Intranasal oxytocin reduces provoked symptoms in female patients with posttraumatic stress disorder despite exerting sympathomimetic and positive chronotropic effects in a randomized controlled trial

Background Posttraumatic stress disorder (PTSD) is a severe psychiatric disease accompanied by neuroendocrine changes such as adrenergic overdrive and hence an elevated cardiovascular morbidity. Current pharmacotherapeutic options for PTSD are less than suboptimal, necessitating the development of PTSD-specific drugs. Although the neuropeptide oxytocin has been repeatedly suggested to be effective in PTSD treatment, there are, to our knowledge, only three studies that have assessed its efficacy on the intensity of PTSD symptoms in PTSD patients – among them one symptom provocation study in male veterans. Methods To evaluate for the first time how oxytocin influences the intensity of provoked PTSD symptoms and, furthermore, cardiac control in female PTSD patients, we assessed their psychic and cardiac response to trauma-script exposure with and without oxytocin pretreatment in a double-blind randomized placebo-controlled study. We used a within-subject design to study 35 female PTSD patients who received oxytocin and placebo in a 2-week interval. Furthermore, we performed a small pilot study to get an idea of the relation of the stress-modulated endogenous oxytocin levels and heart rate - we correlated oxytocin serum levels with the heart rate of 10 healthy individuals before and after exposure to the Trier Social Stress Test (TSST). Results Intranasal oxytocin treatment was followed by a reduction of provoked total PTSD symptoms, in particular of avoidance, and by an elevation in baseline and maximum heart rate together with a drop in the pre-ejection period, a marker for sympathetic cardiac control. Furthermore, we found a positive correlation between endogenous oxytocin levels and heart rate both before and after TSST challenge in healthy control subjects. Conclusions This study provides the first evidence that oxytocin treatment reduces the intensity of provoked PTSD symptoms in female PTSD patients. The small size of both samples and the heterogeneity of the patient sample restrict the generalizability of our findings. Future studies have to explore the gender dependency and the tolerability of the oxytocin-mediated increase in heart rate. This randomized controlled trial was retrospectively registered at the German Trials Register (DRKS00009399) on the 02 October 2015. Electronic supplementary material The online version of this article (doi:10.1186/s12916-017-0801-0) contains supplementary material, which is available to authorized users.


Details on the analysis of serum oxytocin
The detection limit of the used ELISA assay is 12.35 pg/ml with a minimum detectable dose of less than 5.27pg/ml. Furthermore, the manufacturer stated that 20 replications of the analysis of 3 samples on one plate revealed an intra-assay coefficient of variation of <10% and, moreover, that the analysis of 3 samples with low, middle and high oxytocin levels on 3 different plates with 8 replicates in each plate revealed an intra-assay coefficient of variation of <12%. Our analysis revealed an intra-assay coefficient of <7% and an inter-assay coefficient of <8%. None of our measurements was rejected because of poor duplication.
Blood samples for oxytocin analysis were taken at 1330h and 1410h. The samples had a volume of 7,5ml and were immediately processed after clotting. Aliquots of serum (150µl) were stored at -80°C until analysis and were thawed only once, i.e. immediately before ELISA analysis.

Consort Flow
Diagram. This diagram was prepared according to the CONSORT guidelines [41]. Note that this randomized controlled trial has a within-subject design, i.e. all participants received both placebo and verum (oxytocin). PTSD patients were randomly assigned either to the "placebo first" or to the "verum first" group. Subjects of the "placebo first" group received first the placebo treatment and one week later the verum treatment while subjects of the "verum group" received treatments in the opposite order. For further details and for references, see main text.  Settings and locations where the data were collected 7 Interventions 5 The interventions for each group with sufficient details to allow replication, including how and when they were actually administered

8-12
Outcomes 6a Completely defined pre-specified primary and secondary outcome measures, including how and when they were assessed 8 6b Any changes to trial outcomes after the trial commenced, with reasons no changes Sample size 7a How sample size was determined 11 7b When applicable, explanation of any interim analyses and stopping guidelines does not apply Randomisation: Sequence generation 8a Method used to generate the random allocation sequence 9 8b Type of randomisation; details of any restriction (such as blocking and block size) 9 Allocation concealment mechanism 9 Mechanism used to implement the random allocation sequence (such as sequentially numbered containers), describing any steps taken to conceal the sequence until interventions were assigned 9 Implementation 10 Who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions 9 SUPPLEMENTAL Statistical methods 12a Statistical methods used to compare groups for primary and secondary outcomes 11-12 12b Methods for additional analyses, such as subgroup analyses and adjusted analyses does not apply

Results
Participant flow (a diagram is strongly recommended) 13a For each group, the numbers of participants who were randomly assigned, received intended treatment, and were analysed for the primary outcome 7 + Fig.1 13b For each group, losses and exclusions after randomisation, together with reasons Outcomes and estimation 17a For each primary and secondary outcome, results for each group, and the estimated effect size and its precision (such as 95% confidence interval) Sources of funding and other support (such as supply of drugs), role of funders 22 *We strongly recommend reading this statement in conjunction with the CONSORT 2010 Explanation and Elaboration for important clarifications on all the items. If relevant, we also recommend reading CONSORT extensions for cluster randomised trials, non-inferiority and equivalence trials, non-pharmacological treatments, herbal interventions, and pragmatic trials. Additional extensions are forthcoming: for those and for up to date references relevant to this checklist, see www.consort-statement.org.