Cited by 134Posttraumatic Stress Disorder ResearchNeuroendocrine regulation and behaviorStress Responses and Cortisol

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Intranasal Oxytocin to Prevent Posttraumatic Stress Disorder Symptoms: A Randomized Controlled Trial in Emergency Department Patients

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Abstract

Background There are currently few preventive interventions available for posttraumatic stress disorder (PTSD). Intranasal oxytocin administration early after trauma may prevent PTSD, because oxytocin administration was previously found to beneficially impact PTSD vulnerability factors, including neural fear responsiveness, peripheral stress reactivity, and socioemotional functioning. Therefore, we investigated the effects of intranasal oxytocin administration early after trauma on subsequent clinician-rated PTSD symptoms. We then assessed whether baseline characteristics moderated the intervention's effects.Methods We performed a multicenter, randomized, double-blind, placebo-controlled clinical trial. Adult emergency department patients with moderate to severe acute distress (n = 120; 85% accident victims) were randomized to intranasal oxytocin (8 days/40 IU twice daily) or placebo (8 days/10 puffs twice daily), initiated within 12 days posttrauma. The Clinician-Administered PTSD Scale (CAPS) was administered at baseline (within 10 days posttrauma) and at 1.5, 3, and 6 months posttrauma. The intention-to-treat sample included 107 participants (oxytocin: n = 53; placebo: n = 54).Results We did not observe a significant group difference in CAPS total score at 1.5 months posttrauma (primary outcome) or across follow-up (secondary outcome). Secondary analyses showed that participants with high baseline CAPS scores receiving oxytocin had significantly lower CAPS scores across follow-up than participants with high baseline CAPS scores receiving placebo.Conclusions Oxytocin administration early after trauma did not attenuate clinician-rated PTSD symptoms in all trauma-exposed participants with acute distress. However, participants with high acute clinician-rated PTSD symptom severity did show beneficial effects of oxytocin. Although replication is warranted, these findings suggest that oxytocin administration is a promising preventive intervention for PTSD for individuals with high acute PTSD symptoms.

Overview

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TL;DR

In a multicenter randomized placebo-controlled trial, repeated intranasal oxytocin initiated early after trauma did not reduce clinician-rated PTSD symptoms overall in emergency department patients with acute distress. However, secondary moderator analyses found that oxytocin-treated participants with high acute PTSD symptom severity (baseline CAPS ≥45) had significantly lower PTSD symptoms across 6-month follow-up than placebo-treated participants.

Key findings

  • No significant group difference in the primary outcome, CAPS total score at 1.5 months posttrauma: oxytocin n=43, mean 25.84 (SD 22.97) vs placebo n=48, mean 27.44 (SD 22.03); square-root transformed mean difference 0.23 (SE 0.45), t89=0.509, p=.612, Cohen’s d=0.107.
  • Across follow-up, CAPS scores decreased significantly over time (B=-0.35, SE=0.05, t=-7.175, p<.001), but there was no significant overall intervention effect on intercept (B=-0.30, SE=0.37, t=-0.826, p=.409) or linear slope (B=0.04, SE=0.07, t=0.504, p=.614; Cohen’s d=0.133).
  • Baseline CAPS total score significantly moderated the intervention effect on follow-up CAPS scores (baseline CAPS × intervention on intercept: B=-0.73, SE=0.30, t=-2.389, p=.017). For participants with baseline CAPS ≥45, oxytocin was associated with lower CAPS scores across follow-up than placebo (F1,106=8.212, p=.006, Cohen’s d=0.864); for baseline CAPS <45, no significant effect was found (F1,106=0.822, p=.367, Cohen’s d=-0.221).
  • In exploratory pairwise comparisons among participants with baseline CAPS ≥45, oxytocin-treated participants also had lower IES-R (F1,107=8.181, p=.005, Cohen’s d=0.869), HADS-depression (F1,107=7.180, p=.014, Cohen’s d=0.752), and HADS-anxiety (F1,106=4.982, p=.038, Cohen’s d=0.623) scores across follow-up. Overall self-reported PTSD, anxiety, and depression symptoms did not show significant group differences (Cohen’s d: IES-R 0.195; HADS-anxiety 0.207; HADS-depression 0.113).

Methods

  • Multicenter, double-blind, randomized placebo-controlled trial in three Amsterdam emergency departments; adults aged 18–65 with moderate to severe acute distress after trauma were screened, and 120 were randomized. The intention-to-treat sample included 107 participants (oxytocin n=53; placebo n=54); 85% were accident victims.
  • Participants received intranasal oxytocin (40 IU/dose, twice daily for 8 days) or placebo (0.9% NaCl, 10 puffs twice daily), initiated within 12 days posttrauma. The Clinician-Administered PTSD Scale (CAPS) was administered at baseline within 10 days posttrauma and at 1.5, 3, and 6 months; primary outcome was CAPS total score at 1.5 months.
  • Analyses were intention-to-treat in SPSS v22, with multiple imputation for missing outcome data and linear mixed models for follow-up CAPS, IES-R, and HADS scores. Moderator analyses examined sex, childhood trauma, peritraumatic/immediate distress, and baseline acute symptom severity; a preplanned interim analysis after 50% of planned inclusion found conditional power <.20 and recruitment was halted.

Limitations

  • The paper states that inclusion was halted after the interim analysis showed low conditional power, resulting in a modest sample size; replication is important.
  • The paper states considerable variability in baseline CAPS scores: only 40.2% scored above the CAPS ≥45 threshold; screeners may have had lower specificity for PTSD than previously reported, and PTSD screening positives declined from 19.8% at 1.5 months to 6.0% at 6 months. It also notes that 23% reported mental health care use during follow-up, which may have stimulated help-seeking and contributed to symptom decrease.
  • The paper states that >80% of participants visited the ED because of accidents, so trauma type moderation could not be investigated; it also did not investigate different timing, dosage, or duration of oxytocin administration. Evident from the text: the beneficial findings in high acute PTSD symptom participants come from secondary and exploratory analyses and require replication.

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Integrity signals

Registry

Crossref · 10.1016/j.biopsych.2016.11.012

Cites

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  • It may state two separate claims as one. 14
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21 of 21
  • The paper relies on this without support.

    It had not yet been investigated whether oxytocin administration early after trauma may prevent PTSD development.

    “It has not yet been investigated whether oxytocin administration early after trauma may prevent PTSD development.”
  • The paper relies on this without support.

    Actual clinical effects of oxytocin administration in recently trauma-exposed individuals were not investigated.

    “However, actual clinical effects were not investigated.”
  • The paper relies on this without support.

    This study is the largest published clinical randomized controlled trial on effects of intranasal oxytocin on psychiatric symptoms to date.

    “This study is the largest published clinical randomized controlled trial on effects of intranasal oxytocin on psychiatric symptoms to date.”
  • The paper relies on this without support.

    This is the first randomized controlled trial assessing whether sex, trauma history, and baseline symptom severity moderate the effects of repeated oxytocin administration.

    “to the best of our knowledge, this is the first randomized controlled trial assessing whether sex, trauma history, and baseline symptom severity moderate the effects of repeated oxytocin administration.”
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Citations

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  1. deRoon-Cassini, 2014, Prediction of chronic PTSD using early fMRI evidence of emotion dysregulation in trauma survivors, Biol Psychiatry, 75, 169S

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Metadata

Authors
van Zuiden, M., Frijling, J. L., Nawijn, L., Koch, S. B. J., Goslings, J. C., Luitse, J. S., Biesheuvel, T. H., Honig, A., Veltman, D. J., & Olff, M.
Affiliations
  • Amsterdam UMC Location University of Amsterdam (NL)
  • Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
  • OLVG (NL)
  • Arq Psychotrauma Expert Group (NL)
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2017-06
Volume
81
Issue
12
Pages
1030-1040
ISSN
0006-3223 (ISSN-L)
OpenAlex
W2560374635
Cited by
134
References
74
Citations by year
2026: 8 · 2025: 6 · 2024: 7 · 2023: 9 · 2022: 18 · 2021: 19 · 2020: 13 · 2019: 20 · 2018: 26 · 2017: 8
FWCI
23.90
Type
journal article
Language
en
Open access
Locations
  • Biological Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion)
Funders
ZonMw (91210041)
Topics
  • Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
intranasal oxytocin, emergency department patients, placebo-controlled intervention, accident victims, intervention moderators
MeSH terms
Administration, Intranasal, Adolescent, Adult, Aged, Double-Blind Method, Emergency Service, Hospital, Female, Humans, Male, Middle Aged, Oxytocin, Stress Disorders, Post-Traumatic, Treatment Outcome, Young Adult

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