D-cycloserine and Treatment of Feeding Disorders
Condition: Feeding Disorders; Specific Phobia
MeSH terms: Feeding and Eating Disorders
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      The proposed study represents the first attempt to systematically investigate the use of DCS
      as an adjunct to behavioral intervention to address chronic food aversion through an
      randomized control drug trial in children treated at the Marcus Autism Center's Pediatrics
      Feeding Disorders Program. This pilot and feasibility study will involve a total of 16
      participants randomly assigned to experimental conditions: behavioral intervention or
      behavioral intervention + DCS (8 in each group). All participants will receive the same
      behavioral protocol involving three treatment sessions per day (45 minutes in length), for a
      total of 15 sessions across five consecutive days. In addition, participants in the
      behavioral intervention + DCS group will receive a low dose (0.7 mg/kg) of the drug using an
      acute dosing methodology, which has been demonstrated to produce a nearly negligible side
      effect profile with comparable treatment outcomes to chronic dosing. Timing of dosing will
      occur 1 hour prior to behavioral intervention, in line with prior clinical studies. Study
      staff, with consultation from a psychiatrist, will observe administration of DCS to
      participants by caregivers via their preferred method of formula consumption (bottle, cup, or
      tube) in liquid form. Participants will be evaluated during each treatment session and at
      follow-up using trained observers to collect data on mealtime behaviors, including
      acceptance, swallowing, disruption, expulsion, and grams consumed. This type of data
      collection is standard practice in the feeding disorders program. It is hypothesized that
      participants who receive DCS as an adjunct to behavioral intervention will show greater
      improvement in mealtime behaviors as reflected by these measures.
    

Detailed description: 
      -  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.
    

Intervention name(s): Behavioral Intervention; d-cycloserine (DCS); Placebo
Intervention type(s): Behavioral; Drug; Drug
Intervention description(s): 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.; lactose powder
Intervention MeSH terms: Cycloserine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: food refusal; behavioral intervention; D-cycloserine