Augmentation of Brief Habit Reversal Training With D-cycloserine or Placebo
Phase: NA
Conditions: Tourette Disorder, Chronic Tic Disorder
Sponsor: University of California, Los Angeles

Study Protocol 
 
 
 
 
 
 
 
 
Augmentation of Brief Habit Reversal Training with D-Cycloserine or Placebo (DCS+HRT) 
 
 
 
NCT 02582515 
 
 
 
 
Updated October 24, 2016 
 
 
 
 
 
 
 
 
 
 
 

Study Protocol 
 
 
1. Protocol Title: 
 
Augmentation of Brief Habit Reversal Training with D-Cycloserine or Placebo (DCS+HRT) 
 
2.   Investigator(s) and Research Team:  
 
Joseph F. McGuire, Ph.D. 
Principal Investigator 
 
John Piacentini, Ph.D. 
Co-Principal Investigator 
 
Nathaniel Ginder, M.D. 
Co-Investigator 
 
James McCracken, M.D. 
Co-Investigator 
 
Caitlin Choy, B.A. 
Coordinator 
 
3. Abstract:  
 
Habit reversal training (HRT) is a treatment for youth with chronic tic disorders (CTDs). Data 
from large scale studies suggests that 8-10 sessions of HRT can meaningfully reduce tic 
severity for many youth. However, not all youth experience a meaningful reduction, with most 
youth continuing to exhibit tic symptoms after HRT. Emerging research suggests that an 
antibiotic medication called d-cycloserine (DCS) holds promise to improve therapeutic 
reductions for psychosocial interventions for anxiety disorders, obsessive-compulsive disorder, 
and posttraumatic stress disorder. DCS is an antibiotic that has been approved by the United 
States Food and Drug Administration for the treatment of tuberculosis in high doses. At 
substantially lower doses, DCS is suggested to strengthen the learning that occurs in 
psychosocial interventions such as cognitive behavioral therapy and HRT.  
 
This study will evaluate whether a single session of DCS-augmented HRT will lead to better 
symptom improvements compared to a single session of placebo-augmented HRT in youth with 
CTDs. Interested participants with a CTD will complete a screening assessment that includes a 
structured clinical interview and clinical rating scales (Visit 1). Participants who meet eligibility 
criteria will be invited back a week later to complete the session of HRT. At this visit (Visit 2), 
participants will be randomly assigned to receive either a 50 mg DCS pill or 50mg placebo pill. 
Participants, clinicians, and the therapist will be blind to random assignment (DCS or placebo), 
with only the research pharmacy and research coordinator being aware of medication 
assignment. At Visit 2, participants will complete rating scales and a computer task. Afterward, 
the participant will receive a session of HRT. Afterward, participants and clinicians will complete 
rating scales to assess the participant's mastery of components of HRT within session. The 
clinician will use a standardized form to evaluate any possible side effects of DCS. Participants 
will be asked to practice the strategies to control their tics over the next week, and complete a 
homework monitoring form. Participants will be asked to return 1 week later (Visit 3) to evaluate 
their overall tic severity and specifically the severity of targeted tics using standardized rating 
scales. Participants will also be asked about any side effects and evaluate homework 

Study Protocol 
 
compliance using standardized measures by an independent clinician blind to treatment 
condition. 
 
4. Background and Significance: 
Chronic Tic Disorders and Tourette Disorder (collectively referred to henceforth as CTDs) are 
characterized by the childhood onset of tics that persist for more than one year (American 
Psychiatric Association, 2013). Collectively, these conditions are estimated to affect 0.8%-2.0% 
of youth (Centers for Disease Control and Prevention, 2009; Scharf, Miller, Mathews, & Ben-
Shlomo, 2012). For individuals with CTDs, tic symptoms typically emerge in childhood (Bloch & 
Leckman, 2009), and exhibit a fluctuating course with peaks in symptom severity that stabilize 
over a period of weeks (Lin et al., 2002). The limited information available suggests that tics 
reach their greatest severity in adolescence, and subside into early adulthood for some youth 
(Bloch & Leckman, 2009; Bloch et al., 2006). Youth with CTDs are reported to experience 
significant impairment (Conelea et al., 2011; Storch et al., 2007) and poor quality of life 
(Conelea et al., 2011; Storch et al., 2007). Therefore, efficient and effective treatments are 
imperative for youth with CTDs.  
 
Expert reviews and practice parameter papers recommend behavior therapy as a first-line 
intervention for youth with CTDs that have mild-to-moderate tic severity (Murphy, Lewin, Storch, 
Stock, & AACAP Committee on Quality Issues, 2013; Verdellen, Van De Griendt, Hartmann, & 
Murphy, 2011). Behavioral interventions such as Habit Reversal Training (HRT) and its 
successor the Comprehensive Behavioral Intervention for Tics (CBIT) are efficacious in 
reducing tic severity for individuals with CTD (McGuire et al., 2014b; Piacentini et al., 2010; 
Wilhelm et al., 2012) with long-term improvement observed for up to six months (Piacentini et 
al., 2010; Wilhelm et al., 2012; Woods et al., 2011). Despite its therapeutic benefit, only about 
50% of youth exhibit a positive treatment response, with full tic remission being infrequent. 
Thus, there is a clear need to delineate the mechanisms of CBIT and identify strategies to 
improve treatment response to this evidence-based intervention (Scahill et al., 2013).  
 
The behavioral treatment model underlying CBIT (Woods et al., 2008) acknowledges the 
neurological origin of tics (McNaught & Mink, 2011), but suggests that tics are influenced by 
internal and external contextual factors (Conelea & Woods, 2008). Prominently, many 
individuals with CTD experience aversive premonitory urges (internal factors) that are relieved 
by tic expression (Leckman, Walker, & Cohen, 1993; Woods, Piacentini, Himle, & Chang, 2005) 
and are associated with greater tic severity (Reese et al., 2014; Woods et al., 2005). It is 
suggested that the relief from the aversive premonitory urge experienced by tic expression 
serves to negatively reinforce (i.e., strengthen) tic expression (Woods et al., 2008). The primary 
component of CBIT is HRT, which employs mechanisms of both extinction and associative 
learning. In CBIT, patients learn to implement competing responses contingent upon internal 
triggers such as premonitory urges to prevent tics and the associated urge alleviation. 
Consequently, the negative reinforcement cycle between tic expression and urge reduction is 
extinguished. Furthermore, as not all tics have urges and not all urges may be extinguished, 
CBIT facilitates the formation of new learning associations between tic triggers (i.e., premonitory 
urges) and competing responses (e.g., not ticcing) that compete with previously developed 
urge-tic associations (associative learning).   
 
Although previous investigations among youth with CTDs (Lyon et al., 2010) and related 
disorders (e.g., obsessive-compulsive disorder, Storch et al., 2013; anxiety disorders, Walkup et 
al., 2008) have explored the use of pharmacological augmentation strategies to improve 
therapeutic outcomes, findings from these investigations have been mixed. Emerging research 
from translational neuroscience suggests that cognitive enhancers such as d-cycloserine (DCS) 

Study Protocol 
 
present a viable option to safely enhance therapeutic outcomes and expedited treatment gains 
for exposure-based therapies. D-cycloserine is a partial glutamatergic NMDA receptor agonist 
that is approved by the United States Food and Drug Administration to treat tuberculosis in high 
does, but works as a cognitive enhancer for psychosocial interventions in much lower doses 
(e.g., 50 mg).  DCS has been found to enhance extinction (Walker, Ressler, Lu, & Davis, 2002) 
and associative learning (Quartermain, Mower, Rafferty, Herting, & Lanthorn, 1994) across 
numerous animal and human studies (Davis, 2011; Fitzgerald, Seemann, & Maren, 2014).  
 
Exposure-based psychosocial interventions that utilize these mechanisms have demonstrated 
greater therapeutic outcomes and/or expedited therapeutic gains when augmented with DCS 
relative to placebo across a variety of psychiatric disorders (e.g., anxiety disorders, obsessive-
compulsive disorder, post traumatic stress disorder, schizophrenia; Gottlieb et al., 2011; 
McGuire, Lewin, & Storch, 2014a). Moreover, across multiple RCTs of DCS-augmented 
treatment, few side effects have been reported with no serious adverse events identified (Ori et 
al. 2015). Although the results from these RCTs have been mixed across disorders (McGuire et 
al. 2014a), they bear considerable promise. Indeed, DCS-augmentation of HRT may yield 
greater overall reductions in tic severity and/or expedited therapeutic gains resulting from 
enhanced extinction and associative learning.   
 
5. Study Aims 
 
Primary Aim#1: To examine whether a single session of HRT+DCS will produce faster 
reductions in tic severity relative to HRT+placebo for tics targeted in treatment.  
 
Hypothesis#1: We hypothesize that HRT+DCS will produce faster reductions in tic severity 
relative to HRT+placebo for tics targeted in treatment on the Hopkins Motor/Vocal Tic Scale 
(HM/VTS). 
 
6.  Administrative Organization 
 
This study will only take place at the University of California Los Angeles (UCLA). There are no 
other participating study sites, laboratories, data management centers, and/or coordinating 
centers.  
 
7. Study Design 
 
This is a double-blind placebo controlled study that will compare the efficacy of a single session of 
HRT augmented by either DCS or placebo in youth (age 8-17) who have either Tourette Disorder 
or a Persistent Tic Disorder. The sample size was determined based on the feasibility of the 
recruitment period. Participants will complete an initial evaluation to determine eligibility (Visit 1). 
Afterward, eligible youth will be randomly assigned to receive either DCS or placebo prior to a 
single session of HRT (Visit 2).  During this visit, two tics will be targeted for treatment using HRT. 
One week after the therapy session, youth will return (Visit 3) to complete a follow-up assessment 
to determine improvement in tics targeted in treatment. The primary outcome measure will be the 
improvement in two bothersome on the Hopkins Motor/Vocal Tic scale (HM/VTS) at Visit 3.  
 
8. Study Procedures: 
 
Participants: 
 
Included in this study will be up to 20 children and adolescents between the ages of 8 and 17 

Study Protocol 
 
years (inclusive), who meet diagnostic criteria for Tourette Disorder or a Persistent Tic Disorder 
and the inclusion and exclusion criteria.  
 
Recruitment: 
 
Recruitment will occur through the UCLA OCD, Anxiety, and Tic Disorder’s Program, as well as 
the greater Los Angeles Community. 
 
Inclusion/Exclusion Criteria: 
 
Inclusion criteria for this study are as follows: (1) ages 8 years to 17 years (inclusive); (2) meet 
diagnostic criteria for either Tourette Disorder or a Persistent Tic Disorder; (3) moderate tic 
severity or greater as evidenced by a Yale Global Tic Severity Scale (Leckman, Riddle, Hardin, 
& Ort, 1989) total score greater than 13 (>9 for children with motor or vocal tics only); (4) be 
fluent in English; (5) be medication free or on a stable dose of a non-antipsychotic medication 
for 6 weeks with no planned changes. Co-occurring psychiatric disorders are permissible for 
enrollment.  
 
Exclusion criteria for this study are as follows: (1) pregnant or breast feeding; (2) an unstable 
medical condition (e.g., a seizure disorder, kidney or liver disease); (3) current diagnosis of 
substance abuse/dependence; (4) lifetime diagnosis of schizophrenia, autism spectrum 
disorder, bipolar disorder, or psychosis; (5) evidence of a seizure disorder, kidney or liver 
disease, pregnant and/or breast feeding; (6) four or more previous sessions of HRT; or (7) 
currently taking an antipsychotic medication. 
 
Procedures:    
 
The study will consist of three visits over 3 weeks. Visit 1 is a baseline visit to determine 
eligibility, Visit 2 is a single session of HRT with either DCS or placebo, and Visit 3 is a follow-up 
assessment to measure change in tic symptoms.    
 
Prior to coming in for Visit 1, interested children and families will complete a brief telephone 
screen to evaluate eligibility criteria conducted by either the principal investigator or research 
staff. If children and families appear to meet eligibility criteria, they will be scheduled for a 
baseline assessment to ascertain eligibility for participation.   
 
At Visit 1 (Baseline), children and parents interested to participate will meet with the PI and 
other research staff to provide a general explanation of the study including eligibility 
requirements, study aims, and study procedures. The PI will give the consent forms to the 
families and explain what the forms mean. Written informed consent will be required from 
parents and written assent from children.  After consent and assent are obtained, children and 
their parents will complete an assessment battery to determine eligibility, evaluate co-occurring 
psychiatric conditions, and measure tic symptom severity and related constructs that may take 
up to 3 hours to complete. An experienced clinician will conduct the following semi-structured 
clinical interviews with parents and children to identify psychiatric diagnoses, tic severity, 
premonitory urge presence, most bothersome tics, and global tic severity: the Anxiety Disorder 
Interview Schedule-Parent and Child Version (ADIS-C/P); the Yale Global Tic Severity Scale 
(YGTSS); the Individualized Premonitory Urge for Tics Scale (I-PUTS); Hopkins Motor and 
Vocal Tic Scale (HM/VTS) and the Clinical Global Impression of Severity (CGI-S). Children will 
also be asked to complete a standardized 10 minute video observational protocol to identify the 
frequency and severity of tics (Himle et al. 2006). Parents will be asked to complete a 

Study Protocol 
 
demographic questionnaire, a parent-report of the child's tic severity called the Parent Tic 
Questionnaire (PTQ), and a rating scale of ADHD severity called the Swanson Nolan and 
Pelham Scale-4th edition (SNAP-IV). After completing the video observation protocol, children 
will be asked to complete a child-report of tic severity called the Child Tic Questionnaire (CTQ), 
a self-report Premonitory Urge for Tics Scale (PUTS) to measure the child's global premonitory 
urge, and a self-reported rating scale of puberty development called the Peterson Puberty 
Development Scale (PDS). For female participants who have had first menses, a pregnancy 
screen will be conducted. Interested participants who meet full eligibility criteria will be invited 
back to complete Visit 2 (HRT session) approximately 1 week later.  
 
At Visit 2, participants will arrive and will be randomly assigned to receive either a 50 mg 
placebo pill or a 50 mg d-cycloserine pill. Evaluating clinicians, participants, and the therapist 
will be blind to randomization assignment, with only the study coordinator and research 
pharmacy having access to randomization assignment. As d-cycolserine typically takes 1 hour 
to become active in participants' system, children and adult will be re-administered the following 
rating scales to evaluate the current severity of the participant’s tics, most bothersome tics, and 
premonitory urge: the CTQ; PTQ, HM/VTS and I-PUTS. Children will then be asked to complete 
a computer task to evaluate habit learning called the Weather Prediction task. Afterwards, 
children will complete a session of HRT that will target two tics in treatment as identified by the 
HM/VTS. After the participant has completed the session of HRT, the participant will be asked to 
practice the skills learned in the session over the next week and to document practices using a 
homework monitoring form. The therapist will complete a session summary sheet to evaluate 
the patient’s mastery of the skills within session.  After the completion of the HRT session, a 
standard side effect form will also be administered to the participant to assess for any side 
effects. Participants will be asked to return 1 week later for a follow-up assessment. Visit 2 may 
take up to 4 hours to complete.  
 
At Visit 3, participants will complete a battery of tic assessment to monitor change in tic severity. 
These assessments will be administered by a clinician blind to randomization assignment, and 
will include the YGTSS, I-PUTS, HM/VTS, and the Clinical Global Impression of Improvement 
that serves as a global rating of improvement of tics. Participants will also be administered a 
standard side effect form to monitor for any possible side effects of d-cycloserine. Children will 
complete a standardized 10 minute video observational protocol to identify the frequency and 
severity of tics (Himle et al. 2006). Parents will be asked to complete the PTQ to assess parent 
report of tic severity and a homework compliance monitoring form to evaluate the participant’s 
practice of skills learned in HRT over the past week. Children will be asked to complete the CTQ 
to assess child-reported tic severity and the PUTS to evaluate their premonitory urge globally. 
Children will also complete a homework compliance form. This visit may take up to 2 hours.  
Participants and their families will be collectively compensated $30 for each study visit.  
 
 
Tests/Measures Administered: 
 
The following measures and tasks will be administered this study.  
 
Clinician Administered: 
 
Anxiety Disorder Interview Schedule-Parent and Child Version (ADIS-C/P; Silverman & Albano, 
1996).  This is a clinician-administered, structured diagnostic interview based on DSM-IV 
diagnostic criteria. Diagnoses reflect endorsement of symptoms as well as a severity rating 
(patient impairment/distress) of at least 4 on a 0-8 scale. The tic disorder section, created 

Study Protocol 
 
by Dr. Piacentini, will be used to confirm tic diagnoses. The ADIS-C/P is widely used in both 
research and practice. 
 
Yale Global Tic Severity Scale (YGTSS; Leckman et al., 1989). The YGTSS is a semi-
structured interview that examines the presence and severity of motor and phonic tics over 
the previous week across 5 domains: total motor tics, total phonic tics, total tics, overall 
impairment rating, and a global severity score. The YGTSS has well-supported 
psychometric properties (Storch et al., 2005; Leckman et al., 1989).  
 
Individualized Premonitory Urge for Tics Scale (I-PUTS). The I-PUTS is a clinician-
administered scale that assess the frequency, intensity and body region of premonitory 
urges that are associated with tics endorsed on the YGTSS. 
 
Clinical Global Impression – Severity (CGI-S; Guy, 1976). The CGI-S is a 7-point clinician 
rating of illness severity that is anchored by 0 (no illness) and 6 (extremely severe). The 
CGI-S will be used as an overall measure of tic severity.  
 
Clinical Global Improvement (CGI; Guy, 1976). The CGI is a clinician-rated measure of 
treatment response on a 7-point scale ranging from 1 (“very much improved”) to 7 (“very 
much worse”). Response status is defined as a rating of “very much improved” or “much 
improved” and based on the participant’s level of overall tic severity relative to baseline 
(Visit 1).  
 
Hopkins Motor/Vocal Tic Scale (Walkup et al. 1992). Participants nominated up to five motor 
and five vocal tics they deemed most bothersome. These tics are rated by a clinician on a 5-
point scale that ranged as follows: 0 (none), 1 (mild), 2 (moderate), 3 (moderately severe), and 
4 (severe). These ratings incorporated frequency, forcefulness, interference, and subject 
distress. Participants are also asked about whether a premonitory urge is associated with each 
bothersome tic. 
 
Adverse Event Review Form. A modified version of the Safety Monitoring Uniform Report Form 
will be completed at Visit 2 and Visit 3 to monitor for any possible adverse events or side effects 
from the single administration of d-cycloserine or placebo.   
  
Direct Observation Video Recordings: 
Direct Observation of Tics (Himle et al., 2006). An observed tic frequency count will be 
obtained through partial-interval scoring of a 10 minute video recording of participants. After 
video observation is collected, raters will record the number of 10-second intervals during 
which participants have at least one tic. Ten-second intervals are most commonly used in 
tic studies and this method of scoring has been shown to be highly correlated with total tic 
frequency (Woods et al., 1996, 2003; Himle et al., 2006).  
 
Computer Tasks: 
 
The Weather Prediction Task (Knowlton, Squire & Gluck, 1994). The Weather Prediction task is 
a measure of procedural or habit learning that requires gradual acquisition of stimulus-response 
associations.  Participants are asked to predict rain or sunshine based on the presentation of a 
varying combination of a set of four different cards on a computer screen by pressing one of two 
letters on the keyboard.  Each card is independently and probabilistically related to the 

Study Protocol 
 
outcomes, each of which occurs equally often. Participants receive positive or negative 
feedback after each prediction via visual feedback on the computer screen.  The task consists 
of 90 trials lasting approximately 15 minutes.  Accuracy (% correct) and reaction time scores 
across six learning blocks were used as the outcome variables.  
 
Parent Report Forms: 
 
Demographic Form. A demographic form will assess information regarding the participant’s age, 
gender, ethnicity, living situation, parental marital status, parental income, and parental 
occupational status. Additionally, the form will assess the participant’s past treatment history 
and whether they are have taken medications and for what duration of time. Finally, this 
demographic form also inquires about the participant's health including whether the participant 
has an unstable medication condition, is pregnant or breast feeding, and/or has a history of a 
seizure disorder, kidney disease, or liver disease.  
 
Parent Tic Questionnaire (PTQ, Chang et al. 2009).  The PTQ is a 28 item measure comprised of 
14 commonly experienced motor tics and 14 commonly experienced vocal tics. Parents are asked 
to identify whether each of these tics have been absent or present over the past week for their 
child. For tics that are endorsed over the past week, parents are asked to make a separate rating 
of the frequency and intensity of the tic on a 1-4 scale. Items are summed separately for motor 
tics and phonic tics, with all items summed for a total parent-reported rating of tic severity over the 
past week.  
 
Swanson Nolan and Pelham-4th Revision (SNAP-IV, Swanson, 1992). The psychometrically 
sound, parent-rated SNAP-IV (Swanson, 1992) provides a dimensional scaling of the DSM 
items for inattention, impulsivity, hyperactivity, oppositionality, and related behaviors. 
Symptoms are scored by assigning a severity estimate for each item on a 4-point scale.  
 
Parent Reported Homework Compliance. The parent-reported homework compliance form 
consists of 9 questions that ask about the parent’s perception of the child’s duration of practice 
over the past week, and the child’s mastery over the skills learned in HRT across settings (home 
and school).    
 
Child Report Forms: 
 
Child Tic Questionnaire (CTQ). The CTQ is the parallel version of the PTQ, but is reported by the 
child. The CTQ is a 28 item measure comprised of 14 commonly experienced motor tics and 14 
commonly experienced vocal tics. Children are asked to identify whether each of these tics have 
been absent or present over the past week. For tics that are endorsed over the past week, 
children are asked to make a separate rating of the frequency and intensity of the tic on a 1-4 
scale. Items are summed separately for motor tics and phonic tics, with all items summed for a 
total parent-reported rating of tic severity over the past week.  
 
Premonitory Urge for Tics Scale (PUTS; Woods et al. 2005). This is a 9-item scale that 
evaluates the presence and strength of premonitory urges on a global scale, with items 
being rated on a 1 (not at all true) to 4 Likert scale (very much true). The PUTS has been 
used in several randomized controlled trials of HRT (Piacentini et al. 2010). 
 
Child Reported Homework Compliance. The child-reported homework compliance form consists 
of 9 questions that ask about the child’s perception of their duration of practice over the past 

Study Protocol 
 
week, and their mastery over the skills learned in HRT across settings (home and school).    
 
Peterson Puberty Development Scale (PDS). The PDS is an 8-item measure of a child’s pubertal 
development reported by the child. The scale consists of three questions for boys and girls about 
the development of body hair, the occurrence of a growth spurt, and changes in complexion. Two 
additional items are asked of girls, one about breast development and the other about the onset of 
menstruation. Boys are asked about changes in voice and growth of facial hair. With the noted 
exception of menarche (dichotomy), all of the questions are answered on a 4-point scale (1= has 
not yet begun, 2= has barely started, 3= is definitely under way, and 4= growth or development it 
complete). The PDS has been used in randomized controlled trials to assess youth’s pubertal 
development (Walkup et al. 2008).   
 
Therapist Form: 
 
Session Summary Sheet. The session summary sheet is a therapist completed form that identifies 
the tics targeted in session, and monitors the participants habituation to the premonitory urge 
across trials (if present) and mastery of competing response skills for each of the two targeted tics 
in the HRT session.  
 
 
9. Safety Monitoring Plan: 
 
Definition of adverse events, and serious adverse events 
For the purposes of this study, an adverse event is any untoward medical occurrence 
associated with the use of a drug in humans, whether or not considered drug related.  
 
For the purposes of this study, a serious adverse event is characterized as any adverse drug 
event (experience) occurring at any dose that in the opinion of the study investigator results in 
any of the following outcomes: (1) death, (2) life-threatening adverse drug experience, (3) 
inpatient hospitalization or prolongation of existing hospitalization (for > 24 hours), (4) persistent 
or significant incapacity or substantial disruption of the ability to conduct normal life functions, 
(5) congenital anomaly/birth defect, and (6) important medical event (IME) that may jeopardize 
the subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. 
 
Procedures will be used to monitor subject safety 
Adverse events will be systematically assessed at Visits 2 and 3 using a standardized adverse 
event review form (i.e., modified version of the Safety Monitoring Uniform Report Form). This 
will allow study investigators to monitor for any possible adverse events or side effects from the 
single administration of d-cycloserine or placebo.   
  
Who (list names) will identify, document, and report adverse events? 
The study PI will identify and document adverse events when they have been identified during 
the study.  
 
What is the frequency for review of summarized safety information and who will perform the 
review? 
Any serious, unanticipated problems (e.g., serious adverse events) will be reported to the IRB 
within 3 working days of study investigators’ awareness.  
 
What are the stopping rules with regard to efficacy and safety? 

Study Protocol 
 
 
In the event of a serious adverse event, the subject will discontinue study participation and the 
attending psychiatrist (the prescribing physician) will be notified. The research staff will monitor 
the participant closely until the adverse reaction remits. 
 
10. 
Potential Risks of Study Participation 
 
The risks of participating in this project include relatively lengthy psychiatric evaluations, 
participating in a single session of HRT, and the medication (placebo or DCS).  
 
One potential risk of participating in this project includes discomfort associated with the 
psychiatric evaluation and administration of rating scales – either due to the discussion of 
subjectively difficult topics, or due to the length of time required for the interviews and 
questionnaires. In efforts to minimize subject burden, we only chose measures that were central 
to study questions and did not overlap considerably with other study measures. With regard to 
potential discomfort, our experience indicates that most people welcome the opportunity to 
discuss their experiences with a trained clinician; and any information shared by the subject will 
be kept confidential. Additionally, we have done our best to minimize subject burden while 
assessing relevant constructs and maintaining the internal validity of the study. Breaks will be 
given as much as possible to decrease boredom and physical/psychological discomfort. As well, 
we will compensate families $30 for each study visit. This compensation will be split equally 
between parent and child participants.  
 
Another possible risk is that participants may feel subjective distress when learning skills to 
manage their tics as part of habit reversal training (HRT). This effect is usually very transitory 
and mild, and though to be a result of the participant gradually habituating to a distressing 
internal sensation referred to as a premonitory urge.  This effect of HRT will not be described as 
an adverse event, unless a subject or parent specifically descries the reaction as an adverse 
event of participation. However, in general, participants in randomized controlled trials (RCTs) 
find HRT to be beneficial in learning to manage their tics, with no significant adverse events 
reported (Piacentini et al. 2010).  
 
Finally, the potential side effects associated with the administration of DCS include drowsiness, 
headache, prolonged or momentary dizziness, seizures, confusion, hallucinations, weakness, 
coma, rash, vitamin B12 deficiency and/or folate deficiency (both of which may cause weakness 
and anemia), liver enzymes increases (which could cause weakness or bleeding), and shaking. 
However, these side effects are most commonly related with doses greater than 500mg/day and 
when dosed chronically (versus acutely), which is at least ten times greater than what we 
propose to administer in this study. DCS has been approved by the Food and Drug 
Administration for the treatment of tuberculosis for over 20 years, and, as discussed by 
Rothbaum et al. 2008, single-pill administrations have been associated with no adverse effects. 
Furthermore, a recent meta-analysis of over 20 randomized controlled trials of DCS-
augmentation that included multiple doses of DCS within each trial, identified no greater 
adverse event profile relative to placebo with as many as 8 trials reporting no adverse events at 
all. In the event of a moderate or severe adverse event related to the medication, the subject will 
be withdrawn from the study, the attending psychiatrist (Dr. McCracken will be notified), and the 
research staff will monitor the participant closely until the adverse reaction remits.  
 
Although not a risk directly associated with d-cycloserine, there is always the chance that a 
participant may report either the perceived risk of suicidality or suicidality itself. In these cases, 
standard protocol will be followed. If, during an assessment, research staff determines that a 

Study Protocol 
 
youth endorses a serious mental health program such as suicidal behavior, referral information 
and telephone numbers to appropriate community services will be provided. The PI will conduct a 
risk assessment for suicidal ideation and/or behavior. Although unanticipated, if the detected 
problem is imminent and of crisis status, the PI will take appropriate immediate action including 
calling emergency services and/or calling UCLA campus police to escort the youth to the 
emergency department (on-site at UCLA). These situations will be reviewed immediately with the 
PI’s research mentor (Dr. Piacentini), who is a licensed clinical psychologist. 
11. Analysis Plan 
 
Descriptive statistics will be used to characterize the entire sample and two conditions (DCS, 
placebo). Independent sample t-tests and chi-square tests will be used to examine for between-
group differences (DCS versus placebo) for continuous and categorical variables respectively. 
Although no significant differences in conditions are expected due to random assignment, any 
significant between group differences will be controlled for during data analysis. Given that co-
occurring ADHD and alpha-2 agonists have been found to influence tic severity outcomes to 
HRT, these will interested a covariates at baseline.  
 
The primary outcome in this study will be the reduction in bothersome tic severity on the 
HM/VTS for the two tics targeted in treatment. The average score for these two bothersome tics 
will be interested into a repeated measures analysis of variance (ANOVA), with the covariates of 
ADHD diagnosis and alpha-2 agonist status at baseline. The diagnosis of ADHD will be 
identified from the structured clinical interview (ADIS), and alpha-2 agnostic will come from 
demographic information form. This data will be entered across three assessment visits, with a 
between group factor of treatment condition (DCS+HRT or PLBO+HRT).  
 
 
 
 
 

Study Protocol 
 
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