Phase 2 N=53 Randomized Quadruple-blind Treatment

A Controlled Trial of Serotonin Reuptake Inhibitors Added to Stimulant Medication in Youth With Severe Mood Dysregulation

Mood Disorder · Mental Disorder Diagnosed in Childhood · Attention Deficit and Disruptive Behavior Disorder · Attention Deficit Hyperactivity Disorder

Bottom Line

View on ClinicalTrials.gov: NCT00794040 ↗

Enrolled (actual)

Serious AEs

0.0%

Results posted

May 2019

Primary outcome: Primary: Percentage of Participants That "Much Improved" (Score of 2) in, or "Completely Recovered" (Score of 1) From Their Irritability Severity, as Measured With the Clinical Global Impression-Improvement (CGI-I). — 35; 6 estimated percentage of participants — p=0.006

Study Design & Population

Study type: Interventional
Phase: Phase 2
Interventions: Add-on citalopram following optimized methylphenidate (Drug); Add-on placebo following optimized methylphenidate (Drug)
Age: Pediatric · 7+ yrs
Sex: All
Sponsor: National Institute of Mental Health (NIMH)
Primary completion: Feb 2018

Outcome Measures

Outcome	Result	p-value
PRIMARY Percentage of Participants That "Much Improved" (Score of 2) in, or "Completely Recovered" (Score of 1) From Their Irritability Severity, as Measured With the Clinical Global Impression-Improvement (CGI-I).	35; 6	0.006 sig
SECONDARY Irritability Severity at 8th Week of Trial.	3.1; 3.9	0.085
SECONDARY Functional Impairment at 8th Week of Trial	52.6; 47.2	0.124
SECONDARY Depressive Symptoms at 8th Week of Trial	28.6; 30.1	0.993
SECONDARY Anxiety Symptoms at 8th Week of Trial	12.0; 13.4	0.598

Summary

Severe mood dysregulation (SMD) is a very common syndrome in children. Its symptoms include very severe irritability, including persistent anger and frequent outbursts, as well as distractibility, hyperactivity, and other symptoms of attention deficit hyperactivity disorder (ADHD). Many children with SMD receive the diagnosis of bipolar disorder (BD) in the community, although they do not have clear manic episodes (with symptoms such as extreme happiness and decreased need for sleep). Because SMD has not been studied in depth, we do not know which medications are most helpful to those with SMD. This study will evaluate the effectiveness of the stimulant medication methylphenidate (MPH, more commonly known as Ritalin ) when combined (or not combined) with the antidepressant citalopram (Celexa ) in treating symptoms of SMD in children and adolescents. This study will provide information about how to treat SMD in youth. This study will include approximately 80 patients between 7 and 17 years of age with SMD. The patient s symptoms must have started before age 12. The study will consist of four phases carried out over 4 to 5 months. During Phase 1, the patient will undergo blood and urine tests, and will gradually taper off his or her medication. The duration of this phase depends on the patient s medication before starting the study. In Phase 2, the patient remains off all medication for 1 week. In Phase 3, the patient will be treated with MPH for 2 weeks, and then will be randomly assigned to receive either MPH plus citalopram or MPH plus a placebo for a further 8 weeks. In Phase 4, the researchers will evaluate the effectiveness of the medications taken, and begin an open treatment phase using medications that they deem appropriate for that patient (this may include MPH with citalopram and/or other medication combinations). Most patients will be admitted to the Pediatric Behavioral Health Unit at the National Institutes of Health Clinical Center during the medication withdrawal part of the study (Phases 1 and 2). From Phase 3 on, a patient may participate as an inpatient, outpatient, or in day treatment, depending on what is in his or her best interests. ...

Eligibility Criteria

INCLUSION CRITERIA:
Ages 7-17
Abnormal mood (specifically, anger, sadness, and/or irritability), present at least half of the day most days, and of sufficient severity to be noticeable by people 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.
Currently in treatment with a psychiatrist for the symptoms.
The child is failing his/her treatment. To meet this criterion:

i.The child s current CGAS score must be less than or equal to 60.

ii.The child s psychiatrist/treater must agree that the child s response to his/her current treatment is no more than minimal. According to this criterion, it would be clinically appropriate to change the child s current treatment.

iii.On the basis of record review and interviews with child and parent, the research team agrees that the child s response to his/her current treatment is no more than minimal.

iv.The child has a score of greater than 12 on the irritability subscale of the Aberrant Behavior Checklist.

EXCLUSION CRITERIA

As assessed in the mania section of the K-SADS-PL, 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:

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 disorder, schizoaffective illness, more than mild PDD, or PTSD.
Meets criteria for substance use disorder in the three months prior to randomization.
IQ less than 70
The symptoms are due to the direct physiological effects of a drug of abuse, or to a general medical or neurological condition.
Currently pregnant or lactating, or sexually active without using a barrier method of contraception.
Failed an adequate trial (defined as four weeks of consecutive treatment at the minimally effective) or severe ill effects while on citalopram (at least 20 mg) or escitalopram (at least 10 mg).
Hypersensitivity or severe adverse reaction to methylphenidate
A history of serious adverse reactions (psychosis, severely increased activation compared to baseline) to methylphenidate or amphetamines.
Any chronic medical condition that requires medications that are contraindicated with SSRIs or methylphenidate, or any serious chronic or unstable medical disorder.
Medical contraindications to treatment with SSRI or stimulant (e.g. liver, seizure, renal, platelet disorder).

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Data sourced from ClinicalTrials.gov (NCT00794040). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.