Attention Deficit and Disruptive Behavior Disorder, Attention Deficit Hyperactivity Disorder, Mental Disorder Diagnosed in Childhood, Mood Disorder
Conditions
Keywords
Irritability, Attention Deficit Hyperactivity Disorder, Explosive, Tantrums, Bipolar Mood Disorder, Mood Disorder, Childhood Mood Disorder, ADHD
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. ...
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.
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
Sponsors
National Institute of Mental Health (NIMH)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
7 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* 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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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. |
| 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. |
Countries
United States
Participant flow
Recruitment details
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.
Pre-assignment details
Enrolled participants (N=103) went through a medication wash-out period. n=22 participants withdrew assent before or during this period, and 12 participants met exclusion criteria. Then 69 participants began methylphenidate optimization; of those, 4 withdrew assent, 12 did not meet inclusion criteria. n=53 were randomized, and 49 analyzed.
Participants by arm
| Arm | Count |
|---|---|
| Add-on Citalopram Following Optimized Methylphenidate After optimized treatment with methylphenidate, those who meet threshold for chronic irritability are randomized to add-on citalopram (this arm) or placebo | 23 |
| 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 (this arm) | 26 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 4 |
Baseline characteristics
| Characteristic | Add-on Placebo Following Optimized Methylphenidate | Total | Add-on Citalopram Following Optimized Methylphenidate |
|---|---|---|---|
| Age, Continuous | 11.7 years STANDARD_DEVIATION 2.1 | 11.6 years STANDARD_DEVIATION 2.3 | 11.4 years STANDARD_DEVIATION 2.5 |
| Children's Depression Rating Scale (CDRS) collected at Admission | 32.0 units on a scale STANDARD_DEVIATION 7.6 | 30.1 units on a scale STANDARD_DEVIATION 6.9 | 29.7 units on a scale STANDARD_DEVIATION 5.9 |
| Children's Depression Rating Scale (CDRS) collected before Randomization | 34.6 units on a scale STANDARD_DEVIATION 8.6 | 32.1 units on a scale STANDARD_DEVIATION 7.7 | 29.4 units on a scale STANDARD_DEVIATION 5.7 |
| Children's Global Assessment of Severity (CGAS) collected at Admission | 41.7 units on a scale STANDARD_DEVIATION 2.2 | 42.8 units on a scale STANDARD_DEVIATION 4.5 | 44 units on a scale STANDARD_DEVIATION 6.1 |
| Children's Global Assessment of Severity (CGAS) collected before Randomization | 42.9 units on a scale STANDARD_DEVIATION 3.6 | 43.6 units on a scale STANDARD_DEVIATION 3.5 | 44.4 units on a scale STANDARD_DEVIATION 3.3 |
| Clinical Global Impression - Severity (CGI-S) collected at Admission | 4.6 units on a scale STANDARD_DEVIATION 0.5 | 4.5 units on a scale STANDARD_DEVIATION 0.5 | 4.4 units on a scale STANDARD_DEVIATION 0.6 |
| Clinical Global Impression - Severity (CGI-S) collected before Randomization | 4.3 units on a scale STANDARD_DEVIATION 0.6 | 4.2 units on a scale STANDARD_DEVIATION 0.6 | 4.0 units on a scale STANDARD_DEVIATION 0.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 6 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 22 Participants | 42 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Pediatric Anxiety Rating Scale (PARS) collected at Admission | 14.8 units on a scale STANDARD_DEVIATION 4.7 | 15.1 units on a scale STANDARD_DEVIATION 4.8 | 15.7 units on a scale STANDARD_DEVIATION 4.5 |
| Pediatric Anxiety Rating Scale (PARS) collected before Randomization | 15.8 units on a scale STANDARD_DEVIATION 5.2 | 14.8 units on a scale STANDARD_DEVIATION 5.4 | 13.3 units on a scale STANDARD_DEVIATION 5.9 |
| Psychiatric disorders information collected at Admission using the K-SADS-PL Any Anxiety disorder | 15 Participants | 28 Participants | 13 Participants |
| Psychiatric disorders information collected at Admission using the K-SADS-PL Any disorder | 26 Participants | 49 Participants | 23 Participants |
| Psychiatric disorders information collected at Admission using the K-SADS-PL Attention Deficit Hyperactivity Disorder | 24 Participants | 44 Participants | 20 Participants |
| Psychiatric disorders information collected at Admission using the K-SADS-PL Conduct Disorder | 1 Participants | 1 Participants | 0 Participants |
| Psychiatric disorders information collected at Admission using the K-SADS-PL Oppositional Defiant Disorder | 22 Participants | 39 Participants | 17 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 20 Participants | 39 Participants | 19 Participants |
| Region of Enrollment United States | 26 Participants | 49 Participants | 23 Participants |
| Sex: Female, Male Female | 6 Participants | 16 Participants | 10 Participants |
| Sex: Female, Male Male | 20 Participants | 33 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 23 | 0 / 26 |
| other Total, other adverse events | 23 / 23 | 24 / 26 |
| serious Total, serious adverse events | 0 / 23 | 0 / 26 |
Outcome results
Primary
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.
Population: 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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Add-on Citalopram 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). | 35 estimated percentage of participants |
| Add-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). | 6 estimated percentage of participants |
p-value: 0.00695% CI: [2, 68.16]Multilevel growth curve model
Secondary
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.
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Add-on Citalopram Following Optimized Methylphenidate | Anxiety Symptoms at 8th Week of Trial | 12.0 units on a scale | Standard Error 1.2 |
| Add-on Placebo Following Optimized Methylphenidate | Anxiety Symptoms at 8th Week of Trial | 13.4 units on a scale | Standard Error 1.2 |
p-value: 0.59895% CI: [-4.23, 2.19]Multilevel growth curve model
Secondary
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.
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Add-on Citalopram Following Optimized Methylphenidate | Depressive Symptoms at 8th Week of Trial | 28.6 units on a scale | Standard Error 1.8 |
| Add-on Placebo Following Optimized Methylphenidate | Depressive Symptoms at 8th Week of Trial | 30.1 units on a scale | Standard Error 1.8 |
p-value: 0.99395% CI: [-4.76, 4.8]Multilevel growth curve model
Secondary
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.
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Add-on Citalopram Following Optimized Methylphenidate | Functional Impairment at 8th Week of Trial | 52.6 units on a scale | Standard Error 2.3 |
| Add-on Placebo Following Optimized Methylphenidate | Functional Impairment at 8th Week of Trial | 47.2 units on a scale | Standard Error 2.1 |
p-value: 0.12495% CI: [-1.3, 10.74]Wilcoxon (Mann-Whitney)
Secondary
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.
Population: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Add-on Citalopram Following Optimized Methylphenidate | Irritability Severity at 8th Week of Trial. | 3.1 units on a scale | Standard Error 0.3 |
| Add-on Placebo Following Optimized Methylphenidate | Irritability Severity at 8th Week of Trial. | 3.9 units on a scale | Standard Error 0.3 |
p-value: 0.08595% CI: [-1.32, 0.09]Multilevel growth curve model