Transdiagnostic Brain-Behavior Profiling to Enhance Cognitive Behavioral Therapy Response

May 26, 2026 updated by: Heide Klumpp, University of Illinois at Chicago
Many patients with Major Depressive Disorder (MDD) and generalized Social Anxiety Disorder (gSAD) are treated with cognitive behavioral therapy (CBT) but few have meaningful improvement. MDD and gSAD are diseases of brain dysfunction that manifest as impaired emotion regulation; CBT teaches emotion regulation strategies but how it works in the brain remains largely unknown. Individual differences in brain function related to emotion regulation may make some patients better suited for CBT and CBT may remedy the brain dysfunction that underlies these disorders. This project will compare CBT with a placebo psychotherapy (i.e., supportive therapy) in MDD and gSAD to test, validate, and refine brain-based markers and examine mechanisms of change to examine how CBT works and for whom.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Major Depressive Disorder (MDD) and generalized Social Anxiety Disorder (gSAD) are pervasive major public health problems. These disorders are characterized by emotion dysregulation, an inability or inefficiency to regulate negative and positive affect as reflected in common and disorder-specific symptoms (e.g., attentional bias to negative stimuli, excessive/inappropriate negative thoughts, hyperarousal, anhedonia, emotional blunting). Such dysregulation is believed to result from an imbalance between top-down 'emotion regulating' (ER) frontal nodes central in inhibitory control of bottom-up subcortical 'emotion-generating' (EG) nodes in a Fronto-Limbic Affect Regulation and Emotional Salience (FLARES) network. Therefore, successful treatment would be expected to 'normalize' neurofunctional disturbances in the FLARES network, which can be measured with fMRI and more distal units of brain function -- event-related potentials (ERPs) from electroencephalography, startle potentiation from electromyography (EMG), neurocognitive performance, and use of regulation strategies in daily life via self-report. The overarching objective of the proposed study is to understand how, when, and where CBT works and for whom to tailor treatment to improve clinical outcome.

Without precisely identified "targets" and "predictors" of change, CBT response will continue to be unpredictably varied with few achieving meaningful clinical improvement placing them at risk for relapse and recurrence. Our proposal builds on published data from our lab and others and Preliminary Data which shows FLARES function, as assayed with fMRI, ERPs, EMG, and behaviors, is sensitive to change following CBT.

Importantly, both baseline fMRI and non-fMRI units of brain-behavioral measures predict CBT response better than baseline clinical measures. Such knowledge can lead to more precise interventions aimed at capitalizing on 'strengths' or improving 'deficits' that may each exist before CBT and/or explain why CBT does not work for some patients. The dual development of fMRI ('mechanistic') and non-fMRI ('pragmatic') predictors and indices of therapeutic change is aimed at advancing precision medicine while increasing the clinical utility of 'biomarkers' in the outpatient setting. With this objective, we propose to employ well-validated paradigms to test ER and EG in the context of negative stimuli, reward processes, and fear systems in MDD and gSAD to delineate common and disorder-specific mechanisms of change and predictors of CBT outcome. We will enroll 200 patients: 100 MDD (without comorbid gSAD), 100 gSAD (without comorbid MDD) and randomize them to 12 weeks of manualized CBT or 12 weeks of 'placebo' psychotherapy (supportive therapy) (1:1 ratio). Multiple units of FLARES function will be collected in all patients before (Week 0), during (midway/Week 6) and after treatment (Week 12) to ascertain CBT 'dose' effects, and in 40 healthy controls for comparison. Pre-CBT predictors based on binary (responder/non-responder status) and continuous (extent of change) outcomes will be examined midway (Week 6), immediately after treatment (Week 12), and at 6-month follow-up.

Study Type

Interventional

Enrollment (Actual)

203

Phase

  • 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
    • Illinois
      • Chicago, Illinois, United States, 60608
        • University of Illinois at Chicago

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

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Description

Inclusion Criteria:

  1. generally medically and neurologically healthy, including no evidence of mental retardation or serious cognitive impairment that would interfere with protocol adherence and/or task performance
  2. between the ages of 18 - 65 years old, inclusive
  3. right-handed
  4. primary diagnosis of MDD or gSAD based on the SCID DSM-5. Patients will be permitted to have limited comorbid and/or history of internalizing psychopathologies (e.g., generalized anxiety disorder, specific phobia, adjustment disorder)

Exclusion Criteria:

  1. personal current or past manic/hypomanic episode or psychotic symptoms
  2. active suicidal ideation as determined by the Columbia Suicide Severity Rating Scale (C-SSRS)
  3. prior history of standard CBT (failure or success)
  4. any current or recent (past 4 weeks) use of medication (prescription or non-prescription) with psychotropic effects
  5. psychotherapy other than CBT or psychotropic medication use during the study
  6. cognitive dysfunction (traumatic brain injury, mental retardation, dementia)
  7. active moderate or severe alcohol and/or substance use disorders

For healthy controls: history or current Axis I disorder.

Additional exclusion criteria for all participants pertaining to the fMRI scan include:

  1. presence of ferrous-containing metals within the body (e.g., aneurysm clips, shrapnel/retained particles)
  2. inability to tolerate small, enclosed spaces without anxiety (e.g., claustrophobia)

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: Basic Science
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Single

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: CBT
The clinical psychologist will use a manualized CBT approach tailored to MDD or gSAD. Over a 12-week period sessions will include core CBT strategies -- psychoeducation, cognitive intervention (e.g., cognitive restructuring), behavioral changes (i.e., fear exposure, behavioral activation strategies) and relapse prevention.
Behavioral: CBT
CBT works by changing people's attitudes and their behavior by focusing on the thoughts, images, beliefs and attitudes that are held (a person's cognitive processes) and how these processes relate to the way a person behaves, as a way of dealing with emotional problems.
Other Names:
  • Cognitive Behavioral Therapy
Placebo Comparator: ST
The clinical psychologist will use an ST approach that resembles client-centered therapy of Carl Rogers (1951) which has been used as a control psychotherapy. The manual is based on supportive psychotherapy principles. Over a 12-week period, sessions will emphasize reflective listening and elicitation of affect. In contrast to CBT, therapists allow patients to determine the focus of each session, pulling for emotion, validating emotions when possible, and offering empathetic comments. Therapists will refrain from delineating any CBT theoretical framework and avoided cognitive and behavioral techniques that might overlap with CBT.
Behavioral: ST
Treatment designed to improve, reinforce, or sustain a patient's physiological well-being or psychological self-esteem and self-reliance
Other Names:
  • Supportive Therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Changes in Symptom Severity From Baseline to Week 12 Between Treatment Arms
Time Frame: baseline and week 12
Patients were randomized to either 12 weeks of cognitive behavioral therapy or supportive therapy. Healthy control (HC) participants did not receive treatment but completed the same assessments at the same time points as patients. Liebowitz Social Anxiety Scale (LSAS) and Hamilton Depression Rating Scale (HDRS) served as primary outcome measures as they are interviewer based standard clinical measures. A composite score combining LSAS and HDRS was constructed using proportion of maximum scaling (POMS) method to represent symptom severity. Higher scores mean worse outcomes. The minimum value is 0 and the maximum value is 1.
baseline and week 12
Baseline Brain Activity During Emotion Regulation Differences Between Controls and Patients
Time Frame: baseline
Outcomes are parameter estimates (arbitrary units) of brain activity for a priori brain regions of interest (bilateral amygdala, bilateral dorsolateral prefrontal cortex ('DLPFC'), bilateral inferior frontal gyrus ('IFG')) comparing brain activity during task conditions against a baseline condition (look at neutral images; 'Look Neut'). Task conditions are reappraising negative images ('Reappraise') and looking at negative images ('Look Neg'). The Reappraise vs. Look Neut and Look Neg vs. Look Neut are the contrasts of interest. Not all participants who consented to the study completed this task at all time points. Reasons include dropping out of the study, COVID shutdowns, scheduling issues, and participants not consenting to perform task due to use of negative images. Higher values represent greater activation.
baseline
Comparisons Between Emotion Regulation Task Brain Activity at Baseline and After Completing Therapy (12 Weeks).
Time Frame: baseline and 12 weeks
Planned comparisons (i.e., paired t-test). Outcomes are parameter estimates (arbitrary units) of brain activity for a priori brain regions (amygdala, dorsolateral prefrontal cortex (DLPFC), inferior frontal gyrus (IFG)) comparing reappraising negative images ('Reappraise') to baseline condition (look at neutral images; 'Look Neut'). Not all participants who consented to the study completed this task at all time points. Reasons include dropping out of the study, COVID shutdowns, scheduling issues, and participants not consenting to perform task due to use of negative images. Higher values represent greater activation.
baseline and 12 weeks
Baseline Brain Activity During Emotion Regulation as a Predictor of Psychotherapy Outcome Collapsed Across Treatment Arm.
Time Frame: baseline
Outcomes are baseline parameter estimates (arbitrary units) of brain activity for a priori brain regions of interest (bilateral amygdala, bilateral dorsolateral prefrontal cortex ('DLPFC'), bilateral inferior frontal gyrus ('IFG')) comparing active conditions against 'baseline' condition (i.e., look at neutral images; 'Look Neut'). Active conditions are reappraising negative images ('Reappraise') and looking at negative images ('Look Neg'). The Reappraise vs. Look Neut and Look Neg vs. Look Neut are the contrasts of interest. Other outcome measure is symptom severity before and after psychotherapy collapsing across cognitive behavioral therapy and supportive therapy to examine general psychotherapy predictors across psychotherapies. Higher values (arbitrary units) represent greater activation. Aim 5 is a continuation of Aim 4 including symptom measures comprised of HAMD and LSAS composite score of maximum scaling method.
baseline
Baseline Brain Activity During Emotion Regulation as a Predictor of Psychotherapy Outcome Collapsed Across Treatment Arm.
Time Frame: baseline and 12 weeks
This aim is connected to Aim 4 and represents an additional predictor in the regression model. Data analysis results for Aim 4 apply to this data as well. Outcome measure is symptom severity before and after psychotherapy collapsing across cognitive behavioral therapy and supportive therapy. Symptom measures comprised social anxiety (LSAS) and depression (HAMD) composite score proportion of maximum scaling method which ranges from 0 to 1. Higher symptom severity scores represent worse symptoms.
baseline and 12 weeks

Collaborators and Investigators

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

Sponsor

University of Illinois at Chicago

Collaborators

National Institute of Mental Health (NIMH)

Investigators

  • Principal Investigator: Heide Klumpp, PhD, University of Illinois at Chicago

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

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)

July 5, 2017

Primary Completion (Actual)

March 1, 2022

Study Completion (Actual)

March 1, 2022

Study Registration Dates

First Submitted

May 31, 2017

First Submitted That Met QC Criteria

May 31, 2017

First Posted (Actual)

June 5, 2017

Study Record Updates

Last Update Posted (Actual)

June 23, 2026

Last Update Submitted That Met QC Criteria

May 26, 2026

Last Verified

May 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2017-0258
  • 1R01MH112705-01A1 (U.S. NIH Grant/Contract)

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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