The Use of D-Cycloserine to Augment CBT for Pediatric OCD

Although research has demonstrated clear benefits of cognitive behavioral treatment for
children with obsessive-compulsive disorder, typical rates of treatment response are far
from absolute and even treatment responders tend to exhibit continuing symptoms. In one of
the most cited and largest child OCD treatment study to date, only 39% of the participants
showed a robust response to a 12-week course of CBT. In recent years, the basic research
finding that D-Cyclocerine, a partial N-methyl-Daspartate (NMDA) receptor agonist, enhances
extinction of learned fear among rats2 has generated significant interest among clinical
researchers. This is not surprising given that the core component of CBT involves exposing
the individual to the feared stimuli in the absence of the feared consequence (ie,
extinction training). Indeed, data from several trials (for adults with social anxiety,
specific phobia, and OCD) indicate that compared to placebo, when DCS is added to exposure,
participants tend to respond faster and at higher rates to treatment. This significant
development in clinical treatment for anxiety disorders has been examined in only one pilot
study among children with OCD. In this study, the effects of DCS were modest but the
methodology utilized (eg., no objective symptom measure, lack of information regarding
aspects of treatment) make the results difficult to interpret. The present study will help
clarify, albeit in only a preliminary way, whether DCS is a promising addition to the
treatment options available to the OCD treatment provider. The greatest utility of the
augmentation strategy may be the capability to hasten the rate of improvement, and thus,
decrease the discomfort of treatment and decrease treatment drop-out.

*Research Design and Methods: Describe in detail the design and methodology of the study.

A) Overview We propose to examine the preliminary efficacy of D-cycloserine augmentation of
eight sessions (two weeks) of intensive exposure and response prevention treatment
administered to youngsters aged 7-17 with primary OCD. All subjects will be receiving
clinical treatment through the UCLA Child OCD Intensive Outpatient Program and DCS will be
introduced, and will be delivered during the third and fourth week (starting on the 9th IOP
treatment visit) of the subject's participation in the IOP clinical treatment.

To best address these aims, a total twenty-six 7-17 year-old children and adolescents will
be recruited from UCLA Child OCD Intensive Outpatient Program. After completing an
eligibility screen, all qualified participants will undergo a baseline evaluation including
diagnostic as well as symptom assessments before randomization or treatment. This baseline
assessment will be completed no more than 5 days prior to their 9th treatment visit (i.e.,
their first day of DCS medication).

Following these assessments, subjects will be randomized to receive either DCS or placebo
(PBO) 4 times weekly immediately preceding their treatment session for two weeks of
treatment (4 sessions weekly). Study participants will receive the same cognitive-behavior
treatment through IOP whether they are in the active (DCS) or placebo (PBO) condition. In
addition, all subjects will continue clinical treatment in IOP for as long as clinically
indicated. However, responders at study week 2 (CGI-I = 1 or 2) will be reassessed at
three-month follow-up to establish durability of early response. Parents will participate in
the child's clinical assessment, and fill out self-reports, to better help the research team
understand the child's functioning. Please see attached table of procedures for overview.

B. Core Clinical Assessment (Visit 1):

Diagnostic assessment will be based on the Anxiety Disorder Interview Schedule for DSM-IV,
Child Version and Parent Version (ADIS-C & ADIS-P; Silverman & Albano, 1996). The ADIS is a
structured interview schedule designed to obtain information about symptomatology, course,
etiology, and severity of anxiety disorders, mood disorders, and externalizing disorders in
children and adolescents. The following sections will be administered at this visit: all
anxiety disorders (except selective mutism), anxiety disorder NOS, MDD, dysthmia, bipolar,
ADHD, CD, ODD, substance use disorders, and tic disorders. The ADIS currently provides the
basis for psychiatric diagnosis in our ongoing CAMELS Study for which the Child OCD,
Anxiety, & TS program is a collaborating center. All potential research subjects will
undergo ADIS assessment by one of the trained study clinical interviewers. The ADIS
interview will take approximately 90 minutes to complete and will be administered only at
baseline.

All study subjects will complete a core battery of dimensional psychiatric rating scales to
more fully characterize OCD along with other key variables, including demographic status,
other comorbid symptomatology, functional status, and adverse events or side effects. Many
of these measures are derived from recent or ongoing treatment protocols in our OCD, Anxiety
and Tic Disorders Program. In addition to the ADIS, the core battery will include the
following measures:

1. Demographics/History. Provides standardized information regarding demographic status,
medical history, and past history of mental health treatment. (10 minutes, only at
baseline)

2. Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS): is a semi-structured
clinical rating scale assessing OCD severity. The CY-BOCS was developed at Yale
University for the definition of OCD symptoms and severity in children. The CY-BOCS
will only be administered to youngsters with either parent- or child-report of
obsessions or compulsions during the ADIS interview. (30 minutes at baseline
administration; 15 minutes at end of study week 1, week 2, week 4, week 6, week 10, and
3-month follow-up)

3. Child OCD Impact Scale Child OCD Impact Scale (COIS; Piacentini et al., 2003) is a
reliable and valid self-report measure of OCD-related functional impairment. (5-10
minutes at baseline, end of study week 1, week 2, and 3-month follow-up).

4. Children's Depression Inventory - (Kovacs, 1992). The CDI is a psychometrically sound
rating scale comprised of 27 items (rated 0-2) assessing depressive symptomatology over
the preceding 2 weeks. Age and gender-based T-scores are generated for five factors of
depression. (10 minutes at baseline, end of study week 2, and 3-month follow-up).

5. Clinical Global Impression of Severity (CGI-S): A clinician rated instrument designed
to measure overall illness severity at that specific time point. This measure will be
recorded at each time point but is clinician rated and will not affect subject burden.

6. Clinical Global Impression of Improvement (CGI-I): A clinician rated instrument
designed to measure overall symptom improvement at that specific time point relative to
baseline symptom severity. This measure will be recorded at each time point but is
clinician rated and will not affect subject burden.

7. Side Effects and Adverse Events: Side effect and adverse events will be assessed at
every visit using the using an amended Adverse Event Form from another study with which
our group is involved. (5 minutes).

8. Behavioral Approach Test (BAT): We have adapted the BATs for this study from Ollendick
et (2011) who developed BATs specifically for children. When possible, BATs will be
realistic in that children will be asked to approach and/or touch actual feared object
or situation. When that is not possible, children pictures or video will be used. BAT
assessments will be designed idiographically for each participant based upon their
responses to the clinician administered CYBOCS instrument. The task will be
administered at baseline (study week 0), at end of study week 1, and end of treatment
(end of study week 2). The BATs consisted of a series of gradually more difficult steps
(ranging from 7 to 12 steps depending on the specific phobia). Due to the variability
in number of steps on the BATs, percentage of steps completed will be used as the
primary behavioral measure of BAT performance.

For the BAT, the child will be instructed to do their best, but also informed they can
terminate the BAT at any time if they wish to do so. BATs are terminated at the child's
request or when the terminal step is achieved. Children are asked to provide ratings of
their anxiety utilizing SUDS ranging from 0 to 8 (0 = None, 2 = A Little, 4 = Some, 6 = A
Lot, and 8 = Very Much). Ratings are obtained immediately following the last step of the
BAT. (15-20 minutes at baseline, end of study week 1, end of study week 2, and 3-month
follow-up).

Staff training and supervision on these and other project-specific clinical measures will be
coordinated and supervised by senior research study personnel using standardized methods to
maintain reliability over time. This portion of the assessment is estimated to take
approximately 1.5 hours to 2 hours.

F. Procedure:

Following these assessments, a total of 26 eligible subjects from the UCLA IOP will be
randomized by a computer-generated program in the UCLA research pharmacy in a double-blinded
fashion to receive either eight-sessions of DCS augmented exposure plus response prevention
(ERP +DCS) treatment (four times per week for 2 weeks) or eight sessions of placebo and ERP
(ERP+PBO) for the same time period. All study staff and families have no knowledge of
whether the individual youngsters are receiving placebo or DCS. All subjects will be
clinically assessed after the first and second study weeks of treatment and again 12 weeks
later. Additionally, there will be brief assessments (CY-BOCS and CGI measures) for the end
of study weeks 4, 6, and 10. Parents will also participate in the child's clinical
assessment, and fill out self-reports, to better help the research team understand the
child's functioning. Please see attached table of procedures for overview.

Inclusion Criteria:

- Ages 7 through 17 inclusive at the time of initial evaluation.

- Meets DSM-IV diagnostic criteria for OCD.

- Child is fluent English speaker.

- Parent Informed Consent and Child Informed Assent. Parents must agree to their
child's participation in this protocol. Parents will be asked to fill out self-report
questionnaires and participate in assessments that will provide us with more
information about their child, however parents are not considered "participants"
within this protocol, as all treatment is targeted toward their child.

Exclusion Criteria:

- IQ < 80 on the Wechsler Abbreviated Scale of Intelligence (WASI)

- Excessive or Problematic Substance Use or DSM-IV Conduct Disorder within the past 3
months.

- Lifetime DSM-IV diagnosis of PDD, Mania, or Psychotic Disorder.

- Any serious psychiatric, pscyhosocial, or neurological condition (i.e., ADHD, MDD,
anxiety, severe aggression, family discord) requiring immediate treatment).

- Presence of primary hoarding symptoms or mental rituals.

- Having epilepsy, renal insufficiency, or generally poor physical health.

- Pregnancy or having unprotected sex (in females).