Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT02824627 |
| Other study ID # |
0321-16-FB |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 2
|
| First received |
|
| Last updated |
|
| Start date |
January 27, 2017 |
| Est. completion date |
August 10, 2021 |
Study information
| Verified date |
September 2023 |
| Source |
University of Nebraska |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Irritability and emotional dysregulation are recognized as serious aspects of psychopathology
seen in in pediatric psychiatric patients. While various behavioral as well as
psychopharmacological interventions have shown some efficacy in improving irritability and
emotional dysregulation, there are no data determining the neurobiological mechanism of
effect at the neural level. Previous studies have demonstrated that heightened amygdala
response to negative emotional stimuli is closely related to irritability and emotional
dysregulation in children and adolescents. Also, there are studies showing administration of
oxytocin can decrease the heightened amygdala response to negative emotional stimuli across
various psychiatric diagnoses. This study is a double-blind randomized trial of oxytocin for
irritability and emotional dysregulation in the pediatric population. Neuroimaging modalities
of fMRI and MEG are employed to probe the neuro-circuitry changes occurring as a result of
the oxytocin intervention, specifically including heightened amygdala response to negative
emotional stimuli and dysfunctional fronto-amygdala connectivity. The investigators will also
investigate the genetic sequence of the oxytocin receptor in the study participants and its
relationship with symptom profile and neural activity changes. Children and adolescents (age
10-18) with a diagnosis of disruptive mood and/or behavior disorders (including Attention
Deficit/Hyperactivity Disorder [ADHD], Oppositional Defiant Disorder [ODD], Conduct Disorder
[CD], and Disruptive Mood Dysregulation Disorder [DMDD]), and clinically significant levels
of irritability and emotional dysregulation as measured by the Affective Reactivity Index
Scale (score>/= 4).
2 weeks randomized, double-blind treatment with intranasal oxytocin (24 IU daily, or 12 IU
daily if the weight is < 40kg) with assessment of diagnosis, symptom profiles (the Affective
Reactivity Index [ARI], Inventory of Callous-Unemotional Trait [ICU], Behavior Assessment
System for Children, second version [BASC-2], and Clinical Global Impression [CGI]) and pre-
and post-oxytocin treatment neuroimaging (fMRI and MEG). The genetic sample will be obtained
via buccal mucosa sampling.
Participants may receive outpatient clinically indicated follow-up care in the UNMC
department of psychiatry or other local community agency as appropriate.
Description:
1. Clinical assessment
Standard clinical practice at the outpatient clinic of the department of psychiatry, at
University of Nebraska Medical Center involves an initial clinical interview by either a
child and adolescent psychiatrist faculty member, a child and adolescent psychiatry
clinical fellow, or an advanced practice registered nurse. The clinical interview
includes past and current history of psychiatric symptoms/signs, past and current
medical history, and past/current social/academic history. Also the current medication
(if any) and any medical condition that would have interaction with the psychiatric
diagnosis will be reviewed. The child/adolescent will receive the diagnosis of
psychiatric syndrome at the end of the assessment sessions.
2. Recruitment to the study
Participants diagnosed with ADHD/CD/ODD/DMDD and presence of clinically significant
irritability and emotional dysregulation at the clinical assessment session will be
invited to participate in this study afterwards. Participants who respond to
advertisement, after a phone screening session will be also invited.
3. Initial research assessment
Participants who agreed to be enrolled into the protocol will have the initial research
assessment session afterwards. This will be held at the outpatient clinic of the
department of psychiatry, at University of Nebraska Medical Center. Participants will
receive the Schedule for Affective Disorders and Schizophrenia for School-Age
Children-Present and Lifetime Version (K-SADS), to confirm the diagnosis of
ADHD/CD/ODD/DMDD, and to rule out any other psychiatric diagnoses listed in the
exclusion criteria. Their IQ will be measured by the Wechsler Abbreviated Scale of
Intelligence (2-subtest form). Irritability and emotional dysregulation will be measured
by the Affective Reactivity Index (ARI). Only the children and adolescents with
diagnoses of ADHD/CD/ODD/DMDD and clinically significant level of irritability/emotional
dysregulation (score >4 on the ARI) will be enrolled in the study. CBCL, ICU, RPAQ will
be used to measure the symptom profiles and functional impairment of patients with
ADHD/CD/ODD/DMDD at the initiation and end point of their study participation.
4. fMRI visit 1
During the MRI visit 1, participants will receive their first fMRI session immediately
before initiation of oxytocin or placebo treatment. The fMRI visit 1 can happen on the
same day of the initial research assessment after the initial research assessment is
completed.
The Fearful Expression Processing task
This is a shortened version of the paradigm previously utilized by our group (Marsh &
Blair, 2008). During each trial the participant is asked to decide the gender of the
face displayed. The face either demonstrates neutral affect or a morphed intensity of
fear (50%, 100% or 150%). A trial involves: the presentation of a face (1500 ms) and
then a fixation point (1000 ms). There is one run of this task, with 120 face trials (30
neutral, 30 50% fear, 30 100% fear and 30 150% fear) and 60 fixation point trials. In
addition, there are 15 seconds of fixation point trials at the beginning and end of the
run. Task duration is 8 minutes.
The Affective Stroop task
The affective task used here was an adapted version of the paradigm described in
previous work. During each trail the participant is asked to decide how many numbers are
displayed on the screen, instead of the value of the number. For congruent trials, the
numbers were displayed with the same numerosity and number value (e.g., three 3s). For
incongruent trials, the numbers were displayed with different numerosities and number
values (e.g., four 3s). The individual numerical stimuli consisted of three, four, five,
or six 3s, 4s, 5s, or 6s randomly presented within a 9-point grid. There are an equal
number of congruent trials and incongruent trials (48 each for a run). These number
pictures were preceded and followed by emotional stimuli pictures consisting of 48
positive, 48 negative, and 48 neutral pictures selected from the International Affective
Picture System. A trial involves: the presentation of an emotional stimuli (400ms), a
numerical display (400ms), the same emotional stimuli (400ms), and a blank (1300ms).
Subject completed two runs, generating 288 picture-trial events (32 in each 9
categories) and 96 fixation points to generate a baseline.
5. MEG visit 1
MEG visit 1 will take place at the Center for MEG (South Doctors Tower, Ste. 222) on the
day of their scheduled study. The MEG visit 1 can happen on the same day of the initial
research assessment.
The Emotional Stroop task
For the emotional Stroop task (EST), three word lists are prepared, a threat list, a
negative list, and a neutral list. Each list contains 30 monosyllabic words. The threat
words include things encountered in dangerous situation (e.g. gun), the negative words
are negative in valence, but not related to threat (e.g., bad). The neutral words are
not threatening nor negative (e.g., tune). The three words lists are equated across
lexical features including: length, frequency, orthographic, and phonological
neighborhood size. Using the ELP database, the words are also equated on average naming
latency, naming accuracy, lexical decision time, and lexical decision accuracy (Balota
et al., 2007). The task contains 9 experimental blocks, each consisting of 30 color word
naming trials from one of our EST lists. The order of the words within each list is
randomized across presentation blocks. Within each trial, participants first view a
fixation cross for 1 second, which is replaced by a list item that remains on the screen
for 2 seconds. An experimenter codes the participant's response as correct (i.e.,
correct color identification), incorrect (i.e., did not name a color, named the wrong
color, or named the word), or as a noise trial (e.g., the participant coughs, etc.). The
items are centered horizontally/vertically on a 43.5 by 35cm screen and positioned at
eye-level approximately 110cm from the head. Items are presented in red, blue, or green
font, and item color is randomly assigned. Reaction times are measured using a
dual-plane accelerometer attached to the lower lip and digitized at 1kHz using a Grass
amplifier. Voice onset is determined by a sharp increase in the amplitude of the
accelerometer signal, which produces response time accuracy near 1ms.
6. Oxytocin/placebo administration
If the participants are assigned to the oxytocin treatment arm by randomization, they
will be initiated on oxytocin administration after the MRI visit 1 and MEG visit 1.
Following previous studies using intranasal oxytocin administration, subjects weighing
>40kg will receive a total of 24 IU of oxytocin delivered as 2- 6 IU puffs to each
nostril once daily. Subjects weighing <40kg will receive a total of 12 IU of oxytocin
delivered as 1- 6 IU puff to each nostril daily. Participants will receive 14 to 21 days
of daily oxytocin/placebo administration. After 14 days of oxytocin/placebo
administration, participants will be scheduled to have MRI visit 2 and MEG visit 2.
After those two visits are completed, participants will stop oxytocin/placebo
administration. Participants who are assigned to placebo treatment branch will receive
identical bottles and instructions for delivery of all the other ingredients of nasal
spray except oxytocin. The instruction and demonstration will be given to the parents or
legal guardian as the first administration of the nasal spray done at the clinic by
either child and adolescent psychiatrist or advanced practice registered nurse. The
daily administration will be done by dispatching either oxytocin or placebo nasal spray
to the parents of the participants. The oxytocin and placebo nasal spray will be
prepared by the University of Nebraska Medical Center research pharmacist who will be
un-blinded to each subject's treatment assignment. The randomization will be done by the
department of pharmacology by a computer-programmed randomization procedure.
The participants will have 2 weekly visits to the clinic. They will be assessed for
symptom level, nasal spray tolerance, and assessment of adverse effects. Participants
will be initiated on psychiatric treatment if it is indicated by change of their
psychiatric condition (such as worsening of psychiatric symptoms). In this case, they
will not participate in the study any more.
After 14 days -21 days of trial and the completion of 2nd scans of MRI/MEG and final
research assessment, the participants will terminate their participation in this study.
7. MRI visit 2
MRI visit 2 is identical for all participants to MRI visit 1 and will occur at least 14
days and no more than after 21 days after MRI visit 1. The final research assessment
session can occur the same day of MRI visit 2.
8. MEG visit 2
MEG visit 2 is identical for all participants to MEG visit 1 and will occur at least 14
days and no more than after 21 days after MEG visit 1. The final research assessment
session can occur the same day of MRI visit 2.
9. Final research assessment
Final research assessment session will occur at the outpatient clinic of the department of
psychiatry at University of Nebraska Medical Center after the MRI visit 2 and the MEG visit
2. During this session, the child and adolescent psychiatrist and the advanced practice
registered nurse who are the investigators of this study will administer follow-up assessment
of current symptom severity by ARI, CBCL, ICU, RPAQ, as well as compliance with the treatment
and side effects.
Participants will be discharged from the study following the final research assessment, or
their request to terminate study participation.
If during the course of the study it is discovered that the participant has a disorder or
condition that would disqualify him/her (e.g., unexpected side effect of oxytocin that will
necessitate cessation of the treatment or medical compromise that will make it impossible to
continue oxytocin treatment), but needs further evaluation, the participant will be
immediately referred for further clinical assessment and intervention to an appropriate
department of University of Nebraska Medical Center.
