Characterization and Sequential Pharmacotherapy of Severe Mood Dysregulation

NCT01714310 | Completed Phase 2 Results DMC

• 1 other identifier: U01MH093582
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

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.

Conditions

Severe Mood Dysregulation

Keywords

severe mood dysregulation; irritability; lisdexamfetamine; fluoxetine; newly recognized syndrome

Outcome Measures

Primary Outcomes (1)

• Clinical Global Impression-Severity-Severe Mood Dysregulation

  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.

  Baseline through week 12.

Secondary Outcomes (13)

• ADHD-IV Rating Scale

  Baseline through week 12.

• Conners Parent Global Index

  Baseline through week 3.

• Conners Global Index Emotional Lability Subscale - Parent Report

  Baseline to week 3.

• Conners Global Index Restless-Impulsive Subscale Parent Report

  Baseline through week 3.

• Conners Teacher Global Index

  Baseline through week 3.

Other Outcomes (3)

• Pediatric Anxiety Rating Scale

  Baseline through week 12.

• Children's Depression Rating Scale

  Baseline through week 12.

• Affective Reactivity Index Child Report

  Baseline through week 12.

Study Arms (3)

Adjunctive fluoxetine

EXPERIMENTAL

Participants previously titrated with open-label lisdexamfetamine randomized to adjunctive fluoxetine at end of study week 4.

Drug: lisdexamfetamine; Drug: fluoxetine

Adjunctive placebo

PLACEBO COMPARATOR

Participants previously titrated with open-label lisdexamfetamine randomized to adjunctive placebo at end of study week 4.

Drug: lisdexamfetamine; Drug: Placebo

Open Lisdexamfetamine Titration

OTHER

All participants initially titrated with open-label lisdexamfetamine from baseline to end of study week 4.

Drug: lisdexamfetamine

Interventions

lisdexamfetamine DRUG

Titration and open label treatment from baseline visit for 12 week study.

Also known as: Vyvanse

Adjunctive fluoxetine; Adjunctive placebo; Open Lisdexamfetamine Titration

Placebo DRUG

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

Adjunctive placebo

fluoxetine DRUG

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

Also known as: Prozac

Adjunctive fluoxetine

Eligibility Criteria

• Age: 7 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Male and female participants, ages 7-17 years.
• 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).
• Hyperarousal, as defined by at least three of the following symptoms: insomnia, agitation, distractibility, racing thoughts or flight of ideas, pressured speech, intrusiveness.
• 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.
• 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.
• The onset of symptoms must be prior to age 12 years.
• 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.
• Score \> 9 on either the Inattentive or Hyperactive/Impulsive subscales of the baseline ADHD-RS.
• Score \< 12 on the irritability subscale of the Aberrant Behavior Checklist. -

You may not qualify if:

• 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).
• Meets criteria for schizophrenia, schizophreniform, schizoaffective illness, PTSD, or conduct disorder.
• T-score greater than/equal to 60 on baseline Social Responsiveness Scale
• Meets criteria for substance use disorder in the three months prior to baseline.
• Full scale intelligence \< 70.
• The symptoms are due to the direct physiological effects of drug abuse, or to a general medical or neurological condition.
• Currently pregnant or lactating, or sexually active without using an acceptable method of contraception.
• 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.
• Hypersensitivity or severe adverse reaction to methylphenidate.
• History of fainting after exercise, syncope, a young family with sudden cardiac death, or known structural heart defect.
• A serious history of adverse reactions (psychosis, severely increased activation compared to baseline) to methylphenidate or amphetamines.
• Any chronic medical condition that requires medication that is contraindicated with SSRI or stimulant therapy, or any serious chronic or unstable medical disorder.
• Medical contraindication to treatment with SSRI or stimulant therapy. -

Sponsors & Collaborators

• University of California, Los Angeles: lead
• National Institute of Mental Health (NIMH): collaborator
• Shire: collaborator

Study Sites (1)

UCLA Semel Institute

Los Angeles, California, 90095, United States

Location

MeSH Terms

Interventions

Lisdexamfetamine Dimesylate; Fluoxetine

Intervention Hierarchy (Ancestors)

Dextroamphetamine; Amphetamine; Amphetamines; Phenethylamines; Ethylamines; Amines; Organic Chemicals; Propylamines

Limitations and Caveats

Study was designed as an initial feasibility and proof of concept trial. Initial power analysis suggested need to randomize N=50 participants. Recruitment was much more difficult than expected, leading to small sample size.

Results Point of Contact

• Title: James J. McGough, M.D.
• Organization: University of California, Los Angeles

jmcgough@mednet.ucla.edu

310-794-7841

Study Officials

• James J McGough, M.D.

  University of California, Los Angeles

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Clinical Psychiatry

Model Details: Initial arm for open-label titration of lisdexamfetamine followed by randomization of participants who retain eligibility to double blind adjunctive fluoxetine or placebo.

Study Record Dates

• First Submitted: October 20, 2012
• First Posted: October 25, 2012
• Study Start: January 1, 2013
• Primary Completion: June 1, 2016
• Study Completion: June 1, 2016
• Last Updated: February 26, 2018
• Results First Posted: February 26, 2018

Record last verified: 2018-01

Locations

US (1)