Conditions: Mood Disorder Mental Disorder Diagnosed in Childhood Attention Deficit and Disruptive Behavior Disorder Attention Deficit Hyperactivity Disorder
Keywords: Irritability Attention Deficit Hyperactivity Disorder Explosive Tantrums Bipolar Mood Disorder Mood Disorder Childhood Mood Disorder ADHD
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 103
Healthy volunteers: no

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.

Arms:
arm 1: After optimized treatment with methylphenidate, those who meet threshold for chronic irritability are randomized to add-on citalopram or placebo arm 2: After optimized treatment with methylphenidate, those who meet threshold for chronic irritability are randomized to add-on citalopram or placebo

Interventions: intervention 1: Add-on citalopram following optimized methylphenidate intervention 2: Add-on placebo following optimized methylphenidate
Intervention descriptions: intervention 1: After optimized treatment with methylphenidate, those who meet threshold for chronic irritability are randomized to add-on citalopram or placebo intervention 2: After optimized treatment with methylphenidate, those who meet threshold for chronic irritability are randomized to add-on citalopram or placebo

Protocol document:
Prot_000.pdf: 
 
1
Protocol Title:  A controlled trial of citalopram added to methylphenidate in youth with 
severe mood dysregulation 
 
Protocol Number: 09-M-0034 
 
Date: 3 January 2019 
 
Principal Investigator 
Name, Degree 
Branch/Institute 
Bldg/Rm 
Phone 
E-mail 
Argyris Stringaris, M.D., Ph.D. E&D/NIMH 15K/206 301-44-8019 argyris.stringaris@nih.gov 
Lead Associate Investigator 
Name, Degree 
Branch/Institute 
Bldg/Rm 
Phone 
E-mail 
Kenneth Towbin, M.D. ED/NIMH     CRC/1-3616   301-402-4403   towbink@mail.nih.gov 
 
Associate Investigators 
Name, Degree 
Branch/Institute 
Bldg/Rm 
Phone 
E-mail 
Ellen Leibenluft, M.D. EDB/NIMH      15K/203 
      301-496-9435    leibs@mail.nih.gov 
Daniel Pine, M.D.       EDB/NIMH              15K/            301-594-1318   pined@mail.nih.gov  
Kenneth Towbin, MD  ED/NIMH      CRC/1-3616  
301-402-4403   towbink@mail.nih.gov 
Holly Yokum, MSW ED/NIMH 
Bld 10        
301-496-7427    hlowe@mail.nih.gov 
Wanda Wheeler, MSW ED/NIMH 
Bld 10 
301-435-6648    wheelerw@mail.nih.gov 
Gerald Overman, Pharm.D, BCPP,CC/Pharm 10/1N257 301-402-7073  GOverman@mail.nih.gov 
Chana Engel CRNP-PMH ED/NIMH Bld10/1-3633        301-435-1553  engelcr@mail.nih.gov 
Mollie Davis, MSW ED/NIMH 
Bld 10/B1 
       301-496-0650  mollie.davis@nih.gov 
Cheri McNeil, PsyD ED/NIMH 
Bld 10/B1 
      301-594-1661  cheri.mcneil@nih.gov 
 
 
Research Contact  
Name, Degree 
Branch/Institute 
Bldg/Rm 
Phone 
E-mail 
Kenneth Towbin, M.D. MAP/NIMH  CRC/1-3616    301-402-4403    towbink@mail.nih.gov 
 
Medical Advisory Investigator 
Name, Degree 
Branch/Institute 
Bldg/Rm 
Phone 
E-mail 
 
 
 


 
2
Total requested accrual 
 
 160  Patients (separately describe patient groups)     
Youth with bipolar disorder          
  
 
  0   
Volunteers  
 
  
 
Project Uses Ionizing Radiation:   No  
 Yes (attach RSC/RDSC 
documentation) 
 
 
 
 Medically-indicated only 
 
 
 
 Research-related only 
 
 
 
 Both 
 
IND/IDE 
 
 
 No  
Yes (attach FDA documentation) 
 
 
Drug/Device/#_____________________ 
 
 
Sponsor: _________________________ 
 
Durable Power of Attorney   
 No  
 Yes  
 
Multi-institutional Project 
 
 No  
 Yes  
 
 
 
 
 
Institution_________________    FWA #_________  
Date of IRB approval_________ (attach IRB documentation) 
 
Data and Safety Monitoring Board   No   
 Yes  
 
Technology Transfer Agreement  
 No  
 Yes  
Agreement type and number __________________Expiration Date_____________ 
 
Confidential Disclosure Agreement     
 No  
 Yes 
 
Samples are being stored  
 
 
 No   
 Yes  
 


 
3
Table of Contents 
Section  
 
 
 
 
 
 
        
 
Page 
I.  
Précis   
 
 
 
 
 
 
            4 
II.  Introduction/ Scientific Rationale and Hypothesis   
            5 
III.  Subjects  
 
 
 
 
 
 
 
8 
 
A.  Inclusion criteria  
 
 
 
 
 
8 
 
B.  
Exclusion criteria  
 
 
 
 
 
8 
IV. Study Design and Methods  
 
 
 
 
 
9 
A. Study overview 
 
 
 
 
 
 
9 
B. Recruitment 
 
 
 
 
 
 
9 
C. Screening methods 
 
 
 
 
 
 
10 
D. Study design 
 
 
 
 
 
 
10 
E. Study procedures 
 
 
 
 
 
 
11 
F. Termination procedures  
 
 
 
 
13 
G. Follow-up procedures  
 
 
 
 
 
14 
V. Risks/ discomforts  
 
 
 
 
 
 
15 
VI. Subject monitoring  
 
 
 
 
 
 
17 
VII. Outcome measures  
 
 
 
 
 
 
17 
VIII. Statistical Analysis  
 
 
 
 
 
 
18 
IX. Human Subjects Protection  
 
 
 
 
 
19 
A.  Subject selection  
 
 
 
 
 
19 
i. Statement of equitability 
            B.  Justification for inclusion of children 
 
 
 
19 
 
   C.  Safeguards for Vulnerable Populations 
 
 
 
19 
 
D.  Justification for use of placebo and medication withdrawal 
19 
E.  HPSU team participation   
 
 
 
 
20 
F.  Qualifications of investigators  
 
 
 
 
20 
X. Benefits  
 
 
 
 
 
 
 
 
20 
XI. Summary/classification of risk   
 
 
 
 
21 
XII. Consent documents and process  
 
 
 
 
21 
XIII. Data and Safety monitoring   
 
 
 
 
23 
XIV. Quality Assurance                                                                               24 
XV. Adverse event reporting  
 
 
 
 
 
24 
XVI. Alternatives to participation or alternative therapies  
 
24 
XVII. Privacy                                                                                                 24 
XVIII. Confidentiality  
 
 
 
 
 
 
25 
XIX. Conflict of Interest/ Technology Transfer 
 
 
 
25 
XX. Compensation   
 
 
 
 
 
 
25 
XXI. Pharmaceutical Information   
 
             
 
25 
XXII. References  
 
 
 
 
 
 
 
30 
XXIII. Attachments/Appendices 
A. 
Flow sheets (Figures 1)  
 
 
 
 
Attached  
B. Appendix B: CTDB Description  
 
 
 
Attached 
C. Recruiting advertisements 
 
 
to be appended for IRB 
XXIV. Consent forms 


 
4
 
   A. Consent form for patient’s parent or guardian 
to be appended for IRB 
 
   B. Assent form for patient 
 
 
 
to be appended for IRB 
 
     
 
I. PRECIS 
i. Objective: To test the efficacy of citalopram plus methylphenidate vs. placebo plus 
methylphenidate in decreasing irritability in youth with severe mood dysregulation.  
 
ii. Study population: Youth ages 7-17 with severe mood dysregulation (SMD).  SMD is 
characterized by non-episodic, 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 for at least a 
year. 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. 
 
iii. 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.  
 
iv. Outcome measures: The primary outcome measures will be the Aberrant Behavior 
Checklist Irritability subscale and the CGI-I. 
  
 


 
5
II. INTRODUCTION/SCIENTIFIC RATIONALE AND HYPOTHESIS  
Few effective treatments are available for children with severe irritability (Brotman et 
al in press); developing such treatments is important given the prevalence of severe mood 
dysregulation (see below for definition) and disruptive mood dysregulation disorder in 
clinical (Martin et al in press), as well as epidemiological (Althoff et al 2016l Copeland et al 
2013; Brotman et al 2006) samples.  Moreover, high levels of childhood irritability predict 
increased risk for suicidality (Pickles et al 2010; Conner et al 2004) and functional 
impairment in adulthood (Copeland et al 2014; Stringaris et al 2009; Vidal-Ribas et al 
2016).  Although irritability is among the most common reasons that children are brought in 
for psychiatric care, pharmacological studies for irritability are only beginning to emerge.   
There are no solidly established treatments for severe mood dysregulation. One 
unblinded study of stimulants (Blader et al 2016), and one double blind placebo controlled 
trial in adults used selective serotonin reuptake inhibitors (SSRIs) (Coccaro et al 2009; Kim 
et al 2016) and suggested potential benefit. One small double blind placebo controlled trial of 
divalproex also has appeared (Blader, et al 2009).  The use of antipsychotics in youth has 
been increasing over the past several decades (Olfsen et al 2015), which are non-specific, 
associated with significant health risks, and side effect burden (Correll & Blader 2015). 
Using atypical antipsychotic agents, one open trial (Kreiger et al 2011) and one using a 
randomly assigned, double blind design (Gadow et al, 2014) suggested short term, limited 
benefit in the treatment of aggression and irritability. Indeed, reviews continue to call for 
more randomized controlled trials in youth with severe irritability (Benarous et al 2017; 
Tourian et al 2014).  
 
A. Severe Mood Dysregulation 
The term “Severe Mood Dysregulation (SMD)” identifies a group of children and 
adolescents presenting with a pattern of prominent, chronic, extreme irritability.  This entity, 
occurring in more than 3% of children and adolescents in the community (Brotman et al., 
2006), was identified in the context of research on pediatric bipolar disorder (BD).  SMD was 
identified in an attempt to facilitate research on the long-debated nosological status of youth 
with chronic severe irritability as a potential phenotype related to BD (Leibenluft, Charney, 
Towbin, Bhangoo & Pine, 2003). The core clinical characteristics of SMD are persistent, 
non-episodic irritability/anger or sadness, symptoms of hyper-arousal, and increased 
reactivity to negative emotional stimuli in the form of temper outbursts.  The  unbroken 
course of symptoms  of SMD contrasts with the episodic nature of  BD (Leibenluft et al., 
2003). SMD must begin before age 12, persist for at least a year, and cause significant 
impairment. Children with SMD meet criteria for several DSM-IV disorders, with rates of 
ADHD and ODD in excess of 80%; high rates of anxiety (63.3%), and moderate rates of 
lifetime major depressive disorder (20%) (Brotman et al., 2007). Importantly, despite only 
moderate concurrent or past comorbidity with MDD, two longitudinal community studies 
each found that children with SMD faced high risk for depressive disorders but not BD in 
early adulthood (Brotman et al., 2006; Leibenluft et al. 2006). 
 
Beyond these longitudinal data, other research distinguishes SMD from DSM-IV BD. 
Children with BD are significantly more likely to have a parent affected with BD, compared 
to those with SMD (Brotman et al., 2007). Moreover, children with BD and SMD differ in 
the neural processing of some, although not all, affective stimuli (Dickstein et al., 2007, 
Guyer et al., 2007, Rich et al., 2007).  


 
6
Whilst converging evidence from clinical course, family history, and pathophysiology 
differentiate SMD from BD, many children with chronic irritability may be receiving the 
diagnosis of BD in the community, although they do not have discrete episodes and thus do 
not meet DSM-IV criteria for the illness. A recent study (Moreno et al., 2007) found that 
annual rates of BD in the clinic have increased 40-fold in less than a decade. The increase has 
occurred most markedly in boys with comorbid ADHD, characteristics of SMD. 
Furthermore, data from children screened at the NIMH-IRP for Protocols 00-M-0198 and 02-
M-0021, show that the majority of children meeting criteria for SMD are classified as BD in 
the community, whilst only about 20% of children referred to our studies with a community 
diagnosis of BD meet diagnostic criteria for the disorder.  
These findings have significant treatment implications: to the extent that youth with 
SMD suffer from DSM-IV ADHD, anxiety disorders, and/or depression (Brotman et al., 
2007, Brotman et al., 2006), the indicated treatment is Serotonin Reuptake Inhibitors (SSRIs) 
and/or stimulants, two medications that are relatively contraindicated in BD because of 
concerns about precipitating mania (Baumer et al., 2006, Goldberg et al., 2007). The only 
controlled trial in SMD, conducted under our protocol 02-M-0021, compared lithium, 
effective in BD, to placebo; the trial found no evidence for efficacy of lithium treatment.  
This, too, suggests an important difference between SMD and BD, while further emphasizing 
the need for research on therapeutics in SMD.  Our experience screening youth for inclusion 
in 02-M-0021 indicates that a large majority of SMD patients are treated for their putative 
BD with antipsychotic and/or mood stabilizing medication. Both classes of medication are 
used conventionally to treat BD and are associated with relatively serious adverse effects. 
The inferior response of many SMD patients to these agents illustrates the need for more 
effective treatments beyond those typically used in BD.   Indeed, in our experience, youth 
with SMD appear to be receiving medications that are both ineffective and have a higher 
side-effect burden than the first-line medications previously shown to benefit their DSM-IV 
diagnoses (i.e., ADHD, anxiety, depression).  The latter treatments have been avoided in the 
community, due to fears of exacerbating symptoms of BD, while data from our group suggest 
that most of these youth do not, in fact, exhibit symptoms warranting the diagnosis of BD.  
Thus, major questions remain on best treatment practices for SMD.  In youth with SMD, 
treatments appropriate for BD may provide minimal benefit and high side-effect burden; 
treatments appropriate for non-BD mood, anxiety, or disruptive behavior disorders have 
typically been avoided, but may provide benefit. The potential public health significance of 
addressing these questions becomes clear when considering the high prevalence of SMD in 
the community (3.2%, Brotman et al., 2006). 
 
B. Serotonin Reuptake Inhibitors and SMD 
As noted above, SMD youth have high rates of current irritability and anxiety, as well 
as high lifetime rates of MDD, three problems previously shown to be targeted by SSRIs.  
Despite only moderate evidence of efficacy in pediatric MDD, SSRIs are considered the first-
line treatment for this syndrome (McClellan, Kowatch & Findling, 2007), with a recent meta-
analysis demonstrating that both children and adolescents achieve significantly better overall 
response to SSRIs than placebo after 12 weeks of treatment (Hetrick, Merry, McKenzie, 
Sindahl & Proctor, 2007).  SSRIs are also the medication of choice in pediatric anxiety 
disorders (Connolly & Bernstein, 2007) with several placebo-controlled studies 
demonstrating their benefit (Wagner et al., 2004, RUPP, 2001, Birmaher et al., 2003).  Here, 


 
7
the effect size is larger than seen in MDD, further suggesting the possible utility of SSRIs in 
SMD, given the very high rates of anxiety in SMD youth.  Moreover, data from SSRI trials in 
both pediatric MDD and anxiety suggest that SSRIs target irritability in children, core 
features of SMD. In light of these observations, the absence of data on the utility of SSRIs in 
SMD appears quite remarkable.  
Data in adults also suggest the potential utility of SSRIs in the treatment of irritability 
(Bond, 2005).  Specifically, RCTs indicate that SSRIs improve anger symptoms in adults 
presenting with anger concomitant to MDD (Bond, 2005; Fava et al., 1996; Fava et al., 
1993).  Similar findings emerge in Borderline Personality Disorder, associated with extreme 
levels of anger (Binks et al., 2006).  
 
 Use of SSRI’s in youth with SMD introduces concerns about increased suicidal 
thinking and medication-induced switching into mania.   Recently, the FDA imposed a 
“black-box” warning for increased suicidal thinking in youth treated with SSRI’s. Data from 
the FDA indicate that the risk, while statistically significant in large samples, is quite small, 
roughly 2%, in absolute magnitude.  On initial review, there was concern about particularly 
high rates of adverse outcomes with paroxetine and venlafaxine.  However, more detailed 
analysis suggests that rates of adverse behavioral effects are similar for all SSRIs (Hamad et 
al., 2006).  Importantly, the level of clinical monitoring that our subjects will receive far 
exceeds standard care and the recommendations by the FDA as part of the black-box 
warning.   
Regarding SSRI-induced mania, data from our lab, cited above, suggest that there 
may be significant, fundamental pathophysiological differences between SMD and BD.  
Therefore, it is has not been established that youth with SMD have the elevated risk for 
SSRI-induced mania shown by BD youth.  In addition, data in adults suffering from bipolar 
depression treated with SSRIs suggest that the rate of manic switches is low (Amsterdam & 
Shults, 2005; Nemeroff et al., 2001) and may be equal to that observed with placebo 
(Gijsman, Geddes, Rendell, Nolen & Goodwin, 2004). 
 
Five SSRIs have been used to treat anxiety or MDD in children and adolescents, 
although only three are viable for treatment of SMD.  Considerable data document efficacy 
with fluoxetine.  However, fluoxetine’s long half-life is a concern because any severe 
adverse effects could persist for weeks after stopping it.  Similarly, paroxetine seems a less 
desirable choice because high rates of adverse outcomes have been reported (Keller et al., 
2001).   This leaves fluvoxamine, sertraline, and citalopram.  Studies in pediatric anxiety 
document efficacy for fluvoxamine, and there are relatively few data for sertraline or 
citalopram.  The opposite applies to MDD, where positive RCTs have used citalopram or 
sertraline but not fluvoxamine.  Given the prominence of depressive symptoms in the 
presentation and subsequent outcome of youth with SMD, available data provide support for 
considering either citalopram or sertraline.  Ultimately, one can justify the choice of 
citalopram over sertraline because the former shows greater pharmacological specificity and 
fewer drug-drug interactions.     
 
C. SMD, comorbidity with ADHD, and treatment with stimulants 
As noted above, approximately 90% of those with SMD meet DSM-IV criteria for 
DSM-IV ADHD (Brotman et al., 2007) and preliminary evidence suggests that impairing 
sub-threshold symptoms of ADHD are present in the rest. In this protocol, all patients will 
receive treatment with methylphenidate, to target these symptoms, which will then be 


 
8
supplemented by the addition of citalopram vs. placebo, to determine the degree to which 
citalopram provides benefits for mood and anxiety symptoms, beyond placebo.  Based on our 
experience treating SMD youth openly and in the context of the lithium trial conducted under 
02-M-0021, we have concluded that ADHD symptoms are so prominent in this population 
that it will be difficult to discern improvement in other domains (specifically, irritability) 
without first treating their ADHD.  Indeed, given the effectiveness of stimulant medication 
and its use as a first line to treat ADHD symptoms (Pliszka, 2007), we routinely offer this 
treatment to youth with SMD. Thirty-four of 52 (65%) children we have treated at the NIH 
were placed on stimulant medication (3/34 received only atomoxetine) at discharge.  No 
adverse events were encountered during their open treatment with these agents during 
inpatient hospitalization or day treatment. In our experience, treatment with methylphenidate 
(MPH) is well-tolerated in youth with SMD, and their ADHD symptoms respond.  Our 
experience is consistent with data from two studies (one placebo-controlled) indicating that, 
among children with ADHD and mood symptoms similar to those of SMD (e.g., “mania-like 
symptoms” or “multi-morbid ADHD”), the response of their ADHD symptoms to 
methylphenidate is as robust as that of youth with ADHD but no mood symptoms (Galanter 
et al., 2003; Carlson et al., 2003). Indeed, in youth with ADHD, data indicate that irritability 
may even be decreased somewhat by treatment with stimulants (Carlson et al., 2000; 
Galanter et al., 2003).  
 
Specific Aim:  
To demonstrate that citalopram plus methylphenidate will be more effect than placebo plus 
methylphenidate in decreasing irritability in youth with SMD.  
 
Primary Hypothesis: 
SSRIs will reduce irritability and be well tolerated in children and adolescents with SMD 
who are treated concurrently with stimulant medication. 
 
III. Subjects 
 
Description of Study Population: 
 
Up to 160 children age 7-17 who are diagnosed with SMD will be recruited in order 
to reach a total of 80 randomized participants. Those who withdraw or are withdrawn prior to 
randomization will be replaced. 
 
A. Inclusion criteria (all must be met): These are based on the criteria for severe 
mood dysregulation (SMD) outlined in Leibenluft et al., 2003.  
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 


 
9
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 in 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 <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 > 12 on the irritability subscale of the Aberrant 
Behavior Checklist.  
 
 
B. 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< 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
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). 
12. NIMH employees and staff and their immediate family members will be excluded from 
the study per NIMH policy. 
 
IV. STUDY DESIGN AND METHODS 
A. Study overview 
This is a double-blind study of methylphenidate plus placebo vs. methylphenidate 
plus citalopram in pediatric patients with SMD. The study consists of four phases (Phases 1-
4, Fig.1): medication withdrawal (duration flexible), medication-free period (one week), 
initiation of optimal methylphenidate dose (five weeks), and an add-on trial of randomly-
assigned citalopram vs. placebo (in addition to methylphenidate; 8 weeks).  There will also 
be optional open treatment at the end (Post Trial Open Treatment, Fig. 1).  The duration of 
the latter will be such that all patients have the opportunity to have a total of up to 10 weeks 
of citalopram.  The target dose of citalopram will be 20-40 mg/day, titrated using a fixed-
flexible design.  With such a design, dose is increased to 40 mg unless symptoms remit or 
adverse effects occur. The primary outcome measures will be the Aberrant Behavior 
Checklist Irritability subscale and the CGI-I. The blind will be broken after each patient’s 
treatment.  Children will be invited to also enroll in 02-M-0021, which provides for structural 
and functional MRI scanning, MEG scanning, behavioral testing, and longitudinal follow-up.  
 
B. Recruitment 
Patients will be recruited nationwide through mailings to selected physicians, internet 
postings on the NIMH website, announcements in newsletters, contacts with support groups, 
and postings to listservs. Travel expenses for the patient and accompanying parent will be 
reimbursed. Travel and lodging assistance will be available for every-other-weekend visits 
for one parent while the patient is hospitalized. 
 
Recruitment efforts for minority subjects will be enhanced with additional measures. Current 
recruitment strategies will continue because of the widespread nature of the current outreach 
into the community which will expose the study to minority as well as majority populations 
due to the diverse nature of the Washington DC metropolitan area. As noted, increased 
attempts ought to be made in the hopes of enrolling a more diverse population. Outreach is 
currently planned into very rural communities. A concerted effort will also be made to 
highlight this study to the Latino population in Montgomery County through the Up County 
Latino network. Relationships can also be strengthened with the adult bipolar disorder 
researchers at NIMH, which also runs a Hispanic Initiative program, with the goal of cross-
referrals. Additional efforts can be increased with outreach and presentations in Prince 
George's county and other local areas with increased diversity samples.  Local adoption 
support agencies often service international adoption families, and specific outreach will be 
made to these agencies.  
 
NIH Employees and staff will not be directly recruited by or through their supervisors or co-
workers to participate in this study. 


 
11
 
C. Screening methods 
Preliminary Screening: Consent forms and other information about the study will be 
mailed to prospective participants who express interest.  Prospective subjects will be 
screened initially by a clinician, who will use a semi-structured telephone interview 
to assess the child’s clinical course and treatment history.  After the initial telephone 
interview, appropriate records (medical, psychiatric, etc.) will be requested for 
individuals deemed to be potential candidates, and the patient’s treating psychiatrist 
will be consulted.  
 
On-Site Screening (one-two days): After the preliminary screening, those youth who appear 
to qualify for inclusion will be invited to NIMH for a comprehensive medical and psychiatric 
evaluation under the MAP omnibus Screening Protocol 01-M-0254 (P.I. Dr. Carlos Zarate). 
Parents and children will participate in clinical and semi-structured psychiatric interviews 
(K-SADS-PL). Parents and patients will also receive the standardized interview module that 
we developed to identify children who meet the criteria outlined in Appendix A.  Parents will 
complete the Autism Screening Questionnaire, the Social Responsiveness Scale (SRS), and 
the Children’s Communication Checklist, so that children with probable PDD can be 
identified and, if symptoms are severe, excluded from the protocol.  At the end of these 
assessments, a consensus decision will be reached as to whether or not the child meets 
inclusion criteria. 
 
D. Study design 
The anticipated duration of the study (exclusive of open treatment at the end) is 
approximately 12-15 weeks, depending on the time required for medication discontinuation 
(Figure 1).  This time frame includes five phases: 1) medication withdrawal (duration 
flexible, depending on the patient’s medication at admission), 2) medication free period (one 
week), 3) open treatment with methylphenidate ( up to 5 weeks), 4) a randomized trial of 
citalopram plus methylphenidate vs. placebo plus methylphenidate (8 weeks), and 5) open 
treatment as indicated in preparation for return to community care. Specifically, those 
patients who responded to citalopram will be offered an additional 2 weeks of open 
treatment. For those who received placebo and they and their parents wish to have an open 
trial of citalopram, we will offer 8 weeks of initiation and open outpatient citalopram 
treatment, followed by an additional 2 weeks, if they respond.  In this way, all study 
participants will have the opportunity to receive a total of 10 weeks of citalopram treatment. 
Patients who did not respond to citalopram, or those who do not wish to have a trial of this 
medication, will be offered 2-4 weeks of open treatment with the medication(s) that, in the 
treatment team’s judgment, are most likely to benefit the child.  
Medication withdrawal, the medication-free week, the methylphenidate open trial, 
and initial dose stabilization using citalopram/placebo will occur while patients are either 
hospitalized or attending the Behavioral Health Day Treatment Center.  The decision 
between these two treatment settings will depend on whether children live locally and on 
their clinical status. We considered restricting the medication withdrawal phase of the study 
only to an inpatient trial.  However, previous experience suggests that recruitment will be 
facilitated, increasing feasibility, by offering both inpatient and Day Treatment options.  
Moreover, our prior experience also suggests that the similarities between these two options, 


 
12
in terms of overall level of care or supervision provided and the opportunities for staff 
observation of the patient, are much greater than the differences.  During the 8-week 
citalopram/placebo trial and subsequent open treatment, patients can be hospitalized, in day 
treatment, or outpatients, according to what is clinically appropriate. This decision will be 
made based on the child’s current clinical status, previous history, and living situation. We 
considered limiting this to inpatient or day treatment, but believe that this option would 
involve an unnecessary degree of restriction for the patients, including an extended time 
away from home.  We also wish to adhere to the clinical guideline that children should be 
treated in the least restrictive setting capable of meeting their needs. For those subjects who 
live locally and are too unstable to conduct the trial as an outpatient, the option of day 
treatment or hospitalization is available.  For those who live outside the metropolitan area 
and are too unstable for outpatient care, hospitalization will be available. In addition, patients 
who begin the trial as outpatients but whose clinical status deteriorates can be re-hospitalized 
or enter day treatment and continue in the trial.  However, those patients who are stable 
enough to do so will be allowed the less restrictive alternative of outpatient status.  For 
outpatients, close monitoring will be provided via telephone contact and clinic visits, as 
detailed below, and an on-call physician will be available.  
 
E. Study procedures 
At the beginning of the study, children will be evaluated to determine whether their 
clinical needs during the medication withdrawal, medication-free, methylphenidate, and dose 
stabilization phases are best met with day treatment (this is an option only for those who live 
within a 50 mile radius of the NIH Clinical Center) or inpatient treatment. They will be 
admitted to either the Day Treatment or Pediatric Behavioral Health Unit at the NIMH and 
gradually withdrawn from their medication, as clinically tolerated, over a 1 to 6 week period. 
The Day Treatment Center is on the child psychiatry inpatient unit; the hours are 
approximately 8:00 a.m.-4:00 p.m. five days a week.  Day treatment patients whose clinical 
status deteriorates can be hospitalized and continue in the protocol. 
Upon admission to the hospital or Day Treatment program, patients will receive a 
physical examination.  Blood will be drawn for CBC, thyroid and liver function tests, HIV 
and Hepatitis B testing, and electrolytes.  Urine will be obtained for urinalysis, toxicology 
screen, pregnancy (in pubertal girls) and creatinine clearance, and an EKG will be performed. 
The duration of the medication withdrawal phase will depend on the pharmacological 
agents and doses the patient has been receiving prior to admission. However, this phase will 
not exceed 8 weeks. We will draw on our considerable prior experience with medication 
withdrawal among pediatric bipolar patients, as implemented in protocols 00-M-0198 and 
02-M-0021.  Thus, each patient’s withdrawal schedule will be tailored to their regimen and 
the duration will be guided by clinical considerations.  In general, stimulant and 
antidepressant medication will be tapered more rapidly than will mood stabilizing and 
antipsychotic medications. However, exceptions are expected such as when children are 
receiving antidepressants associated with withdrawal symptoms (e.g. paroxetine) which will 
be tapered more gradually than other antidepressants or agents with very long half-lives (e.g. 
aripiprazole). The medication withdrawal phase will continue until the patient has been free 
of medication for 5 half-lives in order to eliminate the direct effects of any current 
psychotropic agents on mood symptoms.  At the end of the medication withdrawal phase, all 
patients will have a one-week medication-free period to assure elimination of all 


 
13
psychotropic medications. All patients will be concurrently enrolled in protocol 02-M-0021 
and some research tasks may be obtained during the medication-free period under this 
concurrent protocol.  
After medication withdrawal, patients will be given methylphenidate 5, 10, 
15, or 20 mg at 8 AM and 1 PM or the equivalent in an extended release form. The 
treating clinicians will have up to 5 weeks to determine the optimal dose.   The 
maximal dose will be 80 mg or 2 mg/kg whichever is smaller. Clinical worsening will 
be defined as a rating of “8” (“much worse”) or greater on the CGI-I, or a clinically 
significant adverse event.  Those experiencing significant worsening or significant 
improvement (“2” or “very much improved”) will be withdrawn from the study, 
stabilized clinically (as needed) and discharged to care in the community. All patients 
will be invited to enroll in 02-M-0021 and participate in the longitudinal follow-up study, 
even if they are ineligible for randomization. 
Those children who, on stimulant medication, still meet inclusion criteria will 
be randomized to receive add-on citalopram or placebo using double-blind 
procedures in a 1:1 ratio. While all patients will undergo the citalopram/placebo 
dose stabilization phase while hospitalized or in day treatment, at the beginning of 
this dose stabilization phase a preliminary decision will be made as to whether the 
patient is likely to undergo the subsequent 8-week citalopram/placebo trial as an 
inpatient, day treatment patient, or outpatient.  The patient’s research physician, 
primary NIMH clinician who performs mood ratings, and nursing staff will be blind to 
treatment assignment.   
The duration of the citalopram/placebo trial is 8 weeks.  The goal for citalopram will 
be to reach a dose between 20 and 40 mg/d.  The dose of citalopram/placebo will begin at 5 
mg daily and increase to 10 mg after five doses.  Thereafter, dosage will increase by 5 mg 
every 5 days until reaching 20 mgs (Day 15).  After one week at 20mg/d (Day 22), patients 
will be discharged to outpatient or Day Treatment status if clinically appropriate. Outpatients 
will be seen in clinic on approximately Days 29 and 43 and will be contacted routinely by a 
clinician on the alternate weeks, so that there is weekly clinical contact. On approximately 
Day 29, when the child is seen in clinic, a dose of 30 mg/d may be prescribed if clinically 
appropriate, and two weeks subsequently (when the child is seen in clinic on approximately 
Day 43) the dose may be increased to 40 mg if clinically appropriate. The maximum dose for 
the study will be 40 mg.   Patients in both the placebo and treatment groups will receive 
study pills once daily.  Dosage adjustments will be also be made as needed to minimize side-
effects.  
During the treatment trial, a patient’s level of care (inpatient, day treatment, 
outpatient with weekly clinical contact) will be determined on clinical grounds by the 
treatment team. There will be a physician on call for the study at all times should parents 
need to contact staff.  Outpatients or day treatment patients whose clinical status deteriorates 
so that they require hospitalization will be admitted for clinical stabilization, but they will not 
be discontinued from the trial. If they continue to deteriorate in the hospital they will be 
withdrawn from the trial and treated clinically until they can be safely transferred to care in 
the community.  
For both inpatients and outpatients, every other week ratings will consist of the CGI-
I, Aberrant Behavior Checklist (ABC), CGAS, CDRS, combined WASH-U-K-SADS and 
Young Mania Rating Scales, Brief Psychiatric Rating Scale for Children (BPRS-C) (where 


 
14
positive psychotic symptoms are noted), Pediatric Anxiety Rating Scale (PARS), the 
Treatment Emergent Symptom Scale, blood pressure, pulse, and weight.  The Treatment 
Emergent Symptom Scale will be administered by a different clinician than the one who 
completes clinical rating scales.  For both inpatients and outpatients, the primary clinician 
will make a best-estimate rating on each scale, based on direct interview of the child, and on 
interview with parent (in the case of outpatients and day treatment patients) and/or nurses (in 
the case of inpatients and day treatment patients).  Inpatients and day treatment patients will 
also be rated weekly by nurses using the Overt Aggression Scale, and the Direct Observation 
Form, and ward teachers will complete the Conners 10-item Abbreviated Teachers Rating 
Scale (ABTRS) on school days and the 39-item Conners Teacher Rating Scale (CTRS) 
weekly.  Research data will be collected and stored using the NIH Clinical Trials Survey 
System (CTSS) and the Clinical Trials Database (CTDB). This allows parents and children to 
log in to a secure, password-protected website and directly enter responses to questionnaires 
and checklists, or enter their responses while at NIH using a wireless-device interface to 
access the NIH-intranet secure CTDB.  The security features and operation of CTDB are 
described in Appendix D.  
Those patients who are treated as inpatients will be confined to the grounds of the 
NIH, unless approved to travel off the grounds by the medical staff.  If patients are approved 
to travel off the NIH grounds, a staff member or adult relative must accompany them. 
 
E. Termination procedures 
Throughout the study, the Principal Investigator will request that an independent 
evaluator, not connected to the protocol, review any case that shows clinical worsening, or a 
serious clinically significant adverse event.  Clinical worsening during the washout period is 
defined as a CGI-I rating of “8” (“much worse”) or greater for two consecutive weeks, and 
during the randomized period as a rating of “8” (“much worse”) or greater, or a drop in the 
CGI-I rating of 2 or more points, for three consecutive weeks.  This CGI-I will compare 
current function to the more impaired of two “baseline” ratings (one baseline rating is 
obtained prior to admission, the other after cessation of medication). As discussed in more 
detail below, comparing current function to the more impaired of these two baseline ratings 
allows us to not terminate a patient whose condition may have worsened in the course of the 
hospitalization but who is still functioning at a level superior to that prior to his/her entry into 
the study. In addition, use of lorazepam PRNs in excess of 4 mg/d for more than one day will 
prompt review by an independent evaluator. Results of the review will be discussed with the 
patient and his/her family.  As always, families are free to discontinue the trial at any point.  
Also, independent evaluations may be requested by the research team or by the HSPU team 
(via a member attending the weekly multidisciplinary meetings).   
If clinical worsening occurs, the one week medication-free phase may be shortened 
and the child advanced more rapidly to randomized treatment.  Clinical worsening will be 
defined as above. 
An independent evaluator may recommend a range of actions. Worsening during the 
period when medication is being discontinued may lead to truncation of the washout period 
and passage to the randomized period, or more frequent monitoring. Worsening during the 
randomized period may lead to removal from the study, closer monitoring and re-assessment, 
or continuation without further changes. In all cases, the subject’s safety will be the first 
priority; a conservative standard will be applied in deciding whether a child should continue 


 
15
in the study.  Only after a patient is removed from the study will the blind be broken.  At this 
point, appropriate clinical care will be provided to stabilize and return the patient to the 
community psychiatrist who provided care prior to the subject’s enrollment in the trial.  
Treatment will be guided by what is considered “best clinical interest.”  A patient who 
received only placebo will be offered an open trial of citalopram. 
In our opinion, it is reasonable to allow children who are “much worse” to 
have a review of their course rather than immediate removal from research. In our 
experience, it is common for children with SMD to have brief but severe occurrences 
of explosive behavior, anxiety, or angry mood. These behaviors and mood shifts are 
sufficient to influence weekly ratings, and sometimes occur in response to events 
quite remote from the unit and patient (e.g. marital disputes, an absent parent suddenly 
surfacing, etc). Accordingly, a period of observation is needed to determine whether the 
observed deterioration will persist and, in that sense, is clinically meaningful.  If subjects 
were discharged from the trial immediately, there is a significant risk that we will exclude 
unnecessarily children undergoing typical fluctuations associated with their condition.  
Indeed, these children may be among those who are most likely to benefit from the treatment 
being studied.   
In addition, this design allows for clinical judgment and consideration of 
circumstances to enter into the decision to remove subjects from the protocol. This averts 
resorting to an “automatic ejection clause” that eclipses clinical judgment when considering 
the overall severity of the patient’s condition, hospital course to date, parents’ concerns, or 
alternative monitoring or unit procedures that might support a patient who is having 
difficulties.  Our experience is that independent evaluations are a better mechanism for 
protection of subjects’ care and interests than restrictive “no alternative” procedures. 
Finally, we have found that, for some children, a “honeymoon period” results 
in less impairment early in the hospitalization (even when children are off 
medication) than later, during the randomized phase. Thus, during the randomized 
phase a patient can decline to a level of functioning below that seen earlier in their 
hospital course, but no more severe than that observed by the family prior to 
admission. Therefore, the rating procedures allow the patient’s clinical condition 
during the trial to be compared, not just to their level of function when off 
medication, but also to their level of function at home, prior to entry into the study.   
In addition to stopping the study because a child’s clinical condition deteriorates, the 
investigators may withdraw a child from the study if his/her symptoms during medication 
tapering or the treatment trial interfere with his/her ability to cooperate, or if the patient’s 
behavior threatens his/her safety and that of others.  Symptoms leading to withdrawal may 
include anxiety, psychosis, or conduct problems. Finally, voluntary withdrawal is always an 
option for a child or parents. We do not plan to study any children off protocol.   
 
F. Follow-up procedures 
After an 8 week trial of citalopram plus methylphenidate vs. placebo plus 
methylphenidate, the blind will be broken for each participant.  The rationale for doing so is 
that, in this severely impaired population, it is important for families to know immediately 
whether or not each patient has received citalopram (and, if they did receive active treatment, 
how they responded) in order to guide clinical treatment for each individual in as timely a 
fashion as possible.  Those children who received placebo will be offered open treatment 


 
16
with citalopram (see below) or other appropriate agents as determined by staff and with the 
agreement of the patient’s family.  Those who received citalopram and did not respond will 
be treated clinically with the goal of achieving sufficient stability to be discharged from the 
study to the care of a psychiatrist in the community. This period of stabilization will 
generally last 1 to 4 weeks.  
Open citalopram treatment will be provided to responders and to individuals who fail 
to respond to placebo. Open citalopram treatment will be provided for both ethical reasons 
(i.e., to allow those patients who got randomized to placebo to receive treatment with active 
medication) and because it would be useful to obtain additional data on potential adverse 
events, even if those data are uncontrolled. The duration for all participants who wish to 
receive citalopram would be 10 weeks.   Specifically, for responders, open treatment will be 
provided for up to 2 weeks, and it is anticipated that they will be discharged during the 
course of this open treatment.  Those who failed to respond to placebo during the blinded 
trial will be invited to receive open treatment with citalopram for 8 weeks followed by up to 
2 weeks of additional open treatment if they respond. While some of the initial 8 weeks of 
citalopram treatment may be as an inpatient or day treatment patient, it is anticipated that 
these patients will be discharged to outpatient status during the final 4 weeks of open 
treatment, if not sooner.  
During the open treatment phase, patients will be monitored in the same manner as 
during the placebo-controlled trial, with every other week clinic visits (and phone calls on 
alternate weeks) for outpatients and close monitoring for day treatment patients and 
inpatients.  All patients will receive ratings every other week, as during the controlled trial. 
During and following the open phase of the trial, all outpatients will be in the care of a 
psychiatrist in their community, with whom we will establish contact when care is 
transferred. During the open citalopram trial, other medications will be allowed as dictated 
by the child’s clinical needs and their safety in combination with citalopram.  
While children are being treated clinically at the NIH (i.e. after they have completed 
the treatment trial but are not yet sufficiently stable for discharge from the study), data from 
clinical rating scales will be recorded and may subsequently be published as uncontrolled 
data.  However, treatment decisions will be guided only by what is in the best interest of the 
patient, with the goal being achieving stability as soon as possible.  All children on 
citalopram will receive an electrocardiogram, CBC with differential, electrolytes, and hepatic 
panel, before discharge from the study.   
As noted above, all participants who enroll in this study will be invited to co-register 
in protocol 02-M-0021 and are eligible to participate in our longitudinal follow-along study 
of SMD. 
 
G. Management of Data and Samples: 
a. Storage 
Every necessary step will be taken to prevent identification of study participants or 
violations of confidentiality of the data and some data will be securely stored in the NIH 
CTDB (appendix B). Samples are not stored or shared.  Saved data include behavioral, 
clinician-, parent- and self-ratings, measures of mood, and side effects. Data will be stored in 
secure servers at NIH and only study investigators will have access to stored data.  
 


 
17
Future use: After the study has ended, the data will be stored for future use and will 
only be accessible to study investigators. Information will be stored using a confidential 
code, stripped of all identifiers, and data will be treated only as groups.  All data entered into 
a database will appear only in coded form. The IRB will be informed of any future use of this 
data subsequent to termination of the protocol.  
 
b. Data and sample sharing plan 
This protocol is not subject to the Genomic Data Sharing (GDS) policy. 
 
Data may be shared with collaborating laboratories at NIH or outside of NIH and/or 
submitted to NIH-designated repositories and databases if consent for sharing was obtained.  
Repositories receiving data from this protocol may be open-access or restricted access.  
 
Data will be stripped of identifiers and may be coded (“de-identified”) or unlinked 
from an identifying code (“anonymized”). When coded data is shared, the key to the code 
will not be provided to collaborators, but will remain at NIH.  Data may be shared with 
investigators and institutions with an FWA or operating under the Declaration of Helsinki 
(DoH) and reported at the time of continuing review.  Sharing with investigators without an 
FWA or not operating under the DoH will be submitted for prospective IRB approval.  
Submissions to NIH-sponsored or supported databases and repositories will be reported at the 
time of Continuing Review.  Submission to non-NIH sponsored or supported databases and 
repositories will be submitted for prospective IRB approval. 
 
Required approvals from the collaborating institution will be obtained and materials 
will be shipped in accordance with NIH and federal regulations.    
 
V. RISKS/DISCOMFORTS 
 
General: By agreeing to participate in this study, subjects will be temporarily forgoing the 
opportunity to receive routine clinical care in the community. The potential disadvantages of 
this will be clearly explained to all patients, along with their options for receiving optimal 
pharmacotherapy and psychotherapy in the community.  Patients will also be told that 
citalopram is available with a physician’s prescription in the community; however, it has no 
FDA approval for use in children or for the treatment of anxiety. 
 
Screening evaluation: All participants will be screened under the MAP Screening Protocol 
(01-M-0254, P.I. Dr. Carlos Zarate).  Risks and benefits of screening are detailed in that 
protocol. 
 
Treatment Trial: Patients could experience worsening of symptoms while tapering 
medications or during the treatment trial whether they are on placebo or citalopram.  During 
the medication withdrawal and initial dose stabilization phases, all patients will be either in 
day treatment or hospitalized so that they can be monitored closely. Nursing staff will 
maintain the patient’s safety at all times.  In our experience withdrawing children and  youth 
with severe mood dysregulation from medication since 2001, none of 40 patients showed 
clinical deterioration during the taper phase to a degree that required reinstating 


 
18
pharmacological treatment and cessation of efforts to discontinue medication. Two of 25 
patients who were randomized were withdrawn because of clinical deterioration. While on 
the Behavioral Health Unit, roughly 20 of 45 patients (44%) who discontinued medication 
improved compared to their preadmission baseline and no longer meet criteria for 
randomization.  The Pediatric Behavioral Health Unit has developed expertise in supporting 
children during medication tapering and when children are medication free.  They have 
expertise in supporting patients in a way to minimize the need for restraints or quiet room 
use.   
         Almost half of the SMD children enrolled in 02-M-0021 have a history of psychiatric 
hospitalization, so for many the experience will not be unfamiliar to them.  Indeed, patients 
who have been hospitalized in the community generally find our inpatient unit to be more 
pleasant than other hospital settings, because of its small size and high staff:patient ratio.  
Provision will be made for parents to visit their children frequently throughout the 
hospitalization and this will be strongly encouraged by nursing staff. Weekly consultations 
with parents, either in person or on the telephone, will be conducted in order to answer 
questions and to discuss their child’s progress during the trial.  In addition, children will be 
allowed to telephone their parents daily, and a variety of activities will be provided to make 
the child’s stay at NIMH more enjoyable.  Schooling will be provided year-round by teachers 
who are particularly adept at educating children with severe psychiatric illnesses.   
           Citalopram is generally well-tolerated in both children and adults, including by 
medically ill patients taking multiple concomitant medications. Side effects that were noted in 
randomized trials to exceed incidence rates of more than 5% or were double the rate observed 
among patients receiving placebo included (Micromedex®): dry mouth, sweating increased, 
tremor, nausea, diarrhea, dyspepsia, vomiting, abdominal pain, general  fatigue, fever, 
arthralgia, myalgia, somnolence, insomnia, anxiety, anorexia, agitation, dysmenorrhea, libido 
decreased, and yawning.  As is standard practice for treatment with any SSRI, staff, patients 
and family will be alerted to risks for the emergence of anxiety, agitation, panic attacks, 
insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor 
restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, 
and suicidal ideation, especially early during antidepressant treatment and when the dose is 
adjusted up or down. As noted in the Introduction, FDA data suggest that youth treated with 
SSRIs have a significantly increased risk for suicidal ideation, compared to those treated with 
placebo, but the absolute risk remains small.  Having said that, the rate in youth with SMD is 
unknown, so patients will be observed closely.   
 
Because of the primary route of elimination is via the liver, we will exclude patients with 
liver enzyme elevation (two-fold increase over upper limits of normality) or a history of liver 
disease.  Risks of bleeding are also reported and we will exclude any patients with abnormal 
baseline CBC or who require routine use of non-steroidal anti-inflammatory drugs that 
decrease coagulation..     
             Citalopram is metabolized by liver enzyme cytochrome P450IIIA4 (CYP3A4) and 
IIC19 (CPY2C19). One advantage of citalopram is that it has been relatively immune to drug-
drug interactions that elevate or depress levels of other SSRIs. The manufacturer of 
citalopram has not reported significant drug-drug interactions, except for NSAIDs as noted 
above. We do not anticipate use of triptan drugs such as sumatriptan with citalopram in this 
study but such interactions could be anticipated and will be watched for during the trial; we 


 
19
will exclude individuals with a history of migraine who require triptan agents for relief of 
migraine symptoms.  
             Adverse medication effects could prolong hospitalization.  If patient and family 
decline further hospitalization at NIH or wish to leave NIH despite being unstable, then they 
may choose inpatient admission at another facility.  In that case they or their insurance 
company will be responsible for costs associated with the hospitalization.  The staff will work 
to stabilize the patient to a level that allows for a safe transfer to another facility if the family 
chooses.  Involuntary psychiatric hospitalization is not an option at NIH, and if such 
commitment is necessary, transfer to an appropriate institution will be facilitated. 
              Patients may find the repeated administration of the rating scales to be unpleasant or 
boring.   
 
VI. SUBJECT MONITORING 
              During the medication withdrawal, medication-free, and dose stabilization phases, 
patients will be on the Pediatric Behavioral Health Unit (in day treatment or inpatient) and 
will be monitored very closely by nursing staff. On the Unit, events that require holds or quiet 
room use will be closely tracked and assessment of the clinical treatment plan will be 
reviewed subsequent to each event. Patients and families are informed about the quiet room, 
“as needed medication,” and policy governing holds/restraints at the consent signing and 
during the orientation to the Pediatric Behavioral Health Unit.  Furthermore, parents are 
informed by nursing staff after each event whenever a hold, quiet room use, or PRN 
medication are needed. In addition, the HSPU will provide ongoing monitoring throughout 
the study. 
 
VII. OUTCOME MEASURES 
 
We will have two primary outcome measures, one of which will be used as a 
continuous measure and the second of which will be treated categorically.  These primary 
outcome measures will be the Aberrant Behavior Checklist—Irritability Subscale (ABC-I), 
which will be treated continuously, and the Clinical Global Improvement Scale (CGI-I), 
which will be treated categorically. As described in the Background section, irritability is the 
most hallmark symptom of SMD. In addition, since it is also important to determine how 
citalopram impacts on the patient’s overall severity of illness and to ascertain a frequently-
used global designation of “responder” status, we will use the CGI-I, which is the most 
commonly used outcome measure in pediatric psychopharmacology trials. The baseline for 
the CGI-I ratings will be the measure obtained at the end of the medication withdrawal phase, 
just before the dose stabilization phase begins, as described in more detail above.    
 
VIII. STATISTICAL ANALYSIS 
             To test the hypothesis that citalopram plus methylphenidate (MPH) will be more 
effective than placebo plus MPH in treating irritability associated with severe mood 
dysregulation, we will compare reductions from baseline scores on the ABC-I after 8-weeks of 
double-blind therapy to the ABC-I score before the start of therapy. Specifically, random 
effects regression will be used to contrast study groups for continuous measures.  For 
continuous measures, each dependent measure (Yj) is predicted by the following model: Yj= 
1j+ 2T + 3jT+ 4I+ 5TI+ Z+ ij where I indicates treatment status; j indexes subjects; T indexes 
time (for repeated measures); 1j is a random effect for the intercept of the jth subject; 2 is the 


 
20
average slope; 3j is a random effect for the slope of the jth subject; 4 is treatment status; 5 is the 
difference in slopes over time between the two groups specified in 4.  Z is the effect of possible 
covariates and ij is the random effect for error. To assess the efficacy of citalopram plus MPH, 
we will test the significance of a group (citalopram+MPH vs. placebo+MPH) by time 
interaction. The level of significance will be p<.05.  This analytic plan also will be used for 
any secondary outcome measures that can be treated continuously. Specifically, in addition to 
the primary measure, the impact of citalopram+MPH vs. citalopram + placebo on the 
secondary measures of CDRS, YMRS, SCAR-H and PARS scores will also be assessed. 
  
For our categorical analysis, a responder analysis will be performed to compare the 
proportion of subjects in each treatment group who met the response criteria. Response rates 
will be analyzed using logistic regression, with the principle study hypothesis being that rates 
of response will be greater in the citalopram+MPH vs. the placebo+MPH cell.  This 
hypothesis is tested as the main effect of treatment group on CGI category (responder vs. 
non-responder).  Response will be defined as a CGI rating of 1 (completely well) or 2 (much 
improved).  
             In all analysis, the intent-to-treat principle will be used, such that all available data 
from all randomized subjects will be included.  Subjects who have a baseline measure and at 
least one other post-baseline rating will be included in the analysis. 
 
The number of subjects withdrawn from the study prior to randomization will be reported 
in the publication resulting from this trial, along with the reasons for their withdrawal.  
          
Sample size estimation 
         We assume a response rate of 60% to citalopram+MPH and 20% to placebo+MPH. 
While, on the surface, this might seem like a somewhat large clinical difference, when SSRIs 
are highly effective in pediatric conditions, such as pediatric anxiety disorders, effect sizes of 
this magnitude are typically found.  Since there are no treatment trials in SMD targeting 
irritability, the placebo response rate is based on the MTA, a large treatment trial in ADHD 
using stimulants (Greenhill et al., 2001; Galanter et al., 2003). Assuming power=0.8 and a 
two-tailed alpha= 0.05, a sample size of 80 (40 in each group) is needed.  However, of 
course, in the event that the response to SSRIs in SMD is more similar to that in pediatric 
MDD than pediatric anxiety, power will be less than 0.8.    
 
Our experience with a previous treatment trial in this population suggests that roughly 
50% of participants my not reach the point of randomization because of behavioral 
improvement, withdrawal from the study because of homesickness, or intolerance of 
medication discontinuation.  Thus we are anticipating enrolling 160 children in order to 
ascertain 80 who will be randomized. 
 
IX. HUMAN SUBJECTS PROTECTION 
A. Subject selection 
                       i. Statement of equitability  
Every attempt will be made to recruit participants nationally from all racial and ethnic 
groups.  Our past experience is that most participants come from our longitudinal studies of 
pediatric bipolar disorder and reflect disproportionate representation of Caucasian children. 
We currently have 88 percent Caucasian individuals, 8 percent African Americans, and 2 
percent Asian individuals in our cohort, with 2 percent whose race was not reported.  
 


 
21
B. Justification for inclusion of children 
As detailed in Section II, severe mood dysregulation is an extremely impairing illness 
for which there are few effective treatments.  Therefore, many youths with the illness 
continue to suffer significant impairment. Current treatment lore that these children have a 
variant of Pediatric Bipolar Disorder has left clinicians wary of giving stimulants and/or 
SSRIs to patients for symptoms of ADHD or anxiety, respectively, in the belief that these 
agents will precipitate mania.  There is a need for research using standard agents.  Since the 
target population for these treatments is children and adolescents with severe mood 
dysregulation, it is essential to conduct controlled trials in a well characterized population.  
 
C. Safeguards for vulnerable populations and sensitive procedures 
Protections for NIH employees, staff and family members participating in this study include 
1) assuring that the participation or refusal to participate will have no effect, either beneficial 
or adverse, on the subject’s employment or position at the NIH, 2) giving employees and 
staff who are interested in participating the “NIH Information Sheet on Employee Research 
Participation” prior to obtaining consent, and 3) assuring that there will be no direct 
solicitation of employees or staff. 
 
D. Justification for use of placebo and medication withdrawal 
             A stimulant-only (placebo+MPH) arm in this trial is justified because of the limited 
data concerning treatment efficacy of any agent in children with severe mood dysregulation. 
The dearth of knowledge on therapeutics is particularly problematic in light of the fact that 
children with SMD suffer considerable morbidity and impairment and are seen commonly in 
treatment settings, where they are treated with a variety of psychotropic agents.  Indeed, we 
anticipate that the typical child referred for the study will be receiving treatment with 
multiple medications with significant side effect risks, none of whose efficacy has been tested 
in a systematic fashion.  As specified above, patients who experience clinical worsening 
during the treatment trial will be terminated from it early and will receive either an open trial 
of citalopram or other appropriate clinical care.  Of the 40 children we have withdrawn from 
medication under protocol 02-M-0021, two had worsening of symptoms to the point of 
requiring removal from research and roughly 50% were clinically improved during the 
medication-free period compared to pre-admission baseline ratings. 
            Our prior experience suggests that a medication-free period provides the unusual 
opportunity to observe children during a phase where their psychiatric symptoms cannot 
easily be attributed to effects from ongoing treatments, providing insights on diagnosis and 
on capacities that could not be observed under heavy medication.  Thus, the superior 
diagnostic assessment that the drug-free period provides is essential.  For example, 
approximately 25% of the 40 patients we have withdrawn from medications were diagnosed 
with conditions following medication-free observation not evident at the initial assessment. 
Indeed, since the patients who enter our discontinuation study are not doing well and often 
are on many medications, there are legitimate questions as to whether their symptoms are 
influenced by treatment with antipsychotics or “mood stabilizers,” both of which are 
commonly prescribed in this population.   
 


 
22
E. HSPU team participation  
We value the support of the HSPU in our studies. Following IRB guidelines, we are 
requesting that the HSPU provide consent/assent monitoring and ongoing oversight during 
the inpatient/Day Treatment portions of the study for all participants.  Once patients are 
discharged to the outpatient portion of the study, we would involve the HSPU on a case-by-
case basis.   
 
F. Qualifications of investigators  
             The principal and co-investigators are well qualified to conduct this investigation. 
Dr. Argyris Stringaris, MD, PhD is a Child and Adolescent Psychiatrist and the Unit 
Chief of the Mood, Brain & Development Unit (MBDU). He is an internationally recognized 
expert in the pathophysiology of mood disorders. He has broad and deep experience working 
with children and adolescents with mood disorders or other serious psychiatric illnesses in a 
clinical research context. He will be obtaining consent for the protocol. 
             Dr. Ellen Leibenluft is an internationally recognized expert on all aspects of pediatric 
bipolar disorder.  Her broad experience has focused on the presentation, course, mechanisms, 
and treatment of the disorder. She also has extensive clinical and research experience in the 
course and treatment of bipolar disorder in adults. She is the Chief of the Section on Mood 
Dysregulation and Neuroscience (SMDN) in the Emotion and Development Branch in the 
Mood and Anxiety Disorders Program.  
             Dr. Daniel Pine is an internationally recognized expert in pediatric neuroscience and 
child and adolescent psychiatry. He has conducted many treatment trials for childhood onset 
anxiety disorders and depression, and has vast experience in all aspects of pediatric 
psychiatric research.  He was previously a lead investigator for the Research Units in 
Pediatric Psychopharmacology for studies of anxiety in children and adolescents and is Chief 
of the Emotion and Development Branch.. 
             Dr. Kenneth Towbin is board-certified in adult and in child and adolescent psychiatry 
and has been Chief of Clinical Child and Adolescent Psychiatry in the Mood and Anxiety 
Disorder Program since its inception.  Dr. Towbin is currently staffed in the Emotion and 
Development Branch and has been the primary clinician for all inpatients treated by SMDN 
including medication discontinuation studies of pediatric bipolar patients and a placebo-
controlled trial of lithium in those with Severe Mood Dysregulation. Dr. Towbin has 
exceptionally strong experience working with children with bipolar disorder or other serious 
psychiatric illnesses in a clinical research context.  
 
 
 
Chana Engel, CRNP-PMH has experience working with adults and children with serious 
psychiatric disorders who works full time with the Emotion and Development Branch..  She will 
be performing routine clinical assessments (e.g. physical examinations, interpreting laboratory 
data, KSADS, clinical assessment for suicide) for patients entering or in the protocol.  She will 
also provide direct care and clinical monitoring of patients in the study. She will be obtaining 
consents.  
 
Holly Yokum, MSW is a licensed clinical Social Worker with decades of experience 
working with adults and children with bipolar spectrum disorder. She works full time in the 
Section on Mood Dysregulation and Neuroscience.  She will be obtaining clinical ratings and 
performing clinical assessment of patients entering the protocol.  She will not be obtaining 
consents for the study.  


 
23
 
 Gerald Overman, Pharm.D, BCPP  Clinical Pharmacy Specialist NIH CC Pharmacy 
Dept provides consultative assistance to the program and to Dr. Towbin.  Dr. Overman will 
provide oversight of the process of delivering coded capsules to the unit and consultation to Dr. 
Towbin on matters related to medication tapering schedules, pharmacokinetics of stimulants, and 
liaison with the Pharmacy Department.  He will not be obtaining consent for this protocol 
 
Wanda Wheeler, MSW is a licensed clinical Social Worker and who works full time in 
the Section on Mood Dysregulation and Neuroscience.  She will be obtaining clinical ratings and 
performing clinical assessment of patients entering the protocol.  She will not be obtaining 
consents for the study.  
  Mollie Davis, MSW is a licensed clinical Social Worker and is credentialed through 
the Clinical Center Social Work Department. She has extensive experience working with 
adults and children with a variety of psychiatric disorder. She is a contractor working full 
time in SMDN.  She will be obtaining clinical ratings and performing clinical assessment of 
patients entering the protocol.  She will not be obtaining consents for the study.  
 
 
Cheri McNeil, PsyD is a licensed clinical Psychologist who is credentialed 
in the NIH Clinical Center as a licensed independent practitioner and works full time for SMDN. 
She has extensive experience working with adults and children with a variety of psychiatric 
disorders. She will be obtaining clinical ratings and performing clinical assessment of patients 
entering the protocol.  She will not be obtaining consents for the study. 
 
 X. BENEFITS 
              It is reasonable to expect that some patients may benefit from citalopram+MPH or 
from MPH alone.  The weight of the evidence favors prospect of benefit. Of course, we 
cannot predict which patients will benefit, so subjects who enter the trial must be informed of 
the possibility that they will see no direct personal benefit from participation.  The research 
evaluations performed in this investigation, including laboratory assays and 
neuropsychological testing, are not designed to benefit study participants.   
               The overall results of the study may provide information leading to new treatments 
for SMD and may be of benefit to others. 
 
XI. SUMMARY/CLASSIFICATION OF RISK 
           The risks associated with citalopram+MPH administration can be classified as a minor 
increment over minimal risk, with a prospect of direct benefit to participants.  As such, 
enrolling children into this study is ethically permissible, despite a greater-than-minimal-risk 
classification, since children entering in the study have severe illness and the potential for 
direct benefit.  As reviewed in Section II, these standard drug treatments for SMD are often 
ineffective, and individual patients will only be included in the current study if their ongoing 
treatment is ineffective. In addition, if citalopram is effective in reducing symptoms of 
irritability this would have a significant public health impact and reduce the suffering of 
many children with this constellation of symptoms. Overall, risk in this study is categorized 
as more than minimal risk with the prospect of direct benefit. 
 
XII. CONSENT DOCUMENTS AND PROCESS 
           The consent process will be conducted by one of the physician investigators or Ms. 
Engel, and the Human Subjects Protection Unit (HSPU) will be present to oversee the 


 
24
procedure and assure protection of the interests of the subjects and their families. HSPU will 
also provide on-going subjects monitoring during hospitalization.  
           Subjects and their legal guardians will be informed that this is the first systematic 
investigation of citalopram as a treatment for symptoms in SMD in young patients, and that 
no one knows if it will be helpful. Because there have been no previous studies of citalopram 
in SMD, subjects and guardians will also be told that there is a chance that the medication 
could worsen their mood symptoms, although we think this unlikely.  Subjects and guardians 
will be informed of the possibility and encouraged to discuss any concerns.  All subjects and 
guardians also will be fully informed about the side-effects of citalopram and MPH.  They 
will be reminded that alternative and potentially effective treatments exist for symptoms of 
SMD.   
            Following these explanations, if subjects and their guardians wish to enroll in the 
citalopram/placebo trial, the study will be described in detail, the consent document reviewed, 
and subjects and guardians will have an opportunity to have their questions answered before 
being asked to sign three identical copies of the consent form.  Children and adolescents will 
be asked to sign assent forms that describe the study in age-appropriate language. They will 
be informed that they have true decision-making authority, and withholding assent means 
they will not continue in the study. Parents and children will be informed that they may 
withdraw their consent/assent at any time and for any reason. Investigator and witness will 
then sign the consents/assents, and one copy of each form will be returned to the study 
participants, another filed in the subject’s research folder, and the third will be entered into 
the NIH medical record. 
 
Consent for participation of minors will be obtained from parents/legal guardians. If the 
parents are married, written consent may be obtained from one parent only.  If the parents are 
not married, written consent will be obtained from: 1) the custodial parent if only one parent 
has legal custody, or 2) from both parents if they share legal custody for medical decision-
making.  For unmarried parents, signature of one parent will also suffice if the other parent is 
deceased, unknown, incompetent, or not reasonably available.  When signature of both 
parents is required, written consent will be obtained in-person from at least one parent.  When 
the second parent is unable to attend the consent process conference in person, the following 
telephone process to obtain written consent will be used.   
 
Sharing of data will be done under a waiver of informed consent if a participant previously 
signed a consent form that did not have information on sharing or if the consent form 
provided options for sharing and the participant did not ask that his/her data not be shared.  
For coded/linked data shared under a waiver of informed consent, those using the shared data 
will not contact or attempt to contact the participant unless the IRB approves such contact.  
Waiver of consent to share these data meets the criteria set out in 45 CFR 46.116(d): 
• The research involves no more than minimal risk to the subjects. The sharing and 
additional use of data does not present more than minimal risks to previous 
participants.  
• The waiver or alteration will not adversely affect the rights and welfare of the subjects. 
Data will have personally identifying information removed and will be coded or 
completely unlinked from any identifying code.   
• The research could not practicably be carried out without the waiver or alteration. Long 
term storage and complete data require the submission of these data.  Understanding 


 
25
of the disease or condition being studied cannot be generated without broad 
contributions to the research effort.   
• We will have been unable to contact those for whom coded data are being used under 
this waiver. In the unlikely event that such participants make contact with us, we will 
provide them with information about the waiver and research use of their data. 
 
Three attempts will be made to reach former minor participants before determining that they 
are unavailable.  The waiver applies only to those whose parents signed a version of the 
consent form that was silent on sharing and who cannot be reached for re-consent.  The 
waiver does not apply to those whose parents explicitly declined sharing/additional uses of 
the data or who requested recontact before deciding.  The waiver does not apply to those who 
were contacted as adults but declined to sign a consent form 
 
 
Telephone Consent Procedures: 
 
The unavailable parent will be provided with a copy of the consent form, usually by fax, 
email, or hard copy.  Once the consent form is received, an Investigator authorized to obtain 
consent will arrange for a telephone call with the parent in the presence of a witness to review 
the study and the consent form and to answer any questions.  If the parent cannot arrange for 
a witness in his/her location, the consenting investigator will have a witness present at NIH 
during the teleconference.  Once the parent agrees to his/her child’s participation, the parent 
and witness (if present with the parent) will sign and date their copy of the consent form.  The 
Investigator will enter a note documenting the consent process in the Medical Record. The 
2nd parent will return their signed copy to the Investigator.  Once the copy with the parent 
signature is received, the Investigator and witness (if present at NIH) will sign and date the 
2nd parent consent form, place the original copy with all signatures in the Medical Record, 
retain a copy for research records, and mail a copy to the parents.  The telephone consent 
process will be documented in the medical record. 
 
Verbal assent will be obtained from minor participants who are old enough to understand 
the nature of the study and its implications, but are too young to provide a signature.  Written 
assent will be obtained from minors older than age seven whenever possible.  Dissent will be 
respected in children of all ages.  The assent process will be documented in the medical 
record. 
 
 Consent for NIH employees and staff will not be obtained by coworkers. 
 
XIII. DATA AND SAFETY MONITORING 
a. 
Data and safety monitor 
Data and safety will be monitored by the Principal Investigator.  
b. Data and safety monitoring plan 
The PI will review data and safety parameters at least annually. The PI will 
document the data and safety review in the research records and at the time of 
continuing review. 
c. 
Criteria for stopping the study or suspending enrollment or procedures 
The study (or the study-specific procedure) will be stopped is there is any Serious 
Adverse Event related to the research. The PI and IRB will determine if changes are 
needed for the research to continue or if it will be closed. Any changes required as 


 
26
conditions for resuming the research must be submitted as an amendment and IRB-
approved before the changes can be implemented.  
 
XIV. QUALITY ASSURANCE (QA) 
a. Quality assurance monitor 
Quality assurance will be monitored by the PI, the research team and the NIMH 
Office of Regulatory Oversight (ORO). 
 
b. Quality assurance plan 
ORO monitors intramural research studies to ensure compliance with GCP, 
organizational policies and regulations.  Audit frequency is determined by the 
ORO SOP based on the study level of risk.  Results of ORO audits are provided to 
the PI, the Clinical Director and the CNS IRB. This study will undergo audits at 
least once every three years and for cause. 
 
XV. ADVERSE EVENT REPORTING 
 
The Principal Investigator is responsible for detecting, documenting, and reporting 
unanticipated problems, adverse events (AEs), including serious adverse events (SAEs), and 
deviations in accordance with NIH policy, IRB requirements, and federal regulations. 
Relatedness to the research of all serious adverse events will be determined by the PI in 
consultation with the Clinical Director (CD) of NIMH.   
 
Serious unanticipated problems, serious adverse events (including deaths) that are not 
unanticipated problems, and serious protocol deviations will be reported to the IRB and CD 
as soon as possible and in writing not more than 7 days after the PI first learns of the event, 
unless immediate reporting is waived for specific serious adverse events as noted 
below.  Unanticipated problems and serious deviations will be reported on the NIH “Problem 
Report Form.”  Serious Adverse Events will be reported on the “Serious Adverse Event 
Report Form.”  Not serious unanticipated problems and not serious deviations will be 
reported to the IRB and CD as soon as possible and in writing on the NIH Problem Report 
Form not more than 14 days after the PI first learns of the event. 
  
All adverse events, deviations, and unanticipated problems will be summarized and reported 
at the time of Continuing Review. 
 
 
XVI. ALTERNATIVES TO PARTICIPATION OR ALTERNATIVE THERAPIES  
Antidepressants (TCAs, MAOIs, SSRIs), mood stabilizers (lithium, carbamazepine, 
lamotrigine and valproate), atypical antipsychotics (e.g. risperidone, olanzapine, quetiapine) 
and psychotherapies (e.g. CBT) could be efficacious for SMD. Before being considered for 
this study, subjects will be reminded that these treatments are available to them in the 
community. This approach will assure that subjects are clearly informed of the standard care 
before being exposed to the risks of citalopram or MPH. 
 
XVII. PRIVACY 
All research activities will be conducted in as private a setting as possible. 


 
27
 
XVIII. CONFIDENTIALITY 
             
Every necessary step will be taken to prevent identification of study participants or 
violations of confidentiality of the data.  Information will be stored using a confidential code 
and data will be treated only as groups.  All data entered into the NIH CTDB database will 
appear only in coded form.  Members of the research team will have access to these coded 
data.  Only staff directly involved in the care of each subject will have access to clinical 
documents that contain identifying information.  This will include research assistants, clinical 
staff, and the study psychiatrist. Please see Appendix B for a description of data security of 
CTDB.     
 
All research activities will be conducted in as private a setting as possible. 
 
XVIX. CONFLICT OF INTEREST/TECHNOLOGY TRANSFER  
 
There is no conflict of interest involved with this study beyond the professional benefit 
from academic publication or presentation of the results. 
 
XVX. COMPENSATION 
 
Subjects will not be compensated for participation in the Stimulant + Citalopram trial. 
Compensation is provided for research activities completed during the medication trial period 
as follows:  
 
 
Amounts 
Ratings (weekly) 
$10 
 
 
Total  
$120-180  
 
Employees and staff who participate during work hours must have permission from their 
supervisor. NIH employees must either participate outside of work hours or take leave in 
order to receive compensation. 
 
XVXI. PHARMACEUTICAL INFORMATION 
A.  Source, formulation, and preparation 
1. Citalopram or placebo capsules 
Citalopram 5mg capsules or matching placebo capsules will be manufactured by Murty 
Pharmacauticals, Inc under current Good Manufacturing Practice (cGMP) regulations. 
1.a Open Label Citalopram 
Citalopram HBr is an orally administered selective serotonin reuptake inhibitor (SSRI) with a 
chemical structure unrelated to that of other SSRIs or of tricyclic, tetracyclic, or other 
available antidepressant agents. Citalopram HBr is a racemic bicyclic 
phthalane derivative designated (±)-1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-
dihydroisobenzofuran-5-carbonitrile, HBr with the following structural formula: 
The molecular formula is C20H22BrFN2O and its molecular weight is 405.35. Citalopram 
HBr occurs as a fine, white to off-white powder. Citalopram HBr is sparingly soluble in water 


 
28
and soluble in ethanol. Citalopram hydrobromide is available as tablets or as an oral solution. 
Citalopram 10 mg tablets are film-coated, oval tablets containing 
citalopram HBr in strengths equivalent to 10 mg citalopram base. Citalopram 20 mg and 40 
mg tablets are film-coated, oval, scored tablets containing citalopram HBr in strengths 
equivalent to 20 mg or 40 mg citalopram base. The tablets also contain the following 
inactive ingredients: copolyvidone, corn starch, crosscarmellose sodium, glycerin, lactose 
monohydrate, magnesium stearate, hypromellose, microcrystalline cellulose, polyethylene 
glycol, and titanium dioxide. Iron oxides are used as coloring agents in the beige (10 mg) and 
pink (20 mg) tablets. Citalopram oral solution contains citalopram HBr equivalent to 
2 mg/mL citalopram base. It also contains the following inactive ingredients: sorbitol, 
purified water, propylene glycol, methylparaben, natural peppermint flavor, and 
propylparaben. 
 
2. Methylphenidate 
Ritalin hydrochloride, methylphenidate hydrochloride USP, is a mild central nervous system 
(CNS) stimulant, available as tablets of 5, 10, and 20 mg for oral administration.  
Methylphenidate hydrochloride is methyl a-phenyl-2-piperidineacetate hydrochloride. 
Methylphenidate hydrochloride USP is a white, odorless, fine crystalline powder. Its 
solutions are acid to litmus. It is freely soluble in water and in methanol, soluble in alcohol, 
and slightly soluble in chloroform and in acetone. Its molecular weight is 269.77. Inactive 
Ingredients. Ritalin tablets: D&C Yellow No. 10 (5-mg and 20-mg tablets), FD&C Green No. 
3 (10-mg tablets), lactose, magnesium stearate, polyethylene glycol, starch (5-mg and 10-mg 
tablets), sucrose, talc, and tragacanth (20-mg tablets).  
 
B. Pharmacology 
1. Citalopram: 
The single- and multiple-dose pharmacokinetics of citalopram are linear and dose-
proportional in a dose range of 10-60 mg/day. Citalopram has a mean terminal half-life of 
about 35 hours and is metabolized in the liver primarily via N-demethylation, deamination, 
and N-oxidation to less lipophilic compounds which are more readily excreted by the kidney 
(Milne & Goa, 1991; Sweetman, 2000).  With once daily dosing, steady state plasma 
concentrations are achieved within approximately one week. At steady state, the extent of 
accumulation of citalopram in plasma, based on the half-life, is expected to be 2.5 times the 
plasma concentrations observed after a single dose. The tablet and oral solution dosage forms 
of citalopram HBr are bioequivalent (Product Information, Celexa®).  
 
Absorption and Distribution 
Following a single oral dose (40 mg tablet) of citalopram, peak blood levels occur at about 4 
hours. The absolute bioavailability of citalopram was about 80% relative to an intravenous 
dose, and absorption is not affected by food. The volume of distribution of 
citalopram is about 12 L/kg and the binding of citalopram (CT), demethylcitalopram (DCT) 
and didemethylcitalopram (DDCT) to human plasma proteins is about 80% (Kragh-Sorensen 
et al., 1981; Milne & Goa, 1991; Sweetman, 2000). 
 
Metabolism and Elimination 


 
29
Following intravenous administrations of citalopram, the fraction of drug recovered 
in the urine as citalopram and DCT was about 10% and 5%, respectively. The systemic 
clearance of citalopram was 330 mL/min, with approximately 20% of that due to renal 
clearance.  
Citalopram is metabolized to demethylcitalopram (DCT), didemethylcitalopram 
(DDCT), citalopram-N-oxide, and a deaminated propionic acid derivative (Milne & Goa, 
1991; Oyehaug & Ostensen, 1984; Overo, 1982). In humans, unchanged citalopram is the 
predominant compound in plasma. At steady state, the concentrations of citalopram’s 
metabolites, DCT and DDCT, in plasma are approximately one-half and one-tenth, 
respectively, that of the parent drug. In vitro studies show that citalopram is at 
least 8 times more potent than its metabolites in the inhibition of serotonin reuptake, 
suggesting that the metabolites evaluated do not likely contribute significantly to the 
antidepressant actions of citalopram. In vitro studies using human liver microsomes indicated 
that CYP3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of 
citalopram. 
 
2. Methylphenidate 
Absorption and Distribution:  
For regular methylphenidate (oral), time to peak concentration is 1 h to 2 h and the 
distribution (Vd) is 6 L/kg with protein binding of 10% to 33% (Kimko et al., 1999). 
Following administration of 0.3 mg of methylphenidate per kg of body weight (mg/kg) the 
blood concentration in children is 10-18 nanograms per mL (Kimko et al., 1999).  Peak 
plasma concentrations showed marked variability between subjects (Kimko et al., 1999). 
Dose-proportionality was demonstrated in peak plasma concentrations and area under the 
concentration-time curve (AUC) values for all brands of methylphenidate. Time to Peak 
Concentration is 1 to 3 hours (Dayton et al., 1970).  
 
Metabolism and Elimination: 
Metabolism is via deesterification into metabolites alpha-phenyl-piperidine acetic acid (PPA, 
ritalinic acid). Excretion is primarily via the kidneys. 78% to 97% is eliminated via the 
kidneys with less than 1% is unchanged and approximately 80% is excreted as PPA.  Fecal 
elimination occurs for 1% to 3%.  The elimination half life is 3 h for methylphenidate and 3-
4 hours for ritalinic acid.  
 
C.  Toxicity 
 
Side effects of citalopram and methylphenidate are also reviewed in Section V. 
 
Toxicity Criteria 
1. Citalopram 
 
In clinical trials of citalopram, there were reports of citalopram overdose, including 
overdoses of up to 2000 mg, with no associated fatalities. During the post-marketing 
evaluation of citalopram, citalopram overdoses, including overdoses of up to 6000 mg, have 
been reported. As with other SSRI’s, a fatal outcome in a patient who has taken an overdose 
of citalopram has been rarely reported. 
 
Symptoms most often accompanying citalopram overdose, alone or in combination 
with other drugs and/or alcohol, included dizziness, sweating, nausea, vomiting, tremor, 


 
30
somnolence, and sinus tachycardia. In more rare cases, observed symptoms included 
amnesia, confusion, coma, convulsions, hyperventilation, cyanosis, rhabdomyolysis, and 
ECG changes (including QTc prolongation, nodal rhythm, ventricular arrhythmia, and one 
possible case of torsades de pointes).     
 
2. Methylphenidate 
 
In overdose with methylphenidate, agitation, tachycardia and lethargy were commonly 
reported following unintentional exposure to immediate-release methylphenidate in children. 
CNS toxic effects may range from restlessness, uncontrolled movements, agitation, 
irritability, confusion and insomnia to marked hyperactivity, seizures, hypertension and coma 
following severe exposure. Although infrequent, death has been reported following overdose. 
Effects appear to be dose-dependent. Severe toxicity has been reported in adolescents and 
adults following intentional methylphenidate misuse. 
  
 
D. Administration 
 
See Section IV E.  
 


 
31
Appendix A: Figure 1: 
 


 
32
Appendix B: CTDB 
 
The Clinical Trials Database Project (CTDB) assists Investigators with the management of 
natural history and clinical trial research projects.  Associated with the project are two major 
components: (1) a set of information technology systems based upon industry standard 
technologies and best practices (e.g. Java, XML, UML); and (2) a team of support staff that 
assist investigators with designing and executing research projects.   
 
The CTDB is a web-based application that supports flexible data capture, and reporting. The 
system is hosted at the NIH in Bethesda, MD.  It is accessible via the Internet through the 
NIH firewall, on both Mac and Windows based computers.  An Oracle relational database is 
utilized to capture and secure data entered through the web interface. 
 
The web interface is organized in to areas for system administration, protocol design, data 
collection, and reporting.  The primary features of the system include the following: 
 
• System Administration functions to secure electronic patient data, and allow PIs to 
control staff access to confidential clinical information. 
• Protocol design tools that allow researchers to customize the system for each 
protocol, including creating data collection instruments, intervals, barcode labels, and 
collaborative tools, as well as to record patient demographics. 
• A Question Library that serves as a central repository for researchers to build protocol 
forms and share common vocabularies. 
• Multi-Site capabilities allow investigators to become the coordinating center for a 
geographically dispersed trial.  
• Data collection tools (e.g., double-key data entry) to ensure the integrity of patient 
response data. 
• The Clinical Data Mart – an ancillary system that integrates patient data and allows 
for data analysis across multiple protocols. 
• A Reporting tool that allows researchers to directly query patient response data and 
facilitates IRB and DSMB reporting.  
• The Clinical Trial Survey System (CTSS) – an ancillary web-based application, 
accessible outside the NIH, that allows patients to remotely respond to clinical 
questionnaires. 
• A Bio-specimen management module that allows users to create custom locations and 
track the biospecimens collected during trials.  The results of bio-specimen analysis 
may also be seamlessly integrated using this module. 
 
Collectively, the CTDB project currently supports 170 research protocols across 10 Institutes 
at NIH: NICHD, NIMH, NINR, NIDDK, NIDCR, CC, NIEHS, NIAMS, NHGRI, and 
NHLBI.  The project has assisted researchers consolidate datasets for over 300 scientific 
publications.  
 
 
 
 


 
33
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SAP_001.pdf: 
Selective serotonin reuptake inhibitor add-on to 
stimulant medication in youth with severe mood 
dysregulation 
 
A double-blind randomized controlled trial of 
adjunctive citalopram in youth with chronic severe 
irritability treated with stimulant  
 
Statistical Analysis Plan 
Version 0.3 
Version started: 21/06/2018 
ClinicalTrials.gov Identifier: NCT00794040  
This SAP has been written based on Protocol 09-M-0034 Amend 12 
 
Trial Statistician: Pablo Vidal-Ribas (from December 12, 2017) 
 
Signature............................................        Date ......June 25, 2018.... 
 
Chief Investigator: Argyris Stringaris 
 
Signature............................................        Date ......June 25, 2018.... 
 
 
 
 


 
 
 
 
 
Contents 
1. 
Quantitative Analysis Plan .............................................................................. 4 
1.1. 
Brief description of the trial ............................................................................... 5 
1.1.1. 
Principal research objectives to be addressed ............................................. 6 
1.1.2. 
Trial design ................................................................................................. 6 
1.1.3. 
Method of allocation of groups ................................................................. 10 
1.1.4. 
Duration of the treatment period ............................................................... 10 
1.1.5. 
Frequency and duration of follow-up ........................................................ 10 
1.1.6. 
Visit windows ........................................................................................... 10 
1.1.7. 
Eligibility screening .................................................................................. 11 
1.1.8. 
Measures ................................................................................................... 11 
1.1.9. 
Sample size estimation (including clinical significance) .......................... 13 
1.1.10. 
Brief description of proposed analyses .................................................. 14 
1.2. 
Data Analysis Plan - Data Description ............................................................. 16 
1.2.1. 
Recruitment, eligibility and representativeness of patients....................... 16 
1.2.2. 
Baseline comparability of randomized groups .......................................... 18 
1.2.3. 
Adherence to allocated treatment and treatment fidelity .......................... 18 
1.2.4. 
Loss to follow-up and other missing data ................................................. 18 
1.2.5. 
Assessing quality of outcome measures .................................................... 18 
1.2.6. 
Adverse event reporting ............................................................................ 19 
1.2.7. 
Descriptive statistics for outcomes measures ............................................ 19 
1.3. 
Data Analysis Plan – Inferential analysis ......................................................... 20 
1.3.1. 
Aims of formal inferences (overview) ...................................................... 20 
1.3.2. 
Analysis of the primary outcome .............................................................. 21 


 
 
 
1.3.3. 
Missing Data ............................................................................................. 23 
1.3.5. 
Sensitivity analysis .................................................................................... 23 
 
 
 
 


 
 
 
Quantitative Analysis Plan 
 
This document details the presentation and analysis strategy for the primary paper 
reporting results from this trial. It is intended that the results reported in this paper will 
follow the strategy set out herein; subsequent papers of a more exploratory nature will 
not be bound by this analysis plan but will be expected to follow the broad principles 
laid down for the principle paper(s). The principles are not intended to curtail 
exploratory analysis or to prohibit sensible statistical and reporting practices but they 
are intended to establish the strategy that will be followed as closely as possible, when 
analyzing and reporting the trial. Reference was made to the trial protocol version 12, 
ICH guidelines on Statistical Principles (ICH E9 (1998)) reference and CONSORT 
guidelines {Moher, 2010 #4089}. 
 
Investigators 
Ellen Leibenluft, MD 
Daniel Pine, MD 
Kenneth Towbin, MD 
Holly Yokum, MSW 
Wanda Wheeler, MSW 
Gerald Overman, PharmD BCPP 
Chana Engel, CRNP-PMH 
Mollie Davis, MSW 
Cheri McNeil, PsyD 
 
Principal Investigator 
Argyris Stringaris, MD PhD 
 
Lead Associate Investigator 
Kenneth Towbin, MD 
 
Analysis Statistician 
Pablo Vidal-Ribas (in consultation with Professor Andrew Pickles, King’s College 
London) 


 
 
 
1.1. Brief description of the trial 
 
Severe mood dysregulation (SMD) is a common syndrome in children and adolescents, 
characterized by 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). However, today we know that SMD 
and BD differ in family history of psychiatric disorders, pathophysiological mechanisms 
and longitudinal outcomes. For example, SMD presents high comorbidity with anxiety 
disorders and is associated with anxiety and depression in longitudinal studies, but not 
with BD. Furthermore, we know that lithium, a medication typically used to treat BD, 
does not improve irritability in youth with SMD. To date, there are no randomized trials 
that have examined pharmacological treatments for SMD with irritability as primary 
outcome.  
 
ADHD is primarily treated with stimulant medication; and the first pharmacological 
option for anxiety and depression are selective serotonin reuptake inhibitors (SSRI). 
Given the presence of ADHD symptoms in SMD, and the specific association with 
anxiety and depression, this study will evaluate the effectiveness of the stimulant 
medication methylphenidate when combined (or not combined) with the SSRI 
citalopram, in treating symptoms of SMD in children and adolescents.  


 
 
 
1.1.1. Principal research objectives to be addressed  
The hypothesis is that we will demonstrate that citalopram added to methylphenidate 
improves irritability symptoms to a greater extent than placebo added to 
methylphenidate. 
 
Primary objectives  
To conduct a Phase II RCT to test the efficacy of citalopram plus methylphenidate vs. 
placebo plus methylphenidate in decreasing irritability in youth with severe mood 
dysregulation. 
 
Secondary objectives 
 
To assess the effects of citalopram + methylphenidate on several secondary measures, 
such as depressive symptoms, anxiety symptoms, side effects, and overall functional 
impairment. 
 
1.1.2. Trial design 
The trial is designed as a double-blind two-arm parallel groups randomized control trial. 
Children and adolescents aged 7-17 years old will be randomized to either a citalopram 
plus methylphenidate arm or a placebo plus methylphenidate arm. 
 
Specifically, the trial is comprised of four mandatory phases and one optional phase. 
During Phase I participants will withdraw of their current medication (duration flexible, 
depending on the patient’s medication at admission). Phase II consists of a medication free 


 
 
 
period (one week). Phase III involves open treatment with methylphenidate to find the 
optimal dose (up to 5 weeks). Phase IV is the treatment phase, in which the randomized trial 
of citalopram plus methylphenidate vs. placebo plus methylphenidate is undertaken (8 
weeks). After Phase IV, blindness will be broken. Finally, an optional Phase V will include 
open treatment as indicated in preparation for return to community care (Figures 1 and 2). 
Medication withdrawal, the medication-free week, the methylphenidate open trial, and 
initial dose stabilization using citalopram/placebo will occur while patients are either 
hospitalized or attending the Day Treatment Center. During the 8-week citalopram/placebo 
trial and subsequent open treatment, patients can be hospitalized, in day treatment, or 
outpatients, according to what is clinically appropriate (Figure 1). Participants will be 
assessed in the clinic weekly. Baseline measures will be collected just after admission 
into the protocol, prior Phase I (Baseline 1), before starting the open trial with 
methylphenidate at Phase III (Baseline 2) and just after randomization in Phase IV 
(Baseline 3).  Outcomes will be based on change in reference to Baseline 1 and Baseline 
3.


 
 
 
Figure 1. Trial design diagram 
 


 
 
 
 
 
Figure 2. Trial design flow diagram 


 
 
 
1.1.3. Method of allocation of groups 
The study was randomized by the Pharmaceutical Development Service of the National 
Institutes of Health Clinical Center Pharmacy Department using a random numbers 
table. It was randomized in alternating blocks of six and four in a 1:1 ratio. 
 
Participants and their parents will be blind to treatment allocation. The patient’s 
research physician, primary NIMH clinician who performs mood ratings, and nursing 
staff will also be blind to treatment allocation.  
1.1.4. Duration of the treatment period 
The duration of the study (exclusive of open treatment at the end) is approximately 12-
15 weeks, depending on the time required for medication discontinuation. As mentioned 
in section 1.1.2 of this document, the active intervention (Phase IV) consists of 8 weeks.  
1.1.5. Frequency and duration of follow-up 
Participants will be assessed in the clinic once a week beginning at the medication 
withdrawal period (Phase I) until the end of the randomized trial period (Phase IV). 
There are no follow-up assessments. 
1.1.6. Visit windows 
The first assessment will take place before the medication withdrawn period (Baseline 
1). The final assessment will take place after the randomized trial (Week 8 of Phase IV). 
Assessments between the first and final collection of measures will be done once a 
week.  


 
 
 
Typically, there was a 2 day visit window (for the inpatients, most were done the same 
day every week) but it might shift slightly for outpatients—except for end of week 8 
which was exact. 
1.1.7. Eligibility screening 
Potential SMD participants will be screened via phone. Those who seem to meet 
inclusion criteria will be seen and screened in person in the clinic. If criteria are met, 
after this point, participants must give written consent to participate in the trial. After 
withdrawn medication period, free medication period, and open trial with 
methylphenidate, participants are rescreened for inclusion criteria prior to 
randomization. Inclusion and exclusion criteria are described in section III.A and III.B 
of the protocol, respectively. 
1.1.8. Measures 
 
The mechanisms for which all of the following measures will be recorded are described 
in detail in the protocol in section IV. 
 
Baseline 
The following demographics will be measured at baseline for the child participant: 
• Ethnicity (White; Asian; Black or African American; Mixed; Unknown) 
• Age (years) 
• Sex  
• Religion (Anglicanism; Baptist; Catholicism; Christian; Greek Orthodox; 
Judaism; Protestantism; Non-Denominational; None; Unknown) 
 


 
 
 
The following measure will be collected during the first on-site screening to evaluate 
inclusion/exclusion criteria: 
 
• Child Schedule for Affective Disorders Present and Lifetime Version (K-SADS-
PL) with an additional supplement for SMD {Kaufman, 1997 #2116}.   
• Autism Screening Questionnaire {Berument, 1999 #4077;Berument, 1999 
#4077}, the Social Responsiveness Scale (SRS) {Constantino, 2003 #4078}, and 
the Children’s Communication Checklist {Bishop, 1998 #4079}, so that children 
with probable PDD can be identified and, if symptoms are severe, excluded 
from the protocol.  
• Full-scale intelligence quotient (FSIQ) was measured by the Wechsler 
Abbreviated Scale of Intelligence (WASI) {Wechsler, 1999 #2479}.  
Outcome measures  
All outcomes measures will be first collected before the medication withdrawn period 
(Baseline 1) and then every other week during this period, and the free medication 
period. The same measures will be collected before the open treatment with 
methylphenidate (Baseline 2) and then every other week until before randomization for 
the trial. Then, the same measures will be collected just after randomization (Baseline 3) 
and then every other week (8 weeks total) until the end of the trial. 
 
Primary outcome measures 
Our primary outcome measure will be the Clinical Global Impressions (CGI) for 
Irritability {Spearing, 1997 #4087}. Specifically, we will measure current severity of 
irritability (CGI-S) and improvement or change in relation to baseline (CGI-I), both 
baseline 1 and baseline 3. 


 
 
 
The CGI is rated on a 7-point scale, with the severity of illness scale (CGI-S) using a 
range of responses from 1 (normal) through to 7 (amongst the most severely ill 
patients). CGI-I scores range from 1 (very much improved) through to 7 (very much 
worse). 
Trial response will be defined as a CGI-I score less than 3 at the trial’s end (i.e., 
children who received scores of 2 [much improved], or 1 [symptom free]). 
  
Secondary outcome measures 
Several secondary outcomes will be used to assess secondary objectives, as mentioned 
in section 1.1.1. Namely, to assess the side effects and adverse events of prescribed 
medications, as well as depressive symptoms, anxiety symptoms and global functional 
impairment: 
 
• Side Effects will be measured with Dosage Record & Treatment Emergent 
Symptom Scale (DOTES) {Garvey, 1991 #4088}. 
• Depressive symptoms will be measured with the Children's Depression Rating 
Scale (CDRS) {Poznanski, 1996 #3011}. 
• Anxiety symptoms will be measured with the Pediatric Anxiety Rating Scale 
(PARS) {Riddle, 2002 #3010}. 
• Global functional impairment will be measured with the Children's Global 
Assessment Scale (CGAS) {Shaffer, 1983 #2478}. 
1.1.9. Sample size estimation (including clinical significance) 
 


 
 
 
The calculation for the protocol assumed a response rate of 60% to citalopram+MPH 
and 20% to placebo+MPH. While, on the surface, this might seem like a somewhat 
large clinical difference, when SSRIs are highly effective in pediatric conditions, such 
as pediatric anxiety disorders, effect sizes of this magnitude are typically found {Ipser, 
2009 #4086}.  
 
Since there are no treatment trials in SMD targeting irritability, the placebo response 
rate is based on the MTA, a large treatment trial in ADHD using stimulants {Galanter, 
2003 #4084;Greenhill, 2001 #4085}. Assuming power=0.8 and a two-tailed alpha= 
0.05, a sample size of 56 (28 in each group) is needed. However, of course, in the event 
that the response to SSRIs in SMD is more similar to that in pediatric MDD than 
pediatric anxiety, power will be less than 0.8 {Wagner, 2004 #4082;Cipriani, 2016 
#4083}. 
 
Our experience with a previous treatment trial in this population suggests that roughly 
50% of participants might not reach the point of randomization because of behavioral 
improvement, withdrawal from the study because of homesickness, or intolerance of 
medication discontinuation. Thus we are anticipating enrolling 112 children in order to 
ascertain 80 who will be randomized. 
1.1.10. Brief description of proposed analyses 
Analyses will be carried out by the trial statistician (PVR), following this SAP, and 
blind to treatment arm, once the database has been locked. Data will be analyzed with 
an intention-to-treat approach (i.e. analyze all those with data in groups as randomized 
irrespective of treatment received). 
 


 
 
 
There will be descriptive statistics reported on the measures mentioned in 1.1.8, with an 
aim to comparing the treatment arms, and to review the patient demographics. 
 
For the primary analysis, to test efficacy of citalopram plus methylphenidate vs. placebo 
plus methylphenidate in decreasing irritability in youth with SMD, a multilevel mixed-
effects growth curve regression will be fitted for all continuous measures.    
 
Further details of the analyses are given later on in this document.  
 
Data summaries and analyses will be carried out in Stata 14.0. 
 
 


 
 
 
1.2. Data Analysis Plan - Data Description 
1.2.1. Recruitment, eligibility and representativeness of patients 
A CONSORT flow chart will be constructed – see Figure 3. The number of patients 
will be summarized using the following categories: total number of patients contacted; 
eligible; consenting; and randomized. 
 
Then by treatment arm: patients compliant and non-compliant with intervention; 
continuing through the trial; withdrawing; and excluded or analyzed. 


 
 
 
 
 
Figure 3. CONSORT Diagram 


 
 
 
1.2.2. Baseline comparability of randomized groups 
Table 1 will present, for all available cases, means and standard deviations (proportions 
and frequencies for categorical variables) disaggregated by treatment group for baseline 
values of variables contributing to the primary and secondary outcomes and background 
participant socio-demographic variables. No statistical significance tests or confidence 
interval will be calculated for the difference between randomized groups on any 
participant level baseline variables. The randomisation of intervention groups to 
participants should have ensured that any imbalance over all measured and unmeasured 
baseline characteristics is due to chance {Altman, 1991 #4080}.  
1.2.3. Adherence to allocated treatment 
Any departures from intended treatment assignment will be described by the number of 
weeks completed. Adherence to allocated treatment will be defined as being adhered 
minimum 6 weeks out of 8 weeks (i.e., minimum 75%)(minimum 6). 
1.2.4. Loss of cases and other missing data 
Table 1 will also present the numbers with endpoint data within each randomized group 
for each outcome. The major known reasons for loss to follow-up will be described and 
any systematic differences by treatment group in the characteristics of those lost will be 
described.  
1.2.5. Assessing quality of outcome measures 
 
Treatment blind analysis will be carried out to assess quality of data collected, checking 
that measures conform to appropriate ranges, that scatter plots show no implausible 
patterns, and dates conform to expectations. 


 
 
 
1.2.6. Adverse event reporting 
 
Adverse side effects will be described and analyzed as a secondary outcome in the 
primary paper, as described in section 1.1.8. Specifically, medication side effects will be 
measured with the Dosage Record & Treatment Emergent Symptom Scale (DOTES). 
Frequencies of the most common adverse events will be tabled and reported if present 
in more than one subject in either of the study groups. 
 
1.2.7. Descriptive statistics for outcomes measures 
The primary and secondary outcomes as listed in section 1.1.8 will be described by 
treatment group and time point. Means and standard deviations or medians and 
interquartile ranges will be used for continuous variables. 
 
 


 
 
 
1.3. Data Analysis Plan – Inferential analysis 
1.3.1. Aims of formal inferences (overview) 
The study analysis and publication plan will follow CONSORT guidelines. This 
statistical analysis plan will be agreed before any inspection and analysis of post 
randomisation assessments.  
 
We powered our study to ask whether citalopram added to methylphenidate improves 
irritability symptoms and functional impairment over placebo added to 
methylphenidate. The formal statistical analyses will estimate the differences in relevant 
variables between patients randomized to citalopram added to methylphenidate 
compared to patients randomized to placebo added to methylphenidate, by intention to 
treat. That is, all randomized patients will be included in the analyses.  
 
Group difference estimates and associated 95% confidence intervals will be reported. 
All data preparation and analysis for the primary paper will be blind to treatment group. 
If any of the data contain information that may disclose blindness, these data will be re-
coded before analysis. The overall significance level will be 5% (two-sided) for the 
primary and secondary outcomes.  
 
Details on the methods for handling missing data are given in sections 1.3.3.  
 
Sensitivity analyses will be used to assess the robustness of conclusions; please refer to 
section 1.3.4 for details of the planned sensitivity analyses. 
 


 
 
 
No interim analysis is planned. 
1.3.2. Analysis of the primary outcome 
The analysis population will include all randomized patients. The primary outcome is 
improvement of irritability as measured with CGI, see section 1.1.8.  
 
To test the treatment effect of adding citalopram to methylphenidate vs adding placebo, 
a multilevel mixed-effects growth curve regression will be used. Specifically, given the 
multilevel structure with repeated assessments clustered within subjects, multilevel 
mixed models will be fitted. For the analysis of the CGI-I the growth curve model will 
be fitted using the xtmixed routine of the Stata statistical program, with restricted 
maximum likelihood (REML) estimation and an exchangeable covariance matrix for the 
covariances of the errors of the repeated measures. The fixed part of the model will 
include the baseline value of the outcome variable, any randomization stratification 
factors, treatment group, week as measure of time, and the interaction of group x week. 
The post-estimation lincom will be used to estimate the group difference at 8th week 
and its 95% confidence interval. Distributional assumptions will be checked by the use 
of Q-Q plots of residuals, and variables will be transformed where required.  
 
The post-estimation lincom will be used to estimate the group difference at the 8th 
week and its 95% confidence interval on the logit scale. To assist in interpretation, this 
conditional or subject-specific effect estimate (and its CI) will be translated to an 
approximate, but more easily understood, marginal or population average estimate. 
Estimates of the group difference for weeks 1 to 8 will be plotted. 
 


 
 
 
The same model will be applied for the CGI-S and other continuous secondary 
outcomes; depressive symptoms (CDRS) and anxiety symptoms (PARS) and the 
differences 
 
Trial response will be defined as a CGI-I score less than 3 at the trial endpoint will be 
reported. An efficient estimate will be obtained by fitting a growth curve model of the 
same form as that for the CGI-I score, but for the repeated binary response fitted by 
maximum likelihood using adaptive quadrature in the Stata program gsem, with 
binomial family and logit link function. The model will include a random intercept. The 
fixed part of the model will include the CGI-S at baseline, treatment group, week as 
measure of time, and the interaction of group x week (a test for a quadratic term will be 
carried out) and will covary by any randomization stratification factors. The post-
estimation lincom will be used to estimate the group difference at the 8th week and 
its 95% confidence interval on the logit scale. To assist in interpretation, this conditional 
or subject-specific effect estimate (and its CI) will be translated to an approximate, but 
more easily understood, marginal or population average estimate. Estimates of the 
group difference for weeks 1 to 8 will be plotted. 
 
Frequencies of the most common adverse events will be tabled and reported if present 
in more than one subject in either of the study groups. 
 


 
 
 
1.3.3. Missing Data 
Account for missing measures will be made under an assumption of a missing-at-
random mechanism.  Since all remaining variables in the analysis are acquired prior to 
randomization there should be no further missing data. 
1.3.4. Sensitivity analysis 
Sensitivity analysis will be undertaken by replicating the main analyses using the Last 
Observation Carried Forward method for the treatment of missing data.  
 
 
References