Inhaled Oxytocin and HPA Axis Reactivity

Anxiety Disorders Clinical Trial

Official title:

The Psychobiology of Resilience in Mother-child Pairs: Inhaled Oxytocin and HPA Axis Reactivity

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03593473
• Other study ID #: 12-2061
• Secondary ID: R01HD093901-01A1
• Status: Completed
• Phase: Phase 2
• Start date: February 7, 2019
• Est. completion date: July 25, 2023

Study information

• Verified date: January 2024
• Source: University of North Carolina, Chapel Hill
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Mothers who were enrolled in the Mood, Mother and Infant study will be eligible to participate in the 6-year follow-up maternal visit. At the time of this visit, mothers will be randomized to a single 24 IU dose of nasal oxytocin or placebo. Following administration of the study drug, women will participate in the Trier Social Stress Test (TSST), and blood samples will be collected to quantify HPA axis reactivity.

Description:

The Mood, Mother and Infant Study is a prospective observational cohort study that began enrollment in May of 2013. Women were recruited in the 3rd trimester of pregnancy and followed prospectively through 12 months postpartum. Mother-infant pairs who completed the 12-month visit will be invited to participate in the current Psychobiology of Resilience in Maternal-Child Pairs follow-up study. The trial described here is a randomized controlled trial embedded within the Psychobiology of Resilience study. Non-pregnant women will be randomized to either 24 IU of nasal oxytocin (OT) or placebo. The Investigational Drug Service (IDS) will use a random number generator to prepare a randomization table. Participants will be block randomized by risk status at enrollment in the Mood, Mother and Infant (MMI) study, as verified by structured clinical diagnostic interview (No history of depression or anxiety, Past depression or anxiety, current depression or anxiety). Both participants and study personnel will be blinded to allocation group. At the end of the protocol, participants will be asked which condition they believed they were in ('oxytocin,' 'control,' 'not sure') to ascertain success of blinding. Forty minutes after treatment, women will undergo the Trier Social Stress Test (TSST), comprised of a speech task and a math task; the TSST reliably induces large and consistent HPA and cardiovascular responses. The TSST is administered as follows: Pre-Task Instructions: (5 minutes) Subjects will be introduced to 3 people (the 'selection committee') and asked to assume the role of a job applicant. Anticipation Period: The subject prepares her speech for 3 minutes in the presence of the committee. Speech: The committee asks the subject to deliver her talk for 5 minutes while being video and audio-recorded. If the subject finishes early, the committee responds with prepared questions to ensure that she speaks for the entire 5 minutes. These questions are designed to be non-harassing but to create a feeling of lack of predictability/controllability (e.g., "Do you have any enemies?") Serial Subtraction (PASST): The committee will ask the subject to subtract the number 7 from 2000 as quickly and accurately as possible for 5 minutes. For each mistake, the committee says "Stop -- mistake -- start over at 2000." Stress Recovery: The subject sits quietly alone for 20 minutes. Blood will be collected at baseline, during the speech and math tasks, and at 10 and 20 minutes of recovery, as HPA-axis responses are reliably found 10-30 minutes following the TSST. Evidence regarding optimal timing of stress testing is conflicting. Visits will be scheduled for 1 pm to increase likelihood of detecting a stress response unopposed by the circadian influence, based on the experience of investigators in our laboratory and published studies of postpartum women. These investigators have found menstrual cycle phase does not affect TSST results; therefore, the date of last menstrual period and hormone use will be recorded, but visits will not be scheduled based on cycle phase.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 105
• Est. completion date: July 25, 2023
• Est. primary completion date: July 25, 2023
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

This study will follow-up the existing Mood, Mother and Infant (MMI) prospective longitudinal cohort (R01HD073220), comprised of 222 mother-infant dyads who were recruited between May 2013 and April 2017 and completed the 12-month MMI visit. In the MMI study, 222 mothers ages 18-45 and their infants were enrolled. Participants were recruited from community clinics in the third trimester of pregnancy and continued to participate in the study through 12 months postpartum. At the 12-month visit, mothers were invited to continue to be followed via online surveys at 6-month intervals; more than 80% of women who have completed the MMI study to date have continued to participate. Enrolled participants in the MMI study met the following inclusion and exclusion criteria:

Inclusion Criteria:

1. Singleton pregnancy;

2. Intention to breastfeed (due to the centrality of breastfeeding to the oxytocin assessment);

3. Intention to remain within 40 miles of the University of North Carolina - Chapel Hill through infant's first birthday;

4. Ability to communicate in English.

Exclusion Criteria:

1. Maternal diagnosis of Axis I disorders other than unipolar depression or anxiety disorders. Women with a history of bipolar disorder were excluded, given their increased risk of postpartum psychosis.

2. Active substance abuse at enrollment in the 3rd trimester of pregnancy (Tobacco, alcohol, illicits);

3. Major congenital anomaly;

4. Chronic medication/medical condition contraindicated for breastfeeding;

5. Current use of tricyclic antidepressants, which alter cortisol and heart rate variability. At enrollment, all participants underwent a Structured Clinical Interview Non-Patient version (SCID-NP). Inclusion Criteria for Inhaled Oxytocin and HPA Axis Reactivity, a substudy of the Psychobiology of Resilience in Mother-Child Pairs follow-up study: 1) Participated in the MMI study 2) Both mother and child willing and able to participate in the 6-year follow-up visits 3) Not pregnant, verified by urine pregnancy test on day of study visit.

Related Conditions & MeSH terms

• Anxiety Disorders
• Depression, Postpartum
• Stress, Psychological

Intervention

Drug:
• Intranasal Oxytocin
Six intranasal sprays of oxytocin. Each insufflation delivers 4 IUs of oxytocin for a total oxytocin dosage of 24 IUs.
• Placebo
Six intranasal sprays of placebo manufactured to mimic oxytocin nasal spray containing all equivalent ingredients except oxytocin.

Locations

Country	Name	City	State
United States	University of North Carolina School of Medicine	Chapel Hill	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
University of North Carolina, Chapel Hill	Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Assessment of effect modification by maternal depression / anxiety on changes in Cortisol (CRT) during Trier Social Stress Test (TSST)	Stratified analyses will be performed to determine the extent to which maternal depression/anxiety modifies the effect of OT/placebo on CRT during the TSST.	-40 minutes, -20 minutes, 0 minutes, +10 minutes, +15 minutes, +28 minutes, +38 minutes, +48 minutes
Other	Assessment of effect modification by maternal depression / anxiety on changes in Adrenocorticotropic hormone (ACTH ) during TSST	Stratified analyses will be performed to determine the extent to which maternal depression/anxiety modifies the effect of OT/placebo on ACTH during the TSST.	-40 minutes, -20 minutes, 0 minutes, +10 minutes, +15 minutes, +28 minutes, +38 minutes, +48 minutes
Other	Assessment of effect modification by maternal depression / anxiety on changes in high frequency heart rate variability, an index of parasympathetic activity, during the TSST	Stratified analyses will be performed to determine the extent to which maternal depression/anxiety modifies the effect of OT/placebo on parasympathetic activity during the TSST.	Minutes -40 to -35, -35 to -30, -30 to -25, -25 to -20, -20 to -15, -15 to -10, -10 to -5, -5 to 0, 0 to 5, 5 to 8, 8 to 13, 13 to 18, 18 to 23, 23 to 28, 28 to 33, 33 to 38, 38 to 43, 43 to 48
Other	Assessment of effect modification by maternal depression / anxiety on changes in pre-ejection period, an index of sympathetic activity, during the TSST	Stratified analyses will be performed to determine the extent to which maternal depression/anxiety modifies the effect of OT/placebo on sympathetic activity during the TSST.	Minutes -40 to -35, -35 to -30, -30 to -25, -25 to -20, -20 to -15, -15 to -10, -10 to -5, -5 to 0, 0 to 5, 5 to 8, 8 to 13, 13 to 18, 18 to 23, 23 to 28, 28 to 33, 33 to 38, 38 to 43, 43 to 48
Other	Assessment of effect modification by OXTR genotype on changes in Cortisol (CRT) during Trier Social Stress Test (TSST)	Stratified analyses will be performed to determine the extent to which maternal depression/anxiety modifies the effect of OT/placebo on CRT during the TSST.	-40 minutes, -20 minutes, 0 minutes, +10 minutes, +15 minutes, +28 minutes, +38 minutes, +48 minutes
Other	Assessment of effect modification by OXTR genotype on changes in Adrenocorticotropic hormone (ACTH ) during TSST	Stratified analyses will be performed to determine the extent to which maternal depression/anxiety modifies the effect of OT/placebo on ACTH during the TSST.	-30 minutes, 0 minutes, +10 minutes, +15 minutes, +28 minutes, +38 minutes
Other	Assessment of effect modification by OXTR genotype changes in high frequency heart rate variability, an index of parasympathetic activity, during the TSST	Stratified analyses will be performed to determine the extent to which maternal depression/anxiety modifies the effect of OT/placebo on parasympathetic activity during the TSST.	Minutes -40 to -35, -35 to -30, -30 to -25, -25 to -20, -20 to -15, -15 to -10, -10 to -5, -5 to 0, 0 to 5, 5 to 8, 8 to 13, 13 to 18, 18 to 23, 23 to 28, 28 to 33, 33 to 38, 38 to 43, 43 to 48
Other	Assessment of effect modification by OXTR genotype on changes in pre-ejection period, an index of sympathetic activity, during the TSST	Stratified analyses will be performed to determine the extent to which maternal depression/anxiety modifies the effect of OT/placebo on sympathetic activity during the TSST.	Minutes -40 to -35, -35 to -30, -30 to -25, -25 to -20, -20 to -15, -15 to -10, -10 to -5, -5 to 0, 0 to 5, 5 to 8, 8 to 13, 13 to 18, 18 to 23, 23 to 28, 28 to 33, 33 to 38, 38 to 43, 43 to 48
Primary	Changes in Cortisol (CRT) during Trier Social Stress Test (TSST)	The study drug will be administered 40 minutes before the TSST. Serum cortisol and Adrenocorticotropic hormone will be measured via peripheral IV 30 minutes before the TSST (-30), at the start of the TSST (0 minutes), and at minutes 10 (during the speech task), 15 (during the math task), 28 and 38 (during recovery).	-40 minutes, -20 minutes, 0 minutes, +10 minutes, +15 minutes, +28 minutes, +38 minutes, +48 minutes
Secondary	Changes in Adrenocorticotropic hormone (ACTH ) during TSST	The study drug will be administered 40 minutes before the TSST. Serum cortisol and Adrenocorticotropic hormone will be measured via peripheral IV 30 minutes before the TSST (-30), at the start of the TSST (0 minutes), and at minutes 10 (during the speech task), 15 (during the math task), 28 and 38 (during recovery).	-40 minutes, -20 minutes, 0 minutes, +10 minutes, +15 minutes, +28 minutes, +38 minutes, +48 minutes
Secondary	Changes in the lagged association between ACTH and CRT during the TSST	Correlations will be quantified between ACTH at time j and CRT at time j+1 to test the extent to which CRT response is blunted by exogenous OT.	ACTH at -40 minutes, -20 minutes, 0 minutes, +10 minutes, +15 minutes, +28 minutes, +38 minutes and Cortisol at -20 minutes, 0 minutes, +10 minutes, +15 minutes, +28 minutes, +38 minutes, +48 minutes
Secondary	Changes in high frequency heart rate variability, an index of parasympathetic activity, during the TSST	Recording of autonomic activity beginning prior to study drug administration (-40 minutes) until the end of recovery from the TSST (+38 minutes). Mobile Impedance Cardiographs (MindWare Tech Ltd, Gahanna, OH) will be used to measure cardiac rate and interbeat interval (IBI). MindWare Heart Rate Variability (HRV) software will be used to derive respiration and to calculate high frequency HRV and respiratory sinus arrhythmia from the IBI series as indices of parasympathetic activity.	Minutes -40 to -35, -35 to -30, -30 to -25, -25 to -20, -20 to -15, -15 to -10, -10 to -5, -5 to 0, 0 to 5, 5 to 8, 8 to 13, 13 to 18, 18 to 23, 23 to 28, 28 to 33, 33 to 38, 38 to 43, 43 to 48
Secondary	Changes in pre-ejection period, an index of sympathetic activity, during the TSST	Recording of autonomic activity beginning prior to study drug administration (-40 minutes) until the end of recovery from the TSST (+38 minutes). Mobile Impedance Cardiographs (MindWare Tech Ltd, Gahanna, OH) will be used to measure pre-ejection period (PEP). PEP will index sympathetic activation.	Minutes -40 to -35, -35 to -30, -30 to -25, -25 to -20, -20 to -15, -15 to -10, -10 to -5, -5 to 0, 0 to 5, 5 to 8, 8 to 13, 13 to 18, 18 to 23, 23 to 28, 28 to 33, 33 to 38, 38 to 43, 43 to 48

External Links

•   Mood, mother and infant study web site