38.4±44.6 (range 8–96, median 11) weeks. Three studieswere conducted in China (n=242), two in Italy(n=125), and one in Korea (n=61). Fifty percent ofthe RCTs (Gulisano et al., 2011; Liu et al., 2011;Yoo et al., 2013) used DSM-IV diagnostic criteria.

Assessment of risk of bias

All RCTs only mentioned ‘randomized allocation’without the description of an adequate method ofrandom sequence generation (Figure 2). The allocationconcealment methods were high risk in five RCTs(83.3%) (Liang et al., 2010; Gulisano et al., 2011;Liu et al., 2011; Rizzo et al., 2012; Wang et al.,2013), and only one RCT (Yoo et al., 2013) providedthe details for the methods of allocation concealment.Furthermore, one RCT (Yoo et al., 2013) was random,double-blind controlled study; the rest were onlyrandom controlled studies. Although three studies(Liang et al., 2010; Liu et al., 2011; Yoo et al.,2013) reported loss to follow-up, only one (Yooet al., 2013) used ITT analysis for incomplete outcomedata. One RCT (Yoo et al., 2013) had a registration ofprotocol, while the other five (Liang et al., 2010;Gulisano et al., 2011; Liu et al., 2011; Rizzo et al.,2012; Wang et al., 2013) were vague whether therewas selective reporting because of the unclear descrip-tions of the pre-registered protocols. Thus, the qualityof the trials in this meta-analysis was relatively low.

Treatment efficacy

In two studies (n=255), there were differences in themean change from baseline to endpoint in YGTSStotal score in the ARI monotherapy compared withTIA monotherapy (Table 1, Figure 3). However, thecombined results of the two studies in tics symptoms(Figure 3) revealed no significant differences betweenthe two groups (SMD: �0.38 (95%CI: �1.32 to0.56); I2=90%, P=0.42) (Figure 3).

aripiprazole for tourette’s syndrome

Copyright © 2015 John Wiley & Sons, Ltd. Hum. Psychopharmacol Clin Exp (2015).DOI: 10.1002/hup

Yoo et al. (2013) studied the clinical efficacy andsafety of ARI compared with placebo in a multicenter,randomized, double-blind trial of 50 children andadolescents who suffered from TS. There was a signif-icant reduction in the total of YGTSS, and ARI waswell tolerated. Further, in the ARI monotherapy versusHAL monotherapy study (Liang et al., 2010) that usedthe YGTSS scale as outcome measurement, the effi-cacy and safety of ARI were similar to HAL.

Adverse events

Four of the six included trials reported ADRs which aresummarized in Table 3. The most common ADRs withARI were: nausea/vomiting (5.9%), drowsiness (5.5%),headache (3.5%), and dizziness (3.5%). The most fre-quent clinically significant ADRs for TIA werenausea/vomiting (5.5%), drowsiness (3.9%), and dizzi-ness (3.9%). Meta-analysis of ADRs (nausea/vomiting,dizziness, dry mouth, and anxiety) (Figure 3) revealedno significant differences between ARI and TIA(RR=0.57 to 1.00 (95% CI=0.14–4.20); I2=0% to69%, P=0.35 to 1.00) (Figure 4).

The most common ADRs with HALwere extrapyrami-dal symptoms (43.5%), drowsiness (15.4), and weakness/lassitude (7.6%); the frequency of extrapyramidal symp-toms was significantly less with ARI (1.5%).Rizzo et al. (2012) studied the metabolic effects of

ARI in 75 children with TS and concluded that PIMsignificantly increased glycemia. Gulisano et al.(2011) studied the cardiovascular safety of ARI forTS and found that ARI did not significantly changethe heart rate or increase QT and QTc interval. How-ever, ARI significantly increased the diastolic and sys-tolic blood pressure while PIM decreased both systolicand diastolic blood pressure.

DISCUSSION

Strengths of the study

To the best of our knowledge, this was the first com-prehensive study to review the clinical efficacy andsafety of ARI for TS. The meta-analysis of the RCTs(ARI monotherapy vs. TIA monotherapy) suggested

Figure 1. PRISMA flow diagram

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Copyright © 2015 John Wiley & Sons, Ltd. Hum. Psychopharmacol Clin Exp (2015).DOI: 10.1002/hup

similar efficacy between the two medications which isconsistent with ARI being a partial agonist at dopami-nergic receptors (Nikolaus et al., 2009; Rickards,2009; Cui et al., 2010), and action on 5HT2A recep-tors. However, the exact ARI’s mechanism of actionin TS remains unclear. There are no clear dosingguidelines for ARI in TS (Greenaway and Elbe,2009), but the dose range from 6.7 to 14.5mg/dayproved to be adequate (Murphy et al., 2005; Davieset al., 2006; Yoo et al., 2006; Budman et al., 2008;Seo et al., 2008). The ARI dose was 10.0±4.3 (range:5–30, median: 11.0) mg/day in the three studies in thismeta-analysis (N=193) (Liang et al., 2010; Gulisanoet al., 2011; Yoo et al., 2013). Thus, a dose of10mg/day appears to be a reasonable target dose forARI in TS, but further studies are needed to find its op-timal dose range.The use of ARI in TS appears generally safe and

well-tolerated. The lack of extrapyramidal symptomswith ARI (1.5%) compared with HAL (43.5%) is at-tributed to ARI’s partial agonist activity at the striataldopamine 2 (D2) receptors (Comings, 1995; Sartoriuset al., 1995). Both sedation (ARI: 2.0% vs. HAL: 0%T

able

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a Weightedmean;

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TIA

=tiapride;

PIM

=pimozide;

PLB=placebo

Figure 2. Risk of bias summary

aripiprazole for tourette’s syndrome

Copyright © 2015 John Wiley & Sons, Ltd. Hum. Psychopharmacol Clin Exp (2015).DOI: 10.1002/hup

vs. TIA: 1.6%) and weight gain with ARI (ARI: 0.5%vs. HAL: 0% vs. TIA: 0%) are ADRs that require closemonitoring. Yoo et al. (2013) found that ARI had sim-ilar rate of adverse event compared to placebo. No fur-ther significant differences in other ADRs were foundbetween ARI and TIA monotherapy.A key strength of this study is the inclusion of Chi-

nese databases in the systematic review which exploredthe use of ARI in non-Western settings. Of note, threeof the six RCTs (Liang et al., 2010; Liu et al., 2011;Wang et al., 2013) were found in the Chinese literature,which is not usually included in the international litera-ture (Ghanizadeh, 2012). Similar to our study, a recentreview also found that ARI was effective for treatingTS, and was safer than some other antipsychotics(Ghanizadeh, 2012). However this review had severalshortcomings such as the lack of inclusion of Chinesestudies, and the safety analysis, quality assessment,and data synthesis were not performed.

Limitations of the study

This review had several limitations. First, it was notpossible to conduct a conclusive meta-analysis onthe basis of six RCTs because of the differences in

terms of control group (HAL, TIA, or PIM), andother aspect of the methodology (open-label ordouble-blind). Such heterogeneity violates basic sta-tistical assumptions and makes the analyses error-prone. Therefore, only two RCTs (ARI monotherapyvs. TIA monotherapy) involving 255 subjects wereincluded in the meta-analysis. This is a relativelysmall sample size coupled with a large age range (6to 18years) prevents more comprehensive data explo-ration. The small sample size also precluded mean-ingful meta-regression analyses of effect sizemoderators. Furthermore, five of the six RCTs wereconducted in single centers with small sample sizes(50 to 82, median=61). Second, significant heteroge-neity of the efficacy results suggests the effect of rel-evant moderator and mediator variables. This may bebecause meta-analysis combines results from trialsthat differ in their methodology, study size, trial dura-tion, country, ARI doses, and interventions. For thesereasons, the random effects model was employed toprovide a conservative estimate of treatment efficacy.A fixed effect model was adopted to analyze adverseevents because there was no heterogeneity concerningadverse effects.

Figure 3. Aripiprazole monotherapy versus tiapride monotherapy for Tourette’s syndrome: forest plot for tic symptoms control in assessed with the total scoreof Yale Global Tic Severity Scale

Table 3. Adverse events reported in the six RTCs

Aripiprazole (%) Haloperidol (%) Tiapride (%)

Nausea/vomiting: 5.9 Extrapyramidal symptoms: 43.5 Nausea/vomiting: 5.5Drowsiness: 5.5 Drowsiness:15.4 Drowsiness: 3.9Headache: 3.5 Weakness/lassitude: 7.6 Dizziness: 3.9Dizziness: 3.5 Anxiety: 3.1Loss of appetite: 3.0 Loss of appetite: 3.1Nasopharyngitis: 2.0 Weakness/lassitude: 2.4Sedation: 2.0 Dry mouth:2.4Extrapyramidal symptoms: 1.5 Insomnia: 1.6Weakness/lassitude: 1.5 Sedation: 1.6Akathisia: 1.5 Akathisia: 1.6Dry mouth: 1.5 Headache: 1.6Prolonged QT on ECG: 1.0 Extrapyramidal symptoms: 1.6Increased appetite: 1.0 Nocturnal enuresis: 0.8Liver function test abnormalities: 0.5Insomnia: 0.5Upper respiratory tract infection:0.5Anxiety: 1.0Weight gain: 0.5

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Copyright © 2015 John Wiley & Sons, Ltd. Hum. Psychopharmacol Clin Exp (2015).DOI: 10.1002/hup

CONCLUSION

This comprehensive review found that ARI has similarefficacy to TIA and HAL for TS. Extrapyramidalsymptoms were significantly less frequent with ARIcompared to HAL. ARI could be considered as analternative treatment option for TS at a recommendeddose of 10mg/day, but large-scale studies are neededto confirm its optimal use for TS in children andadolescents.

CONFLICT OF INTEREST

The authors declare that they have no conflicts of inter-est concerning this article.

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