Oxytocin is a psychologically interesting and physiologically complex neuropeptide. Due to its involvement in fear processing and social functioning, oxytocin has been discussed as a potential biomarker for posttraumatic stress disorder (PTSD). This dissertation’s first arm (studies 1 - 5) explored oxytocin’s involvement along the pathway from traumatic event exposure to PTSD symptom development, manifestation, and remission. Studies 1 and 2 covered the stage of PTSD symptom development and its pharmacological prevention. They are based on data from a double-blind, multicenter, randomized, placebo-controlled trial which evaluated the effects of repeated intranasal oxytocin administration early posttrauma on PTSD symptoms one and a half, three and six months later. Study 1 demonstrated that the intervention’s effects, which were beneficial in individuals with high acute PTSD symptoms, were independent of sex and hormonal contraception use. Study 2 demonstrated that higher blood oxytocin concentrations, as assessed early posttrauma, were associated with higher PTSD symptoms at the follow-up timepoints in women using hormonal contraception. No prognostic effects were observed in men or cycling women. Interaction effects with the intervention were observed in none of the groups. Study 3 is a systematic review which summarized studies that investigated endogenous oxytocin concentrations, oxytocin receptor gene DNA variation and methylation in trauma exposed individuals and such with manifest PTSD symptoms. Data on oxytocin receptor gene functioning were insufficient for meta-analysis. The meta-analyses on endogenous oxytocin concentrations showed that they were neither a good biomarker for traumatic event exposure, nor for PTSD symptoms. Especially the observed impact of the biochemical analysis method seems problematic when using endogenous oxytocin concentrations as potential diagnostic biomarker. Studies 4 and 5 covered the stage of PTSD symptom remission related to psychotherapeutic treatment. They are based on data from a randomized, waitlist-controlled trial which investigated the effectiveness of an internet-based trauma-focused cognitive behavioral therapy (TF-CBT) in male German Armed Forces service members. Study 4 showed that blood oxytocin concentrations were not influenced by trauma exposure or PTSD symptoms. Analyzing PTSD symptoms and blood oxytocin concentrations of service members who underwent the TF-CBT before, immediately and 3 months after the intervention revealed no mean changes. However, while PTSD symptoms were stable within individuals, oxytocin concentrations were not. Study 5 indicated that higher blood oxytocin concentrations before intervention onset were associated with more positive patient therapeutic alliance ratings during and after the intervention, even though these findings need to be interpreted cautiously due to the low temporal stability of oxytocin concentrations. Thus, the impact of the biochemical analysis method (study 3) and the low temporal stability of endogenous oxytocin concentrations (studies 4 and 5) challenge their assumed eligibility as a PTSDspecific biomarker. Therefore, the second arm of this dissertation aimed at identifying physiological confounders of endogenous oxytocin concentrations, to increase knowledge about factors that need to be controlled for. Studies 6 and 7 are systematic reviews and meta-analyses which summarized studies that investigated endogenous oxytocin concentrations in healthy humans. Study 6 showed that oxytocin concentrations, as derived from extracted blood samples, were higher in samples with higher percentages of women and higher if samples were collected later in the day. Study 7 showed that in naturally cycling women, oxytocin concentrations increased during the follicular phase, peaked at ovulation, and decreased during the luteal phase. As a translational research project, this dissertation points out typical challenges associated with transferring findings from basic scientific studies in animals and healthy humans to the clinical context. While there is indication for beneficial effects of repeated intranasal administration after recent trauma exposure, these findings need replication and a more profound investigation of moderators. Observing that endogenous oxytocin concentrations depend on the biochemical analysis method and are highly variable within individuals, this dissertation detected some common problems related to such measurements. Controlling for relevant confounders, such as time of day, sex, and menstrual cycle phase might increase the reliability of endogenous oxytocin concentrations. However, it appears that other translation-specific challenges, such as the questionable correlation between oxytocin’s brain region-specific actions and its peripheral availability, still need to be resolved. To conclude, while PTSD is an ideal disorder to implement a translational research perspective, given our current knowledge on endogenous oxytocin concentrations, they are not ideal biomarkers.
