A Placebo-Controlled Trial of D-Cycloserine and Exposure Therapy for Combat-PTSD

Study Overview
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Brief Summary
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The primary aim of this project is to examine whether administration of D-Cycloserine (DCS), a partial N-methyl-D-aspartate (NMDA) receptor agonist that has been shown to facilitate fear extinction, enhances the therapeutic benefit of exposure-based cognitive behavioral therapy (CBT) in OEF/OIF veterans with PTSD.

Detailed Description
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War-zone-related posttraumatic stress disorder (PTSD) is a major psychiatric disorder that includes specific disabling symptoms and impairments that interfere with a soldier's ability to do his or her job. There is strong evidence for cognitive behavior therapy (CBT) in treating PTSD in civilians, which suggests a prescription for returning veterans, but approximately 40% of patients retain a PTSD diagnosis (e.g., Foa et al., 1999) and drop-out rates are  25%. It is imperative to develop novel evidence-based early interventions that are more acceptable to recent veterans and less draining of treatment resources. If CBT can be shortened and its efficacy boosted by cognitive enhancers then it is more likely that soldiers will get the most efficacious treatments for acute stress and PTSD. Our aim is to develop a program that is brief and effective, but will have long-term benefits for veterans by virtue of its greater amenability to self-management and treatment adherence beyond the therapy context. This study is a randomized, controlled, double-blind treatment trial comparing CBT plus DCS to CBT plus placebo. Participants will be 68 OEF/OIF veterans with PTSD randomly assigned to CBT plus DCS or CBT plus placebo. Procedures to screen subjects prior to randomization include a detailed phone screen, administration and collection of questionnaires, a medical assessment, and two baseline structured clinical interviews. Following randomization, both groups will receive the identical 6 session exposure-based CBT protocol. The DCS-augmented group will receive 50 mg of DCS 30 minutes prior to the four CBT sessions involving imaginal exposure, whereas the placebo-augmented group will receive a placebo pill prior to these sessions. Assessment interviews conducted by independent evaluators will occur at pre-treatment, post-treatment, and at 3, and 6-month follow-up. Self-report measures will also be administered at screening, throughout the 6 weeks of treatment, and at 3- and 6- month follow up. Comparison(s): OEF/OIF veterans with PTSD treated with CBT plus DCS, compared to OEF/OIF veterans with PTSD treated with CBT plus placebo.

Official Title
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A Placebo-Controlled Trial of D-Cycloserine and Exposure Therapy for Combat-PTSD

Conditions
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Combat Disorders, Stress Disorders, Post-Traumatic

Intervention / Treatment
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* Behavioral: Exposure therapy
* Drug: D-Cycloserine
* Other: Placebo pill


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female outpatients 18 years of age or older who served in Operation Iraqi Freedom or Operation Enduring Freedom (OIF/OEF) and who have a primary diagnosis (designated by the patient as the most important source of distress of PTSD. Willingness and ability to comply with the requirements of the study protocol. Exclusion Criteria: A lifetime history of: bipolar disorder schizophrenia psychosis delusional disorders or obsessive-compulsive disorder organic brain syndrome cognitive dysfunction that could interfere with capacity to engage in therapy a history of substance or alcohol dependence (other than nicotine) in the last 6 months or otherwise unable to commit to refraining from alcohol use during the acute period of study participation. Patients with significant suicidal ideation or who have enacted suicidal behaviors within 6 months prior to intake will be excluded from study participation and referred for appropriate services. Patients must be off concurrent psychotropic medication (e.g., antidepressants, anxiolytics, beta blockers) for at least 2 weeks prior to initiation of randomized treatment. Serious medical illness or instability for which hospitalization may be likely within the next year. Patients with a current or past history of seizures Pregnant women, lactating women, and women of childbearing potential who are not using medically accepted forms of contraception (e.g., intra uterine device, oral contraceptives, barrier devices, condoms and foam, or implanted progesterone rods stabilized for at least 3 months). Any concurrent psychotherapy initiated within 3 months of baseline, or ongoing psychotherapy of any duration specifically targeting PTSD is excluded. General supportive therapy initiated > 3 months prior is acceptable. Patients with seizures or ongoing severe cognitive impairment that compromised mental status. Patients receiving Isoniazid. Patients unable to understand study procedures and participate in the informed consent process. Patients with a history of renal insufficiency (creatinine clearance less than 50 mL/min).

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: D-Cycloserine<br>Brief imaginal exposure therapy plus DCS pill | Behavioral: Exposure therapy<br>* A manualized form of treatment that involves vividly visualizing indexed trauma with the guidance of a therapist<br>Drug: D-Cycloserine<br>* A partial NMDA agonist that has been shown in human trials to facilitate and strengthen extinction with CBT.<br>|
| Placebo Comparator: Placebo<br>Brief imaginal exposure therapy plus Placebo pill | Behavioral: Exposure therapy<br>* A manualized form of treatment that involves vividly visualizing indexed trauma with the guidance of a therapist<br>Other: Placebo pill<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinician Administered PTSD Scale-IV | A 17-item, semi-structured interview of PTSD symptoms. The range of scores is 0-136, with a higher value representing a worse outcome. | Pre Intervention | 
| Clinician Administered PTSD Scale-IV | A 17-item, semi-structured interview of PTSD symptoms. The range of scores is 0-136, with a higher value representing a worse outcome. | Post Intervention | 
| Clinician Administered PTSD Scale-IV | A 17-item, semi-structured interview of PTSD symptoms. The range of scores is 0-136, with a higher value representing a worse outcome. | 3 month follow-up | 
| Clinician Administered PTSD Scale-IV | A 17-item, semi-structured interview of PTSD symptoms. The range of scores is 0-136, with a higher value representing a worse outcome. | 6 month follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PTSD Checklist | A 17-item, self-report measure of PTSD symptoms. The range of scores is 17-85, with a higher value representing a worse outcome. | Pre Intervention | 
| PTSD Checklist | A 17-item, self-report measure of PTSD symptoms. The range of scores is 17-85, with a higher value representing a worse outcome. | Post intervention | 
| PTSD Checklist | A 17-item, self-report measure of PTSD symptoms. The range of scores is 17-85, with a higher value representing a worse outcome. | 3 month follow-up | 
| PTSD Checklist | A 17-item, self-report measure of PTSD symptoms. The range of scores is 17-85, with a higher value representing a worse outcome. | 6 month follow-up | 
| Beck Depression Inventory | A 21-item, self-report measure of depression symptoms. The range of scores is 0-63, with a higher value representing a worse outcome. | Pre intervention | 
| Beck Depression Inventory | A 21-item, self-report measure of depression symptoms. The range of scores is 0-63, with a higher value representing a worse outcome. | Post intervention | 
| Beck Depression Inventory | A 21-item, self-report measure of depression symptoms. The range of scores is 0-63, with a higher value representing a worse outcome. | 3 month follow-up | 
| Beck Depression Inventory | A 21-item, self-report measure of depression symptoms. The range of scores is 0-63, with a higher value representing a worse outcome. | 6 month follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cognitive Behavior Therapy, Cognitive enhancers, Combat Disorders, D-Cycloserine, Stress Disorders, Post-Traumatic