Clinical trial NCT02505984
Conditions: Depression, Postpartum Anxiety
Keywords: oxytocin, bonding child development
Sponsor: Massachusetts General Hospital
Start date: 2016-01-01; Completion date: 2023-05-01
Enrollment: 56 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to test a new treatment for preventing childbirth-related mental illness in postpartum mothers. The treatment is aimed at enhancing maternal bonding, reducing postpartum depression (PPD) and anxiety in mothers at risk, and promoting child development. To this end, the investigators will test the clinical utility of intranasal (IN) oxytocin (OXT) administered to mothers during the first postpartum days.

Detailed description:
Postpartum depression (PPD) is a debilitating disorder which imposes a threat to mother and infant health. An estimated 600,000 American women suffer from PPD annually, making it one of the most frequent complications of pregnancy. Available secondary preventive interventions are often ineffective, which calls for identifying novel means for prevention. Impaired mother-infant bonding is a hallmark of PPD. Depressed mothers may have difficulties developing maternal feelings and providing sensitive care. In turn, impaired bonding may worsen mother's depression. Conventional pharmacotherapy does not help with bonding impairment.

This study will attempt to fill in the current gap in effective preventive interventions for pregnant mothers at risk. Evidence in postpartum mothers indicates that high peripartum OXT levels are associated with enhanced maternal behavior and low levels with depression. Data also indicates that in depressed mothers, OXT levels may decrease during the first days following childbirth rather than increase as is the norm. Therefore, the investigators will test the therapeutic effects of OXT in women at risk for PPD. It is hypothesized that administration of IN-OXT (total daily dose 48 IU) over the course of four days from as early as day one postpartum in comparison to placebo will 1) enhance mother-infant bonding, 2) reduce depressive and anxiety symptoms at 5 days postpartum, and 3) facilitate child development.

Arms: arm 1: Sub-group of participants receiving oxytocin nasal spray (Syntocinon) arm 2: Sub-group of participants receiving placebo nasal spray
Interventions: intervention 1: Oxytocin intervention 2: Placebo
Intervention descriptions: intervention 1: Study participants will be randomized to a placebo or drug group. intervention 2: Study participants will be randomized to a placebo or drug group.

Protocol documents:
ICF_002.pdf: 
 
NCT02505984 
 
Preventing Postpartum Depression with Intranasal Oxytocin 
 
Date of document: 2/15/2024 
 



























Prot_000.pdf: 
 
NCT02505984 
 
Preventing Postpartum Depression with Intranasal Oxytocin 
 
Date of document: 1/13/2021 
 
 


Ver. 1.13.2021 
  
 
2 
 
DETAILED STUDY PROTOCOL 
 
 
Testing the Efficacy of Intranasal Oxytocin for the 
 Prevention of Postpartum Depression and PTSD 
 
 
Sponsor: National Institute of Health (NIH), Brain and Behavior Research Foundation 
(NARSAD), MGH Executive Committee on Research (ECOR) 
 
Research Site: Massachusetts General Hospital 
 
Principal Investigator: Sharon Dekel, PhD 
 
Co-Investigators: Roger K Pitman, MD; Lee S Cohen, MD; Anjali J Kaimal, MD; Elizabeth 
Lawson, MD; Kaloyan Tanev, MD; Scott P Orr, PhD 
 
Medical Monitor: Paul Cannistraro, M.D. 
 
Version: 1.13.2021 
 
1. BACKGROUND AND SIGNIFICANCE 
 
   1.1. Postpartum depression. [Note: Although postpartum depression is a time-honored 
diagnosis, the DSM-5 lists the diagnosis Peripartum Depression instead, in recognition of cases 
in which depression may have its onset even prior to parturition. However, because the focus of 
this proposal is the prevention of depressive symptoms following parturition, we will use the 
term postpartum depression (PPD) throughout this proposal.] PPD is a debilitating disorder. New 
mothers must struggle with the adverse consequences of depression and at the same time be 
responsible for parenting their child. PPD poses a threat to mother and infant health, which in 
extreme cases may involve maternal suicide and/or infanticide. An estimated 600,000 American 
women suffer from PPD annually, making it one of the most frequent complications of 
pregnancy. Available secondary preventive interventions often are ineffective, which calls for 
identifying novel approaches (O’Hara and McCabe, 2013).  
 
Impaired infant-mother bonding is a hallmark of PPD (O’Higgins et al., 2013). Depressed 
mothers have more difficulties developing maternal feelings towards their infant and are less 
likely to provide sensitive caregiving, providing fewer opportunities for reciprocal engagement. 
In turn, bonding impairments may worsen the mother’s depression, creating a vicious cycle. 
Resultant disruptions in the early mother–infant relationship may engender insecure attachment, 
with consequent lifelong disruptions in the child’s socioemotional and cognitive development. 
 
   1.2. Postpartum posttraumatic stress disorder (PP-PTSD). Posttraumatic stress symptoms have 
also been described in mothers following a traumatic childbirth experience, and these may 
overlap with PPD (Söderquist et al., 2009), creating further maternal morbidity as well as 


Ver. 1.13.2021 
  
 
3 
diminishing mother-infant bonding (Parfitt and Ayers, 2009). As our study and others show, 
women who develop PP-PTSD are also at risk for suffering from bonding impairment (Dekel et 
al., 2018) and interruption in the mother-infant bonding relationship in the sensitive postpartum 
period which can adversely modify the child’s developmental trajectory.  
 
   1.3. Current treatment status. Antidepressant medication is the most common treatment for 
PPD and also for PP-PTSD, although there is no evidence that antidepressant perform better than 
placebo and women who breastfeed are ambivalent about taking the drug (O’Hara and McCabe, 
2013). There is no treatment that specifically targets PP-PTSD (Olde et al., 2006). Moreover, 
antidepressant has not been found to help with bonding impairments. Antidepressants do not 
prevent PP-PTSD (Dekel et al., 2016). To date there are two direct interventions to promote 
bonding, viz., baby massage and coaching; both are partially effective at best. There is a need for 
a brief, inexpensive, feasible treatment to enhance bonding. Here we propose a novel 
intervention aimed at enhancing maternal bonding, and reducing PPD and posttraumatic 
symptom severity. We will test the heretofore uninvestigated clinical preventive potential of the 
posterior pituitary peptide hormone oxytocin (OXT), administered intranasally (IN), to mothers 
during the first postpartum days. 
 
    1.4. Theoretical basis for administering oxytocin. In addition to IN-OXT’s putative anxiolytic 
and antidepressant properties (Bakermans-Kranenburg and van IJzendoorn, 2013), a large body 
of research supports OXT’s role in the maintenance of maternal behavior across species. OXT 
knockout mice display deficits in maternal behavior, and exogenous administration of OXT 
enhances it. Recent evidence in postpartum mothers indicates that high peripartum OXT levels 
are associated with enhanced maternal behavior (Feldman et al., 2007), and low levels with 
depressive symptoms (Skrundz et al., 2011). Low OXT levels during bonding have been 
documented in depressed women (Stuebe et al., 2013), suggesting that OXT deficiency is an 
underlying mechanism of impaired bonding in PPD. Exogenous OXT administration has been 
found to enhance maternal brain responses in women (Riem et al., 2011), as well as to reduce the 
fear response in healthy humans (Acheson et al., 2013), suggesting it may also be a promising 
candidate for PP-PTSD. In a non-postpartum sample, IN OXT given to individuals at risk for 
PTSD following trauma exposure shows beneficial effects of the treatment in lowering non-
postpartum PTSD (van Zuiden et al., 2017). Abnormalities in the biological stress response 
manifested in dysregulations in the hypothalamic-pituitary-adrenal (HPA) axis is a hallmark of 
PTSD. OXT deficiency may heighten the stress response in humans (Donadon et al., 2018) in 
part through failure to reestablish bodily homeostasis following exposure to the trauma. Low 
OXT after traumatic exposure has been documented in individuals with PTSD. OXT production 
peaks in labor (Fuchs et al., 2016), as is the norm, and has been associated with extinction of the 
memory for the traumatic nature of the birth experience (Brindle et al., 1991; Brett and 
Baxendale, 2001). This accords with OXT’s specific role in reducing traumatic memory 
overconsolidation to protect against PTSD. Thus, increase of OXT in the immediate postpartum 
may protect women following a traumatic delivery. 
 
   1.5. Intranasal oxytocin and brain access. For exogenous OXT to enhance bonding it must 
exert effects on the central nervous system (CNS) through brain OXT receptors. IN 
administration of OXT has been found to produce significantly increased OXT levels in 
cerebrospinal fluid (CSF) after IN delivery (Striepens et al., 2013). Side effects were not 


Ver. 1.13.2021 
  
 
4 
observed after the delivery of short-term 18 to 40 IU IN-OXT to humans (MacDonald et al., 
2011), including postpartum women (Rupp et al., 2014). Of direct relevance to the proposed 
project, a study that investigated the role of sequential IN-OXT in promoting lactation at a dose 
of 4 IU in each nostril q 4h (total daily dose 48 IU), from as early as one day postpartum, found 
no safety concerns (e.g., Fewtrell et al., 2006). Administration of OXT was documented to 
reduce the fear response in healthy humans (Acheson et al., 2013). In an animal model, central 
OXT administration in the immediate post-stressor phase reduced PTSD-like behavior (Cohen et 
al., 2010). A few studies support of the use of OXT to facilitate fear extinction in the treatment 
of individuals suffering from PTSD (Koch et al., 2014; Koch et al., 2016). However, given the 
unpredictable nature of traumatic events, designing prospective studies to test OXT’s protective 
role is challenging. A recent study of sequential IN-OXT administration after (day 12) an 
automobile accident shows some beneficial effects for PTSD reduction (van Zuiden et al., 2016). 
Along these lines, it is suggested that there might be a <window of opportunity= for a preventive 
intervention in the first days following traumatic exposure, viz, before the trauma memory is 
consolidated and symptoms arise (Zohar et al., 2011). 
 
   1.6. Significance of the study. Our study will attempt to fill the current gap in effective 
preventive interventions for pregnant mothers at risk. No study has yet examined the therapeutic 
effects of OXT on maternal bonding as well as on early PPD and PP-PTSD symptoms. If we 
succeed in establishing the effectiveness of this highly feasible preventive intervention, it could 
become a stand-alone treatment for bonding impairment. Our intervention may also offer hope 
for women at risk for the aversive complications of childbirth-related psychopathology. 
Strengthening the important process of mother-infant bonding from the very beginning of the 
child’s life may also have long-lasting positive implications of the child’s psychological 
development. We further expect that our findings will advance the scientific knowledge 
concerning the major role of OXT in social interaction, and its anti-anxiety and anti-depressive 
properties in humans. Research on the clinical potential of IN-OXT for treating mental illness, 
although promising, is in its infancy, and our study may provide knowledge concerning issues of 
dosage and timing in order to achieve sustained central nervous system effects. Lastly, our 
findings may revise central concepts in postpartum psychopathology. Obtaining data that 
attribute PPD to a bonding impairment, and the prevention of PPD by enhancing bonding, may 
challenge the current psychiatric conceptualization of PPD as merely a subtype of depression. 
Implication of posttraumatic stress symptoms in PPD may shift the focus of postpartum mental 
health to include traumatic stress responses. Evidence of sustained OXT effects on bonding may 
provide empirical support in favor of a sensitive period for mother-infant bonding in the early 
postpartum period, which would have important health care implications. 
 
2. SPECIFIC AIM 
 
   2.1. The primary hypothesis is that administration of a course of four days of IN-OXT at a dose 
of 4 IU in each nostril q 4h (total daily dose 48 IU), from as early as one day postpartum, 
initiated immediately following delivery, in comparison to placebo (PLA), will: 1) enhance 
mother-infant bonding, and 2) reduce PPD and PP-PTSD symptoms, at 5 days and again at two 
months postpartum, in mothers at risk for bonding failure and PPD.  
   


Ver. 1.13.2021 
  
 
5 
   2.2. We further hypothesize that bonding level will mediate the hypothesized beneficial effect 
of IN-OXT on depressive symptoms. Secondarily, we also hypothesize that IN-OXT will have 
positive effects on breastfeeding, and that improved breastfeeding will improve depression. 
 
3. SUBJECT SELECTION 
 
For Oxytocin study 
 
   3.1. Inclusion Criteria. 1) Third-trimester pregnant women being followed at the MGH 
Obstetrics Program who are at risk of PPD as indicated by their scoring >9 on a prenatal 
administration of the Edinburgh Postnatal Depression Scale (EPDS). (Note: Although the 
adjective <Postnatal= refers to the use of the EPDS during the postpartum period, this instrument 
is also used as a prepartum screening instrument for PPD risk.) Additionally, we will enroll 
women with score of >21 on the Peritraumatic Distress Inventory (PDI) who might also be at 
risk for bonding impairment from PPD and PP-PTSD.  
 
   3.2. Exclusion criteria. 1) Age <18 or >50; 2) Failure to participate in regular prenatal check-
ups; 3) Current diagnosis of psychosis; 4) Obstetric complication (e.g., preeclampsia, excessive 
hemorrhaging, gestational diabetes insipidus, emergency Caesarian section resulting in the 
newborn being admitted to the NICU). Note that planned Caesarian section will not serve as an 
exclusion criterion because immediate contact with the newborn occurs after the procedure.); 5) 
Use of potentially confounding or interacting medications (e.g. antidiuretic hormone, steroids); 
6) Complicating pediatric medical condition in the newborn.; 7) suicidality (candidates 
indicating 2+ on EPDS item 10 will be further assessed by PI, a licensed clinical psychologist); 
8) current substance abuse. 
 
   3.3. Recruitment methods. 3596 women delivered a baby at Massachusetts General Hospital 
(MGH) in 2012. During proposed five-year project period, we plan to recruit 110 subjects (Sbjs) 
(who satisfy the inclusion and exclusion criteria) and expect a drop-out rate of 20% between 
assessments, resulting in an anticipated final sample of 56 women. Additionally, we plan to 
recruit and study 88 partners (starting at day 1 postpartum, taking into account women’s drop-out 
rate between pre-partum and day 1 postpartum assessments), also expecting a drop-out rate of 
20% between assessments, resulting in a final sample of 56 partners. 
 
4. SUBJECT ENROLLMENT 
 
Study candidates will be primarily enrolled through social workers, medical assistants and nurses 
at MGH OB/GYN. After administering and scoring the EPDS, the social workers, medical 
assistants, and nurses will introduce the study and obtain permission from the study candidate to 
be contacted by study staff. We will also identify potential study candidates through their EPDS 
score in their medical records. We will then approach physicians of qualified candidates to 
obtain permission that their patient will participate in the study and permission that study staff 
contact candidate, if not approached through other OB staff. Physicians will not take part in the 
study recruitment. Candidates will secondarily be enrolled via study flyers and by study 
announcement in the hospital’s websites. 
 


Ver. 1.13.2021 
  
 
6 
5. STUDY PROCEDURES 
 
   5.1. Design.  
Phase I: Screening (two stages).  
First, study candidates (third trimester of pregnancy) will undergo screening via self-report 
questionnaire, the EPDS, to identify women at risk for PPD. Next, study candidates will be 
further screened over the telephone or in person at the OB by a study staff.  For exclusion 
criteria, use of potentially confounding or interacting medications (e.g. antidiuretic hormone, 
steroids), and current mental disorders assessed by the mini Structural Clinical Interview for 
DSM (mini SCID). The treating obstetrician will be asked regarding contraindicating medical 
conditions (e.g., preeclampsia). Also, candidates’ medical records will be reviewed for exclusion 
criteria. For those who will be enrolled from the Mothers Wellbeing Study, we will enroll them 
based on their PDI score obtained as part of the Mothers Wellbeing Study. Medical records will 
be reviewed for exclusion. 
 
Phase II: Assessment. i) At approximately 32 weeks of pregnancy, study Sbj will complete 
additional self-report questionnaires and 40 mL of blood will be collected from Sbj, if she 
agrees. ii) Postpartum (PP) Day 1, Sbj will complete further self-report questionnaires. Starting 
8 hours after delivery with modification in the start time up to 12 hours postpartum if needed, 
Sbj will self-administer the first dose of study medication in the hospital. In cases of delays due 
to medical procedures (e.g., emergency C-section) medication start time will be extended to up 
to 24 hours post-delivery. iii) PP Days 1-4, Sbj will continue to self-administer the medication in 
the hospital and then at home. iv) Approximately PP Day 5, Sbj will complete additional self-
report questionnaires. v) 2 months, but with modification up to approximately 3 months PP, Sbj 
will complete the same self-report measures and participate in a short video-clip with her infant. 
40 mL of blood will be collected from Sbj, if she agrees. Following this, PI will answer any 
questions Sbj may have and make mental health treatment referral, if indicated and desired. 
Women enrolled through the Mothers Wellbeing Study will begin this study at PP Day 1.  
 
   5.1.1. Assessment # 1 (after approximately 32 weeks pregnancy). At MGH, Sbj will provide 
written informed consent after a full explanation of the procedures. Alternatively, for the 
convenience of the Sbj given their condition as well as to adhere to their visits to the OB, Sbj 
will be consented by the study physician over the phone in the presence of the PI or Research 
Fellow. If the consenting process occurs via telephone, the PI will first meet with the candidate 
and give her the written consent for her to review. She will then review the Consent Form with 
the study physician over the phone. The PI will be able to address any questions that may arise 
after the phone call. At this time, Sbj will be asked for her permission for study staff to contact 
her partner. Sbj will be provided with the <Partner Study Introduction Letter= to give to her 
partner, which invites the partner to participate in the study. Her decision on this matter will not 
affect her enrollment in the study. Next, study staff will email a copy of the consent form to the 
Sbj. The study doctor will sign the document upon receipt from Sbj. Next, study staff and the PI 
will administer assessment to Sbj via self-report questionnaires (60 minutes total) pertaining to 
demographics, medication usage (Medication Questionnaire [MED]), attachment (Maternal-Fetal 
Attachment Scale [MFAS]), mental health (Brief Symptom Inventory [BSI], PTSD CheckList 
for DSM-5 [PCL-5 1]), personality (Five Factory Inventory [NEO-FFI]), relationships and social 
support (Experiences in Close Relationships-Revised Questionnaire [ECR-R] and 


Ver. 1.13.2021 
  
 
7 
Multidimensional Scale of Perceived Social Support [MSPSS]), trauma history (Life Events 
Checklist for DSM-5 [LEC-5], Childhood Trauma Questionnaire Short Form [CTQSF]), sleep 
(Bergen Insomnia Scale [BIS]), and expectations about delivery (Wijma Delivery 
Expectancy/Experience Questionnaire [W-DEQ 1]). All study questionnaires will be completed 
electronically, with the option to complete hard copies. If needed, self-report measures may be 
completed remotely. Following this, Sbj will be taught to self-administer the nasal spray 
containing either drug or placebo. Finally, if agreed by Sbj, 40 mL of blood will be collected 
from Sbj from venipuncture specimens performed for the purpose of this study and related 
studies. Samples will be later analyzed for hormone levels (e.g., oxytocin and cortisol) and DNA. 
Sbj (and her partner, if involved) will be contacted approximately 1 month after Assessment 1 as 
a reminder about her participation in the study.  
 
 5.1. 2. Assessment # 2 and initial study medication administration (approximately 8 hours after 
delivery). Study staff will receive epic notification indicating that Sbj has been admitted to the 
Labor and Delivery Unit (L&D). Sbj will complete questionnaires (25 minutes total) at MGH’s 
postpartum unit targeting mental health (BSI), peritraumatic responses (Peritraumatic 
Dissociative Experiences Questionnaire [PDEQ], Peritraumatic Distress Inventory [PDI], [W-
DEQ 2]), depressive symptoms [EPDS], maternal bonding (Mother-to-Infant Bonding Scale 
[MIBS], and medication (MED). Additionally, as prescribed in the physicians order sheet (OXT 
order sheet), Sbj will self-administer the study medication (Syntocinon 40 mg/ml or placebo 
nasal spray, per randomization schedule), 1 spray into each nostril, before feeding their baby if 
possible, q 4 hours, including nighttime.  
 
   5.1.3. Continued study medication administration (up to 4 days after delivery). Sbj will 
continue using the spray as instructed over 4 consecutive days. Sbj will complete a diary 
recording their use of the study medication over the 4-day period (10 minutes total). Drug diary 
will be completed electronically, with the option to complete a hard copy version. Sbj will be 
called after the assessment #2 to provide any assistance with the study medication or the diary, 
and to monitor responses to questionnaires. Sbj will also be called or texted as a reminder to use 
the spray over the 4 days, if desired. Further, as part of routine hospital care, Sbjs’ vital signs are 
taken in the postpartum unit before medication administration and are consistently monitored by 
the nurses during the course of the Sbjs’ hospital stay as part of routine hospital care. 
 
   5.1.4. Assessment # 3 (approximately 5 days after delivery). Sbj will complete self-report 
questionnaires (30 minutes total) pertaining to mental health (EPDS, PCL-5 2, BSI, PTGI), 
breastfeeding (Index of Breastfeeding Status [IBS]), maternal bonding and attachment (MIBS, 
Postpartum Bonding Questionnaire [PBQ], Maternal Attachment Inventory [MAI]), childbirth 
experience (W-DEQ 2), and medication (MED). Sbj will be called after assessment to monitor 
responses to questionnaires. Additionally, if Sbj’s partner expressed interest in participating in 
the study, they will receive the <Partner Recruitment Letter= and, upon implied consent, will 
complete the EPDS (EPDS-P) and MIBS (MIBS-P) adapted for partners. Partners will complete 
all questionnaires electronically, with the option to complete hard copies. 
 
   5.1.5. Assessment # 4 (approximately 2 months after delivery). Sbj will complete (40 minutes 
total) concerning mental health (EPDS, PCL-5 2, BSI), bonding (MIBS, PBQ), breastfeeding 
(IBS), child development and temperament (Ages and Stages Questionnaire, 2 months [ASQ-3], 


Ver. 1.13.2021 
  
 
8 
Infant Behavior Questionnaire [IBQ-R]), psychological growth (PTGI) and medication (MED), 
administered by PI and study staff research assistants. If needed, self-report measures may be 
completed remotely.  Sbj will also participate in a short video-clip of free play with their infant 
(10 minutes total) obtained by research staff (see Video Completion Form), which will later be 
coded using Coding Interactive Behavior (CIB). Sbj is instructed to freely interact with baby. 
Assessment may be completed at Sbjs home, if desired. Child development will also be 
measured by the Bayley Scales of Infant Development (Bayley-III), relevant for the age group 
studied. The Bayley-III, which focuses on observational behavior, will be conducted by PI or by 
trained research staff, supervised by PI. Finally, if agreed by Sbj, 40 mL of blood will be 
collected from Sbj from venipuncture specimens performed for the purpose of this study and 
related studies. Samples will be later analyzed for hormone levels (e.g., oxytocin and cortisol) 
and DNA. After completion, a member of the study team will answer any questions Sbj may 
have about the study and provide mental health referral, as needed and desired. Additionally, 
partner’s enrolled in the study will complete the EPDS-P and MIBS-P. 
 
6. BIOSTATISTICAL ANALYSIS  
 
   6.1. Statistical analysis will be performed via a mixed model for repeated measures, with Drug 
(OXT vs. PLA) as a Class factor, psychometric scores as univariate and/or simultaneous 
multivariate dependent measures, additional covariates as appropriate, and Sbj as a random 
effect. Currently available mixed model analytic programs are able to handle missing data. Effect 
sizes will be employed in power analyses to calculate sample sizes for subsequent larger studies. 
Path analysis will be employed to test the role of bonding as a mediating factor of drug effect on 
depression outcome. 
 
   6.2. Power analysis. The major goal of this first study is to obtain measures of effect size that 
can be used to calculate sample size requirements for a subsequent, larger study, should the data 
from this study be promising. Thus, even if we are unable to meet the recruitment goals below, 
the study will still obtain useful and important data. That being said, we offer the following 
power analysis below, should recruitment go as well as hoped. 
 
   Because of the novelty of this project’s hypothesis, no data are available regarding the potential 
protective effect of IN-OXT against the development of PPD, from which to estimate an effect 
size for the proposed study. However, a meta-analysis of studies of the effect of intranasal OXT 
in both healthy and clinical groups with implications for pharmacotherapy yielded an estimated 
effect size of d=0.32 (Bakermans-Kranenburg and van IJzendoorn, 2013), on which we will base 
our power analysis. With α set at 0.05, and 1-β (i.e., power) set at 0.80, n=56 Sbjs 
(approximately 28 completed Sbjs in each of two groups) will be required to detect an effect size 
of d=0.32 in a simple t-test analysis comparing OXT and PLA subjects. Estimating dropouts at 
20% between assessments, 70 and 88 Sbjs and partners will have to complete the second and 
first postpartum assessments, respectively, and 110 Sbjs will be required to complete the pre-
partum assessment. Of all pre-partum women given psychometrics, an estimated 20% will be 
found to be at-risk, requiring the administration of psychometrics to 550 study candidates. To 
summarize: 
 
550 administered psychometrics 


Ver. 1.13.2021 
  
 
9 
110 women identified at risk, pass final screening, and complete pre-partum assessment  
88 women randomized, and complete assessment #2; 88 partners complete assessment #1 at day 
1 postpartum 
70 women complete assessment #3; 70 partners complete assessment #2 at day 5 postpartum 
56 women complete participation; 56 partners complete participation  
  
   6.3. Successful results.  
As above, successful results will consist of our obtaining sufficient data that, if promising, will 
allow planning of a further, more definitive study of the effective role of IN-OXT in enhancing 
maternal bonding and/or preventing postpartum depressive and or posttraumatic symptoms, 
including calculating sample size requirements. Successful results also pertain to gaining 
knowledge about the potential positive effects of IN-OXT on mother at risk and knowledge about 
the feasibility of the intervention. Given the under-researched area of PP-PTSD, successful 
findings will include knowledge about the prevalence, course and risk factors of posttraumatic 
stress and its relations with depressive symptoms and mother-infant bonding. 
 
7. RISKS AND DISCOMFORTS 
 
   7.1. Study Medication. OXT nasal spray has been previously administered to women following 
childbirth. There are reports of mild side effects at a dosage to promote lactation for as early as 
day 1 postpartum (e.g., Fewtrell et al., 2006; Ruis et al., 1981). Mild complaints may include: 
breast and nipple discomfort (13-20 out of 100) and uterine cramps (5 out of 100). However, 
such side effects were also reported by women receiving placebo (Stern, 1961). As indicated in 
the drug brochure, women experiencing painful uterine cramps should not drive or operate 
machinery. Other uncommon side effects include bleeding from the nose after using the drug (1 
out of 48) (Huntingford, 1961), unfamiliar sensation in the nose (5 out of 100), and complaint 
about taste (1 out of 100) (Stern, 1961). Use of the drug by participants who experience 
postpartum depression was reported to transiently lower mood (Mah et al., 2013). A subsequent 
study, however, by the same group did not mention these outcomes (Mah et al., 2015), nor were 
these outcomes reported elsewhere (Clarici et al., 2015). A recent study by Mah and colleagues 
(2017), based on the 2013 sample, reports no effect of IN-OXT on maternal sensitive interaction 
with own baby but more negative care giving response to another’s baby. The authors warrant 
further research on IN-OXT in depressed mothers. Other potential undesirable effects mentioned 
in the nasal spray package insert but not encountered in the literature include: headache, nausea, 
rash and allergic dermatitis (all rare).  
 
   7.2. Questionnaires and video recording. Sbj may experience emotional distress from 
answering questions concerning their mental health and childbirth experience. Interacting with 
their infant on camera may cause Sbj discomfort.  
 
   7.3. Blood drawn. Sbj may experience discomfort from having blood drawn. Side effects may 
include bruising, swelling at the injection site, dizziness and lightheadedness. 
  
   7.4. Unknown Risks. There may be other risks and side effects that are not known at this time. 
If any significant new findings develop during the course of this study that may affect the risk: 
benefit ratio for participants, appropriate institutional reporting protocol will be followed. 


Ver. 1.13.2021 
  
 
10 
 
8. POTENTIAL BENEFITS 
 
   8.1. Potential benefits to participating individuals. First, women with PPD have an increased 
incidence of lactation problems (Assarian et al., 2014), and they are at risk for breastfeeding 
failure and cessation (see Figueiredo et al., 2013, for a review). This can be unfortunate, because 
breastfeeding helps to reduce PPD symptoms (Fairlie et al., 2009; Figueiredo et al., 2014; 
Ystrom, 2012). Therefore, it is reasonable to expect that a significant portion of our Sbjs (and 
their newborns) who receive active drug will benefit from the lactation-promoting effect of IN-
OXT, with consequent benefit to infant nutrition and reduction in maternal anxiety. Second, in a 
recent study of women with PPD three months following delivery (Mah et al., 2015), IN-OXT 
was found to enhance the quality of mother-infant bonding and maternal protective behavior. 
Hence, our proposed active intervention may benefit the newborn as well. Third, women who 
receive active drug may be protected from developing PPD and bonding impairment. Other less 
substantive benefits include, if this turns out to be the case, the use of IN-OXT may reduce or 
obviate the need for antidepressant medication, with a reduction of possible transmission via 
secretion into maternal milk. Further, PPD is often accompanied by symptoms of anxiety and 
irritability (Righetti-Veltema et al., 2003). OXT has been shown to attenuate the neural 
response to arousing stimuli (Rupp et al., 2013) and to reduce amygdala activation in response to 
infant crying (Riem et al., 2011). Thus we have reason to expect that OXT may prevent to some 
degree PP-PTSD symptoms in women at risk.  
 
   8.2. Potential benefits to society. The information collected from this study may enable 
researchers to obtain knowledge on the effectiveness of oxytocin for enhancing bonding and 
preventing depressive and posttraumatic symptoms in postpartum women. If the findings are 
promising, this study may serve as a platform for larger-scale studies that may ultimately support 
a new drug indication for postpartum women at risk.  
 
9. MONITORING AND QUALITY ASSURANCE 
 
9.1. Administration of Protocol.  
The protocol will be conducted in accordance with the protocol submitted to and approved by the 
Partners MGH IRB, as well as by NARSAD and ECOR. Sbjs will not be recruited until written 
notification of approval of the research project is issued by the IRB and NARSAD and ECOR 
are notified of the approval.  
 
   9.2. Data Monitoring. Given the reduced risk of this study, monitoring by the PI and Partners 
IRB should be sufficient. A physician investigator will review all laboratory/questionnaire 
results. The PI will closely monitor emotional dysregulation and concerning responses to 
questionnaire items that inquire about suicidality (BSI, question #9, responses of 2 or more; 
EPDS question #10, responses of <sometimes= or <yes, quite often=). Women who report 
suicidality in the screening and consent to the study will be monitored by the PI during their 
study participation. Likewise, the PI will monitor subjects who report suicidality in subsequent 
study assessments. If needed, the PI will conduct a suicidality assessment. Based on Sbj’s 
response, several actions will take place, including frequent contact with Sbj during study 
participation, suicide contract, referral for psychiatric consultation and treatment for medication, 


Ver. 1.13.2021 
  
 
11 
if needed, and, in extreme cases, hospitalization. PI, who is a licensed clinical psychologist, will 
immediately evaluate subject suicide-related responses as data becomes available and will 
immediate attempt to contact subject for assessment and appropriate triage. The PI will review 
cases that are clinically significant and will notify the IRB in case of adverse events that may 
influence the IRB decision to continue or not the study trials, in accordance with IRB’s policies. 
In the event possible serious or adverse effects of participation, Paul Cannistraro, M.D., an MGH 
psychiatrist who has served as a Medical Monitor on other studies conducted by the MGH PTSD 
group, and who is not an investigator on the present study, will be available to review the event 
and make recommendations to the PI and the IRB.  
9.3. Communication between Principal Investigator and Sponsor. The PI will provide written 
reports about the study progress to NARSAD. Six months after the project start date, the PI will 
send an interim report followed by a second report one year later. A final report will be sent 
within 90 days of the grant termination. The final report will include a narrative pertaining to the 
main findings of the study and information about additional grants, if relevant. NARSAD will 
also obtain from the PI copies of relevant presentations and publications generated by the study. 
Additionally, annual and final progress report will be submitted to NIH. If any change is 
considered in the protocol, an amendment will first be sent to the IRB, and significant changes in 
the protocol will be sent to NARSAD for review and approval. We will notify the FDA of 
significant changes to the protocol and we will send a report to the FDA of adverse events that 
are serious, related, and unexpected within 90 days.  
 
10. REFERENCES 
Acheson, D., Feifel, D., De Wilde, S., McKinney, R., Lohr, J., & Risbrough, V. (2013). The 
effect of intranasal oxytocin treatment on conditioned fear extinction and recall in a healthy 
human sample. Psychopharmacology, 229, 199–208. http://doi.org/10.1007/s00213-013-
3099-4 
Assarian, F., Moravveji, A., Ghaffarian, H., Eslamian, R., & Atoof, F. (2014). The association of 
postpartum maternal mental health with breastfeeding status of mothers: a case-control 
study. Iranian Red Crescent Medical Journal, 16(3), e14839. 
http://doi.org/10.5812/ircmj.14839 
Bakermans-Kranenburg, M. J., & van IJzendoorn, M. H. (2013). Sniffing around oxytocin: 
review and meta-analyses of trials in healthy and clinical groups with implications for 
pharmacotherapy. Transl Psychiatry, 3, e258. http://doi.org/10.1038/tp.2013.34\ntp201334 
[pii] 
Brett, M. & Baxendale, S. Motherhood and memory: a review. Psychoneuroendocrinology 26, 
339-362 (2001). 
 
Brindle, P. M., Brown, M. W., Brown, J., Griffith, H. B. & Turner, G. M. Objective and 
subjective memory impairment in pregnancy. Psychological medicine 21, 647-653 
(1991). 
 


Ver. 1.13.2021 
  
 
12 
Britton, J. C., Phan, K. L., Taylor, S. F., Fig, L. M., & Liberzon, I. (2005). Corticolimbic blood 
flow in posttraumatic stress disorder during script-driven imagery. Biological Psychiatry, 
57, 832-840. 
 
Brunet A, Orr SP, Tremblay J, Robertson K, Nader K, Pitman RK. (2008). Effect of post-
retrieval proparanolol on psychophysiologic responding during subsequent script-driven 
traumatic imagery in post-traumatic stress disorder. Journal of Psychiatric Research, 
42(6):503-6. 
Clarici, A., Pellizzoni, S., Guaschino, S., Alberico, S., Bembich, S., Giuliani, R., Short, A., 
Guarino, G., & Paanksepp, J. (2015). Intranasal administration of oxytocin in postnatal 
depression: implications for psychodynamic psychotherapy from a randomized double-blind 
pilot study. Frontiers in Psychology, 426(6). http://doi.org/10.3389/fpsyg.2015.00426 
Clout, D., & Brown, R. (2015). Sociodemographic, pregnancy, obstetric, and postnatal predictors 
of postpartum stress, anxiety and depression in new mothers. Journal of Affective 
Disorders, 188, 60-67. 
 
Cohen, H. et al. Hippocampal Microinfusion of Oxytocin Attenuates the Behavioural Response 
to Stress by Means of Dynamic Interplay with the Glucocorticoid‐Catecholamine 
Responses. Journal of neuroendocrinology 22, 889-904 (2010). 
 
Dekel S, Solomon Z, & Ein-Dor T. (2016). PTSD symptoms lead to modification in the memory 
of the trauma: A prospective study of former prisoners of war. Journal of Clinical 
Psychiatry, 77:290-296.  
 
Dekel, S. et al. Trauma and posttraumatic stress disorder. Massachusetts General Hospital 
Comprehensive Clinical Psychiatry 2nd edition (2016). 
 
Dekel, S., Thiel, F., Dishy, G., & Ashenfarb, A. L. (2018). Is childbirth-induced PTSD 
associated with low maternal attachment?. Archives of Women's Mental Health, 1-4. 
 
Donadon, M. F., Martin-Santos, R. & Osório, F. d. L. The associations between oxytocin and 
trauma in humans: a systematic review. Frontiers in pharmacology 9, 154 (2018). 
Fairlie, T. G., Gillman, M. W., & Rich-Edwards, J. (2009). High pregnancy-related anxiety and 
prenatal depressive symptoms as predictors of intention to breastfeed and breastfeeding 
initiation. Journal of Women’s Health, 18(7), 945–53. http://doi.org/10.1089/jwh.2008.0998 
Feldman, R., Weller, A., Zagoory-Sharon, O., & Levine, A. (2007). Evidence for a 
neuroendocrinological foundation of human affiliation: Plasma oxytocin levels across 
pregnancy and the postpartum period predict mother-infant bonding. Psychological Science, 
18, 965–970. http://doi.org/10.1111/j.1467-9280.2007.02010.x 
Fewtrell, M. S., Loh, K. L., Blake, A., Ridout, D. A., & Hawdon, J. (2006). Randomised, double 
blind trial of oxytocin nasal spray in mothers expressing breast milk for preterm infants. 


Ver. 1.13.2021 
  
 
13 
Archives of Disease in Childhood. Fetal and Neonatal Edition, 91, F169–F174. 
http://doi.org/10.1136/adc.2005.081265 
Figueiredo, B., Canário, C., & Field, T. (2014). Breastfeeding is negatively affected by prenatal 
depression and reduces postpartum depression. Psychological Medicine, 44(5), 927–36. 
http://doi.org/10.1017/S0033291713001530 
Figueiredo, B., Dias, C. C., Brandão, S., Canário, C., & Nunes-Costa, R. (n.d.). Breastfeeding 
and postpartum depression: state of the art review. Jornal de Pediatria, 89(4), 332–8. 
http://doi.org/10.1016/j.jped.2012.12.002 
Frijling, J. L., van Zuiden, M., Koch, S. B., Nawijn, L., Veltman, D. J., & Olff, M. (2016). 
Intranasal oxytocin affects amygdala functional connectivity after trauma script-driven 
imagery in distressed recently trauma-exposed individuals. Neuropsychopharmacology, 41, 
1286.  
 
Fuchs, A., Möhler, E., Reck, C., Resch, F. & Kaess, M. The early mother-to-child bond and its 
unique prospective contribution to child behavior evaluated by mothers and teachers. 
Psychopathology 49, 211-216 (2016). 
 
Grekin R, O'Hara MW. Prevalence and risk factors of postpartum posttraumatic stress disorder: 
A meta-analysis. Clinical Psychology Review 2014;34(5):389-401.  
 
Hariri AR, Mattay VS, Tessitore A, et al. Serotonin transporter genetic variation and the 
response of the human amygdala. Science 2002;297:400-3. 
 
Hayes, U. L., Balaban, S., Smith, J. Z., Perry‐Jenkins, M., & Powers, S. I. (2010). Role of pelvic 
sensory signalling during delivery in postpartum mental health. Journal of Reproductive and 
Infant Psychology, 28, 307-323. 
Huntingford, P. J. (1961). Intranasal use of synthetic oxytocin in management of breast-feeding. 
British Medical Journal, 1(5227), 709–11. Retrieved from 
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1953339&tool=pmcentrez&ren
dertype=abstract 
Keane TM, Kolb LC, Kaloupek DG, Orr SP, Blanchard EB, Thomas RG, Hsieh FY, & Lavori 
PW. (1998). Utility of psychophysiological measurement in the diagnosis of 
posttraumatic stress disorder: results from a Department of Veterans Affairs Cooperative 
Study. Journal of Consulting and Clinical Psychology, 66(6):914-23. 
 
Koch, S. B. et al. Intranasal oxytocin as strategy for medication-enhanced psychotherapy of 
PTSD: salience processing and fear inhibition processes. Psychoneuroendocrinology 40, 
242-256, doi:10.1016/j.psyneuen.2013.11.018 (2014). 
 
Koch, S. B. et al. Intranasal Oxytocin Administration Dampens Amygdala Reactivity towards 
Emotional Faces in Male and Female PTSD Patients. Neuropsychopharmacology : 


Ver. 1.13.2021 
  
 
14 
official publication of the American College of Neuropsychopharmacology 41, 1495-
1504, doi:10.1038/npp.2015.299 (2016). 
MacDonald, E., Dadds, M. R., Brennan, J. L., Williams, K., Levy, F., & Cauchi, A. J. (2011). A 
review of safety, side-effects and subjective reactions to intranasal oxytocin in human 
research. Psychoneuroendocrinology. http://doi.org/10.1016/j.psyneuen.2011.02.015 
Mah, B. L., Bakermans-Kranenburg, M. J., Van IJzendoorn, M. H., & Smith, R. (2015). 
Oxytocin promotes protective behavior in depressed mothers: a pilot study with the 
enthusiastic stranger paradigm. Depression and Anxiety, 32(2), 76–81. 
http://doi.org/10.1002/da.22245 
Mah, B. L., Van Ijzendoorn, M. H., Out, D., Smith, R. & Bakermans-Kranenburg, M. J. The 
Effects of Intranasal Oxytocin Administration on Sensitive Caregiving in Mothers with 
Postnatal Depression. Child Psychiatry Hum Dev 48, 308-315, doi:10.1007/s10578-016-
0642-7 (2017). 
Mah, B. L., Van IJzendoorn, M. H., Smith, R., & Bakermans-Kranenburg, M. J. (2013). 
Oxytocin in postnatally depressed mothers: Its influence on mood and expressed emotion. 
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 40, 267–272. 
http://doi.org/10.1016/j.pnpbp.2012.10.005 
O’Hara, M. W., & McCabe, J. E. (2013). Postpartum depression: current status and future 
directions. Annu Rev Clin Psychol, 9, 379–407. http://doi.org/10.1146/annurev-clinpsy-
050212-185612 
O’Higgins, M., Roberts, I. S. J., Glover, V., & Taylor, A. (2013). Mother-child bonding at 1 
year; associations with symptoms of postnatal depression and bonding in the first few 
weeks. Archives of Women’s Mental Health, 16(5), 381–9. http://doi.org/10.1007/s00737-
013-0354-y 
Olde E, van der Hart O, Kleber RJ, & van Son MJ. (2006). Posttraumatic stress following 
childbirth: A review. Clinical Psychology Review, 26(1):1-16.  
Parfitt, Y., & Ayers, S. (2009, December 19). The effect of postnatal symptoms of post-traumatic 
stress and depression on the couple’s relationship and parent-baby bond. Journal of 
Reproductive and Infant Psychology. Taylor & Francis. 
http://doi.org/10.1080/02646830802350831  
Riem, M. M. E., Bakermans-Kranenburg, M. J., Pieper, S., Tops, M., Boksem, M. A. S., 
Vermeiren, R. R. J. M., … Rombouts, S. A. R. B. (2011). Oxytocin modulates amygdala, 
insula, and inferior frontal gyrus responses to infant crying: A randomized controlled trial. 
Biological Psychiatry, 70, 291–297. http://doi.org/10.1016/j.biopsych.2011.02.006 


Ver. 1.13.2021 
  
 
15 
Righetti-Veltema, M., Bousquet, A., & Manzano, J. (2003). Impact of postpartum depressive 
symptoms on mother and her 18-month-old infant. European Child & Adolescent 
Psychiatry, 12(2), 75–83. http://doi.org/10.1007/s00787-003-0311-9 
Ruis, H., Rolland, R., Doesburg, W., Broeders, G., & Corbey, R. (1981). Oxytocin enhances 
onset of lactation among mothers delivering prematurely. British Medical Journal (Clinical 
Research Ed.), 283(6287), 340–2. Retrieved from 
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1506140&tool=pmcentrez&ren
dertype=abstract 
Rupp, H. A., James, T. W., Ketterson, E. D., Sengelaub, D. R., Ditzen, B., & Heiman, J. R. 
(2013). Lower sexual interest in postpartum women: relationship to amygdala activation 
and intranasal oxytocin. Hormones and Behavior, 63(1), 114–21. 
http://doi.org/10.1016/j.yhbeh.2012.10.007 
Rupp, H. A., James, T. W., Ketterson, E. D., Sengelaub, D. R., Ditzen, B., & Heiman, J. R. 
(2014). Amygdala response to negative images in postpartum vs nulliparous women and 
intranasal oxytocin. Social Cognitive and Affective Neuroscience, 9(1), 48–54. 
http://doi.org/10.1093/scan/nss100 
Skrundz, M., Bolten, M., Nast, I., Hellhammer, D. H., & Meinlschmidt, G. (2011). Plasma 
oxytocin concentration during pregnancy is associated with development of postpartum 
depression. Neuropsychopharmacology : Official Publication of the American College of 
Neuropsychopharmacology, 36, 1886–1893. http://doi.org/10.1038/npp.2011.74 
Söderquist, J., Wijma, B., Thorbert, G., & Wijma, K. (2009). Risk factors in pregnancy for post-
traumatic stress and depression after childbirth. BJOG: An International Journal of 
Obstetrics and Gynaecology, 116, 672–680. http://doi.org/10.1111/j.1471-
0528.2008.02083.x 
Stern, B. D. (1961). MILK LET-DOWN-The Use of Intranasal Oxytocin for Nursing Mothers. 
California Medicine, 95(3), 168–9. Retrieved from 
http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1574469&tool=pmcentrez&ren
dertype=abstract 
Striepens, N., Kendrick, K. M., Hanking, V., Landgraf, R., Wüllner, U., Maier, W., & 
Hurlemann, R. (2013). Elevated cerebrospinal fluid and blood concentrations of oxytocin 
following its intranasal administration in humans. Scientific Reports, 3, 3440. 
http://doi.org/10.1038/srep03440 
Stuebe, A. M., Grewen, K., & Meltzer-Brody, S. (2013). Association between maternal mood 
and oxytocin response to breastfeeding. Journal of Women’s Health (2002), 22, 352–61. 
http://doi.org/10.1089/jwh.2012.3768 


Ver. 1.13.2021 
  
 
16 
Swain, J. E., Tasgin, E., Mayes, L. C., Feldman, R., Todd Constable, R., & Leckman, J. F. (2008). 
Maternal brain response to own baby‐cry is affected by cesarean section delivery. Journal 
of Child Psychology and Psychiatry, 49, 1042-1052. 
 
van Zuiden, Mirjam, Jessie L Frijling, Laura Nawijn, Saskia B.J Koch, J. Carel Goslings,  
Jan S Luitse, Tessa H Biesheuvel, Adriaan Honig, Dick J Veltman, and Miranda Olff. 
"Intranasal Oxytocin to Prevent Posttraumatic Stress Disorder Symptoms: A Randomized 
Controlled Trial in Emergency Department Patients." Biological Psychiatry 81.12 (2017): 
1030-040. Web. 
 
Ystrom, E. (2012). Breastfeeding cessation and symptoms of anxiety and depression: a 
longitudinal cohort study. BMC Pregnancy and Childbirth, 12, 36. 
http://doi.org/10.1186/1471-2393-12-36 
Zohar, J. et al. New insights into secondary prevention in post-traumatic stress disorder. 
Dialogues in clinical neuroscience 13, 301-309 (2011). 
 

SAP_001.pdf: 
 
NCT02505984 
 
Preventing Postpartum Depression with Intranasal Oxytocin 
 
Date of document: 12/27/2024 
 
 


Data Analysis 
The final sample size includes 38 eligible women randomly assigned to oxytocin administration 
(n = 18) or placebo (n = 20). Missing data were allowed such that 18.59% of the data were 
missing, with 23 different patterns. Jamshidian and Jalal’s non-parametric Missing Completely 
At Random (MCAR) test indicated that the data was Missing At Random (MAR): Hawkins’s test, 
2median(6) = 14.33, pmedian = .026, and Anderson-Darlin’s rank test, Tmedian = 5.88, pmedian = .005. 
Missing data was handled by Multiple Imputation (Rubin, 2009) with 50 complete sets. The 
reported basic results are the pooled outcome of the MI procedure. Before the primary analyses, 
we examined the normal distribution of all the quantitative study measures using a series of 
Anderson-Darling normality tests. Basic analyses for study group comparison on outcome 
measures for each time point were performed using Mann-Whitney U tests.