Using the Neuroscience of Fear Extinction for Anxiety Reduction (UNFEAR)

September 30, 2021 updated by: Tali Manber Ball, PhD, Stanford University

Developing a Mechanistic Neurobiological Model of Exposure Therapy Response Based on Fear Extinction Theory

Social anxiety disorder affects as many as 12% of Americans, resulting in significant distress and disability. Although exposure therapy is one of the best treatments available, as many as 25% of patients do not respond and we do not know why. Extinction learning is thought to be the mechanism of exposure therapy, and the neuroscience of extinction learning has advanced significantly since exposure therapy was developed; however, there has been little application towards improved clinical outcomes.

This project aims to improve exposure therapy response for patients with social anxiety disorder by directly linking exposure therapy response to the neurobiology of extinction learning. It also aims to increase our scientific understanding of how brain circuits work to support extinction learning. To do this, 80 adults with social anxiety disorder will randomly be assigned to either receive exposure therapy right away, or to wait before therapy. Participants will all complete a functional magnetic resonance imaging scan to assess extinction learning before the therapy.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Terminated

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

The best available treatment for social anxiety disorder is exposure therapy; however, 25% of socially anxious patients do not respond to an adequate course of exposure therapy and it is unclear why. Prior attempts to identify non-responders using clinical and demographic features have been largely unsuccessful, highlighting the need to examine constructs that are more closely tied to the mechanism of treatment (i.e., extinction learning and recall) and the organ of dysfunction (i.e., the brain). The neurobiology of extinction learning and recall is well understood from decades of animal and pre-clinical laboratory work, which has highlighted the importance of the amygdala, dorsal anterior cingulate cortex (dACC), and ventromedial prefrontal cortex (vmPFC). However, this knowledge has not been leveraged to improve exposure therapy response, despite the assumption that response relies on extinction learning and its successful recall.

Thus, a critical long-term goal is to improve exposure therapy response by tailoring therapy based on the neurobiological profile of each patient. This project addresses that goal by directly linking neurobiological profiles of extinction learning and recall with clinical symptoms and therapy response. A major objective of this project is therefore to build a mechanistic predictive model of exposure therapy response based on the neurobiology of extinction learning and recall.

To accomplish this goal, the investigators will recruit 80 adults with social anxiety disorder who will be randomized to 10 sessions of exposure-focused therapy or waitlist. The primary clinical outcome measure will be the Liebowitz Social Anxiety Scale (LSAS), a validated and widely used measure that assesses anxiety and avoidance symptoms. Pre-therapy, participants will also undergo an experimental protocol for extinction learning and recall. Participants will first view a neutral abstract image repeatedly paired with a loud aversive noise, and another image that is never paired (fear acquisition phase). Following this, participants will view the same images without aversive consequences (extinction learning phase). Better extinction learning will be defined as greater reductions in skin conductance within the extinction learning phase. Brain activation during extinction learning will be assessed in the amygdala, dACC, and vmPFC. Finally, participants will view the same images without aversive consequences one week later (extinction recall phase). Better extinction recall will be defined as less skin conductance during extinction recall relative to fear acquisition. The central hypothesis is that greater activation in the vmPFC during extinction learning will predict both extinction recall and therapy response over and above symptom severity.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
32

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • California
      • Palo Alto, California, United States, 94304
        • Stanford University Department of Psychiatry & Behavioral Sciences

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 50 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • age 18-50
  • primary diagnosis of social anxiety disorder
  • fluent spoken and written English
  • able to provide informed consent.

Exclusion Criteria:

  • history of mania or psychosis
  • current moderate or severe substance use disorder
  • current major depression greater than moderate severity
  • high risk for suicide
  • prior traumatic brain injury with loss of consciousness >5 minutes
  • general medical condition or impediment to vision, hearing, or motor function likely to interfere with assessments
  • prior exposure therapy (>2 sessions)
  • current use of psychotropic medication
  • current psychotherapy other than couples counseling
  • post-menopausal status
  • pregnancy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Immediate therapy
Participants randomized to the immediate therapy arm will receive a weekly individual psychotherapy intervention called Coordinated Anxiety Learning and Management (CALM). The CALM program is an evidence based, exposure-focused therapy (http://calmtoolsforliving.org). Its computer-assisted format guides the therapist through psychoeducation, an introduction to cognitive restructuring, in-session and at-home exposures, and relapse prevention. Therapy will be delivered in 10 weekly 50-minute sessions within a 12 week period.
Behavioral: Coordinated Anxiety Learning and Management (CALM)
Exposure-focused cognitive behavioral therapy
No Intervention: Waitlist
Participants randomized to the waitlist arm will receive no intervention for 12 weeks. After this 12 week period they will receive a the same weekly individual psychotherapy intervention as the immediate therapy group: Coordinated Anxiety Learning and Management (CALM). The CALM program is an evidence based, exposure-focused therapy (http://calmtoolsforliving.org). Its computer-assisted format guides the therapist through psychoeducation, an introduction to cognitive restructuring, in-session and at-home exposures, and relapse prevention. Therapy will be delivered in 10 weekly 50-minute sessions within a 12 week period.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Liebowitz Social Anxiety Scale (LSAS)
Time Frame: 12 weeks
A validated, widely-used measure of social anxiety severity, with anxiety and avoidance subscales. Subscales range from 0 to 72, with higher scores indicating greater anxiety and avoidance symptoms. A total score is computed by summing the two subscales (range: 0 to 144, higher scores indicate greater social anxiety severity).
12 weeks

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Patient Health Questionnaire (PHQ-9)
Time Frame: 12 weeks
A validated and widely-used measure of depression symptom severity, ranging from 0 to 27, with higher scores indicating greater depression severity.
12 weeks
Brief Fear of Negative Evaluation (BFNE)
Time Frame: 12 weeks
A validated measure of fear of negative evaluation, a key concept in social anxiety disorder, ranging from 0 to 32, with higher scores indicating greater fear of negative evaluation.
12 weeks
World Health Organization Quality of Life scale (WHO-QOL)
Time Frame: 12 weeks
A validated measure of quality of life, which has subscales for physical health, psychological health, social relationships, and environment. Subscales scores are each transformed into a 0-100 range, with higher scores indicating better quality of life. There is no total score and the subscales are not combined.
12 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Stanford University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 14, 2018

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
September 30, 2021

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
September 30, 2021

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
March 7, 2018

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
March 7, 2018

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
March 14, 2018

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
October 8, 2021

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
September 30, 2021

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
September 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • IRB-44722

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

We plan to voluntarily share the raw fMRI data generated by this project through openfmri.org, a project of the Stanford Center for Reproducible Neuroscience. OpenfMRI is a recommended repository for several academic journals. There is no cost for researchers or analysts for use of this repository; the OpenfMRI repository uses a Public Domain license. We will fully de-identify and anonymize our data before uploading to the database, consistent with the OpenfMRI policy. Furthermore, the purpose, risks, and benefits of data sharing will be included in our consent form, and participants will be given the opportunity to exclude their data from the repository. Only participants who consent to and provide HIPAA authorization for this use will have their data uploaded.

IPD Sharing Time Frame

We anticipate uploading the final research data of all consenting participants no later than 5 years after the completion of the study.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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