Characterization and Sequential Pharmacotherapy of Severe Mood Dysregulation

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by University of California, Los Angeles
Sponsor:
Collaborators:
Shire
Information provided by (Responsible Party):
James McGough, University of California, Los Angeles
ClinicalTrials.gov Identifier:
NCT01714310
First received: October 20, 2012
Last updated: April 9, 2014
Last verified: April 2014
  Purpose

This project will characterize children and adolescents with severe mood dysregulation (SMD) and conduct a pilot study of combination pharmacotherapy as a basis for future intervention trials.

Eligible participants assessed for SMD will have 4 weeks open titration with lisdexamfetamine (LDX) to optimal dose, followed by double-blind randomization to fluoxetine (N=25) or placebo (N=25) in combination with optimized LDX for an additional 8 weeks. Participants will be monitored for clinical response and adverse events.

Specific aims are:

#1: To define youth meeting SMD criteria in terms of psychiatric comorbidity, neurocognitive functioning, and a potential "bio-signature" derived from electroencephalography (EEG).

Specific hypotheses to be tested include: 1) that SMD participants will differ in comparison to non-SMD individuals in our pre-existing database on patterns of a) psychiatric comorbidity, b) symptoms, c) behavioral ratings, and d) neurocognitive functioning, and 2) that a distinct EEG bio-signature will be confirmed in individuals formally diagnosed with SMD.

#2: To conduct a preliminary study of sequential pharmacotherapy for SMD with a stimulant followed by randomized, placebo-controlled selective serotonin re-uptake inhibitor (SSRI) therapy to evaluate the feasibility of recruitment and enrollment and assess the suitability of the proposed combination treatment as a basis for future clinical investigations.

Specific hypotheses to be tested include: 1) that significant improvement in Clinical Global Impression - Improvement -SMD (CGI-I-SMD) scores and other secondary measures are evident after open-label LDX titration; 2) that participants randomized to fluoxetine will demonstrate additional significant improvement in CGI-I-SMD scores and other secondary measures in comparison to participants randomized to placebo; 3) that combination LDX and SSRI therapy is safe and well tolerated, and 4) that EEG profiles will normalize with treatment.


Condition Intervention Phase
Severe Mood Dysregulation
Drug: lisdexamfetamine
Drug: Placebo
Drug: fluoxetine
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Characterization and Sequential Pharmacotherapy of Severe Mood Dysregulation

Resource links provided by NLM:


Further study details as provided by University of California, Los Angeles:

Primary Outcome Measures:
  • Clinical Global Impression-Improvement-Severe Mood Dysregulation [ Time Frame: Change from baseline at 12 weeks. ] [ Designated as safety issue: No ]
    A categorical clinician rating of overall improvement from baseline, modified by the National Institute of Mental Health to assess specific domains pertinent to Severe Mood Dysregulation.


Secondary Outcome Measures:
  • Pediatric Anxiety Rating Scale (PARS) [ Time Frame: Change from baseline to weeks 4 -12. ] [ Designated as safety issue: No ]
    A dimensional rating of pediatric anxiety symptoms designed for NIMH trials

  • Children's Depression Rating Scale [ Time Frame: Change from baseline to weeks 4-12. ] [ Designated as safety issue: No ]
    A dimensional rating of depressive symptoms validated for children and adolescents.

  • ADHD-IV Rating Scale [ Time Frame: Change from baseline at week 4. ] [ Designated as safety issue: No ]
    A dimensional rating of ADHD symptoms.

  • ADHD IV Rating Scale [ Time Frame: Change from baseline at week 12. ] [ Designated as safety issue: No ]
    A dimensional measure of ADHD symptoms.

  • Columbia Suicide Severity Scales [ Time Frame: Change from baseline at weeks 4-12. ] [ Designated as safety issue: Yes ]
    A structured assessment of suicidal ideation and activity.

  • Barnes Akathisia Scale [ Time Frame: Change from baseline at weeks 4-12. ] [ Designated as safety issue: Yes ]
    A dimensional measure of abnormal movements and akathisia based on physical examination.

  • Children's Affective Lability Scale [ Time Frame: Change from baseline at weeks 4-12. ] [ Designated as safety issue: No ]
    A parent completed measure of emotional reactivity.

  • Physical Symptom Checklist [ Time Frame: Changes from baseline at weeks 1-12. ] [ Designated as safety issue: Yes ]
    A structured parent completed checklist of side effects commonly occurring with stimulant and SSRI therapy.

  • Revised Modified Overt Aggression Scale [ Time Frame: Change from baseline at weeks 4-12. ] [ Designated as safety issue: No ]
    A parent rated retrospective assessment of oppositional and aggressive behaviors

  • Screen for Children's Affective Reactivity [ Time Frame: Change from baseline at weeks 4-12. ] [ Designated as safety issue: No ]
    A parent completed measure of children's emotional reactivity.

  • Affective Reactivity Index [ Time Frame: Change from baseline at weeks 4 to 12. ] [ Designated as safety issue: No ]
    A dimensional measure of emotional reactivity.


Other Outcome Measures:
  • Electroencephalography (EEG) [ Time Frame: Changes from baseline at week 12. ] [ Designated as safety issue: No ]
    EEG profiles of cortical activity.


Estimated Enrollment: 50
Study Start Date: January 2013
Estimated Study Completion Date: July 2015
Estimated Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: lisdexamfetamine, fluoxetine
Open treatment with lisdexamfetamine with blinded treatment with fluoxetine beginning at visit 4.
Drug: lisdexamfetamine
Titration and open label treatment for 12 week study.
Other Name: Vyvanse
Drug: fluoxetine
Placebo Comparator: lisdexamfetamine, placebo
Open treatment with lisdexamfetamine with blinded treatment with placebo beginning at visit 4.
Drug: lisdexamfetamine
Titration and open label treatment for 12 week study.
Other Name: Vyvanse
Drug: Placebo

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   7 Years to 17 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male and female participants, ages 7-17 years.
  2. Abnormal mood (specifically anger, sadness, and/or irritability), present at least half of the day most days and of sufficient severity to be noticeable in the child's environment (e.g. parents, teachers, peers).
  3. Hyperarousal, as defined by at least three of the following symptoms: insomnia, agitation, distractibility, racing thoughts or flight of ideas, pressured speech, intrusiveness.
  4. Compared to his/her peers, the child exhibits markedly increased reactivity to negative emotional stimuli that is manifest verbally and/or behaviorally. For example, the child responds to frustration with extended temper tantrums (inappropriate for age and/or precipitating event), verbal rages, and/or aggression toward people or property. Such events occur, on average, at least three times a week.
  5. Criteria 2, 3, and 4 are currently present and have been present for at least 12 months without any symptom free periods exceeding two months.
  6. The onset of symptoms must be prior to age 12 years.
  7. The symptoms are severe in at least one setting (e.g. violent outbursts, extreme verbal abuse, assaultiveness at home, school, or with peers). In addition. There are at least mild symptoms (distractibility, intrusiveness) in a second setting.
  8. Score > 9 on either the Inattentive or Hyperactive/Impulsive subscales of the baseline ADHD-RS.
  9. Score < 12 on the irritability subscale of the Aberrant Behavior Checklist. -

Exclusion Criteria:

  1. As evidenced in the mania section of the Kiddie-Schedule for Affective Disorders and Schizophrenia, the individual exhibits any of these cardinal bipolar symptoms in distinct periods lasting more than 1 day, and therefore meets criteria for bipolar disorder not otherwise specified (NOS):

    i) Elevated or expansive mood. ii) Grandiosity or inflated self esteem. iii) Decreased need for sleep. iv) Increase in goal-directed activity (this can result in the excessive involvement in pleasurable activities that have a high potential for painful consequences).

  2. Meets criteria for schizophrenia, schizophreniform, schizoaffective illness, PTSD, or conduct disorder.
  3. T-score greater than/equal to 60 on baseline Social Responsiveness Scale
  4. Meets criteria for substance use disorder in the three months prior to baseline.
  5. Full scale intelligence < 70.
  6. The symptoms are due to the direct physiological effects of drug abuse, or to a general medical or neurological condition.
  7. Currently pregnant or lactating, or sexually active without using an acceptable method of contraception.
  8. Failed an adequate trials (defined as four weeks of consecutive treatment at the minimally effective dose) or severe ill effects while on therapeutic doses of SSRI therapy.
  9. Hypersensitivity or severe adverse reaction to methylphenidate.
  10. History of fainting after exercise, syncope, a young family with sudden cardiac death, or known structural heart defect.
  11. A serious history of adverse reactions (psychosis, severely increased activation compared to baseline) to methylphenidate or amphetamines.
  12. Any chronic medical condition that requires medication that is contraindicated with SSRI or stimulant therapy, or any serious chronic or unstable medical disorder.
  13. Medical contraindication to treatment with SSRI or stimulant therapy. -
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01714310

Contacts
Contact: Jennifer Cowen, Ph.D. 310-825-6170 jcowen@mednet.ucla.edu
Contact: James J McGough, M.D. 310-794-7841 jmcgough@mednet.ucla.edu

Locations
United States, California
UCLA Semel Institute Recruiting
Los Angeles, California, United States, 90095
Contact: Jennifer Cowen, Ph.D.    310-825-6170    jcowen@mednet.ucla.edu   
Contact: James J. McGough, M.D.    310-794-7841    jmcgough@mednet.ucla.edu   
Sub-Investigator: Sandra Loo, Ph.D.         
Sub-Investigator: Patricia Walshaw, Ph.D.         
Sponsors and Collaborators
University of California, Los Angeles
Shire
Investigators
Principal Investigator: James J McGough, M.D. University of California, Los Angeles
  More Information

No publications provided

Responsible Party: James McGough, Professor of Clinical Psychiatry, University of California, Los Angeles
ClinicalTrials.gov Identifier: NCT01714310     History of Changes
Other Study ID Numbers: U01MH093582, U01MH093582
Study First Received: October 20, 2012
Last Updated: April 9, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by University of California, Los Angeles:
severe mood dysregulation
irritability
lisdexamfetamine
fluoxetine
newly recognized syndrome

Additional relevant MeSH terms:
Fluoxetine
Dextroamphetamine
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Serotonin Agents
Physiological Effects of Drugs
Antidepressive Agents, Second-Generation
Antidepressive Agents
Psychotropic Drugs
Central Nervous System Agents
Therapeutic Uses
Dopamine Uptake Inhibitors
Dopamine Agents
Central Nervous System Stimulants

ClinicalTrials.gov processed this record on July 26, 2014