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

Study Overview
=================
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.

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.

Official Title
-----------------
SSRI-Induced Activation Syndrome in Pediatric Obsessive Compulsive Disorder

Conditions
-----------------
Obsessive-Compulsive Disorder

Intervention / Treatment
-----------------
* Drug: Regular Titration
* Drug: Placebo
* Drug: Slow Titration


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 7 Years
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Regular Titration<br>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<br>* Sertraline will be administered in standard dosing. Treatment with sertraline will last 18 weeks.<br>|
| Placebo Comparator: Placebo<br>Placebo plus cognitive behavioral therapy | Drug: Placebo<br>* The placebo will be administered in the same manner as sertraline. Treatment with placebo will last 18 weeks.<br>|
| Experimental: Slow Titration<br>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<br>* Sertraline will be administered in slow titration. Treatment with sertraline will last 18 weeks.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Global Impression - Severity of Activation (CGI-SA) | 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. | Measured at screening, baseline and weekly until end of week 8 after baseline, then monthly for two months and finally at end of study | 
| Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) Total Score | 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). | Measured at Week 18 or End of Study | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
OCD, Antidepressive Agents, Second-Generation, Placebos, Cognitive Behavior Therapy, Child Psychiatry, Activation Syndrome, Psychometrics