Trial Outcomes & Findings for A Controlled Trial of Serotonin Reuptake Inhibitors Added to Stimulant Medication in Youth With Severe Mood Dysregulation (NCT NCT00794040)

Last Updated: 2019-05-07

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

103 participants

Primary outcome timeframe

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

Results posted on

2019-05-07

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.

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.

Participant milestones

Participant milestones
Measure	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	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)
Overall Study STARTED	25	28
Overall Study COMPLETED	22	23
Overall Study NOT COMPLETED	3	5

Reasons for withdrawal

Reasons for withdrawal
Measure	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	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)
Overall Study Withdrawal by Subject	3	4
Overall Study Physician Decision	0	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Add-on Citalopram Following Optimized Methylphenidate n=23 Participants After optimized treatment with methylphenidate, those who meet threshold for chronic irritability are randomized to add-on citalopram (this arm) or placebo	Add-on Placebo Following Optimized Methylphenidate n=26 Participants After optimized treatment with methylphenidate, those who meet threshold for chronic irritability are randomized to add-on citalopram or placebo (this arm)	Total n=49 Participants Total of all reporting groups
Age, Continuous	11.4 years STANDARD_DEVIATION 2.5 • n=99 Participants	11.7 years STANDARD_DEVIATION 2.1 • n=107 Participants	11.6 years STANDARD_DEVIATION 2.3 • n=206 Participants
Sex: Female, Male Female	10 Participants n=99 Participants	6 Participants n=107 Participants	16 Participants n=206 Participants
Sex: Female, Male Male	13 Participants n=99 Participants	20 Participants n=107 Participants	33 Participants n=206 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=99 Participants	3 Participants n=107 Participants	6 Participants n=206 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	20 Participants n=99 Participants	22 Participants n=107 Participants	42 Participants n=206 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants	1 Participants n=107 Participants	1 Participants n=206 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Asian	1 Participants n=99 Participants	0 Participants n=107 Participants	1 Participants n=206 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=99 Participants	0 Participants n=107 Participants	0 Participants n=206 Participants
Race (NIH/OMB) Black or African American	0 Participants n=99 Participants	3 Participants n=107 Participants	3 Participants n=206 Participants
Race (NIH/OMB) White	19 Participants n=99 Participants	20 Participants n=107 Participants	39 Participants n=206 Participants
Race (NIH/OMB) More than one race	3 Participants n=99 Participants	2 Participants n=107 Participants	5 Participants n=206 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants	1 Participants n=107 Participants	1 Participants n=206 Participants
Region of Enrollment United States	23 Participants n=99 Participants	26 Participants n=107 Participants	49 Participants n=206 Participants
Clinical Global Impression - Severity (CGI-S) collected at Admission	4.4 units on a scale STANDARD_DEVIATION 0.6 • n=99 Participants	4.6 units on a scale STANDARD_DEVIATION 0.5 • n=107 Participants	4.5 units on a scale STANDARD_DEVIATION 0.5 • n=206 Participants
Children's Global Assessment of Severity (CGAS) collected at Admission	44 units on a scale STANDARD_DEVIATION 6.1 • n=99 Participants	41.7 units on a scale STANDARD_DEVIATION 2.2 • n=107 Participants	42.8 units on a scale STANDARD_DEVIATION 4.5 • n=206 Participants
Children's Depression Rating Scale (CDRS) collected at Admission	29.7 units on a scale STANDARD_DEVIATION 5.9 • n=99 Participants	32.0 units on a scale STANDARD_DEVIATION 7.6 • n=107 Participants	30.1 units on a scale STANDARD_DEVIATION 6.9 • n=206 Participants
Pediatric Anxiety Rating Scale (PARS) collected at Admission	15.7 units on a scale STANDARD_DEVIATION 4.5 • n=99 Participants	14.8 units on a scale STANDARD_DEVIATION 4.7 • n=107 Participants	15.1 units on a scale STANDARD_DEVIATION 4.8 • n=206 Participants
Psychiatric disorders information collected at Admission using the K-SADS-PL Any disorder	23 Participants n=99 Participants	26 Participants n=107 Participants	49 Participants n=206 Participants
Psychiatric disorders information collected at Admission using the K-SADS-PL Attention Deficit Hyperactivity Disorder	20 Participants n=99 Participants	24 Participants n=107 Participants	44 Participants n=206 Participants
Psychiatric disorders information collected at Admission using the K-SADS-PL Oppositional Defiant Disorder	17 Participants n=99 Participants	22 Participants n=107 Participants	39 Participants n=206 Participants
Psychiatric disorders information collected at Admission using the K-SADS-PL Conduct Disorder	0 Participants n=99 Participants	1 Participants n=107 Participants	1 Participants n=206 Participants
Psychiatric disorders information collected at Admission using the K-SADS-PL Any Anxiety disorder	13 Participants n=99 Participants	15 Participants n=107 Participants	28 Participants n=206 Participants
Clinical Global Impression - Severity (CGI-S) collected before Randomization	4.0 units on a scale STANDARD_DEVIATION 0.5 • n=99 Participants	4.3 units on a scale STANDARD_DEVIATION 0.6 • n=107 Participants	4.2 units on a scale STANDARD_DEVIATION 0.6 • n=206 Participants
Children's Global Assessment of Severity (CGAS) collected before Randomization	44.4 units on a scale STANDARD_DEVIATION 3.3 • n=99 Participants	42.9 units on a scale STANDARD_DEVIATION 3.6 • n=107 Participants	43.6 units on a scale STANDARD_DEVIATION 3.5 • n=206 Participants
Children's Depression Rating Scale (CDRS) collected before Randomization	29.4 units on a scale STANDARD_DEVIATION 5.7 • n=99 Participants	34.6 units on a scale STANDARD_DEVIATION 8.6 • n=107 Participants	32.1 units on a scale STANDARD_DEVIATION 7.7 • n=206 Participants
Pediatric Anxiety Rating Scale (PARS) collected before Randomization	13.3 units on a scale STANDARD_DEVIATION 5.9 • n=99 Participants	15.8 units on a scale STANDARD_DEVIATION 5.2 • n=107 Participants	14.8 units on a scale STANDARD_DEVIATION 5.4 • n=206 Participants

PRIMARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	Add-on Citalopram Following Optimized Methylphenidate n=23 Participants After optimized treatment with methylphenidate, those who meet threshold for chronic irritability are randomized to add-on citalopram (this arm) or placebo	Add-on Placebo Following Optimized Methylphenidate n=26 Participants After optimized treatment with methylphenidate, those who meet threshold for chronic irritability are randomized to add-on citalopram or placebo (this arm)
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	6 estimated percentage of participants

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	Add-on Citalopram Following Optimized Methylphenidate n=23 Participants After optimized treatment with methylphenidate, those who meet threshold for chronic irritability are randomized to add-on citalopram (this arm) or placebo	Add-on Placebo Following Optimized Methylphenidate n=26 Participants After optimized treatment with methylphenidate, those who meet threshold for chronic irritability are randomized to add-on citalopram or placebo (this arm)
Irritability Severity at 8th Week of Trial.	3.1 units on a scale Standard Error 0.3	3.9 units on a scale Standard Error 0.3

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Add-on Citalopram Following Optimized Methylphenidate n=23 Participants After optimized treatment with methylphenidate, those who meet threshold for chronic irritability are randomized to add-on citalopram (this arm) or placebo	Add-on Placebo Following Optimized Methylphenidate n=26 Participants After optimized treatment with methylphenidate, those who meet threshold for chronic irritability are randomized to add-on citalopram or placebo (this arm)
Functional Impairment at 8th Week of Trial	52.6 units on a scale Standard Error 2.3	47.2 units on a scale Standard Error 2.1

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Add-on Citalopram Following Optimized Methylphenidate n=23 Participants After optimized treatment with methylphenidate, those who meet threshold for chronic irritability are randomized to add-on citalopram (this arm) or placebo	Add-on Placebo Following Optimized Methylphenidate n=26 Participants After optimized treatment with methylphenidate, those who meet threshold for chronic irritability are randomized to add-on citalopram or placebo (this arm)
Depressive Symptoms at 8th Week of Trial	28.6 units on a scale Standard Error 1.8	30.1 units on a scale Standard Error 1.8

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	Add-on Citalopram Following Optimized Methylphenidate n=23 Participants After optimized treatment with methylphenidate, those who meet threshold for chronic irritability are randomized to add-on citalopram (this arm) or placebo	Add-on Placebo Following Optimized Methylphenidate n=26 Participants After optimized treatment with methylphenidate, those who meet threshold for chronic irritability are randomized to add-on citalopram or placebo (this arm)
Anxiety Symptoms at 8th Week of Trial	12.0 units on a scale Standard Error 1.2	13.4 units on a scale Standard Error 1.2

Adverse Events

Add-on Citalopram Following Optimized Methylphenidate

Serious events: 0 serious events

Other events: 23 other events

Deaths: 0 deaths

Add-on Placebo Following Optimized Methylphenidate

Serious events: 0 serious events

Other events: 24 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Dr Argyris Stringaris

Mood, Brain and Development Unit, Emotion and Development Branch, National Institute of Mental Health, National Institutes of Health

Phone: (301) 443-8019

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Other adverse events
Measure	Add-on Citalopram Following Optimized Methylphenidate n=23 participants at risk After optimized treatment with methylphenidate, those who meet threshold for chronic irritability are randomized to add-on citalopram (this arm) or placebo	Add-on Placebo Following Optimized Methylphenidate n=26 participants at risk After optimized treatment with methylphenidate, those who meet threshold for chronic irritability are randomized to add-on citalopram or placebo (this arm)
Gastrointestinal disorders Dry mouth	13.0% 3/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	15.4% 4/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Gastrointestinal disorders Drooling	8.7% 2/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	0.00% 0/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Gastrointestinal disorders Increased thirst	13.0% 3/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	11.5% 3/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Gastrointestinal disorders Trouble swallowing	8.7% 2/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	11.5% 3/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Gastrointestinal disorders Nausea	43.5% 10/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	30.8% 8/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Gastrointestinal disorders Vomiting	21.7% 5/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	11.5% 3/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Gastrointestinal disorders Stomach pains	56.5% 13/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	61.5% 16/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Gastrointestinal disorders Bloated abdomen	13.0% 3/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	0.00% 0/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Gastrointestinal disorders Changes in stool	34.8% 8/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	23.1% 6/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Cardiac disorders Change in heart rate fast/slow	4.3% 1/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	7.7% 2/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Nervous system disorders Drowsiness morning/afternoon	30.4% 7/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	11.5% 3/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Nervous system disorders Dizziness	21.7% 5/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	3.8% 1/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
General disorders Tiredness/fatigue	52.2% 12/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	34.6% 9/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
General disorders Insomnia	73.9% 17/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	92.3% 24/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
General disorders Early morning awakening	13.0% 3/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	11.5% 3/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
General disorders Appetite changes	100.0% 23/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	80.8% 21/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
General disorders Weight changes	56.5% 13/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	50.0% 13/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
General disorders Fever	4.3% 1/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	11.5% 3/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Renal and urinary disorders Enuresis	4.3% 1/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	7.7% 2/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Eye disorders Eyes sensitive to light	4.3% 1/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	7.7% 2/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
General disorders Headache	47.8% 11/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	46.2% 12/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Ear and labyrinth disorders Ringing or buzzing in ears	0.00% 0/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	7.7% 2/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
General disorders Runny nose	26.1% 6/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	26.9% 7/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
General disorders Easy bruising	8.7% 2/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	7.7% 2/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Psychiatric disorders Anger	82.6% 19/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	84.6% 22/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Psychiatric disorders Agression	73.9% 17/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	46.2% 12/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Psychiatric disorders Nervousness	65.2% 15/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	50.0% 13/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Psychiatric disorders Clingy/separation anxiety	56.5% 13/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	30.8% 8/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Psychiatric disorders Loss of interest/apathy	30.4% 7/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	23.1% 6/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Psychiatric disorders Poor concentration	39.1% 9/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	30.8% 8/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Psychiatric disorders Disorganized thinking	8.7% 2/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	3.8% 1/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Psychiatric disorders Speech changes	30.4% 7/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	23.1% 6/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Psychiatric disorders Intrusiveness	73.9% 17/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	57.7% 15/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Musculoskeletal and connective tissue disorders Restless/Inability to sit still	69.6% 16/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	73.1% 19/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Musculoskeletal and connective tissue disorders Stiffness/Involuntary movements	8.7% 2/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	19.2% 5/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Musculoskeletal and connective tissue disorders Extreme stiffness/Lack of movement	8.7% 2/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	0.00% 0/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Musculoskeletal and connective tissue disorders Muscle twitches	4.3% 1/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	7.7% 2/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Musculoskeletal and connective tissue disorders Motor tics	34.8% 8/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	42.3% 11/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Respiratory, thoracic and mediastinal disorders Difficulty breathing	13.0% 3/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	7.7% 2/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.
Respiratory, thoracic and mediastinal disorders Severe or chronic cough	8.7% 2/23 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.	3.8% 1/26 • Adverse event information was collected weekly during the study, including the 8th weeks of the trial. Adverse events were ascertained by checklists. These were completed by nurses (during inpatient admission) or parents (after discharge), all of whom were blind to treatment assignment, and instructed to rate what they observed without reference to changes from baseline irritability, time of day or severity of the presentation. Information on suicidality and manic symptoms were also routinely collected.