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.

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.

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. -

See Participant Flow descriptions.

Baseline through study week 12.

Adverse events were collected via structured ratings, including the Columbia Suicide Severity Rating Scale and the Side Effects Rating Scale.

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.