Oxytocin on Irritability/Emotional Dysregulation of Disruptive Behavior and Mood Disorders
Condition: Mood Disorder; Disruptive Behavior Disorders
MeSH terms: Mood Disorders; Mental Disorders; Problem Behavior; Attention Deficit and Disruptive Behavior Disorders
Study type: Interventional
Phase: Phase 2

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.
    

Detailed 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.
    

Intervention name(s): Oxytocin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): A growing body of data shows that intra-nasal administration of oxytocin has promise for treating a host of psychiatric disorders. Considerable data indicates that oxytocin reduces amygdala response to negative stimuli in patients with generalized anxiety disorder, borderline personality disorder, and post-traumatic stress disorder. Given that one of the potential underlying neurobiological mechanisms of irritability and emotional dysregulation in pediatric population with disruptive behavior and mood disorder is the hyperactivity of amygdala to negative emotional stimuli, and that oxytocin reduces this, it is critical to determine the extent to which this intervention improves irritability and emotional dysregulation in children and adolescents with disruptive behavior and mood disorders.; Inactive substance administered in volume equivalent to volume administered in active treatment arm.
Other intervention name(s): Pitocin; Saline
Intervention MeSH terms: Oxytocin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment