Articles

Comparative efficacy, tolerability, and acceptability of

pharmacological interventions for the treatment of children,
adolescents, and young adults with Tourette’s syndrome:
a systematic review and network meta-analysis
Luis C Farhat, Emily Behling, Angeli Landeros-Weisenberger, Jessica L S Levine, Pedro Macul Ferreira de Barros, Ziyu Wang, Michael H Bloch

Summary
Background In clinical practice guidelines there is no consensus about the medications that should be initially offered Lancet Child Adolesc Health 2022
to children and young people with Tourette’s syndrome. To provide a rigorous evidence base that could help guide Published Online
decision making and guideline development, we aimed to compare the efficacy, tolerability, and acceptability of December 14, 2022
https://doi.org/10.1016/
pharmacological interventions for Tourette’s syndrome.
S2352-4642(22)00316-9
Child Study Center
Methods For this systematic review and network meta-analysis, we searched the Cochrane Central Register of (L C Farhat MD, E Behling MD,
Controlled Trials, Embase, PsycINFO, PubMed, Web of Science, the WHO International Clinical Trials Registry A Landeros-Weisenberger MD,
Platform, and ClinicalTrials.gov, for published and unpublished studies from database inception to Nov 19, 2021. We J L S Levine BA, Z Wang,
Prof M H Bloch MD), and
included double-blind randomised controlled trials of any medication administered as a monotherapy for at least
Department of Psychiatry
1 week against another medication or placebo in children and adolescents (aged ≥4 years and ≤18 years), adults (A Landeros-Weisenberger,
(>18 years), or both, diagnosed with Tourette’s syndrome according to standardised criteria. We excluded studies that Prof M H Bloch), Yale University
exclusively recruited participants with comorbid attention-deficit hyperactivity disorder or obsessive-compulsive School of Medicine,
New Haven, CT, USA;
disorder. The primary outcome was change in severity of tic symptoms (efficacy). Secondary outcomes were treatment
Department of Psychiatry,
discontinuations due to adverse events (tolerability) and for any reason (acceptability). Pharmacological interventions Faculdade de Medicina FMUSP,
were examined considering medication categories and medications individually in separate analyses. Summary data Universidade de São Paulo,
were extracted and pooled with a random-effects network meta-analysis to calculate standardised mean differences São Paulo, Brazil (L C Farhat,
P Macul Ferreira de Barros MD)
for efficacy and odds ratios for tolerability and acceptability, with 95% CIs. The Confidence in Network Meta-Analysis
Correspondence to:
(CINeMA) framework was used to assess the certainty of evidence. The protocol was pre-registered in PROSPERO
Prof Michael H Bloch, Child Study
(CRD42022296975). Center, Yale University School of
Medicine, New Haven, CT 06519,
Findings Of the 12 088 records identified through the database search, 88 records representing 39 randomised USA
michael.bloch@yale.edu
controlled trials were included in the network meta-analysis; these 39 randomised controlled trials comprised
4578 partici­pants (mean age 11·8 [SD 4·5] years; 3676 [80·8%] male participants) and evaluated 23 individual
medications distributed across six medication categories. When considering medication categories, first-generation
(standardised mean difference [SMD] –0·65 [95% CI –0·79 to –0·51]; low certainty of evidence) and second-generation
(–0·71 [–0·88 to –0·54]; moderate certainty of evidence) antipsychotic drugs, as well as α-2 agonists
(–0·21 [–0·39 to –0·03]; moderate certainty of evidence), were more efficacious than placebo. First-generation and
second-generation antipsychotic drugs did not differ from each other (SMD 0·06 [95% CI –0·14 to 0·25]; low certainty
of evidence). However, both first-generation (SMD 0·44 [95% CI 0·21 to 0·66]) and second-generation
(0·49 [0·25 to 0·74]) antipsychotic drugs outperformed α-2 agonists, with moderate certainty of evidence.
Similar findings were observed when individual medications were considered: aripiprazole (SMD –0·60 [95% CI
–0·83 to –0·38]), haloperidol (–0·51 [–0·88 to –0·14]), olanzapine (–0·83 [–1·49 to –0·18]), pimozide (–0·48
[–0·84 to –0·12]), risperidone (–0·66 [–0·98 to –0·34]), and clonidine (–0·20 [–0·37 to –0·02]) all outperformed
placebo, with moderate certainty of evidence. Antipsychotic medications did not differ from each other, but there was
low to very low certainty of evidence for these comparisons. However, aripiprazole (SMD –0·40 [95% CI –0·69 to
–0·12]) and risperidone (–0·46 [–0·82 to –0·11]) outperformed clonidine, with moderate certainty of evidence.
Heterogeneity or inconsistency only emerged for a few comparisons. In terms of tolerability and acceptability, there
were no relevant findings for any of the efficacious medication categories or individual medications against each
other or placebo, but there was low to very low certainty of evidence associated with these comparisons.

Interpretation Our analyses show that antipsychotic drugs are the most efficacious intervention for Tourette’s
syndrome, while α-2 agonists are also more efficacious than placebo and could be chosen by those who elect not to
take antipsychotic drugs. Shared decision making about the degree of tic-related severity and distress or impairment,
the trade-offs of efficacy and safety between antipsychotic drugs and α-2 agonists, and other highly relevant individual
factors that could not be addressed in the present analysis, should guide the choice of medication for children and
young people with Tourette’s syndrome.

www.thelancet.com/child-adolescent Published online December 14, 2022 https://doi.org/10.1016/S2352-4642(22)00316-9 1

 Articles
Funding None.
Copyright © 2022 Elsevier Ltd. All rights reserved.
Introduction
Tourette’s syndrome (also known as Tourette’s disorder)
is a neurodevelopmental disorder characterised by one or
more phonic and several motor tics that develop during
childhood or adolescence and last longer than 1 year.1
Prevalence estimates from epidemiological studies
indicate that three in 1000 to nine in 1000 young people
live with Tourette’s syndrome in Asia, Europe, and
North America.2 Children and adolescents experience
distress, functional impairments, or both, through the
effect of the disorder on their physical, social, and
academic lives and are often stigmatised.3 Although
the severity of Tourette’s syndrome tends to diminish
throughout adolescence and into early adulthood,4
population-based epidemio­ logical studies have shown
that it is associated with several negative outcomes
in adult life, including academic under­ achievement,
substance use, transport accidents, and suicidality.5
Pharmacological treatment is generally recommended
for children and young people with Tourette’s syndrome
who continue to experience distress or impairments
after receiving evidenced-based psychotherapy such
as Comprehensive Behavioural Intervention for Tics
(CBIT).6,7 However, in recently published guidelines
from the American Academy of Neurology (AAN)6 and
Research in context
Evidence before the study
Recent treatment guidelines from the American Academy of
Neurology (published in 2019) and the European Society for the
Study of Tourette’s Syndrome (published in 2022) have differing
views about the medications that should be offered first to
children and young people with Tourette’s syndrome. These
inconsistencies arise because double-blind randomised controlled
trials of pharmacological interventions for Tourette’s syndrome
are scarce, small, and mostly placebo controlled, so that direct
comparison between pharmacological interventions is difficult.
Network meta-analyses enable pooling of direct and indirect
evidence, and are therefore essential to inform evidence-based
decision making, including in Tourette’s syndrome. We searched
PubMed on Aug 17, 2022, without any language restrictions with
the search string “(((Tourette AND Syndrome) OR Tourette OR
(tic AND disorder)) AND (pharmacotherapy OR pharmacological
OR pharma*) AND (“meta-analysis as topic”[MeSH] OR Meta-
Analysis OR metaanaly* OR meta-analy*))”; we identified and
inspected 89 records, and found no network meta-analyses of
double-blind randomised controlled trials of pharmacological
interventions for Tourette’s syndrome.
Added value of this study
The findings from this network meta-analysis represent,
to the best of our knowledge, the most comprehensive
2 www.thelancet.com/child-adolescent Published online December 14, 2022 https://doi.org/10.1016/S2352-4642(22)00316-9
the European Society for the Study of Tourette Syndrome
(ESSTS)7 there is no consensus about the medications
that should be offered to children and young people
as first-line pharmacological interventions. Although
the AAN gives preference to α-2 agonists, such as
clonidine and guanfacine, the ESSTS recommends that
aripiprazole, tiapride, or risperidone should be offered
first. These inconsistencies in recommendations are
observed in the real-world setting as pharma­coepidemio­
logical studies indicate that antipsychotic drugs are the
most used pharmacological intervention in Europe,8,9
whereas α-2 agonists are more commonly prescribed in
the USA.10 Notably, the National Institute for Health and
Care Excellence in the UK does not provide any guidance
about Tourette’s syndrome.
Treatment recommendations are inconsistent because
double-blind randomised controlled trials of pharma­
cological interventions for Tourette’s syndrome are
scarce, small, and mostly placebo controlled, which
makes it difficult to determine the comparative effects of
medications. Previous efforts to collate the available
evidence relied on standard, pairwise meta-analyses.11–13
Network meta-analyses facilitate estimation of the
comparative effects of two or more interventions even
when they have not been investigated in head-to-head
evidence base to guide the choice of medications for children
and young people with Tourette’s syndrome. We found that
antipsychotic drugs (aripiprazole, haloperidol, olanzapine,
pimozide, and risperidone) and α-2 agonists (clonidine)
showed efficacy compared with placebo in reducing the
severity of tic symptoms. When comparing different
pharmacological interventions, there were no differences
between individual antipsychotics, but there was a low to
very low certainty of evidence associated with these
comparisons. However, antipsychotics (aripiprazole and
risperidone) were more efficacious than α-2 agonists
(clonidine).
Implications of the available evidence
Antipsychotic drugs are the most efficacious treatment for
the management of tic symptoms, whereas α-2 agonists are
also more efficacious than placebo and could be used by
individuals who elect not to take antipsychotic drugs. Shared
decision making, taking into account the degree of tic-related
severity and distress or impairment, the trade-offs of efficacy
and safety between antipsychotic drugs and α-2 agonists,
and other highly relevant individual factors that could not be
addressed in the present analysis, should guide the choice of
medication for children and young people with Tourette’s
syndrome.

randomised controlled trials, and they provide the
highest level of evidence required to inform treatment
guidelines.14 However, to the best of our knowledge, there
are no network meta-analyses of double-blind ran­
domised controlled trials evaluating the relative effects of
pharmacological interventions for children and young
people with Tourette’s syndrome.
To fill this gap, we aimed to do a systematic review and
network meta-analysis of pharmacological interventions
evaluated in double-blind randomised controlled trials
for the treatment of Tourette’s syndrome. We aimed to
compare medications against placebo and each other
in terms of change in severity of tic symptoms, dropouts
due to adverse events , and all-cause dropouts.
Methods
Search strategy and selection criteria
In this systematic review and network meta-analysis, we
included double-blind randomised controlled trials that
enrolled children and adolescents (aged ≥4 years and
≤18 years), adults (>18 years), or both, with a primary
diagnosis of Tourette’s syndrome according to the
Diagnostic and Statistical Manual of Mental Disorders
(DSM-III, DSM-III-R, DSM-IV, DSM-IV-TR, and DSM5),
the International Classification of Diseases (ICD-9,
ICD-10, and ICD-11), or the Chinese Classification of
Mental Disorders, third edition. Randomised controlled
trials that also recruited participants with persistent tic
disorders other than Tourette’s syndrome were eligible
for inclusion. We did not restrict eligibility by medication
but required that the drugs were administered as a
monotherapy for at least 1 week. We also placed no
restrictions on language or publication year. More details
of the eligibility criteria are provided in the appendix (p 6).
To avoid violation of the transitivity assumption,15 we
excluded randomised controlled trials that did not
require participants to discontinue antipsychotic medi­
cations, but we did not exclude studies that allowed
participants to maintain other psychotropic medications
because most randomised controlled trials of Tourette’s
syndrome do not account for the presence of comorbid­
ities and allow for their co-treatment (eg, treatment of
attention-deficit hyperactivity disorder [ADHD] with
α-2 agonists). However, we excluded studies in which
all participants had comorbid ADHD or obsessive com­
pulsive disorder because those randomised controlled
trials either evaluated treatments that would only
be indicated for individuals with the comorbidity
(eg, stimulants, atomoxetine, and fluoxetine) or they
evaluated treatments whose effects could be modified
by the comorbid disorder (eg, α-2 agonists for Tourette’s
syndrome plus ADHD).12
We searched the Cochrane Central Register of
Controlled Trials, Embase, PsycINFO, PubMed, Web
of Science, the WHO International Clinical Trials
Registry Platform, and ClinicalTrials.gov, from the date
of database inception to Nov 19, 2021. The search strategy
www.thelancet.com/child-adolescent Published online December 14, 2022 https://doi.org/10.1016/S2352-4642(22)00316-9
Articles
included terms related to tic disorders, including
Tourette’s syndrome, and randomisation (appendix
pp 7–9). We also hand-searched reports from the
US Food and Drug Administration, European Medicines
Agency, and relevant drug manufacturers, retrieved
from their respective websites, as well as references of
previous systematic reviews and guidelines, to identify
additional relevant studies. We contacted study authors
and drug manufacturers to obtain unpublished infor­
mation and data.
Pairs of researchers (LCF and EB, JLSL, or PMFdB)
independently reviewed the records to select the studies.
Any discrepancies were double checked and resolved by
discussion with another member of the review team
(MHB). Summary data were extracted from eligible
randomised controlled trials by one researcher (LCF)
and independently checked by another (MHB). We
extracted characteristics of the study, participants, and
inter­
ventions, as well as outcome data at the study
endpoint. We pooled groups of the same medication at
different doses for randomised controlled trials that
randomly assigned participants to multiple doses of the
same pharmacological agent (ie, fixed-dose randomised
controlled trials with multiple groups) because we con­
sidered that all doses administered in those randomised
controlled trials were therapeutic. More details of study
selection and data extraction are provided in the
appendix (pp 10–11).
Data analysis
The primary outcome was efficacy, measured as a change
in severity of tic symptoms. Where multiple rating scales
were provided, we preferred those that were recommended
by a panel of experts16—namely, the Yale Global Tic See Online for appendix
Severity Scale,17 the Shapiro Tourette’s Syndrome Severity
Scale,18 and the Tourette’s Syndrome-Clinical Global
Impressions,19 in that order. We also extracted data on the
basis of other rating scales if those were the only data
reported. Changes from baseline scores were preferred
over endpoint scores. Intention-to-treat analyses were
preferred, and we used the method adopted by the study
to handle missing data, usually mixed-model repeated
measures or last observation carried forward. We also
extracted data from participants who completed the study
(modified intention-to-treat analyses) if that was the only
analysis reported. We calculated missing SDs from
p values, t values, and standard errors, or imputed them
with a validated method (appendix p 11).20 Secondary
outcomes were the tolerability of medications, measured
as treatment discon­tinuations due to adverse events, and
the acceptability of medications, measured as all-cause
dropout rates.
Most pharmacological interventions were examined
in single, or few, small-scale, randomised controlled
trials. There­fore, besides examining each medication
individually, we also did analyses for medication categories
when groupings were considered pertinent. We used
3
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We initially did pairwise random-effects meta-analyses

11 630 records identified in database search for every comparison. We computed standardised mean
3069 PubMed
4813 Embase
difference (SMD) for continuous outcomes (efficacy)
1190 Cochrane Central Register of Controlled Trials and odds ratios (ORs) for dichotomous outcomes
1304 PsycINFO (tolerability and acceptability), both presented with
1254 Web of Science
95% CIs. For efficacy, we chose SMD as the effect size
index so that mean differences between treatments in
2522 duplicates excluded different scales were standardised to a uniform scale
before they were combined. In that way, studies for
which the mean difference was the same proportion of
9108 titles and abstracts screened
the SD had the same effect size, regardless of the actual
scales used to make the measurements.21 We evaluated
8634 records excluded after screening of title and abstract* the degree of heterogeneity through the I² statistic and
through visual inspection of the forest plots. We did not
458 studies identified from clinical trial
registers
draw funnel plots because none of the comparisons had
236 WHO International Clinical Trials at least ten trials.
Registry Platform We considered the transitivity assumption plausible
222 ClinicalTrials.gov
given the sufficiently narrow eligibility criteria. We further
evaluated the plausibility of the transitivity assumption by
932 full-text articles assessed comparing the distribution of clinical and methodological
characteristics across comparisons (appendix pp 12–17).
846 excluded after full-text assessment
We then did a random-effects network meta-analysis
231 duplicates in a frequentist framework. We assumed a common
284 not randomised controlled trials heterogeneity variance τ² across the various treatment
17 not double-blind randomised controlled trials
68 not Tourette's syndrome comparisons. We used P-scores to rank treatments.22
38 data not available We quantified heterogeneity as low, moderate, or high
34 comorbid Tourette's syndrome
30 study design not relevant to this analysis
by comparing τ² with its empirical distribution.23,24 We
144 intervention not relevant to this analysis evaluated statistical inconsistency globally (design-by-
treatment interaction)25 and locally (separate indirect
from direct evidence).26
86 records representing 37 randomised controlled
trials included in network meta-analysis The robustness of our findings was examined in
analyses done by excluding sets of studies with the
following characteristics: participants’ mean age older
2 additional studies identified through than 18 years; participants with persistent tic disorders
manual searches (references of
systematic reviews and meta-analyses, other than Tourette’s syndrome; Tourette’s syndrome
industry websites, and Google Scholar) diagnosed according to the Chinese Classification
of Mental Disorders, third edition; high risk of bias;
88 records representing 39 randomised controlled
and crossover without pre-crossover data. Additionally,
trials included in network meta-analysis for medication categories, we did sensitivity analyses
in which we excluded tiapride from first-generation
antipsychotic drugs. Last, for medication categories, we
also lumped all antipsychotic drugs into a single node.
Figure 1: Study selection
*Main reasons for exclusion during screening of title and abstract were as follows: the studies did not focus on tic All outputs from the sensitivity analyses are freely
disorders, were not clinical trials, or did not assess pharmacological interventions. available in the Open Science Framework.
We assessed the risk of bias of randomised controlled
For the datasets in the Open the WHO Anatomical Therapeutic Chemical Classifi­ trials with the Cochrane tool.27 We plotted comparison-
Science Framework see https:// cation to inform our groupings. The following medication adjusted funnel plots to investigate publication bias.28 We
doi.org/10.17605/OSF.IO/
YW629
categories were evaluated: dopaminergic agents (levodopa, assessed the certainty of findings from the network meta-
pergolide, and pramipexole), vesicular monoamine analyses with the Confidence in Network Meta-Analysis
transporter 2 (VMAT2) inhibitors (deutetrabenazine (CINeMA) framework.29 A detailed description of the
and valbenazine), α-2 agonists (clonidine and guanfacine), methods to assess the risk of bias and certainty of
first-generation anti­ psychotic drugs (haloperidol, evidence is provided in the appendix (pp 18–20).
pimozide, and tiapride), second-generation anti­psychotic All analyses were done in R with packages meta
drugs (aripiprazole, olanzapine, risperidone, and (version 4.19-2)30 and netmeta (version 1.5-0).31 This
ziprasidone), and traditional Chinese medicine remedies systematic review and network meta-analysis was done
(5-Ling, Chagma Xifeng, Choudongning, Ningdong, and according to the Cochrane Handbook32 and reported
Xifeng Zhidong). according to the PRISMA-NMA statement.33 The

4 www.thelancet.com/child-adolescent Published online December 14, 2022 https://doi.org/10.1016/S2352-4642(22)00316-9

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Recruiting Age range, Proportion Diagnosis Medication* Treatment Number of Study Outcomes Funding
country (year years (mean) of male (diagnostic duration, participants design reported
of study) participants criteria) weeks
Shapiro et al USA 8–65 (21·1) 72% Tourette’s syndrome Haloperidol 6 57 Parallel STSS Non-
(1989)34 (DSM-III) (0·5–10 [4·5] mg per industry
day); pimozide
(1–20 [10·6] mg per
day); placebo
Sallee et al USA 7–16 (10·2) 78% Tourette’s syndrome Haloperidol 6 22 Cross- TSGS Hybrid
(1997)35 (DSM-III-R) (1–8 [3·5] mg per day); over
pimozide (1–6 [3·4] mg
per day); placebo
Sallee et al USA 7–17 (11·5) 79% Tourette’s syndrome Ziprasidone 8 28 Parallel YGTSS-TTS; Pfizer
(2000)36 or persistent tic (5–40 [28·2] mg per adverse events,
disorder (DSM-IV) day); placebo all-cause
dropouts
Dion et al Canada (1993) 14–65 78% Tourette’s syndrome Risperidone 8 48 Parallel STSS; adverse Janssen
(2002)37 (DSM-III-R) (0·25–6 [2·5] mg per events, all-cause
day); placebo dropouts
Scahill et al USA (1997) 7–65 (19·8) 88% Tourette’s syndrome Risperidone 8 34 Parallel YGTSS-TTS; all- Hybrid
(2003)38 (DSM-IV) (0·5–4 [2·5] mg per day); cause dropouts
placebo
Yoo et al (2013)39 South Korea 6–18 (10·95) 87% Tourette’s syndrome Aripiprazole 10 61 Parallel YGTSS-TTS; all- Otsuka
(2008) (DSM-IV) (2–20 [11] mg per day); cause dropouts
placebo
31-10-272 Multiple 7–17 (11·9) 77% Tourette’s syndrome Aripiprazole 8 135 Parallel YGTSS-TTS; Otsuka
(NCT01418339) (2011) (DSM-IV-TR) (52·5–110 [75·3] mg per adverse events,
week); placebo all-cause
dropouts
31-10-273 Multiple 7–17 (11·9) 76% Tourette’s syndrome Aripiprazole 8 83 Parallel YGTSS-TTS; Otsuka
(NCT01418352) (2011) (DSM-IV-TR) (52·5/77·5/110 mg per adverse events,
week); placebo all-cause
dropouts
Sallee et al Multiple 7–17 (11·5) 78% Tourette’s syndrome Aripiprazole 8 133 Parallel YGTSS-TTS; Otsuka
(2017)40 (2012) (DSM-IV) (5, 10/10, 20 mg per adverse events,
day); placebo all-cause
dropouts
Bruggerman et al Multiple 10–65 88% Tourette’s syndrome Pimozide (1–6 [2·9] mg 12 50 Parallel STSS; adverse Janssen
(2001)41 (DSM-III-R) per day); risperidone events, all-cause
(0·5–6 [3·8] mg per day) dropouts
Gilbert et al USA 7–17 (11) 79% Tourette’s syndrome Pimozide (1–4 [2·4] mg 4 19 Cross- YGTSS; adverse Hybrid
(2004)42 or persistent tic per day); risperidone over events, all-cause
disorder (DSM-IV- (1–4 [2·5] mg per day) dropouts
TR)
Ji et al (2005)43 China (2003) 8–16 (10·45) 92% Tourette’s syndrome Haloperidol; olanzapine 4 60 Parallel YGTSS; all-cause Not reported
(DSM-IV) dropouts
Li et al (2010)44 China (2007) 8–16 (8·54) 93% Tourette’s syndrome Haloperidol (2–12 mg 4 60 Parallel YGTSS; all-cause Not reported
(CCDM-3) per day); risperidone dropouts
(0·5–2 mg per day)
Leckman et al USA (1984) 7–48 (15·6) 80% Tourette’s syndrome Clonidine ([4·4] µg/kg 12 47 Parallel STSS; adverse Hybrid
(1991)45 (DSM-III) per day); placebo events, all-cause
dropouts
Goetz et al USA 8–62 (19·2) 77% Tourette’s syndrome Clonidine 12 30 Cross- RVBTRS Boehringer
(1987)46 (DSM-III) (2·5–15 µg/kg per day); over Ingelheim
placebo
Cummings et al USA 6–16 (10·4) 83% Tourette’s syndrome Guanfacine 4 24 Parallel YGTSS-TTS Hybrid
(2002)47 or persistent tic (0·5–2 [1·92] mg per
disorder (DSM-IV) day); placebo
Du et al (2008)48 China 6–18 (10·1) 84% Tourette’s syndrome Clonidine adhesive 3 437 Parallel YGTSS-TTS; all- Shanxi
or persistent tic patch (1, 1·5, 2 mg per cause dropouts Ruifulai
disorder (CCMD-3) week); placebo adhesive
patch
(Table continues on next page)

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Recruiting Age range, Proportion Diagnosis Medication* Treatment Number of Study Outcomes Funding
country (year years (mean) of male (diagnostic duration, participants design reported
of study) participants criteria) weeks
(Continued from previous page)
Murphy et al USA (2012) 6–17 (11·1) 68% Tourette’s syndrome Guanfacine 8 34 Parallel YGTSS-TTS; Shire
(2017)49 or persistent tic (1–4 [2·6] mg per day); adverse events,
disorder (DSM-IV) placebo all-cause
dropouts
Gaffney et al USA 7–17 (11·4) 91% Tourette’s syndrome Risperidone 8 21 Parallel YGTSS; adverse Hybrid
(2002)50 (DSM-III-R) (0·03–0·06 mg/kg per events, all-cause
day [1·5 mg per day]); dropouts
clonidine (2·5–5 µg/kg
per day [0·18 mg/d])
T-Forward USA (2015) 18–64 (35·1) 67% Tourette’s syndrome Valbenazine (40/80 mg 8 124 Parallel YGTSS-TTS; Neurocrine
(NCT02581865) (DSM-IV/5) per day); placebo adverse events,
all-cause
dropouts
T-Force GREEN USA (2016) 6–17 (11·7) 79% Tourette’s syndrome Valbenazine (10, 20/ 20, 6 98 Parallel YGTSS-TTS; Neurocrine
(NCT02679079) (DSM-IV/5) 40 mg per day); placebo adverse events,
all-cause
dropouts
T-Force GOLD USA (2017) 6–17 (12·3) 84% Tourette’s syndrome Valbenazine (20–80 mg 12 127 Parallel YGTSS-TTS; Neurocrine
(NCT03325010) (DSM-IV/5) per day); placebo adverse events,
all-cause
dropouts
Coffey et al Multiple 6–16 (11·7) 75% Tourette’s syndrome Deutetrabenazine 8 158 Parallel YGTSS-TTS; Teva
(2021)51 (2018) (DSM-5) (6, 36/ 12, 48 mg per adverse events,
day); placebo all-cause
dropouts
Jankovic et al Multiple 6–16 (11·5) 87% Tourette’s syndrome Deutetrabenazine 12 119 Parallel YGTSS-TTS; Teva
(2021)52 (2018) (DSM-5) (6–48 [39·4] mg per adverse events,
day); placebo all-cause
dropouts
Gilbert et al USA 7–17 79% Tourette’s syndrome Pergolide 6 24 Cross- YGTSS; adverse Non-
(2000)53 or persistent tic (0·15–0·3 [0·2] mg per over events, all-cause industry
disorder (DSM-IV) day); placebo dropouts
Gilbert et al USA (1999) 7–17 (10·7) 73% Tourette’s syndrome Pergolide 8 57 Parallel YGTSS-TTS; all- Non-
(2003)54 or persistent tic (0·025–0·45 [0·43] mg cause dropouts industry
disorder (DSM-IV) per day); placebo
Gordon et al USA 6–65 Not reported Tourette’s syndrome Carbidopa/levodopa 8 30 Parallel YGTSS-TTS; Non-
(2013)55 or persistent tic ([450] mg per day); adverse events, industry
disorder (DSM-IV) placebo all-cause
dropouts
Kurlan et al Multiple 6–17 (11·8) 84% Tourette’s syndrome Pramipexole 6 63 Parallel YGTSS-TTS; Boehringer
(2012)56 (2008) (DSM-IV) (0·125–0·5 [0·43] mg adverse events, Ingelheim
per day); placebo all-cause
dropouts
Nicolson et al Canada 7–18 (11·9) 70% Tourette’s syndrome Metoclopramide 8 28 Parallel YGTSS-TTS; Non-
(2005)57 or persistent tic (5–40 [32·9] mg per adverse events, industry
disorder (DSM-IV) day); placebo all-cause
dropouts
Toren et al Israel 12–46 (21·7) 67% Tourette’s syndrome Ondansetron (24 mg per 3 30 Parallel YGTSS-TTS; Non-
(2005)58 (DSM-IV) day); placebo adverse events, industry
all-cause
dropouts
Jankovic et al USA (2004) 7–65 (16·5) 90% Tourette’s syndrome Topiramate 10 29 Parallel YGTSS-TTS; Janssen
(2010)59 (DSM-IV) (50–200 [118] mg per adverse events,
day); placebo all-cause
dropouts
Gilbert et al USA (2014) 7–17 (12·9) 80% Tourette’s syndrome Ecopipam (50, 100 mg 4 40 Cross- YGTSS-TTS; Psyadon
(2018)60 (DSM-5) per day); placebo over adverse events,
all-cause
dropouts
(Table continues on next page)

6 www.thelancet.com/child-adolescent Published online December 14, 2022 https://doi.org/10.1016/S2352-4642(22)00316-9

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Recruiting Age range, Proportion Diagnosis Medication* Treatment Number of Study Outcomes Funding
country (year years (mean) of male (diagnostic duration, participants design reported
of study) participants criteria) weeks
(Continued from previous page)
Mahableshwarkar Multiple 6–17 (12·7) 73% Tourette’s syndrome Ecopipam (2mg/kg per 12 153 Parallel YGTSS-TTS Emalex
et al (2022; (2019) (DSM-5) day); placebo
NCT04007991)
Zhao et al China (2006) 7–18 (12·22) 89% Tourette’s syndrome Ningdong (1 g/kg); 8 68 Parallel YGTSS-TTS Non-
(2010)61 (DSM-IV-TR) placebo industry
Guo et al (2018)62 China (2007) 4–18 (9·76) 74% Tourette’s syndrome Choudongning (2·7, 6 240 Parallel YGTSS-TTS; all- Not reported
(CCMD-3) 5·4 g per day); tiapride cause dropouts
(66, 200 mg per day)
Zheng et al China (2008) 5–18 (9·8) 85% Tourette’s syndrome 5-Ling (15, 22·5 g per 8 603 Parallel YGTSS-TTS; Tasly
(2016)63 (DSM-IV) day); tiapride (200, adverse events,
400 mg per day); all-cause
placebo dropouts
Yang et al China (2009) 4–17 81% Tourette’s syndrome Choudongning (2·7, 6 600 Parallel YGTSS; all-cause Not reported
(2016)64 (CCDM-3) 5·4 g per day); tiapride dropouts
(66, 200 mg per day);
placebo
Ma et al (2014)65 China (2010) 4–18 (9·49) 86% Tourette’s syndrome Xifeng Zhidong (1·59, 4 160 Parallel YGTSS; all-cause Heilongjiang
(DSM-IV) 4·77 g per day); placebo dropouts Jiren
Hu et al (2014)66 China 4–18 (9·73) 80% Tourette’s syndrome Changma Xifeng (1·59, 4 444 Parallel YGTSS-TTS Not reported
(CCMD-3) 4·77 g per day);
tiapride (66, 200 mg per
day)
CCMD-3=Chinese Classification of Mental Disorders, third edition. DSM=Diagnostic and Statistical Manual of Mental Disorders. RVBTRS=Rush Video-Based Tic Rating Scale. STSS=Shapiro Tourette Syndrome
Severity Scale. TSGS=Tourette Syndrome Global Scale. YGTSS=Yale Global Tic Severity Scale. YGTSS-TTS=Yale Global Tic Severity Scale-Total Tic Score. *Medications are separated by a semi-colon and dosages for
each medication are presented within parentheses. For fixed-dose randomised controlled trials, multiple dosages of the same medication are separated by a solidus. For some fixed-dose randomised controlled
trials, dosages were stratified by bodyweight or age (ie, participants below a certain bodyweight or age threshold received lower doses than those above the threshold); in those circumstances, doses are
separated by a comma. For flexible-dose studies, starting doses and the maximum dose in the titration schedule are separated by a hyphen; if the mean endpoint dose was provided, this is reported with square
brackets.

Table: Characteristics of included studies

PRISMA-NMA checklist is provided in the appendix
(pp 2–4). The protocol was pre-registered in PROSPERO
(CRD42022296975). Changes to the prespecified
protocol, with reasons, are listed in the appendix (p 5).
Role of the funding source
There was no funding source for this study.
Results
We initially retrieved 11 630 records through the
database search and screened 9108 records after
excluding duplicates. Of these, 474 records were
selected for further assessment, along with 458 records
identified in trial registers. Of the 932 full-text
records inspected, 846 were excluded and 86 records
representing 37 randomised controlled trials were
included. Manual searches contributed to the
identification of two additional records published in
Chinese that reported on two additional studies
(figure 1). The list of excluded records with reasons for
exclusion (pp 21–76) and the list of included records,
including clinical trial registrations (pp 77–82), are
provided in the appendix.
Of the 39 randomised controlled trials, 33 had been
published34–66 and six were only identified in clinical trial
registration platforms (T-Forward [NCT02581865], T-Force
GREEN [NCT02679079], T-Force GOLD [NCT03325010],
31-10-272 [NCT01418339], 31-10-273 [NCT01418352], and
Mahableshwarkar et al [NCT04007991]). These trials
comprised 4578 participants with a mean age of 11·8
(SD 4·5) years, of whom 3676 (80·8%) were male.
29 randomised controlled trials exclusively recruited
children and adolescents, nine recruited both children and
adolescents and adults, and one exclusively recruited
adults. Of the nine studies that recruited mixed samples of
children and adolescents and adults, seven included
participants with a mean or median age younger than
24 years. Additionally, 30 of 39 randomised controlled
trials exclusively recruited participants with a diagnosis of
Tourette’s syndrome, whereas nine recruited participants
with either Tourette’s syndrome or other persistent tic
disorders. Moreover, 34 of 39 randomised controlled
trials adopted DSM criteria to establish diagnoses;
18 of 39 randomised controlled trials were done in the
USA exclusively and seven were done in the USA alongside
other countries. The randomised controlled trials had a
mean sample size of 118 (SD 150) participants and lasted
for a median of 8 weeks (IQR 6–8). 23 pharmacological
interventions were investigated against each other or
placebo. All randomised controlled trials contributed data
for the efficacy meta-analyses; different rating scales were
used to measure the change in severity of tic symptoms

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A
Domain-level risk-of-bias assessments for each study are
Dopaminergic agents (n=100) provided in the appendix (pp 83–101).
4 When analysing the effects of treatments, we focused on
Placebo network meta-analysis estimates (ie, combining direct
(n=1018)
5 and indirect evidence) in which the 95% CIs excluded the
possibility of no difference between interventions. More
VMAT2 inhibitors
(n=344) 4 details are provided in the appendix, in terms of the results
of pairwise meta-analyses (pp 102–26), as well as network
5
plots for secondary outcomes (pp 127–28), the league
7 Traditional Chinese table for individual medications (pp 129–31), treatment
medicine remedies
(n=1273)
ranking according to P-scores (p 132), heterogeneity
4
and inconsistency statistics (p 133), comparison-adjusted
funnel plots (pp 134–39), and domain-level certainty of
4 evidence assessments for each comparison (pp 140–58).
α-2 agonists (n=412) In terms of network geometry, there were several head-
1
to-head comparisons when medications were grouped,
Second-generation antipsychotic and the networks were well connected. When med­
drugs (n=382)
4 ications were evaluated individually, most inter­ventions
First-generation antipsychotic
drugs (n=640) relied exclusively on placebo-controlled trials and the
networks were star shaped (figure 2).
B When considering medication categories, α-2 agonists
Levodopa (n=13) (SMD –0·21 [95% CI –0·39 to –0·03]; moderate certainty
Pergolide (n=45) 2 1 Placebo of evidence), first-generation antipsychotic drugs (–0·65
Pramipexole (n=42) 1 (n=1154) 1 Topiramate (n=14) [–0·79 to –0·51]; low certainty of evidence), second-
2 1
Deutetrabenazine (n=160) Ondansetron (n=13) generation antipsychotic drugs (–0·71 [–0·88 to –0·54];
3 1 moderate certainty of evidence), and traditional Chinese
Valbenazine (n=184) Metoclopramide (n=14) medicine remedies (–0·69 [–0·83 to –0·56]; very low
3 2 certainty of evidence) were more efficacious than placebo
Clonidine (n=384) 2 Ecopipam (n=93) (figure 3).
2 1 When comparing different pharmacological inter­
Guanfacine (n=28) 2 Xifeng Zhidong (n=79) ventions, α-2 agonists were less efficacious than first-
1 1 generation antipsychotic drugs (SMD 0·44 [95% CI
2 1
Haloperidol (n=98) 2 Ningdong (n=33)
0·21–0·66]; moderate certainty of evidence), second-
1
2
4 1 generation antipsychotic drugs (0·49 [0·25–0·74];
1 moderate certainty of evidence), and traditional Chinese
Pimozide (n=72) 2 Choudongning (n=471)
medicine remedies (0·48 [0·26–0·70]; moderate certainty
Tiapride (n=470)
1
Changma Xifeng (n=328) of evidence; figure 3).
1 5-Ling (n=362) Placebo was more well tolerated (OR 0·33 [95% CI
Aripiprazole (n=230) 1
2
Ziprasidone (n=16) 0·15–0·73]; moderate certainty of evidence) and accepted
Olanzapine (n=25)
Risperidone (n=111) (0·42 [0·26–0·69]; moderate certainty of evidence)
than VMAT2 inhibitors, but less well accepted (1·60
Figure 2: Network plots for efficacy for medication categories (A) and medications individually (B) [1·05– 2·43]; low certainty of evidence) than traditional
The nodes are coloured according to their medication category, and their size is proportional to the number of Chinese medicine remedies (figure 3). There were no
groups that included that treatment. The number of studies for each comparison is illustrated by the number additional relevant findings for any efficacious medi­
besides the black line, and its thickness is proportional to the precision of the direct estimate for that comparison.
The number of participants who were included in the analyses for each treatment are shown in parentheses. cation category against each other or against placebo in
VMAT2=vesicular monoamine transporter 2. terms of either tolerability or acceptability (low to very low
certainty of evidence), with the exception that traditional
across studies, including the Yale Global Tic Severity Scale Chinese medicine remedies were more well accepted
(seven studies), the Yale Global Tic Severity Scale-Total Tic than alfa-2 agonists (OR 0·45 [95% CI 0·21–0·97]; very
Score (26 studies), the Shapiro Tourette’s Syndrome low certainty of evidence; figure 3).
Severity Scale (four studies), the Tourette Syndrome Global When considering medications individually, several
Scale67 (one study), and the Rush Video-Based Tic Rating pharmacological interventions were more efficacious
Scale68 (one study). 23 randomised controlled trials than placebo (figure 4), including clonidine (SMD –0·20
contributed data for the tolerability meta-analysis and [95% CI –0·37 to –0·02]; moderate certainty of
32 contributed data for the acceptability meta-analysis evidence); haloperidol (–0·51 [–0·88 to –0·14]; moderate
(table). 11 studies were rated as having a high risk of certainty of evidence), pimozide (–0·48 [–0·84 to –0·12];
bias, 21 had a moderate risk, and seven had a low risk. moderate certainty of evidence); tiapride (–0·69

8 www.thelancet.com/child-adolescent Published online December 14, 2022 https://doi.org/10.1016/S2352-4642(22)00316-9

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1·80‡ (0·34 to 9·42) 0·63‡ (0·06 to 6·24) 0·77‡ (0·09 to 6·74) 1·26‡ (0·22 to 7·20) 0·53‡ (0·04 to 7·53) 0·59‡ (0·14 to 2·50)
Dopaminergic agents
2·39‡ (0·82 to 6·97) 1·40‡ (0·45 to 4·40) 0·71‡ (0·25 to 2·06) 1·05‡ (0·36 to 3·07) 0·63‡ (0·22 to 1·79) 1·01‡ (0·39 to 2·62)

0·35‡ (0·05 to 2·46) 0·43‡ (0·07 to 2·60) 0·70‡ (0·20 to 2·46) 0·29‡ (0·03 to 3·13) 0·33* (0·15 to 0·73)
0·12‡ (–0·26 to 0·49) VMAT2 inhibitors
0·59‡ (0·26 to 1·31) 0·30† (0·15 to 0·59) 0·44* (0·22 to 0·88) 0·27† (0·14 to 0·51) 0·42* (0·26 to 0·69)

1·22‡ (0·12 to 12·74) 2·01‡ (0·29 to 13·89) 0·84‡ (0·05 to 14·01) 0·93‡ (0·16 to 5·54)
0·24† (–0·14 to 0·62) 0·12† (–0·12 to 0·37) α–2 agonists
0·51‡ (0·23 to 1·13) 0·75‡ (0·34 to 1·67) 0·45‡ (0·21 to 0·97) 0·72‡ (0·38 to 1·37)

1·64† (0·39 to 6·88) 0·69‡ (0·10 to 4·66) 0·76‡ (0·15 to 3·85)

0·68* (0·32 to 1·04) 0·56† (0·34 to 0·79) 0·44* (0·21 to 0·66) First-generation
antipsychotic drugs
1·49‡ (0·81 to 2·72) 0·89‡ (0·59 to 1·36) 1·43‡ (0·88 to 2·31)

0·42‡ (0·05 to 3·71) 0·46‡ (0·18 to 1·22)

0·74* (0·36 to 1·11) 0·62* (0·38 to 0·86) 0·49* (0·25 to 0·74) 0·06† (–0·14 to 0·25) Second-generation
antipsychotic drugs 0·60‡ (0·33 to 1·10) 0·96‡ (0·59 to 1·57)

1·11‡ (0·12 to 10·28)

0·72* (0·36 to 1·08) 0·61† (0·39 to 0·83) 0·48* (0·26 to 0·70) 0·04‡ (–0·07 to 0·16) –0·01‡ (–0·21 to 0·19) Traditional Chinese
medicine remedies
1·60† (1·05 to 2·43)

0·03‡ –0·09† –0·21* –0·65† –0·71* –0·69‡

Placebo
(–0·31 to 0·36) (–0·26 to 0·09) (–0·39 to –0·03) (–0·79 to –0·51) (–0·88 to –0·54) (–0·83 to –0·56)

Figure 3: League table of efficacy, tolerability, and acceptability of pharmacological interventions in network meta-analysis
Efficacy is reported as standardised mean differences with 95% CIs (white boxes). For efficacy, standardised mean differences below 0 favour the column-defining
treatment. Tolerability (yellow boxes) and acceptability (blue boxes) are reported as odds ratios with 95% CIs. For tolerability and acceptability, odds ratios below 1
favour the column-defining treatment. Findings for which 95% CIs exclude the possibility of no difference between interventions are shown in bold. VMAT2=vesicular
monoamine transporter 2. *Moderate certainty of evidence. †Low certainty of evidence. ‡Very low certainty of evidence.

[–0·87 to –0·52]; low certainty of evidence); aripiprazole
(–0·60 [–0·83 to –0·38]; moderate certainty of evidence),
olanzapine (–0·83 [–1·49 to –0·18]; moderate certainty
of evidence), risperidone (–0·66 [–0·98 to –0·34];
moderate certainty of evidence), and ziprasidone (–1·10
[–1·93 to –0·27]; low certainty of evidence); 5-Ling
(–0·59 [–0·78 to –0·40]; very low certainty of evi­
dence), Changma Xifeng (–0·75 [–1·03 to –0·47];
very low certainty of evidence), Choudongning (–0·74
[–0·92 to –0·56]; very low certainty of evidence),
Ningdong (–0·96 [–1·48 to –0·44]; very low certainty of
evidence), and Xifeng Zhidong (–0·96 [–1·29 to –0·63];
very low certainty of evidence); ecopipam (–0·34
[–0·63 to –0·06]; moderate certainty of evidence);
metoclopramide (–1·11 [–1·93 to –0·29]; low certainty of
evidence); and topiramate (–0·88 [–1·68 to –0·09]; low
certainty of evidence).
When comparing different pharmacological inter­
ventions (appendix pp 129–31), there were no differences
between any antipsychotic drugs, traditional Chinese
medicine remedies, metoclopramide, and topiramate
(low to very low certainty of evidence). However, clonidine
was less efficacious than tiapride (SMD 0·50 [95% CI
0·25–0·74]; low certainty of evidence); aripiprazole
(0·40 [0·12–0·69]; moderate certainty of evidence),
risperidone (0·46 [0·11–0·82]; moderate certainty of
evidence), and ziprasidone (0·90 [0·50–1·75]; low certainty
of evidence); 5-Ling (0·39 [0·13–0·65]; low certainty of
evidence); Changma Xifeng (0·55 [0·22–0·88]; low
certainty of evidence); Choudongning (0·54 [0·29–0·79];
low certainty of evidence); Ningdong (0·76 [0·21–1·31];
moderate certainty of evidence), and Xifeng Zhidong
(0·76 [0·39–1·13]; moderate certainty of evidence).
Additionally, ecopipam was less effica­cious than tiapride
(SMD 0·35 [95% CI 0·01–0·69]; very low certainty
of evidence), Choudongning (0·40 [0·06–0·74]; low
certainty of evidence), Ningdong (0·61 [0·02–1·21];
very low certainty of evidence), and Xifeng Zhidong
(0·61 [0·18–1·05]; low certainty of evidence).
Only valbenazine was less well tolerated (OR 3·63
[95% CI 1·46–9·05]; moderate certainty of evidence) and
accepted (2·77 [1·53–5·02]; moderate certainty of evidence)
than placebo (figure 4). There were no additional relevant
findings for any efficacious medication against each
other or against placebo in terms of either tolerability or
acceptability (low to very low certainty of evidence;
appendix pp 129–31).
There was no evidence of heterogeneity in any of the
networks (appendix p 133). There was evidence of some
inconsistency in the network meta-analysis of efficacy
for medication categories (appendix p 133). Although the
design-by-treatment interaction test was non-significant
(Q=8·45, p=0·13), two of seven loops showed incon­
sistency. Both comparisons involved traditional Chinese
medicine remedies, either against placebo (Δ–0·30;
p=0·09) or against first-generation antipsychotic drugs

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(Δ0·41; p=0·04). There was no evidence of inconsistency

A Change in tic symptom severity (efficacy) Standardised mean for the remaining network meta-analyses (appendix
difference (95% CI)
p 133). There was no evidence of publication bias for any
Metoclopramide −1·11 (−1·93 to −0·29)
Ziprasidone −1·10 (−1·93 to −0·27) of the network meta-analyses (appendix pp 134–39).
Ningdong −0·96 (−1·48 to −0·44) The findings did not change considerably in sensitivity
Xifeng Zhidong −0·96 (−1·29 to −0·63)
Topiramate −0·88 (−1·68 to −0·09)
analyses. A summary of the changes observed in each
Olanzapine −0·83 (−1·49 to −0·18) sensitivity analysis is provided in the appendix (pp 159–60),
Changma Xifeng −0·75 (−1·03 to −0·47) and all outputs from the sensitivity analyses are freely
Choudongning −0·74 (−0·92 to −0·56)
Tiapride −0·69 (−0·87 to −0·52) available in the Open Science Framework.
Risperidone −0·66 (−0·98 to −0·34)
Aripiprazole −0·60 (−0·83 to −0·38)
5-Ling −0·59 (−0·78 to −0·40)
Discussion
Haloperidol −0·51 (−0·88 to −0·14) Our study is, to the best of our knowledge, the first
Pimozide −0·48 (−0·84 to −0·12) network meta-analysis of double-blind randomised
Ecopipam −0·34 (−0·63 to −0·06)
Ondansetron −0·24 (−1·00 to 0·52) controlled trials of pharmacological interventions for
Guanfacine −0·24 (−0·75 to 0·28) Tourette’s syndrome. In terms of efficacy, several
Clonidine −0·20 (−0·37 to −0·02)
Valbenazine −0·14 (−0·37 to 0·08) medications showed a greater change in severity of tic
Pergolide −0·08 (−0·58 to 0·43) symptoms compared with placebo. Some of these
Deutetrabenazine −0·02 (−0·27 to 0·23)
Pramipexole 0·00 (−0·53 to 0·53)
medications had a low to very low certainty of evidence
Levodopa 0·32 (−0·44 to 1·08) because they were only evaluated in individual
−1·5 −1·0 −0·5 0 0·5 1·0 1·5 randomised controlled trials with a high risk of bias
(metoclopramide, topiramate, and ziprasidone) or
B Dropouts due to adverse events (tolerability) Odds ratio (95% CI)
because they were evaluated in randomised controlled
Metoclopramide 0·39 (0·03 to 4·92) trials that restricted eligibility to certain traditional
Clonidine 0·66 (0·07 to 5·89)
Pramipexole 0·93 (0·08 to 10·86)
Chinese medicine diagnoses, thus limiting general­
Topiramate 0·93 (0·05 to 16·42) isability to individuals in western populations and people
Ecopipam 1·10 (0·02 to 58·28) with Tourette’s syndrome in general (tiapride and
Pimozide 1·18 (0·09 to 16·29)
5-Ling 1·63 (0·08 to 34·09) traditional Chinese medicine remedies). Therefore, these
Deutetrabenazine 1·74 (0·33 to 9·18) findings must be interpreted with caution. Nevertheless,
Aripiprazole 1·75 (0·52 to 5·93)
Pergolide 2·20 (0·17 to 28·14)
all other antipsychotic drugs (aripiprazole, haloperidol,
Risperidone 2·35 (0·29 to 19·08) olanzapine, pimozide, and risperidone), clonidine, and
Ziprasidone 2·42 (0·09 to 64·70) ecopipam (a D1 and D5 antagonist) showed efficacy
Levodopa 2·50 (0·20 to 31·00)
Tiapride 2·88 (0·12 to 71·35) compared with placebo in reducing the severity of
Ondansetron 3·21 (0·12 to 85·20) tic symptoms, with moderate certainty of evidence.
Guanfacine 3·58 (0·14 to 94·30)
Valbenazine 3·63 (1·46 to 9·05)
Regarding comparisons between pharmacological inter­
ventions, there were no significant differences between
0·1 0·5 1 2 10
antipsychotic drugs (low to very low certainty of
C Dropouts for any reason (acceptability) Odds ratio (95% CI) evidence), but antipsychotic drugs were more efficacious
than α-2 agonists (moderate certainty of evidence). In
Ziprasidone 0·20 (0·02 to 2·23)
Topiramate 0·33 (0·06 to 1·73) terms of tolerability and acceptability, there were no
Haloperidol 0·36 (0·03 to 4·52) relevant findings for any of the efficacious medications
Choudongning 0·62 (0·35 to 1·09)
Pergolide 0·67 (0·17 to 2·63)
against each other or against placebo (low to very low
5-Ling 0·67 (0·39 to 1·16) certainty of evidence).
Tiapride 0·75 (0·44 to 1·27) Overall, our results suggest that antipsychotic drugs
Metoclopramide 0·85 (0·10 to 7·04)
Aripiprazole 0·92 (0·49 to 1·74) are the most efficacious medication category in the
Xifeng Zhidong 1·00 (0·06 to 16·27) management of Tourette’s syndrome. Because there
Ecopipam 1·10 (0·02 to 58·28)
Guanfacine 1·14 (0·14 to 9·21)
were no differences in efficacy between any pairs of
Levodopa 1·20 (0·24 to 6·06) antipsychotic drugs individually based on the available
Clonidine 1·43 (0·73 to 2·81) evidence, the choice of antipsychotic medication should
Pimozide 1·56 (0·27 to 8·96)
Risperidone 1·59 (0·49 to 5·13) be guided mainly by its tolerability while also considering
Deutetrabenazine 1·67 (0·70 to 3·99) the drugs that have been studied in double-blind
Pramipexole 1·95 (0·20 to 18·65)
Olanzapine 2·07 (0·07 to 60·09)
randomised controlled trials. Nevertheless, whether
Ondansetron 2·15 (0·17 to 26·67)
Valbenazine 2·77 (1·53 to 5·02)

0·1 0·5 1 2 10
Figure 4: Forest plots showing standardised mean difference for efficacy (A)
Favours medication Favours placebo and odds ratios for tolerability (B) and for acceptability (C) in the network
meta-analysis for each medication individually against placebo
Moderate certainty of evidence Low certainty of evidence Very low certainty of evidence
Data in parentheses are 95% CIs.

10 www.thelancet.com/child-adolescent Published online December 14, 2022 https://doi.org/10.1016/S2352-4642(22)00316-9


antipsychotic drugs should be used as a first-line pharma­
cological intervention in the treatment of Tourette’s
syndrome is debatable because these medications
are potentially toxic and could lead to burdensome
adverse events, particularly in children and adolescents.
Specifically, aripiprazole, haloperidol, olanzapine, and
risperidone have been associated with sedation,
extrapyramidal adverse effects, and metabolic changes
such as bodyweight gain, metabolic syndrome, and
diabetes in children and adolescents.69 These metabolic
adverse events are likely to be underappreciated in short-
duration randomised controlled trials, which might
underestimate the potential impact of these pharma­
cological interventions in children and adolescents who
require medication for longer periods. Children and
adolescents might also be more vulnerable to somatic
serious adverse events with antipsychotic drugs.70
Our results also showed that a-2 agonists are more
efficacious than placebo. Specifically, we found that
clonidine was more efficacious than placebo, but we
were unable to identify a similar effect in favour of
guanfacine. Given that clonidine and guanfacine have
similar pharmacodynamic properties (ie, both are
direct-acting agonists for α-2 receptors), this finding
might seem unexpected. However, guanfacine was only
examined in 28 participants across two randomised
controlled trials and therefore its effect sizes were
marked by imprecision, with wide 95% CIs. Although
α-2 agonists are also associated with adverse events
such as hypotension, sedation, and electrocardiographic
alterations (eg, QTc prolongation),71 these adverse events
are often considered less worrisome because they
typically resolve after the medication is discontinued.
In terms of choosing a specific medication, shared
decision making should consider the degree of tic-related
severity and distress or impairment, the trade-offs of
efficacy and safety between antipsychotic drugs and
α-2 agonists, and other highly relevant individual factors
that could not be addressed in the present study since
our analyses were based only on summary data.72,73 For
instance, owing to the potential adverse events associated
with antipsychotic drugs, caregivers and clinicians might
be reluctant to administer these medications to children
and adolescents or to individuals who are overweight
or obese. Additionally, for individuals with comorbid
ADHD, α-2 agonists might have increased efficacy,
possibly because treatment of co-occurring ADHD might
also contribute to improvement of Tourette’s syndrome.
We excluded studies that only recruited participants with
a dual diagnosis of Tourette’s syndrome plus ADHD to
ensure that we followed the transitivity assumption in
our network meta-analysis.15 However, most randomised
controlled trials that were included in our systematic
review and network meta-analysis did not exclude
participants on the basis of the presence of ADHD,
and therefore our findings might also be applicable
to participants with Tourette’s syndrome plus ADHD.
www.thelancet.com/child-adolescent Published online December 14, 2022 https://doi.org/10.1016/S2352-4642(22)00316-9
Articles
Patients, caregivers, and clinicians are often faced
with the conundrum of either relying on the scarce
data available from randomised controlled trials of
α-2 agonists for Tourette’s syndrome plus ADHD or
generalising from a larger set of literature on Tourette’s
syndrome, and preferences might vary.74 Therefore,
future research should directly examine whether the
treatment effect of α-2 agonists for Tourette’s syndrome
in the context of ADHD is larger than that observed for
Tourette’s syndrome in general.
Our study also highlights potential avenues for
future randomised controlled trials of Tourette’s
syndrome. There were relatively few head-to-head trials
of pharmacological interventions, and future research
should aim to compare medications, particularly anti­
psychotic drugs and α-2 agonists, against each other
in large, well-designed randomised controlled trials.
Ecopipam has shown efficacy against placebo in
preliminary studies and is a promising potential inter­
vention for Tourette’s syndrome.60 However, it should be
emphasised that ecopipam is an investigational product
that has yet to be evaluated in a phase 3 randomised
controlled trial. Although the initial findings are
promising and suggest that this medication might
be a potential alternative to antipsychotic drugs or
α-2 agonists, more studies are needed. We also found a
large effect size in favour of topiramate against placebo,
but unfortunately this intervention for Tourette’s
syndrome had only been evaluated in one randomised
controlled trial. Future investigations should consider
replicating that preliminary study in a larger sample.
Our study also identified several traditional Chinese
medicine remedies that were more efficacious than
placebo in randomised controlled trials exclusively done
in China and often with additional traditional Chinese
medicine-based diagnoses. Replication of these findings
through studies done in other settings is required to
clarify whether these findings are generalisable to other
ethnic groups and to patients with Tourette’s syndrome
in general.
Overall, there were few randomised controlled trials
and participants per treatment node, which restricted
our power to detect significant differences, particularly
for dichotomous outcomes. Indeed, almost all com­
parisons for tolerability and acceptability had a low to
very low certainty of evidence, largely because of
imprecise effect sizes. To increase the power of
treatment nodes, we also analysed data considering
medication categories when groupings were considered
pertinent. We opted to consider tiapride as a first-
generation antipsychotic drug given its D2-receptor
antagonist properties, but we recognise that this
classification might not be entirely appropriate.
However, we did a sensitivity analysis in which we
excluded tiapride from first-generation antipsychotic
drugs and found similar findings. We also considered
aripiprazole as a second-generation anti­psychotic drug
11
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following previous research,70,75,76 although we recognise
that this medication is pharmacologically distinct from
other medications within that group.
Additionally, to avoid loss of data given the scarcity of
randomised controlled trials, we pooled data from
randomised controlled trials that recruited children,
adolescents, and adults34,37,38,41,45,46,55,58,59 or that recruited
adults exclusively (T-Forward; NCT02581865). We recog­
nise that adults with Tourette’s syndrome might
represent a subtype of all patients with the disorder and
might have distinct biological characteristics because
longitudinal studies have shown that most children
with Tourette’s syndrome show an improvement in,
or remission of, tic symptoms during adolescence.4
However, because a relatively large number of random­
ised controlled trials recruited mixed samples, we
decided that it would be arbitrary to exclude some
randomised controlled trials on the basis of an
investigator-driven age cutoff, particularly because most
of these randomised controlled trials34,38,41,45,46,58,59 ended
up including participants with a mean age younger than
24 years. Besides, there are no strong data to suggest
that children and adults with Tourette’s syndrome
respond differently to pharmacological treatment.
Hence, we decided to do a primary analysis involving all
age groups and to do a sensitivity analysis specifically
examining studies that exclusively recruited children
and adolescents with a mean age younger than 18 years,
as done in previous studies of Tourette’s syndrome11 and
other psychiatric disorders;77 the findings of this analysis
were similar to the main findings. We also accounted
for the inclusion of data from adults in the main
analyses by downgrading the certainty of evidence due
to indirectness for studies in which the mean age of
participants was older than 24 years.
Our study has limitations. We cannot rule out
the possibility of missing information, despite our best
efforts to include all available double-blind randomised
controlled trials and to retrieve unpublished data. The
outcomes that were evaluated in our study have some
shortcomings. For efficacy, although change in severity of
tic symptoms is an important factor for assessing
treatment response in routine clinical practice and has
been typically used as the primary outcome in randomised
controlled trials of pharmacological interventions for
Tourette’s syndrome, it is possible that this outcome is
not a priority for patients with Tourette’s syndrome.
Additionally, different rating scales were used to measure
change in severity of tic symptoms across studies.
Although all but two scales were recommended by
experts,16 there are some differences in content of the
instruments.78 Unfortunately, to the best of our knowledge
there is no core outcome set for randomised controlled
trials of Tourette’s syndrome; additional research is
needed to address this gap to ensure homogeneity across
studies while also considering outcomes that matter to
patients (eg, as done in studies for depression).79 For
12 www.thelancet.com/child-adolescent Published online December 14, 2022 https://doi.org/10.1016/S2352-4642(22)00316-9
tolerability, we considered treatment discontinuations
due to adverse events instead of individual adverse events
but we recognise that an examination of individual
adverse events would be more clinically informative;
future research should examine this outcome directly.
Similarly, for acceptability, we considered treatment
discontinuations for any reason because few randomised
controlled trials reported patient-derived or caregiver-
derived instruments for this outcome. Nevertheless,
using dropout rates as proxies for tolerability and
acceptability is a typical procedure in network meta-
analyses of other psychiatric disorders.77,80,81 Additionally,
we pooled multiple groups of the same medication from
fixed-dose randomised controlled trials; this procedure
might potentially dilute the effects of higher doses.
However, this procedure was only adopted for five fixed-
dose randomised controlled trials that involved
three medi­ cations (aripiprazole, deutetrabenazine, and
valbenazine). Nonetheless, additional research should
consider evaluating the dose–response associations82 for
certain medication categories when more data become
available. Additionally, most studies were based on the
short term (around 2 months of data) and predominantly
enrolled male participants. Because the severity of
Tourette’s syndrome waxes and wanes and the disorder
predominantly affects male individuals with a 3:1 or
4:1 ratio,83 it is understandable that randomised controlled
trials had these character­istics. However, these features
of the included randomised controlled trials limited
evaluation of the medium-term and long-term effects
of pharmacological interventions and the generalisability
of evidence to female individuals with Tourette’s
syndrome. Longer-duration randomised controlled trials
with increased coverage of female participants are
therefore warranted.
In conclusion, from a clinical perspective, several
psychotherapies have shown efficacy in the treatment
of Tourette’s syndrome and should be considered
before, or concurrently to, medication use in children
and young people with Tourette’s syndrome. If
pharmacological interventions are required despite
evidence-based psychotherapies, this network meta-
analysis represents the best available evidence base to
guide the choice of medications for children and young
people with Tourette’s syndrome. Our findings indicate
that antipsychotic drugs are the most efficacious
treatment for the management of tic symptom severity,
while α-2 agonists are also more efficacious than
placebo and could be used by those who elect not to
take antipsychotic drugs. Shared decision making
should consider the degree of tic-related severity and
distress or impairment, the trade-offs of efficacy and
safety between antipsychotic drugs and α-2 agonists,
and other highly relevant individual factors that can
only be addressed in individual participant data
analyses. We hope these results will inform parents,
clinicians, and future guideline developers.

Contributors
LCF, EB, AL-W, and MHB designed the study. LCF did the literature
searches, and LCF, EB, JLSL, PMFdB, and ZW screened records,
retrieved reports of the relevant studies, and selected included studies.
MHB resolved conflicts in study selection. LCF and MHB identified and
linked multiple publications of individual studies and extracted data.
LCF contacted trial investigators for additional information and did the
statistical analysis with input from MHB. LCF and MHB verified and
interpreted the data. LCF and MHB wrote the first draft and EB, AL-W,
JLSL, PMFdB, and ZW critically reviewed the report for important
intellectual content and approved the final submitted version.
All authors had full access to all the data in the study and accept
responsibility for the decision to submit for publication.
Declaration of interests
LCF is supported by grant #21/08540-0 from the São Paulo Research
Foundation (FAPESP). PMFdB is supported by grant 88887.612255/2021-00
from Coordenção de Aperfeiçoamento de Pessoal de Nível Superior
(CAPES). MHB has received grant or research support from Therapix
Biosciences, Emalex Biosciences, Neurocrine Biosciences, Janssen
Pharmaceuticals, Biohaven Pharmaceuticals, the US National Institutes of
Health, the Lesbian Health Fund, the Yale Foundation for Lesbian and Gay
Studies (FLAGS), and Patterson Foundation. MHB has served on the
advisory board and data monitoring and safety board of Therapix
Biosciences. MHB serves as associate editor of the Journal of Child
Psychology and Psychiatry and is on the editorial boards of the Journal of
Child and Adolescent Psychopharmacology and Depression & Anxiety.
MHB has received royalties from Wolters Kluwer for Lewis’s Child and
Adolescent Psychiatry: A Comprehensive Textbook, Fifth Edition. MHB has
received moonlighting pay from the Veteran’s Administration. All other
authors declare no competing interests.
Data sharing
The dataset and codes for the analyses are freely available online in the
Open Science Framework database.
Acknowledgments
We thank all the authors of the included studies.
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