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Study flow diagram illustrating the process for inclusion of studies.
Figures and Tables -
Figure 1

Study flow diagram illustrating the process for inclusion of studies.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Figures and Tables -
Figure 2

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

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)

⊕⊕⊝⊝
Lowa

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)

⊕⊕⊝⊝
Lowa

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.

Figures and Tables -
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

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)

⊕⊕⊝⊝
Lowa

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)

⊕⊕⊝⊝
Lowa

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.

Figures and Tables -
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

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 lowa

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 lowa

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.

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

Figures and Tables -
Table 1. Comparisons
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.

Figures and Tables -
Table 2. Attention deficit hyperactivity disorder symptom severity scales used in this review
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

Figures and Tables -
Table 3. Tic severity symptom scales used in this review
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.

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Table 4. Description of scales used in included studies