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

NCT00794040 | Completed Phase 2 Results

• 2 other identifiers: 09003409-M-0034
• Study Type: interventional
• Target: 103
• Locations: 1 country
• Sites: 1

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. ...

Conditions

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

Keywords

Irritability; Attention Deficit Hyperactivity Disorder; Explosive; Tantrums; Bipolar Mood Disorder; Mood Disorder; Childhood Mood Disorder; ADHD

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (4)

• Irritability Severity at 8th Week of Trial.

  Collected weekly during the 8th week trial. The 8th-week outcome is reported.

• Functional Impairment at 8th Week of Trial

  Collected weekly during the 8th week trial. The 8th-week outcome is reported.

• Depressive Symptoms at 8th Week of Trial

  Collected weekly during the 8th week trial. The 8th-week outcome is reported.

• Anxiety Symptoms at 8th Week of Trial

  Collected weekly during the 8th week trial. The 8th-week outcome is reported.

Study Arms (2)

Add-on citalopram following optimized methylphenidate

ACTIVE COMPARATOR

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

Add-on placebo after optimized methylphenidate

PLACEBO COMPARATOR

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

Interventions

Add-on citalopram following optimized methylphenidate DRUG

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 placebo following optimized methylphenidate DRUG

After optimized treatment with methylphenidate, those who meet threshold for chronic irritability are randomized to add-on citalopram or placebo

Add-on placebo after optimized methylphenidate

Eligibility Criteria

• Age: 7 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

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• 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.

Sponsors & Collaborators

• National Institute of Mental Health (NIMH): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Amsterdam JD, Shults J. Comparison of fluoxetine, olanzapine, and combined fluoxetine plus olanzapine initial therapy of bipolar type I and type II major depression--lack of manic induction. J Affect Disord. 2005 Jul;87(1):121-30. doi: 10.1016/j.jad.2005.02.018.

  PMID: 15923042 BACKGROUND

• Baumer FM, Howe M, Gallelli K, Simeonova DI, Hallmayer J, Chang KD. A pilot study of antidepressant-induced mania in pediatric bipolar disorder: Characteristics, risk factors, and the serotonin transporter gene. Biol Psychiatry. 2006 Nov 1;60(9):1005-12. doi: 10.1016/j.biopsych.2006.06.010. Epub 2006 Aug 30.

  PMID: 16945343 BACKGROUND

• Binks CA, Fenton M, McCarthy L, Lee T, Adams CE, Duggan C. Pharmacological interventions for people with borderline personality disorder. Cochrane Database Syst Rev. 2006 Jan 25;(1):CD005653. doi: 10.1002/14651858.CD005653.

  PMID: 16437535 BACKGROUND

• Towbin K, Vidal-Ribas P, Brotman MA, Pickles A, Miller KV, Kaiser A, Vitale AD, Engel C, Overman GP, Davis M, Lee B, McNeil C, Wheeler W, Yokum CH, Haring CT, Roule A, Wambach CG, Sharif-Askary B, Pine DS, Leibenluft E, Stringaris A. A Double-Blind Randomized Placebo-Controlled Trial of Citalopram Adjunctive to Stimulant Medication in Youth With Chronic Severe Irritability. J Am Acad Child Adolesc Psychiatry. 2020 Mar;59(3):350-361. doi: 10.1016/j.jaac.2019.05.015. Epub 2019 May 23.

  PMID: 31128268 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Mood Disorders; Attention Deficit Disorder with Hyperactivity; Attention Deficit and Disruptive Behavior Disorders; Bipolar Disorder

Condition Hierarchy (Ancestors)

Mental Disorders; Neurodevelopmental Disorders; Bipolar and Related Disorders

Limitations and Caveats

The sample size was smaller than initially planned. Our primary measure of irritability Aberrant Behavior Checklist - Irritability subscale, did not prove suitable for the current study due to its design (i.e., different environments and informants)

Results Point of Contact

• Title: Dr Argyris Stringaris
• Organization: Mood, Brain and Development Unit, Emotion and Development Branch, National Institute of Mental Health, National Institutes of Health

argyris.stringaris@nih.gov

(301) 443-8019

Study Officials

• Argyris Stringaris, M.D.

  National Institute of Mental Health (NIMH)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 18, 2008
• First Posted: November 19, 2008
• Study Start: November 17, 2008
• Primary Completion: February 1, 2018
• Study Completion: February 1, 2018
• Last Updated: May 7, 2019
• Results First Posted: May 7, 2019

Record last verified: 2018-02-01

Locations

US (1)