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

Phase 2

Completed

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

Interventions: Drug: Add-on placebo following optimized methylphenidate
Drug: Add-on citalopram following optimized methylphenidate

Registration Number: NCT00794040

Lead Sponsor: National Institute of Mental Health (NIMH)

Brief 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.

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Detailed Description: Objective: To test the efficacy of citalopram plus methylphenidate vs. placebo plus methylphenidate in decreasing irritability in youth with severe mood dysregulation.

Study population: Youth ages 7-17 with severe mood dysregulation (SMD). SMD is characterized by nonepisodic, impairing irritability (defined as increased reactivity to negative emotional stimuli at least 3 times/week and angry or sad mood, most days, most of the time, noticeable to others) and hyperarousal (three of: distractibility, intrusiveness, pressured speech, racing thoughts, agitation, insomnia), with onset before age 12. Many of these children receive the diagnosis of bipolar disorder (BD) in the community, although they do not meet DSM-IV criteria for BD because of the lack of distinct manic episodes.

Design: Medication withdrawal, followed by a 5-week dose stabilization phase of methylphenidate and an 8-week double-blind, placebo-controlled treatment trial of citalopram plus methylphenidate vs. placebo plus methylphenidate. There will also be optional open treatment at the end, so that all patients have the opportunity to have a total of up to 10 weeks of citalopram plus methylphenidate. The target dose of citalopram will be 20-40 mg/day.

Outcome measures: The primary outcome measures will be the Aberrant Behavior Checklist Irritability subscale and the CGI-I.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 103

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Add-on placebo after optimized methylphenidate	Add-on placebo following optimized methylphenidate	After optimized treatment with methylphenidate, those who meet threshold for chronic irritability are randomized to add-on citalopram or placebo
Add-on citalopram following optimized methylphenidate	Add-on citalopram following optimized methylphenidate	After optimized treatment with methylphenidate, those who meet threshold for chronic irritability are randomized to add-on citalopram or placebo

Primary Outcome Measures

Name	Time	Method
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).	Collected weekly during the 8-week trial. The 8th-week outcome is reported.	A measure of change of irritability severity taking the baseline before randomization as a reference. Scores range 1 to 8, in which 1=Completely recovered,... 5=Unchanged,... 8=Much worse. Percentage of participants who responded are based on an estimation and might not match exactly with discrete numbers of participants based on the denominator.

Secondary Outcome Measures

Name	Time	Method
Irritability Severity at 8th Week of Trial.	Collected weekly during the 8th week trial. The 8th-week outcome is reported.	Clinical Global Impression-Severity (CGI-S): A measure of severity of irritability scale (from 1=Normal, not at all ill to 7=Among the most extremely ill patients).
Depressive Symptoms at 8th Week of Trial	Collected weekly during the 8th week trial. The 8th-week outcome is reported.	Difference in depressive symptoms at 8th week of trial as measured with Children's Depression Rating Scale (CDRS) with scores ranging 17-113, where scores \>40 are considered over the clinical threshold, and scores \<28 are considered within the healthy range.
Anxiety Symptoms at 8th Week of Trial	Collected weekly during the 8th week trial. The 8th-week outcome is reported.	Difference in anxiety symptoms at 8th week of trial as measured with the Pediatric Anxiety Rating Scale (PARS) with scores ranging 0-25. Higher values represent a worse outcome.
Functional Impairment at 8th Week of Trial	Collected weekly during the 8th week trial. The 8th-week outcome is reported.	Difference in functional impairment at 8th week of trial as measured with Children's Global Impression Scale (CGAS) with scores ranging from 1=Most impaired to 100=Not impaired at all.