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Characterization and Sequential Pharmacotherapy of Severe Mood Dysregulation

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ClinicalTrials.gov Identifier: NCT01714310
Recruitment Status : Completed
First Posted : October 25, 2012
Results First Posted : February 26, 2018
Last Update Posted : February 26, 2018
Sponsor:
Collaborators:
National Institute of Mental Health (NIMH)
Shire
Information provided by (Responsible Party):
James McGough, University of California, Los Angeles

Brief Summary:

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 or disease Intervention/treatment Phase
Severe Mood Dysregulation Drug: lisdexamfetamine Drug: Placebo Drug: fluoxetine Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 34 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Initial arm for open-label titration of lisdexamfetamine followed by randomization of participants who retain eligibility to double blind adjunctive fluoxetine or placebo.
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Characterization and Sequential Pharmacotherapy of Severe Mood Dysregulation
Study Start Date : January 2013
Actual Primary Completion Date : June 2016
Actual Study Completion Date : June 2016

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Adjunctive fluoxetine
Participants previously titrated with open-label lisdexamfetamine randomized to adjunctive fluoxetine at end of study week 4.
Drug: lisdexamfetamine
Titration and open label treatment from baseline visit for 12 week study.
Other Name: Vyvanse

Drug: fluoxetine
Initiated at end of study week 4 and continued to study week 12.
Other Name: Prozac

Placebo Comparator: Adjunctive placebo
Participants previously titrated with open-label lisdexamfetamine randomized to adjunctive placebo at end of study week 4.
Drug: lisdexamfetamine
Titration and open label treatment from baseline visit for 12 week study.
Other Name: Vyvanse

Drug: Placebo
Initiated at end of study week 4 and continued to study week 12.

Open Lisdexamfetamine Titration
All participants initially titrated with open-label lisdexamfetamine from baseline to end of study week 4.
Drug: lisdexamfetamine
Titration and open label treatment from baseline visit for 12 week study.
Other Name: Vyvanse




Primary Outcome Measures :
  1. Clinical Global Impression-Severity-Severe Mood Dysregulation [ Time Frame: Baseline through week 12. ]
    A dimensional clinician rating of overall SMD related impairment, modified by the National Institute of Mental Health to assess specific domains pertinent to Severe Mood Dysregulation. Minimum score = 1. Maximum score = 7. Higher scores means greater impairment.


Secondary Outcome Measures :
  1. ADHD-IV Rating Scale [ Time Frame: Baseline through week 12. ]
    A dimensional rating of ADHD symptoms, with scores ranging from 0 - 54, and higher scores indicating greater symptom severity.

  2. Conners Parent Global Index [ Time Frame: Baseline through week 3. ]
    Parent completed dimensional measure of ADHD symptoms, with score range from 0 - 30 and higher scores indicating more severe symptoms.

  3. Conners Global Index Emotional Lability Subscale - Parent Report [ Time Frame: Baseline to week 3. ]
    A sub scale of the Conners Global Index, with scores ranging from 0 - 12, with higher scores indicating more impairment.

  4. Conners Global Index Restless-Impulsive Subscale Parent Report [ Time Frame: Baseline through week 3. ]
    A dimensional parent report measure of restless-impulsive symptoms, with scores ranging from 0 to 21, and higher scores indicating greater impairment.

  5. Conners Teacher Global Index [ Time Frame: Baseline through week 3. ]
    Teacher completed dimensional measure of ADHD symptoms, with scores ranging from 0 - 30, and higher scores indicating more severe impairment.

  6. Affective Reactivity Index - Parent Report [ Time Frame: Baseline through week 12. ]
    A parent completed dimensional measure of emotional reactivity, with scores ranging from 0-12, and higher scores indicating greater severity.

  7. Revised Modified Overt Aggression Scale - Total Score [ Time Frame: Baseline through week 12. ]
    A parent rated retrospective dimensional assessment of oppositional and aggressive behaviors, with scores ranging from 0-40, and higher scores indicating greater severity.

  8. Clinical Global Impression - Improvement [ Time Frame: Percentage improved at week 4 for Open Lisdexamfetamine group and at week 12 for fluoxetine and placebo groups. ]
    Percentage improved by treatment group

  9. Height [ Time Frame: Baseline through week 12. ]
    A dimensional measure assessed in cms.

  10. Weight [ Time Frame: Baseline through week 12. ]
    Weight in kg.

  11. Pulse [ Time Frame: Baseline through week 12. ]
    Heart rate in beats per minute.

  12. Systolic Blood Pressure [ Time Frame: Baseline through week 12. ]
    Systolic Blood Pressure measured in mmHG

  13. Diastolic Blood Pressure [ Time Frame: Baseline through week 12. ]
    Diastolic Blood pressure measured in mmHG.


Other Outcome Measures:
  1. Pediatric Anxiety Rating Scale [ Time Frame: Baseline through week 12. ]
    Clinician completed dimensional assessment of anxiety symptoms.

  2. Children's Depression Rating Scale [ Time Frame: Baseline through week 12. ]
    Clinician completed dimensional rating of depressive symptoms.

  3. Affective Reactivity Index Child Report [ Time Frame: Baseline through week 12. ]
    Dimensional self-report of irritability, with total score 1-12, and higher scores indicating greater severity.



Information from the National Library of Medicine

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Ages Eligible for Study:   7 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
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. -

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01714310


Locations
United States, California
UCLA Semel Institute
Los Angeles, California, United States, 90095
Sponsors and Collaborators
University of California, Los Angeles
National Institute of Mental Health (NIMH)
Shire
Investigators
Principal Investigator: James J McGough, M.D. University of California, Los Angeles

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 ( U.S. NIH Grant/Contract )
U01MH093582 ( U.S. NIH Grant/Contract )
First Posted: October 25, 2012    Key Record Dates
Results First Posted: February 26, 2018
Last Update Posted: February 26, 2018
Last Verified: January 2018

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

Additional relevant MeSH terms:
Fluoxetine
Lisdexamfetamine Dimesylate
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Serotonin Agents
Physiological Effects of Drugs
Antidepressive Agents, Second-Generation
Antidepressive Agents
Psychotropic Drugs
Cytochrome P-450 CYP2D6 Inhibitors
Cytochrome P-450 Enzyme Inhibitors
Enzyme Inhibitors
Central Nervous System Stimulants
Dopamine Uptake Inhibitors
Dopamine Agents