Tic, Tourettes Syndrome
Conditions
Keywords
Tic disorders,, Tourette syndrome, Chronic Tic Disorders
Brief summary
Tourette syndrome is a childhood-onset neuropsychiatric disorder characterized by multiple motor and vocal tics that last for at least a year in duration. Currently, there exist several effective pharmacological treatments for childhood tics including alpha-2 agonist medications (guanfacine and clonidine) and neuroleptics (antipsychotic) medications. These medications, however, have significant side-effects and are only partially efficacy in treating tics. N-acetylcysteine (NAC) is a natural supplement that acts as an antioxidant and glutamate modulating agent. NAC has been used safely for decades in doses 20-40 times higher than in this trial as an antidote for acetaminophen overdose. The only side-effect commonly seen with NAC is nausea and this side-effect is seldom seen in the doses used in this trial. NAC has recently been demonstrated to be effective in a double-blind, placebo-controlled trial in adults with trichotillomania (chronic hair pulling). Hairpulling is hypothesized to be closely related to tics because these conditions (1) have similar clinical characteristics -- both groups typically experience urges before engaging in pulling or tics, (2) neuroimaging studies suggest they involve similar brain circuits -- the basal ganglia, (3) the same pharmacological treatments (neuroleptics) may be effective for both conditions and (4) they tend to be inherited together in families. In other trials NAC has evidence of some efficacy in treating diverse psychiatric conditions such as bipolar depression, schizophrenia and cocaine dependence. The investigators are conducting this trial to determine if NAC is an effective treatment for tics.
Interventions
DRUGN-Acetylcysteine (NAC)
1 600mg capsule twice a day for 2 weeks and then 2 600mg capsules twice a day for the remaining 10 weeks of the trial.
DRUGPlacebo
1 600mg Capsule twice a day for two weeks then 2 600mg capsules twice a day for the remaining 10 weeks of the study. Children receiving placebo will be offered the active intervention after the double-blind portion of the trial.
Sponsors
American Academy of Child Adolescent Psychiatry.
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
8 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Children aged 8-17 years. * Primary diagnosis of Tourette syndrome or chronic tic disorder. * Duration of tics greater than 1 year. * Significant Current tic symptoms: Current YGTSS score greater than or equal to 22 with a TS diagnosis or greater than or equal to 14 with a chronic tic disorder.
Exclusion criteria
* Comorbid bipolar disorder, psychotic disorder, substance use disorder, developmental disorder or mental retardation (IQ\<70). * Recent change (less than 4 weeks) in medications that have potential effects on tic severity (such as neuroleptic medications, dopamine agonists, alpha-2 agonists (guanfacine, clonidine or prazosin), SSRIs, clomipramine, naltrexone, lithium, psychostimulants, or anxiolytics). Medication change is defined to include dose changes or medication discontinuation. * Recent change in behavioral treatment for Tourette syndrome or comorbid conditions (i.e. OCD) within the last 4 weeks or initiation of behavioral therapy for tics within the last 12 weeks. * Asthma requiring medication use within the last 3 months * Known hypersensitivity or previous anaphylactoid reaction to acetylcysteine or any components in its preparation * Positive pregnancy test or drug screening test. * Previous use of N-acetylcysteine (dose greater than 600mg for more than 2 weeks)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Improvement in Tic Severity | 12 weeks | Yale Global Tic Severity Scale is a standard psychiatric measure that rates tics from 0 (no tics) to 100 (most severe tics). It separately rates motor tics and vocal tics in 5 subscales (number, frequency, intensity, complexity and interference) where the maximum severity score for motor tics is 25 and for vocal tics is 25. Giving us the Total Tic Severity Score maximum of 50. The additional Impairment Scale rates the degree of disability caused by the tics ranging from 0 (none) to 50 (severe). When these two scores are added we get the Yale Global Tic Severity Scale Score. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Improvement of Premonitory Urges | 12 weeks | Premonitory Urge for Tics Scale (PUTS). Items are rated on a scale of 1-4 from least to most. A total score is calculated by summing the scores of all items. Nine is the minimum possible score. A score of 12.5-24.5 indicates medium intensity of premonitory urges for tics. A score of 25-30.5 indicates high intensity which may be associated with marked impairment. Scores 31 and above indicate extremely high intensity with probable severe impairment. A score of 36 is the maximum score possible. |
| Improvement in OCD Severity | 12 weeks | Childrens' Yale-Brown Obsessive-Compulsive Scale (CY-BOCS). 10-item scale. Each item is rated from 0-4. A sum total is calculated by adding items 1-10. 0-7: Subclinical. 8-15: Mild. 16-23: Moderate. 24-31: Severe. 32-40: Extreme. |
| Overall Improvement | 12 weeks | Clinical Global Impression - Improvement Scale (CGI-I). The CGI is a 7-point scare that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention. 1 = Very much improved; 2 = Much improved; 3 = Minimally improved; 4 = No change; 5 = Minimally worse; 6 = Much worse; 7 = Very much worse. |
| Number of Participants With Adverse Effects | 12 weeks | Number of participants with adverse events according to the Pediatric Adverse Events Rating Scale |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| N-Acetylcysteine N-Acetylcysteine (NAC): 1 600mg capsule twice a day for 2 weeks and then 2 600mg capsules twice a day for the remaining 10 weeks of the trial. | 17 |
| Placebo Placebo: 1 600mg Capsule twice a day for two weeks then 2 600mg capsules twice a day for the remaining 10 weeks of the study. Children receiving placebo will be offered the active intervention after the double-blind portion of the trial. | 14 |
| Total | 31 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 |
Baseline characteristics
| Characteristic | N-Acetylcysteine | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 12.4 years STANDARD_DEVIATION 1.4 | 11.5 years STANDARD_DEVIATION 2.8 | 11.9 years STANDARD_DEVIATION 2.17 |
| Age of onset | 6.8 years STANDARD_DEVIATION 1.4 | 6.1 years STANDARD_DEVIATION 2.4 | 6.4 years STANDARD_DEVIATION 1.17 |
| Gender Female | 5 Participants | 2 Participants | 7 Participants |
| Gender Male | 12 Participants | 12 Participants | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 17 | 7 / 14 |
| serious Total, serious adverse events | 0 / 17 | 0 / 14 |
Outcome results
Primary
Improvement in Tic Severity
Yale Global Tic Severity Scale is a standard psychiatric measure that rates tics from 0 (no tics) to 100 (most severe tics). It separately rates motor tics and vocal tics in 5 subscales (number, frequency, intensity, complexity and interference) where the maximum severity score for motor tics is 25 and for vocal tics is 25. Giving us the Total Tic Severity Score maximum of 50. The additional Impairment Scale rates the degree of disability caused by the tics ranging from 0 (none) to 50 (severe). When these two scores are added we get the Yale Global Tic Severity Scale Score.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-Acetylcysteine | Improvement in Tic Severity | 24.3 units on a scale | Standard Deviation 7.9 |
| Placebo | Improvement in Tic Severity | 21.3 units on a scale | Standard Deviation 4.6 |
Secondary
Improvement in OCD Severity
Childrens' Yale-Brown Obsessive-Compulsive Scale (CY-BOCS). 10-item scale. Each item is rated from 0-4. A sum total is calculated by adding items 1-10. 0-7: Subclinical. 8-15: Mild. 16-23: Moderate. 24-31: Severe. 32-40: Extreme.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-Acetylcysteine | Improvement in OCD Severity | 4.4 units on a scale | Standard Deviation 8 |
| Placebo | Improvement in OCD Severity | 11.5 units on a scale | Standard Deviation 9.8 |
Secondary
Improvement of Premonitory Urges
Premonitory Urge for Tics Scale (PUTS). Items are rated on a scale of 1-4 from least to most. A total score is calculated by summing the scores of all items. Nine is the minimum possible score. A score of 12.5-24.5 indicates medium intensity of premonitory urges for tics. A score of 25-30.5 indicates high intensity which may be associated with marked impairment. Scores 31 and above indicate extremely high intensity with probable severe impairment. A score of 36 is the maximum score possible.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-Acetylcysteine | Improvement of Premonitory Urges | 24.7 units on a scale | Standard Deviation 4.9 |
| Placebo | Improvement of Premonitory Urges | 24.1 units on a scale | Standard Deviation 4.8 |
Secondary
Number of Participants With Adverse Effects
Number of participants with adverse events according to the Pediatric Adverse Events Rating Scale
Time frame: 12 weeks
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| N-Acetylcysteine | Number of Participants With Adverse Effects | Fatigue | 0 participants |
| N-Acetylcysteine | Number of Participants With Adverse Effects | Chest pain | 0 participants |
| N-Acetylcysteine | Number of Participants With Adverse Effects | Sadness or depressed mood | 0 participants |
| N-Acetylcysteine | Number of Participants With Adverse Effects | Syncope | 0 participants |
| N-Acetylcysteine | Number of Participants With Adverse Effects | Insomnia | 0 participants |
| N-Acetylcysteine | Number of Participants With Adverse Effects | Stomach ache | 0 participants |
| N-Acetylcysteine | Number of Participants With Adverse Effects | Irritability | 0 participants |
| N-Acetylcysteine | Number of Participants With Adverse Effects | Nausea | 0 participants |
| N-Acetylcysteine | Number of Participants With Adverse Effects | Decreased appetite | 0 participants |
| N-Acetylcysteine | Number of Participants With Adverse Effects | Vomiting | 0 participants |
| N-Acetylcysteine | Number of Participants With Adverse Effects | Headache | 1 participants |
| Placebo | Number of Participants With Adverse Effects | Vomiting | 0 participants |
| Placebo | Number of Participants With Adverse Effects | Headache | 1 participants |
| Placebo | Number of Participants With Adverse Effects | Irritability | 0 participants |
| Placebo | Number of Participants With Adverse Effects | Sadness or depressed mood | 1 participants |
| Placebo | Number of Participants With Adverse Effects | Fatigue | 0 participants |
| Placebo | Number of Participants With Adverse Effects | Insomnia | 0 participants |
| Placebo | Number of Participants With Adverse Effects | Decreased appetite | 0 participants |
| Placebo | Number of Participants With Adverse Effects | Chest pain | 0 participants |
| Placebo | Number of Participants With Adverse Effects | Syncope | 0 participants |
| Placebo | Number of Participants With Adverse Effects | Stomach ache | 2 participants |
| Placebo | Number of Participants With Adverse Effects | Nausea | 3 participants |
Secondary
Overall Improvement
Clinical Global Impression - Improvement Scale (CGI-I). The CGI is a 7-point scare that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention. 1 = Very much improved; 2 = Much improved; 3 = Minimally improved; 4 = No change; 5 = Minimally worse; 6 = Much worse; 7 = Very much worse.
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-Acetylcysteine | Overall Improvement | 3.3 units on a scale | Standard Deviation 1.1 |
| Placebo | Overall Improvement | 3.4 units on a scale | Standard Deviation 1.1 |