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Neurofunctional Predictors of Escitalopram Treatment Response in Adolescents With Anxiety (FiESTAA)

Primary Purpose

Anxiety

Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Escitalopram
Placebo
Sponsored by
University of Cincinnati
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Anxiety focused on measuring Anxiety, Adolescents with Anxiety

Eligibility Criteria

12 Years - 17 Years (Child)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Inclusion - Anxiety Subjects:

  • Diagnostic and Statistical Manual-IV (Text Revision) criteria for generalized anxiety disorder diagnosed by the Anxiety Disorders Interview Schedule (ADIS-IV)
  • Baseline Pediatric Anxiety Rating Scale (PARS) score ≥15 at baseline
  • Ages 12-17 years 11 months old
  • Fluent in English
  • Provision of written informed consent by a legal guardian and written assent by the subject
  • Tanner scale stages II-V, in order to include only post-pubescent subjects and minimize brain changes associated with the onset of puberty
  • Does not have a history of intolerance, non-response or hypersensitivity to escitalopram
  • No co-occurring Diagnostic and Statistical Manual-IV (Text Revision) diagnosis mood (except dysthymia, depression not otherwise specified), eating, pervasive developmental disorder or psychotic disorders
  • Subjects will be excluded if there are any lifetime diagnosis of mental retardation (intelligence quotient < 70)
  • Subjects with any history of alcohol or drug dependence or any alcohol abuse within the past 6 months (nicotine dependence is permitted) will be excluded
  • No new psychotherapy will be permitted during study participation and if the patient is engaged in psychotherapy, it must have been stable for 1 month prior to baseline
  • Females will not be eligible to participate if pregnant, breast feeding or lactating.

Inclusion - Healthy Subjects:

  • Ages of 12-17 years and 11 months
  • No history of any Diagnostic and Statistical Manual-IV (Text Revision) Axis I disorders (nicotine dependence is permitted)
  • No first-degree relatives with an affective or psychotic disorder
  • No medications with central nervous system effects within 5 half-lives
  • Fluent in English
  • Tanner stage II-V
  • Provision of informed consent and assent.

Exclusion Criteria:

Exclusion - Generalized Anxiety Disorder Patients & Healthy Subjects:

  • Contraindication to an magnetic resonance imaging (MRI) scan (e.g., braces or claustrophobia)
  • An unstable medical or neurological illness that could influence fMRI or magnetic resonance spectroscopy results
  • Subjects will be excluded if there are any lifetime diagnosis of mental retardation or intelligence quotient < 70)
  • A positive pregnancy test
  • Adolescents will be excluded for treatment with a medication with central nervous system effects that requires more than 5 days of a screening period in order to minimize the length of time between screening and baseline and maximize patient safety, while recognizing that a longer taper period is required of some medications
  • Adolescents with any history of major medical or neurological disorders that may result in neurofunctional or neurochemical abnormalities including loss of consciousness for >10 minutes will be excluded
  • No co-occurring Diagnostic and Statistical Manual-IV (Text Revision) diagnosis mood (other than dysthymia or Depression Not Otherwise Specified), eating, pervasive developmental disorder or psychotic disorders
  • Subjects will be excluded if there are any lifetime diagnosis of mental retardation or intelligence quotient < 70
  • Subjects with any history of alcohol or drug dependence or any alcohol abuse within the past 6 months (nicotine dependence is permitted) will be excluded
  • No new psychotherapy will be permitted during study participation and if the patient is engaged in psychotherapy, it must have been stable for 1 month prior to baseline
  • Females will not be eligible to participate if pregnant, breast feeding or lactating
  • The patient lives >100 miles from the University of Cincinnati or is not able to attend follow-up visits

Sites / Locations

  • University of Cincinnati, Department of Psychiatry & Behavioral Neuroscience

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Placebo Comparator

No Intervention

Arm Label

Escitalopram

Placebo

Healthy Controls

Arm Description

Patients being randomized to receive escitalopram, at an initial dose of 5 mg (oral) daily for 2 days. On day 3, escitalopram will be increased to 10 mg daily and continued for 7 days. Then, on day 10, escitalopram will be increased to 15 mg. At the week 4 visit, the dose of escitalopram may be increased to 20 mg, based on the investigator's clinical judgment and if significant anxiety symptoms are still present.

Patients will receive placebo (sugar pill) at an initial dose of 5 mg daily for 2 days. On day 3, placebo will be increased to 10 mg daily and continued for 7 days to match the experimental group.

Healthy adolescents will receive fMRI scans at the same time points, which will provide assessments of the stability of neurophysiologic measures and will be used to adjust and interpret comparisons within the patients (i.e., whether patient values are changing toward or away from those of healthy adolescents).

Outcomes

Primary Outcome Measures

Early escitalopram-related functional brain activity changes during emotional processing
To determine if escitalopram treatment (over a 2 week period) increases functional brain activation during the processing of emotional images while performing a continuous processing task with emotional and neutral distracters (CPT-END) (also over a 2 week period).

Secondary Outcome Measures

Change in functional activity in the ventrolateral prefrontal cortex (from baseline to week 2) and improvement in Pediatric Anxiety Rating Scale score (at week 8/early termination)
To determine if the change in functional activity in the ventrolateral prefrontal cortex (from baseline to week 2) predicts improvement in Pediatric Anxiety Rating Scale score from baseline to week 8/early termination.
Change in functional connectivity between the ventrolateral prefrontal cortex and the amygdala (from baseline to week 2) and improvement in Pediatric Anxiety Rating Scale score (at week 8/early termination)
To determine if the change in functional connectivity between the ventrolateral prefrontal cortex and the amygdala (from baseline to week 2) predicts improvement in Pediatric Anxiety Rating Scale score from baseline to week 8/early termination.
Change in glutamate concentrations in the anterior cingulate cortex predict improvement in Pediatric Anxiety Rating Scale score from baseline to week 8/early termination.
To determine if change in glutamate concentrations in the anterior cingulate cortex predict improvement in Pediatric Anxiety Rating Scale score from baseline to week 8/early termination.
Change in γ-aminobutyric acid concentrations in the anterior cingulate (from baseline to week 2) predicts improvement in Pediatric Anxiety Rating Scale score from baseline to week 8 (or early termination)
To determine if the change in γ-aminobutyric acid concentrations in the anterior cingulate (from baseline to week 2) predicts improvement in Pediatric Anxiety Rating Scale score from baseline to week 8 (or early termination)

Full Information

First Posted
June 2, 2016
Last Updated
November 4, 2020
Sponsor
University of Cincinnati
Collaborators
National Institute of Mental Health (NIMH)
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1. Study Identification

Unique Protocol Identification Number
NCT02818751
Brief Title
Neurofunctional Predictors of Escitalopram Treatment Response in Adolescents With Anxiety
Acronym
FiESTAA
Official Title
Neurofunctional Predictors of Escitalopram Treatment Response in Adolescents With Anxiety
Study Type
Interventional

2. Study Status

Record Verification Date
November 2020
Overall Recruitment Status
Completed
Study Start Date
May 2015 (Actual)
Primary Completion Date
May 2019 (Actual)
Study Completion Date
May 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Cincinnati
Collaborators
National Institute of Mental Health (NIMH)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Neurofunctional Predictors of Escitalopram Treatment Response in Adolescents with Anxiety. To determine the effects of escitalopram on functional activation patterns during a Continuous Performance Task with Emotional and Neutral Distracters, the CPT-END. To examine baseline functional activity and functional connectivity profiles in the ventrolateral prefrontal cortex as markers of subsequent treatment response to escitalopram in adolescents with generalized anxiety disorder (GAD). To use proton magnetic resonance spectroscopy (1H MRS) to examine glutamatergic and γ-aminobutyric acid (GABA)-related abnormalities in the anterior cingulate in adolescents with GAD as compared to healthy adolescents.
Detailed Description
The long-term goal of this study is to explore the neurobiological basis of generalized anxiety disorder (GAD) using a validated functional MRI (fMRI) paradigm and functional connectivity analyses with a cohort of GAD patients and healthy subjects and generating feasibility and preliminary data regarding treatment-related effects of escitalopram on brain functional activation and Fc patterns in pediatric GAD. An additional goal is to identify biological markers in saliva and urine that will predict treatment response in pediatric subjects with GAD. The central hypothesis of this proposal is that core dysfunction within the prefrontal-amygdala network, which the investigators and others have observed in GAD, will be normalized by successful treatment. The rationale underlying this hypothesis is that, despite the high prevalence of GAD, there is a need to understand its neurobiology and to identify biomarkers of treatment response and the mechanisms by which selective serotonin reuptake inhibitors (SSRIs) putatively effect changes in the neurocircuitry of pediatric GAD.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Anxiety
Keywords
Anxiety, Adolescents with Anxiety

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
84 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Escitalopram
Arm Type
Experimental
Arm Description
Patients being randomized to receive escitalopram, at an initial dose of 5 mg (oral) daily for 2 days. On day 3, escitalopram will be increased to 10 mg daily and continued for 7 days. Then, on day 10, escitalopram will be increased to 15 mg. At the week 4 visit, the dose of escitalopram may be increased to 20 mg, based on the investigator's clinical judgment and if significant anxiety symptoms are still present.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Patients will receive placebo (sugar pill) at an initial dose of 5 mg daily for 2 days. On day 3, placebo will be increased to 10 mg daily and continued for 7 days to match the experimental group.
Arm Title
Healthy Controls
Arm Type
No Intervention
Arm Description
Healthy adolescents will receive fMRI scans at the same time points, which will provide assessments of the stability of neurophysiologic measures and will be used to adjust and interpret comparisons within the patients (i.e., whether patient values are changing toward or away from those of healthy adolescents).
Intervention Type
Drug
Intervention Name(s)
Escitalopram
Other Intervention Name(s)
Lexapro
Intervention Description
Patients being randomized to receive escitalopram.
Intervention Type
Other
Intervention Name(s)
Placebo
Other Intervention Name(s)
Sugar Pill
Intervention Description
Patients being randomized to receive placebo.
Primary Outcome Measure Information:
Title
Early escitalopram-related functional brain activity changes during emotional processing
Description
To determine if escitalopram treatment (over a 2 week period) increases functional brain activation during the processing of emotional images while performing a continuous processing task with emotional and neutral distracters (CPT-END) (also over a 2 week period).
Time Frame
From baseline to week 2 of treatment
Secondary Outcome Measure Information:
Title
Change in functional activity in the ventrolateral prefrontal cortex (from baseline to week 2) and improvement in Pediatric Anxiety Rating Scale score (at week 8/early termination)
Description
To determine if the change in functional activity in the ventrolateral prefrontal cortex (from baseline to week 2) predicts improvement in Pediatric Anxiety Rating Scale score from baseline to week 8/early termination.
Time Frame
from baseline to week 8 (or early termination)
Title
Change in functional connectivity between the ventrolateral prefrontal cortex and the amygdala (from baseline to week 2) and improvement in Pediatric Anxiety Rating Scale score (at week 8/early termination)
Description
To determine if the change in functional connectivity between the ventrolateral prefrontal cortex and the amygdala (from baseline to week 2) predicts improvement in Pediatric Anxiety Rating Scale score from baseline to week 8/early termination.
Time Frame
from baseline to week 8 (or early termination)
Title
Change in glutamate concentrations in the anterior cingulate cortex predict improvement in Pediatric Anxiety Rating Scale score from baseline to week 8/early termination.
Description
To determine if change in glutamate concentrations in the anterior cingulate cortex predict improvement in Pediatric Anxiety Rating Scale score from baseline to week 8/early termination.
Time Frame
from baseline to week 8 (or early termination)
Title
Change in γ-aminobutyric acid concentrations in the anterior cingulate (from baseline to week 2) predicts improvement in Pediatric Anxiety Rating Scale score from baseline to week 8 (or early termination)
Description
To determine if the change in γ-aminobutyric acid concentrations in the anterior cingulate (from baseline to week 2) predicts improvement in Pediatric Anxiety Rating Scale score from baseline to week 8 (or early termination)
Time Frame
from baseline to week 8 (or early termination)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Inclusion - Anxiety Subjects: Diagnostic and Statistical Manual-IV (Text Revision) criteria for generalized anxiety disorder diagnosed by the Anxiety Disorders Interview Schedule (ADIS-IV) Baseline Pediatric Anxiety Rating Scale (PARS) score ≥15 at baseline Ages 12-17 years 11 months old Fluent in English Provision of written informed consent by a legal guardian and written assent by the subject Tanner scale stages II-V, in order to include only post-pubescent subjects and minimize brain changes associated with the onset of puberty Does not have a history of intolerance, non-response or hypersensitivity to escitalopram No co-occurring Diagnostic and Statistical Manual-IV (Text Revision) diagnosis mood (except dysthymia, depression not otherwise specified), eating, pervasive developmental disorder or psychotic disorders Subjects will be excluded if there are any lifetime diagnosis of mental retardation (intelligence quotient < 70) Subjects with any history of alcohol or drug dependence or any alcohol abuse within the past 6 months (nicotine dependence is permitted) will be excluded No new psychotherapy will be permitted during study participation and if the patient is engaged in psychotherapy, it must have been stable for 1 month prior to baseline Females will not be eligible to participate if pregnant, breast feeding or lactating. Inclusion - Healthy Subjects: Ages of 12-17 years and 11 months No history of any Diagnostic and Statistical Manual-IV (Text Revision) Axis I disorders (nicotine dependence is permitted) No first-degree relatives with an affective or psychotic disorder No medications with central nervous system effects within 5 half-lives Fluent in English Tanner stage II-V Provision of informed consent and assent. Exclusion Criteria: Exclusion - Generalized Anxiety Disorder Patients & Healthy Subjects: Contraindication to an magnetic resonance imaging (MRI) scan (e.g., braces or claustrophobia) An unstable medical or neurological illness that could influence fMRI or magnetic resonance spectroscopy results Subjects will be excluded if there are any lifetime diagnosis of mental retardation or intelligence quotient < 70) A positive pregnancy test Adolescents will be excluded for treatment with a medication with central nervous system effects that requires more than 5 days of a screening period in order to minimize the length of time between screening and baseline and maximize patient safety, while recognizing that a longer taper period is required of some medications Adolescents with any history of major medical or neurological disorders that may result in neurofunctional or neurochemical abnormalities including loss of consciousness for >10 minutes will be excluded No co-occurring Diagnostic and Statistical Manual-IV (Text Revision) diagnosis mood (other than dysthymia or Depression Not Otherwise Specified), eating, pervasive developmental disorder or psychotic disorders Subjects will be excluded if there are any lifetime diagnosis of mental retardation or intelligence quotient < 70 Subjects with any history of alcohol or drug dependence or any alcohol abuse within the past 6 months (nicotine dependence is permitted) will be excluded No new psychotherapy will be permitted during study participation and if the patient is engaged in psychotherapy, it must have been stable for 1 month prior to baseline Females will not be eligible to participate if pregnant, breast feeding or lactating The patient lives >100 miles from the University of Cincinnati or is not able to attend follow-up visits
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Jeffrey Strawn
Organizational Affiliation
University of Cincinnati
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Cincinnati, Department of Psychiatry & Behavioral Neuroscience
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45219
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
32857933
Citation
Strawn JR, Mills JA, Schroeder H, Mossman SA, Varney ST, Ramsey LB, Poweleit EA, Desta Z, Cecil K, DelBello MP. Escitalopram in Adolescents With Generalized Anxiety Disorder: A Double-Blind, Randomized, Placebo-Controlled Study. J Clin Psychiatry. 2020 Aug 25;81(5):20m13396. doi: 10.4088/JCP.20m13396.
Results Reference
result
PubMed Identifier
32721213
Citation
Lu L, Li H, Mills JA, Schroeder H, Mossman SA, Varney ST, Cecil KM, Huang X, Gong Q, Levine A, DelBello MP, Sweeny JA, Strawn JR. Greater Dynamic and Lower Static Functional Brain Connectivity Prospectively Predict Placebo Response in Pediatric Generalized Anxiety Disorder. J Child Adolesc Psychopharmacol. 2020 Dec;30(10):606-616. doi: 10.1089/cap.2020.0024. Epub 2020 Jul 24.
Results Reference
result
PubMed Identifier
34580419
Citation
Lu L, Li H, Baumel WT, Mills JA, Cecil KM, Schroeder HK, Mossman SA, Huang X, Gong Q, Sweeney JA, Strawn JR. Acute neurofunctional effects of escitalopram during emotional processing in pediatric anxiety: a double-blind, placebo-controlled trial. Neuropsychopharmacology. 2022 Apr;47(5):1081-1087. doi: 10.1038/s41386-021-01186-0. Epub 2021 Sep 27.
Results Reference
derived
PubMed Identifier
33548492
Citation
Lu L, Mills JA, Li H, Schroeder HK, Mossman SA, Varney ST, Cecil KM, Huang X, Gong Q, Ramsey LB, DelBello MP, Sweeney JA, Strawn JR. Acute Neurofunctional Effects of Escitalopram in Pediatric Anxiety: A Double-Blind, Placebo-Controlled Trial. J Am Acad Child Adolesc Psychiatry. 2021 Oct;60(10):1309-1318. doi: 10.1016/j.jaac.2020.11.023. Epub 2021 Feb 4.
Results Reference
derived

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Neurofunctional Predictors of Escitalopram Treatment Response in Adolescents With Anxiety

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