Anxiety and Recurrent Abdominal Pain in Children

• Sponsor: John V. Campo, M.D. (Other)
• Overall Status: Completed
• CT.gov ID: NCT00962039
• Collaborator: National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 81
• Location: 1
• Arms: 2
• Duration (Months): 69
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

This study aims to determine whether citalopram is a useful, well-tolerated, and safe treatment for children and adolescents ages 7 to 18 years with functional abdominal pain. The study hypothesis is that citalopram will be better than placebo in producing clinical improvement and reductions in abdominal pain. It is also hypothesized that citalopram and placebo will not differ in terms of safety and tolerability.

Condition or Disease	Intervention/Treatment	Phase
Abdominal Pain; Anxiety	Drug: Citalopram; Drug: Placebo	Phase 2/Phase 3

Detailed Description

This study aims to determine the relative efficacy, tolerability, and safety of the citalopram in the treatment of pediatric functional recurrent abdominal pain (FAP) in children and adolescents ages 7 to 18 years, inclusive. The goal is to recruit and randomize 100 subjects to citalopram or placebo. Secondary aims include to determine if citalopram is superior to placebo in reducing comorbid anxiety and depressive symptoms in children and adolescents with FAP, to explore potential mediators (i.e., anxiety, depression) and moderators (e.g., age, gender, referral from primary or specialty care) of treatment response, and to explore the durability and tolerability of citalopram treatment 18 weeks following completion of the double-blind treatment phase with the goal of generating data useful to the development of future studies. The study is novel in conducting recruitment, assessment, and treatment in traditional medical settings. Limited exclusion criteria and the delivery of study assessments and interventions within routine practice settings provide for considerably greater external validity than the typical efficacy study.

Study hypotheses:

1. Citalopram will be superior to placebo in producing clinical improvement and reductions in abdominal pain.

2. Citalopram and placebo will not differ in tolerability or safety.

Study Design

• Study Type: Interventional
• Actual Enrollment: 81 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Anxiety and Recurrent Abdominal Pain in Children
• Study Start Date: Jul 1, 2004
• Actual Primary Completion Date: Apr 1, 2010
• Actual Study Completion Date: Apr 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Citalopram Citalopram was initiated at 10 mg daily for one week, with dosage increased to 20 mg daily during week 2, with an optional increase to 40 mg daily at week 4 or thereafter if response was judged to be suboptimal (CGI-I or CGI-S > 2).	Drug: Citalopram; Participants will be randomly assigned to citalopram or placebo in a parallel groups design for 8 weeks of double-blind treatment beginning with 10 mg per day week 1, 20 mg per day week 2, and 40 mg per day week 4 or thereafter if response is suboptimal and there are no significant side effects.; Other Names: Celexa
Placebo Comparator: Placebo Placebo administered in capsules identical to those containing citalopram using microcrystalline cellulose.	Drug: Placebo; Participants will be randomly assigned to citalopram or placebo in a parallel groups design for 8 weeks of double-blind treatment beginning with 10 mg per day week 1, 20 mg per day week 2, and 40 mg per day week 4 or thereafter if response is suboptimal and there are no significant side effects.

Outcome Measures

Primary Outcome Measures

1. Clinical Global Impression Scale - Improvement (CGI-I) Will be Used to Assess Overall Global Illness Improvement. CGI-I Scores of 1 (Very Much Improved) or 2 (Much Improved) Indicate an Acceptable Treatment Response. [The CGI will be completed at weeks 2, 4, and 8]

   Clinical Global Impression Scale - Improvement (CGI-I) is a 7-point scale, with lower values being more favorable, used to assess overall global illness improvement. The CGI is a clinician-completed measure, with values ranging from 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), to 7 (very much worse). CGI-I scores of 1 (very much improved) or 2 (much improved) were considered to indicate an acceptable treatment response. A global measure of functional status was chosen as a primary outcome due to the broad array of symptomatology seen in pediatric RAP and the ambiguous relationship between functional status and symptoms of pain, anxiety, and depression in pediatric RAP. The CGI-I is a dichotomous primary outcome measure of global clinical improvement with clinical response be defined as a CGI-I score of 1 or 2 for at least two consecutive weeks.

2. Clinical Global Impression Scale - Severity (CGI-S) [Weeks 0, 2, 4, and 8]

   Clinical Global Impression Scale - Severity (CGI-S) is a 7-point scale is a clinician-completed measure that requires the clinician to rate the severity of the patient's illness at the time of assessment relative to the clinician's past experience with patients who have the same diagnosis. Considering total clinical experience, a patient is assessed on severity of illness at the time of rating, with values ranging from 1 (normal, not at all ill), 2 (borderline ill), 3 (mildly ill), 4 (moderately ill), 5 (markedly ill), 6 (severely ill), to 7 (extremely ill).

3. Abdominal Pain Index (API) [Weeks 0, 2, 4, and 8]

   The API is a well-validated and reliable measure of abdominal pain assessing the frequency, duration, and intensity of abdominal pain consisting of five items assessing the frequency, duration, and intensity of abdominal pain experienced during the prior 2 weeks. Two of the items are scored from 0 to 5, one is scaled 0 to 8, and two are scaled 0 to 10, with lower scores considered to be better than higher scores. Item scores are standardized using Z-scores and then summed to yield an index of abdominal pain that has been sensitive to change in previous epidemiological and treatment studies of FAP. Alpha reliability ranged from 0.80 to 0.93. The API will be a continuous primary outcome measure of abdominal pain.

Secondary Outcome Measures

1. Pediatric Anxiety Rating Scale (PARS) [Weeks 0, 2, 4, and 8]

   Pediatric Anxiety Rating Scale (PARS) is a clinician administered measure of anxiety in children and adolescents. The PARS is comprised of a 50-item symptom checklist used to determine the presence or absence of specific anxiety symptoms during the prior week and 7 severity/impairment items, each scored from 0 to 5 . The the score on the 7 items allows the clinician to rate symptom severity and associated impairment on a range from 0 to 35, with higher scores reflecting greater symptom severity and associated impairment. The PARS is characterized by high interrater reliability (ICC = 0.97), adequate internal consistency (α = 0.64), and fair test-retest reliability (ICC = 0.55). There is preliminary support for convergent and divergent validity, and the PARS has demonstrated sensitivity to treatment effects in previously conducted clinical trials.

2. Children's Depression Rating Scale - Revised (CDRS-R) [Weeks 0, 2, 4, and 8]

   Children's Depression Rating Scale - Revised (CDRS-R) is a clinician administered measure of depression in children and adolescents and provides data necessary to diagnose depressive disorder and rate the severity of depressive symptoms over time. The CDRS-R is composed of 17 items, most rated on a 1 to 7 scale, with a minimum score of 17 and a maximum of 113. Higher scores reflect greater depression severity, with scores of 40 and above generally considered to be reflective of a depressive diagnosis.

3. Children's Global Assessment Scale (C-GAS) [Weeks 0, 2, 4, and 8]

   Children's Global Assessment Scale (C-GAS) is an interview-based adaptation of the Global Assessment Scale developed to assess child and adolescent functioning during a specified time period. Scores range from one to 100, with scores of 70 or below reflecting abnormally low functioning and higher scores reflecting better functioning. The C-GAS has demonstrated reliability, as well as discriminant and concurrent validity. A CGAS score of < 70 will be a requirement at study entry.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 7 Years to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• At least 3 episodes of abdominal pain during the previous 3 months associated with functional impairment in the absence of explanatory physical disease following clinically appropriate medical assessment.

• Age 7 years 0 months to 18 years 11 months, inclusive, at initial evaluation.

• Significant global functional impairment as reflected by a score less than 70 on the Children's Global Assessment Scale

• Residing with a primary caretaker (i.e., parent, legal guardian, relative functioning as a parent, or foster parent) who has known the child well for at least 6 months prior to study entry and has legal authority to consent to participation.

Exclusion Criteria:

• Physical disease sufficient to explain the subjective distress and functional impairment suffered by the subject.

• FAP with atypical features:

1. Abnormal abdominal or rectal examination

2. GI bleeding (i.e., hematest positive stool or hematemesis)

3. History of recurrent or persistent fever associated with the abdominal pain

4. Involuntary weight loss (> 5% of body weight) over the previous 3 months

5. Previous laboratory evidence suggesting explanatory physical disease

6. Persistent nighttime awakenings due to abdominal pain (at least once per week and

4 per month)

1. Persistent or bilious vomiting (at least once per week and > 4 per month)

2. Abdominal pain exclusively associated with menstruation

3. Dysuria

• Physical disease in which citalopram monotherapy or study participation might prove to be disadvantageous or incompatible with quality care, including bleeding disorder characterized by prolonged bleeding time, uncontrolled epilepsy, or poorly controlled diabetes mellitus.

• Psychiatric problem or disorder in which citalopram monotherapy or study participation might prove to be disadvantageous or incompatible with quality care, including evidence that the child is a serious acute danger to self or others, anorexia nervosa, bulimia nervosa, schizophrenia, schizoaffective disorder, alcohol or substance abuse/dependence, or bipolar disorder.

• History of mental retardation as defined by full scale IQ < 70 on previous testing or participation in special education placement for mild to severe mental retardation.

• Inadequate English speaking abilities of child or parent(s) to complete study measures and/or communicate with study examiners.

• Adequate prior trial of citalopram, escitalopram, or another selective serotonin reuptake inhibitor or venlafaxine. Adequate trial is defined as at least 4 weeks of citalopram 20 mg/day, escitalopram 10 mg/day, fluoxetine 20 mg/day, fluvoxamine 100 mg/day, paroxetine 20 mg/day, sertraline 50 mg/day, or venlafaxine 75 mg/day.

• Concurrent use of non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, or anticoagulant medications.

• Treatment for physical or psychiatric illness initiated within the prior 4 weeks or escalating in dosage or intensity.

• History of hypersensitivity to citalopram or serotonin-syndrome.

• Participation in any investigational drug study within thirty days of study entry.

• Pregnancy

• Sexually active female subjects refusing to use a medically accepted method of birth control during the study, or who engaged in unprotected sexual activity during the 30 days prior to the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Research Institute at Nationwide Children's Hospital	Columbus	Ohio	United States	43205

Sponsors and Collaborators

• John V. Campo, M.D.
• National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: John V Campo, MD, The Research Institute at Nationwide Children's Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

• Campo JV, Perel J, Lucas A, Bridge J, Ehmann M, Kalas C, Monk K, Axelson D, Birmaher B, Ryan N, Di Lorenzo C, Brent DA. Citalopram treatment of pediatric recurrent abdominal pain and comorbid internalizing disorders: an exploratory study. J Am Acad Child Adolesc Psychiatry. 2004 Oct;43(10):1234-42.

• Responsible Party: John V. Campo, M.D., Chief Of Child & Adolescent Psychiatry -Medical Director, Nationwide Children's Hospital
• ClinicalTrials.gov Identifier: NCT00962039
• Other Study ID Numbers: 5R01MH069715-04; 5R01MH069715-04; DAHBR B4-TBI
• First Posted: Aug 19, 2009
• Last Update Posted: Jun 11, 2020
• Last Verified: May 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by John V. Campo, M.D., Chief Of Child & Adolescent Psychiatry -Medical Director, Nationwide Children's Hospital: Abdominal Pain; Anxiety
• Additional relevant MeSH terms: Abdominal Pain; Anxiety Disorders; Citalopram

Study Results

Participant Flow

Recruitment Details	Subjects were clinically referred from primary care and specialty pediatric gastroenterology and were impaired as reflected by a score of less than 70 on the Children's Global Assessment Scale (CGAS).
Pre-assignment Detail	Potential subjects with physical disease responsible for the abdominal pain, eating disorder, bipolar disorder, psychosis, alcohol/drug abuse, intellectual disability (IQ < 70), pregnancy, or prior trial of SSRI antidepressant or venlafaxine were excluded.

Arm/Group Title	Citalopram	Placebo
Arm/Group Description	Citlaopram: Participants were randomly assigned to citalopram or placebo in a parallel groups design for 8 weeks of double-blind treatment beginning with 10 mg per day week 1, 20 mg per day week 2, and 40 mg per day week 4 or thereafter if response was suboptimal and there were no significant side effects.	Placebo: Participants were randomly assigned to citalopram or placebo in a parallel groups design for 8 weeks of double-blind treatment beginning with 10 mg per day week 1, 20 mg per day week 2, and 40 mg per day week 4 or thereafter if response was suboptimal and there were no significant side effects.
Period Title: Overall Study
STARTED	40	41
COMPLETED	35	37
NOT COMPLETED	5	4

Baseline Characteristics

Arm/Group Title	Citalopram	Placebo	Total
Arm/Group Description	This double blind, placebo-controlled trial randomized 81 subjects ages 7 to 18 years in parallel groups to citalopram (n=40) or placebo (n=41) for 8 weeks. Citalopram was initiated at 10 mg per day week 1, 20 mg per day week 2, and 40 mg per day week 4 or thereafter if response was suboptimal and there were no significant side effects. Subjects were recruited by clinical referral from both the primary care and specialty pediatric gastroenterology clinical settings. In addition to meeting criteria for FAP, subjects were required to be significantly impaired as reflected by a score of less than 70 on the Children's Global Assessment Scale (CGAS). Potential subjects with physical disease responsible for the observed abdominal pain, eating disorder, bipolar disorder, psychosis, alcohol/drug abuse, intellectual disability (IQ < 70), pregnancy, or prior trial of SSRI antidepressant or venlafaxine were excluded.	This double blind, placebo-controlled trial randomized 81 subjects ages 7 to 18 years in parallel groups to citalopram (n=40) or placebo (n=41) for 8 weeks. Citalopram was initiated at 10 mg per day week 1, 20 mg per day week 2, and 40 mg per day week 4 or thereafter if response was suboptimal and there were no significant side effects. Subjects were recruited by clinical referral from both the primary care and specialty pediatric gastroenterology clinical settings. In addition to meeting criteria for FAP, subjects were required to be significantly impaired as reflected by a score of less than 70 on the Children's Global Assessment Scale (CGAS). Potential subjects with physical disease responsible for the observed abdominal pain, eating disorder, bipolar disorder, psychosis, alcohol/drug abuse, intellectual disability (IQ < 70), pregnancy, or prior trial of SSRI antidepressant or venlafaxine were excluded.	Total of all reporting groups
Overall Participants	40	41	81
Age (Count of Participants)
<=18 years	40 100%	41 100%	81 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	29 72.5%	33 80.5%	62 76.5%
Male	11 27.5%	8 19.5%	19 23.5%

Outcome Measures

1. Primary Outcome

Title	Clinical Global Impression Scale - Improvement (CGI-I) Will be Used to Assess Overall Global Illness Improvement. CGI-I Scores of 1 (Very Much Improved) or 2 (Much Improved) Indicate an Acceptable Treatment Response.
Description	Clinical Global Impression Scale - Improvement (CGI-I) is a 7-point scale, with lower values being more favorable, used to assess overall global illness improvement. The CGI is a clinician-completed measure, with values ranging from 1 (very much improved), 2 (much improved), 3 (minimally improved), 4 (no change), 5 (minimally worse), 6 (much worse), to 7 (very much worse). CGI-I scores of 1 (very much improved) or 2 (much improved) were considered to indicate an acceptable treatment response. A global measure of functional status was chosen as a primary outcome due to the broad array of symptomatology seen in pediatric RAP and the ambiguous relationship between functional status and symptoms of pain, anxiety, and depression in pediatric RAP. The CGI-I is a dichotomous primary outcome measure of global clinical improvement with clinical response be defined as a CGI-I score of 1 or 2 for at least two consecutive weeks.
Time Frame	The CGI will be completed at weeks 2, 4, and 8

Outcome Measure Data

Analysis Population Description

Analysis week 8

Arm/Group Title	Citalopram	Placebo
Arm/Group Description	Citalopram was initiated at 10 mg daily for one week, with dosage increased to 20 mg daily during week 2, with an optional increase to 40 mg daily at week 4 or thereafter if response was judged to be suboptimal (CGI-I or CGI-S > 2). Citalopram: Participants will be randomly assigned to citalopram or placebo in a parallel groups design for 8 weeks of double-blind treatment beginning with 10 mg per day week 1, 20 mg per day week 2, and 40 mg per day week 4 or thereafter if response is suboptimal and there are no significant side effects.	Placebo administered in capsules identical to those containing citalopram using microcrystalline cellulose. Placebo: Participants will be randomly assigned to citalopram or placebo in a parallel groups design for 8 weeks of double-blind treatment beginning with 10 mg per day week 1, 20 mg per day week 2, and 40 mg per day week 4 or thereafter if response is suboptimal and there are no significant side effects.
Measure Participants	40	41
CGI-I Week 2	3.48	3.68
CGI-I Week 4	3.03	3.38
CGI-I Week 8	2.65	3.24

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Citalopram, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.92
	Comments	Analyses were conducted over 8 week follow-up.
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.12 to 0.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Clinical Global Impression Scale - Severity (CGI-S)
Description	Clinical Global Impression Scale - Severity (CGI-S) is a 7-point scale is a clinician-completed measure that requires the clinician to rate the severity of the patient's illness at the time of assessment relative to the clinician's past experience with patients who have the same diagnosis. Considering total clinical experience, a patient is assessed on severity of illness at the time of rating, with values ranging from 1 (normal, not at all ill), 2 (borderline ill), 3 (mildly ill), 4 (moderately ill), 5 (markedly ill), 6 (severely ill), to 7 (extremely ill).
Time Frame	Weeks 0, 2, 4, and 8

Outcome Measure Data

Analysis Population Description

Analysis week 8

Arm/Group Title	Citalopram	Placebo
Arm/Group Description	Citalopram was initiated at 10 mg daily for one week, with dosage increased to 20 mg daily during week 2, with an optional increase to 40 mg daily at week 4 or thereafter if response was judged to be suboptimal (CGI-I or CGI-S > 2). Citalopram: Participants will be randomly assigned to citalopram or placebo in a parallel groups design for 8 weeks of double-blind treatment beginning with 10 mg per day week 1, 20 mg per day week 2, and 40 mg per day week 4 or thereafter if response is suboptimal and there are no significant side effects.	Placebo administered in capsules identical to those containing citalopram using microcrystalline cellulose. Placebo: Participants will be randomly assigned to citalopram or placebo in a parallel groups design for 8 weeks of double-blind treatment beginning with 10 mg per day week 1, 20 mg per day week 2, and 40 mg per day week 4 or thereafter if response is suboptimal and there are no significant side effects.
Measure Participants	40	41
CGI-S Week 0	4.31	4.39
CGI-S Week 2	3.83	4.03
CGI-S Week 4	3.56	3.86
CGI-S Week 8	2.76	3.51

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Citalopram, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.034
	Comments
	Method	Chi-squared
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -0.15 to -0.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Abdominal Pain Index (API)
Description	The API is a well-validated and reliable measure of abdominal pain assessing the frequency, duration, and intensity of abdominal pain consisting of five items assessing the frequency, duration, and intensity of abdominal pain experienced during the prior 2 weeks. Two of the items are scored from 0 to 5, one is scaled 0 to 8, and two are scaled 0 to 10, with lower scores considered to be better than higher scores. Item scores are standardized using Z-scores and then summed to yield an index of abdominal pain that has been sensitive to change in previous epidemiological and treatment studies of FAP. Alpha reliability ranged from 0.80 to 0.93. The API will be a continuous primary outcome measure of abdominal pain.
Time Frame	Weeks 0, 2, 4, and 8

Outcome Measure Data

Analysis Population Description

Analysis week 8

Arm/Group Title	Citalopram	Placebo
Arm/Group Description	Citalopram was initiated at 10 mg daily for one week, with dosage increased to 20 mg daily during week 2, with an optional increase to 40 mg daily at week 4 or thereafter if response was judged to be suboptimal (CGI-I or CGI-S > 2). Citalopram: Participants will be randomly assigned to citalopram or placebo in a parallel groups design for 8 weeks of double-blind treatment beginning with 10 mg per day week 1, 20 mg per day week 2, and 40 mg per day week 4 or thereafter if response is suboptimal and there are no significant side effects.	Placebo administered in capsules identical to those containing citalopram using microcrystalline cellulose. Placebo: Participants will be randomly assigned to citalopram or placebo in a parallel groups design for 8 weeks of double-blind treatment beginning with 10 mg per day week 1, 20 mg per day week 2, and 40 mg per day week 4 or thereafter if response is suboptimal and there are no significant side effects.
Measure Participants	40	41
API-C Week 0	0.45	0.47
API-C Week 2	-0.14	0.06
API-C Week 4	-0.21	0.08
API-C Week 8	-0.36	-0.03

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Citalopram, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.261
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.03
	Confidence Interval	(2-Sided) 95%; -0.07 to 0.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Pediatric Anxiety Rating Scale (PARS)
Description	Pediatric Anxiety Rating Scale (PARS) is a clinician administered measure of anxiety in children and adolescents. The PARS is comprised of a 50-item symptom checklist used to determine the presence or absence of specific anxiety symptoms during the prior week and 7 severity/impairment items, each scored from 0 to 5 . The the score on the 7 items allows the clinician to rate symptom severity and associated impairment on a range from 0 to 35, with higher scores reflecting greater symptom severity and associated impairment. The PARS is characterized by high interrater reliability (ICC = 0.97), adequate internal consistency (α = 0.64), and fair test-retest reliability (ICC = 0.55). There is preliminary support for convergent and divergent validity, and the PARS has demonstrated sensitivity to treatment effects in previously conducted clinical trials.
Time Frame	Weeks 0, 2, 4, and 8

Outcome Measure Data

Analysis Population Description

Analysis week 8

Arm/Group Title	Citalopram	Placebo
Arm/Group Description	Citalopram was initiated at 10 mg daily for one week, with dosage increased to 20 mg daily during week 2, with an optional increase to 40 mg daily at week 4 or thereafter if response was judged to be suboptimal (CGI-I or CGI-S > 2). Citalopram: Participants will be randomly assigned to citalopram or placebo in a parallel groups design for 8 weeks of double-blind treatment beginning with 10 mg per day week 1, 20 mg per day week 2, and 40 mg per day week 4 or thereafter if response is suboptimal and there are no significant side effects.	Placebo administered in capsules identical to those containing citalopram using microcrystalline cellulose. Placebo: Participants will be randomly assigned to citalopram or placebo in a parallel groups design for 8 weeks of double-blind treatment beginning with 10 mg per day week 1, 20 mg per day week 2, and 40 mg per day week 4 or thereafter if response is suboptimal and there are no significant side effects.
Measure Participants	40	41
PARS Week 0	7.38	9.73
PARS Week 2	4.00	6.78
PARS Week 4	2.57	5.76
PARS Week 8	2.69	5.55

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Citalopram, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.519
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 95%; -0.36 to 0.18
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Children's Depression Rating Scale - Revised (CDRS-R)
Description	Children's Depression Rating Scale - Revised (CDRS-R) is a clinician administered measure of depression in children and adolescents and provides data necessary to diagnose depressive disorder and rate the severity of depressive symptoms over time. The CDRS-R is composed of 17 items, most rated on a 1 to 7 scale, with a minimum score of 17 and a maximum of 113. Higher scores reflect greater depression severity, with scores of 40 and above generally considered to be reflective of a depressive diagnosis.
Time Frame	Weeks 0, 2, 4, and 8

Outcome Measure Data

Analysis Population Description

Analysis week 8

Arm/Group Title	Citalopram	Placebo
Arm/Group Description	Citalopram was initiated at 10 mg daily for one week, with dosage increased to 20 mg daily during week 2, with an optional increase to 40 mg daily at week 4 or thereafter if response was judged to be suboptimal (CGI-I or CGI-S > 2). Citalopram: Participants will be randomly assigned to citalopram or placebo in a parallel groups design for 8 weeks of double-blind treatment beginning with 10 mg per day week 1, 20 mg per day week 2, and 40 mg per day week 4 or thereafter if response is suboptimal and there are no significant side effects.	Placebo administered in capsules identical to those containing citalopram using microcrystalline cellulose. Placebo: Participants will be randomly assigned to citalopram or placebo in a parallel groups design for 8 weeks of double-blind treatment beginning with 10 mg per day week 1, 20 mg per day week 2, and 40 mg per day week 4 or thereafter if response is suboptimal and there are no significant side effects.
Measure Participants	40	41
CDRS-R Week 0	34.50	39.23
CDRS-R Week 2	27.81	31.89
CDRS-R Week 4	24.97	28.35
CDRS-R Week 8	23.88	28.39

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Citalopram, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.704
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.12
	Confidence Interval	(2-Sided) 95%; -0.77 to 0.52
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Children's Global Assessment Scale (C-GAS)
Description	Children's Global Assessment Scale (C-GAS) is an interview-based adaptation of the Global Assessment Scale developed to assess child and adolescent functioning during a specified time period. Scores range from one to 100, with scores of 70 or below reflecting abnormally low functioning and higher scores reflecting better functioning. The C-GAS has demonstrated reliability, as well as discriminant and concurrent validity. A CGAS score of < 70 will be a requirement at study entry.
Time Frame	Weeks 0, 2, 4, and 8

Outcome Measure Data

Analysis Population Description

Analysis week 8

Arm/Group Title	Citalopram	Placebo
Arm/Group Description	Citalopram was initiated at 10 mg daily for one week, with dosage increased to 20 mg daily during week 2, with an optional increase to 40 mg daily at week 4 or thereafter if response was judged to be suboptimal (CGI-I or CGI-S > 2). Citalopram: Participants will be randomly assigned to citalopram or placebo in a parallel groups design for 8 weeks of double-blind treatment beginning with 10 mg per day week 1, 20 mg per day week 2, and 40 mg per day week 4 or thereafter if response is suboptimal and there are no significant side effects.	Placebo administered in capsules identical to those containing citalopram using microcrystalline cellulose. Placebo: Participants will be randomly assigned to citalopram or placebo in a parallel groups design for 8 weeks of double-blind treatment beginning with 10 mg per day week 1, 20 mg per day week 2, and 40 mg per day week 4 or thereafter if response is suboptimal and there are no significant side effects.
Measure Participants	40	41
CGAS Week 0	54.42	54.07
CGAS Week 2	59.24	58.05
CGAS Week 4	63.27	59.14
CGAS Week 8	66.72	61.22

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Citalopram, Placebo
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.046
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.59
	Confidence Interval	(2-Sided) 95%; 0.01 to 1.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	8 weeks
Arm/Group Title	Citalopram		Placebo
Arm/Group Description	Citlaopram: Participants were randomly assigned to citalopram or placebo in a parallel groups design for 8 weeks of double-blind treatment beginning with 10 mg per day week 1, 20 mg per day week 2, and 40 mg per day week 4 or thereafter if response was suboptimal and there were no significant side effects.		Placebo: Participants were randomly assigned to citalopram or placebo in a parallel groups design for 8 weeks of double-blind treatment beginning with 10 mg per day week 1, 20 mg per day week 2, and 40 mg per day week 4 or thereafter if response was suboptimal and there were no significant side effects.
All Cause Mortality
	Citalopram		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Citalopram		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/40 (0%)		0/41 (0%)
Other (Not Including Serious) Adverse Events
	Citalopram		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	31/40 (77.5%)		36/41 (87.8%)
Cardiac disorders
palpitations	12/40 (30%)		12/41 (29.3%)
Ear and labyrinth disorders
earache	5/40 (12.5%)		4/41 (9.8%)
hearing disturbance	5/40 (12.5%)		4/41 (9.8%)
Eye disorders
vision disturbance	2/40 (5%)		3/41 (7.3%)
eye irritation	3/40 (7.5%)		2/41 (4.9%)
Gastrointestinal disorders
gastric distress	13/40 (32.5%)		14/41 (34.1%)
nausea or vomiting	21/40 (52.5%)		24/41 (58.5%)
bowel movement disturbance	20/40 (50%)		21/41 (51.2%)
General disorders
fatigue	20/40 (50%)		28/41 (68.3%)
body aches	29/40 (72.5%)		31/41 (75.6%)
dry mouth	5/40 (12.5%)		2/41 (4.9%)
nosebleed	4/40 (10%)		4/41 (9.8%)
throat pain	11/40 (27.5%)		10/41 (24.4%)
sweating	2/40 (5%)		2/41 (4.9%)
accidental injuries	3/40 (7.5%)		2/41 (4.9%)
sleep disturbance	21/40 (52.5%)		28/41 (68.3%)
fever	2/40 (5%)		2/41 (4.9%)
hair loss	2/40 (5%)		0/41 (0%)
Infections and infestations
upper respiratory infection	10/40 (25%)		11/41 (26.8%)
Metabolism and nutrition disorders
appetite or weight change	11/40 (27.5%)		20/41 (48.8%)
Nervous system disorders
dizziness	16/40 (40%)		16/41 (39%)
headache	31/40 (77.5%)		36/41 (87.8%)
motor disturbances (tics, twitches)	5/40 (12.5%)		3/41 (7.3%)
hyperactive	11/40 (27.5%)		18/41 (43.9%)
memory disturbance	3/40 (7.5%)		1/41 (2.4%)
Psychiatric disorders
aggression	3/40 (7.5%)		1/41 (2.4%)
nightmares	4/40 (10%)		1/41 (2.4%)
irritability	8/40 (20%)		17/41 (41.5%)
anxiety and panic	7/40 (17.5%)		15/41 (36.6%)
mood lability	3/40 (7.5%)		2/41 (4.9%)
sadness, depression	9/40 (22.5%)		10/41 (24.4%)
Renal and urinary disorders
urinary disturbance	7/40 (17.5%)		10/41 (24.4%)
Skin and subcutaneous tissue disorders
itching	11/40 (27.5%)		8/41 (19.5%)

Limitations/Caveats

Relatively small sample size, potentially without sufficient power to detect meaningful between group differences.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.