N-acetylcysteine (NAC) for Children With Tourette Syndrome

Double-Blind, Placebo-Controlled Trial of N-acetylcysteine (NAC) for the Treatment of Children With Tourette Syndrome

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.

Study Overview

• Status: Completed
• Conditions: Tic; Tourettes Syndrome
• Intervention / Treatment: Drug: N-Acetylcysteine (NAC); Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale Child Study Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: N-Acetylcysteine; NAC was titrated up to a maximum dose of 2400 mg over the course of 2 weeks. Subjects were assigned 600 mg twice a day for weeks 1-2, and then were assigned 1200 mg twice a day for the remainder of the 12 week study.	Drug: 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.
Placebo Comparator: Placebo; Placebo: Subjects were assigned to take two capsules twice a day for weeks 1-2, and then were assigned 4 capsules twice a day for the remainder of the 12 week study.	Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	12 weeks
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.	12 weeks
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.	12 weeks
Number of Participants With Adverse Effects	Number of participants with adverse events according to the Pediatric Adverse Events Rating Scale	12 weeks

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: American Academy of Child Adolescent Psychiatry.
• Investigators: Principal Investigator: Michael H. Bloch, MD, MS, Yale University

Publications and helpful links

General Publications

• Singer HS, Morris C, Grados M. Glutamatergic modulatory therapy for Tourette syndrome. Med Hypotheses. 2010 May;74(5):862-7. doi: 10.1016/j.mehy.2009.11.028. Epub 2009 Dec 21.
• Berk M, Copolov D, Dean O, Lu K, Jeavons S, Schapkaitz I, Anderson-Hunt M, Judd F, Katz F, Katz P, Ording-Jespersen S, Little J, Conus P, Cuenod M, Do KQ, Bush AI. N-acetyl cysteine as a glutathione precursor for schizophrenia--a double-blind, randomized, placebo-controlled trial. Biol Psychiatry. 2008 Sep 1;64(5):361-8. doi: 10.1016/j.biopsych.2008.03.004. Epub 2008 Apr 23.
• Grant JE, Odlaug BL, Kim SW. N-acetylcysteine, a glutamate modulator, in the treatment of trichotillomania: a double-blind, placebo-controlled study. Arch Gen Psychiatry. 2009 Jul;66(7):756-63. doi: 10.1001/archgenpsychiatry.2009.60.
• Bloch MH, Leckman JF. Clinical course of Tourette syndrome. J Psychosom Res. 2009 Dec;67(6):497-501. doi: 10.1016/j.jpsychores.2009.09.002.
• Berk M, Copolov DL, Dean O, Lu K, Jeavons S, Schapkaitz I, Anderson-Hunt M, Bush AI. N-acetyl cysteine for depressive symptoms in bipolar disorder--a double-blind randomized placebo-controlled trial. Biol Psychiatry. 2008 Sep 15;64(6):468-75. doi: 10.1016/j.biopsych.2008.04.022. Epub 2008 Jun 5.
• Ng F, Berk M, Dean O, Bush AI. Oxidative stress in psychiatric disorders: evidence base and therapeutic implications. Int J Neuropsychopharmacol. 2008 Sep;11(6):851-76. doi: 10.1017/S1461145707008401. Epub 2008 Jan 21.
• Bloch MH, Panza KE, Yaffa A, Alvarenga PG, Jakubovski E, Mulqueen JM, Landeros-Weisenberger A, Leckman JF. N-Acetylcysteine in the Treatment of Pediatric Tourette Syndrome: Randomized, Double-Blind, Placebo-Controlled Add-On Trial. J Child Adolesc Psychopharmacol. 2016 May;26(4):327-34. doi: 10.1089/cap.2015.0109. Epub 2016 Mar 30.

Helpful Links

• Yale Child Study Center TS/OCD Clinic

Study record dates

Study Major Dates

• Study Start: July 1, 2010
• Primary Completion (Actual): January 1, 2014
• Study Completion (Actual): January 1, 2014

Study Registration Dates

• First Submitted: July 27, 2010
• First Submitted That Met QC Criteria: July 28, 2010
• First Posted (Estimate): July 29, 2010

Study Record Updates

• Last Update Posted (Actual): February 10, 2017
• Last Update Submitted That Met QC Criteria: December 19, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Keywords: Tourette syndrome; Tic disorders,; Chronic Tic Disorders
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Disease; Genetic Diseases, Inborn; Basal Ganglia Diseases; Movement Disorders; Neurodegenerative Diseases; Heredodegenerative Disorders, Nervous System; Neurodevelopmental Disorders; Tic Disorders; Syndrome; Tourette Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Protective Agents; Respiratory System Agents; Antioxidants; Antidotes; Free Radical Scavengers; Expectorants; Acetylcysteine; N-monoacetylcystine
• Other Study ID Numbers: YCSC1004006637

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No