Effects of Sertraline on Brain Connectivity in Adolescents With OCD

• Sponsor: University of Minnesota (Other)
• Overall Status: Completed
• CT.gov ID: NCT02797808
• Collaborator: National Institute of Mental Health (NIMH) (NIH)
• Enrollment: 41
• Location: 1
• Arms: 2
• Duration (Months): 42
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

The investigators will examine how treatment with sertraline for 12 weeks impacts frontal-striatal-thalamic circuitry (FSTC) in this OCD sample.

Condition or Disease	Intervention/Treatment	Phase
OCD	Drug: Sertraline; Other: No Intervention	Phase 1/Phase 2

Detailed Description

To examine FSTC using advanced multi-modal imaging techniques, including resting-state functional magnetic resonance imaging (R-fMRI) and high angular resolution diffusion imaging (HARDI), in 25 medication-free adolescents youths with OCD (ages 8-17) in comparison with 25 matched healthy controls.

Hypotheses: (A) Based on the pilot data, adolescents youths with OCD will show lower functional connectivity in FSTC at baseline when compared with controls, and , lower functional connectivity in FSTC will correlate with greater severity on CY-BOCS. (B) Adolescents Youths with OCD will also show abnormalities in structural connectivity in FSTC at baseline when compared with controls, and structural and functional connectivity will be related. (C) The investigators will explore relations between OCD dimensions and functional connectivity measures, and predict that the repeating/ordering dimension will correlate with orbitofrontal cortex (OFC) connections, hoarding will correlate with rostral anterior cingulate cortex (ACC) connections, and forbidden thoughts will correlate with caudal ACC connections.

To investigate how sertraline impacts functional connectivity in FSTC in adolescents with OCD.

Hypothesis: After 12 weeks of sertraline treatment, functional connectivity measures within FSTC for the OCD group will (on average) increase compared to baseline and will no longer be significantly different when compared with controls. Non-responders may show a different pattern (i.e. failure to show these changes).

Study Design

• Study Type: Interventional
• Actual Enrollment: 41 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Basic Science
• Official Title: Effects of Sertraline on Brain Connectivity in Adolescents With OCD (Obsessive-Compulsive Disorder)
• Study Start Date: Aug 1, 2013
• Actual Primary Completion Date: Jan 31, 2017
• Actual Study Completion Date: Jan 31, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Children with OCD Children with obsessive compulsive disorder, not currently on medication for OCD	Drug: Sertraline; Impact of sertraline on functional brain connectivity; Other Names: Zoloft
Active Comparator: Healthy Control Children Children without obsessive compulsive disorder	Other: No Intervention; Healthy control non-intervention

Outcome Measures

Primary Outcome Measures

1. CY-BOCS Total Score at 12-weeks [12 weeks]

   The Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) a clinician-rated semi-structured instrument assessing OCD severity over the previous 7 days in children ages 6 to 17 years. Items are scored from 0 (none) to 4 (extreme) and total score ranges from 0 to 40 with higher scores indicating greater impairment. All 19 items are rated, but only items 1-10 are used to determine the total score. The total CY-BOCS score is the sum of items 1-10; the obsession and compulsion subtotals are the sums of items 1-5 and 6-10, respectively. At this time, items 1A and 6A are not being used in the scoring. Items 17 (global severity) and 18 (global improvement) are adapted from the Clinical Global Impression Scale to provide measures of overall functional impairment associated with the presence of obsessive-compulsive symptoms.

2. Longitudinal 2-Group Resting State Functional Conectivity (RSFC) Analyses [12 weeks]

   Participants had whole brain fMRI at baseline &12 weeks. Whole brain connectivity in 6 striatal ROIs was performed. Two-way mixed effects ANOVAs were performed with FEAT. Clusters were significant if p <.0042 based on .05/(6 ROIs x 2 tests/ROI). Mean z-score was found for each time point in each subject's connectivity map in each significant cluster. Within-group paired-sample t tests examined RSFC change over time in these metrics for each group. To investigate group X time interactions from the 2-way ANOVA, we compared mean z-scores within each significant cluster at baseline & 12 weeks. Resulting numbers represented striatal connectivity for each individual at each time point. Within group paired sample t-tests examined RSFC change over time for each group. Bonferroni correction was applied to alpha level (2-tailed, p<0.5/6 =.0083) for multiple testing. We do not have an a priori hypothesis as to whether increase or decrease in RSFC is a better outcome. Unit of measure is z-score.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 8 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria (OCD):

• OCD as the primary Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) diagnosis based on the Anxiety Disorders Interview Schedule (ADIS) for DSM-IV, Child Version

• Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) score of greater than 15

Exclusion Criteria (OCD):

• lifetime diagnosis of bipolar disorder, schizophrenia, or substance abuse/dependence on ADIS

• Intelligence Quotient (IQ) < 80 on Wechsler Abbreviated Scales of Intelligence (WASI)

• positive urine drug screen

• MRI-incompatible features (e.g., metal implants, claustrophobia)

• current or recent trial of psychotropic medication (within the past 4 8 weeks or past 6 12 weeks for fluoxetine)

• non-response in > 2 selective serotonin reuptake inhibitor (SSRI) trials of adequate dose/duration

• positive pregnancy test

• history of seizure disorder or serious head injury

Inclusion Criteria (Controls):

• Healthy 8-17 year olds

Exclusion criteria (controls):

• No psychiatric diagnoses

• No immediate family history of OCD

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Minnesota	Minneapolis	Minnesota	United States	55454

Sponsors and Collaborators

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

Investigators

• Principal Investigator: Gail A Bernstein, MD, University of Minnesota

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Oct 10, 2017

More Information

Publications

None provided.

• Responsible Party: University of Minnesota
• ClinicalTrials.gov Identifier: NCT02797808
• Other Study ID Numbers: 1105M99532; 5R21MH101395-02
• First Posted: Jun 13, 2016
• Last Update Posted: Jan 5, 2021
• Last Verified: Dec 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by University of Minnesota: OCD
• Additional relevant MeSH terms: Sertraline

Study Results

Participant Flow

Arm/Group Title	Obsessive-compulsive Disorder	Healthy Controls
Arm/Group Description	Sertraline: Impact of sertraline on functional brain connectivity	No Intervention: Healthy control non-intervention
Period Title: Overall Study
STARTED	23	18
COMPLETED	16	15
NOT COMPLETED	7	3

Baseline Characteristics

Arm/Group Title	Obsessive-compulsive Disorder	Healthy Controls	Total
Arm/Group Description	Sertraline: Impact of sertraline on functional brain connectivity	No Intervention: Healthy control non-intervention	Total of all reporting groups
Overall Participants	23	18	41
Age (Count of Participants)
<=18 years	23 100%	18 100%	41 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	13.4 (2.6)	13.4 (2.9)	13.4 (2.75)
Sex: Female, Male (Count of Participants)
Female	15 65.2%	13 72.2%	28 68.3%
Male	8 34.8%	5 27.8%	13 31.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 4.3%	0 0%	1 2.4%
Not Hispanic or Latino	22 95.7%	18 100%	40 97.6%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 8.7%	0 0%	2 4.9%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 4.3%	1 5.6%	2 4.9%
White	10 43.5%	13 72.2%	23 56.1%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	10 43.5%	4 22.2%	14 34.1%
Region of Enrollment (Count of Participants)
United States	23 100%	18 100%	41 100%
CY-BOCS Total Score at Baseline (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	24.8 (6.9)	0 (0)	24.8 (6.9)

Outcome Measures

1. Primary Outcome

Title	CY-BOCS Total Score at 12-weeks
Description	The Children's Yale-Brown Obsessive Compulsive Scale (CY-BOCS) a clinician-rated semi-structured instrument assessing OCD severity over the previous 7 days in children ages 6 to 17 years. Items are scored from 0 (none) to 4 (extreme) and total score ranges from 0 to 40 with higher scores indicating greater impairment. All 19 items are rated, but only items 1-10 are used to determine the total score. The total CY-BOCS score is the sum of items 1-10; the obsession and compulsion subtotals are the sums of items 1-5 and 6-10, respectively. At this time, items 1A and 6A are not being used in the scoring. Items 17 (global severity) and 18 (global improvement) are adapted from the Clinical Global Impression Scale to provide measures of overall functional impairment associated with the presence of obsessive-compulsive symptoms.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

2 additional participants with OCD and 1 Healthy Control were removed from this analysis due to motion effects in the neuroimaging data.

Arm/Group Title	Children With OCD	Healthy Control Children
Arm/Group Description	Sertraline: Impact of sertraline on functional brain connectivity	No Intervention: Healthy control non-intervention
Measure Participants	14	14
Mean (Standard Deviation) [units on a scale]	14.1 (8.5)	0 (0)

2. Primary Outcome

Title	Longitudinal 2-Group Resting State Functional Conectivity (RSFC) Analyses
Description	Participants had whole brain fMRI at baseline &12 weeks. Whole brain connectivity in 6 striatal ROIs was performed. Two-way mixed effects ANOVAs were performed with FEAT. Clusters were significant if p <.0042 based on .05/(6 ROIs x 2 tests/ROI). Mean z-score was found for each time point in each subject's connectivity map in each significant cluster. Within-group paired-sample t tests examined RSFC change over time in these metrics for each group. To investigate group X time interactions from the 2-way ANOVA, we compared mean z-scores within each significant cluster at baseline & 12 weeks. Resulting numbers represented striatal connectivity for each individual at each time point. Within group paired sample t-tests examined RSFC change over time for each group. Bonferroni correction was applied to alpha level (2-tailed, p<0.5/6 =.0083) for multiple testing. We do not have an a priori hypothesis as to whether increase or decrease in RSFC is a better outcome. Unit of measure is z-score.
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

2 additional participants with OCD and 1 Healthy Control were removed from this analysis due to motion effects in the neuroimaging data.

Arm/Group Title	Children With OCD	Healthy Control Children
Arm/Group Description	Sertraline: Impact of sertraline on functional brain connectivity	No Intervention: Healthy control non-intervention
Measure Participants	14	14
Connectivity z-scores for right putamen at baseline	0.15 (1.04)	1.44 (1.06)
Connectivity z-scores for right putamen at 12 weeks	1.89 (0.85)	0.60 (0.98)
Connectivity z-scores for left putamen at baseline	1.46 (1.14)	2.41 (1.19)
Connectivity z-scores for left putamen at week 12	3.03 (1.54)	0.89 (0.99)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Children With OCD, Healthy Control Children
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0083
	Comments	Independent-sample t tests were used to compare the RSFC metrics between groups at baseline and 12 weeks. Bonferroni correction was applied to the alpha level (2-tailed, p<.05/6= .0083) for multiple testing.
	Method	ANOVA
	Comments

Adverse Events

Time Frame	12 weeks
Arm/Group Title	Obsessive-compulsive Disorder		Healthy Controls
Arm/Group Description	Sertraline: Impact of sertraline on functional brain connectivity		No Intervention: Healthy control non-intervention
All Cause Mortality
	Obsessive-compulsive Disorder		Healthy Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/23 (0%)		0/18 (0%)
Serious Adverse Events
	Obsessive-compulsive Disorder		Healthy Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/23 (4.3%)		0/18 (0%)
Nervous system disorders
Seizure	1/23 (4.3%)	1	0/18 (0%)	0
Other (Not Including Serious) Adverse Events
	Obsessive-compulsive Disorder		Healthy Controls
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/23 (34.8%)		0/18 (0%)
General disorders
Medication Side Effect	8/23 (34.8%)	21	0/18 (0%)	0

Limitations/Caveats

[Not Specified]

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.