Characterization and Sequential Pharmacotherapy of Severe Mood Dysregulation
Condition: Severe Mood Dysregulation
Intervention: lisdexamfetamine; Placebo; fluoxetine
Intervention description: Titration and open label treatment from baseline visit for 12 week study.; Initiated at end of study week 4 and continued to study week 12.; Initiated at end of study week 4 and continued to study week 12.
Intervention MeSH terms: Lisdexamfetamine Dimesylate; Fluoxetine
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
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)
Enrollment: 34.0
Sex: All
Minimum age: 7 Years
Maximum age: 17 Years
Healthy volunteers: No
Keywords: severe mood dysregulation; irritability; lisdexamfetamine; fluoxetine; newly recognized syndrome

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.
    

Eligibility 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. -