D-cycloserine and Treatment of Feeding Disorders

- Extinction of fear is thought to use similar learning mechanisms as learning or
conditioning of fear, and both are blocked by antagonists at the glutamatergic
N-methyl-D-aspartate (NMDA) receptor. Furthermore, agonists at this site appear to
augment some forms of learning in animal and human trials. The process of extinction of
conditioned fear was initially shown to be facilitated by D-Cycloserine (DCS), an NMDA
agonist, given in individual doses prior to extinction training in an animal model.
There is growing evidence that a similar effect is found in human subjects undergoing
controlled exposure therapy for specific phobia. This translational research proposal
represents a randomized-control study with the goal of determining whether a drug that
acutely enhances learning in both human and animal research will facilitate the
extinction of fear that occurs with behavioral therapy for children with food aversion.
Specifically, it is proposed that a single dose of DCS, given shortly before each of 5
days of behavioral therapy sessions utilizing escape extinction, will significantly
enhance the rate of response and possibly the efficacy of treatment for pediatric food
aversion. To this end, the investigators propose to enroll 16 participants with food
aversion. Participants will be randomly assigned to receive behavioral intervention
alone or in combination with 0.7mg/kg DCS. Behavioral ratings and outcomes will be
assessed by independent assessors blind to subject condition. Participants will be
assessed pre-treatment and at a one month follow-up session to assess long term
effects.

- This type of combined treatment -- specific pharmacotherapeutic augmentation of
behavioral therapy -- would be novel in pediatric populations with food aversion and
would potentially be generalizable to many different forms of behavioral intervention
for a wide range of pediatric disorders. The potential for detrimental health outcomes
associated with feeding disorders, combined with their complex biopsychosocial
etiology, intensifies the need to identify and refine effective treatments. If this
translational research is successful, the ability of a relatively benign agent
administered acutely before a behavioral therapy session to facilitate the extinction
process could have important clinical, humanitarian, and economic advantages.

Specific Aims: The entire proposed study is designed to achieve the following specific aims:

1. To explore whether d-cycloserine (DCS), an NMDA partial agonist, facilitates extinction
of food aversion in children using extinction based behavioral intervention.

2. To explore whether any facilitation in extinction produced by DCS in behavioral
intervention evidenced within session and immediately post-treatment results in
long-term gains in treatment response as compared to behavioral intervention alone.

2.2 Research Hypotheses: The following hypotheses will be tested:

1. DCS will facilitate extinction in children. It is predicted that the children who
receive behavioral intervention combined with 0.7mg/kg DCS will evidence more rapid
improvement in mealtime behavior (acceptance, swallowing, disruptions, expulsions,
grams consumed) than children receiving behavioral intervention alone.

2. Facilitation in therapeutic response aided by DCS will result in long-term gains. It is
predicted that the group of patients who receive behavioral intervention combined with
0.7 mg/kg DCS will evidence more improvement at the follow-up assessment as compared to
baseline behavior (acceptance, swallowing, disruptions, expulsions, grams consumed)
than the group who receives behavioral intervention alone.

Gender and Minority Participants' Inclusion Plan. Patients of all races and ethnic groups
will be entered, both males and females. The investigators will recruit from the year long
waiting list for behavioral services at the Feeding Disorders Program. The investigators
will advertise via fliers at the Marcus Autism Center, as well as local pediatric and
gastroenterological practices in the Atlanta area. (See Flyer Info to review content of the
flyer). The racial composition of Atlanta is 71% white, 26% black, and 3% other (based on
the 1990 US Census). Approximately 1% of these persons are of Hispanic origins. The gender
composition of Atlanta is 51% female. This study will provide free treatment, thus ensuring
equal opportunities for all to learn about and participate in this study. The treatment
setting is located in a racially diverse county (DeKalb County), is easily accessible by
public transportation and is wheelchair accessible. It is therefore expected that the study
sample will closely approximate the demographic composition of Atlanta.

Treatment:

Behavioral Intervention: Treatment will commence following the pre-treatment assessment.
Participants will be randomly assigned to one of two treatment groups: behavioral
intervention alone or behavioral intervention plus medication. All participants will be
treated for a period of 5 consecutive days. A total of 3, 45-minute meals will be held at
regularly scheduled times (e.g., 9:00 a.m., 10:30 a.m., and 12:00 p.m.) each day for a total
of 15 meals throughout treatment. Trained feeding therapists from the Marcus Autism Center's
Pediatric Feeding Disorders Program will conduct sessions in treatment rooms equipped with
one-way mirrors and an adjacent observation room to allow caregivers to watch all treatment
sessions. Behavioral intervention targeting severe feeding disorders involves the
combination of escape extinction and antecedent manipulation of food presentation to lessen
the aversive quality of the meal. This allows treatment to address the consequences
maintaining food refusal in the least restrictive environment while ameliorating possible
side effects associated with extinction procedures. Please refer to the nonremoval of the
spoon + representation + redistribution (NRS + REP + RED) protocol for a detailed example
the proposed treatment. Data will be collected during each meal and all behavioral treatment
sessions will be video recorded for the purpose of ensuring accurate protocol implementation
and assessing reliability. Caregivers will be trained on the protocol during the last
session of treatment to promote transition of the protocol into the home setting.

Medication: As described above, the investigators will compare behavioral intervention alone
to behavioral intervention plus 0.7mg/kg DCS. Patients will be instructed to take the
medication under the supervision of study personnel one hour prior to the first treatment
session. A placebo will also be given to participants in the behavior only condition using a
similar method of administration.

Design and Plan: The proposed design is to randomly assign 16 participants with food
aversion to behavioral intervention or behavioral intervention plus 0.7mg/kg DCS to be taken
acutely one hour prior to the onset of the first treatment session each day. All
participants will receive three, 45 minute treatment sessions per day for a period of five
days. Study medications will be administered in the clinic supervised by study personnel to
ensure compliance. The investigators will be using the Children's Healthcare of Atlanta
Investigational Drug Service (IDS) to provide both drug and placebo. Participants will be
assessed pre-treatment and at one month following the termination of treatment by a blinded
independent assessor.

Inclusion Criteria:

- Present with partial food refusal as evidenced by greater than 50% of caloric needs
met by bottle, formula, or tube feedings, thus eliminating children whose lack of
consumption is related to a skill deficit

- Have a medical history significant for an organic factor (e.g., gastrointestinal
issues) which precipitated or played a role in the development of feeding concerns,
thus capturing children whose food aversion mimics animal and human models of anxiety
and aversion

- Between the ages of 18 months and 6 years

- Live within 2 hours of the Feeding Disorders Program at Marcus Autism Center to
increase retention and maximize attendance

- English speaking

Exclusion Criteria:

- Patients with previous behavioral treatment for feeding disorder

- Patients with active medical conditions requiring ongoing hospitalization

- Patients unwilling to take study medication