Oxytocin to Enhance Integrated Treatment for AUD and PTSD

Study Overview
=================
Brief Summary
-----------------
The primary objective of the proposed Stage II study is to examine the efficacy of oxytocin (OT) as compared to placebo in reducing (1) alcohol use disorder (AUD) symptoms, and (2) post-traumatic stress disorder (PTSD) symptoms among Veterans receiving COPE therapy (Concurrent Treatment of PTSD and Substance Use Disorders using Prolonged Exposure). To evaluate purported neurobiological mechanisms of change, we will employ functional magnetic resonance imaging (fMRI) at pre- and post-treatment.

Detailed Description
-----------------
Alcohol use disorder (AUD) and posttraumatic stress disorder (PTSD) frequently co-occur and are associated with significant morbidity, mortality, and health care expenditures. Military Veterans are at increased risk for co-occurring AUD and PTSD, with prevalence rates 2-4 times higher than the general population. Our group developed an integrated intervention entitled Concurrent Treatment of PTSD and Substance Use Disorders using Prolonged Exposure (COPE). COPE incorporates empirically validated cognitive-behavioral techniques for AUD with Prolonged Exposure (PE) therapy for PTSD. Several randomized controlled trials among Veterans and civilians demonstrate efficacy of COPE in significantly reducing AUD and PTSD symptoms. Despite the positive findings, there remains substantial room for improving treatment outcomes and enhancing retention. Accumulating data suggest that the neuropeptide oxytocin (OT) is a promising candidate to enhance psychosocial interventions for co-occurring AUD and PTSD, as OT targets neurobiological and behavioral dysregulation common to both disorders. Preclinical and clinical studies demonstrate the ability of OT to ameliorate a variety of alcohol-related behaviors (e.g., craving, withdrawal symptoms, tolerance, ethanol self-administration), enhance fear extinction, and promote prosocial behaviors associated with successful psychosocial treatment outcomes. In a randomized controlled pilot study, our group found that OT administration prior to weekly Prolonged Exposure (PE) therapy sessions was safe, well-tolerated, and resulted in accelerated reduction in PTSD symptoms as compared to placebo. Although the empirical and theoretical support for augmenting psychosocial interventions such as COPE with OT is robust, no studies to date have examined this combined approach. The primary objective of the proposed Stage II study is to examine the efficacy of OT as compared to placebo in reducing (1) AUD symptoms, and (2) PTSD symptoms among Veterans (50% women) receiving COPE therapy. To accomplish this, we will employ a manualized, evidence-based, cognitive-behavioral intervention (COPE); a randomized, double-blind, placebo-controlled study design; and standardized, repeated dependent measures of clinical outcomes at multiple time points. In addition, to investigate neurobiological mechanisms of change, we will employ functional magnetic resonance imaging (fMRI) at pre-and post-treatment .

Official Title
-----------------
Oxytocin to Enhance Integrated Exposure-Based Treatment of Co-occurring Alcohol Use Disorder and PTSD

Conditions
-----------------
PTSD, Alcohol Use Disorder

Intervention / Treatment
-----------------
* Drug: 40 IU Intranasal Oxytocin
* Drug: Placebo
* Behavioral: Concurrent Treatment of PTSD and Substance Use Disorders using Prolonged Exposure


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female; U.S. military Veteran, any race or ethnicity; aged 18-70 years. Able to provide written informed consent. Meet DSM-5 diagnostic criteria for current moderate to severe alcohol use disorder. Meet DSM-5 diagnostic criteria for current PTSD as assessed by the CAPS-5. Participants may also meet criteria for a mood disorder (except bipolar affective disorder, see Exclusion Criteria) or anxiety disorders. Concurrent substance use disorders (e.g., marijuana) are acceptable provided alcohol is the participant's primary substance of choice. Participants taking psychotropic medications will be required to be maintained on a stable dose for at least 4 weeks before study initiation. Exclusion Criteria: Meeting DSM-5 criteria for a history of or current psychotic or bipolar affective disorders, or with current suicidal or homicidal ideation and intent. Those participants will be referred clinically for services. Participants on psychotropic medications which have been initiated during the past 4 weeks. Acute alcohol withdrawal as indicated by CIWA-Ar scores >8. Pregnancy or breastfeeding for women. For MRI scan component: history of seizures or severe head injury, implanted metal devices or other metal (e.g., shrapnel). These participants will be eligible to enroll in the clinical trial but will not be eligible to participate in the neuroimaging component of the study. Currently enrolled in behavioral treatment for AUD or PTSD.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oxytocin Treatment Group<br>Participants will receive 12 weekly sessions of Concurrent Treatment of PTSD and Substance Use Disorders using Prolonged Exposure (COPE Therapy), plus intranasal Oxytocin. 40-IU dose of Oxytocin self-administered 30 minutes prior to the start of each weekly COPE session. | Drug: 40 IU Intranasal Oxytocin<br>* 40 IU Intranasal Oxytocin self administered 30 minutes prior to each COPE session.<br>* Other names: oxytocin;Behavioral: Concurrent Treatment of PTSD and Substance Use Disorders using Prolonged Exposure<br>* 12 weekly sessions of COPE therapy for PTSD and AUD.<br>* Other names: COPE;|
| Active Comparator: Placebo Group<br>Participants will receive 12 weekly sessions of Concurrent Treatment of PTSD and Substance Use Disorders using Prolonged Exposure (COPE Therapy), plus placebo (intranasal saline spray). Intranasal dose of saline spray self-administered 30 minutes prior to the start of each weekly COPE session. | Drug: Placebo<br>* Placebo (intranasal saline spray) self administered 30 minutes prior to each COPE session.<br>* Other names: saline;Behavioral: Concurrent Treatment of PTSD and Substance Use Disorders using Prolonged Exposure<br>* 12 weekly sessions of COPE therapy for PTSD and AUD.<br>* Other names: COPE;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in alcohol use | Change in percent days abstinent and heavy drinking days as measured by the TimeLine Follow-Back (TLFB). | From baseline to week 12 and 3 and 6 month follow ups | 
| Change in PTSD symptom severity - clinician rated | Change in clinician-rated PTSD symptom severity will be measured with the Clinician Administered PTSD Scale for DSM-5 (CAPS-5). | From baseline to week 12 and 3 and 6 month follow ups | 
| Change in PTSD symptom severity - self report | Change in self-reported PTSD symptom severity will be measured with the PTSD Checklist for DSM-5 (PCL-5). | From baseline to week 12 and 3 and 6 month follow ups |