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CADTH Health Technology Review
Authors; Deepa Jahagirdar, and Quenby Mahood.
Attention-deficit/hyperactivity disorder (ADHD) is 1 of the most commonly diagnosed childhood conditions.1 Autism spectrum disorder (ASD) and oppositional defiance disorder (ODD) are related to ADHD with symptomatic overlap. Symptoms that can be present in all the conditions include hyperactivity, impulsivity, behavioural issues, and inattention. Hyperactivity is more common in young children; this may evolve into impulsivity in adolescence and remain as such throughout the life course. Inattention is often diagnosed later2 and can remain in adulthood.3 The symptoms can affect academics, social skills, and occupational performance. While difficulty keeping up with school and making friends may start in childhood, forgetfulness, prioritization, and difficulty organizing tasks can continue to inhibit executive function as an adult.3
Pharmacological treatment for these conditions includes psychostimulant (simply called stimulant) medications most commonly as a first option, and non-stimulant medications as alternatives. Stimulant medications increase the brain activity of producing dopamine and norepinephrine while the mechanism of non-stimulant medications can vary.4 Selective norepinephrine reuptake inhibitors such as atomoxetine prevent reuptake of the same neurotransmitters, thus increasing concentrations. In contrast, alpha-2-agonists such as guanfacine and clonidine may mimic the effects of the neurotransmitters though their exact mechanism of action is unknown.4 While stimulants are usually the first line treatment, non-stimulant medications can be more desirable in some situations.5 They may be indicated when stimulant medications worsen co-occurring tic disorders, the person has a background of substance use, or have other intolerable side effects. In addition, symptoms may not always respond to stimulants necessitating trials with other options.5
Among the non-psychostimulants, guanfacine hydrochloride (used herein interchangeably with guanfacine) is an emerging and important choice to control ADHD, ASD, and ODD symptoms, but evidence is limited. The aim of this review is to summarize the evidence regarding the clinical and cost-effectiveness of guanfacine compared to stimulants and non-stimulants drugs for ADHD, autism spectrum disorder and ODD, as well as the evidence-based guidelines.
A limited literature search was conducted by an information specialist on key resources including MEDLINE, Embase, PsycINFO, the Cochrane Library, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search strategy comprised controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concept was guanfacine. Search filters were applied to limit retrieval to health technology assessments, systematic reviews, meta-analyses, or network meta-analyses, randomized controlled trials (RCTs), controlled clinical trials, guidelines, or economic studies. Comments, newspaper articles, editorials, conference abstracts and letters were excluded. Where possible, retrieval was limited to the human population. The search was completed on May 31, 2022 and limited to English language documents published since January 1, 2017.
One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.
Selection Criteria.
Articles were excluded if they did not meet the selection criteria outlined in Table 1, they were duplicate publications, or were published before 2017. Systematic reviews in which all relevant studies were captured in other more recent or more comprehensive systematic reviews were excluded.6-14 Primary studies retrieved by the search were excluded if they were captured in 1 or more included systematic reviews.15 Guidelines with unclear methodology were also excluded.
The included publications were critically appraised by 1 reviewer using the following tools as a guide: A MeaSurement Tool to Assess systematic Reviews 2 (AMSTAR 2)16 for systematic reviews, the “Questionnaire to assess the relevance and credibility of a network meta-analysis”17 for network meta-analyses, the Downs and Black checklist18 for randomized and non-randomized studies, and the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument19 for guidelines. Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included publication were described narratively.
A total of 274 citations were identified in the literature search. Following screening of titles and abstracts, 231 citations were excluded and 43 potentially relevant reports from the electronic search were retrieved for full-text review. 18 potentially relevant publications were retrieved from the grey literature search for full-text review. Of the 61 potentially relevant articles, 54 publications were excluded for various reasons, while 7 publications met the inclusion criteria and were included in this report. These comprised 4 systematic reviews, 2 randomized controlled trials (RCTs), and 1 evidence-based guideline. There were no economic evaluations that met the inclusion criteria. Appendix 1 presents the PRISMA20 flow chart of the study selection.
Additional references of potential interest are provided in Appendix 7. The overlap of primary studies in the included systematic review is available in Appendix 5.
All 4 systematic reviews had broader search inclusion criteria than relevant to this report. Two included systematic reviews, 1 with 203 eligible RCTs,21 and the other with 8 eligible RCTs,22 had 1 relevant RCT each reporting about guanfacine. Both these systematic reviews included only double-blinded RCTs. Another systematic review included 12 RCTs related to guanfacine out of 133 studies; open or blinded RCTs were eligible.23 The final systematic review included 13 out of 73 studies pertaining to guanfacine.24 It was not specified whether the included RCTs were blinded.24 The systematic reviews included articles from 1980 to November 2021,21 database inception to April 2021,23 from database inception to September 2017,22 and to up to March 29, 2017.24
The systematic reviews had some overlap. The only guanfacine study in Osland, 201822 was also included in Cortese, 2018,23 which included 12 RCTs. However, the systematic review by Osland, 201822 was retained because it reported outcomes related to tic disorders not reported by Cortese et al.23 Seven primary studies overlapped between Luan, 201724 and Cortese, 201823(Appendix 5).
Of the RCTs, 1 was a multi-centre double-blinded design with 201 participants, where patients were randomized to receive either guanfacine or placebo.25 The other trial was a crossover design with a 10-day washout period, meaning, the participants (40 in total) switched from their initial treatment assignment to the alternative (guanfacine or placebo) after allowing 10 days for the effect of the first to wane.26 The participants received concurrent treatment with a psychostimulant.26
The guideline was developed by the UK’s National Institute for Health and Care Excellence (NICE).27 The guidelines identified evidence through a systematic search of multiple electronic databases. The quality of the evidence was rated according to Grading of Recommendations, Assessment, Development and Evaluations (GRADE). The final recommendations adopted a language-based rating system, where “should offer” and “do not offer” reflect the recommendations with highest level of confidence, while “should consider and should not consider” reflect a lower level of confidence.
The systematic reviews originated from the UK,22,23 Germany21 and China.24 One RCT was conducted at 71 Japanese centres between October 2016 and July 201725 while the other RCT was conducted at a single centre in Canada though the study period was not specified.26 The guideline was developed by the NICE in the UK.27
One systematic review included children and adults (analyzed separately) diagnosed with ASD using at least Diagnostic and Statistical Manual (DSM)-III or other validated diagnostic tools.21 Two systematic reviews included individuals diagnosed with ADHD.23,24 One systematic review, included children and adults diagnosed with primary ADHD according to DSM-III, DSM-III-R, DSM-IV(TR), DSM-5, International Classification of Disease (ICD)-9, or ICD-10.23 The other systematic review included only children aged 6 to 18 with a DSM-IV diagnosis of ADHD.24 Another systematic review also included only children 18 or younger with a diagnoses of both ADHD and a chronic tic disorder.22 In the systematic reviews without age restriction, the studies pertaining to guanfacine were done in children only.21,23
One of the RCTs was conducted in children aged 6 to 12 years with a primary diagnosis of predominantly inattentive, hyperactive or impulsive, or combined subtype based on DSM-IV diagnosis of ADHD. The children had to be taking a stable methylphenidate or amphetamine (stimulant) regimen for at least 30 days with ongoing executive function difficulties.26 The other trial was done in adults at least 18 years old, with a DSM-V diagnoses of ADHD).25
The guideline targeted health care professionals, commissioners, people with ADHD as well as families and carers.27
The systematic reviews included a variety of pharmacological interventions, though only analyses related to guanfacine were considered for this review. One systematic review included dietary-supplements in addition to medications, except for those given in combination with behavioural interventions or risperidone.21 Findings comparing guanfacine to dietary-supplements were not included in this review. Another systematic review specified amphetamines, atomoxetine, bupropion, clonidine, guanfacine, methylphenidate and modafinil given as oral therapy, alone or in combination with other drugs.23 One systematic review included any pharmacological treatment for ADHD given orally alone or in combination with another drug,22 while the another systematic review included atomoxetine, bupropion, clonidine, guanfacine, methylphenidate and lisdexamfetamine.24 Two studies specified the minimum duration of treatment as 7 days,21,23 while another specified 3 weeks.24
In 1 RCT, the intervention was guanfacine titrated from 2 mg per day to 4 mg to 6 mg per day over 5 weeks to optimize the dose. This period was followed by a 5-week maintenance on the same dose, then tapering over 2 weeks.25 In the crossover RCT, guanfacine was initiated at 1 mg per day and optimized over 4 weeks to a maximum of 4 mg per day. The optimization was followed by an 8-week maintenance period, then tapering over 11 days and a 10-day washout period.26
The guideline considered various pharmacological treatment though in this review only recommendations pertaining to guanfacine were included.27
Two systematic reviews included placebo-controlled studies only,21,22 and 2 systematic reviews included studies with placebo or other drugs as comparators.23,24 In 2 systematic reviews, the duration of treatment had to be at least 7 days,21,23 while in another the minimum study duration had to be 3 weeks.24
All the systematic reviews reported change in ADHD symptoms outcomes, assessed by any validated scales and reported the finding using standardized mean difference (SMD).22-24 However, 1 systematic reviews specified only accepting the ADHD Rating Scale (ADHD-RS).24 Where included, parent, teacher and clinician ratings were analyzed separately.21-23 In the systematic review involving people with ASD, changes in repetitive behaviour, and social communication difficulties were reported as additional outcomes.21
Two systematic reviews with network meta-analysis reported SMD and 95% confidence intervals (CIs) based on the different scales.21,23 However, 1 systematic review limited meta-analysis to studies with a common scale, and reported a mean difference (MD) and 95% CI in the change in ADHD-RS.24 The systematic review of studies involving with people with ADHD and a chronic tic disorder reported tic severity using any valid scale such as the YGTSS total tic score as additional an outcome.22 Two systematic reviews measured clinical global functioning as secondary outcomes using the Clinical Global Impression- Improvement (CGI-I) tool.21,23 All reviews collected safety information, e.g., the number of adverse events.
The 2 RCTs had different primary outcomes. One used only the Behaviour Rating Inventory of Executive Function–Parent (BRIEF-P) score at all visits outside of the maintenance period.26 Secondary outcomes included changes in total score on the ADHD-RS-IV, Clinical Global Impression-Severity of illness (CGI-S), and the CGI-I. The other RCT25 used the change in baseline score on the Japanese version of the ADHD-RS-IV with adult prompts. Secondary outcomes included the change from baseline in ADHD-RS-IV subscale, and Behaviour Rating Inventory of Executive Function - Adult Version (BRIEF-A) scores for executive function. Safety outcomes in both trials included adverse events, vital sign measurements, physical examinations (weight and height).25,26 The Japanese trial additionally collected electrocardiogram parameters, while the Canadian study also measured safety using the used the Columbia Suicide Severity Rating Scale (CSSRS), which asks a series of ‘yes’ or ‘no’ questions to assess suicide risk.26
The included guideline’s major outcomes were quality of life, ADHD symptoms, and the CGI-I scale. In addition, it collected information on serious adverse events, behavioural and functional outcomes, emotional dysregulation, academic outcomes, substance use and self-harm where available.
Details on the included measurement scales used to assess the outcomes are available in Appendix 6.
Additional details regarding the characteristics of included publications are provided in Appendix 2.
All 4 systematic reviews had clear research questions and Population, Intervention, Comparator, Outcome (PICO) criteria.21-24 They all searched at least 7 databases for relevant studies, with 3 systematic reviews using supplemental search methods such as handsearching reference lists,21-23 thus, limiting the potential of missing pertinent studies. Risk of bias in studies was assessed using the Cochrane risk of bias tool.21-24 The systematic reviews handled primary studies rated as having high risk of bias in different ways. One systematic review downgraded the overall evidence quality,22 while 2 others conducted sensitivity analyses these studies in meta-analyses.21,23 One systematic review did not present the results of study bias analysis, making it challenging to understand the quality of evidence. This was also the only review that did not provide an overall assessment of evidence quality challenging the interpretation of the findings.24
Three of the systematic reviews conducted random effects pairwise and network meta-analyses.21,23,24 They all compared effect estimates derived from the network versus pairwise analysis, which helps to demonstrate the robustness of the analysis.21,23,24 Three systematic reviews also assessed study heterogeneity,21,23,24 though 2 of these did not discuss the findings or implications.23,24 Two systematic reviews conducted additional sensitivity analyses to ensure robustness of effects against common issues such as different study baseline characteristics and the impact of excluding studies with high risk of bias.21,23 The third systematic review did not conduct sensitivity analysis.24
Both included RCTs had clear research questions and inclusion criteria.25,26 Computerized software was used for treatment assignment and randomization, and both studies had adequate power to detect treatment effects. One study described using sealed envelopes and identical tables for treatment and placebo to maintain blinding,25 while the other trial did not provide specifics of the randomization, making it less clear whether blinding was adequately achieved.26 The study arms were balanced in 1 study,26 while in the other, the treatment group was younger than the placebo group (i.e., age less than 30 years was 47% in the treatment group compared to 39% in placebo group). There was no apparent adjustment for this imbalance, meaning it is unclear if age may have driven some of the observed effects.25 Both RCTs were funded by a grant from Shire, the drug manufacturer of guanfacine, raising concerns of conflict of interest.25,26
The overall quality of the included guideline was high.27 The intended users and target population, scope and purpose were clear, and the methodology for the literature review followed systematic approaches. Members of the committee to develop the guideline had a variety of backgrounds which would bring different perspectives. Where there were conflicts of interests, committee members withdrew from certain discussions. The guideline was also subjected to an online consultation period, which solicited comments from stakeholders on the draft recommendations that were incorporated as appropriate. The limitations of the guideline included lack of clarity on the process of developing the draft recommendations given the evidence, as well as no formal external peer review. There was however an online feedback period open to the public and invited stakeholders.
Additional details regarding the strengths and limitations of included publications are provided in Appendix 3.
Two systematic reviews compared the effectiveness of guanfacine to psychostimulant drugs.23,24 Guanfacine was not significantly different than methylphenidate in clinician-rated symptoms, parent-rated symptoms, or teacher-rated symptoms.23 from indirect comparisons. Similarly, guanfacine was not significantly different than methylphenidate on the ADHD-RS in both network meta-analysis and pairwise comparisons.24
Indirect comparison in 1 systematic review found that amphetamines were superior to guanfacine to improve ADHD symptoms as rated by both clinicians and parents.23 Amphetamines were also associated with greater positive response on the CGI-I.23 However, another systematic review did not find a statistically significant difference in its indirect comparison of guanfacine to lisdexamphetamine to improve ADHD symptoms.24 No direct evidence for this drug comparison was available.
In terms of safety, the tolerability of guanfacine was similar to methylphenidate and amphetamines in 1 systematic review.23 However, another systematic review found that guanfacine was associated with greater odds of withdrawals due to adverse events compared to methylphenidate.24 The systematic review also found that compared to lisdexamphetamine, the odds were higher with guanfacine for withdrawal due to lack of efficacy and increased abdominal pain.24
Three systematic reviews had quantitative comparisons of the efficacy of guanfacine and atomoxetine. Guanfacine was potentially inferior to atomoxetine in 1 systematic review of people with ASD though finding bordered on being statistically insignificant in an indirect comparison.21 Two other systematic reviews did not find a statistically significant difference between guanfacine and atomoxetine in indirect comparisons of clinician, teacher or parent ratings,23 or both indirect and direct comparisons on the ADHD-RS.24
In indirect comparisons, 2 reviews did not find statistically significant differences between guanfacine and clonidine on clinician or teacher ratings of ADHD symptoms,23 or on the ADHD-RS.24 Guanfacine was also not associated with statistically significant differences to ADHD symptoms compared to bupropion or modafinil in an indirect comparison in 1 systematic review.23
One systematic review found that guanfacine was associated with greater improvement to ADHD symptoms compared (indirectly) to 15 different medications among patients with ASD, including riluzole and fluoxetine.21 This same review did not find any statistically significant differences in repetitive behaviours or socio-communication difficulties in indirect comparisons to 21 medications.
In terms of safety and side effects, 1 systematic review found no significant differences in tolerance, or the occurrence of any adverse event compared to atomoxetine among people with ASD.21 However another systematic review found higher odds of withdrawals due to adverse events associated with guanfacine compared to atomoxetine,24 as well as increased likelihood of nausea.24
Guanfacine was also associated with more adverse events compared to sapropterin, dimethylglycine and sertraline in the review of people with ASD.21
Guanfacine was consistently found to be more effective than placebo to improve ADHD symptoms in the systematic reviews and clinical trials.21-26 Direct and indirect comparisons of guanfacine to placebo were reported in the reviews that conducted network meta-analysis.
Guanfacine was also associated with greater odds of positive response than placebo on the CGI-I in 2 systematic reviews.21,23 and 1 RCT.26 The assessment scales were however inconsistent. For example, guanfacine was associated with a greater improvement to symptoms than placebo based on clinician ratings though not in the teacher or parent-rated scales.23 In 1 systematic review without meta-analysis that assessed the reduction in tic symptoms using the YGTSS total tic score, the treatment with guanfacine was associated with greater symptoms reduction than placebo.22
In the 1 systematic review among people with ASD, the effect of guanfacine was not statistically significantly better than placebo for improving socio-communication difficulties or repetitive behaviours21
In addition to symptoms, guanfacine was more effective to improve executive function than placebo in both the clinical trials. In 1 RCT in children, BRIEF-P scores improved more in the guanfacine group than the placebo group.26 Similarly, the RCT in adults found statistically significant improvements on the Inhibit, Initiate, and Plan/Organize dimensions of the BRIEF-A scales, but not the other dimensions.25
On safety, guanfacine was associated with statistically significantly increased odds of sedation,21 fatigue,24 abdominal pain,24 total adverse events,21 and dropouts due to adverse events23,24 compared to placebo. One systematic review found no statistically significant difference in laboratory test results, weight, or cardiovascular tests though 1 person dropped out of the study due to sedation.22 In 1 RCT in adults, 19.8% (n = 19) of adverse events led to discontinuation in the guanfacine versus 3% (n = 3) in the placebo group, while 81% (n = 82) versus 62% (n = 62) experienced an adverse event in the guanfacine versus placebo group, respectively.25 In the RCT among children, adverse event were 41 (87%) in the guanfacine group and 41 (85%) placebo group. Further, no participant demonstrated suicide risk using the CSSRS while in the treatment arm.26
There were no studies identified that met the inclusion criteria available, therefore, no summary can be provided.
There were no studies identified that met the inclusion criteria, therefore, no summary can be provided.
There were no studies identified that met the inclusion criteria, therefore, no summary can be provided.
The 1 included guideline27 recommended offering (i.e., based on strongest evidence) atomoxetine or guanfacine to children aged 5 years and over and young people only if they cannot tolerate methylphenidate or lisdexamfetamine, or their symptoms have not responded to these stimulants. Further, they recommended considering (i.e., based on weaker evidence) changing from a stimulant medication to guanfacine in children aged 5 years and older if they have stimulant-related tics. Finally, they recommended not to offer (i.e., strongest evidence) guanfacine for adults without consulting a tertiary ADHD service.
Appendix 4 presents the main study findings and authors’ conclusions.
The main limitation is that the evidence is based on a lot of indirectness and uncertainty in the head-to-head comparisons, limiting the confidence in comparisons of guanfacine versus other non-psychostimulants and stimulant medications. The systematic reviews as well as the included studies were generally of sufficient quality. However, the quantity of primary studies with head-to-head comparisons and in subpopulations is limited. One systematic review concluded that the evidence quality for the guanfacine comparisons was moderate versus placebo, low versus atomoxetine and very for comparisons to clonidine, methylphenidate and modafinil.’23 Two other systematic reviews concluded that the quality of evidence was low for the ASD population due to indirectness and imprecision,21 and very low for children with ADHD and tics.22
Also, only 1 study was conducted in adults, only 1 study was completed in Canada, and there were no studies that explicitly discussed people with ODD. Therefore, the generalizability of the findings to the general Canadian population with ADHD, ASD and ODD is unclear.
Finally, the included RCTs were both funded by Shire, the manufacturer of Intuniv, creating a potential conflict of interest and uncertainty about editorial independence regarding the interpretation of findings.
This rapid review report included 4 systematic reviews, 2 RCTs and 1 evidence-based guideline. It adds to the current evidence base by synthesizing current evidence for clinical effectiveness and guidelines pertaining to using guanfacine for ADHD, ASD and ODD. The evidence suggests that guanfacine is generally more effective than placebo to improve ADHD symptoms among those with ADHD or ASD,21-26 but with a higher potential for adverse events. Three systematic review found limited evidence of a significant difference in effectiveness between guanfacine and psychostimulants or non-psychostimulants,21,23,24 but there may be greater risk of adverse events such as increased fatigue and abdominal pain.24 The available 2018 guidelines by NICE is in line with these findings, only suggesting guanfacine if children cannot tolerate or do not respond to psychostimulants.27 The evidence among adults with ADHD was limited to 1 clinical trial which found guanfacine was more effective than placebo to improve ADHD symptoms.25
Compared to a previous CADTH report on the same topic,28 this review expands the research questions to more precisely compare guanfacine to psychostimulants and non-psychostimulants. Further, it includes 3 systematic reviews and 2 new RCTs, and a guideline that were unavailable in the previous report. The NICE guidelines identified in the current review recommended guanfacine in situations of intolerability or non-response.27 However, this review aligns with the previous 1 in finding that the comparisons between guanfacine and other drugs for ADHD and related conditions are largely based on indirect evidence.
There is limit evidence about using guanfacine to treat ADHD, autism spectrum disorder, and oppositional defiance disorder in adults. Further, there was no evidence related to using guanfacine in people with ODD, indicating that the generalizability of the findings to this group is unknown. Also, due to the lack of evidence on cost-effectiveness, health care resource utilization studies may be useful to understand cost implications.29 There is a need for studies comparing guanfacine to other medications in adult populations and people with ODD, and for evaluating the comparative cost-effectiveness analyses of the treatments.
autism spectrum disorder
Attention-deficit/ hyperactive disorder
ADHD rating scale
Behavioural Rating Inventory of Executive Function–Adult
Behavioural Rating Inventory of Executive Function–Parent
Clinical Global Impressions-Improvement
Clinical Global Impressions-Severity of Illness
Columbia Suicide Severity Rating Scale
Diagnostic and Statistical Manual
Grading of Recommendations, Assessment, Development and Evaluations
health technology assessment
International Classification of Disease
mean difference
oppositional defiance disorder
odds ratio
randomized controlled trial
Yale Global Tic Severity Scale
Selection of Included Studies.
Note that this appendix has not been copy-edited.
Characteristics of Included Systematic Reviews and Network Meta-Analyses.
Characteristics of Included Primary Clinical Studies.
Characteristics of Included Guideline.
Note that this appendix has not been copy-edited.
Strengths and Limitations of Systematic Reviews and Network Meta-Analyses Using AMSTAR 216 and the ISPOR Questionnaire.
Strengths and Limitations of Clinical Studies Using the Downs and Black Checklist.
Strengths and Limitations of Guideline Using AGREE II.
Note that this appendix has not been copy-edited.
Summary of Findings Included Systematic Reviews and Network Meta-Analyses.
Summary of Findings of Included Primary Clinical Studies.
Summary of Recommendations in Included Guideline.
Note that this appendix has not been copy-edited.
Overlap in Relevant Primary Studies between Included Systematic Reviews.
Note that this appendix has not been copy-edited.
ADHD Rating Scale, ADHD Rating Scale IV (ADHD-RS)24-26: completed independently by a parent or teacher, and scored by a clinician. The scale consists of 2 subscales: inattention (9 items) and hyperactivity-impulsivity (9 items) for a total of 18 items. The total score can range from 0 to 54; a higher score means worse ADHD symptoms.
Behaviour Rating Inventory of Executive Function–Parent (BRIEF-P)26: an 86-item questionnaire completed by parents to assess executive function in children. Raw scores are transformed to T-scores of which above 65 is considered clinically significant.
Behaviour Rating Inventory of Executive Function - Adult Version (BRIEF-A)25: like the BRIEF-P but for adults, it includes 75 items to assess adult executive function behaviours.
Clinical Global Impressions- Severity of illness (CGI-S)21,23,25,26: Scale ranges from 1 (no symptoms) to 7 (very severe symptoms).
Clinical Global Impressions-Improvement (CGI-I)21,23,25,26: Scale ranges from 1 (most improvement) to 7 (least improvement): Three or less means improvement, 4 means no change, 5 to 7 means worse.
Yale Global Tic Severity Scale (YGTSS) total tic score22: tool to quantify the severity of tic symptoms in children aged 6 to 17. A higher score indicates more severe tics symptoms: the Total Tic Severity Score has a range of 0 to 50, and the Global Severity Score has a range of 0 to 100.
Note that this appendix has not been copy-edited.
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