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CompletedNCT00794040Updated May 7, 2019Results posted

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

A Phase 2 interventional study of Add-on citalopram following optimized methylphenidate and Add-on placebo following optimized methylphenidate in Mood Disorder, Mental Disorder Diagnosed in Childhood and Attention Deficit and Disruptive Behavior Disorder, sponsored by National Institute of Mental Health (NIMH). Completed at 1 site in United States. Open to participants aged 7 Years to 17 Years. Per ClinicalTrials.gov, last updated 2019-05-07.

Sponsored by National Institute of Mental Health (NIMH) · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
103
Allocation
Randomized
Ages
7 Years to 17 Years
Sex
All
01

Study 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.

...

Read the 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.

02

Conditions studied

  • 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
03

In context

Hyperkinesis

729 studies on the registry are indexed under Hyperkinesis; 25 are open to participants now.

This study's enrollment of 103 is above the median of 80 across 583 interventional studies indexed under Hyperkinesis.

Browse Hyperkinesis studies →

Lead sponsor

National Institute of Mental Health (NIMH) is the lead sponsor of 359 studies on the registry; 46 are open to participants now.

Of its 25 completed or terminated interventional studies of FDA-regulated products, 24 (96%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
7 Years to 17 Years
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  1. Ages 7-17

    1. 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).
    2. Hyperarousal, as defined by at least three of the following symptoms: insomnia, agitation, distractibility, racing thoughts or flight of ideas, pressured speech, intrusiveness
    3. 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
    4. 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.
    5. The onset of symptoms must be prior to age 12 years.
    6. 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.
    7. Currently in treatment with a psychiatrist for the symptoms.

    8. 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

EXCLUSION CRITERIA:

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  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).
05

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomized
Intervention model
Parallel assignment
Masking
Quadruple (Participant, Care provider, Investigator, Outcomes assessor)
Enrollment
103 participants (actual)

Study arms

  • Active comparator
    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

    Drug: Add-on citalopram following optimized methylphenidate

  • Placebo comparator
    Add-on placebo after optimized methylphenidate

    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

  • DrugAdd-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

  • DrugAdd-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

06

What researchers measure

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.

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

Secondary outcomes

  1. 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).

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

  2. 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.

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

  3. 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.

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

  4. 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.

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

07

Results

Posted May 7, 2019
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)

Participant flow

Recruitment was conducted at the National Institute of Mental Health Division of Intramural Research Programs (NIMH DIRP) from November 2008 until January 2018. The inpatient part of the study took place at the Child Psychiatric Unit of the NIH Clinical Center.

Participant flow — Overall Study
MilestoneAdd-on Citalopram Following Optimized MethylphenidateAdd-on Placebo Following Optimized Methylphenidate
Started2528
Completed2223
Not completed35
Withdrew: Withdrawal by subject34
Withdrew: Physician decision01

Outcome measures

PrimaryPercentage 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.

Time frame:
Collected weekly during the 8-week trial. The 8th-week outcome is reported.
Reported as:
Number · estimated percentage of participants
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).
estimated percentage of participantsAdd-on Citalopram Following Optimized MethylphenidateAdd-on Placebo Following Optimized Methylphenidate
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).356
Statistical analysis
  • Add-on Citalopram Following Optimized Methylphenidate vs Add-on Placebo Following Optimized Methylphenidate · Multilevel growth curve model · p = 0.006 (priori threshold p\<0.05) · Odds ratio (or): 11.7 · 95% CI 2.00 to 68.16
SecondaryIrritability 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).

Time frame:
Collected weekly during the 8th week trial. The 8th-week outcome is reported.
Reported as:
Mean · units on a scale
Irritability Severity at 8th Week of Trial.
units on a scaleAdd-on Citalopram Following Optimized MethylphenidateAdd-on Placebo Following Optimized Methylphenidate
Irritability Severity at 8th Week of Trial.3.1 ± 0.33.9 ± 0.3
Statistical analysis
  • Add-on Citalopram Following Optimized Methylphenidate vs Add-on Placebo Following Optimized Methylphenidate · Multilevel growth curve model · p = 0.085 (priori threshold \<0.05) · Mean difference (final values): -0.62 · 95% CI -1.32 to 0.09
SecondaryFunctional 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.

Time frame:
Collected weekly during the 8th week trial. The 8th-week outcome is reported.
Reported as:
Mean · units on a scale
Functional Impairment at 8th Week of Trial
units on a scaleAdd-on Citalopram Following Optimized MethylphenidateAdd-on Placebo Following Optimized Methylphenidate
Functional Impairment at 8th Week of Trial52.6 ± 2.347.2 ± 2.1
Statistical analysis
  • Add-on Citalopram Following Optimized Methylphenidate vs Add-on Placebo Following Optimized Methylphenidate · Wilcoxon (Mann-Whitney) · p = 0.124 (priori threshold p\<0.05) · Mean difference (final values): 4.72 · 95% CI -1.30 to 10.74
SecondaryDepressive 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.

Time frame:
Collected weekly during the 8th week trial. The 8th-week outcome is reported.
Reported as:
Mean · units on a scale
Depressive Symptoms at 8th Week of Trial
units on a scaleAdd-on Citalopram Following Optimized MethylphenidateAdd-on Placebo Following Optimized Methylphenidate
Depressive Symptoms at 8th Week of Trial28.6 ± 1.830.1 ± 1.8
Statistical analysis
  • Add-on Citalopram Following Optimized Methylphenidate vs Add-on Placebo Following Optimized Methylphenidate · Multilevel growth curve model · p = 0.993 (priori threshold p\<0.05) · Mean difference (final values): 0.02 · 95% CI -4.76 to 4.80
SecondaryAnxiety 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.

Time frame:
Collected weekly during the 8th week trial. The 8th-week outcome is reported.
Reported as:
Mean · units on a scale
Anxiety Symptoms at 8th Week of Trial
units on a scaleAdd-on Citalopram Following Optimized MethylphenidateAdd-on Placebo Following Optimized Methylphenidate
Anxiety Symptoms at 8th Week of Trial12.0 ± 1.213.4 ± 1.2
Statistical analysis
  • Add-on Citalopram Following Optimized Methylphenidate vs Add-on Placebo Following Optimized Methylphenidate · Multilevel growth curve model · p = 0.598 (priori threshold p\<0.05) · Mean difference (final values): 1.02 · 95% CI -4.23 to 2.19

Adverse events

Collected over Adverse event information was collected weekly during the study, including the 8th weeks of the trial.. Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Add-on Citalopram Following Optimized Methylphenidate0/23 (0%)0/23 (0%)23/23 (100%)
Add-on Placebo Following Optimized Methylphenidate0/26 (0%)0/26 (0%)24/26 (92.3%)
Most frequent other events
Showing 10 of 47
Most frequent other events
EventAdd-on Citalopram Following Optimized MethylphenidateAdd-on Placebo Following Optimized Methylphenidate
Appetite changesGeneral disorders23/2321/26
InsomniaGeneral disorders17/2324/26
AngerPsychiatric disorders19/2322/26
AgressionPsychiatric disorders17/2312/26
IntrusivenessPsychiatric disorders17/2315/26
Restless/Inability to sit stillMusculoskeletal and connective tissue disorders16/2319/26
NervousnessPsychiatric disorders15/2313/26
Stomach painsGastrointestinal disorders13/2316/26
Weight changesGeneral disorders13/2313/26
Clingy/separation anxietyPsychiatric disorders13/238/26

Baseline characteristics

Whereas 53 participants were randomized, 49 participants were analyzed using intent-to-treat analysis. The first 4 participants recruited were excluded because a different version of the primary outcome measure (i.e., CGI) was collected in these participants and therefore was not comparable to the remaining participants.

Age, Continuous
Age, Continuous(years)Add-on Citalopram Following Optimized MethylphenidateAdd-on Placebo Following Optimized MethylphenidateTotal
Mean11.4 ± 2.511.7 ± 2.111.6 ± 2.3
Sex: Female, Male
Sex: Female, Male(Participants)Add-on Citalopram Following Optimized MethylphenidateAdd-on Placebo Following Optimized MethylphenidateTotal
Female10616
Male132033
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Add-on Citalopram Following Optimized MethylphenidateAdd-on Placebo Following Optimized MethylphenidateTotal
Hispanic or Latino336
Not Hispanic or Latino202242
Unknown or Not Reported011
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Add-on Citalopram Following Optimized MethylphenidateAdd-on Placebo Following Optimized MethylphenidateTotal
American Indian or Alaska Native000
Asian101
Native Hawaiian or Other Pacific Islander000
Black or African American033
White192039
More than one race325
Unknown or Not Reported011
Region of Enrollment
Region of Enrollment(Participants)Add-on Citalopram Following Optimized MethylphenidateAdd-on Placebo Following Optimized MethylphenidateTotal
United States232649
Clinical Global Impression - Severity (CGI-S) collected at Admission
Clinical Global Impression - Severity (CGI-S) collected at Admission(units on a scale)Add-on Citalopram Following Optimized MethylphenidateAdd-on Placebo Following Optimized MethylphenidateTotal
Mean4.4 ± 0.64.6 ± 0.54.5 ± 0.5
Children's Global Assessment of Severity (CGAS) collected at Admission
Children's Global Assessment of Severity (CGAS) collected at Admission(units on a scale)Add-on Citalopram Following Optimized MethylphenidateAdd-on Placebo Following Optimized MethylphenidateTotal
Mean44 ± 6.141.7 ± 2.242.8 ± 4.5
Children's Depression Rating Scale (CDRS) collected at Admission
Children's Depression Rating Scale (CDRS) collected at Admission(units on a scale)Add-on Citalopram Following Optimized MethylphenidateAdd-on Placebo Following Optimized MethylphenidateTotal
Mean29.7 ± 5.932.0 ± 7.630.1 ± 6.9

6 further baseline measures are reported on the registry.

08

Study locations

1 site
  • National Institutes of Health Clinical Center, 9000 Rockville Pike
    Bethesda, Maryland 20892, United States
09

References and documents

Publications

  • 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. PubMed 15923042 ↗
  • 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. PubMed 16945343 ↗
  • 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. PubMed 16437535 ↗
  • 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. PubMed 31128268 ↗

Study documents

  • Study protocol · Jan 3, 2019
  • Statistical analysis plan · Jun 25, 2018

Documents are hosted by the registry — open the source record to download them.

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on May 7, 2019, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT00794040
Lead sponsor
National Institute of Mental Health (NIMH)
Responsible party
Sponsor
First posted
Nov 19, 2008
Start date
Nov 17, 2008
Primary completion
Feb 1, 2018
Completion
Feb 1, 2018
Results posted
May 7, 2019
Last update
May 7, 2019

Study contacts

Argyris Stringaris, M.D.
principal investigator · National Institute of Mental Health (NIMH)
View the source record on ClinicalTrials.gov ↗

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