Effectiveness of Sertraline and Cognitive Behavioral Therapy in Treating Pediatric Obsessive-Compulsive Disorder

• Sponsor: University of Florida (Other)
• Overall Status: Completed
• CT.gov ID: NCT00382291
• Collaborator: National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 56
• Locations: 2
• Arms: 3
• Duration (Months): 24
• Patients Per Site: 28
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

This study measures the occurrence of certain side effects linked to antidepressant use and evaluates the effectiveness of the medication sertraline plus cognitive behavioral therapy to treat people with obsessive-compulsive disorder.

Condition or Disease	Intervention/Treatment	Phase
Obsessive-Compulsive Disorder	Drug: Regular Titration; Drug: Placebo; Drug: Slow Titration	Phase 4

Detailed Description

Obsessive-compulsive disorder (OCD) is an anxiety disorder that is associated with recurring repetitive behaviors and persistent unwanted thoughts. People with OCD often carry out ritual-like behaviors such as counting, cleaning, or washing their hands in order to momentarily ease their anxiety. A current treatment for people with OCD is the class of antidepressants called selective serotonin reuptake inhibitors (SSRIs). A recent re-analysis of clinical trials on children with psychiatric conditions found that the risk of suicidal thoughts and behavior when on SSRI-antidepressants was considerably higher than when on placebo. The data also revealed that antidepressant-associated suicidal behavior was not limited to children with depression, but also affected children with OCD and other anxiety disorders. Although the process responsible for increased suicidality is unknown, it may be initiated by a set of symptoms collectively called SSRI induced activation syndrome, which is thought to be common, particularly in children and teens. However, there is a lack of knowledge on this syndrome, including its role in suicidal behavior and how it can be prevented. This study will evaluate a new behavioral test to measure certain side effects linked to antidepressant use. This study will also evaluate the effectiveness of the SSRI sertraline plus cognitive behavioral therapy (CBT) to treat people with OCD.

Potential participants will undergo an initial screening visit that will include an interview on psychological symptoms associated with OCD and possible family history of OCD. Eligible participants will then undergo a physical exam, blood draw, DNA sampling, and pregnancy test if applicable. Participants will be randomly assigned to receive either sertraline or placebo daily for 18 weeks. At weekly study visits, participants will receive their study drug, complete questionnaires about symptoms of OCD, and undergo vital sign measurements. At specified visits, participants will also perform a task (Stop Signal Task) on a computerized assessment device to measure attention and impulse control and may have blood drawn. For the first 4 weeks participants will wear a wristwatch-like device (actigraph) to monitor sleep patterns. During the first three visits, participants will receive supportive psychotherapy. At Visit 4, participants will begin receiving 60-minute CBT sessions, which will continue until the final visit. The final visit will include a second physical exam, questionnaires, and blood testing.

Study Design

• Study Type: Interventional
• Actual Enrollment: 56 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Diagnostic
• Official Title: SSRI-Induced Activation Syndrome in Pediatric Obsessive Compulsive Disorder
• Study Start Date: Feb 1, 2009
• Actual Primary Completion Date: Feb 1, 2011
• Actual Study Completion Date: Feb 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Regular Titration Regular titration of Sertraline plus cognitive behavioral therapy. The titration schedule used a flexible upward titration from 25 mg/day to 200 mg/day over 9 weeks unless higher doses were not tolerated, after which the dosage was adjusted as a function of tolerability. If tolerated, maximum dose could be achieved in 5 weeks.	Drug: Regular Titration; Sertraline will be administered in standard dosing. Treatment with sertraline will last 18 weeks.
Placebo Comparator: Placebo Placebo plus cognitive behavioral therapy	Drug: Placebo; The placebo will be administered in the same manner as sertraline. Treatment with placebo will last 18 weeks.
Experimental: Slow Titration Slow titration of Sertraline plus cognitive behavior therapy. The titration schedule utilized a slower titration schedule relative to the RegSert arm. Unless unable to tolerate higher doses, children remained on 25mg/day for the first two weeks, 50mg/day from weeks 3-4, 75mg/day for weeks 5-6, 100mg/day for week 7, 150mg/day for week 8, and 200mg/day for week 9 until the end of the study.	Drug: Slow Titration; Sertraline will be administered in slow titration. Treatment with sertraline will last 18 weeks.

Outcome Measures

Primary Outcome Measures

1. Clinical Global Impression - Severity of Activation (CGI-SA) [Measured at screening, baseline and weekly until end of week 8 after baseline, then monthly for two months and finally at end of study]

   The CGI-SA was adapted from the Clinical Global Impressions - Severity of Illness (CGI-SI) rating (Guy, 1976). The CGI-SI is commonly used in clinical studies of children and adults and has been extensively validated (Zaider et al., 2003). On the CGI-SA clinicians rate the severity of activation symptoms on a range from 0 (no activation) to 7 (extremely severe symptoms, functionally highly impaired and/or extreme distress). We report values representing Median+/-Std Dev for the maximum CGI-SA obtained over the course of study.

2. Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) Total Score [Measured at Week 18 or End of Study]

   The CY-BOCS (Scahill et al., 1997) is a semi-structured, clinician rated instrument to measure OCD symptom severity in youth. The CY-BOCS contains a symptom checklist and a severity scale. Through the symptom checklist the clinician assesses current and past experiences of over 60 potential obsessions and compulsions. The Total Score represents the sum of obsession severity and compulsion severity which each consist of five clinician ratings on a Likert scale (range from 0 (none) to 4 (extreme), for time spent, interference, distress, resistance and control over symptoms). Summing of obsession and compulsion severity (range 0-20 on each) produces the Total CY-BOCS score (range 0-40, with 0 representing the best and 40 the worst outcome). Studies have documented good psychometric properties of the CY-BOCS (Gallant et al., 2008; Scahill et al., 1997; Storch et al., 2004).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 7 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Principal diagnosis of OCD with at least a 6-month duration, as determined by structured clinical interview (schedule for affective disorders and schizophrenia for school-age children)

• As long as OCD is the principal diagnosis, co-morbid depression, attention deficit hyperactivity disorder, tic disorder, or another anxiety disorder is allowable

• Diagnosis of trichotillomania or body dysmorphic disorder provided OCD symptoms are the predominant presenting features

• Meets clinical criteria for Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) (e.g., abrupt onset and dramatic fluctuations in symptoms)

Exclusion Criteria:

• Prior adequate trial of sertraline

• Allergy to sertraline

• History of rheumatic fever or serious autoimmune disorder

• Diagnosis of bipolar disorder, autism, schizophrenia, mental retardation, or chronic degenerative neurological disease

• Current anorexia nervosa with symptoms of body image distortion (symptoms of anorexia secondary to obsessions [e.g., contamination] are permitted)

• Unable to safely swallow study medication after pill swallowing education

• Unwillingness of children's parents to commit to accompanying their child for multiple study visits and to be responsible for medication compliance

• Suicidal intent (suicidal ideation will not be an automatic exclusion; however, risk will be gauged carefully and the participant must contract for safety)

• Suicide attempt in the 12 months prior to study entry

• Pregnancy

• Taking monoamine oxidase inhibitors (MAOIs) within 4 weeks of study entry or fluoxetine within 5 weeks of study entry

• Taking other psychotropic medications other than sedative or hypnotics for insomnia

• Substance abuse or dependence within 6 months prior to study entry

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Florida	Gainesville	Florida	United States	32611
2	University of South Florida	Tampa	Florida	United States	33701

Sponsors and Collaborators

• University of Florida
• National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Tanya K. Murphy, MD, University of South Florida
• Principal Investigator: Regina Bussing, M.D., University of Florida

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of Florida
• ClinicalTrials.gov Identifier: NCT00382291
• Other Study ID Numbers: R01MH078594; R01MH078594; DSIR 84-CTM
• First Posted: Sep 29, 2006
• Last Update Posted: Mar 12, 2013
• Last Verified: Dec 1, 2012

• Keywords provided by University of Florida: OCD; Antidepressive Agents, Second-Generation; Placebos; Cognitive Behavior Therapy; Child Psychiatry; Activation Syndrome; Psychometrics
• Additional relevant MeSH terms: Compulsive Personality Disorder; Obsessive-Compulsive Disorder

Study Results

Participant Flow

Recruitment Details	The study was performed at two child and adolescent psychiatric clinics within university medical centers: Gainesville, Florida (FL) (UF) and Tampa, FL (USF). Recruitment started in early 2009 and ended in late 2010.
Pre-assignment Detail	Fifteen participants were excluded after screening: 7/15 did not meet inclusion/exclusion criteria and 8/15 withdrew consent.

Arm/Group Title	Placebo Plus CBT	Regular Sertraline Titration Plus CBT	Slow Sertraline Titration Plus CBT
Arm/Group Description	Placebo plus cognitive behavior therapy (CBT).	Regular titration of sertraline (RegSert) plus cognitive behavior therapy. The titration schedule used a flexible upward titration from 25 mg/day to 200 mg/day over 9 weeks unless higher doses were not tolerated, after which the dosage was adjusted as a function of tolerability. If tolerated, maximum dose could be achieved in 5 weeks.	Slow titration of sertraline (SloSert)plus cognitive behavior therapy. The titration schedule utilized a slower titration schedule relative to the RegSert arm. Unless unable to tolerate higher doses, children remained on 25mg/day for the first two weeks, 50mg/day from weeks 3-4, 75mg/day for weeks 5-6, 100mg/day for week 7, 150mg/day for week 8, and 200mg/day for week 9 until the end of the study.
Period Title: Overall Study
STARTED	18	17	21
COMPLETED	14	10	13
NOT COMPLETED	4	7	8

Baseline Characteristics

Arm/Group Title	Placebo	Regular Titration	Slow Titration	Total
Arm/Group Description	Placebo plus cognitive behavior therapy.	Regular titration of sertraline plus cognitive behavior therapy.	Slow titration of sertraline plus cognitive behavior therapy.	Total of all reporting groups
Overall Participants	18	17	21	56
Age (Count of Participants)
<=18 years	18 100%	17 100%	21 100%	56 100%
Between 18 and 65 years	0 0%	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	7 38.9%	7 41.2%	8 38.1%	22 39.3%
Male	11 61.1%	10 58.8%	13 61.9%	34 60.7%

Outcome Measures

1. Primary Outcome

Title	Clinical Global Impression - Severity of Activation (CGI-SA)
Description	The CGI-SA was adapted from the Clinical Global Impressions - Severity of Illness (CGI-SI) rating (Guy, 1976). The CGI-SI is commonly used in clinical studies of children and adults and has been extensively validated (Zaider et al., 2003). On the CGI-SA clinicians rate the severity of activation symptoms on a range from 0 (no activation) to 7 (extremely severe symptoms, functionally highly impaired and/or extreme distress). We report values representing Median+/-Std Dev for the maximum CGI-SA obtained over the course of study.
Time Frame	Measured at screening, baseline and weekly until end of week 8 after baseline, then monthly for two months and finally at end of study

Outcome Measure Data

Analysis Population Description

Per protocol, Intent to treat

Arm/Group Title	Placebo	Regular Titration	Slow Titration
Arm/Group Description	Placebo plus cognitive behavior therapy.	Regular titration of sertraline plus cognitive behavior therapy.	Slow titration of sertraline plus cognitive behavior therapy.
Measure Participants	18	17	21
Median (Standard Deviation) [units on a scale]	.50 (1.50)	2.00 (1.35)	2.00 (1.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Regular Titration, Slow Titration
	Comments	Data were analyzed using two-sided Kruskal-Wallis test with level of significance = .05. Null hypothesis was that there were no group differences. The maximum CGI-SA obtained over course of study was the outcome measure.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.2106
	Comments
	Method	Kruskal-Wallis
	Comments

2. Primary Outcome

Title	Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) Total Score
Description	The CY-BOCS (Scahill et al., 1997) is a semi-structured, clinician rated instrument to measure OCD symptom severity in youth. The CY-BOCS contains a symptom checklist and a severity scale. Through the symptom checklist the clinician assesses current and past experiences of over 60 potential obsessions and compulsions. The Total Score represents the sum of obsession severity and compulsion severity which each consist of five clinician ratings on a Likert scale (range from 0 (none) to 4 (extreme), for time spent, interference, distress, resistance and control over symptoms). Summing of obsession and compulsion severity (range 0-20 on each) produces the Total CY-BOCS score (range 0-40, with 0 representing the best and 40 the worst outcome). Studies have documented good psychometric properties of the CY-BOCS (Gallant et al., 2008; Scahill et al., 1997; Storch et al., 2004).
Time Frame	Measured at Week 18 or End of Study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Regular Titration	Slow Titration
Arm/Group Description	Placebo plus cognitive behavior therapy.	Regular titration of sertraline plus cognitive behavior therapy. The titration schedule used a flexible upward titration from 25 mg/day to 200 mg/day over 9 weeks unless higher doses were not tolerated, after which the dosage was adjusted as a function of tolerability. If tolerated, maximum dose could be achieved in 5 weeks.	Slow titration of sertraline plus cognitive behavior therapy. The titration schedule utilized a slower titration schedule relative to the RegSert arm. Unless unable to tolerate higher doses, children remained on 25mg/day for the first two weeks, 50mg/day from weeks 3-4, 75mg/day for weeks 5-6, 100mg/day for week 7, 150mg/day for week 8, and 200mg/day for week 9 until the end of the study.
Measure Participants	18	17	21
Mean (Standard Deviation) [units on a scale]	16.28 (7.11)	16.35 (9.60)	17.67 (7.28)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Regular Titration, Slow Titration
	Comments	Data were analyzed using ANCOVA modeling with two-sided testing and level of significance = .05. The dependent variable was last measured CY-BOCS score, the independent variable was randomized group assignment and the covariate was the CY-BOCS score at baseline. The null hypothesis was that there were no group differences.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.8831
	Comments
	Method	ANCOVA
	Comments

Adverse Events

Time Frame	For individual study participants Adverse Events were collected from point of informed consent to end of study (up to 19 weeks plus required wash-out periods for completers). For the entire study adverse events were collected from 2/09 to 2/11.
Arm/Group Title	Placebo		Regular Titration		Slow Titration
Arm/Group Description	Placebo plus cognitive behavior therapy.		Regular titration of sertraline plus cognitive behavior therapy.		Slow titration of sertraline plus cognitive behavior therapy.
All Cause Mortality
	Placebo		Regular Titration		Slow Titration
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Regular Titration		Slow Titration
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/18 (5.6%)		1/17 (5.9%)		0/21 (0%)
Psychiatric disorders
Depersonalization	0/18 (0%)	0	1/17 (5.9%)	1	0/21 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pneumonia	1/18 (5.6%)	1	0/17 (0%)	0	0/21 (0%)	0
Other (Not Including Serious) Adverse Events
	Placebo		Regular Titration		Slow Titration
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/18 (61.1%)		12/17 (70.6%)		18/21 (85.7%)
Gastrointestinal disorders
diarrhea	2/18 (11.1%)	3	5/17 (29.4%)	8	8/21 (38.1%)	14
Nervous system disorders
Insomnia	3/18 (16.7%)	10	8/17 (47.1%)	12	6/21 (28.6%)	8
Headache	9/18 (50%)	12	9/17 (52.9%)	24	12/21 (57.1%)	27

Limitations/Caveats

Temporary study suspension led to smaller number of subjects enrolled than initially planned and resulted in smaller number of subjects analyzed, reducing power.

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.