Background
Given the high rates of exposure to traumatic events (70-90%) [
1‐
4] and a 7-8% lifetime prevalence of PTSD [
1,
5], easily applicable interventions that effectively prevent PTSD are an important public health need. Currently, little evidence is available for effective interventions that prevent the development of PTSD which can be administered early after trauma exposure [
6]. Single-session psychological debriefing [
7,
8] as well as multiple sessions of preventive Behavioral Therapy [
9] administered within 3 months following traumatic events do not reduce distress, or prevent PTSD. Recently, a pilot study found that 3 sessions of prolonged exposure therapy administered within 2 weeks after trauma reduced post-traumatic stress reactions at 1 and 3 months post-trauma [
10]. Other secondary preventive psychological interventions, such as brief Cognitive Behavioral Therapy (CBT), have yielded promising results [
11,
12] but can be applied only several weeks after trauma, when trauma-exposed individuals may already have developed acute PTSD.
Pharmacologically, prolonged administration of the beta-receptor blocking agent propranolol early after trauma did not result in fewer PTSD symptoms [
13,
14]. In a small sample of participants Zohar et al. [
15] recently showed that a single bolus of high dose hydrocortisone in trauma-exposed individuals at an Emergency Department (ED) resulted in fewer PTSD symptoms at 2 weeks and 3 months post-trauma relative to those who received placebo. Similarly, in another recent report of 64 traumatic injury patients it was demonstrated that those who received a 10-day course of low dose oral hydrocortisone started within 12 hours of the injury reported fewer PTSD and depression symptoms at 1 and 3 months post-trauma follow-up than those who were treated with placebo [
16].
Developing interventions that target vulnerability factors associated with PTSD development is a promising way to explore new early treatment strategies for prevention [
17‐
19] An increased risk of PTSD development is associated with pre-existing dysregulations of (para)sympathetic [
17,
18] and hypothalamic-pituitary-adrenal axes [
20,
21], as well as dysregulations of central fear responses prior to [
22] and shortly after trauma exposure [
23,
24]. In addition, a lack of perceived social support early after trauma is strongly related to increased PTSD risk [
25‐
27].
Intranasal administration of the neuropeptide oxytocin is a candidate preventive pharmacological intervention after trauma, since oxytocin regulates neuroendocrine, psychophysiological and fear responses as well as socio-emotional processes [
28].
Oxytocin is synthesized in the hypothalamus from where it is widely distributed in the brain [
29]. In addition, oxytocin is released into the bloodstream by the pituitary gland where it acts as a hormone and stimulates smooth muscle tissue contraction in e.g. childbirth and lactation. In pioneering studies on the role of oxytocin in social behavior, it was found to facilitate pair-bonding and partner preference in the socially monogamous prairie vole [
30,
31]. Human endogenous oxytocin levels increase during safe social contact [
32,
33], but also during distress. Increased oxytocin activity during distress [
34,
35] and its attenuating effects on HPA axis [
36] and autonomic nervous system activity [
37] may indicate a regulatory function of oxytocin in physiological stress.
In humans, intranasal oxytocin administration is thought to result in endogenous release of the hormone in a feed-forward fashion [
38]. Indeed, the recent finding that a single intranasal administration of oxytocin (16 IU) resulted in elevated salivary oxytocin levels up to 7 hours post-administration while the peptide has a half time of approximately 10 minutes, supports this hypothesis [
39].
Several human studies showed that intranasal oxytocin can facilitate trust and prosocial behavior [
40,
41]. Furthermore, intranasal oxytocin regulates responses of the HPA axis [
42] and the (para)sympathetic nervous system [
43]. In addition, intranasal oxytocin also dampened the central fear response by lowering amygdala activity [
44‐
46] and potentially enhancing fear regulation by increasing top-down control of the prefrontal cortex over the amygdala [
47].
Recently, a variety of interindividual and contextual factors that influence the effects of intranasal oxytocin have come to light. Factors such as gender [
48], attachment style [
49], and early parental experiences [
50] appear to moderate the effects of intranasal oxytocin on several outcome measures [
51,
52]. These findings imply that the effects of intranasal oxytocin need to be assessed accounting for these potentially moderating factors.
Preclinical studies have provided support for oxytocin treatment as a promising strategy for preventing PTSD-like behavior. In rats, a single central oxytocin administration either immediately or 7 days after a severe stressor was associated with reduced PTSD-like behavior 1 week after administration in comparison to placebo [
53]. Furthermore, central oxytocin administration in rats 10 minutes prior to fear conditioning did not affect fear conditioning, but did subsequently decrease fear expression and facilitated fear extinction [
54]. The same study showed that central oxytocin administrated 10 minutes prior to extinction training (at 1 day after fear acquisition) inhibited fear extinction, indicating that timing of oxytocin administration relative to traumatic memory consolidation may be important in determining whether oxytocin promotes or inhibits fear extinction. However, this finding is not supported by the study of Cohen et al. [
53], where both treatment times (i.e. immediately after severe stress exposure or 7 days later) showed a similar decrease in PTSD-like behavior.
To date, no reports on the effects of intranasal oxytocin in recently traumatized human individuals have been published. One very small study showed beneficial acute effects of intranasal oxytocin in patients who had already developed PTSD. In 18 PTSD patients a reduction in anxiety, restlessness, irritability and even acute PTSD symptoms was found 50 minutes after a single dose of oxytocin compared to placebo treatment [
55].
In summary, based upon these findings and given the well-documented vulnerability factors for PTSD development, we propose that intranasal oxytocin applied early after trauma may prevent the development of PTSD, through regulating fear and stress responses and socio-emotional processes such as perceptions of social support [
28].
Research aims and hypotheses
The primary aim of the ‘BONDS’ (Boosting Oxytocin after trauma: Neurobiology and the Development of Stress-related psychopathology) study is to investigate the effectiveness of early intranasal oxytocin administration in reducing PTSD symptoms at 1.5 month post-trauma in trauma-exposed ED patients at increased risk of PTSD. We expect that the oxytocin group will report fewer PTSD symptoms at the follow-up assessment compared to the placebo group.
As a secondary aim we will investigate whether intranasal oxytocin affects PTSD severity scores at 3 and 6 months follow-up and other psychopathology symptoms (e.g. major depressive disorder, panic disorder, specific phobia) and quality of life at 1.5, 3 and 6 months follow-up.
We will also assess moderating effects of gender, trauma type (e.g. motor vehicle accident, assault, etc.) type, history of (childhood) trauma, coping style, attachment style, and perceived social support on the main study outcome measures. Furthermore, we will investigate differences in psychophysiological, neuroendocrine, and epigenetic measures between intervention groups at 1.5 month follow-up. We hypothesize that baseline characteristics will moderate the effects of intranasal oxytocin and that the experimental intervention will be associated with more favorable outcomes on psychological, psychophysiological, neuroendocrine and epigenetic measures at the follow-up assessments compared to placebo treatment.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
MO designed the study. JLF and MvZ drafted the manuscript. All authors contributed to the development and implementation of the study protocol at the Emergency Departments (Sint Lucas Andreas Hospital, AMC and VUmc) and Trauma Centers (AMC and VUmc). MO and MvZ arranged collaborations with the participating laboratories. JLF, LN, and SBJK conduct all participant-related study procedures. All authors contributed to editing the manuscripts and read and approved the final manuscript.