Individual variation in plasma oxytocin and vasopressin levels in relation to the development of combat-related PTSD in a large military cohort

Abstract

In an attempt to decrease the risk of developing mental health problems after military deployment, it is important to find biological markers to identify those at risk. Oxytocin (OT) and arginine vasopressin (AVP) are potential biomarkers for the development of posttraumatic stress disorder (PTSD) because they are involved in the regulation of stress and anxiety. Therefore, the aim was to examine whether plasma OT (pOT) and AVP (pAVP) levels before and after deployment are biomarkers for the development of posttraumatic stress symptoms over time in addition to other known risk factors. This study is part of a large prospective cohort study on candidate markers for stress-related mental health symptoms and resiliency after deployment to a combat zone; Prospective Research in Stress-related Military Operations (PRISMO; N = 907). Data was collected prior to deployment and follow-ups were performed at 1 and 6 months, and 1, 2, and 5 years post-deployment. Blood samples were collected in the first three assessments. The levels of pOT and pAVP were not significantly related to the development of PTSD symptoms over time. The results confirm that age, the experience of early life trauma, combat-related stressors and the presence of depressive symptoms are predictive for the development of PTSD symptoms over time. These findings showed that peripherally measured OT and AVP currently do not qualify as useful susceptibility biomarkers for the development of PTSD symptoms over time in military men after combat.

Introduction

Military personnel are at increased risk of developing mental health problems after deployment to a combat zone (Reijnen et al., 2015, Smith et al., 2008). In US combat veterans, a threefold increase in posttraumatic stress symptoms was found three years after deployment to Iraq or Afghanistan (Smith et al., 2008). In Dutch military personnel, a high level of posttraumatic stress symptoms was reported by 9% of the participants at six months and 13% at 5 years after deployment to Afghanistan compared to 4% prior to deployment (Eekhout et al., 2016b). Moreover, military personnel with mental health problems place an increased burden on consumption of (mental) health care (Eekhout et al., 2016a). Age, early life trauma and combat-related stressors were reported to be risk factors for the development of PTSD symptoms (Eekhout et al., 2016b). In addition to these factors, it is important to find biological susceptibility markers to identify those at risk for the development of combat-related posttraumatic stress disorder (PTSD).

Two potentially useful markers that have been proposed are oxytocin (OT) and arginine vasopressin (AVP; Kang et al., 2015). Both OT and AVP are nonapeptides, which are produced in the hypothalamus and secreted in the bloodstream by the posterior pituitary (Ludwig and Leng, 2006). They are potentially interesting because of their role in social behavior and in the regulation of stress and anxiety (Ditzen et al., 2009, Heinrichs et al., 2003, Neumann and Landgraf, 2012). Moreover, individual differences in the levels of these neuropeptides have been suggested to relate to symptoms of various psychiatric disorders (Meyer-Lindenberg et al., 2011).

Oxytocin is often reported to exert anxiolytic effects and to facilitate social interaction. For instance, intranasal administration of OT was found to decrease salivary cortisol levels during social stress (Linnen et al., 2012), decrease subjective ratings of anxiety in response to stress (Heinrichs et al., 2003), dampen amygdala activity to negative stimuli or fear-inducing visual stimuli (Domes et al., 2007, Kirsch et al., 2005) and increase emotion recognition and in-group trust (MacDonald and Feifel, 2013, Van IJzendoorn and Bakermans-Kranenburg, 2012). Therefore, OT is often studied as a promising treatment target for psychiatric disorders such as schizophrenia and autism (MacDonald and Feifel, 2013, Striepens et al., 2011) and also for PTSD (Olff et al., 2010). Yet, cross-sectional studies on the peripheral OT levels in PTSD patients compared to healthy controls present inconsistent findings. For instance, in a group of pregnant women with PTSD, plasma OT (pOT) levels were not associated with PTSD (Seng et al., 2013). Also, no association was found between pOT levels and PTSD status in a group of traumatized individuals (Olff et al., 2013). In contrast, after controlling for childhood trauma, lower salivary OT levels were found in policemen with PTSD compared to healthy trauma-exposed controls, but not in women (Frijling et al., 2015).

Whereas central OT exerts anxiolytic and antidepressant effects, AVP is associated with anxiogenic and depressive actions (Neumann and Landgraf, 2012). For instance, increased cortisol responses to a psychosocial stressor were found after intranasal administration of AVP (Shalev et al., 2011). Furthermore, increased plasma AVP (pAVP) levels during the processing of negative stimuli were found to be positively associated with amygdala activation in men (Motoki et al., 2016). Therefore, they suggested that pAVP might be a valid biological marker for the individual differences in anxiogenic effects in males. Higher pAVP levels are also reported to be associated with psychiatric disorders, such as major depressive disorder (Londen et al., 1997) and PTSD (de Kloet et al., 2008). In male veterans with PTSD, pAVP levels were elevated in comparison to both traumatized veterans and non-traumatized civilians (de Kloet et al., 2008). However, no difference in salivary AVP levels was found between police officers with and without PTSD (Frijling et al., 2015).

Although OT and AVP might be promising biological markers for PTSD, recent literature doubts whether peripherally measured OT and AVP levels reflect the level of central activity (Grinevich et al., 2016, Neumann and Landgraf, 2012). Recent studies found no correlation between the levels of pOT and those measured in cerebrospinal fluid (CSF) (Jokinen et al., 2012, Kagerbauer et al., 2013) and similar doubts are present about AVP (Kagerbauer et al., 2013). Thus, it is questionable whether peripherally measured OT and AVP could be associated with behavioral changes. Another major concern is the validity of the methods used to measure OT and AVP levels, since values reported in the literature largely differ based on the method used (Leng and Ludwig, 2016, McCullough et al., 2013, Szeto et al., 2011). A third concern is that in exogenous administration studies, but also in studies on endogenous levels, sample sizes are relatively small and possibly underpowered, so reported findings might not represent true effects (Walum et al., 2016). Moreover, in a recent review and preliminary meta-analysis no evidence was found for altered pOT and pAVP levels in several psychiatric disorders (Rutigliano et al., 2016).

Although, recent literature regarding peripherally measured OT and AVP in relation to PTSD presents inconsistent findings, reliable comparison of studies is difficult because methods differ, sample sizes are relatively small and effects might be gender specific. In addition, to the authors' knowledge, limited research is done on the predictive value of peripheral OT and AVP levels for the development of PTSD symptoms over a prolonged period. Therefore, we intended to contribute to the current discussion by assessing basal pOT and pAVP levels in a large cohort of military men before and after deployment and tested whether these hormones can serve as potential biomarkers for the development of posttraumatic stress symptoms over time in addition to other known risk factors.