Pharmacological treatment for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders

Sydney T Osland; Thomas DL Steeves; Tamara Pringsheim

doi:10.1002/14651858.CD007990.pub3

注意力缺陷多动障碍（ADHD）与抽动障碍共病儿童患者的药物治疗

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Versión publicada: 26 junio 2018 Historial de versiones

https://doi.org/10.1002/14651858.CD007990.pub3

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摘要

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研究背景

本系统综述是发表于2011年第四期的原始Cochrane系统综述的更新。

注意力缺陷多动障碍（Attention deficit hyperactivity disorder, ADHD）是最常见的共病精神障碍，会使抽动障碍复杂化。通常用于治疗ADHD症状的药物包括兴奋剂，比如哌醋甲酯和安非他明；非兴奋剂，例如托莫西汀；三环类抗抑郁药；和α激动剂。α激动剂也被用来治疗抽动。由于ADHD症状对抽动障碍儿童的影响，ADHD的治疗通常比抽动障碍的医疗管理更重要。然而，几十年来，临床医生一直不愿使用兴奋剂来治疗患有ADHD和抽动障碍的儿童，因为他们担心抽动会恶化。

研究目的

评价药物治疗对ADHD与抽动障碍共病儿童的ADHD和抽动障碍症状的影响。

检索策略

我们于2017年9月检索了CENTRAL、MEDLINE、Embase和其他12个数据库。我们还检索了两个试验注册库并联系该领域的专家以获取任何正在进行的或未发表的研究。

纳入排除标准

我们纳入了关于专门用于ADHD与抽动障碍共病儿童的任何药物治疗的随机、双盲、对照试验。我们纳入了平行对照和交叉研究。

资料收集与分析

我们使用Cochrane标准的方法学流程，两名系统综述作者独立筛选研究、使用标准化表格提取资料、评价偏倚风险、并使用GRADE方法对证据的总体质量进行评级。

主要结果

我们在本系统综述中纳入了8项随机对照试验（其中4项为交叉试验），涉及510名受试者（443名男孩，67名女孩）。这些研究的受试者是患有ADHD和慢性抽动障碍的儿童。所有研究均在美国进行，持续时间为3至22周。八项研究中有五项由慈善组织或政府机构资助，或两者兼而有之。一项研究由药物制造商资助。另外两项研究没有具体说明资金来源。所纳入的研究因盲法而偏倚风险较低；因随机序列生成、分配方案隐藏和损耗偏倚而存在低偏倚风险或偏倚风险不明确；以及因选择性结局报告而存在低或高偏倚风险。由于重要的临床异质性和分析单位的问题，我们无法在meta分析中合并任何研究。

一些试验评价了多种药物。所评价的药物包括哌醋甲酯、可乐定、地昔帕明、右旋安非他明、胍法辛、托莫西汀和地普林。哌醋甲酯、托莫西汀和可乐定的证据质量低，而地昔帕明、右旋安非他明、胍法辛和地普雷尼治疗ADHD与抽动障碍共病儿童的证据质量极低。除使用次甲优降宁的研究外，所有研究都报告了ADHD症状的改善。使用胍法辛、地昔帕明、哌醋甲酯、可乐定以及哌醋甲酯和可乐定组合治疗的儿童的抽动症状也有所改善。在一项研究中，抽动限制了哌醋甲酯剂量的进一步增加。在一项研究中，高剂量的右旋安非他明似乎会加重抽动症状，尽管这项研究的时间被限制在三周内。食欲抑制或体重减轻与哌醋甲酯、右旋安非他明、托莫西汀和地昔帕明有关。失眠与哌醋甲酯和右旋安非他明有关，镇静与可乐定有关。

作者结论

在对可能相关的研究进行更新检索后，我们没有发现符合我们纳入标准的新研究，因此我们的结论没有改变。

哌醋甲酯、可乐定、胍法辛、地昔帕明和托莫西汀似乎可以减轻抽动障碍儿童的ADHD症状，尽管现有证据质量为低质量到极低质量。虽然没有证据表明兴奋剂会使大多数患有抽动障碍的人的抽动症状恶化，但在个别病例中可能会加剧抽动的症状。在这些情况下，用α激动剂或托莫西汀治疗可能是另一种选择。尽管有证据表明地昔帕明可以改善儿童的抽动和ADHD，但其安全问题可能会继续限制其在该人群中的使用。

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

简语概要

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抽动障碍儿童注意力缺陷多动障碍（ADHD）的药物治疗

系统综述问题

在患有ADHD和抽动障碍的儿童中，ADHD药物如何影响这两种疾病的症状？

系统综述背景

多达一半患有抽动障碍（重复动作发声组合）的儿童也患有ADHD（多动、冲动和保持注意力的问题）。对于儿童来说，ADHD的症状往往比他们的抽动症状更严重。从历史上看，兴奋剂药物加重抽动症状的能力已经限制了它们在患有慢性抽动障碍（自第一次抽动发作后持续一年以上）和ADHD的儿童中的使用。为了评价所报告的现象的证据，我们检索了关于专门针对患有抽动障碍的儿童的ADHD药物的临床试验。

检索日期

证据检索截至2017年9月。

研究特征

我们在本系统综述中纳入了8项研究，涉及510名受试者（443名男孩，67名女孩）。这些研究的受试者是患有ADHD和慢性抽动障碍的儿童。所纳入的研究评价了几种不同的治疗ADHD的药物，包括兴奋剂（哌醋甲酯、右旋安非他明）和非兴奋剂（可乐定、胍法辛、地昔帕明、托莫西汀和地普林）。所有研究均在美国进行，持续时间为3至22周。

研究资金来源

八项研究中有五项由慈善组织或政府机构资助，或两者兼而有之。一项研究由药物制造商资助。另外两项研究没有具体说明该研究的资金来源。

主要研究结果

本系统综述中的试验表明，几种兴奋剂和非兴奋剂药物可以改善患有ADHD和抽动障碍的儿童的ADHD症状。在高剂量下，右旋安非他明最初可能会加重一些儿童的抽动症状，而右旋安非他明和哌醋甲酯剂量的增加可能会因抽动症状加重而受到限制。然而，对于大多数儿童来说，使用兴奋剂药物可以改善抽动和ADHD的症状。

证据质量

哌醋甲酯、托莫西汀和可乐定的证据质量低，而地昔帕明、右旋安非他明、胍法辛和地普雷尼治疗抽动障碍儿童ADHD的证据质量极低。证据受到试验数量少、受试者数量少和所纳入的研究的偏倚风险的限制。

Authors' conclusions

Implications for practice

Drugs of the stimulant class have generally been thought to provide the most reliable and robust treatment responses for symptoms of ADHD in children with tics. Given the methodological difficulties inherent in comparing effect sizes across studies with divergent inclusion criteria, efficacy measures, and designs, this review can provide no evidence‐based recommendations for choosing between treatment options. Stimulants will likely continue to be considered as first‐line treatment for children with moderate‐to‐severe symptoms of ADHD in children with tic disorders. Although, overall, stimulants have not been shown to worsen tics in most participants with tic disorders, they may still exacerbate tics in individual cases. In these instances, treatment with alpha agonists or atomoxetine could be considered as alternatives. Although there is evidence that desipramine may improve both tics and ADHD in children, safety concerns will likely continue to limit its use.

Implications for research

This study highlights the need for adherence to minimal common standards of study design and efficacy measures of pharmacological treatments of tics and ADHD for different agents to enable subsequent comparison of results. A variety of newer agents appear to improve symptoms of ADHD and therefore are candidates for double‐blind, placebo‐controlled, head‐to‐head trials in children with tic disorders and ADHD. These agents include: lisdexamfetamine, a long‐acting stimulant prodrug (Biederman 2007); the newer antidepressant bupropion, a dual norepinephrine and dopamine reuptake inhibitor (Conners 1996); the novel non‐stimulant, modafinil, an agent with both dopaminergic and postsynaptic alpha‐1 adrenergic effects (Kahbazi 2009); and nicotine, which enhances noradrenergic and dopaminergic transmission (Potter 2004; Shytle 2002).

Larger, confirmatory studies with the existing agents used for treatment of ADHD would be desirable, including studies of guanfacine and clonidine, as well as studies of the established stimulants in the longer‐acting forms that are now more commonly used, and the long‐acting form of guanfacine. Longer‐term evaluation of dextroamphetamine would also be warranted given ongoing concerns over its ability to exacerbate tics in a small number of participants.

The agents used to treat isolated ADHD may improve ADHD symptoms in participants with comorbid tic disorders. This suggests that the pathophysiology of ADHD may be similar in both groups. Each of the agents reviewed in this study has a different mechanism of action or has preferential effects on different receptor subtypes. A more detailed analysis of the interaction between the specific mechanism of action of each agent and its symptomatic effects on ADHD and tics may provide further insights into the underlying pathophysiology of both conditions.

Summary of findings

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Summary of findings for the main comparison. Methylphenidate compared with placebo for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders

Methylphenidate compared with placebo for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders
Patient or population: children with ADHD and comorbid tic disorders Intervention: methylphenidate Comparison: placebo
Outcomes	Effect of treatment	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
ADHD symptom‐related behavior Measured by standardized rating scales: Conners' Abbreviated Teacher Rating Scale, Conners' Abbreviated Parent Rating Scale, IOWA Conners' Teacher Rating Scale, Mothers' Objective Method for Subgrouping, Continuous Performance Task, Conners' Teacher Rating Scale, Conners' Continuous Performance Task	Tourette's Syndrome Study Group 2002 showed a significant treatment effect using the Conners' Abbreviated Teacher Rating Scale (3.3 points, 98.3% CI −0.2 to 6.8; P = 0.02).	229 (3 studies)	⊕⊕⊝⊝ Low^a	–
	Gadow 2007 showed that all doses (0.1 mg/kg, 0.3 mg/kg, 0.5 mg/kg) of methylphenidate were superior to placebo on all rating scales (Conners' Abbreviated Teacher/Parent Rating Scale, IOWA Conners' Teacher Rating Scale, Mothers' Objective Method for Subgrouping, Continuous Performance Test), with a dose‐dependent effect (F = 24.7; P = 0.001)
	Castellanos 1997 showed significantly decreased hyperactivity at all doses (15 mg, 25 mg, 45 mg).
Tic severity Measured by standardized rating scales: Yale Global Tic Severity Scale, Tourette Syndrome Severity Scale, Tourette Syndrome Clinical Global Impression Scale, Global Tic Rating Scale, 2‐Minute Tic and Habit Count, Tic Symptom Self‐Report	Tourette's Syndrome Study Group 2002 found a significant treatment effect using the Yale Global Tic Severity Scale (11.0 points, 98.3% CI 2.1 to 19.8; P = 0.003).	229 (3 studies)	⊕⊕⊝⊝ Low^a	–
	Gadow 2007 found no difference on the Yale Global Tic Severity Scale but found an improvement in tic severity at all doses (0.1 mg/kg, 0.3 mg/kg, 0.5 mg/kg) on the Global Tic Rating Scale completed by teachers (F = 5.33; P = 0.002)
	Castellanos 1997 found no effect of drug on tic severity for second and third cohorts. Tic severity was significantly greater during week 2 in the first cohort (P < 0.01)
ADHD: attention deficit hyperactivity disorder; CI: confidence interval.
GRADE Working Group grades of evidence High quality: we are very confidence that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded two levels due to limitations in study design and implementation, and imprecision of results.

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Summary of findings 2. Clonidine compared with placebo for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders

Clonidine compared with placebo for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders
Patient or population: children with ADHD and comorbid tic disorders Intervention: clonidine Comparison: placebo
Outcomes	Effect of treatment	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
ADHD symptom‐related behavior Measured by standardized rating scales: Conners' Abbreviated Teacher Rating Scale, Conners' Abbreviated Parent Rating Scale, IOWA Conners' Teacher Rating Scale, Conners' Continuous Performance Task, Child Behaviour Checklist, Gordon Diagnostic System, Clinical Evaluation of Language Function, Matching Familial Figures Test, Porteus Maze Test, Restricted Academic Test	Tourette's Syndrome Study Group 2002 found a significant treatment effect using the Conners' Abbreviated Teacher Rating Scale (3.3 points, 98.3% CI −0.2 to 6.8; P = 0.02).	170 (2 studies)	⊕⊕⊝⊝ Low^a	–
	Singer 1995 found no significant difference on any ADHD outcome measures, except the nervous/overactive subscale of the Child Behaviour Checklist (boys aged 6‐11 years).
Tic severity Measured by standardized rating scales: Yale Global Tic Severity Scale, Tourette Syndrome Severity Scale, Global Tic Rating Scale, Tic Symptom Self‐Report, Hopkins Motor/Vocal Scale	Tourette's Syndrome Study Group 2002 showed a significant treatment effect using the Yale Global Tic Severity Scale (10.9 points, 98.3% CI 2.1 to 19.7; P = 0.003).	170 (2 studies)	⊕⊕⊝⊝ Low^a	–
	Singer 1995 found no significant difference on measures of tic severity.
ADHD: attention deficit hyperactivity disorder; CI: confidence interval.
GRADE Working Group grades of evidence High quality: we are very confidence that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded two levels due to limitations in study design and implementation, and imprecision of results.

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Summary of findings 3. Desipramine compared with placebo for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders

Desipramine compared with placebo for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders
Patient or population: children with ADHD and comorbid tic disorders Intervention: desipramine Comparison: placebo
Outcomes	Effect of treatment	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
ADHD symptom‐related behavior Measured by standardized rating scales: Child Behaviour Checklist, Gordon Diagnostic System, Clinical Evaluation of Language Function, Matching Familial Figures Test, Porteus Maze Test, Restricted Academic Test, ADHD Rating Scale IV ‐ Parent Version; ADHD Parent Linear Analogue Scale	Spencer 2002 showed a decrease in scores on the ADHD Rating Scale IV ‐ Parent Version (week 0 = 46 (SD 5.9) points; week 6 = 24 (SD 12) points; P < 0.001).	75 (2 studies)	⊕⊝⊝⊝ Very low^a	–
	Singer 1995 showed that desipramine was superior to placebo on the Parent Linear Analogue Scale for Hyperactivity (desipramine: 32.8 (SD 1.3) points; placebo: 64.4 (SD 0.6) points; P < 0.05). Hyperactivity subscale of the Child Behavior Checklist showed drug effects for males aged 6 to 11 years (desipramine: 68.6 (SD 1.4) points; placebo: 75.8 (SD 1.0) points; P < 0.05).
Tic severity Measured by standardized rating scales: Yale Global Tic Severity Scale, Tourette Syndrome Severity Scale, Hopkins Motor/Vocal Scale; ADHD Parent Linear Analogue Scale	Spencer 2002 showed a decrease in scores on the Yale Global Tic Severity Scale (week 0 = 63 (SD 18) points; week 6: 43 (SD 23) points; P < 0.001).	75 (2 studies)	⊕⊝⊝⊝ Very low^a	–
	Singer 1995 showed that desipramine was superior to placebo on the Parent Linear Analogue Scale of tic severity (desipramine: 30.0 (SD 0.7) points; placebo: 47.4 SD 1.8 points; P < 0.05). There were no differences on the other measures of tic severity (Tourette Syndrome Severity Scale, Hopkins Motor/vocal scale, Yale Global Tic Severity Scale).
ADHD: attention deficit hyperactivity disorder; SD: standard deviation.
GRADE Working Group grades of evidence High quality: we are very confidence that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded two levels due to limitations in study design and implementation, and imprecision of results.

Background

Description of the condition

The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, currently recognizes three chronic tic disorders: Tourette syndrome, chronic motor tic disorder, and chronic vocal tic disorder (APA 2013). Tourette syndrome consists of multiple motor tics and one or more vocal tics that have persisted for longer than one year. In both chronic motor tic disorder and chronic vocal disorder, tics must also persist for longer than one year but the spectrum of tics is limited to either motor or vocal subtypes, respectively. Together these disorders affect just over 2% of children (Knight 2012). They fall within a clinical spectrum, with a presumed shared underlying neurobiology.

Chronic tic disorders are frequently complicated by the presence of comorbid psychiatric disorders, of which attention deficit hyperactivity disorder (ADHD) is one of the most prevalent (Martino 2013). The clinical implications of a comorbid diagnosis of ADHD in children with tic disorders are significant. The risk for aggressive and delinquent behavior, and conduct difficulties in children with tic disorders is posed largely by the presence of ADHD (Cavanna 2009), and the greatest independent predictor of psychosocial quality of life in children with tic disorders is ADHD symptom severity (Pringsheim 2007). In contrast, the presence of a tic disorder has limited impact on ADHD outcomes (Spencer 2001).

Rates of association between tic disorders and ADHD are much higher than would be expected due to chance alone. Kurlan 2002 used direct interviews in a community‐based study of school children to determine the prevalence of tic disorders and any comorbid psychopathology. They included 1596 children aged nine to 17 years from 10 New York state school districts over a four‐year period. In this study, 38% of children with tics had a comorbid diagnosis of ADHD. Clinic‐based studies yield even higher rates of comorbid ADHD. In a review of a multi‐site, international database of 3500 people with tic disorders, Freeman 2000 reported that 60% of children with tic disorders also had ADHD, with a range of 33% to 91% among sites reporting more than 50 cases.

The association between tic disorders and ADHD is a compelling one and a number of investigators have proposed that the disorders share a common pathophysiology, reflecting alterations in noradrenergic and dopaminergic transmission inadequately modulating corticostriatal circuits, and thus failing to inhibit intrusive thoughts, sensory input, and motor responses (Steeves 2008). Neurochemical models based on dopaminergic and noradrenergic dysfunction have likewise guided considerations for their treatment.

Description of the intervention

Medications most commonly used to treat ADHD symptoms include the stimulants methylphenidate and amphetamine, followed by non‐stimulants (such as atomoxetine), tricyclic antidepressants, and alpha agonists (Wilens 2006). Due to the impact of ADHD on the child with a tic disorder, treatment for ADHD symptoms is a greater priority than medical treatment for tics. For many decades, clinicians were reluctant to use stimulants to treat symptoms of ADHD in children with tics for fear of worsening the tics. In the 1970s and early 1980s, several case reports and small case series were published of children who experienced the onset or worsening of tics after the use of stimulants for the treatment of ADHD (Golden 1974; Lowe 1982). Despite new evidence that suggests that this relationship was temporal and not causal (Tourette's Syndrome Study Group 2002), package inserts and advertising for US Food and Drug Administration‐approved stimulants for ADHD continue to include warnings against the use of these medications for children with comorbid tic disorders.

How the intervention might work

There appears to be some commonality in the mechanisms of action of medications used for ADHD that may be related to either direct or indirect modulation of dopamine and norepinephrine neurotransmission. Stimulants block the reuptake of dopamine and norepinephrine into the presynaptic neuron (methylphenidate) or increase the release of these monoamines into the extraneuronal space (amphetamines) (Seiden 1993). Atomoxetine specifically inhibits presynaptic reuptake of norepinephrine, resulting in increased norepinephrine levels in the synapse (Bymaster 2002). The efficacy of tricyclic antidepressants in the treatment of ADHD is likewise thought to be mediated by their action on catecholamine reuptake, particularly on norepinephrine. The alpha‐2 adrenergic agonists appear to alter basal adrenergic tone (Buccafusco 1992). Clonidine stimulates alpha‐2A, ‐2B, and ‐2C receptors, while guanfacine is selective for alpha‐2A receptors. Alpha‐2A and ‐2C receptors are mainly found in the central nervous system, while the alpha‐2B receptors are in vascular smooth muscle. Alpha‐2 agonism inhibits norepinephrine release from the presynaptic neuron, resulting in a reduction of activity in noradrenergic pathways and an attenuation of the sympathetic stress response.

Why it is important to do this review

Given the high frequency of comorbidity of chronic tic disorders and ADHD, the effects of ADHD symptoms on psychosocial quality of life in people with tics, and the concern amongst clinicians about the potential of worsening tics with use of stimulant medications, an up‐to‐date systematic review of pharmacological treatments of ADHD in children with tics is needed. We synthesized the existing evidence for clinicians serving this patient population on the efficacy of these agents for treatment of symptoms of ADHD and their effect on tics. While physicians specializing in this area of practice may already be aware of this literature, children and families affected by ADHD and comorbid tic disorders frequently have concerns about the use of medications and potential worsening of the symptoms of either condition, and often seek advice on these points.

Objectives

To assess the effects of pharmacological treatments for ADHD in children with comorbid tic disorders on symptoms of ADHD and tics.

Methods

Criteria for considering studies for this review

Types of studies

Randomized, double‐blind, controlled trials of any pharmacological treatment for ADHD used specifically in children with comorbid tic disorders. The term double‐blind implies that trial participants, clinicians, and outcome assessors were blinded to treatment allocation. We included both parallel‐group and cross‐over study designs.

Types of participants

Children aged 18 years or younger with a clinical diagnosis of ADHD and a chronic tic disorder (Tourette syndrome, chronic motor tic disorder, or chronic vocal tic disorder). With respect to diagnostic classification systems, acceptable ADHD diagnoses included:

attention‐deficit/hyperactivity disorder (APA 1987; APA 2000; APA 2013);
attention deficit disorder (APA 1980); and
hyperkinetic disorder (WHO 2005).

Types of interventions

Any pharmacological treatment for ADHD (stimulant and non‐stimulant), at any dose, taken orally alone or in combination with another drug, compared to placebo.

Types of outcome measures

Primary outcomes

ADHD and tic symptom severity measured by validated clinician, teacher, or parent report scales. Specifically, we evaluated:
- ADHD symptom‐related behavior in the home setting assessed with, for example, Conners Abbreviated Symptom Questionnaire (ASQ) for Parents (Conners 1990), or ADHD Rating Scale (DuPaul 2016);
- ADHD symptom‐related behavior in the school setting assessed with, for example, Conners ASQ for Teachers (Conners 1990); and
- tic severity assessed with, for example, Yale Global Tic Severity Scale (TGTSS) (Leckman 1989), Tic Symptom Self‐Report Scale (Leckman 1998), or the Tourette Syndrome Severity Scale (Shapiro 1988).

Secondary outcomes

Adverse effects, including:
- cardiovascular effects such as changes in heart rate, blood pressure, or the electrocardiogram; and
- weight changes.

Search methods for identification of studies

We ran searches for this update in June 2016 and again on 20 September 2017. Search strategies for each database are reported in Appendix 1. Search strategies from the previous version of this review are in Appendix 2.

Electronic searches

For this update, we searched the electronic databases and trial registers listed below. Some new databases have been added since the previous review and others were no longer available to us. These changes are reported in Differences between protocol and review.

Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 8), in the Cochrane Library, and which includes the Cochrane Developmental, Psychosocial and Learning Problem Specialised Register (searched 20 September 2017).
MEDLINE Ovid (1946 to September week 1 2017).
MEDLINE In‐Process and Other Non‐Indexed Citations Ovid (searched 20 September 2017).
MEDLINE E‐pub Ahead of Print Ovid (searched 20 September 2017).
Embase Ovid (1974 to 19 September 2017).
CINAHL EBSCO (Cumulative Index to Nursing and Allied Health Literature; 1937 to 20 September 2017).
PsycINFO Ovid (1806 to September week 2 2017).
Science Citation Index ‐ Expanded Web of Science (SCI; 1970 to 19 September 2017).
Social Sciences Citation Index Web of Science (SSCI; 1970 to 19 September 2017).
Conference Proceedings Citation Index ‐ Science Web of Science (1990 to 19 September 2017).
Conference Proceedings Citation Index ‐ Social Science and Humanities Web of Science (1990 to 19 September 2017).
Cochrane Database of Systemic Reviews (CDSR; 2017, Issue 9) part of the Cochrane Library (searched 20 September 2017).
Database of Abstracts and Reviews of Effects (DARE; 2015, Issue 2. Final Issue) part of the Cochrane Library (searched 6 July 2016).
Epistemonikos (www.epistemonikos.org; searched 20 September 2017).
WorldCat (www.worldcat.org; searched 20 September 2017).
ClinicalTrials.gov (clinicaltrials.gov; searched 20 September 2017).
World Health Organization International Clinical Trials Registry Platform (WHO ICTRP; www.who.int/ictrp/en; searched 20 September 2017).

Searching other resources

We contacted the Tourette Syndrome Study Group (based in North America) and other experts in the field, including investigators from all review articles and primary studies identified through searches for this review, to determine if there were any ongoing trials or unpublished results in this area.

Data collection and analysis

Selection of studies

Two review authors (TP and TS) independently assessed titles and abstracts of references retrieved from the searches and selected all potentially relevant studies. Next, they retrieved copies of these articles, which they read in detail and assessed for eligibility (Criteria for considering studies for this review). We resolved any disputes regarding the fulfilment of inclusion criteria by discussion. Review authors were not blinded to the names of the trial authors, institutions, or journals of publication.

We recorded our decisions in a study flow diagram (Moher 2009).

Data extraction and management

Two review authors (TP and TS) independently extracted the following data from each included study and entered it into predesigned summary forms.

Study procedures, including recruitment, diagnosis, medication, dosage, duration, and clinical setting.
Study design (i.e. randomized or quasi‐randomized).
Randomization method.
Method of allocation concealment.
Method of blinding.
Inclusion and exclusion criteria for participants.
Number of participants (total/per group).
Age distribution.
Gender.
Loss of follow‐up.
Premature discontinuation of study, and reasons for discontinuation.
Outcome.
Method of analysis (intention‐to‐treat, per protocol).
Comparability of groups at baseline.

They then compared the extracted data to ensure accuracy. Next, one review author (TP) entered the data into Review Manager 5 (RevMan 5) (Review Manager 2014), and a second review author (TS) checked them. We resolved discrepancies by consensus. As no further studies were included following the July 2016 search, this process was not repeated.

Assessment of risk of bias in included studies

Two review authors (TP and TS) independently assessed the risk of bias in the included studies for each of the seven domains in Appendix 3, and assigned ratings of low risk of bias, high risk of bias, and unclear risk of bias (Higgins 2017). We resolved any discrepancies by consensus.

Measures of treatment effect

Due to significant clinical heterogeneity (differences between studies in the interventions used and how they were administered, and differences in outcomes measured), and incomplete reporting of the results from cross‐over trials, we were unable to conduct a meta‐analysis of study data. We attempted to obtain additional information from authors, but, due to the length of time since many of the trials were performed, this information was either not available or our queries went unanswered. Thus, we have presented the results for studies individually. We recorded the methods that were not pertinent to this version of the review in Appendix 4, for use in an update. See our protocol (Pringsheim 2009).

Unit of analysis issues

Unit‐of‐analysis issues occurred in this review as none of the included cross‐over studies presented paired data for analysis but rather provided the means and standard deviations (SD) for each treatment type. See Appendix 4 and Pringsheim 2009.

Dealing with missing data

We attempted to obtain missing information directly from study authors; however, this did not yield the missing information. We contacted Castellanos regarding additional results from his trial (Castellanos 1997), but, due to the long period which had elapsed since his study was performed, the information was no longer accessible. We also contacted the authors of Tourette's Syndrome Study Group 2002 and Feigin 1996 requesting more information on results but received no replies to our letters. See Appendix 4 and Pringsheim 2009.

Assessment of heterogeneity

We assessed clinical heterogeneity by comparing the distribution of important participant factors between trials and methodological heterogeneity by comparing trial designs. See also Appendix 4 and Pringsheim 2009.

Assessment of reporting biases

As there was an insufficient number of studies found for each treatment type, we did not create funnel plots to assess publication bias. See Appendix 4 and Pringsheim 2009.

Data synthesis

We did not synthesize results in a meta‐analysis by treatment type because of important clinical heterogeneity and unit‐of‐analysis issues (see the Results section for descriptions of the nature of the heterogeneity encountered). Thus, we have presented the data for each study individually. See Appendix 4 and Pringsheim 2009.

'Summary of findings' table

We created 'Summary of findings' tables using Review Manager 2014, which report the effect estimate for our primary outcomes (ADHD and tic symptom severity) measured at study endpoint, the number of participants, and our ratings for the quality of the evidence. Two review authors (TP and SO) used the GRADE method to assess the quality of the body of evidence for each outcome. While randomized trials are considered high‐quality evidence, we downgraded the level of evidence to moderate or low for all outcomes due to the presence of limitations in the design of available studies, and the overall small number of studies and participants included in studies in this area. This means it is likely that further research could have an important impact on our confidence in the estimate of the effect and may change the estimate.

Subgroup analysis and investigation of heterogeneity

We did not perform a subgroup analysis. See Appendix 4 and Pringsheim 2009.

Sensitivity analysis

We did not perform a sensitivity analysis due to the small number of trials and the inability to conduct a meta‐analysis. See Appendix 4 and Pringsheim 2009.

Results

Description of studies

Results of the search

In the original review, we found 599 citations, of which 21 qualified for further review. Of these, eight met our inclusion criteria (Criteria for considering studies for this review). Of the remaining 13, eight were republications of data already presented in the eight studies included in the review and were listed as secondary publications. The remaining five studies were excluded with reasons (see Excluded studies).

For this update, our search yielded 508 records, once duplicates were removed. We excluded 507 records at title and abstract stage, and retrieved one full‐text report for further inspection. This was subsequently excluded due to lack of double‐blinding (see Excluded studies).

The study review process is summarized in a PRISMA flow diagram (Figure 1).

Figure 1

Study flow diagram illustrating the process for inclusion of studies.

Included studies

See Characteristics of included studies tables.

Study designs

We included eight randomized controlled trials (RCTs) of pharmacological treatments for ADHD in children with comorbid tic disorders (Allen 2005; Castellanos 1997; Feigin 1996; Gadow 2007; Scahill 2001; Singer 1995; Spencer 2002; Tourette's Syndrome Study Group 2002), four of which were cross‐over trials (Castellanos 1997; Feigin 1996; Gadow 2007; Singer 1995).

Location

All studies took place in the USA (Allen 2005; Castellanos 1997; Feigin 1996; Gadow 2007; Scahill 2001; Singer 1995; Spencer 2002; Tourette's Syndrome Study Group 2002).

Participants

The studies included 510 children (443 boys, 67 girls) with diagnoses of ADHD and Tourette syndrome or chronic motor or vocal tic disorder. Sample sizes ranged from 22 in Castellanos 1997 to 148 in Allen 2005.

Interventions

Three trials assessed multiple agents (Castellanos 1997; Singer 1995; Tourette's Syndrome Study Group 2002), and ranged in duration from three (Castellanos 1997) to 22 weeks (Singer 1995).

Castellanos 1997 was a complex placebo‐controlled, cross‐over study, which randomized 22 children into three cohorts, each sequentially receiving for three weeks either placebo or one of three different dosage titrations of methylphenidate (low: 15 mg, medium: 25 mg, high: 45 mg), and one of three different dosage titrations of dextroamphetamine (low: 7.5 mg, medium: 15 mg, high: 22.5 mg).
Singer 1995 was a placebo‐controlled, three‐phase cross‐over study in 34 children, of clonidine, desipramine, and placebo. Each treatment was taken four times daily for six weeks, separated by a one‐week washout period.
Tourette's Syndrome Study Group 2002 was a parallel‐group trial, which randomized 136 children to a flexible dose of methylphenidate (37 children), clonidine (34 children), clonidine plus methylphenidate (33 children), or placebo (32 children) for 16 weeks each (see Table 1).

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Table 1. Comparisons

Comparisons	Trial(s)
Methylphenidate versus placebo	Castellanos 1997 Gadow 2007 Tourette's Syndrome Study Group 2002
Clonidine versus placebo	Singer 1995 Tourette's Syndrome Study Group 2002
Methylphenidate plus clonidine versus placebo	Tourette's Syndrome Study Group 2002
Dextroamphetamine versus placebo	Castellanos 1997
Guanfacine versus placebo	Scahill 2001
Atomoxetine versus placebo	Allen 2005
Desipramine versus placebo	Singer 1995 Spencer 2002
Deprenyl versus placebo	Feigin 1996
Desipramine versus clonidine	Singer 1995

The remaining five trials assessed single agents.

Allen 2005 assessed atomoxetine 0.5 mg/kg per day to 1.5 mg/kg per day (76 children), a highly selective, non‐stimulant noradrenergic reuptake inhibitor, versus placebo (72 children) in a parallel‐group trial of 18 weeks' duration with 148 children (131 boys, 17 girls). Participants considered to be clinical non‐responders at week 12 of the study were allowed to withdraw early from the double‐blind study and enter an open‐label study of the drug.
Feigin 1996 assessed the effects of deprenyl, a type B monoamine oxidase inhibitor, compared to placebo in 24 children (21 boys, 3 girls). Children were randomized to treatment with deprenyl 5 mg or matching placebo, given twice daily, for eight weeks and then crossed over to the alternate treatment after a six‐week washout period.
Gadow 2007 assessed methylphenidate in a single agent, cross‐over trial with placebo in which 71 children (57 boys, 14 girls) were randomized to three sequential doses of methylphenidate (0.1 mg/kg, 0.3 mg/kg, and 0.5 mg/kg), given twice daily, seven days a week for two weeks each.
Scahill 2001 assessed guanfacine 1.5 mg to 3 mg per day (an alpha‐2 receptor agonist), divided into three daily doses, versus placebo in a parallel‐group trial of eight weeks' duration. The study randomized 34 children (31 boys, 3 girls) to guanfacine or placebo.
Spencer 2002 compared desipramine versus placebo in 41 children (34 boys, 7 girls) in a parallel‐group trial in which desipramine was titrated weekly up to 3.5 mg/kg per day and given twice daily for six weeks.

Outcome measures

All trials included both ADHD and tic outcomes. Most trials did not specify a primary outcome. The scales chosen to measure ADHD severity varied considerably between studies (Table 2). All studies used the YGTSS for one measure of tic severity. Table 3 lists other measures of tic severity that the studies used. A description of each scales' items and scoring is included in Table 4.

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Table 2. Attention deficit hyperactivity disorder symptom severity scales used in this review

Scale/measure	Allen 2005	Castellanos 1997	Feigin 1996	Gadow 2007	Scahill 2001	Singer 1995	Spencer 2002	Tourette's Syndrome Study Group 2002
Conners Abbreviated Teacher Rating Scale	–	–	–	Yes	–	–	–	Yes
Conners Abbreviated Parent Rating Scale	–	–	–	Yes	–	–	–	Yes
IOWA Conners Teacher Rating Scale	–	–	–	Yes	–	–	–	Yes
Mothers' Objective Method for Subgrouping	–	–	–	Yes	–	–	–	–
Continuous Performance Task	–	–	–	Yes	Yes	–	–	–
ADHD Rating Scale‐IV: Parent Version	Yes	–	–	–	Yes	–	Yes	–
Clinical Global Impression Scale – Overall – Severity	Yes	–	–	–	Yes	–	–	–
Clinical Global Impression Scale – ADHD/Psychiatric Symptoms	Yes	–	–	–	–	–	–	–
ADHD Teacher 39‐Item Conners Rating Scale	–	Yes	–	–	–	–	–	–
DuPaul ADHD Scale	–	–	Yes	–	–	–	–	–
Parent Conners Questionnaire Hyperactivity Index	–	–	–	–	Yes	–	–	–
Child Behaviour Checklist	–	–	–	–	–	Yes	–	–
Gordon Diagnostic System	–	–	–	–	–	Yes	–	–
Clinical Evaluation of Language Function	–	–	–	–	–	Yes	–	–
Matching Familial Figures Test	–	–	–	–	–	Yes	–	–
Porteus Maze Test	–	–	–	–	–	Yes	–	–
Restricted Academic Test	–	–	–	–	–	Yes	–	–
Conners Continuous Performance Task	–	–	–	–	–	–	–	Yes

ADHD: attention deficit hyperactivity disorder; IOWA: inattention/overactivity with aggression.

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Table 3. Tic severity symptom scales used in this review

Scale/measure	Allen 2005	Castellanos 1997	Feigin 1996	Gadow 2007	Scahill 2001	Singer 1995	Spencer 2002	Tourette's Syndrome Study Group 2002
Yale Global Tic Severity Scale	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Tourette Syndrome Severity Scale	–	–	–	Yes	–	Yes	–	–
Tourette Syndrome Clinical Global Improvement	Yes	–	–	Yes	–	–	–	–
Global Tic Rating Scale	–	–	–	Yes	–	–	–	Yes
2‐Minute Tic and Habit Count	–	–	–	Yes	–	–	–	–
Tic Symptom Self‐Report	Yes	–	–	–	–	–	–	Yes
Goetz Tic Severity Scale	–	–	Yes	–	–	–	–	–
Hopkins Motor/Vocal Scale	–	–	–	–	–	Yes	–	–

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Table 4. Description of scales used in included studies

Scale/measure	Number of items	Scoring
Conners' Abbreviated Symptoms Questionnaire for Teachers (ASQ)	10 items pertaining to the child's behavior	Rated on a 4‐point Likert scale, ranging from 0 (not at all), 1 (just a little), 2 (pretty much) to 3 (very much true), with a possible total score ranging from 0 to 30. Higher scores indicate worse symptoms
Yale Global Tic Severity Scale (YGTSS)	5 items on the number, frequency, intensity, complexity, and interference from motor tics, and 5 items on the number, frequency, intensity, complexity, and interference from vocal tics, and 1 item on overall impairment	The Total Motor Tic Score is derived by adding the 5 motor tics items (each item ranges from 0 to 5, total motor tic score ranges from 0 to 25). The Total Vocal Tic Score is derived by adding the 5 phonic tics items (each item ranges from 0 to 5, total vocal tic ranges from 0 to 25). The Total Tic Score is a summation of the Total Motor Tic and Total Vocal Tic Scores. The Overall Impairment Rating is rated on a 51‐point scale anchored by 0 (no impairment) and 50 (severe impairment). Finally, the Global Severity Score is a summation of the Total Motor Tic Score, Total Vocal Tic Score, and Overall Impairment Rating (range 0 to 100). Higher scores indicate worse symptoms.
Global Tic Rating Scale	9 items, with the first 5 referring to the frequency of motor (3 items) and phonic tics (2 items) according to body region, which are summed to produce motor and phonic tic frequency subscores, respectively	All items are rated on a scale from 0 (never) to 3 (very much). Total score ranges from 0 to 27. Higher scores indicate worse symptoms
ADHD Rating Scale IV ‐ Parent Version	18‐item questionnaire. 9 questions each on inattention and hyperactivity‐impulsivity, where the odd‐numbered items represent the inattention subscale, and the even‐numbered items represent the hyperactive/impulsive subscale	Items coded on 4‐point Likert scale using scores 1 (never or rarely), 2 (sometimes), 3 (often), or 4 (very often). Total score ranges from 18 to 52. Raw scores are converted to percentiles.
ADHD Parent Linear Analogue Scale	10‐cm line on which both the parent and physician separately rank symptoms	The ends of each line represent 0 (no symptoms) and 10 (most severe)
Child Behaviour Checklist (CBCL)	113 items across 8 subscales assessing maladaptive behavioral and emotional problems: withdrawn somatic complaints anxious/depressed social problems thought problems attention problems delinquent problems aggressive behavior	Items are coded from 0 to 2, scored 0 (not at all), 1 (somewhat true), or 2 (very true). CBCL profile for each category, with scores below the 95th percentile in the normal range, and above the 98th percentile in the clinical range. Higher scores indicate worse symptoms.
Conners' Abbreviated Parent Rating Scale	48 items across 6 subscales: conduct problems learning problems psychosomatic impulsive/hyperactive anxiety hyperactivity index	All items are rated on a scale from 0 (never) to 3 (very much). Total score ranges from 0 to 144. Higher scores indicate worse symptoms
IOWA Conners' Teacher Rating Scale	10 items. Consists of 5‐item subscales designed to assess inattention/overactivity and aggression Inattention/overactivity: fidgeting hums and makes other odd noises excitable, impulsive inattentive, easily distracted fails to finish things he starts (short attention span) Aggression: quarrelsome acts "smart," temper outbursts (explosive and unpredictable behavior) defiant unco‐operative	Scored 0 (not at all), 1 (just a little), 2 (pretty much), or 3 (very much). Total score ranges from 0 to 30. Higher scores indicate worse symptoms
Mothers' Objective Method for Subgrouping	Contains 10 (hyperactivity or ADHD, or both) symptoms arranged in a checklist format. Generates a hyperactivity scale score and an aggression scale score	1 indicates checked and 0 unchecked. Total score ranges from 0 to 10. Higher scores indicate worse symptoms
Continuous Performance Task (CPT)	Computer‐administered and scored measure of sustained visual attention and motor response inhibition. The test takes about 15 minutes to administer and yields measures of omissions, commissions, and reaction time.	Omission errors measure inattention, commission errors measure impulsivity
Conners' Teacher Rating Scale	39 items clustered into 5 factors, including conduct problems, daydreaming, inattention, anxious‐fearful, and hyperactive behavior ADHD Teacher 39‐Item	All items are rated on a scale from 0 (never) to 3 (very much). Total score ranges from 0 to 137. Raw scores for each scale are converted to T scores, incorporating normative adjustments for age and sex, with scores of at least 70 considered clinically elevated
Conners' Continuous Performance Task (CPT)	Visual‐motor task. Respondents must rapidly and accurately hit the space bar after every letter presented except the letter 'X'. Several variables may be derived from the Conners' CPT, including errors of omission and commission, mean hit reaction time (RT), mean hit RT standard error.	Omission errors measure inattention, commission errors measure impulsivity
Tourette Syndrome Severity Scale	5‐item scale Are the tics noticeable to others? Do the tics elicit comments? Is the patient considered odd or bizarre? Do the tics interfere with functioning? Is the patient incapacitated, homebound, or hospitalized?	Higher scores indicates worse symptoms
Tourette Syndrome Clinical Global Impression (CGI) Scale	Observer‐rated scale that measures illness severity (CGI‐S), or global improvement (CGI‐I)	7‐point scale, with the severity of illness scale (CGI‐S) using a range of responses from 1 (normal) to 7 (among the most severely ill people). CGI‐I scores range from 1 (very much improved) to 7 (very much worse)
2‐Minute Tic and Habit Count	The physician counts separately the number of brief, jerky (i.e. tics) and rhythmic (i.e. stereotypic, habit) movements and vocalizations during quiet conversation in an office setting.	Higher scores indicates worse symptoms
Tic Symptom Self‐Report	40‐item checklist containing 20 motor tic items and 20 phonic tic items	0–3 scale corresponding with absent (score of 0) to very frequent and forceful (score of 3). Total score ranges from 0 to 120. Higher scores indicate worse symptoms
Goetz Tic Severity Scale	Videotape protocol involving a 10‐minute film of people placed in front of a video camera in a quiet room. 2 body views are recorded, full frontal body (far) and head and shoulders only (near), under 2 conditions: relaxed with the examiner in the room, and relaxed with the patient alone in the room 5 domains are rated: number of body areas involved with tics motor tic intensity phonic tic intensity frequency of motor tics frequency of phonic tics	0–4 scoring format. For all domains, 0 represents normal function without evidence of tic disability. Higher scores indicate worse symptoms
Hopkins Motor/Vocal Scale	Consists of a series of linear analog scales (10 cm) on which both the parent and physician separately rank each tic (motor and vocal) symptom, taking into consideration its frequency, intensity, degree of interference, and impairment	The ends of each line represent 0 (no tics) and 10 (most severe). The line can be subdivided roughly into 4 ranges: mild, moderate, moderately severe, and severe
Du Paul ADHD Rating Scale	14 items, assessing separate factors of inattention and hyperactivity‐impulsivity	Rated on a 0 (normal) to 3 (severe) scale, yielding a total score ranging from 0 to 42. Higher scores indicate worse symptoms
Parent Conners' Questionnaire Hyperactivity Index	10‐item rating scale identifying hyperactive children	Each item is rated from 0 to 3 (range 0–30). Higher scores indicate worse symptoms

ADHD: attention deficit hyperactivity disorder.

Excluded studies

We excluded six studies from this review. See Characteristics of excluded studies tables.

In the original review, we excluded five studies (Howson 2004; Law 1999; Niederhofer 2003; Nolan 1999; Sallee 1994). We excluded:

one study of iofexidine in children with tic disorders and ADHD, as the manuscript was retracted from the journal due to plagiarism and possible fraudulent results (Niederhofer 2003);
one study of methylphenidate in children with ADHD, which excluded children with severe motor or vocal tics and Tourette syndrome from the study and did not report the effects of methylphenidate on ADHD symptoms (Law 1999);
one study that looked at the effects of stimulant withdrawal on tics in children with ADHD (Nolan 1999), and therefore did not meet the inclusion criteria (Criteria for considering studies for this review);
two studies that assessed the effects of pharmacological treatments on cognition and attention but not the primary outcomes of ADHD or tic severity (Howson 2004; Sallee 1994).

In this update, we excluded one study because it did not utilize a double‐blind protocol (Lyon 2010).

Risk of bias in included studies

See also 'Risk of bias' tables, in the Characteristics of included studies tables, and Figure 2.

Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Allocation

We judged sequence generation to be at low risk of bias for three studies (Feigin 1996; Spencer 2002; Tourette's Syndrome Study Group 2002). The remaining five studies did not describe sequence generation and we judged these studies at unclear risk of bias on this domain.

Five studies adequately described allocation concealment (Allen 2005; Gadow 2007; Singer 1995; Spencer 2002; Tourette's Syndrome Study Group 2002). The remaining three studies inadequately described allocation concealment, preventing us from making a judgement on whether or not it was adequate.

Blinding

Blinding of participants, clinicians, and outcome assessors were evaluated separately and was a requirement for inclusion. Therefore, all included studies were at low risk of performance and detection bias.

Incomplete outcome data

Three of the eight studies did not adequately addressed incomplete outcome data. Feigin 1996 had a very high dropout of study participants after the first period of the study, especially in the treatment group, and it was unclear if data from participants who dropped out of the study were included in the analysis. Gadow 2007 did not explain how they handled incomplete data sets in the analysis. Castellanos 1997 provided few raw data from study results; the reported only F scores and P values for analysis of variance tests. In addition, all of the above studies, which were cross‐over studies, did not provide paired data for analysis. Rather, each study provided only means and SDs for each treatment type and, with the exception of Castellanos 1997, did not provide original data. The remaining five studies adequately addressed incomplete outcome data.

Selective reporting

Singer 1995 did not provide outcome data for many variables described as collected in the Methods section, only presenting data for those scales showing significant changes. Also, they often reported 'male only' results. Consequently, we judged this study at high risk of reporting bias. Castellanos 1997 was at high risk of bias as very few data were presented on the results of the analysis. We judged the remaining five studies at low risk of reporting bias.

Other potential sources of bias

Allen 2005 had a high rate of early treatment termination at 12 weeks in both treatment groups and thus was at high risk of other bias. None of the other studies appeared to have other potential sources of bias and thus were at low risk of other bias.

Effects of interventions

See: Summary of findings for the main comparison Methylphenidate compared with placebo for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders; Summary of findings 2 Clonidine compared with placebo for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders; Summary of findings 3 Desipramine compared with placebo for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders

All treatments, with the exception of deprenyl, were efficacious in treating the symptoms of ADHD. Tic symptoms improved in children treated with methylphenidate, clonidine, methylphenidate plus clonidine, guanfacine and desipramine (see summary of findings Table for the main comparison; summary of findings Table 2; summary of findings Table 3). Fear of worsening tics limited dose increases of methylphenidate in one study (Tourette's Syndrome Study Group 2002). High‐dose dextroamphetamine appeared to worsen tics in one study (Castellanos 1997), although the length of this study was only three weeks.

Primary outcomes: attention deficit hyperactivity disorder and tic symptom severity

Methylphenidate

The Tourette's Syndrome Study Group 2002 parallel‐group study randomized children to: clonidine, flexible dose of methylphenidate, clonidine plus methylphenidate, or placebo, for 16 weeks each. The primary outcome was the change from baseline to week 16 in the ADHD Conners ASQ for Teachers; the main secondary outcome was the change from baseline in the YGTSS. On the ASQ, there was a statistically significant treatment effect in comparison to placebo with methylphenidate alone (3.3 points, 98.3% confidence interval (CI) −0.2 to 6.8; P = 0.02, reported in study) and with clonidine plus methylphenidate (6.3 points, 98.3% CI 2.8 to 9.8; P < 0.001). YGTSS scores also improved compared to placebo, with a statistically significant treatment effect observed for methylphenidate alone (11.0 points, 98.3% CI 2.1 to 19.8; P = 0.003), and for methylphenidate plus clonidine (11.0 points, 98.3% CI 2.1 to 19.8; P = 0.003).

The lowest rate of reported adverse effects occurred in the methylphenidate‐only group: 20% of participants treated with methylphenidate reported a worsening of tics as an adverse event compared to 22% receiving placebo (and 26% treated with clonidine alone). Paradoxically, however, tics limited further dosage increases more often for participants assigned to methylphenidate alone (35%) than for participants assigned to methylphenidate plus clonidine (15%), clonidine alone (18%), or placebo (19%).

In the Gadow 2007 cross‐over trial, which randomized children to three different doses of methylphenidate and placebo for two weeks each, the primary outcome was the YGTSS score. Regarding ADHD symptoms, all three doses of methylphenidate were superior to placebo on all rating scales used, including the ASQ. There was a dose‐dependent effect, with methylphenidate 0.5 mg/kg showing superiority to the lower doses of methylphenidate on the ASQ. Mean scores on the ASQ were: 11.6 (SD 6.9) points during placebo treatment; 8.0 (SD 6.0) points with methylphenidate 0.1 mg/kg; 7.3 (SD 5.8) points with methylphenidate 0.3 mg/kg; and 5.7 (SD 5.1) points with methylphenidate 0.5 mg/kg (F = 24.7; P < 0.001).

On the YGTSS, there was no difference in tic severity between treatments with respect to mean total motor, total phonic, impairment, or global severity scores. The teacher ratings on the Global Tic Rating Scale, however, indicated an improvement in tic severity with methylphenidate treatment compared to placebo with all doses (F ratio 5.33; P = 0.002); although one measure, the two‐minute tic/habit count, found an increase in simple motor tics during treatment with methylphenidate 0.3 mg/kg and methylphenidate 0.5 mg/kg compared to placebo (F = 3.96; P = 0.009).

In the Castellanos 1997 cross‐over trial in which children were randomized to three weeks each of methylphenidate, dextroamphetamine, and placebo, methylphenidate significantly decreased hyperactivity at all doses. In the first cohort of 10 participants, analysis of variance of total tic severity showed that tic severity was significantly greater during the second week of methylphenidate treatment (P < 0.01) than during any of the placebo weeks, or during the third week of methylphenidate treatment. In the second and third cohorts of participants, there was no significant main effect of drug on tic severity.

A meta‐analysis of studies evaluating methylphenidate was not possible for several reasons. First, the cross‐over trial by Gadow 2007 presented data as means and SDs for each methylphenidate dosage and placebo, rather than providing a paired analysis. Meta‐analysis of these data, therefore, runs the risk of a unit‐of‐analysis error. Second, the manuscript for Castellanos 1997 only provided F scores from the analysis of variance of tic severity as it related to drug and dosage. No other raw data were provided and, on contacting the study author, these data were no longer available.

Dextroamphetamine

Castellanos 1997 was a placebo‐controlled, cross‐over study of dextroamphetamine, which randomized 20 children into three cohorts. Each child received one of three different dosage titrations of dextroamphetamine to a target dosage of 7.5 mg, 15 mg, or 22.5 mg, twice daily for three weeks. In all cohorts, dextroamphetamine significantly decreased hyperactivity, measured by teachers using the Conners 39‐item Teacher Rating Scale, but there was no significant interaction between drug and dose, indicating that additional improvements in hyperactivity were not observed for higher doses.

In the first cohort of 10 participants, tic severity was significantly greater during the second (15 mg twice daily) and third (22.5 mg twice daily) weeks of dextroamphetamine treatment compared to the weeks on placebo (F = 3.50, 98.3% CI 4 to 36; P = 0.03, reported in study). In the second cohort of six participants, there was no significant main effect of the drug on tic severity. In the third cohort of four participants, there was a trend for tic severity to be greater with dextroamphetamine, but this did not reach statistical significance.

Clonidine

In the Tourette's Syndrome Study Group 2002, in comparison to placebo, there was a statistically significant treatment effect on the ASQ with clonidine alone (3.3 points, 98.3% CI –0.2 to 6.8; P = 0.02), and with clonidine plus methylphenidate (6.3 points, 98.3% CI 2.8 to 9.8; P < 0.0001). YGTSS scores also improved compared to placebo, with a statistically significant treatment effect observed for clonidine alone (10.9 points, 98.3% CI 2.1 to 19.7; P = 0.003), and for clonidine plus methylphenidate (11.0 points, 98.3% CI 2.1 to 19.8; P = 0.003).

Singer 1995 was a three‐arm cross‐over study comparing clonidine 0.05 mg, given four times daily, to placebo and desipramine 25 mg given four times daily. The authors did not define a primary outcome and presented data for only those scales showing significant changes. In this study, clonidine did not show a significant difference compared to either placebo or desipramine on any of the outcome measures of ADHD and tic severity, with the exception of the nervous/overactive subscale of the Child Behavior Checklist in a subgroup of boys aged six to 11 years, in which clonidine was superior to placebo.

We were unable to perform a meta‐analysis of the two studies evaluating clonidine for two reasons. The Tourette's Syndrome Study Group 2002 trial presented data as means and SDs for each treatment type rather than in a paired analysis, creating a risk for a unit‐of‐analysis error. The studies also had significant clinical heterogeneity: duration of treatment of six weeks in Singer 1995 versus 16 weeks for Tourette's Syndrome Study Group 2002. As clinical response times for clonidine can take several months, a difference of 10 weeks of treatment time between studies is likely to be clinically significant.

Guanfacine

Scahill 2001 was an eight‐week, parallel‐group trial of guanfacine versus placebo in 34 children; there was no primary outcome defined. After eight weeks of treatment, guanfacine significantly reduced symptoms of ADHD and tics measured by the ADHD Rating Scale Total Score completed by the teacher (guanfacine: 37.2 (SD 8.4) points at baseline, 23.6 (SD 13.6) points at endpoint; placebo: 34.4 (SD 9.3) points at baseline, 31.7 (SD 11.2) points at endpoint (t = 2.80, df = 32; P < 0.01)), and the YGTSS total tic score (guanfacine: 15.2 (SD 6.6) points at baseline, 10.7 (SD 7.0) points at endpoint; placebo: 15.4 (SD 7.0) points at baseline, 15.4 (SD 5.5) points at endpoint (t = 2.02, df = 30; P = 0.05)).

Atomoxetine

In Allen 2005, a parallel‐group study of atomoxetine in 148 children (0.5 mg/kg/day to 1.5 mg/kg/day), the primary stated objective was to test the hypothesis that atomoxetine does not worsen tics in participants with ADHD and a comorbid tic disorder (i.e. is non‐inferior relative to placebo). The primary efficacy measure was the YGTSS total tic score and secondary assessment measures included the ADHD Rating Scale total score, parent version. With respect to measures of ADHD severity, children in the atomoxetine group had a mean decrease of 10.9 (SD 10.9) points on the ADHD Rating Scale total score compared to a decrease of 4.9 (SD 10.3) points in the placebo group (P = 0.002).

On the primary outcome measure, tic severity measured using the YGTSS, atomoxetine was non‐inferior relative to placebo after 18 weeks of treatment. The lower limit of the one‐sided CI for the difference in mean change between the two treatment groups (placebo and atomoxetine) was 0.27, which, being greater than the prespecified lower limit of –3.7, indicated non‐inferiority. The atomoxetine group showed a greater mean improvement in the YGTSS at the endpoint (–5.5 (SD 6.9) points) compared to placebo (–3.0 (SD 8.7) points), but this difference was not statistically significant (P = 0.06).

Desipramine

Two studies evaluated desipramine in children with ADHD and a chronic tic disorder: the Spencer 2002 parallel‐group study of 41 children, comparing placebo to desipramine titrated weekly up to 3.5 mg/kg/day for six weeks, and the Singer 1995 cross‐over study comparing desipramine to both placebo and clonidine.

Spencer 2002 did not specify a primary outcome, although they assessed ADHD severity using the ADHD rating scale and tic severity with the YGTSS. At week six, compared to baseline, both ADHD symptoms and tic severity significantly improved in children treated with desipramine whereas they did not in children treated with placebo. The ADHD rating scale score decreased from 46 (SD 5.9) points at week zero to 24 (SD 12) points at week six (P < 0.001), and the YGTSS score decreased from 63 (SD 18) points at week zero to 43 (SD 23) points at week six (P < 0.001). There were no changes in measures of anxiety, obsessive‐compulsive behaviors, or depression between desipramine and placebo.

In the study by Singer 1995, with respect to ADHD symptoms, desipramine was superior to placebo (and clonidine) in the Parent Linear Analogue Scale for Hyperactivity (P < 0.05), with a mean score of 32.8 (SD 1.3) points during desipramine treatment compared to 64.4 (SD 0.6) points during placebo treatment (and 51.6 (SD 2.2) during clonidine treatment). The hyperactivity subscale of the Child Behavior Checklist demonstrated a statistically significant drug effect only for boys aged six to 11 years for desipramine compared to both clonidine and placebo treatment (P < 0.05). Hyperactivity subscale scores were 68.6 (SD 1.4) points during desipramine treatment compared to 75.8 (SD 1.0) points during placebo treatment (and 70.7 (SD 1.2) points during clonidine treatment).

With respect to effect on tic severity, desipramine was superior to both placebo and clonidine (P < 0.05) on the Parent Linear Analogue Scale. Mean scores were 30.0 (SD 0.7) points during desipramine treatment compared to 47.4 (SD 1.8) points during placebo treatment (and 41.4 (SD 1.1) points during clonidine treatment). Other measures of tic severity, including the Tourette Syndrome Severity Scale and the YGTSS, did not demonstrate significant differences between treatment groups.

Singer 1995 was a cross‐over trial that presented data as means and SDs for each treatment type, rather than in a paired analysis. We were unable to perform a meta‐analysis of Singer 1995 and Spencer 2002 because of the risk of a unit‐of‐analysis error.

Deprenyl

In the Feigin 1996 cross‐over trial of deprenyl versus placebo, the primary outcome measure for ADHD was the total score on the DuPaul ADHD Scale, and the primary outcome measure for tics was the total score on the YGTSS. The primary analysis revealed no significant improvement on the DuPaul ADHD Scale with deprenyl (mean improvement 1.3 points, 95% CI –2.7 to 5.3; P = 0.50). The YGTSS total score improved by a mean of 9.3 points with deprenyl (95% CI –0.4 to 19.0; P = 0.06), but this was not statistically significant. Nine of the 24 participants dropped out of the study before entering the second treatment period (six who had received deprenyl and three who had received placebo).

Secondary outcomes: adverse effects

Methylphenidate

In Gadow 2007, there were higher levels of somatic symptoms (sleep and appetite problems, headache, stomach upset, dizziness) on the Stimulant Side Effects Checklist during methylphenidate treatment than with placebo (F = 8.1; P < 0.001). Diastolic blood pressure was higher during treatment with methylphenidate 0.5 mg/kg or 0.1 mg/kg compared with placebo; and heart rate was higher during treatment with methylphenidate 0.3 mg/kg and 0.5 mg/kg compared to placebo.

In Castellanos 1997, appetite suppression with transient weight loss occurred in three children during methylphenidate treatment, and initial insomnia occurred in two children with methylphenidate.

Dextroamphetamine

In Castellanos 1997, appetite suppression with transient weight loss occurred in four children on dextroamphetamine. Initial insomnia occurred in 10 children on dextroamphetamine.

Clonidine

In Tourette's Syndrome Study Group 2002, sedation was common in children receiving clonidine, with 48% of the clonidine‐treated participants reporting this adverse effect compared to 14% of participants treated with methylphenidate and 6% with placebo.

In Singer 1995, specific adverse effects were not reported. The authors reported that 15/34 children experienced at least one drug‐related problem during placebo treatment, compared to 28/34 children during clonidine treatment.

Guanfacine

In Scahill 2001, there was no significant difference between the guanfacine and placebo groups in any adverse effects, including laboratory test results, weight, or cardiovascular parameters. One participant in the guanfacine group withdrew at week four of the study due to sedation.

Atomoxetine

In Allen 2005, rates of decreased appetite and nausea were significantly higher in participants treated with atomoxetine than with placebo (decreased appetite: 16% with atomoxetine versus 3% with placebo; P = 0.01; nausea: 16% with atomoxetine versus 1% with placebo; P = 0.002). The atomoxetine group showed a mean decrease of bodyweight at endpoint (–0.9 (SD 1.9) kg) that was significantly different from the weight gain seen in the placebo group (1.6 (SD 2.3) kg). Participants receiving atomoxetine also had a significant increase in heart rate (+8.3 (SD 12.0) beats per minute) compared to the decrease in heart rate seen in the placebo group (–1.2 (SD 12.7) beats per minute). Electrocardiography revealed a decrease in QT interval in the atomoxetine group versus a slight increase in the placebo group.

Desipramine

In Spencer 2002, there were no serious adverse events. Children treated with desipramine had significantly higher rates of appetite suppression (24%) compared to placebo (0%) (P < 0.02). Mild but statistically significant increases in diastolic blood pressure and pulse rate also occurred in the desipramine‐treated participants.

In Singer 1995, specific adverse effects were not reported. The authors stated that 15/34 children reported at least one drug‐related problem during placebo treatment compared to 26/34 children during desipramine treatment.

Deprenyl

In Feigin 1996, adverse events were not reported to have occurred more frequently with treatment with deprenyl than with placebo; however, the authors did not include a description of adverse events by treatment group.

Discussion

Summary of main results

The findings of this review suggest that there are a number of medicines available to treat children with ADHD and comorbid tic disorders. All the agents, with the exception of deprenyl, reported improvements in symptoms of ADHD in children with tic disorders, however, the quality of evidence available was low.

The data from Tourette's Syndrome Study Group 2002 suggest that methylphenidate and clonidine have similar efficacy in treating symptoms of ADHD, and their combination is superior to either treatment alone. These findings may be seen as contrary to clinical experience, which has traditionally proposed that stimulants are more effective in treating ADHD symptoms than alpha agonists (Connor 1999). This unexpected result may have been due to the doses of methylphenidate used in the study which, at 25 mg/day, is lower than doses used in clinical practice for all but very young children. In Singer 1995, desipramine was superior to clonidine for the treatment of ADHD symptoms. However, this trial has limited applicability for two reasons. First, in general, the effects of clonidine may take several months to become apparent and a six‐week trial of this medication would likely be inadequate to evaluate efficacy. Second, desipramine is now used only on rare occasions in children because of concerns about cardiac toxicity (Amitai 2006).

The three studies of methylphenidate suggested that this drug does not worsen tics in the majority of children. It should be noted that the dose of methylphenidate in Tourette's Syndrome Study Group 2002 was on the lower end of what is used in clinical practice (mean 26 mg daily). There has been only one study of dextroamphetamine on tic symptoms. Castellanos 1997 found worsening of tics during the second (15 mg twice daily) and third (22.5 mg twice daily) weeks of dextroamphetamine treatment compared to the weeks on placebo. As treatment was for only three weeks, it is not clear if worsening of tic symptoms would have resolved over time. The dosages used in this study are on the high end of what is used in clinical practice. There was no further clinical benefit for ADHD symptoms with the higher doses of dextroamphetamine compared to the lower dosage used (7.5 mg twice daily), which did not worsen tics. The result from this single study suggested that the lower dosage of dextroamphetamine could be considered when treating children with comorbid ADHD and tics.

Tics do not appear to worsen with alpha agonists, and the majority of studies reported an improvement in tic severity with this class of drug. Tics significantly improved in both trials studying desipramine (Singer 1995; Spencer 2002); however, safety concerns have meant that it is no longer routinely used in children (Riddle 1993). The effect of atomoxetine on tic severity was non‐inferior to placebo (Allen 2005).

Overall completeness and applicability of evidence

Overall, there was a small number of trials assessing pharmacological treatments for ADHD in children with tic disorders. There are some gaps in the current available evidence, with no trials of long‐acting stimulants in children with tic disorders or trials using a number of newer ADHD treatments (see Implications for research). As ADHD and tic disorders frequently occur together, the evidence is applicable clinically. The evidence is limited by the short duration of the majority of trials.

Quality of the evidence

Important methodological limitations reduced the impact of most of the trials included in this review, with the body of evidence considered low for methylphenidate, atomoxetine, and clonidine, and very low for desipramine, dextroamphetamine, guanfacine, and deprenyl. Many of the trials were small, selective outcome reporting was occasionally an issue, and reporting of results from cross‐over trials was generally poor with no studies presenting paired data for analysis.

Potential biases in the review process

We did not identify any potential biases in the review process.

Agreements and disagreements with other studies or reviews

Bloch 2009 conducted a meta‐analysis on the treatment of ADHD in children with comorbid tic disorders. Their study included the same trials as those reported in our review but they double counted one trial as two, mistaking a separate report, Gadow 2007, as an additional trial. They have drawn similar conclusions to our systematic review but elected to perform a meta‐analysis of the data, despite the degree of clinical heterogeneity and the unit‐of‐analysis issues identified above, which, in our view, would preclude such an analysis. Additionally, Cohen 2015 conducted a meta‐analysis of RCTs of psychostimulants for ADHD, focusing specifically on data related to the onset of tics reported in these trials. They concluded that the use of psychostimulants was not associated with new onset of, or increase in, the severity of pre‐existing tics. Their study included 22 trials, none of which are included in our review, and their findings supported our conclusions.

Figure 1

Study flow diagram illustrating the process for inclusion of studies.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Summary of findings for the main comparison. Methylphenidate compared with placebo for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders

Methylphenidate compared with placebo for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders
Patient or population: children with ADHD and comorbid tic disorders Intervention: methylphenidate Comparison: placebo
Outcomes	Effect of treatment	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
ADHD symptom‐related behavior Measured by standardized rating scales: Conners' Abbreviated Teacher Rating Scale, Conners' Abbreviated Parent Rating Scale, IOWA Conners' Teacher Rating Scale, Mothers' Objective Method for Subgrouping, Continuous Performance Task, Conners' Teacher Rating Scale, Conners' Continuous Performance Task	Tourette's Syndrome Study Group 2002 showed a significant treatment effect using the Conners' Abbreviated Teacher Rating Scale (3.3 points, 98.3% CI −0.2 to 6.8; P = 0.02).	229 (3 studies)	⊕⊕⊝⊝ Low^a	–
	Gadow 2007 showed that all doses (0.1 mg/kg, 0.3 mg/kg, 0.5 mg/kg) of methylphenidate were superior to placebo on all rating scales (Conners' Abbreviated Teacher/Parent Rating Scale, IOWA Conners' Teacher Rating Scale, Mothers' Objective Method for Subgrouping, Continuous Performance Test), with a dose‐dependent effect (F = 24.7; P = 0.001)
	Castellanos 1997 showed significantly decreased hyperactivity at all doses (15 mg, 25 mg, 45 mg).
Tic severity Measured by standardized rating scales: Yale Global Tic Severity Scale, Tourette Syndrome Severity Scale, Tourette Syndrome Clinical Global Impression Scale, Global Tic Rating Scale, 2‐Minute Tic and Habit Count, Tic Symptom Self‐Report	Tourette's Syndrome Study Group 2002 found a significant treatment effect using the Yale Global Tic Severity Scale (11.0 points, 98.3% CI 2.1 to 19.8; P = 0.003).	229 (3 studies)	⊕⊕⊝⊝ Low^a	–
	Gadow 2007 found no difference on the Yale Global Tic Severity Scale but found an improvement in tic severity at all doses (0.1 mg/kg, 0.3 mg/kg, 0.5 mg/kg) on the Global Tic Rating Scale completed by teachers (F = 5.33; P = 0.002)
	Castellanos 1997 found no effect of drug on tic severity for second and third cohorts. Tic severity was significantly greater during week 2 in the first cohort (P < 0.01)
ADHD: attention deficit hyperactivity disorder; CI: confidence interval.
GRADE Working Group grades of evidence High quality: we are very confidence that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded two levels due to limitations in study design and implementation, and imprecision of results.

Summary of findings for the main comparison. Methylphenidate compared with placebo for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders

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Summary of findings 2. Clonidine compared with placebo for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders

Clonidine compared with placebo for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders
Patient or population: children with ADHD and comorbid tic disorders Intervention: clonidine Comparison: placebo
Outcomes	Effect of treatment	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
ADHD symptom‐related behavior Measured by standardized rating scales: Conners' Abbreviated Teacher Rating Scale, Conners' Abbreviated Parent Rating Scale, IOWA Conners' Teacher Rating Scale, Conners' Continuous Performance Task, Child Behaviour Checklist, Gordon Diagnostic System, Clinical Evaluation of Language Function, Matching Familial Figures Test, Porteus Maze Test, Restricted Academic Test	Tourette's Syndrome Study Group 2002 found a significant treatment effect using the Conners' Abbreviated Teacher Rating Scale (3.3 points, 98.3% CI −0.2 to 6.8; P = 0.02).	170 (2 studies)	⊕⊕⊝⊝ Low^a	–
	Singer 1995 found no significant difference on any ADHD outcome measures, except the nervous/overactive subscale of the Child Behaviour Checklist (boys aged 6‐11 years).
Tic severity Measured by standardized rating scales: Yale Global Tic Severity Scale, Tourette Syndrome Severity Scale, Global Tic Rating Scale, Tic Symptom Self‐Report, Hopkins Motor/Vocal Scale	Tourette's Syndrome Study Group 2002 showed a significant treatment effect using the Yale Global Tic Severity Scale (10.9 points, 98.3% CI 2.1 to 19.7; P = 0.003).	170 (2 studies)	⊕⊕⊝⊝ Low^a	–
	Singer 1995 found no significant difference on measures of tic severity.
ADHD: attention deficit hyperactivity disorder; CI: confidence interval.
GRADE Working Group grades of evidence High quality: we are very confidence that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded two levels due to limitations in study design and implementation, and imprecision of results.

Summary of findings 2. Clonidine compared with placebo for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders

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Summary of findings 3. Desipramine compared with placebo for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders

Desipramine compared with placebo for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders
Patient or population: children with ADHD and comorbid tic disorders Intervention: desipramine Comparison: placebo
Outcomes	Effect of treatment	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
ADHD symptom‐related behavior Measured by standardized rating scales: Child Behaviour Checklist, Gordon Diagnostic System, Clinical Evaluation of Language Function, Matching Familial Figures Test, Porteus Maze Test, Restricted Academic Test, ADHD Rating Scale IV ‐ Parent Version; ADHD Parent Linear Analogue Scale	Spencer 2002 showed a decrease in scores on the ADHD Rating Scale IV ‐ Parent Version (week 0 = 46 (SD 5.9) points; week 6 = 24 (SD 12) points; P < 0.001).	75 (2 studies)	⊕⊝⊝⊝ Very low^a	–
	Singer 1995 showed that desipramine was superior to placebo on the Parent Linear Analogue Scale for Hyperactivity (desipramine: 32.8 (SD 1.3) points; placebo: 64.4 (SD 0.6) points; P < 0.05). Hyperactivity subscale of the Child Behavior Checklist showed drug effects for males aged 6 to 11 years (desipramine: 68.6 (SD 1.4) points; placebo: 75.8 (SD 1.0) points; P < 0.05).
Tic severity Measured by standardized rating scales: Yale Global Tic Severity Scale, Tourette Syndrome Severity Scale, Hopkins Motor/Vocal Scale; ADHD Parent Linear Analogue Scale	Spencer 2002 showed a decrease in scores on the Yale Global Tic Severity Scale (week 0 = 63 (SD 18) points; week 6: 43 (SD 23) points; P < 0.001).	75 (2 studies)	⊕⊝⊝⊝ Very low^a	–
	Singer 1995 showed that desipramine was superior to placebo on the Parent Linear Analogue Scale of tic severity (desipramine: 30.0 (SD 0.7) points; placebo: 47.4 SD 1.8 points; P < 0.05). There were no differences on the other measures of tic severity (Tourette Syndrome Severity Scale, Hopkins Motor/vocal scale, Yale Global Tic Severity Scale).
ADHD: attention deficit hyperactivity disorder; SD: standard deviation.
GRADE Working Group grades of evidence High quality: we are very confidence that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.
^aDowngraded two levels due to limitations in study design and implementation, and imprecision of results.

Summary of findings 3. Desipramine compared with placebo for attention deficit hyperactivity disorder (ADHD) in children with comorbid tic disorders

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Table 1. Comparisons

Comparisons	Trial(s)
Methylphenidate versus placebo	Castellanos 1997 Gadow 2007 Tourette's Syndrome Study Group 2002
Clonidine versus placebo	Singer 1995 Tourette's Syndrome Study Group 2002
Methylphenidate plus clonidine versus placebo	Tourette's Syndrome Study Group 2002
Dextroamphetamine versus placebo	Castellanos 1997
Guanfacine versus placebo	Scahill 2001
Atomoxetine versus placebo	Allen 2005
Desipramine versus placebo	Singer 1995 Spencer 2002
Deprenyl versus placebo	Feigin 1996
Desipramine versus clonidine	Singer 1995

Table 1. Comparisons

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Table 2. Attention deficit hyperactivity disorder symptom severity scales used in this review

Scale/measure	Allen 2005	Castellanos 1997	Feigin 1996	Gadow 2007	Scahill 2001	Singer 1995	Spencer 2002	Tourette's Syndrome Study Group 2002
Conners Abbreviated Teacher Rating Scale	–	–	–	Yes	–	–	–	Yes
Conners Abbreviated Parent Rating Scale	–	–	–	Yes	–	–	–	Yes
IOWA Conners Teacher Rating Scale	–	–	–	Yes	–	–	–	Yes
Mothers' Objective Method for Subgrouping	–	–	–	Yes	–	–	–	–
Continuous Performance Task	–	–	–	Yes	Yes	–	–	–
ADHD Rating Scale‐IV: Parent Version	Yes	–	–	–	Yes	–	Yes	–
Clinical Global Impression Scale – Overall – Severity	Yes	–	–	–	Yes	–	–	–
Clinical Global Impression Scale – ADHD/Psychiatric Symptoms	Yes	–	–	–	–	–	–	–
ADHD Teacher 39‐Item Conners Rating Scale	–	Yes	–	–	–	–	–	–
DuPaul ADHD Scale	–	–	Yes	–	–	–	–	–
Parent Conners Questionnaire Hyperactivity Index	–	–	–	–	Yes	–	–	–
Child Behaviour Checklist	–	–	–	–	–	Yes	–	–
Gordon Diagnostic System	–	–	–	–	–	Yes	–	–
Clinical Evaluation of Language Function	–	–	–	–	–	Yes	–	–
Matching Familial Figures Test	–	–	–	–	–	Yes	–	–
Porteus Maze Test	–	–	–	–	–	Yes	–	–
Restricted Academic Test	–	–	–	–	–	Yes	–	–
Conners Continuous Performance Task	–	–	–	–	–	–	–	Yes
ADHD: attention deficit hyperactivity disorder; IOWA: inattention/overactivity with aggression.

Table 2. Attention deficit hyperactivity disorder symptom severity scales used in this review

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Table 3. Tic severity symptom scales used in this review

Scale/measure	Allen 2005	Castellanos 1997	Feigin 1996	Gadow 2007	Scahill 2001	Singer 1995	Spencer 2002	Tourette's Syndrome Study Group 2002
Yale Global Tic Severity Scale	Yes	Yes	Yes	Yes	Yes	Yes	Yes	Yes
Tourette Syndrome Severity Scale	–	–	–	Yes	–	Yes	–	–
Tourette Syndrome Clinical Global Improvement	Yes	–	–	Yes	–	–	–	–
Global Tic Rating Scale	–	–	–	Yes	–	–	–	Yes
2‐Minute Tic and Habit Count	–	–	–	Yes	–	–	–	–
Tic Symptom Self‐Report	Yes	–	–	–	–	–	–	Yes
Goetz Tic Severity Scale	–	–	Yes	–	–	–	–	–
Hopkins Motor/Vocal Scale	–	–	–	–	–	Yes	–	–

Table 3. Tic severity symptom scales used in this review

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Table 4. Description of scales used in included studies

Scale/measure	Number of items	Scoring
Conners' Abbreviated Symptoms Questionnaire for Teachers (ASQ)	10 items pertaining to the child's behavior	Rated on a 4‐point Likert scale, ranging from 0 (not at all), 1 (just a little), 2 (pretty much) to 3 (very much true), with a possible total score ranging from 0 to 30. Higher scores indicate worse symptoms
Yale Global Tic Severity Scale (YGTSS)	5 items on the number, frequency, intensity, complexity, and interference from motor tics, and 5 items on the number, frequency, intensity, complexity, and interference from vocal tics, and 1 item on overall impairment	The Total Motor Tic Score is derived by adding the 5 motor tics items (each item ranges from 0 to 5, total motor tic score ranges from 0 to 25). The Total Vocal Tic Score is derived by adding the 5 phonic tics items (each item ranges from 0 to 5, total vocal tic ranges from 0 to 25). The Total Tic Score is a summation of the Total Motor Tic and Total Vocal Tic Scores. The Overall Impairment Rating is rated on a 51‐point scale anchored by 0 (no impairment) and 50 (severe impairment). Finally, the Global Severity Score is a summation of the Total Motor Tic Score, Total Vocal Tic Score, and Overall Impairment Rating (range 0 to 100). Higher scores indicate worse symptoms.
Global Tic Rating Scale	9 items, with the first 5 referring to the frequency of motor (3 items) and phonic tics (2 items) according to body region, which are summed to produce motor and phonic tic frequency subscores, respectively	All items are rated on a scale from 0 (never) to 3 (very much). Total score ranges from 0 to 27. Higher scores indicate worse symptoms
ADHD Rating Scale IV ‐ Parent Version	18‐item questionnaire. 9 questions each on inattention and hyperactivity‐impulsivity, where the odd‐numbered items represent the inattention subscale, and the even‐numbered items represent the hyperactive/impulsive subscale	Items coded on 4‐point Likert scale using scores 1 (never or rarely), 2 (sometimes), 3 (often), or 4 (very often). Total score ranges from 18 to 52. Raw scores are converted to percentiles.
ADHD Parent Linear Analogue Scale	10‐cm line on which both the parent and physician separately rank symptoms	The ends of each line represent 0 (no symptoms) and 10 (most severe)
Child Behaviour Checklist (CBCL)	113 items across 8 subscales assessing maladaptive behavioral and emotional problems: withdrawn somatic complaints anxious/depressed social problems thought problems attention problems delinquent problems aggressive behavior	Items are coded from 0 to 2, scored 0 (not at all), 1 (somewhat true), or 2 (very true). CBCL profile for each category, with scores below the 95th percentile in the normal range, and above the 98th percentile in the clinical range. Higher scores indicate worse symptoms.
Conners' Abbreviated Parent Rating Scale	48 items across 6 subscales: conduct problems learning problems psychosomatic impulsive/hyperactive anxiety hyperactivity index	All items are rated on a scale from 0 (never) to 3 (very much). Total score ranges from 0 to 144. Higher scores indicate worse symptoms
IOWA Conners' Teacher Rating Scale	10 items. Consists of 5‐item subscales designed to assess inattention/overactivity and aggression Inattention/overactivity: fidgeting hums and makes other odd noises excitable, impulsive inattentive, easily distracted fails to finish things he starts (short attention span) Aggression: quarrelsome acts "smart," temper outbursts (explosive and unpredictable behavior) defiant unco‐operative	Scored 0 (not at all), 1 (just a little), 2 (pretty much), or 3 (very much). Total score ranges from 0 to 30. Higher scores indicate worse symptoms
Mothers' Objective Method for Subgrouping	Contains 10 (hyperactivity or ADHD, or both) symptoms arranged in a checklist format. Generates a hyperactivity scale score and an aggression scale score	1 indicates checked and 0 unchecked. Total score ranges from 0 to 10. Higher scores indicate worse symptoms
Continuous Performance Task (CPT)	Computer‐administered and scored measure of sustained visual attention and motor response inhibition. The test takes about 15 minutes to administer and yields measures of omissions, commissions, and reaction time.	Omission errors measure inattention, commission errors measure impulsivity
Conners' Teacher Rating Scale	39 items clustered into 5 factors, including conduct problems, daydreaming, inattention, anxious‐fearful, and hyperactive behavior ADHD Teacher 39‐Item	All items are rated on a scale from 0 (never) to 3 (very much). Total score ranges from 0 to 137. Raw scores for each scale are converted to T scores, incorporating normative adjustments for age and sex, with scores of at least 70 considered clinically elevated
Conners' Continuous Performance Task (CPT)	Visual‐motor task. Respondents must rapidly and accurately hit the space bar after every letter presented except the letter 'X'. Several variables may be derived from the Conners' CPT, including errors of omission and commission, mean hit reaction time (RT), mean hit RT standard error.	Omission errors measure inattention, commission errors measure impulsivity
Tourette Syndrome Severity Scale	5‐item scale Are the tics noticeable to others? Do the tics elicit comments? Is the patient considered odd or bizarre? Do the tics interfere with functioning? Is the patient incapacitated, homebound, or hospitalized?	Higher scores indicates worse symptoms
Tourette Syndrome Clinical Global Impression (CGI) Scale	Observer‐rated scale that measures illness severity (CGI‐S), or global improvement (CGI‐I)	7‐point scale, with the severity of illness scale (CGI‐S) using a range of responses from 1 (normal) to 7 (among the most severely ill people). CGI‐I scores range from 1 (very much improved) to 7 (very much worse)
2‐Minute Tic and Habit Count	The physician counts separately the number of brief, jerky (i.e. tics) and rhythmic (i.e. stereotypic, habit) movements and vocalizations during quiet conversation in an office setting.	Higher scores indicates worse symptoms
Tic Symptom Self‐Report	40‐item checklist containing 20 motor tic items and 20 phonic tic items	0–3 scale corresponding with absent (score of 0) to very frequent and forceful (score of 3). Total score ranges from 0 to 120. Higher scores indicate worse symptoms
Goetz Tic Severity Scale	Videotape protocol involving a 10‐minute film of people placed in front of a video camera in a quiet room. 2 body views are recorded, full frontal body (far) and head and shoulders only (near), under 2 conditions: relaxed with the examiner in the room, and relaxed with the patient alone in the room 5 domains are rated: number of body areas involved with tics motor tic intensity phonic tic intensity frequency of motor tics frequency of phonic tics	0–4 scoring format. For all domains, 0 represents normal function without evidence of tic disability. Higher scores indicate worse symptoms
Hopkins Motor/Vocal Scale	Consists of a series of linear analog scales (10 cm) on which both the parent and physician separately rank each tic (motor and vocal) symptom, taking into consideration its frequency, intensity, degree of interference, and impairment	The ends of each line represent 0 (no tics) and 10 (most severe). The line can be subdivided roughly into 4 ranges: mild, moderate, moderately severe, and severe
Du Paul ADHD Rating Scale	14 items, assessing separate factors of inattention and hyperactivity‐impulsivity	Rated on a 0 (normal) to 3 (severe) scale, yielding a total score ranging from 0 to 42. Higher scores indicate worse symptoms
Parent Conners' Questionnaire Hyperactivity Index	10‐item rating scale identifying hyperactive children	Each item is rated from 0 to 3 (range 0–30). Higher scores indicate worse symptoms
ADHD: attention deficit hyperactivity disorder.

Table 4. Description of scales used in included studies

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摘要

研究背景

研究目的

检索策略

纳入排除标准

资料收集与分析

主要结果

作者结论

PICO

PICO

Population

Intervention

Comparison

Outcome

简语概要

抽动障碍儿童注意力缺陷多动障碍（ADHD）的药物治疗

Resumen visual

Authors' conclusions

Implications for practice

Implications for research

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

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Data synthesis

'Summary of findings' table

Subgroup analysis and investigation of heterogeneity

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Results

Description of studies

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Included studies

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Location

Participants

Interventions

Outcome measures

Excluded studies

Risk of bias in included studies

Allocation

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Incomplete outcome data

Selective reporting

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Effects of interventions

Primary outcomes: attention deficit hyperactivity disorder and tic symptom severity

Methylphenidate

Dextroamphetamine

Clonidine

Guanfacine

Atomoxetine

Desipramine

Deprenyl

Secondary outcomes: adverse effects

Methylphenidate