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Cited by 59Posttraumatic Stress Disorder ResearchNeuroendocrine regulation and behaviorStress Responses and Cortisol

Efficacy of oxytocin administration early after psychotrauma in preventing the development of PTSD: study protocol of a randomized controlled trial

Open access
Frijling, Jessie L, van Zuiden, Mirjam, Koch, Saskia BJ, Nawijn, Laura, Goslings, J Carel, Luitse, Jan S, Biesheuvel, Tessa H, Honig, Adriaan +4 more·2014·BMC Psychiatry
DOI 10.1186/1471-244x-14-92PMC PMC3986606
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Abstract

BACKGROUND: Currently few evidence based interventions are available for the prevention of PTSD within the first weeks after trauma. Increased risk for PTSD development is associated with dysregulated fear and stress responses prior to and shortly after trauma, as well as with a lack of perceived social support early after trauma. Oxytocin is a potent regulator of these processes. Therefore, we propose that oxytocin may be important in reducing adverse consequences of trauma. The 'BONDS' study is conducted in order to assess the efficacy of an early intervention with intranasal oxytocin for the prevention of PTSD. METHODS/DESIGN: In this multicenter double-blind randomized placebo-controlled trial we will recruit 220 Emergency Department patients at increased risk of PTSD. Trauma-exposed patients are screened for increased PTSD risk with questionnaires assessing peri-traumatic distress and acute PTSD symptoms within 7 days after trauma. Baseline PTSD symptom severity scores and neuroendocrine and psychophysiological measures will be collected within 10 days after trauma. Participants will be randomized to 7.5 days of intranasal oxytocin (40 IU) or placebo twice a day. Follow-up measurements at 1.5, 3 and 6 months post-trauma are collected to assess PTSD symptom severity (the primary outcome measure). Other measures of symptoms of psychopathology, and neuroendocrine and psychophysiological disorders are secondary outcome measures. DISCUSSION: We hypothesize that intranasal oxytocin administered early after trauma is an effective pharmacological strategy to prevent PTSD in individuals at increased risk, which is both safe and easily applicable. Interindividual and contextual factors that may influence the effects of oxytocin treatment will be considered in the analysis of the results. TRIAL REGISTRATION: Netherlands Trial Registry: NTR3190.

AI snapshot

Written from the paper’s full text.

TL;DR

The BONDS study protocol describes a multicenter, double-blind, randomized placebo-controlled trial testing whether intranasal oxytocin (40 IU twice daily for 7.5 days) started within 10 days of trauma prevents PTSD in Emergency Department patients at increased risk. No outcome data are reported; the paper presents the rationale, design, hypotheses, and planned analyses.

Key findings

  • The trial will recruit 220 trauma-exposed ED patients (18–65 years) scoring above cut-offs on the Trauma Screening Questionnaire (TSQ ≥ 5) and/or Peritraumatic Distress Inventory (PDI ≥ 17) within 7 days of trauma, randomized to intranasal oxytocin (40 IU) or placebo twice daily for 7.5 days.
  • The primary hypothesis is that the oxytocin group will report fewer PTSD symptoms (CAPS score) at 1.5 months post-trauma than placebo; secondary aims cover PTSD severity at 3 and 6 months, other psychopathology, quality of life, and psychophysiological, neuroendocrine, and epigenetic measures.
  • Sample size was calculated to detect a small-to-medium effect size of d = 0.4, corresponding to a 9.52-point lower CAPS score in the oxytocin group (based on an SD of 23.81), requiring 100 participants per arm plus 10% attrition allowance.
  • The authors hypothesize that baseline characteristics (gender, trauma type, childhood trauma history, coping style, attachment style, perceived social support) will moderate oxytocin's effects.

Methods

  • Design: multicenter, double-blind, randomized placebo-controlled trial with 2 baseline assessments (T1–T2) and 4 post-intervention assessments (T3–T6); randomization stratified by gender.
  • Sample and procedures: 220 ED patients from 3 Amsterdam EDs (2 level 1 Trauma Centers) meeting the DSM-IV PTSD A1 criterion; screening with TSQ and PDI; baseline PTSD symptom severity, neuroendocrine (salivary cortisol, DHEAS, hair cortisol, plasma oxytocin/AVP), psychophysiological (heart rate variability), and (epi)genetic measures collected within 10 days post-trauma; follow-up at 1.5, 3, and 6 months.
  • Analysis: intention-to-treat comparison of mean CAPS scores between arms at 1.5 months (primary), with 95% confidence intervals and p < 0.05; secondary and exploratory analyses use linear mixed models and subgroup moderation analyses.

Limitations

  • Stated: recruiting a large number of participants is challenging given the acute nature of the trial and stringent inclusion criteria; it is difficult to contact all trauma-exposed individuals in time.
  • Stated: there is no direct evidence that the chosen timing (start by day 10 post-trauma) and duration of the intervention are optimal, and preclinical findings differ on whether timing relative to trauma determines benefit or harm.
  • Stated: the most effective intranasal oxytocin dose is unknown due to a lack of dose–response studies, and applying multiple sprays per dose carries a risk of ineffective delivery.
  • Evident from the text: this is a protocol, so no efficacy or safety outcomes are yet available; the study uses DSM-IV criteria because DSM-5 had not been published at the start of recruitment.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1186/1471-244x-14-92

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 104 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    In our own research group, a score of 5 or higher on the TSQ provided optimal sensitivity and specificity for PTSD diagnosis at 1 month post-trauma in Trauma Resuscitation Room patients.

    “In our own research group, we have observed that a score of 5 or higher on the TSQ provided optimal sensitivity and specificity for PTSD diagnosis at 1 month post-trauma in Trauma Resuscitation Room patients [60].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Mouthaan J, Sijbrandij M, Reitsma JB, Gersons BPR, Olff M: Early screening for posttraumatic stress disorder: a comparative accuracy study. in preparation

      Not checked in the free run.

  • Findingown data

    In our own research group, a score of 17 or higher on the PDI provided optimal sensitivity and specificity for PTSD diagnosis at 1 month post-trauma in Trauma Resuscitation Room patients.

    “In our own research group, we have observed that a score of 17 or higher on the PDI provided optimal sensitivity and specificity for PTSD diagnosis at 1 month post-trauma in Trauma Resuscitation Room patients [60].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Mouthaan J, Sijbrandij M, Reitsma JB, Gersons BPR, Olff M: Early screening for posttraumatic stress disorder: a comparative accuracy study. in preparation

      Not checked in the free run.

  • Premisecitation

    Currently, little evidence is available for effective interventions that prevent the development of PTSD which can be administered early after trauma exposure.

    “Currently, little evidence is available for effective interventions that prevent the development of PTSD which can be administered early after trauma exposure [6].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Management of Post-Traumatic Stress Working Group: VA/DoD clinical practice guideline for management of post-traumatic stress. 2010, Washington, DC: Veterans Health Administration, Department of Defense

      Not checked in the free run.

  • Premisecitation

    Intranasal oxytocin administration is thought to result in endogenous release of the hormone in a feed-forward fashion.

    “In humans, intranasal oxytocin administration is thought to result in endogenous release of the hormone in a feed-forward fashion [38].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Weisman O, Zagoory-Sharon O, Feldman R: Intranasal oxytocin administration is reflected in human saliva. Psychoneuroendocrinology. 2012, 37 (9): 1582-1586. 10.1016/j.psyneuen.2012.02.014. source

      Not checked in the free run.

  • Premisecitation

    Increased risk of PTSD development is associated with pre-existing dysregulations of (para)sympathetic and hypothalamic-pituitary-adrenal axes.

    “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].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [17] Shaikh al Arab A, Guedon-Moreau L, Ducrocq F, Molenda S, Duhem S, Salleron J, Chaudieu I, Bert D, Libersa C, Vaiva G: Temporal analysis of heart rate variability as a predictor of post traumatic stress disorder in road traffic accidents survivors. J Psychiatr Res. 2012, 46 (6): 790-796. 10.1016/j.jpsychires.2012.02.006. source

      Not checked in the free run.

    • cites [18] Apfel BA, Otte C, Inslicht SS, McCaslin SE, Henn-Haase C, Metzler TJ, Makotkine I, Yehuda R, Neylan TC, Marmar CR: Pretraumatic prolonged elevation of salivary MHPG predicts peritraumatic distress and symptoms of post-traumatic stress disorder. J Psychiatr Res. 2011, 45 (6): 735-741. 10.1016/j.jpsychires.2010.11.016. source

      Not checked in the free run.

    • cites [20] Van Zuiden M, Geuze E, Willemen HL, Vermetten E, Maas M, Amarouchi K, Kavelaars A, Heijnen CJ: Glucocorticoid receptor pathway components predict Posttraumatic Stress Disorder symptom development: a prospective study. Biol Psychiatry. 2011, 71 (4): 309-316. source

      Not checked in the free run.

    • cites [21] McFarlane AC, Barton CA, Yehuda R, Wittert G: Cortisol response to acute trauma and risk of posttraumatic stress disorder. Psychoneuroendocrinology. 2011, 36 (5): 720-727. 10.1016/j.psyneuen.2010.10.007. source

      Not checked in the free run.

  • May combine two claims. 27
  • Classified as probably not a substantial claim. 29

  • May combine two claims.

    Premisecitation

    Single-session psychological debriefing administered within 3 months following traumatic events does not reduce distress or prevent PTSD.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [7] Sijbrandij M, Olff M, Reitsma JB, Carlier IV, Gersons BP: Emotional or educational debriefing after psychological trauma. Randomised controlled trial. Br J Psychiatry. 2006, 189: 150-155. 10.1192/bjp.bp.105.021121. source

      Not checked in the free run.

    • cites [8] Rose S, Bisson J, Wessely S: A systematic review of single-session psychological interventions (‘debriefing’) following trauma. Psychother Psychosom. 2003, 72 (4): 176-184. 10.1159/000070781. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Human endogenous oxytocin levels increase during safe social contact, but also during distress.

    “Human endogenous oxytocin levels increase during safe social contact [32,33], but also during distress.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [32] Holt-Lunstad J, Birmingham WA, Light KC: Influence of a “warm touch” support enhancement intervention among married couples on ambulatory blood pressure, oxytocin, alpha amylase, and cortisol. Psychosom Med. 2008, 70 (9): 976-985. 10.1097/PSY.0b013e318187aef7. source

      Not checked in the free run.

    • cites [33] Seltzer LJ, Ziegler TE, Pollak SD: Social vocalizations can release oxytocin in humans. Proc Biol Sci. 2010, 277 (1694): 2661-2666. 10.1098/rspb.2010.0567. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A single bolus of high dose hydrocortisone in trauma-exposed individuals at an Emergency Department resulted in fewer PTSD symptoms at 2 weeks and 3 months post-trauma relative to placebo.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Zohar J, Yahalom H, Kozlovsky N, Cwikel-Hamzany S, Matar MA, Kaplan Z, Yehuda R, Cohen H: High dose hydrocortisone immediately after trauma may alter the trajectory of PTSD: interplay between clinical and animal studies. Eur Neuropsychopharmacol. 2011, 21 (11): 796-809. 10.1016/j.euroneuro.2011.06.001. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    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.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Olff M: Bonding after trauma: on the role of social support and the oxytocin system in traumatic stress. Eur J Psychotraumatol. 2012, 3: doi:10.3402/ejpt.v3i0.18597

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Increased oxytocin activity during distress and its attenuating effects on HPA axis and autonomic nervous system activity may indicate a regulatory function of oxytocin in physiological stress.

    “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.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [34] Tops M, van Peer JM, Korf J, Wijers AA, Tucker DM: Anxiety, cortisol, and attachment predict plasma oxytocin. Psychophysiology. 2007, 44 (3): 444-449. 10.1111/j.1469-8986.2007.00510.x. source

      Not checked in the free run.

    • cites [35] Turner RA, Altemus M, Enos T, Cooper B, McGuinness T: Preliminary research on plasma oxytocin in normal cycling women: investigating emotion and interpersonal distress. Psychiatry. 1999, 62 (2): 97-113. source

      Not checked in the free run.

    • cites [36] Altemus M, Deuster PA, Galliven E, Carter CS, Gold PW: Suppression of hypothalmic-pituitary-adrenal axis responses to stress in lactating women. J Clin Endocrinol Metab. 1995, 80 (10): 2954-2959.

      Not checked in the free run.

    • cites [37] Light KC, Grewen KM, Amico JA: More frequent partner hugs and higher oxytocin levels are linked to lower blood pressure and heart rate in premenopausal women. Biol Psychol. 2005, 69 (1): 5-21. 10.1016/j.biopsycho.2004.11.002. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Three sessions of prolonged exposure therapy administered within 2 weeks after trauma reduced post-traumatic stress reactions at 1 and 3 months post-trauma.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Rothbaum BO, Kearns MC, Price M, Malcoun E, Davis M, Ressler KJ, Lang D, Houry D: Early intervention may prevent the development of posttraumatic stress disorder: a randomized pilot civilian study with modified prolonged exposure. Biol Psychiatry. 2012, 72 (11): 957-963. 10.1016/j.biopsych.2012.06.002. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Intranasal oxytocin can facilitate trust and prosocial behavior.

    “Several human studies showed that intranasal oxytocin can facilitate trust and prosocial behavior [40,41].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [40] Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E: Oxytocin increases trust in humans. Nature. 2005, 435 (7042): 673-676. 10.1038/nature03701. source

      Not checked in the free run.

    • cites [41] Van Ijzendoorn MH, Bakermans-Kranenburg MJ: A sniff of trust: meta-analysis of the effects of intranasal oxytocin administration on face recognition, trust to in-group, and trust to out-group. Psychoneuroendocrinology. 2012, 37 (3): 438-443. 10.1016/j.psyneuen.2011.07.008. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Multiple sessions of preventive Behavioral Therapy administered within 3 months following traumatic events do not reduce distress or prevent PTSD.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Roberts NP, Kitchiner NJ, Kenardy J, Bisson JI: Systematic review and meta-analysis of multiple-session early interventions following traumatic events. Am J Psychiatry. 2009, 166 (0002–953; 3): 293-301. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Participants will be randomly assigned to 1 of the 2 intervention groups, stratified by gender, ensuring that both genders are equally distributed over the 2 intervention groups.

    “Participants will be randomly assigned to 1 of the 2 intervention groups, stratified by gender, ensuring that both genders are equally distributed over the 2 intervention groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductcitation

    The Dutch version of the TSQ has good reliability and validity.

    “The Dutch version has a good reliability and validity [66].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [66] Dekkers AM, Olff M, Naring GW: Identifying persons at risk for PTSD after trauma with TSQ in the Netherlands. Community Ment Health J. 2010, 46 (1): 20-25. 10.1007/s10597-009-9195-6. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Intranasal oxytocin dampens the central fear response by lowering amygdala activity and potentially enhancing fear regulation by increasing top-down control of the prefrontal cortex over the amygdala.

    “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].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [44] Domes G, Heinrichs M, Glascher J, Buchel C, Braus DF, Herpertz SC: Oxytocin attenuates amygdala responses to emotional faces regardless of valence. Biol Psychiatry. 2007, 62 (10): 1187-1190. 10.1016/j.biopsych.2007.03.025. source

      Not checked in the free run.

    • cites [45] Kirsch P, Esslinger C, Chen Q, Mier D, Lis S, Siddhanti S, Gruppe H, Mattay VS, Gallhofer B, Meyer-Lindenberg A: Oxytocin modulates neural circuitry for social cognition and fear in humans. J Neurosci. 2005, 25 (49): 11489-11493. 10.1523/JNEUROSCI.3984-05.2005. source

      Not checked in the free run.

    • cites [46] Singer T, Snozzi R, Bird G, Petrovic P, Silani G, Heinrichs M, Dolan RJ: Effects of oxytocin and prosocial behavior on brain responses to direct and vicariously experienced pain. Emotion. 2008, 8 (6): 781-791. source

      Not checked in the free run.

    • cites [47] Sripada CS, Phan KL, Labuschagne I, Welsh R, Nathan PJ, Wood AG: Oxytocin enhances resting-state connectivity between amygdala and medial frontal cortex. Int J Neuropsychopharmacol. 2012, 16 (02): 255-260. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The BONDS study is a multicenter double-blind randomized placebo-controlled trial in recently traumatized ED patients with increased risk of PTSD.

    “The ‘BONDS’ study is a multicenter double-blind randomized placebo-controlled trial in recently traumatized ED patients with increased risk of PTSD.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The study has been approved by the Institutional Review Board of the Academic Medical Center and is conducted following guidelines of Good Clinical Practice in accordance with the principles of the Declaration of Helsinki.

    “The study has been approved by the Institutional Review Board of the Academic Medical Center (AMC) (registration number 11/273) and is conducted following guidelines of Good Clinical Practice (GCP) in accordance with the principles of the Declaration of Helsinki.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A dose of 40 IU oxytocin twice a day is comparable to the doses previously used in human studies investigating effects of multiple treatments of oxytocin and does not produce significant side effects or adverse outcomes.

    “A dose of 40 IU twice a day is comparable to the doses previously used in human studies investigating effects of multiple treatments of oxytocin [61,62] and does not produce significant side effects or adverse outcomes [63].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [61] Feifel D, Macdonald K, Nguyen A, Cobb P, Warlan H, Galangue B, Minassian A, Becker O, Cooper J, Perry W, Lefebvre M, Gonzales J, Hadley A: Adjunctive intranasal oxytocin reduces symptoms in schizophrenia patients. Biol Psychiatry. 2010, 68 (7): 678-680. 10.1016/j.biopsych.2010.04.039. source

      Not checked in the free run.

    • cites [62] Ohlsson B, Truedsson M, Bengtsson M, Torstenson R, Sjolund K, Bjornsson ES, Simren M: Effects of long-term treatment with oxytocin in chronic constipation; a double blind, placebo-controlled pilot trial. Neurogastroenterol Motil. 2005, 17 (5): 697-704. 10.1111/j.1365-2982.2005.00679.x. source

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    • cites [63] Macdonald E, Dadds MR, Brennan JL, Williams K, Levy F, Cauchi AJ: A review of safety, side-effects and subjective reactions to intranasal oxytocin in human research. Psychoneuroendocrinology. 2011, 36 (8): 1114-1126. 10.1016/j.psyneuen.2011.02.015. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All study medication is prepared by the hospital pharmacy of the Slotervaart Hospital, Amsterdam, under Good Manufacturing Practice (GMP) licence.

    “All study medication is prepared by the hospital pharmacy of the Slotervaart Hospital, Amsterdam, under Good Manufacturing Practice (GMP) licence.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A TSQ cut-off score of 5 has good sensitivity (0.84) and specificity (0.92).

    “Since we administer the questionnaire relatively early post-trauma (i.e. within the first week compared to 1 to 3 weeks post-trauma) and a cut-off score of 5 still has a good sensitivity (0.84) and specificity (0.92) [58], we use the lower cut-off score of 5 to signal increased risk.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] Walters JT, Bisson JI, Shepherd JP: Predicting post-traumatic stress disorder: validation of the Trauma Screening Questionnaire in victims of assault. Psychol Med. 2007, 37 (1): 143-150. 10.1017/S0033291706008658. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Independent quality monitoring of the trial is performed to assure the quality of the study.

    “To assure the quality of our study, independent quality monitoring of the trial is performed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Intranasal oxytocin regulates responses of the HPA axis and the (para)sympathetic nervous system.

    “Furthermore, intranasal oxytocin regulates responses of the HPA axis [42] and the (para)sympathetic nervous system [43].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [42] Heinrichs M, Baumgartner T, Kirschbaum C, Ehlert U: Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress. Biol Psychiatry. 2003, 54 (12): 1389-1398. 10.1016/S0006-3223(03)00465-7. source

      Not checked in the free run.

    • cites [43] Norman GJ, Cacioppo JT, Morris JS, Malarkey WB, Berntson GG, DeVries AC: Oxytocin increases autonomic cardiac control: Moderation by loneliness. Biol Psychol. 2011, 86 (3): 174-180. 10.1016/j.biopsycho.2010.11.006. source

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  • May combine two claims.

    Premisecitation

    Central oxytocin administration in rats 10 minutes prior to fear conditioning did not affect fear conditioning, but subsequently decreased fear expression and facilitated fear extinction.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Toth I, Neumann ID, Slattery DA: Central administration of oxytocin receptor ligands affects cued fear extinction in rats and mice in a timepoint-dependent manner. Psychopharmacology (Berl). 2012, 223 (2): 149-158. 10.1007/s00213-012-2702-4. source

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  • May combine two claims.

    Interpretationcitation

    Central oxytocin administered 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.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Toth I, Neumann ID, Slattery DA: Central administration of oxytocin receptor ligands affects cued fear extinction in rats and mice in a timepoint-dependent manner. Psychopharmacology (Berl). 2012, 223 (2): 149-158. 10.1007/s00213-012-2702-4. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The oxytocin and placebo bottles are re-labeled so that they appear identical.

    “The bottles are re-labeled so that the oxytocin and placebo bottles appear identical.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The trial has been registered in the Netherlands Trial Registry (NTR3190).

    “The trial has been registered in the Netherlands Trial Registry and can be found at http://www.trialregister.nl (NTR3190).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    High-frequency HRV is an index for parasympathetic nervous system functioning.

    “R-R intervals obtained from the equipment will be used to calculate high-frequency HRV (HF-HRV) as an index for parasympathetic nervous system functioning [88].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [88] Quintana DS, Heathers JA, Kemp AH: On the validity of using the Polar RS800 heart rate monitor for heart rate variability research. Eur J Appl Physiol. 2012, 112: 4179-4180. 10.1007/s00421-012-2453-2. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The reliability of the HADS was high in a sample of Dutch traumatized persons.

    “The reliability was high in a sample of Dutch traumatized persons [73].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73] Spinhoven P, Ormel J, Sloekers PP, Kempen GI, Speckens AE, Van Hemert AM: A validation study of the Hospital Anxiety and Depression Scale (HADS) in different groups of Dutch subjects. Psychol Med. 1997, 27 (2): 363-370. 10.1017/S0033291796004382. source

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  • May combine two claims.

    Study design and conductcitation

    The PDEQ is valid and reliable.

    “The PDEQ is valid and reliable [86].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [86] Sijbrandij M, Engelhard IM, Opmeer BC, van de Schoot R, Carlier IV, Gersons BP, Olff M: The structure of peritraumatic dissociation: a cross validation in clinical and nonclinical samples. J Trauma Stress. 2012, 25 (4): 475-479. 10.1002/jts.21716. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    The Dutch WHOQOL-BREF has good validity and reliability.

    “The Dutch WHO-QOL-BREF has good validity and reliability [78].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] Trompenaars FJ, Masthoff ED, Van Heck GL, Hodiamont PP, De Vries J: Content validity, construct validity, and reliability of the WHOQOL-Bref in a population of Dutch adult psychiatric outpatients. Qual Life Res. 2005, 14 (1): 151-160. 10.1007/s11136-004-0787-x. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The Dutch version of the MINI has been validated.

    “The Dutch version has been validated [71].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [71] Van Vliet IM, De Beurs E: [The MINI-International Neuropsychiatric Interview. A brief structured diagnostic psychiatric interview for DSM-IV en ICD-10 psychiatric disorders]. Tijdschr Psychiatr. 2007, 46 (6): 393-397.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    The ECR has high reliability and validity.

    “The questionnaire has a high reliability and validity [83].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [83] Ravitz P, Maunder R, Hunter J, Sthankiya B, Lancee W: Adult attachment measures: a 25-year review. J Psychosom Res. 2010, 69 (4): 419-432. 10.1016/j.jpsychores.2009.08.006. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    DNA methylation regulates gene expression, which may induce lasting changes in stress reactivity.

    “Through DNA methylation, environmental experiences regulate gene expression, which may induce lasting changes in stress reactivity [91,92].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [91] Weaver IC, Cervoni N, Champagne FA, D’Alessio AC, Sharma S, Seckl JR, Dymov S, Szyf M, Meaney MJ: Epigenetic programming by maternal behavior. Nat Neurosci. 2004, 7 (8): 847-854. 10.1038/nn1276. source

      Not checked in the free run.

    • cites [92] Szyf M: The early life social environment and DNA methylation: DNA methylation mediating the long-term impact of social environments early in life. Epigenetics. 2011, 6 (8): 971-978. 10.4161/epi.6.8.16793. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The Dutch version of the IES-R has been validated.

    “The Dutch version has been validated [60].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Mouthaan J, Sijbrandij M, Reitsma JB, Gersons BPR, Olff M: Early screening for posttraumatic stress disorder: a comparative accuracy study. in preparation

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The Dutch version of the STAI-state has been validated.

    “The STAI-state consists of 20 4-point scale items (range 20–80) and the Dutch version has been validated [80].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Van der Ploeg H: Validity of the zelf-beoordelings-vragenlijst (a Dutch version of the spielberger state-trait anxiety inventory). Ned Tijdschr Psychol. 1980, 35 (4): 243-249.

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    Sample size calculation was based on the minimal effect size considered to be clinically relevant in the prevention of PTSD symptom development and on previous results of studies on the effects of long-term oxytocin administration in reducing psychiatric symptoms.

    “Sample size calculation was based on the minimal effect size considered to be clinically relevant in the prevention of PTSD symptom development and on previous results of studies on the effects of long-term oxytocin administration in reducing psychiatric symptoms.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    All analyses will be conducted on the basis of intention-to-treat (ITT).

    “All analyses will be conducted on the basis of intention-to-treat (ITT).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    The SSL-6 has good construct validity and high reliability.

    “The list has good construct validity and high reliability [81].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Van Sonderen E: Sociale steun lijst-interacties (SSL-I) en sociale steun lijst-discrepanties (SSL-D): een handleiding [social support list-interactions (SSL-I) and social support list-discripancies (SSL-D): a manual]. 1993, Groningen: Noordelijk Centrum voor Gezondheidsvraagstukken, Rijksuniversiteit Groningen

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    The CSI has been found to be valid and reliable.

    “The CSI has been found to be valid and reliable [84].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84] Amirkhan JH: Criterion validity of a coping measure. J Pers Assess. 1994, 62 (2): 242-261. 10.1207/s15327752jpa6202_6. source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductcitation

    The SHC has satisfactory validity and reliability.

    “The survey has been tested and has satisfactory validity and reliability [76].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [76] Eriksen HR, Ihlebaek C, Ursin H: A scoring system for subjective health complaints (SHC). Scand J Public Health. 1999, 27 (1): 63-72. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The Dutch version of the CAPS has been validated.

    “The Dutch version has been validated [69].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Hovens JE, van DP, Klaarenbeek MT, Bramsen I, Schreuder JN, Rivero VV: The assessment of posttraumatic stress disorder: with the Clinician Administered PTSD Scale: Dutch results. J Clin Psychol. 1994, 50 (3): 325-340. 10.1002/1097-4679(199405)50:3<325::AID-JCLP2270500304>3.0.CO;2-M. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Differential levels of DNA methylation of genes related to stress reactivity have already been associated with PTSD and early life stress.

    “Differential levels of DNA methylation of genes related to stress reactivity have already been associated with PTSD and early life stress [93-95].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [93] Smith AK, Conneely KN, Kilaru V, Mercer KB, Weiss TE, Bradley B, Tang Y, Gillespie CF, Cubells JF, Ressler KJ: Differential immune system DNA methylation and cytokine regulation in post‒traumatic stress disorder. Am J Med Genet B Neuropsychiatr Genet. 2011, 156 (6): 700-708. 10.1002/ajmg.b.31212. source

      Not checked in the free run.

    • cites [94] Roth TL, Lubin FD, Funk AJ, Sweatt JD: Lasting epigenetic influence of early-life adversity on the BDNF gene. Biol Psychiatry. 2009, 65 (9): 760-769. 10.1016/j.biopsych.2008.11.028. source

      Not checked in the free run.

    • cites [95] Uddin M, Aiello AE, Wildman DE, Koenen KC, Pawelec G, de Los SR, Goldmann E, Galea S: Epigenetic and immune function profiles associated with posttraumatic stress disorder. Proc Natl Acad Sci U S A. 2010, 107 (20): 9470-9475. 10.1073/pnas.0910794107. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Pre-trauma risk factors for PTSD have been established.

    “Even though pre-trauma risk factors have been established [102], this knowledge cannot yet be used to assess pre-trauma individual PTSD risk.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Van Zuiden M, Heijnen CJ, Maas M, Amarouchi K, Vermetten E, Geuze E, Kavelaars A: Glucocorticoid sensitivity of leukocytes predicts PTSD, depressive and fatigue symptoms after military deployment: a prospective study. Psychoneuroendocrinology. 2012, 37 (11): 1822-1836. 10.1016/j.psyneuen.2012.03.018. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The BONDS study's broader recruitment strategy, including trauma-exposed individuals with minor injuries, will yield better generalizable results with stronger implications for general practice than a narrower strategy.

    “Although we do exclude some trauma types (e.g. domestic violence and other ongoing traumatizing events) we believe that our more heterogeneous population will yield better generalizable results with stronger implications for general practice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Despite recruitment challenges, it remains possible to assess the potential effect of the intervention in the population that can be included in the BONDS study, because it is an RCT on efficacy and not an epidemiological study.

    “However, since the BONDS study is an RCT on the efficacy of an intervention and not an epidemiological study, it remains possible to assess the potential effect of the intervention in the population that we are able to include in the study.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Only individuals with increased risk of PTSD should receive any form of primary or secondary preventive intervention.

    “In addition, the current notion is that only individuals with increased risk of PTSD should receive any form of (primary or secondary) preventive interventions [101].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [101] Kearns MC, Ressler KJ, Zatzick D, Rothbaum BO: Early interventions for PTSD: a review. Depress Anxiety. 2012, 29 (10): 833-842. 10.1002/da.21997. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Higher objective injury severity scores due to a potential traumatic event do not predict later PTSD symptoms.

    “In addition, it has been reported that higher objective injury severity scores due to a potential traumatic event do not predict later PTSD symptoms [100].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [100] Delahanty DL, Raimonde AJ, Spoonster E, Cullado M: Injury severity, prior trauma history, urinary cortisol levels, and acute PTSD in motor vehicle accident victims. J Anxiety Disord. 2003, 17 (2): 149-164. 10.1016/S0887-6185(02)00185-8. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    There is a lack of dose-response studies of intranasal oxytocin, so it is not known which dose of intranasal oxytocin is most effective.

    “Another possible limitation of the trial is that we do not know which dose of intranasal oxytocin is most effective, since there is a lack of dose–response studies of intranasal oxytocin.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    It is difficult to contact all trauma-exposed individuals in time.

    “It proves to be difficult to contact all trauma-exposed individuals in time.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductreasoning

    The trial will include 110 participants per study group at T1 to allow for 10% attrition, yielding 220 participants in total.

    “To allow for 10% attrition (estimated from our previous study in a similar population) we will include 110 participants in each study group at T1. Therefore we will include 220 participants in total.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    If effective, oxytocin administration will be an easily applicable method to reduce adverse psychological outcome as a result of trauma exposure.

    “If effective, oxytocin administration will be an easily applicable method to reduce adverse psychological outcome as a result of trauma exposure.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The studies examining differential oxytocin doses were single administration studies on non-clinical outcome measures.

    “However, these studies were single administration studies on non-clinical outcome measures.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [103] Goldman MB, Gomes AM, Carter CS, Lee R: Divergent effects of two different doses of intranasal oxytocin on facial affect discrimination in schizophrenic patients with and without polydipsia. Psychopharmacology (Berl). 2011, 216 (1): 101-110. 10.1007/s00213-011-2193-8. source

      Not checked in the free run.

    • cites [104] Cardoso C, Ellenbogen MA, Orlando MA, Bacon SL, Joober R: Intranasal oxytocin attenuates the cortisol response to physical stress: a dose–response study. Psychoneuroendocrinology. 2012, 38 (3): 399-407. source

      Not checked in the free run.

    • cites [105] Hall SS, Lightbody AA, McCarthy BE, Parker KJ, Reiss AL: Effects of intranasal oxytocin on social anxiety in males with fragile X syndrome. Psychoneuroendocrinology. 2012, 37 (4): 509-518. 10.1016/j.psyneuen.2011.07.020. source

      Not checked in the free run.

48 of 48

  • The paper relies on this without support.

    No reports on the effects of intranasal oxytocin in recently traumatized human individuals have been published.

    “To date, no reports on the effects of intranasal oxytocin in recently traumatized human individuals have been published.”

  • The paper relies on this without support.

    A CAPS score of 45 is required for a PTSD diagnosis.

    “Based on a SD of 23.81, a small-to-medium effect size of d = 0.4 would result in a 9.52-point lower CAPS score in the oxytocin-treated group compared to the placebo group at 1 month post-intervention (a CAPS score of 45 is required for a PTSD-diagnosis).”

  • The authors state this as an assumption.

    The group difference of 9.52 points on the CAPS is clinically relevant.

    “We consider this group difference on the CAPS to be clinically relevant.”

  • The paper relies on this without support.

    Evidence-based interventions that prevent PTSD in the first few weeks post-trauma are much needed.

    “This is highly relevant since evidence-based interventions that prevent PTSD in the first few weeks post-trauma are much needed.”

  • The paper relies on this without support.

    Intranasal oxytocin acts on risk factors associated with PTSD development (lack of social support and dysregulated stress and fear responses).

    “Intranasal oxytocin is a promising pharmacological agent for PTSD prevention, since it acts on risk factors associated with PTSD development, i.e. a lack of social support and dysregulated stress and fear responses.”
5 of 5

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Prevailing hypotheses suggest that oxytocin may uniquely help mitigate barriers to engaging in behavioral treatments that specifically target avoidance, which would thereby allow patients who might otherwise be unable to tolerate PE to engage effectively, complete the treatment, obtain an adequate therapeutic dose, and experience long-term remission of PTSD.

    “Prevailing hypotheses suggest that oxytocin may uniquely help mitigate barriers to engaging in behavioral treatments that specifically target avoidance (Preckel et al., 2014), which would thereby allow patients who might otherwise be unable to tolerate PE to engage effectively, complete the treatment, obtain an adequate therapeutic dose, and experience long-term remission of PTSD (Frijling et al.,”

    From Augmenting Prolonged Exposure therapy for PTSD with intranasal oxytocin: a randomized, placebo-controlled pilot trial (2018) · cites this paper as Frijling et al., 2014

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

  • Attachment subscale maximum is inconsistent with its item scale

    Minor

    Each attachment subscale has 18 items scored on a 7-point scale. With the stated minimum of 18, the maximum would be 126, not 49.

    Reported 49 · recomputed 126

1 of 1

The citation lists haven’t been fetched yet

References 109 · Cited by 59

Research works printed but not linked: 3

  1. Van der Ploeg H: Validity of the zelf-beoordelings-vragenlijst (a Dutch version of the spielberger state-trait anxiety inventory). Ned Tijdschr Psychol. 1980, 35 (4): 243-249.
  2. Van Sonderen E: Sociale steun lijst-interacties (SSL-I) en sociale steun lijst-discrepanties (SSL-D): een handleiding [social support list-interactions (SSL-I) and social support list-discripancies (SSL-D): a manual]. 1993, Groningen: Noordelijk Centrum voor Gezondheidsvraagstukken, Rijksuniversiteit Groningen
  3. Elashoff JD: nQuery Advisor (Version 7.0) [Computer software]. 2007, Boston, MA: Statistical Solutions

Authors
Frijling, J. L., van Zuiden, M., Koch, S. B., Nawijn, L., Goslings, J. C., Luitse, J. S., Biesheuvel, T. H., Honig, A., Bakker, F. C., Denys, D., Veltman, D. J., & Olff, M.
Affiliations
  • Amsterdam UMC Location University of Amsterdam (NL)
  • Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
  • Sint Lucas Andreas Hospital (NL)
  • Netherlands Institute for Neuroscience (NL)
Corresponding author
Frijling, Jessie L
ORCID
Venue
BMC Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2014-03-28
Volume
14
Issue
1
Pages
92-92
ISSN
1471-244X (ISSN-L)
DOI
10.1186/1471-244x-14-92
PMC
PMC3986606
OpenAlex
W2029231688
Semantic Scholar
d3755f5ab7ddb5f30a335ae3f75c42338bd6089e
Cited by
59
References
109
Citations by year
2025: 2 · 2024: 5 · 2023: 3 · 2022: 4 · 2021: 4 · 2020: 4 · 2019: 6 · 2018: 8 · 2017: 6 · 2016: 4 · 2015: 10 · 2014: 3
FWCI
9.00
Type
journal article
Language
en
Open access
Licence
Locations
  • BMC Psychiatry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion)
Funders
ZonMw (91210041, 110614)
Topics
  • Social Sciences › Psychology › Clinical Psychology › Posttraumatic Stress Disorder Research
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
oxytocin, post-traumatic stress disorder prevention, psychotrauma, intranasal administration, emergency department patients, social support, psychophysiological measures, pharmacological prophylaxis
MeSH terms
Administration, Intranasal, Adolescent, Adult, Aged, Double-Blind Method, Fear, Female, Humans, Male, Middle Aged, Netherlands, Oxytocin, Stress Disorders, Post-Traumatic, Young Adult

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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