Approach-Avoidance Conflict-a Multi-level Predictor for Therapy Response

NCT ID: NCT02807480

Last Updated: 2024-03-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 121 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2016-06-30
• Study Completion Date: 2022-03-04

Brief Summary

This project aims to identify brain and behavioral characteristics of individuals experiencing symptoms of generalized anxiety disorder that will predict the effectiveness of Exposure-based therapy versus Behavioral Activation Therapy. Brain imaging aspects of the study will use functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). Behavioral assessments will include self-report questionnaires, computer-based and observational tasks, and interviews. Assessments will focus on how individuals process positive information (such as reward) and negative information (such as distressing images), as well as how people make decisions. These assessments will be conducted across 2-3 in-person sessions prior to beginning the treatment, and will be repeated across 2-3 in-person sessions after completing treatment. A blood draw will also be conducted pre- and post- treatment. Both the Exposure-based and Behavior Activation therapy will consist of 10, 90-minute weekly therapy sessions conducted in small groups.

Detailed Description

Generalized anxiety disorder (GAD) is the most common anxiety disorder in primary care, with lifetime prevalence rates of 6%. GAD leads to significant individual and socioeconomic burden (e.g., due to days lost at work and increased health care utilization). Although there is significant comorbidity with major depressive disorder (MDD), a GAD diagnosis conveys a much poorer prognosis, with only 58% with GAD vs. 80% with MDD alone obtaining remission in two years. This highlights the importance of effectively treating GAD, for improving mental and physical health and decreasing socioeconomic burden. First-line treatments include medication (e.g., selective serotonin reuptake inhibitors [SSRIs]) and psychotherapy (e.g., cognitive behavioral therapy [CBT]). While both are superior to placebo, only 40-60% experience significant improvement, with at least 25% relapsing within a year. Thus, long-lasting improvements are occurring in less than 50% of patients. This ineffectiveness has been moderately associated with symptom severity, illness duration, and comorbidity, but these findings do not provide any strategies for improving treatment effectiveness. The current study will seek to identify behavioral or cognitive-affective predictors that indicate how well a patient is responding to treatment so that interventions can be further individualized to more effectively treat refractory patients.

The overall aim of this study are to identify whether neural, biological, and behavioral responses related to the arbitration of conflicting avoidance and approach drives can predict response to Exposure-based versus Behavioral Activate therapy for individuals with generalized anxiety disorder (with or without co-morbid major depressive disorder). This will be accomplished using behavioral, functional magnetic resonance imaging (fMRI), and genetic analyses pre and post Behavioral Activation therapy. Research subjects will include treatment-seeking individuals with clinically significant symptoms of unipolar depression. Diagnosis will be assessed using structured clinical interviews. Anxious and depressive symptom severity, personality characteristics, and general functioning will be collected via self-report paper-and-pencil questionnaires. Objective measures of approach, avoidance, and conflict behavioral responses will be collected using computer-administered testing and related neural responsivity will be measured using fMRI. For exploratory aims, a blood draw will be collect pre and post-treatment to examine genetic factors that may predict response to behavior therapy. This research has the potential to identify neural and behavioral approach-avoidance characteristics that can help predict which patients are likely to respond to Exposure-based versus Behavioral Activation therapy (i.e., predictors of treatment effectiveness) and reveal targets for future treatment modifications.

Aim 1: Examine relationships among approach-avoidance behavior and neural responses, and baseline GAD symptom severity.

Hypothesis 1.1: Approach and conflict arbitration behavior will explain significant variance in baseline symptoms above and beyond avoidance-related behavior.

Hypothesis 1.2: Approach (striatum) and conflict arbitration (lateral PFC) neural activity will explain significant variance in baseline symptoms above and beyond avoidance-related (amygdala) neural activity.

Aim 2: Examine how multi-level approach-avoidance behavior and neural responses predict individualized response to Exposure-based therapy for GAD (compared to Behavioral Activation).

Hypothesis 2.1: Approach-related and conflict arbitration behavior will help predict treatment response above and beyond avoidance-related behavior and baseline symptom severity.

Hypothesis 2.2: Activity in approach-related and conflict arbitration neural circuitry will predict treatment response above and beyond activity in avoidance-related neural circuitry.

Aim 3: Identify the changes in approach-avoidance processes that relate to Exposure therapy elicited functional improvement (compared to Behavioral Activation).

Hypothesis 3.1: The degree to which conflict arbitration abilities increase with treatment will positively relate to functional improvement from pre- to post-treatment.

The statistical analysis plan was described within a protocol paper published in 2020 (Santiago et al., 2020), which is cited in the References section.

Conditions

Generalized Anxiety Disorder

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

Exposure-based therapy

Participants will complete 10, 90-minute sessions of Exposure-based therapy, conducted using a group format. Each group will include 8-12 participants. Exposure-based therapy seeks to increase abilities to manage anxiety through repeated practice in facing the situations or thoughts that are the focus of worry or fear. All participants will complete computer-based behavioral assessments, surveys and interviews, functional magnetic resonance imaging (fMRI), and electroencephalography (EEG).

Group Type: EXPERIMENTAL

Exposure-based therapy

Intervention Type: BEHAVIORAL

Exposure-based therapy

Computer-based behavioral assessment

Intervention Type: BEHAVIORAL

Computer-based tasks during which participants respond to images on the screen, including abstract images, emotional faces, and pleasant and unpleasant images.

Surveys and Interviews

Intervention Type: BEHAVIORAL

Surveys and interviews in which participants will be asked to answer questions related to their mental and physical health history and current symptoms.

Magnetic resonance imaging (MRI)

Intervention Type: DEVICE

Magnetic resonance imaging (MRI) will be used to obtain information concerning the structure of the brain, as well as to assess changes associated with blood flow in the brain while participants are completing behavioral tasks (see description of computer-based behavioral assessment intervention).

Electroencephalography (EEG)

Intervention Type: DEVICE

Electroencephalography (EEG) will be used to assess changes in the electrical activity of the brain while participants are completing behavioral tasks (see description of computer-based behavioral assessment intervention).

Behavioral Activation therapy

Participants will complete 10, 90-minute sessions of Behavioral Activation therapy, conducted using a group format. Each group will include 8-12 participants. Behavioral Activation therapy seeks to target behaviors that might maintain or worsen negative mood. All participants will complete computer-based behavioral assessments, surveys and interviews, functional magnetic resonance imaging (fMRI), and electroencephalography (EEG).

Group Type: EXPERIMENTAL

Behavioral Activation therapy

Intervention Type: BEHAVIORAL

Behavioral Activation therapy

Computer-based behavioral assessment

Intervention Type: BEHAVIORAL

Computer-based tasks during which participants respond to images on the screen, including abstract images, emotional faces, and pleasant and unpleasant images.

Surveys and Interviews

Intervention Type: BEHAVIORAL

Surveys and interviews in which participants will be asked to answer questions related to their mental and physical health history and current symptoms.

Magnetic resonance imaging (MRI)

Intervention Type: DEVICE

Magnetic resonance imaging (MRI) will be used to obtain information concerning the structure of the brain, as well as to assess changes associated with blood flow in the brain while participants are completing behavioral tasks (see description of computer-based behavioral assessment intervention).

Electroencephalography (EEG)

Intervention Type: DEVICE

Electroencephalography (EEG) will be used to assess changes in the electrical activity of the brain while participants are completing behavioral tasks (see description of computer-based behavioral assessment intervention).

Interventions

Exposure-based therapy

Exposure-based therapy

Intervention Type: BEHAVIORAL

Behavioral Activation therapy

Behavioral Activation therapy

Intervention Type: BEHAVIORAL

Computer-based behavioral assessment

Computer-based tasks during which participants respond to images on the screen, including abstract images, emotional faces, and pleasant and unpleasant images.

Intervention Type: BEHAVIORAL

Surveys and Interviews

Surveys and interviews in which participants will be asked to answer questions related to their mental and physical health history and current symptoms.

Intervention Type: BEHAVIORAL

Magnetic resonance imaging (MRI)

Magnetic resonance imaging (MRI) will be used to obtain information concerning the structure of the brain, as well as to assess changes associated with blood flow in the brain while participants are completing behavioral tasks (see description of computer-based behavioral assessment intervention).

Intervention Type: DEVICE

Electroencephalography (EEG)

Electroencephalography (EEG) will be used to assess changes in the electrical activity of the brain while participants are completing behavioral tasks (see description of computer-based behavioral assessment intervention).

Intervention Type: DEVICE

Eligibility Criteria

Inclusion Criteria

1. Age: 18-55

2. All genders

3. All races

4. Eligibility as clinically significant anxiety will be determined by:

• Scoring greater than 7 on the Overall Anxiety Severity and Impairment Scale (OASIS) or greater than 10 on the generalized anxiety disorder 7-item scale (GAD-7) and/or diagnosis of Generalized Anxiety Disorder.
• Self-report that they are interested in obtaining treatment for anxiety.
• Anxiety symptoms are the primary disorder of concern.

5. Able to provide written, informed consent

6. Have sufficient proficiency in English language to understand and complete interviews, questionnaires, and all other study procedures

Exclusion Criteria

1. Has a history of unstable liver or renal insufficiency; glaucoma; significant and unstable cardiac, vascular, pulmonary, gastrointestinal, endocrine, neurologic, hematologic, rheumatologic, or metabolic disturbance; or any other condition that would make participation not be in the best interest (e.g., compromise the well-being) of the subject or that could prevent, limit, or confound the protocol-specified assessments.

2. A history of drug or alcohol abuse in the past 6 months,

3. Has any of the following diagnostic and statistical manual (DSM-5) disorders:

• Schizophrenia Spectrum and Other Psychotic Disorders
• Bipolar and Related Disorders
• Obsessive-Compulsive and Related Disorders
• Anorexia or Bulimia Nervosa
• Substance use disorder within 6 months

4. Moderate to severe traumatic brain injury (>30 min. loss of consciousness or >24 hours posttraumatic amnesia) or other neurocognitive disorder with evidence of neurological deficits, neurological disorders, or severe or unstable medical conditions that might be compromised by participation in the study.

5. Active suicidal ideation with intent or plan

6. Current use of a medication that could affect brain functioning (e.g., anxiolytics, antipsychotics, mood stabilizers). However, participants reporting current use of prescribed antidepressants (selective serotonin reuptake inhibitors [SSRIs]) will be included as long as the dose has been stable for 6 weeks prior to enrolling in the study.

7. Prescription of a medication outside of the accepted range, as determined by the best clinical practices and current research

8. Taking drugs that affect the fMRI hemodynamic response.

9. MRI contraindications including: cardiac pacemaker, metal fragments in eyes/skin/body (shrapnel), aortic/aneurysm clips, prosthesis, by-pass surgery/coronary artery clips, hearing aid, heart valve replacement, shunt (ventricular or spinal), electrodes, metal plates/pins/screws/wires, or neuro/bio-stimulators (TENS unit), persons who have ever been a professional metal worker/welder, history of eye surgery/eyes washed out because of metal, vision problems uncorrectable with lenses, inability to lie still on one's back for 60-120 minutes; prior neurosurgery; tattoos or cosmetic makeup with metal dyes, unwillingness to remove body piercings, and pregnancy

10. Unwillingness or inability to complete any of the major aspects of the study protocol, including magnetic resonance imaging (i.e., due to claustrophobia), blood draws, or behavioral assessment. However, failing to complete some individual aspects of these assessment sessions will be acceptable (i.e., being unwilling to answer individual items on some questionnaires or being unwilling to complete a behavioral task)

11. Non-correctable vision or hearing problems

12. Report of severe depressive symptoms, as indicated by a score greater than 17 on the Patient Health Questionnaire 9-item (PHQ-9).

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Institute of Mental Health (NIMH)

NIH

Sponsor Role: collaborator

Laureate Institute for Brain Research, Inc.

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Robin L Aupperle, Ph.D.

Role: PRINCIPAL_INVESTIGATOR

Laureate Institute for Brain Research

Locations

Laureate Institute for Brain Research

Tulsa, Oklahoma, United States

Countries

United States

References

Cuijpers P, Sijbrandij M, Koole S, Huibers M, Berking M, Andersson G. Psychological treatment of generalized anxiety disorder: a meta-analysis. Clin Psychol Rev. 2014 Mar;34(2):130-40. doi: 10.1016/j.cpr.2014.01.002. Epub 2014 Jan 10.

Reference Type: BACKGROUND

PMID: 24487344 (View on PubMed)

Arch JJ, Ayers CR. Which treatment worked better for whom? Moderators of group cognitive behavioral therapy versus adapted mindfulness based stress reduction for anxiety disorders. Behav Res Ther. 2013 Aug;51(8):434-42. doi: 10.1016/j.brat.2013.04.004. Epub 2013 May 2.

Reference Type: BACKGROUND

PMID: 23747582 (View on PubMed)

Aupperle RL, Paulus MP. Neural systems underlying approach and avoidance in anxiety disorders. Dialogues Clin Neurosci. 2010;12(4):517-31. doi: 10.31887/DCNS.2010.12.4/raupperle.

Reference Type: BACKGROUND

PMID: 21319496 (View on PubMed)

Aupperle RL, Melrose AJ, Francisco A, Paulus MP, Stein MB. Neural substrates of approach-avoidance conflict decision-making. Hum Brain Mapp. 2015 Feb;36(2):449-62. doi: 10.1002/hbm.22639. Epub 2014 Sep 15.

Reference Type: BACKGROUND

PMID: 25224633 (View on PubMed)

Aupperle RL, Sullivan S, Melrose AJ, Paulus MP, Stein MB. A reverse translational approach to quantify approach-avoidance conflict in humans. Behav Brain Res. 2011 Dec 1;225(2):455-63. doi: 10.1016/j.bbr.2011.08.003. Epub 2011 Aug 6.

Reference Type: BACKGROUND

PMID: 21843556 (View on PubMed)

Santiago J, Akeman E, Kirlic N, Clausen AN, Cosgrove KT, McDermott TJ, Mathis B, Paulus M, Craske MG, Abelson J, Martell C, Wolitzky-Taylor K, Bodurka J, Thompson WK, Aupperle RL. Protocol for a randomized controlled trial examining multilevel prediction of response to behavioral activation and exposure-based therapy for generalized anxiety disorder. Trials. 2020 Jan 6;21(1):17. doi: 10.1186/s13063-019-3802-9.

Reference Type: BACKGROUND

PMID: 31907032 (View on PubMed)

Berg H, McDermott TJ, Kuplicki R, Yeh HW, Thompson WK, Smith R, Akeman E, Kirlic N, Clausen A, Cannon M, White E, Martell CR, Wolitzky-Taylor KB, Craske MG, Abelson JL, Paulus MP, Aupperle RL. Prediction of generalized anxiety disorder treatment outcomes with neurobehavioral responses to approach-avoidance conflict: a randomized clinical trial. Transl Psychiatry. 2025 Jul 5;15(1):231. doi: 10.1038/s41398-025-03460-x.

Reference Type: DERIVED

PMID: 40617801 (View on PubMed)

Berg H, Eun YJ, Yu X, McDermott TJ, Akeman E, Kuplicki R, Yeh HW, Thompson W, Martell CR, Wolitzky-Taylor KB, Craske MG, Paulus MP, Aupperle RL. Neural activity to reward and loss predicting treatment outcomes for adults with generalized anxiety disorder: A randomized clinical trial. J Mood Anxiety Disord. 2025 Mar;9:100107. doi: 10.1016/j.xjmad.2025.100107. Epub 2025 Jan 8.

Reference Type: DERIVED

PMID: 40384942 (View on PubMed)

Berg H, Akeman E, McDermott TJ, Cosgrove KT, Kirlic N, Clausen A, Cannon M, Yeh HW, White E, Thompson WK, Choquette EM, Sturycz-Taylor CA, Cochran G, Ramirez S, Martell CR, Wolitzky-Taylor KB, Craske MG, Abelson JL, Paulus MP, Aupperle RL. A randomized clinical trial of behavioral activation and exposure-based therapy for adults with generalized anxiety disorder. J Mood Anxiety Disord. 2023 Jun;1:100004. doi: 10.1016/j.xjmad.2023.100004. Epub 2023 Jun 9.

Reference Type: DERIVED

PMID: 38384390 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

1K23MH108707-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2015-006-02

Identifier Type: -

Identifier Source: org_study_id