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Cited by 57Posttraumatic Stress Disorder ResearchNeuroendocrine regulation and behaviorStress Responses and Cortisol

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

Open access
Sack, M., Spieler, D., Wizelman, L., Epple, G., Stich, J., Zaba, M., Schmidt, U.·2017·BMC Medicine
DOI 10.1186/s12916-017-0801-0PMC PMC5314583
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Abstract

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.

AI snapshot

Written from the paper’s full text.

TL;DR

In a double-blind randomized placebo-controlled within-subject trial, intranasal oxytocin reduced trauma-script-provoked total PTSD symptoms in female PTSD patients while increasing heart rate and decreasing pre-ejection period. A small healthy-woman TSST pilot found endogenous oxytocin serum levels positively correlated with heart rate before and after stress.

Key findings

  • Intranasal oxytocin significantly reduced provoked total PTSD symptoms on the RSDI versus placebo: mean 2.44 (SD 0.90) vs 2.87 (SD 1.1), p = 0.012, Cohen’s d = 0.459.
  • Avoidance symptoms showed a trend toward reduction with oxytocin: mean 1.92 (SD 1.4) vs 2.52 (SD 1.8), p = 0.093; re-experiencing (p = 0.15) and dissociation (p = 0.26) were not significant.
  • Oxytocin increased maximum heart rate during trauma-script challenge: 93.8 bpm (SD 15.2) vs 88.1 bpm (SD 12.6), p = 0.020, and decreased pre-ejection period: 70.0 ms (SD 17.7) vs 74.2 ms (SD 12.9), p = 0.007. Baseline heart rate was also elevated by oxytocin (p = 0.02).
  • In 10 healthy women undergoing the TSST, oxytocin serum levels correlated positively with heart rate before and after stress; correlations remained significant after controlling for age, BMI, and ovarian cycle.

Methods

  • Randomized, double-blind, placebo-controlled within-subject trial in 35 adult female Caucasian patients with full DSM-IV PTSD, recruited November 2010–December 2012; patients received 24 IU intranasal oxytocin or placebo before trauma-script exposure and served as their own controls.
  • Primary outcome was efficacy of intranasal oxytocin on PTSD symptoms provoked by trauma-script exposure, assessed with the RSDI; cardiac parameters (HR, HRV, PEP) and respiration were also measured at baseline and during trauma-script exposure, analyzed with linear mixed models.
  • An additional pilot experiment studied 10 healthy non-traumatized unmedicated women before and after the Trier Social Stress Test, measuring oxytocin serum levels by ELISA, cortisol, heart rate, and subjective stress; relationships were analyzed with Pearson correlations and partial correlations.

Limitations

  • Stated in the paper: small sample sizes in both the patient and healthy-control samples, heterogeneity of the patient sample (broad age range, differences in pharmacotherapy and trauma types), inclusion of women only, and failure to include ovarian cycle phase as a covariate in the patient analysis limit generalizability.
  • Stated in the paper: blinding integrity was not assessed; the authors also note the possibility of unknown unintended long-term consequences and that the small TSST correlation may be a methodological artifact driven by small sample size.
  • Evident from the text: the abstract reports a 2-week interval between oxytocin and placebo, while the Methods section states a 1-week interval; the paper also reports no male PTSD patients, so gender dependency remains untested.

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

Integrity signals

Registry

Crossref · 10.1186/s12916-017-0801-0

Cites

Statistics

Claims the paper makes

0 of 40 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Oxytocin treatment did not significantly reduce dissociative symptoms provoked by trauma-script exposure in female PTSD patients.

    “Analysis of the three different symptom clusters revealed that the oxytocin-mediated reduction in dissociative and re-experiencing symptoms was not significant (Table 2).”
    • Also stated in: § Intranasal oxytocin reduces provoked PTSD symptoms · plain
      “RSDI-Dissociation | | 2.26 (1.8) | | 1.96 (1.4) | 1.2 (34) | 0.26 | 0.195 (−0.13–0.52)”
    Quote in the paperNot a substantial claim
  • Findingown data

    Oxytocin treatment significantly increased maximum heart rate compared to placebo during trauma-script challenge in female PTSD patients (p = 0.020).

    “HR max (bpm) | | 88.1 (12.6) | | 93.8 (15.2) | 12.8 (34) | 0.020* | 0.605 (0.34–0.87)”
    • Also stated in: § Results · plain
      “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.”
    Quote in the paperSubstantial claim
  • Findingown data

    Oxytocin treatment attenuated avoidance symptoms provoked by trauma-script exposure in female PTSD patients with a trend toward statistical significance (p = 0.093).

    “However, oxytocin treatment attenuated avoidance – at least with a trend for statistical significance (Table 2, p = 0.093).”
    • Also stated in: § Intranasal oxytocin reduces provoked PTSD symptoms · hedged
      “RSDI-Avoidance | | 2.52 (1.8) | | 1.92 (1.4) | 3.0 (34) | 0.093t | 0.289 (−0.14–0.72)”
    Quote in the paperSubstantial claim
  • Findingown data

    Oxytocin treatment increased baseline heart rate compared to placebo in female PTSD patients with a trend toward statistical significance (p = 0.059).

    “HR (bpm) | 75.9 (9.6) | 82.1 (11.4) | 77.9 (8.9) | 87.2 (15.0) | 3.0 (34) | 0.059t | 0.291 (−0.00–0.50)”
    • Also stated in: § Results · plain
      “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.”
    Quote in the paperSubstantial claim
  • Findingown data

    The patient cohort consisted of 35 adult female Caucasian patients with full PTSD.

    “we recruited 35 adult female Caucasian patients with full PTSD”
    • Also stated in: § Demographics and clinical characteristics of the PTSD patient sample · plain
      “The mean age of the 35 white Caucasian female PTSD patients included was 39.8 years (range 22–70 years).”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 45
  • May combine two claims. 12
  • The quote only partly states this claim. 1

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

    Findingown data

    PTSD symptoms were the major complaint of the patient sample.

    “All patients fulfilled DSM-IV diagnostic criteria for PTSD, and PTSD symptoms were their major complaint.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The mean SCID-D score of the cohort was 12.7.

    “the mean SCID-D score of the cohort was >10, namely 12.7 (Table 1).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Oxytocin treatment did not significantly reduce re-experiencing symptoms provoked by trauma-script exposure in female PTSD patients.

    “Analysis of the three different symptom clusters revealed that the oxytocin-mediated reduction in dissociative and re-experiencing symptoms was not significant (Table 2).”
    • Also stated in: § Intranasal oxytocin reduces provoked PTSD symptoms · plain
      “RSDI-Re-experiencing | | 3.74 (1.3) | | 3.30 (1.2) | 2.2 (34) | 0.15 | 0.342 (−0.11–0.70)”
    Quote in the paperNot a substantial claim

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

    Findingown data

    19 participants (54.3%) were diagnosed with a dissociative disorder.

    “With regards comorbidities, 19 participants (54.3%) were diagnosed with a dissociative disorder.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    6 patients (17.1%) had a borderline-personality disorder.

    “six (17.1%) a borderline-personality disorder.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The mean age of the patient cohort was 39.8 years.

    “The mean age of the 35 white Caucasian female PTSD patients included was 39.8 years (range 22–70 years).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Most patients (74%) suffered from early relational trauma.

    “Most patients (n = 26, 74%) suffered from early relational trauma.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    11 patients (31.4%) had an anxiety disorder.

    “11 (31.4%) an anxiety disorder”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The mean age at first traumatization was 7.7 years.

    “The mean age at first traumatization was 7.7 years (range 2–22 years).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    22 patients (62.9%) reported a sexual trauma.

    “Thus, 22 (62.9%) of our patients reported a sexual trauma.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    10 patients (28.6%) had a somatoform disorder.

    “ten (28.6%) a somatoform disorder”
    Quote in the paperNot a substantial claim

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

    Findingown data

    23 patients (65.7%) had a current depressive disorder.

    “Moreover, 23 patients (65.7%) had a current depressive disorder”
    Quote in the paperNot a substantial claim

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

    Findingcitation

    The TSST experiment included 10 healthy adult Caucasian women.

    “The 10 healthy adult Caucasian women assessed here for their endogenous oxytocin plasma levels, cortisol serum levels, HR and subjective stress response constitute a subsample of a previously published cohort [21]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Zaba M, Kirmeier T, Ionescu IA, Wollweber B, Buell DR, Gall-Kleebach DJ, et al. Identification and characterization of HPA-axis reactivity endophenotypes in a cohort of female PTSD patients. Psychoneuroendocrinology. 2015;55:102–15. source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Intranasal oxytocin treatment did not significantly affect baseline HRV, PEP, or RESP in female PTSD patients.

    “but no significant differences in the other psychophysiological variables tested at baseline (HRV, PEP, RESP) (Additional file 1: Table S2).”
    Quote in the paperSubstantial claim

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

    Findingown data

    Oxytocin treatment did not significantly affect respiration rate compared to placebo in female PTSD patients (p = 0.95).

    “RESP (bpm) | 15.6 (3.0) | 17.1 (3.8) | 15.1 (3.1) | 16.7 (4.2) | 0.01 (34) | 0.95 | 0.001 (−0.39–0.41)”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    There were no important changes to methods after trial commencement and no drop-outs.

    “There were no important changes to methods after trial commencement and no drop-outs.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Oxytocin has an undisputed role in cardiovascular regulation.

    “apart from oxytocin’s undisputed role in cardiovascular regulation [24]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Gutkowska J, Jankowski M. Oxytocin revisited: its role in cardiovascular regulation. J Neuroendocrinol. 2012;24:599–608. source

      Not checked in the free run.

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

    Study design and conductnone given

    The spray bottles containing either oxytocin or placebo were labeled with a code number by a staff member not otherwise involved in the study.

    “The spray bottles containing either oxytocin or placebo were labeled with a code number by a staff member not otherwise involved in the study.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    All patients included in the RCT were also included in analyses.

    “All patients included in this RCT were also included in analyses.”
    Quote in the paperNot a substantial claim

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

    Study design and conductnone given

    Patients were randomized using a predefined computer-based block-wise randomization plan performed by a staff member from another institute.

    “Patients were randomized using a predefined computer-based block-wise randomization plan performed by a staff member from another institute (the TUM data center).”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    In case of non-normal distribution, non-parametric tests were conducted, and since results did not differ from parametric analysis, only LMM results are reported.

    “In case of a non-normal distribution of the data, non-parametric tests (Mann–Whitney tests) were conducted. Since the latter results did not differ from the parametric analysis, we report only the results from the LMM.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Oxytocin treatment, especially oxytocin bolus application, can lead to tachycardia.

    “there are numerous publications reporting that oxytocin treatment, especially oxytocin bolus application, can lead to tachycardia [25, 26].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [25] Brotánek V, Kazda S. Differences in the vasodepressor reaction to oxytocin in men and nonpregnant and pregnant women. Am J Obstet Gynecol. 1965;93:547–52. source

      Not checked in the free run.

    • cites [26] Butwick AJ, Coleman L, Cohen SE, Riley ET, Carvalho B. Minimum effective bolus dose of oxytocin during elective Caesarean delivery. Br J Anaesth. 2010;104:338–43. 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 conductown data

    The study made every effort to keep blinding integrity, but did not assess it.

    “We made every effort to keep blinding integrity, however, we did not assess it.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The RSDI's predicted three-factor solution is supported by confirmatory factor analyses, including tests for sample invariance across measurement and structural models in three different samples, with the fully constrained model exhibiting good model fit.

    “The predicted three-factor solution is supported by confirmatory factor analyses, including tests for sample invariance across measurement and structural models in three different samples, with the fully constrained model exhibiting good model fit.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Hopper JW, Frewen PA, Sack M, Lanius RA, Kolk BA. The Responses to Script-Driven Imagery Scale (RSDI): assessment of state posttraumatic symptoms for psychobiological and treatment research. J Psychopathol Behav Assess. 2007;29:249–68. source

      Not checked in the free run.

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

    Premisecitation

    Oxytocin has been reported to reduce heart rate.

    “oxytocin has been reported to reduce HR [24]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Gutkowska J, Jankowski M. Oxytocin revisited: its role in cardiovascular regulation. J Neuroendocrinol. 2012;24:599–608. source

      Not checked in the free run.

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

    Study design and conductown data

    The study calculated a sample size of 34 prior to the study assuming an effect size of 0.5, two-tailed alpha 0.05, and power 0.80.

    “Assuming an effect size of 0.5, we calculated a sample size of 34 prior to the study [Input: tail(s) = 2; effect size dz = 0.5; α error probability = 0.05; power (1 − β error probability) = 0.80. Output: non-centrality parameter δ = 2.9154759; critical t = 2.0345153; degrees of freedom = 33; total sample size = 34; actual power = 0.8077775].”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Oxytocin significantly increased overall autonomic cardiac control by elevating high frequency heart rate variability and decreasing pre-ejection period.

    “In the latter study, oxytocin significantly increased overall autonomic cardiac control because it elevated high frequency heart rate variability (HRV) and decreased the pre-ejection period (PEP), a well-known indicator of sympathetic cardiac control.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Norman GJ, Cacioppo JT, Morris JS, Malarkey WB, Berntson GG, Devries AC. Oxytocin increases autonomic cardiac control: moderation by loneliness. Biol Psychol. 2011;86:174–80. source

      Not checked in the free run.

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

    Study design and conductnone given

    Both the investigators and the patients were blinded to the intervention type until the end of the study.

    “Both the investigators and the patients were blinded to the intervention type until the end of the study.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The RSDI measures state re-experiencing, avoidance and dissociative symptoms evoked by script-driven trauma imagery.

    “The RSDI measures state re-experiencing, avoidance and dissociative symptoms evoked by script-driven trauma imagery.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Hopper JW, Frewen PA, Sack M, Lanius RA, Kolk BA. The Responses to Script-Driven Imagery Scale (RSDI): assessment of state posttraumatic symptoms for psychobiological and treatment research. J Psychopathol Behav Assess. 2007;29:249–68. source

      Not checked in the free run.

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

    Study design and conductcitation

    The RCT followed the CONSORT guidelines.

    “The RCT followed the CONSORT guidelines [40]; the CONSORT diagram is provided in Additional file 1: Figure S1 and the CONSORT checklist in Additional file 1: Table S1.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Moher D, Hopewell S, Schulz KF, Montori V, Gotzsche PC, Devereaux PJ, et al. CONSORT 2010 Explanation and Elaboration: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340:c869. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There are only two studies thus far that have analyzed the efficacy of oxytocin on PTSD symptom intensity in PTSD patients, among them one symptom provocation study in male veterans.

    “There are, to the best of our knowledge, only two studies thus far that have analyzed the efficacy of oxytocin on PTSD symptom intensity in PTSD patients, among them one symptom provocation study that was performed in a cohort of male veterans [10].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Pitman RK, Orr SP, Lasko NB. Effects of intranasal vasopressin and oxytocin on physiologic responding during personal combat imagery in Vietnam veterans with posttraumatic stress disorder. Psychiatry Res. 1993;48:107–17. source

      Not checked in the free run.

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

    Premisecitation

    The RSDI was developed to provide a brief and face valid measure of state PTSD and dissociative symptoms elicited by script-driven imagery.

    “The 11-item RSDI was developed to provide a brief and face valid measure of state PTSD and dissociative symptoms elicited by script-driven imagery, a widely used symptom provocation method in PTSD research.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Hopper JW, Frewen PA, Sack M, Lanius RA, Kolk BA. The Responses to Script-Driven Imagery Scale (RSDI): assessment of state posttraumatic symptoms for psychobiological and treatment research. J Psychopathol Behav Assess. 2007;29:249–68. 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 healthy control subjects were free from trauma history, any medication, and any type of psychopathology in their lifetime.

    “They were recruited in the Trauma Outpatient Clinic of the Max Planck Institute of Psychiatry in Munich by advertisement and were free from trauma history, from any medication and from any type of psychopathology in their lifetime as detailed previously [21].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Zaba M, Kirmeier T, Ionescu IA, Wollweber B, Buell DR, Gall-Kleebach DJ, et al. Identification and characterization of HPA-axis reactivity endophenotypes in a cohort of female PTSD patients. Psychoneuroendocrinology. 2015;55:102–15. source

      Not checked in the free run.

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

    Premisecitation

    Parasympathetic activity is lower in Croatian combat veterans with PTSD.

    “and to be lower in Croatian combat veterans [56].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Jovanovic T, Norrholm SD, Sakoman AJ, Esterajher S, Kozarić-Kovačić D. Altered resting psychophysiology and startle response in Croatian combat veterans with PTSD. Int J Psychophysiol. 2009;71:264–8. source

      Not checked in the free run.

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

    Premisecitation

    Parasympathetic activity influences basal heart rate in PTSD patients.

    “parasympathetic activity was found to influence basal HR in PTSD patients [55]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Hopper JW, Spinazzola J, Simpson WB, van der Kolk BA. Preliminary evidence of parasympathetic influence on basal heart rate in posttraumatic stress disorder. J Psychosom Res. 2006;60:83–90. source

      Not checked in the free run.

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

    Premisecitation

    The healthy subjects presented here constitute a subsample of a previously published cohort.

    “The healthy subjects presented here constitute a subsample of a previously published cohort [21]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Zaba M, Kirmeier T, Ionescu IA, Wollweber B, Buell DR, Gall-Kleebach DJ, et al. Identification and characterization of HPA-axis reactivity endophenotypes in a cohort of female PTSD patients. Psychoneuroendocrinology. 2015;55:102–15. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Heart rate and sympathetic activity are already enhanced in PTSD.

    “which are both known to be already enhanced in PTSD [54].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Lipov E. Post traumatic stress disorder (PTSD) as an over activation of sympathetic nervous system: an alternative view. J Trauma Treat. 2013;3:181. source

      Not checked in the free run.

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

    Premisecitation

    Intranasal oxytocin did not affect provoked PTSD symptoms in male veterans.

    “Pitman and colleagues [42], who, in contrast to us, did not find an effect of intranasal oxytocin on provoked PTSD symptoms in male veterans.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [42] Pitman RK, Orr SP, Forgue DF, de Jong JB, Claiborn JM. Psychophysiologic assessment of posttraumatic stress disorder imagery in Vietnam combat veterans. Arch Gen Psychiatry. 1987;44:970–5. source

      Not checked in the free run.

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

    Premisecitation

    Oxytocin attenuates avoidance behavior in rodents.

    “previous studies found that oxytocin attenuated avoidance behavior in rodents [59, 60].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [59] Gaffori OJW, De Wied D. Bimodal effect of oxytocin on avoidance behavior may be caused by the presence of two peptide sequences with opposite action in the same molecule. Eur J Pharmacol. 1988;147:157–62. source

      Not checked in the free run.

    • cites [60] Kovacs G, Vecsei L, Telegdy G. Opposite action of oxytocin to vasopressin in passive avoidance behavior in rats. Physiol Behav. 1978;20:801–2. source

      Not checked in the free run.

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

    Study design and conductnone given

    The study was retrospectively registered at the German Trials Register (DRKS00009399) on 02 October 2015.

    “This randomized controlled trial was retrospectively registered at the German Trials Register (DRKS00009399) on the 02 October 2015.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Gender differences in oxytocin effects have been repeatedly described.

    “Gender differences in oxytocin effects have been repeatedly described [22, 23]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [22] Hoge EA, Anderson E, Lawson EA, Bui E, Fischer LE, Khadge SD, et al. Gender moderates the effect of oxytocin on social judgments. Hum Psychopharmacol. 2014;29:299–304. source

      Not checked in the free run.

    • cites [23] Nishi D, Hashimoto K, Noguchi H, Kim Y, Matsuoka Y. Serum oxytocin, posttraumatic coping and C-reactive protein in motor vehicle accident survivors by gender. Neuropsychobiology. 2015;71:196–201. source

      Not checked in the free run.

  • The quote only partly states this claim.

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

    Oxytocin treatment exerted sympathomimetic effects in female PTSD patients, as indicated by a drop in pre-ejection period.

    “despite exerting sympathomimetic and positive chronotropic effects”
    • Also stated in: § Results · plain
      “a marker for sympathetic cardiac control”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Pre-ejection period (PEP) is a well-known indicator of sympathetic cardiac control.

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing).

    Premisecitation

    Oxytocin's central nervous effects might be a consequence of its peripheral actions.

    “it has been suggested that the central nervous effects of oxytocin might be a consequence of its peripheral actions [57]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Leng G, Ludwig M. Intranasal oxytocin: myths and delusions. Biol Psychiatry. 2016;79:243–50. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationreasoning

    The positive chronotropic effect of oxytocin occurs through oxytocin-elicited activation of the sympathetic nervous system rather than through dampening of the parasympathetic nervous system.

    “we hypothesize that the positive chronotropic effect of oxytocin observed here occurs through an oxytocin-elicited activation of the SNS rather than through an oxytocin-mediated dampening of the PNS.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The sympathetic nervous system is overactive in PTSD.

    “it is well accepted that the SNS is overactive in PTSD [54].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Lipov E. Post traumatic stress disorder (PTSD) as an over activation of sympathetic nervous system: an alternative view. J Trauma Treat. 2013;3:181. source

      Not checked in the free run.

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

    Premisecitation

    Intranasal oxytocin increases heart rate and decreases PEP in healthy individuals.

    “another research group that found intranasal oxytocin to increase the HR and to decrease PEP in healthy individuals [32].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [32] Norman GJ, Cacioppo JT, Morris JS, Malarkey WB, Berntson GG, Devries AC. Oxytocin increases autonomic cardiac control: moderation by loneliness. Biol Psychol. 2011;86:174–80. source

      Not checked in the free run.

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

    Premisecitation

    Oxytocin has been proposed as an effective novel drug treatment for PTSD.

    “oxytocin has been repeatedly proposed as an effective novel drug treatment for PTSD [3, 58]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] Koch SBJ, van Zuiden M, Nawijn L, Frijling JL, Veltman DJ, Olff M. Intranasal oxytocin as strategy for medication-enhanced psychotherapy of PTSD: salience processing and fear inhibition processes. Psychoneuroendocrinology. 2014;40:242–56. source

      Not checked in the free run.

    • cites [58] Olff M, Langeland W, Witteveen A, Denys D. A psychobiological rationale for oxytocin in the treatment of posttraumatic stress disorder. CNS Spectr. 2010;15:522–30. source

      Not checked in the free run.

  • May combine two claims.

    Study design and conductown data

    The relatively small sample size and heterogeneity of the patient sample, analysis of women only, and lack of ovarian cycle phase as covariate limit the generalizability of the results.

    “The relatively small sample size of both samples and the heterogeneity of the patient sample (e.g., the broad range of age, differences in pharmacotherapy and in trauma types) as well as the facts that we analyzed women only and did not include the ovarian cycle phase as a covariate in the analysis of the patient sample limit the generalizability of our results.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The TSST is a standardized social stress experiment.

    “the TSST, a standardized social stress experiment [44]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Kirschbaum C, Pirke K-M, Hellhammer DH. The “Trier Social Stress Test”–a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology. 1993;28:76–81. source

      Not checked in the free run.

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

    Study design and conductown data

    The study used a within-subject design in which patients received oxytocin and placebo in a 1-week interval in double-blind randomized order.

    “All patients served as their own controls and were thus assessed twice, that is, they received, in a 1-week interval, oxytocin in one experiment and placebo in the other (within-subject design) in a double-blind randomized order.”
    Quote in the paperSubstantial claim
50 of 50

  • The paper relies on this without support.

    PTSD is more prevalent in women.

    “because PTSD is more prevalent in women.”

  • The paper relies on this without support.

    Pre-ejection period (PEP) is a well-known indicator of sympathetic cardiac control.

    “a well-known indicator of sympathetic cardiac control”

  • The authors state this as an assumption.

    Intranasally administered oxytocin that reaches cerebrospinal fluid also reaches the brain.

    “and thus, assumingly, also the brain.”

  • The paper relies on this without support.

    The trauma-script challenge provokes PTSD symptoms in female PTSD patients.

    “intranasal oxytocin reduces the trauma script-provoked expression of PTSD symptoms”
4 of 4

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?

  • A recent experimental study found that a single dose of oxytocin increased heart rate response to trauma related stimuli while reducing self-reported trauma-related imagery among people with PTSD.

    “Furthermore, a recent experimental study found that a single dose of oxytocin increased heart rate response to trauma related stimuli while reducing self-reported trauma-related imagery among people with PTSD (Sack et al., 2017).”

    From Meta-analytic review of the effects of a single dose of intranasal oxytocin on threat processing in humans (2018) · cites this paper as Sack et al., 2017

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • ConsistentF(1, 19) = 24.89reported p < .001 · recomputed p < .001

    “F(1, 19) = 24.89, p < .001”

  • ConsistentF(1, 19) = 37.4reported p < .001 · recomputed p < .001

    “F(1, 19) = 37.40, p < .001”

2 of 2

Self-check

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

Each contradiction between two passages listed here was confirmed by an independent check.

  • Treatment interval reported as both one and two weeks

    Major

    The abstract says patients received oxytocin and placebo two weeks apart, whereas the methods say the two experiments were one week apart.

  • Mean SCID-D score differs from Table 1

    Minor

    The results give the cohort's mean SCID-D score as 12.7, but Table 1 reports 12.1.

  • Heart-rate p-value conflicts with Table 2

    Minor

    The results describe the post-challenge heart-rate effect as a trend and cite p = 0.59; the corresponding HR row in Table 2 reports p = 0.059.

  • Discussion mislabels heart-rate measurements

    Minor

    The discussion calls 77.9 bpm an oxytocin challenge value and 82.1 bpm an oxytocin baseline value. Table 2 identifies 77.9 bpm as the oxytocin baseline and 82.1 bpm as the placebo trauma-script value.

  • Education percentage does not match the cohort size

    Minor

    Eight of 35 patients is 22.86%, which rounds to 23% rather than the reported 22%.

    Reported 22 · recomputed 22.857143

5 of 5

The citation lists haven’t been fetched yet

References 60 · Cited by 57

Research works printed but not linked: 2

  1. Wittchen HU, Zaudig M, Frydrich T. SKID Strukturiertes Klinisches Interview für DSM-IV Achse I und II, Deutsche Version [SCID structured clinical interview for DSM-IV Axis I and II, German Version]. Gött: Hogrefe; 1997.
  2. Gast U, Oswald T, Zundorf F. Structured Clinical Interview for DSM–IV Dissociative Disorders (SCID-D). Gött: Hogrefe; 2000. German version.

Authors
Sack, M., Spieler, D., Wizelman, L., Epple, G., Stich, J., Zaba, M., & Schmidt, U.
Affiliations
  • TUM Klinikum (DE)
  • Max Planck Institute of Psychiatry (DE)
Corresponding author
Schmidt, U.
ORCID
Venue
BMC Medicine
Publisher
Springer Science and Business Media LLC
Published
2017-02-17
Volume
15
Issue
1
Pages
40-40
ISSN
1741-7015 (ISSN-L)
DOI
10.1186/s12916-017-0801-0
PMC
PMC5314583
OpenAlex
W2588458990
Semantic Scholar
54cfbcad939dba21d4c27ba44b17b856ba0603f4
Cited by
57
References
60
Citations by year
2026: 4 · 2025: 2 · 2024: 4 · 2023: 6 · 2022: 4 · 2021: 7 · 2020: 9 · 2019: 7 · 2018: 11 · 2017: 3
FWCI
10.15
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • BMC Medicine (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion, cc-by)
  • Max Planck Digital Library (submittedVersion, other-oa)
  • mediaTUM – the media and publications repository of the Technical University Munich (Technical University Munich) (submittedVersion)
Funders
Private Horst Kübler Foundation, Bad Ragaz
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
post-traumatic stress disorder, intranasal oxytocin, female patients, heart rate, pre-ejection period, avoidance symptoms, endogenous oxytocin, Trier Social Stress Test, stress response
MeSH terms
Administration, Intranasal, Adult, Female, Humans, Male, Middle Aged, Oxytocin, Stress Disorders, Post-Traumatic, Sympathomimetics, Treatment Outcome

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.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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