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

 ...
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.
-  INCLUSION CRITERIA:

 1. Ages 7-17

 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 by
 people 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. Currently in treatment with a psychiatrist for the symptoms.

 9. 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:

 1. 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)

 2. Meets criteria for schizophrenia, schizophreniform disorder, schizoaffective
 illness, more than mild PDD, or PTSD.

 3. Meets criteria for substance use disorder in the three months prior to
 randomization.

 4. IQ less than 70

 5. The symptoms are due to the direct physiological effects of a drug of abuse, or
 to a general medical or neurological condition.

 6. Currently pregnant or lactating, or sexually active without using a barrier
 method of contraception.

 7. 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).

 8. Hypersensitivity or severe adverse reaction to methylphenidate

 9. A history of serious adverse reactions (psychosis, severely increased activation
 compared to baseline) to methylphenidate or amphetamines.

 10. Any chronic medical condition that requires medications that are contraindicated
 with SSRIs or methylphenidate, or any serious chronic or unstable medical
 disorder.

 11. Medical contraindications to treatment with SSRI or stimulant (e.g. liver,
 seizure, renal, platelet disorder).