Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT05207436 |
| Other study ID # |
1227284 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
January 17, 2022 |
| Est. completion date |
December 31, 2022 |
Study information
| Verified date |
June 2023 |
| Source |
San Diego Veterans Healthcare System |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
In 2019 VA mandated that all Veterans seeking mental health care have access to flexible
family mental health services in VA (VHA directive 1163.04). This study aims to respond to
this mandate by further improving an evidence-based PTSD treatment designed to decrease PTSD
symptoms and improve relationship satisfaction for Veterans and their romantic partners.
Brief Cognitive-Behavioral Conjoint Therapy (B-CBCT), an 8-session dyadic psychotherapy for
PTSD, has been found to significantly reduce PTSD symptoms, but the effects of B-CBCT on
relationship satisfaction are less reliable and robust. Pharmacological augmentation of
psychotherapy utilizing intranasal oxytocin, a neurohormone that influences mechanisms of
trauma recovery and social behavior, may help improve relationship satisfaction outcomes. If
successful, the proposed study will advance knowledge of strategies for improving Veterans'
quality of life by improving their intimate relationships along with PTSD symptoms.
Description:
Military Veterans often experience challenges reintegrating into their communities after
military service, due in part to mental health problems such as posttraumatic stress disorder
(PTSD). PTSD, a psychiatric disorder that develops in response to exposure to traumatic
events, disproportionately affects Veterans, leads to poorer physical health, and impairs
psychosocial functioning and quality of life. Mitigating the negative effects of PTSD on
Veterans' health, functioning, and well-being is therefore a major goal of the VA.
The premise that interpersonal relationships play a key role in resilience, risk, and
recovery from trauma is supported by research showing a robust association between PTSD and
social support. Treatment approaches that bolster Veterans' internal strengths and enhance
the capacity of their social environments to provide support are most likely to have powerful
effects on well-being.
Many Service Members and Veterans with PTSD experience impairment and distress within
intimate relationships at greater levels than among civilian couples. Consistent with this,
Veterans seeking treatment for PTSD often identify relationships as targets of intervention
and express the desire to involve close others in treatment. The VA has been responsive to
these needs, as shown by the continuum of services available to Veterans and their families
through the VA Family Services program. The Veterans' Mental Health and Other Care
Improvements Act of 2008 stated that marriage and family counseling were to be available to
Veterans to facilitate their treatment and rehabilitation. In 2009, VA began an initiative to
select evidence-based family therapies and train mental health providers in these treatments.
More recently, Directive 1163.04 indicated that Veterans with a mental health diagnosis
should be asked about their interest in having family involved in their care and be offered
marital and family counseling. The VA Family Services program supports several treatment
approaches to meet the diverse mental health needs of Veterans and their loved ones. One such
option for Veterans who want to simultaneously improve their PTSD symptoms and their
relationship functioning is Cognitive-Behavioral Conjoint Therapy (CBCT) for PTSD. The VA has
been disseminating CBCT since 2013.
CBCT is a PTSD-specific cognitive-behavioral psychotherapy attended by the couple that uses
close relationships as the vehicle for recovery. Across 15 75-minute sessions, this
manualized therapy addresses the patient's PTSD and relationship functioning simultaneously
via its focus on PTSD psychoeducation within relationship contexts, communication skills,
behavioral approach exercises, and cognitive interventions. CBCT effectively treats PTSD,
exhibiting large within-group effect sizes on clinician-rated PTSD symptoms.
Across studies, however, CBCT has had less robust, more variable effects on relationship
satisfaction than on PTSD. This is likely because the factors governing relationship
satisfaction are complex and rely on a number of independent, interpersonal factors. The
largest published study of CBCT (N = 40 dyads), in which CBCT was compared to a waitlist
control group, found a moderate within-group effect (g = 0.64) and between-group effect (g =
0.47) of CBCT on Veterans' relationship satisfaction. This sample, however, was composed of
only about 25% Veterans. Given that Veteran couples are known to have lower relationship
satisfaction than non-Veteran couples, it is important to further examine CBCT among Veteran
couples that are more representative of couples seen in general VA practice to increase
generalizability of findings. However, preliminary data from couples treated as part of VA's
dissemination of CBCT suggest that effects on relationship satisfaction are noticeably
smaller than in previous studies. This may be due, in part, to poor engagement in the
intervention. Couples experience many logistical obstacles to engaging in care (e.g., the
need to coordinate schedules, lack of childcare). Veterans with PTSD can encounter additional
obstacles related to beliefs about mental health and mental health treatment.
To address these obstacles to treatment engagement, Dr. Leslie Morland (PI) recently
completed a study of an 8-session version of CBCT (B-CBCT) delivered either in-office or via
telehealth to home compared to a family education control condition. She and her team
similarly found robust reductions in PTSD symptoms in B-CBCT (B-CBCT within-group d's =
1.05-1.12, between-group d's = 0.59-0.76) but only a small effect on both partners'
relationship satisfaction that was on par with the family education condition (B-CBCT
within-group d = 0.38; between-group d's = 0.04-0.12).
Medications that potentiate the mechanisms of action in psychotherapy could enhance their
effects. The neuropeptide oxytocin appears to be a promising medication because it mediates
processes central to PTSD and relationship functioning. Oxytocin is a 9-amino-acid
nonapeptide hormone produced by the paraventricular and supraoptic nuclei of the hypothalamus
that regulates human emotions, social cognition, and social behaviors. Endogenous oxytocin
assists in milk production for breastfeeding, induces contractions during childbirth, is
released during orgasm, may reduce urine volume, and may induce sodium release from the
kidneys. Intravenous oxytocin is used in medical practice to induce labor in pregnant women
and to increase muscle tone in the uterus in the case of postpartum bleeding. Oxytocin is
released to several brain areas, including the amygdala, hypothalamus, hippocampus, insula,
and striatum, and effects are mediated by oxytocin receptors found in these regions.
Intranasal administration of oxytocin may offer understanding of the causal effects of
oxytocin on human behavior. Intranasal oxytocin is safe and easy to administer, with a short
half-life that makes it highly suitable for adding to behavioral interventions. Intranasal
oxytocin is best known for its widespread effects on affiliative processes and behaviors. For
example, intranasal oxytocin increases trust, empathy, generosity, positive communication,
and emotional disclosure. Oxytocin also improves social cognition, including emotion
recognition and empathic accuracy. The combination of intranasal oxytocin with provision of
social support suppresses cortisol release and subjective responses to social stress.
Intranasal oxytocin can be conceptualized as a "psychotherapy process catalyst", in that
oxytocin could enhance patients' openness to intervention, attention to others'
communication, and willingness and ability to develop therapeutic alliance. A recent
systematic review of 14 studies of the effects of intranasal oxytocin on PTSD symptoms
concluded that there is tentative evidence for the clinical utility of intranasal oxytocin
for PTSD, although more studies with chronic administration are needed. To date, only one
pilot study has examined the effects of oxytocin-enhanced psychotherapy for PTSD. Findings
indicated that participants randomized to Prolonged Exposure (PE) for PTSD augmented with
oxytocin demonstrated lower PTSD and depression symptoms and had higher working alliance
scores compared to participants randomized to PE with placebo. A large, two-site phase II
randomized controlled trial (RCT) of oxytocin-enhanced PE is currently being conducted in the
VA by a Collaborator on this project (PI: Dr. Julianne Flanagan; NCT04228289).
Administering intranasal oxytocin in a safe, therapeutic context in which interpersonal
skill-building takes place is hypothesized to lead to prosocial effects and facilitated
recovery. CBCT is therefore the ideal treatment platform for oxytocin augmentation. CBCT and
oxytocin are both inherently interpersonal and could operate in a coordinated, synergistic
manner to improve relationship satisfaction. For example, facilitating positive communication
could enhance all aspects of the therapy, including both partners' sharing of thoughts and
feelings and their ability to join together in cognitive restructuring of trauma-related
beliefs that interfere with recovery. Findings that intranasal oxytocin increases neural
activation to socially rewarding stimuli and facilitates social approach behavior suggest
that it could help Veterans and their partners embrace social situations, which is central to
CBCT behavioral interventions. Lastly, generalization of improvements in trust, empathy,
positive communication, and approach behavior could help Veterans participate more fully with
their families (e.g., improved parenting skills) and many other domains of society (e.g.,
education and employment). To date, however, oxytocin has not been tested as an adjuvant to
CBCT nor any relationship-focused therapy for trauma-exposed Veterans.
Based on compelling pre-clinical data implicating the oxytocin system in affiliative
behavior, the study of intranasal oxytocin in humans expanded very rapidly. However, these
developments were followed by calls for caution after acknowledgment of lack of replicability
of findings, methodological limitations such as low statistical power, and poor understanding
of the pharmacodynamics of intranasal delivery of synthetic oxytocin. Intranasal oxytocin is
thought to exert effects by bypassing the blood-brain barrier and reaching the brain directly
(i.e., nose-to-brain transport), but definitive data have been lacking. More recently,
pre-clinical, primate, and human research have converged to indicate that intranasal oxytocin
does, in fact, reach the brain to a degree that leads to clinically relevant changes in
behavior, ostensibly through olfactory and trigeminal nerve fibers. Another issue that has
affected the translation of oxytocin research to treatment has been the lack of dose-ranging
studies in humans. Notably, most intranasal oxytocin studies have administered only one dose
of intranasal oxytocin, typically 24 or 40 international units. The pharmacodynamics of
repeated oxytocin administration are not well-established, but given the short half-life of
intranasal oxytocin (i.e., 20 or more minutes in cerebrospinal fluid and 2 minutes in blood),
repeated dosing (e.g., daily, weekly) is not hypothesized to operate differently than single
doses.
The proposed study to augment CBCT with intranasal oxytocin and to examine its effects on
intimate relationship adjustment, social functioning more generally, and quality of life
directly addresses the mission of the VA, as outlined in the VA fiscal year (FY) 2018-2024
Strategic Plan. Specifically, the proposed study seeks to advance knowledge of how to help
Veterans have good quality of life-which the VA identifies as including satisfying
relationships-in three ways: First, findings will inform whether B-CBCT social functioning
outcomes can be improved with adjunctive medication. Second, if oxytocin enhances the
mechanisms described in this proposal as predicted, it could further strengthen rationale for
providers administering eight-session B-CBCT rather than 15-session CBCT. Effectively
truncating CBCT would mean that more patients could be seen by the same number of VA
providers, potentially improving Veterans' access to treatment. Greater effectiveness and
efficiency of treatment could lead to lower costs to VA. Third, by targeting mechanisms that
are salient to all interpersonal relationships (e.g., trust), oxytocin could help the effects
of CBCT extend to non-intimate relationships, thereby improving overall quality of life and
potentially having effects on other issues facing the VA (such as suicide) which is known to
be related to interpersonal difficulties. Lastly, improving Veterans' social environments
could help them maintain their gains and respond effectively to future stressors-potentially
lowering the likelihood of future need for episodes of care.
