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

• Sponsor: US Department of Veterans Affairs (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT00371176
• Collaborator: (none)
• Enrollment: 26
• Location: 1
• Arms: 2
• Duration (Months): 69
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Combat Disorders; Stress Disorders, Post-Traumatic	Behavioral: Exposure therapy; Drug: D-Cycloserine; Other: Placebo pill	N/A

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Placebo-Controlled Trial of D-Cycloserine and Exposure Therapy for Combat-PTSD
• Study Start Date: Oct 1, 2006
• Actual Primary Completion Date: Sep 1, 2011
• Actual Study Completion Date: Jul 1, 2012

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Clinician Administered PTSD Scale-IV [Pre Intervention]

   A 17-item, semi-structured interview of PTSD symptoms. The range of scores is 0-136, with a higher value representing a worse outcome.

2. Clinician Administered PTSD Scale-IV [Post Intervention]

   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. Clinician Administered PTSD Scale-IV [3 month follow-up]

   A 17-item, semi-structured interview of PTSD symptoms. The range of scores is 0-136, with a higher value representing a worse outcome.

4. Clinician Administered PTSD Scale-IV [6 month follow-up]

   A 17-item, semi-structured interview of PTSD symptoms. The range of scores is 0-136, with a higher value representing a worse outcome.

Secondary Outcome Measures

1. PTSD Checklist [Pre Intervention]

   A 17-item, self-report measure of PTSD symptoms. The range of scores is 17-85, with a higher value representing a worse outcome.

2. PTSD Checklist [Post intervention]

   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. PTSD Checklist [3 month follow-up]

   A 17-item, self-report measure of PTSD symptoms. The range of scores is 17-85, with a higher value representing a worse outcome.

4. PTSD Checklist [6 month follow-up]

   A 17-item, self-report measure of PTSD symptoms. The range of scores is 17-85, with a higher value representing a worse outcome.

5. Beck Depression Inventory [Pre intervention]

   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. Beck Depression Inventory [Post intervention]

   A 21-item, self-report measure of depression symptoms. The range of scores is 0-63, with a higher value representing a worse outcome.

7. Beck Depression Inventory [3 month follow-up]

   A 21-item, self-report measure of depression symptoms. The range of scores is 0-63, with a higher value representing a worse outcome.

8. Beck Depression Inventory [6 month follow-up]

   A 21-item, self-report measure of depression symptoms. The range of scores is 0-63, with a higher value representing a worse outcome.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VA Boston Health Care System	Boston	Massachusetts	United States	02130

Sponsors and Collaborators

• US Department of Veterans Affairs

Investigators

• Principal Investigator: Brett T. Litz, PhD, VA Boston Health Care System

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: US Department of Veterans Affairs
• ClinicalTrials.gov Identifier: NCT00371176
• Other Study ID Numbers: ORD-NIMH-20061
• First Posted: Sep 1, 2006
• Last Update Posted: Feb 4, 2014
• Last Verified: Dec 1, 2013

• Keywords provided by US Department of Veterans Affairs: Cognitive Behavior Therapy; Cognitive enhancers; Combat Disorders; D-Cycloserine; Stress Disorders, Post-Traumatic
• Additional relevant MeSH terms: Disease; Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic; Combat Disorders; Cycloserine

Study Results

Participant Flow

Recruitment Details	The recruitment period was 2007 to 2011. Participants were recruited through VA clinician referrals and public advertising (e.g., flyers and radio ads).

Arm/Group Title	D-Cycloserine Plus Exposure	Placebo Plus Exposure
Arm/Group Description	Treatment entailed six 60-90 minute sessions. Session 1 focused on psychoeducation and building of rapport, sessions 2-5 of brief imaginal exposure therapy plus a 50 mg DCS pill 30 minutes prior to each session, and session 6 consisted of a review of treatment gains, discussion of relapse-prevention strategies, and termination.	Treatment entailed six 60-90 minute sessions. Session 1 focused on psychoeducation and building of rapport, sessions 2-5 of brief imaginal exposure therapy plus a placebo pill 30 minutes prior to each session, and session 6 consisted of a review of treatment gains, discussion of relapse-prevention strategies, and termination.
Period Title: Overall Study
STARTED	13	13
Completed Treatment	10	9
COMPLETED	8	5
NOT COMPLETED	5	8

Baseline Characteristics

Arm/Group Title	D-Cycloserine Plus Exposure	Placebo Plus Exposure	Total
Arm/Group Description	Brief imaginal exposure therapy plus DCS pill	Brief imaginal exposure therapy plus Placebo pill	Total of all reporting groups
Overall Participants	13	13	26
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	13 100%	13 100%	26 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	32.77 (9.85)	31.62 (9.10)	32.19 (9.31)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	13 100%	13 100%	26 100%
Region of Enrollment (participants) [Number]
United States	13 100%	13 100%	26 100%

Outcome Measures

1. Primary Outcome

Title	Clinician Administered PTSD Scale-IV
Description	A 17-item, semi-structured interview of PTSD symptoms. The range of scores is 0-136, with a higher value representing a worse outcome.
Time Frame	Pre Intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	D-Cycloserine Plus Exposure	Placebo Plus Exposure
Arm/Group Description	Brief imaginal exposure therapy plus DCS pill	Brief imaginal exposure therapy plus Placebo pill
Measure Participants	13	13
Mean (Standard Deviation) [units on a scale]	69.85 (23.24)	73.38 (16.35)

2. Secondary Outcome

Title	PTSD Checklist
Description	A 17-item, self-report measure of PTSD symptoms. The range of scores is 17-85, with a higher value representing a worse outcome.
Time Frame	Pre Intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	D-Cycloserine Plus Exposure	Placebo Plus Exposure
Arm/Group Description	Brief imaginal exposure therapy plus DCS pill	Brief imaginal exposure therapy plus Placebo pill
Measure Participants	13	13
Mean (Standard Deviation) [units on a scale]	37.85 (8.76)	39.00 (8.77)

3. Secondary Outcome

Title	PTSD Checklist
Description	A 17-item, self-report measure of PTSD symptoms. The range of scores is 17-85, with a higher value representing a worse outcome.
Time Frame	Post intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	D-Cycloserine Plus Exposure	Placebo Plus Exposure
Arm/Group Description	Brief imaginal exposure therapy plus DCS pill	Brief imaginal exposure therapy plus Placebo pill
Measure Participants	13	13
Mean (Standard Deviation) [units on a scale]	34.11 (21.09)	24.18 (14.95)

4. Primary Outcome

Title	Clinician Administered PTSD Scale-IV
Description	A 17-item, semi-structured interview of PTSD symptoms. The range of scores is 0-136, with a higher value representing a worse outcome.
Time Frame	Post Intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	D-Cycloserine Plus Exposure	Placebo Plus Exposure
Arm/Group Description	Brief imaginal exposure therapy plus DCS pill	Brief imaginal exposure therapy plus Placebo pill
Measure Participants	13	13
Mean (Standard Deviation) [units on a scale]	72.33 (28.68)	53.73 (26.22)

5. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	D-Cycloserine Plus Exposure	Placebo Plus Exposure
Arm/Group Description	Brief imaginal exposure therapy plus DCS pill	Brief imaginal exposure therapy plus Placebo pill
Measure Participants	9	11
Mean (Standard Deviation) [units on a scale]	62.57 (32.17)	58.20 (26.17)

6. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	D-Cycloserine Plus Exposure	Placebo Plus Exposure
Arm/Group Description	Brief imaginal exposure therapy plus DCS pill	Brief imaginal exposure therapy plus Placebo pill
Measure Participants	9	11
Mean (Standard Deviation) [units on a scale]	62.20 (32.17)	55.50 (27.02)

7. Secondary Outcome

Title	PTSD Checklist
Description	A 17-item, self-report measure of PTSD symptoms. The range of scores is 17-85, with a higher value representing a worse outcome.
Time Frame	3 month follow-up

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	D-Cycloserine Plus Exposure	Placebo Plus Exposure
Arm/Group Description	Brief imaginal exposure therapy plus DCS pill	Brief imaginal exposure therapy plus Placebo pill
Measure Participants	9	11
Mean (Standard Deviation) [units on a scale]	33.29 (14.68)	26.91 (16.40)

8. Secondary Outcome

Title	PTSD Checklist
Description	A 17-item, self-report measure of PTSD symptoms. The range of scores is 17-85, with a higher value representing a worse outcome.
Time Frame	6 month follow-up

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	D-Cycloserine Plus Exposure	Placebo Plus Exposure
Arm/Group Description	Brief imaginal exposure therapy plus DCS pill	Brief imaginal exposure therapy plus Placebo pill
Measure Participants	9	11
Mean (Standard Deviation) [units on a scale]	29.20 (13.16)	27.25 (15.83)

9. Secondary Outcome

Title	Beck Depression Inventory
Description	A 21-item, self-report measure of depression symptoms. The range of scores is 0-63, with a higher value representing a worse outcome.
Time Frame	Pre intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	D-Cycloserine Plus Exposure	Placebo Plus Exposure
Arm/Group Description	Brief imaginal exposure therapy plus DCS pill	Brief imaginal exposure therapy plus Placebo pill
Measure Participants	13	13
Mean (Standard Deviation) [units on a scale]	24.85 (15.31)	21.48 (9.24)

10. Secondary Outcome

Title	Beck Depression Inventory
Description	A 21-item, self-report measure of depression symptoms. The range of scores is 0-63, with a higher value representing a worse outcome.
Time Frame	Post intervention

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	D-Cycloserine Plus Exposure	Placebo Plus Exposure
Arm/Group Description	Brief imaginal exposure therapy plus DCS pill	Brief imaginal exposure therapy plus Placebo pill
Measure Participants	13	13
Mean (Standard Deviation) [units on a scale]	28.56 (16.25)	14.18 (10.81)

11. Secondary Outcome

Title	Beck Depression Inventory
Description	A 21-item, self-report measure of depression symptoms. The range of scores is 0-63, with a higher value representing a worse outcome.
Time Frame	3 month follow-up

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	D-Cycloserine Plus Exposure	Placebo Plus Exposure
Arm/Group Description	Brief imaginal exposure therapy plus DCS pill	Brief imaginal exposure therapy plus Placebo pill
Measure Participants	9	11
Mean (Standard Deviation) [units on a scale]	24.57 (14.43)	13.90 (10.59)

12. Secondary Outcome

Title	Beck Depression Inventory
Description	A 21-item, self-report measure of depression symptoms. The range of scores is 0-63, with a higher value representing a worse outcome.
Time Frame	6 month follow-up

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	D-Cycloserine Plus Exposure	Placebo Plus Exposure
Arm/Group Description	Brief imaginal exposure therapy plus DCS pill	Brief imaginal exposure therapy plus Placebo pill
Measure Participants	9	11
Mean (Standard Deviation) [units on a scale]	22.25 (17.73)	15.38 (11.43)

Adverse Events

Arm/Group Title	D-Cycloserine Plus Exposure		Placebo Plus Exposure
Arm/Group Description	Brief imaginal exposure therapy plus DCS pill		Brief imaginal exposure therapy plus Placebo pill
All Cause Mortality
	D-Cycloserine Plus Exposure		Placebo Plus Exposure
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	D-Cycloserine Plus Exposure		Placebo Plus Exposure
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/13 (0%)
Other (Not Including Serious) Adverse Events
	D-Cycloserine Plus Exposure		Placebo Plus Exposure
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		0/13 (0%)

Limitations/Caveats

The study experienced sustained recruitment difficulties, ultimately recruiting a smaller number of participants (N=26) than originally projected (N=68).

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.