This application addresses Broad Challenge Area """"""""(04): Clinical Research"""""""" and Specific Challenge Topic """"""""04-MH-103: Interventions That Target Symptom Dimensions of Childhood-Onset Mental Disorders."""""""" The family of cognitive-behavioral therapies (CBT) is a recommended intervention for posttraumatic stress disorder (PTSD) in practice guidelines based on meta-analyses of randomized studies. Although there are fewer studies in children and adolescents, these have shown similar effectiveness for CBT. But complete cure is rare. Most persons who remit below the level of full diagnosis still have enduring symptoms and impairment. Accordingly, there is a need for treatment advances. D-cycloserine (DCS), an antibiotic used to treat tuberculosis and urinary tract infections, is a partial agonist at the glycine modulatory site of the N-methyl- D-aspartic acid (NMDA) receptor. DCS was found to enhance learning and memory in several animal models and in human patients with Alzheimer's disease. DCS also produces a dose-dependent facilitation of extinction of fear-potentiated startle in the rat. However, DCS only produces an extinction effect as an adjunct, i.e., when paired with behavioral extinction training, not when simply given alone. Multiple preclinical and clinical studies have now been conducted, and a meta-analysis concluded that adjunctive use of DCS enhanced fear extinction when coupled with extinction trials (animals) or exposure-based psychotherapy (humans). This proposal will extend this model by conducting a randomized clinical trial of CBT plus DCS (CBT+DCS) versus CBT plus placebo (CBT+P) in 56 7-12 years-old youth with PTSD. This will be the second known trial of adjunctive DCS to treat PTSD and the first in children.
Specific Aim 1 :
The first aim i s to show a greater effectiveness of CBT+DCS versus CBT+P for reducing PTSD symptoms in 7-12 years-old children with PTSD. Both groups will receive manualized 12-session CBT.
Specific Aim 2 :
The second aim i s to show more rapid effectiveness of CBT+DCS versus CBT+P by reduction of subjective units of distress (SUDS) earlier in treatment. Ancillary Aims:
These aims are to explore the mechanism of change and neurobiological correlates that are facilitated by DCS by showing concurrent changes in a suspected underlying endophenotype (attentional bias to threat on a dot probe task) and correlated neurobiological measures (heart period variability and cortisol regulation). This application recognizes the complex interplay between underlying mechanisms and phenotypic manifestation of symptoms. By measuring attentional bias to threat, and two well-known neurobiological measures of stress, heart period variability and cortisol regulation, prospectively in a design of pre- and post- intervention, this may improve our understanding of risk mechanisms, possible biomarkers, and new ways of classifying disorders based on more objective and neurobiological measures. D-cycloserine (DCS) represents an additional treatment modality that would provide greater and more rapid remission of posttraumatic stress disorder. The addition of DCS to cognitive behavioral therapy would be easier to implement and more acceptable to patients than traditional medication because DCS only needs to be taken about half a dozen times or less during therapy with no need to build drug levels or stay on a maintenance dose. The safety profile of DCS is well-known from its use for over 50 years to treat infections, and the risk of serious side effects would be minimal, especially when taken at low doses over short periods as in this study.
D-cycloserine (DCS) represents an additional treatment modality that would provide greater and more rapid remission of posttraumatic stress disorder. The addition of DCS to cognitive behavioral therapy would be easier to implement and more acceptable to patients than traditional medication because DCS only needs to be taken about half a dozen times or less during therapy with no need to build drug levels or stay on a maintenance dose. The safety profile of DCS is well-known from its use for over 50 years to treat infections, and the risk of serious side effects would be minimal, especially when taken at low doses over short periods as in this study.
