Clinical trial NCT03211013: Study of the Effects of Oxytocin on Attentional Bias and Startle in PTSD
Official title: Placebo-Controlled Study of the Effects of Oxytocin on Attentional Bias and Startle in PTSD
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Posttraumatic Stress Disorder
Keywords: oxytocin
PTSD
attention bias
startle
Lead sponsor: Palo Alto Veterans Institute for Research
Sponsor class: OTHER
First posted: 2017-07-07
Enrollment: 17
Sex: MALE
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Randomized double-blind crossover design, in which all participants will undergo 2 sessions, receiving either oxytocin nasal spray or placebo nasal spray in random order.
Primary purpose: BASIC_SCIENCE

Brief summary: The investigators will test whether intranasal oxytocin (24 IU vs placebo) will induce effects on attention bias and startle comparable to those the investigators have shown to be induced by the presence (vs absence) of a service dog in Veterans diagnosed with PTSD. This possibility is suggested by a 2015 study showing that urinary oxytocin levels are elevated in association with mutual gaze between dogs and their owners.

Detailed description: Background and significance:

Chronic severe posttraumatic stress disorder (PTSD) is among the most prevalent and expensive diagnoses addressed by the U.S. Army Medical Department and the Veterans Health Administration. While progress has been made in PTSD treatment, data from the World Mental Health Survey have recently shown that rates of recovery from combat-related PTSD, world-wide, are approximately one-half the rates of recovery from other trauma types. Furthermore, other recent studies have reported that effect sizes shown by evidence-based treatments for PTSD when applied to male patients are approximately half of what they are when applied to female patients. These results suggest the VA has far to go in achieving efficacious and effective behavioral treatments for this diagnosis affecting a large proportion of its patient population.

In the course of a DoD-funded study (Can a Canine Companion Modify Cardiac Autonomic Reactivity and Tone in PTSD) our laboratory has found that the presence of a service canine in the testing chamber in close proximity to the participant is associated with modification of visual attentional bias away from angry faces signalling social threat along with attenuation of autonomic responses to loud tones. The attenuation of bias towards social threat is of particular relevance to the social impairments seen in this disorder.Veterans with chronic severe PTSD frequently manifest impairments in the execution of key social roles such as those of spouse, parent and employee.

Service canine companionship and oxytocin (OT) appear to be on parallel tracks as novel candidate PTSD treatments or treatment enhancers. A wealth of anecdotal evidence has emerged from U.S. military clinical settings supporting the benefits of service canine companionship and canine-assisted interventions for military personnel with deployment-related mental health conditions; however, rigorously empirical support for this approach remains sparse. A growing literature exploring the role(s) of the OT system in PTSD now includes a number of encouraging findings. For example, in PTSD, OT modulates amygdala hemodynamic responses to emotional faces and increases anterior insula hemodynamic responses to social rewards. Intranasal OT administration normalizes amygdala functional connectivity in PTSD and increased subjective compassion for other persons. These findings align with findings in healthy persons. After intranasal administration, normal adults gaze more at the eye region of faces, have better memory for faces, are better able to infer the mental states of others, have more positive communications, are more generous, rate faces as more trustworthy owe, and exhibit increased trust behavior. OT also attenuates startle in healthy persons, attenuates amygdala responses to fear-inducing stimuli, and inhibits the stress-responsive release of cortisol. In turn, the human findings generally agree with a large animal literature showing that OT plays an important role in social behaviors such as partner preference, social bonding, and social cognition, while OT dysregulation produces a variety of social impairments.

A recent study published in Science showing that urinary OT levels are elevated in association with mutual gaze between dogs and their owners suggests these two lines of research may be converged on the target of PTSD. The investigators will compare the pattern of results of tests of attention bias and startle induced by intranasal OT (vs placebo) to those the investigators have shown to be induced by the presence (vs absence) of a service dog in Veterans diagnosed with PTSD.

Specific Aim 1: To test the effects of a single-dose OT administration in adults with PTSD on the pattern of performance on a set of laboratory tasks which have previously been administered to similar persons who were or were not accompanied by a service canine on separate occasions.

Hypothesis 1: Following single-dose OT administration, participants will exhibit attenuation of attentional bias toward negatively-valenced content, in general, and toward facial cues denoting social threat, in particular.

Hypothesis 2: Following single-dose OT administration, participants will exhibit reduced cardioacceleratory responses to loud tones and attenuated autonomic responses to a math stressor.

Preliminary power calculations indicate that a sample of 40 subjects in this within-subjects design will yield excellent power to detect a medium size effect (Critical t(38) = 2.02, α = .05, 1- β = .90) for the primary attentional bias measures.

Eligibility criteria: Inclusion Criteria:

* US military Veteran
* Current posttraumatic stress disorder
* Medically healthy

Exclusion Criteria:

* DSM-5 diagnosis of schizophrenia, schizoaffective disorder, or psychotic disorder
* Active drug or alcohol use disorder within past 90 days
* Currently participating in a clinical drug trial
* Regular nasal obstruction or nosebleeds (use of saline or nasal decongestant permitted if subject has transient cold only)
* Active medical problems: unstable seizures, significant physical illness (e.g., serious liver, renal, or cardiac pathology)
* Sensitivity to preservatives, in particular E 216, E 218, and chlorobutanol hemihydrate
* Significant hearing or vision impairments
* Habitually drinks large volumes of water

Primary outcomes:
measure: Change in attentional bias
timeFrame: 1-2 weeks
measure: Change in startle response -heart rate
timeFrame: 1-2 weeks
Secondary outcomes:
Other outcomes:
measure: Change in startle response -EDA
timeFrame: 1-2 weeks
measure: Change in startle response -EMG
timeFrame: 1-2 weeks
Locations:
city: Menlo Park
country: United States
facility: VA Palo Alto Health Care System
state: California
Study officials:
affiliation: VA Palo Alto Health Care System
name: Steven H Woodward, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Nagasawa M, Mitsui S, En S, Ohtani N, Ohta M, Sakuma Y, Onaka T, Mogi K, Kikusui T. Social evolution. Oxytocin-gaze positive loop and the coevolution of human-dog bonds. Science. 2015 Apr 17;348(6232):333-6. doi: 10.1126/science.1261022. Epub 2015 Apr 16.
citation: Ayers LW, Missig G, Schulkin J, Rosen JB. Oxytocin reduces background anxiety in a fear-potentiated startle paradigm: peripheral vs central administration. Neuropsychopharmacology. 2011 Nov;36(12):2488-97. doi: 10.1038/npp.2011.138. Epub 2011 Jul 27.
citation: Baumgartner T, Heinrichs M, Vonlanthen A, Fischbacher U, Fehr E. Oxytocin shapes the neural circuitry of trust and trust adaptation in humans. Neuron. 2008 May 22;58(4):639-50. doi: 10.1016/j.neuron.2008.04.009.
citation: Beery AK, Zucker I. Oxytocin and same-sex social behavior in female meadow voles. Neuroscience. 2010 Aug 25;169(2):665-73. doi: 10.1016/j.neuroscience.2010.05.023. Epub 2010 May 16.
citation: Benjet C, Bromet E, Karam EG, Kessler RC, McLaughlin KA, Ruscio AM, Shahly V, Stein DJ, Petukhova M, Hill E, Alonso J, Atwoli L, Bunting B, Bruffaerts R, Caldas-de-Almeida JM, de Girolamo G, Florescu S, Gureje O, Huang Y, Lepine JP, Kawakami N, Kovess-Masfety V, Medina-Mora ME, Navarro-Mateu F, Piazza M, Posada-Villa J, Scott KM, Shalev A, Slade T, ten Have M, Torres Y, Viana MC, Zarkov Z, Koenen KC. The epidemiology of traumatic event exposure worldwide: results from the World Mental Health Survey Consortium. Psychol Med. 2016 Jan;46(2):327-43. doi: 10.1017/S0033291715001981. Epub 2015 Oct 29.
citation: Ditzen B, Schaer M, Gabriel B, Bodenmann G, Ehlert U, Heinrichs M. Intranasal oxytocin increases positive communication and reduces cortisol levels during couple conflict. Biol Psychiatry. 2009 May 1;65(9):728-31. doi: 10.1016/j.biopsych.2008.10.011. Epub 2008 Nov 22.
citation: Domes G, Heinrichs M, Michel A, Berger C, Herpertz SC. Oxytocin improves "mind-reading" in humans. Biol Psychiatry. 2007 Mar 15;61(6):731-3. doi: 10.1016/j.biopsych.2006.07.015. Epub 2006 Nov 29.
citation: Ellenbogen MA, Linnen AM, Cardoso C, Joober R. Intranasal oxytocin attenuates the human acoustic startle response independent of emotional modulation. Psychophysiology. 2014 Nov;51(11):1169-77. doi: 10.1111/psyp.12263. Epub 2014 Aug 1.
citation: Frijling JL, van Zuiden M, Koch SB, Nawijn L, Veltman DJ, Olff M. Effects of intranasal oxytocin on amygdala reactivity to emotional faces in recently trauma-exposed individuals. Soc Cogn Affect Neurosci. 2016 Feb;11(2):327-36. doi: 10.1093/scan/nsv116. Epub 2015 Sep 17.
citation: Guastella AJ, Mitchell PB, Dadds MR. Oxytocin increases gaze to the eye region of human faces. Biol Psychiatry. 2008 Jan 1;63(1):3-5. doi: 10.1016/j.biopsych.2007.06.026. Epub 2007 Sep 21.
citation: Galovski TE, Blain LM, Chappuis C, Fletcher T. Sex differences in recovery from PTSD in male and female interpersonal assault survivors. Behav Res Ther. 2013 Jun;51(6):247-55. doi: 10.1016/j.brat.2013.02.002. Epub 2013 Mar 1.
citation: 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 Dec 7;25(49):11489-93. doi: 10.1523/JNEUROSCI.3984-05.2005.
citation: Koch SB, van Zuiden M, Nawijn L, Frijling JL, Veltman DJ, Olff M. Intranasal Oxytocin Normalizes Amygdala Functional Connectivity in Posttraumatic Stress Disorder. Neuropsychopharmacology. 2016 Jul;41(8):2041-51. doi: 10.1038/npp.2016.1. Epub 2016 Jan 7.
citation: Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E. Oxytocin increases trust in humans. Nature. 2005 Jun 2;435(7042):673-6. doi: 10.1038/nature03701.
citation: Macbeth AH, Stepp JE, Lee HJ, Young WS 3rd, Caldwell HK. Normal maternal behavior, but increased pup mortality, in conditional oxytocin receptor knockout females. Behav Neurosci. 2010 Oct;124(5):677-85. doi: 10.1037/a0020799.
citation: Nawijn L, van Zuiden M, Koch SB, Frijling JL, Veltman DJ, Olff M. Intranasal oxytocin increases neural responses to social reward in post-traumatic stress disorder. Soc Cogn Affect Neurosci. 2017 Feb 1;12(2):212-223. doi: 10.1093/scan/nsw123.
citation: Palgi S, Klein E, Shamay-Tsoory SG. Oxytocin improves compassion toward women among patients with PTSD. Psychoneuroendocrinology. 2016 Feb;64:143-9. doi: 10.1016/j.psyneuen.2015.11.008. Epub 2015 Nov 17.
citation: Rimmele U, Hediger K, Heinrichs M, Klaver P. Oxytocin makes a face in memory familiar. J Neurosci. 2009 Jan 7;29(1):38-42. doi: 10.1523/JNEUROSCI.4260-08.2009.
citation: Rubenstein DA, Debboun M, Burton R. Canine-assisted therapy in military medicine. Perspectives: commander's introduction. US Army Med Dep J. 2012 Apr-Jun:1-4. No abstract available.
citation: Theodoridou A, Rowe AC, Penton-Voak IS, Rogers PJ. Oxytocin and social perception: oxytocin increases perceived facial trustworthiness and attractiveness. Horm Behav. 2009 Jun;56(1):128-32. doi: 10.1016/j.yhbeh.2009.03.019. Epub 2009 Apr 1.
citation: Wade D, Varker T, Kartal D, Hetrick S, O'Donnell M, Forbes D. Gender difference in outcomes following trauma-focused interventions for posttraumatic stress disorder: Systematic review and meta-analysis. Psychol Trauma. 2016 May;8(3):356-64. doi: 10.1037/tra0000110. Epub 2016 Feb 8.
citation: Zak PJ, Stanton AA, Ahmadi S. Oxytocin increases generosity in humans. PLoS One. 2007 Nov 7;2(11):e1128. doi: 10.1371/journal.pone.0001128.