Farhat2013 Tourette Tratamento Farmacologico

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Platform, and ClinicalTrials.gov, for published and unpublished studies from database inception to Nov 19, 2021.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
[email protected]
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 the European Society for the Study of Tourette Syndrome

Tourette’s syndrome (also known as Tourette’s disorder) (ESSTS)7 there is no consensus about the medications
is a neurodevelopmental disorder characterised by one or that should be offered to children and young people
more phonic and several motor tics that develop during as first-line pharmacological interventions. Although
childhood or adolescence and last longer than 1 year.1 the AAN gives preference to α-2 agonists, such as
Prevalence estimates from epidemiological studies clonidine and guanfacine, the ESSTS recommends that
indicate that three in 1000 to nine in 1000 young people aripiprazole, tiapride, or risperidone should be offered
live with Tourette’s syndrome in Asia, Europe, and first. These inconsistencies in recommendations are
North America.2 Children and adolescents experience observed in the real-world setting as pharmacoepidemio
distress, functional impairments, or both, through the logical studies indicate that antipsychotic drugs are the
effect of the disorder on their physical, social, and most used pharmacological intervention in Europe,8,9
academic lives and are often stigmatised.3 Although whereas α-2 agonists are more commonly prescribed in
the severity of Tourette’s syndrome tends to diminish the USA.10 Notably, the National Institute for Health and
throughout adolescence and into early adulthood,4 Care Excellence in the UK does not provide any guidance
population-based epidemio logical studies have shown about Tourette’s syndrome.
that it is associated with several negative outcomes Treatment recommendations are inconsistent because
in adult life, including academic under achievement, double-blind randomised controlled trials of pharma
substance use, transport accidents, and suicidality.5 cological interventions for Tourette’s syndrome are
Pharmacological treatment is generally recommended scarce, small, and mostly placebo controlled, which
for children and young people with Tourette’s syndrome makes it difficult to determine the comparative effects of
who continue to experience distress or impairments medications. Previous efforts to collate the available
after receiving evidenced-based psychotherapy such evidence relied on standard, pairwise meta-analyses.11–13
as Comprehensive Behavioural Intervention for Tics Network meta-analyses facilitate estimation of the
(CBIT).6,7 However, in recently published guidelines comparative effects of two or more interventions even
from the American Academy of Neurology (AAN)6 and when they have not been investigated in head-to-head
Research in context
Evidence before the study evidence base to guide the choice of medications for children
Recent treatment guidelines from the American Academy of and young people with Tourette’s syndrome. We found that
Neurology (published in 2019) and the European Society for the antipsychotic drugs (aripiprazole, haloperidol, olanzapine,
Study of Tourette’s Syndrome (published in 2022) have differing pimozide, and risperidone) and α-2 agonists (clonidine)
views about the medications that should be offered first to showed efficacy compared with placebo in reducing the
children and young people with Tourette’s syndrome. These severity of tic symptoms. When comparing different
inconsistencies arise because double-blind randomised controlled pharmacological interventions, there were no differences
trials of pharmacological interventions for Tourette’s syndrome between individual antipsychotics, but there was a low to
are scarce, small, and mostly placebo controlled, so that direct very low certainty of evidence associated with these
comparison between pharmacological interventions is difficult. comparisons. However, antipsychotics (aripiprazole and
Network meta-analyses enable pooling of direct and indirect risperidone) were more efficacious than α-2 agonists
evidence, and are therefore essential to inform evidence-based (clonidine).
decision making, including in Tourette’s syndrome. We searched
Implications of the available evidence
PubMed on Aug 17, 2022, without any language restrictions with
Antipsychotic drugs are the most efficacious treatment for
the search string “(((Tourette AND Syndrome) OR Tourette OR
the management of tic symptoms, whereas α-2 agonists are
(tic AND disorder)) AND (pharmacotherapy OR pharmacological
also more efficacious than placebo and could be used by
OR pharma*) AND (“meta-analysis as topic”[MeSH] OR Meta-
individuals who elect not to take antipsychotic drugs. Shared
Analysis OR metaanaly* OR meta-analy*))”; we identified and
decision making, taking into account the degree of tic-related
inspected 89 records, and found no network meta-analyses of
severity and distress or impairment, the trade-offs of efficacy
double-blind randomised controlled trials of pharmacological
and safety between antipsychotic drugs and α-2 agonists,
interventions for Tourette’s syndrome.
and other highly relevant individual factors that could not be
Added value of this study addressed in the present analysis, should guide the choice of
The findings from this network meta-analysis represent, medication for children and young people with Tourette’s
to the best of our knowledge, the most comprehensive syndrome.
2 www.thelancet.com/child-adolescent Published online December 14, 2022 https://doi.org/10.1016/S2352-4642(22)00316-9

Articles
randomised controlled trials, and they provide the included terms related to tic disorders, including
highest level of evidence required to inform treatment Tourette’s syndrome, and randomisation (appendix
guidelines.14 However, to the best of our knowledge, there pp 7–9). We also hand-searched reports from the
are no network meta-analyses of double-blind ran US Food and Drug Administration, European Medicines
domised controlled trials evaluating the relative effects of Agency, and relevant drug manufacturers, retrieved
pharmacological interventions for children and young from their respective websites, as well as references of
people with Tourette’s syndrome. previous systematic reviews and guidelines, to identify
To fill this gap, we aimed to do a systematic review and additional relevant studies. We contacted study authors
network meta-analysis of pharmacological interventions and drug manufacturers to obtain unpublished infor
evaluated in double-blind randomised controlled trials mation and data.
for the treatment of Tourette’s syndrome. We aimed to Pairs of researchers (LCF and EB, JLSL, or PMFdB)
compare medications against placebo and each other independently reviewed the records to select the studies.
in terms of change in severity of tic symptoms, dropouts Any discrepancies were double checked and resolved by
due to adverse events , and all-cause dropouts. discussion with another member of the review team
(MHB). Summary data were extracted from eligible
Methods randomised controlled trials by one researcher (LCF)
Search strategy and selection criteria and independently checked by another (MHB). We
In this systematic review and network meta-analysis, we extracted characteristics of the study, participants, and
included double-blind randomised controlled trials that inter
ventions, as well as outcome data at the study
enrolled children and adolescents (aged ≥4 years and endpoint. We pooled groups of the same medication at
≤18 years), adults (>18 years), or both, with a primary different doses for randomised controlled trials that
diagnosis of Tourette’s syndrome according to the randomly assigned participants to multiple doses of the
Diagnostic and Statistical Manual of Mental Disorders same pharmacological agent (ie, fixed-dose randomised
(DSM-III, DSM-III-R, DSM-IV, DSM-IV-TR, and DSM5), controlled trials with multiple groups) because we con
the International Classification of Diseases (ICD-9, sidered that all doses administered in those randomised
ICD-10, and ICD-11), or the Chinese Classification of controlled trials were therapeutic. More details of study
Mental Disorders, third edition. Randomised controlled selection and data extraction are provided in the
trials that also recruited participants with persistent tic appendix (pp 10–11).
disorders other than Tourette’s syndrome were eligible
for inclusion. We did not restrict eligibility by medication Data analysis
but required that the drugs were administered as a The primary outcome was efficacy, measured as a change
monotherapy for at least 1 week. We also placed no in severity of tic symptoms. Where multiple rating scales
restrictions on language or publication year. More details were provided, we preferred those that were recommended
of the eligibility criteria are provided in the appendix (p 6). by a panel of experts16—namely, the Yale Global Tic See Online for appendix
To avoid violation of the transitivity assumption,15 we Severity Scale,17 the Shapiro Tourette’s Syndrome Severity
excluded randomised controlled trials that did not Scale,18 and the Tourette’s Syndrome-Clinical Global
require participants to discontinue antipsychotic medi Impressions,19 in that order. We also extracted data on the
cations, but we did not exclude studies that allowed basis of other rating scales if those were the only data
participants to maintain other psychotropic medications reported. Changes from baseline scores were preferred
because most randomised controlled trials of Tourette’s over endpoint scores. Intention-to-treat analyses were
syndrome do not account for the presence of comorbid preferred, and we used the method adopted by the study
ities and allow for their co-treatment (eg, treatment of to handle missing data, usually mixed-model repeated
attention-deficit hyperactivity disorder [ADHD] with measures or last observation carried forward. We also
α-2 agonists). However, we excluded studies in which extracted data from participants who completed the study
all participants had comorbid ADHD or obsessive com (modified intention-to-treat analyses) if that was the only
pulsive disorder because those randomised controlled analysis reported. We calculated missing SDs from
trials either evaluated treatments that would only p values, t values, and standard errors, or imputed them
be indicated for individuals with the comorbidity with a validated method (appendix p 11).20 Secondary
(eg, stimulants, atomoxetine, and fluoxetine) or they outcomes were the tolerability of medications, measured
evaluated treatments whose effects could be modified as treatment discontinuations due to adverse events, and
by the comorbid disorder (eg, α-2 agonists for Tourette’s the acceptability of medications, measured as all-cause
syndrome plus ADHD).12 dropout rates.
We searched the Cochrane Central Register of Most pharmacological interventions were examined
Controlled Trials, Embase, PsycINFO, PubMed, Web in single, or few, small-scale, randomised controlled
of Science, the WHO International Clinical Trials trials. Therefore, besides examining each medication
Registry Platform, and ClinicalTrials.gov, from the date individually, we also did analyses for medication categories
of database inception to Nov 19, 2021. The search strategy when groupings were considered pertinent. We used

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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

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

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

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antipsychotic drugs should be used as a first-line pharma Patients, caregivers, and clinicians are often faced
cological intervention in the treatment of Tourette’s with the conundrum of either relying on the scarce
syndrome is debatable because these medications data available from randomised controlled trials of
are potentially toxic and could lead to burdensome α-2 agonists for Tourette’s syndrome plus ADHD or
adverse events, particularly in children and adolescents. generalising from a larger set of literature on Tourette’s
Specifically, aripiprazole, haloperidol, olanzapine, and syndrome, and preferences might vary.74 Therefore,
risperidone have been associated with sedation, future research should directly examine whether the
extrapyramidal adverse effects, and metabolic changes treatment effect of α-2 agonists for Tourette’s syndrome
such as bodyweight gain, metabolic syndrome, and in the context of ADHD is larger than that observed for
diabetes in children and adolescents.69 These metabolic Tourette’s syndrome in general.
adverse events are likely to be underappreciated in short- Our study also highlights potential avenues for
duration randomised controlled trials, which might future randomised controlled trials of Tourette’s
underestimate the potential impact of these pharma syndrome. There were relatively few head-to-head trials
cological interventions in children and adolescents who of pharmacological interventions, and future research
require medication for longer periods. Children and should aim to compare medications, particularly anti
adolescents might also be more vulnerable to somatic psychotic drugs and α-2 agonists, against each other
serious adverse events with antipsychotic drugs.70 in large, well-designed randomised controlled trials.
Our results also showed that a-2 agonists are more Ecopipam has shown efficacy against placebo in
efficacious than placebo. Specifically, we found that preliminary studies and is a promising potential inter
clonidine was more efficacious than placebo, but we vention for Tourette’s syndrome.60 However, it should be
were unable to identify a similar effect in favour of emphasised that ecopipam is an investigational product
guanfacine. Given that clonidine and guanfacine have that has yet to be evaluated in a phase 3 randomised
similar pharmacodynamic properties (ie, both are controlled trial. Although the initial findings are
direct-acting agonists for α-2 receptors), this finding promising and suggest that this medication might
might seem unexpected. However, guanfacine was only be a potential alternative to antipsychotic drugs or
examined in 28 participants across two randomised α-2 agonists, more studies are needed. We also found a
controlled trials and therefore its effect sizes were large effect size in favour of topiramate against placebo,
marked by imprecision, with wide 95% CIs. Although but unfortunately this intervention for Tourette’s
α-2 agonists are also associated with adverse events syndrome had only been evaluated in one randomised
such as hypotension, sedation, and electrocardiographic controlled trial. Future investigations should consider
alterations (eg, QTc prolongation),71 these adverse events replicating that preliminary study in a larger sample.
are often considered less worrisome because they Our study also identified several traditional Chinese
typically resolve after the medication is discontinued. medicine remedies that were more efficacious than
In terms of choosing a specific medication, shared placebo in randomised controlled trials exclusively done
decision making should consider the degree of tic-related in China and often with additional traditional Chinese
severity and distress or impairment, the trade-offs of medicine-based diagnoses. Replication of these findings
efficacy and safety between antipsychotic drugs and through studies done in other settings is required to
α-2 agonists, and other highly relevant individual factors clarify whether these findings are generalisable to other
that could not be addressed in the present study since ethnic groups and to patients with Tourette’s syndrome
our analyses were based only on summary data.72,73 For in general.
instance, owing to the potential adverse events associated Overall, there were few randomised controlled trials
with antipsychotic drugs, caregivers and clinicians might and participants per treatment node, which restricted
be reluctant to administer these medications to children our power to detect significant differences, particularly
and adolescents or to individuals who are overweight for dichotomous outcomes. Indeed, almost all com
or obese. Additionally, for individuals with comorbid parisons for tolerability and acceptability had a low to
ADHD, α-2 agonists might have increased efficacy, very low certainty of evidence, largely because of
possibly because treatment of co-occurring ADHD might imprecise effect sizes. To increase the power of
also contribute to improvement of Tourette’s syndrome. treatment nodes, we also analysed data considering
We excluded studies that only recruited participants with medication categories when groupings were considered
a dual diagnosis of Tourette’s syndrome plus ADHD to pertinent. We opted to consider tiapride as a first-
ensure that we followed the transitivity assumption in generation antipsychotic drug given its D2-receptor
our network meta-analysis.15 However, most randomised antagonist properties, but we recognise that this
controlled trials that were included in our systematic classification might not be entirely appropriate.
review and network meta-analysis did not exclude However, we did a sensitivity analysis in which we
participants on the basis of the presence of ADHD, excluded tiapride from first-generation antipsychotic
and therefore our findings might also be applicable drugs and found similar findings. We also considered
to participants with Tourette’s syndrome plus ADHD. aripiprazole as a second-generation antipsychotic drug

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following previous research,70,75,76 although we recognise tolerability, we considered treatment discontinuations

that this medication is pharmacologically distinct from due to adverse events instead of individual adverse events
other medications within that group. but we recognise that an examination of individual
Additionally, to avoid loss of data given the scarcity of adverse events would be more clinically informative;
randomised controlled trials, we pooled data from future research should examine this outcome directly.
randomised controlled trials that recruited children, Similarly, for acceptability, we considered treatment
adolescents, and adults34,37,38,41,45,46,55,58,59 or that recruited discontinuations for any reason because few randomised
adults exclusively (T-Forward; NCT02581865). We recog controlled trials reported patient-derived or caregiver-
nise that adults with Tourette’s syndrome might derived instruments for this outcome. Nevertheless,
represent a subtype of all patients with the disorder and using dropout rates as proxies for tolerability and
might have distinct biological characteristics because acceptability is a typical procedure in network meta-
longitudinal studies have shown that most children analyses of other psychiatric disorders.77,80,81 Additionally,
with Tourette’s syndrome show an improvement in, we pooled multiple groups of the same medication from
or remission of, tic symptoms during adolescence.4 fixed-dose randomised controlled trials; this procedure
However, because a relatively large number of random might potentially dilute the effects of higher doses.
ised controlled trials recruited mixed samples, we However, this procedure was only adopted for five fixed-
decided that it would be arbitrary to exclude some dose randomised controlled trials that involved
randomised controlled trials on the basis of an three medi cations (aripiprazole, deutetrabenazine, and
investigator-driven age cutoff, particularly because most valbenazine). Nonetheless, additional research should
of these randomised controlled trials34,38,41,45,46,58,59 ended consider evaluating the dose–response associations82 for
up including participants with a mean age younger than certain medication categories when more data become
24 years. Besides, there are no strong data to suggest available. Additionally, most studies were based on the
that children and adults with Tourette’s syndrome short term (around 2 months of data) and predominantly
respond differently to pharmacological treatment. enrolled male participants. Because the severity of
Hence, we decided to do a primary analysis involving all Tourette’s syndrome waxes and wanes and the disorder
age groups and to do a sensitivity analysis specifically predominantly affects male individuals with a 3:1 or
examining studies that exclusively recruited children 4:1 ratio,83 it is understandable that randomised controlled
and adolescents with a mean age younger than 18 years, trials had these characteristics. However, these features
as done in previous studies of Tourette’s syndrome11 and of the included randomised controlled trials limited
other psychiatric disorders;77 the findings of this analysis evaluation of the medium-term and long-term effects
were similar to the main findings. We also accounted of pharmacological interventions and the generalisability
for the inclusion of data from adults in the main of evidence to female individuals with Tourette’s
analyses by downgrading the certainty of evidence due syndrome. Longer-duration randomised controlled trials
to indirectness for studies in which the mean age of with increased coverage of female participants are
participants was older than 24 years. therefore warranted.
Our study has limitations. We cannot rule out In conclusion, from a clinical perspective, several
the possibility of missing information, despite our best psychotherapies have shown efficacy in the treatment
efforts to include all available double-blind randomised of Tourette’s syndrome and should be considered
controlled trials and to retrieve unpublished data. The before, or concurrently to, medication use in children
outcomes that were evaluated in our study have some and young people with Tourette’s syndrome. If
shortcomings. For efficacy, although change in severity of pharmacological interventions are required despite
tic symptoms is an important factor for assessing evidence-based psychotherapies, this network meta-
treatment response in routine clinical practice and has analysis represents the best available evidence base to
been typically used as the primary outcome in randomised guide the choice of medications for children and young
controlled trials of pharmacological interventions for people with Tourette’s syndrome. Our findings indicate
Tourette’s syndrome, it is possible that this outcome is that antipsychotic drugs are the most efficacious
not a priority for patients with Tourette’s syndrome. treatment for the management of tic symptom severity,
Additionally, different rating scales were used to measure while α-2 agonists are also more efficacious than
change in severity of tic symptoms across studies. placebo and could be used by those who elect not to
Although all but two scales were recommended by take antipsychotic drugs. Shared decision making
experts,16 there are some differences in content of the should consider the degree of tic-related severity and
instruments.78 Unfortunately, to the best of our knowledge distress or impairment, the trade-offs of efficacy and
there is no core outcome set for randomised controlled safety between antipsychotic drugs and α-2 agonists,
trials of Tourette’s syndrome; additional research is and other highly relevant individual factors that can
needed to address this gap to ensure homogeneity across only be addressed in individual participant data
studies while also considering outcomes that matter to analyses. We hope these results will inform parents,
patients (eg, as done in studies for depression).79 For clinicians, and future guideline developers.

Articles
Contributors 12 Weisman H, Qureshi IA, Leckman JF, Scahill L, Bloch MH.

LCF, EB, AL-W, and MHB designed the study. LCF did the literature Systematic review: pharmacological treatment of tic disorders—
searches, and LCF, EB, JLSL, PMFdB, and ZW screened records, efficacy of antipsychotic and alpha-2 adrenergic agonist agents.
retrieved reports of the relevant studies, and selected included studies. Neurosci Biobehav Rev 2013; 37: 1162–71.
MHB resolved conflicts in study selection. LCF and MHB identified and 13 Pringsheim T, Holler-Managan Y, Okun MS, et al. Comprehensive
linked multiple publications of individual studies and extracted data. systematic review summary: treatment of tics in people with Tourette
LCF contacted trial investigators for additional information and did the syndrome and chronic tic disorders. Neurology 2019; 92: 907–15.
statistical analysis with input from MHB. LCF and MHB verified and 14 Leucht S, Chaimani A, Cipriani AS, Davis JM, Furukawa TA,
interpreted the data. LCF and MHB wrote the first draft and EB, AL-W, Salanti G. Network meta-analyses should be the highest level of
evidence in treatment guidelines. Eur Arch Psychiatry Clin Neurosci
JLSL, PMFdB, and ZW critically reviewed the report for important
2016; 266: 477–80.
intellectual content and approved the final submitted version.
15 Salanti G. Indirect and mixed-treatment comparison, network,
All authors had full access to all the data in the study and accept
or multiple-treatments meta-analysis: many names, many benefits,
responsibility for the decision to submit for publication. many concerns for the next generation evidence synthesis tool.
Declaration of interests Res Synth Methods 2012; 3: 80–97.
LCF is supported by grant #21/08540-0 from the São Paulo Research 16 Martino D, Pringsheim TM, Cavanna AE, et al. Systematic review of
Foundation (FAPESP). PMFdB is supported by grant 88887.612255/2021-00 severity scales and screening instruments for tics: critique and
from Coordenção de Aperfeiçoamento de Pessoal de Nível Superior recommendations. Mov Disord 2017; 32: 467–73.
(CAPES). MHB has received grant or research support from Therapix 17 Leckman JF, Riddle MA, Hardin MT, et al. The Yale Global Tic
Biosciences, Emalex Biosciences, Neurocrine Biosciences, Janssen Severity Scale: initial testing of a clinician-rated scale of tic severity.
J Am Acad Child Adolesc Psychiatry 1989; 28: 566–73.
Pharmaceuticals, Biohaven Pharmaceuticals, the US National Institutes of
Health, the Lesbian Health Fund, the Yale Foundation for Lesbian and Gay 18 Shapiro AK, Shapiro ES, Young JG, Feinberg TE. Measurement in
tic disorder’s severity. In: Cohen DJ, Bruun RD, Leckman JF, eds.
Studies (FLAGS), and Patterson Foundation. MHB has served on the
Tourette’s syndrome and tic disorders: clinical understanding and
advisory board and data monitoring and safety board of Therapix treatment. New York, NY: John Wiley & Sons, 1988.
Biosciences. MHB serves as associate editor of the Journal of Child
19 Leckman JF, Towbin KE, Ort SI, Cohen DJ. Clinical assessment of
Psychology and Psychiatry and is on the editorial boards of the Journal of tic disorders severity. In: Cohen DJ, Bruun RD, Leckman JF, eds.
Child and Adolescent Psychopharmacology and Depression & Anxiety. Tourette’s syndrome and tic disorders: clinical understanding and
MHB has received royalties from Wolters Kluwer for Lewis’s Child and treatment. New York, NY: John Wiley & Sons, 1988.
Adolescent Psychiatry: A Comprehensive Textbook, Fifth Edition. MHB has 20 Furukawa TA, Barbui C, Cipriani A, Brambilla P, Watanabe N.
received moonlighting pay from the Veteran’s Administration. All other Imputing missing standard deviations in meta-analyses can provide
authors declare no competing interests. accurate results. J Clin Epidemiol 2006; 59: 7–10.
Data sharing 21 Higgins JPT, Li T, D’eeks JJ. In: Chapter 6. Choosing effect
The dataset and codes for the analyses are freely available online in the measures and computing estimates of effect. In: Higgins JPT,
For the datasets in the Open
Thomas J, Chandler J, et al, eds. Cochrane Handbook for
Open Science Framework database. Science Framework see https://
Systematic Reviews of Interventions, version 63 (updated
February, 2022). Cochrane, 2022. https://training.cochrane.org/ doi.org/10.17605/OSF.IO/
Acknowledgments
handbook (accessed Oct 27, 2022). YW629
We thank all the authors of the included studies.
22 Rücker G, Schwarzer G. Ranking treatments in frequentist network
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Articles

Comparative efficacy, tolerability, and acceptability of

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

Copyright © 2022 Elsevier Ltd. All rights reserved.

Introduction the European Society for the Study of Tourette Syndrome

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We initially did pairwise random-effects meta-analyses

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Table: Characteristics of included studies

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

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

1·11‡ (0·12 to 10·28)

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

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

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following previous research,70,75,76 although we recognise tolerability, we considered treatment discontinuations

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Contributors 12 Weisman H, Qureshi IA, Leckman JF, Scahill L, Bloch MH.

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