Characterization and Sequential Pharmacotherapy of Severe Mood Dysregulation
Condition: Severe Mood Dysregulation
Study type: Interventional
Phase: Phase 2

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.
    

Detailed description: 
      Background

      The increased frequency of diagnosed pediatric bipolar disorder has emerged as one of the
      greatest controversies in child and adolescent psychiatry. Beginning with reports that 20% of
      prepubertal of children with Attention-Deficit/Hyperactivity Disorder (ADHD) met criteria for
      juvenile mania, a view arose that bipolar children were more irritable than euphoric and more
      chronic than episodic, compared with the typical adult. Concurrently, there was a 4 to 6-fold
      increase in inpatient discharges and 40-fold increase in office-based visits for pediatric
      bipolar disorder, although many of these failed to meet formal Diagnostic and Statistical
      Manual (DSM) criteria. Concerns have been raised that any child with impulsive, volatile
      behavior is apt to be diagnosed as bipolar.

      Some attempted to inform valid symptomatic boundaries by proposing a differentiation of
      narrow versus broad pediatric bipolar phenotypes. The narrow phenotype was defined by strict
      DSM criteria for mania or hypomania, including discrete episodes of grandiosity and euphoria.
      In contrast, the broad phenotype, also referred to as severe mood dysregulation (SMD), was
      defined by chronic, non-episodic illness lacking hallmark symptoms of grandiosity and
      euphoria, but typified by severe irritability and hyperarousal. Work at the National
      Institute of Mental Health (NIMH) demonstrated that patterns of adolescent irritability are
      stable and distinct, with episodic irritability leading to mania and simple phobia, and
      chronic irritability leading to diagnosed depression and ADHD. On structured assessment,
      children with SMD were highly comorbid for major depression (20%), anxiety (64%),
      oppositional defiant disorder (83%), and ADHD (87%). Others also found increased rates of
      ADHD and anxiety. In addition, the broad and narrow phenotypes could be differentiated
      according to electroencephalography (EEG) measures. SMD youth have impaired face emotion
      recognition deficits correlated with dysfunctional family relationships and were less
      influenced by emotional distracters during tasks of attention. A recent study revealed
      patterns of amygdala hypoactivation similar to depression, further supporting links between
      chronic irritability and subsequent depressive episodes.

      In response to the perceived over-diagnosis of pediatric DSM bipolar disorder, acknowledgment
      that the "classic" adult bipolar phenotype does occur in prepubertal youth, and increased
      recognition that SMD is a distinct behavioral and/or biological syndrome, the DSM-5 Child
      Disorders Workgroup proposed a new diagnostic category named temper dysregulation disorder
      with dysphoria (TDD). Criteria for TDD were largely based on SMD, however, the requirement
      for hyperarousal was removed and minor changes were made in age of onset and exclusion
      criteria. Unlike SMD, TDD lacks any demonstrated scientific basis or history of prior
      research. As such, it seems prudent at this time to continue research on the
      better-established SMD category with an expectation that any information derived will have
      ready applicability as work on TDD progresses.

      One preliminary report suggests that SMD has a lifetime prevalence of 3.3% among those ages
      9-19. Recent longitudinal studies further indicate that children with SMD have increased
      rates of adult mood and anxiety disorders, substance abuse, suicidality, and poorer overall
      functioning. Given this significant morbidity, it is essential that the investigators
      increase understanding of children with chronic irritability and affective instability.
      Impulsive aggression in childhood has been identified as a significant public health concern
      that cuts across currently defined diagnostic categories. These youth demonstrate increased
      difficulties with school adjustment, peer interactions, cognitive deficits, problem-solving,
      and physical abuse - a developmental trajectory predictive of significant adult dysfunction.

      Current community practice emphasizes use of second-generation antipsychotic agents for
      children with impulsive aggression. While risperidone has proven effective for irritability
      associated with pervasive developmental disorders [25,26] and second-generation
      antipsychotics have been effective in pediatric bipolar disorder, these agents are associated
      with significant weight gain and other metabolic effects. Use of these medications is
      associated with decreased utilization of psychosocial interventions. Given the relationship
      of SMD with ADHD, anxiety, and unipolar depression, investigations of drugs from other
      classes with targeted effects and better side effect profiles, such as mood stabilizers,
      antidepressants, and stimulants, are certainly warranted. In fact, the DSM-5 Workgroup has
      specifically called for clinical trials stating it is "critically important" to assess
      whether stimulants and SSRIs should be first line treatments in SMD-affected youth. The only
      published medication trial in SMD youth is a double-blind placebo controlled study of lithium
      conducted by the intramural group at NIMH, which failed to demonstrate effects. Other
      informative investigations include small positive studies of methylphenidate versus placebo
      for ADHD plus oppositional defiant disorder and aggression, open-label stimulant followed by
      adjuvant divalproex vs. placebo for ADHD and aggression, and stimulant augmentation with
      double-blind risperidone versus placebo in ADHD with treatment resistant aggression. These
      studies are notably heterogeneous in design and choice of outcome measures. No clear
      predictors of response have been reported.

      Most existing SMD research has been conducted by a single intramural group at NIMH. It is
      imperative that investigations of SMD be expanded to other research groups to ensure that
      results generalize to broad clinical settings. Additional research is required to delineate
      clinical phenomenology that will inform subsequent efforts at diagnostic classification.
      Further work is also necessary to establish the appropriate foundation for future clinical
      interventions research. This should include pilot studies of various medication classes that
      might prove useful in management of SMD, as well as examination of various outcome measures
      that are likely to be useful in both medication and psychosocial intervention trials.

      Overview

      The study will include comprehensive phenotyping of 65 patients meeting criteria for SMD,
      including assessment of comorbid psychopathology, language disorder, neurocognition, and EEG.
      Potential endophenotypes and diagnostic boundaries will be assessed in relation to our large
      existing database of children and adolescents with internalizing and externalizing disorders,
      as well as non-clinical controls. Eligible participants with SMD will proceed to a pilot
      study of sequential pharmacotherapy with an initial 4-week titration of open label
      lisdexamfetamine (LDX) followed by 8 weeks adjunctive therapy with randomized fluoxetine or
      placebo. Statistical analyses will address diagnostic boundaries of SMD compared with other
      disorders and emphasize initial determinations of the potential efficacy and tolerability of
      stimulant and SSRI treatments for SMD. There will be an added emphasis on effect size
      estimates and determination of optimal outcome measures in anticipation of future large-scale
      studies.

      Project Visits and Procedures

      Following baseline visit (week 0), eligible participants will undergo undergo open-label
      stepwise titration with one week each of low, medium, and high dose LDX during study weeks 1,
      2, and 3. The study physician may modify titration due to emergent side effects following
      routine practice standards.

      At the end of study week 3, the clinician will determine "optimal" stimulant dose based on
      review of parent and teacher-completed Conners Global Index scales and all available adverse
      event and side effects data, using procedures similar to those used in other studies.
      Participants will remain on this optimal stimulant dose for the remainder of the study,
      unless side effects necessitate some downward dose adjustment.

      At study week 4, participants who fail to achieve CGI-I-SMD score < 4 will be randomized to
      double blind adjunctive treatment with either fluoxetine or placebo.

      A forced dose, stepwise, upward titration of one week each of 5, 10, and 20 mg
      fluoxetine/placebo will occur at during week 5, 6, and 7. The treating physician may modify
      this titration schedule in response to emergent side effect following routine practice
      standards. Participants will remain on their week 7 doses of fluoxetine/placebo until the
      study's final visit, unless side effects necessitate some downward titration.

      Side effects, adverse events, and medication compliance will be assessed at each visit. Major
      outcome assessments will occur at baseline (week 0) , end of week 4, and end of week 12.

      Arrangements will be made to transfer participants to standard clinical care following week
      12.
    

Intervention name(s): lisdexamfetamine; Placebo; fluoxetine
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 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.
Other intervention name(s): Vyvanse; Prozac
Intervention MeSH terms: Lisdexamfetamine Dimesylate; Fluoxetine
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
Keywords: severe mood dysregulation; irritability; lisdexamfetamine; fluoxetine; newly recognized syndrome