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

Study Overview
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Brief Summary
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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. ...

Detailed Description
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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.

Official Title
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A Controlled Trial of Citalopram Added to Methylphenidate in Youth With Severe Mood Dysregulation

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

Intervention / Treatment
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* Drug: Add-on citalopram following optimized methylphenidate
* Drug: Add-on placebo following optimized methylphenidate


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Add-on citalopram following optimized methylphenidate<br>After optimized treatment with methylphenidate, those who meet threshold for chronic irritability are randomized to add-on citalopram or placebo | Drug: Add-on citalopram following optimized methylphenidate<br>* After optimized treatment with methylphenidate, those who meet threshold for chronic irritability are randomized to add-on citalopram or placebo<br>|
| Placebo Comparator: Add-on placebo after optimized methylphenidate<br>After optimized treatment with methylphenidate, those who meet threshold for chronic irritability are randomized to add-on citalopram or placebo | Drug: Add-on placebo following optimized methylphenidate<br>* After optimized treatment with methylphenidate, those who meet threshold for chronic irritability are randomized to add-on citalopram or placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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). | 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. | Collected weekly during the 8-week trial. The 8th-week outcome is reported. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Irritability Severity at 8th Week of Trial. | 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). | Collected weekly during the 8th week trial. The 8th-week outcome is reported. | 
| Functional Impairment at 8th Week of Trial | 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. | Collected weekly during the 8th week trial. The 8th-week outcome is reported. | 
| Depressive Symptoms at 8th Week of Trial | 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. | Collected weekly during the 8th week trial. The 8th-week outcome is reported. | 
| Anxiety Symptoms at 8th Week of Trial | 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. | Collected weekly during the 8th week trial. The 8th-week outcome is reported. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Irritability, Attention Deficit Hyperactivity Disorder, Explosive, Tantrums, Bipolar Mood Disorder, Mood Disorder, Childhood Mood Disorder, ADHD