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

Not Applicable

Completed

Conditions: Generalized Anxiety Disorder

Interventions: Behavioral: Exposure-based therapy
Behavioral: Behavioral Activation therapy
Behavioral: Computer-based behavioral assessment
Behavioral: Surveys and Interviews
Device: Magnetic resonance imaging (MRI)
Device: Electroencephalography (EEG)

Registration Number: NCT02807480

Lead Sponsor: Laureate Institute for Brain Research, Inc.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 121

Inclusion Criteria

Age: 18-55
All genders
All races
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.
Able to provide written, informed consent
Have sufficient proficiency in English language to understand and complete interviews, questionnaires, and all other study procedures

Exclusion Criteria

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.
A history of drug or alcohol abuse in the past 6 months,
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
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.
Active suicidal ideation with intent or plan
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.
Prescription of a medication outside of the accepted range, as determined by the best clinical practices and current research
Taking drugs that affect the fMRI hemodynamic response.
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
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)
Non-correctable vision or hearing problems
Report of severe depressive symptoms, as indicated by a score greater than 17 on the Patient Health Questionnaire 9-item (PHQ-9).

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Exposure-based therapy	Computer-based behavioral assessment	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).
Behavioral Activation therapy	Computer-based behavioral assessment	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).
Exposure-based therapy	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).
Exposure-based therapy	Surveys and Interviews	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).
Exposure-based therapy	Electroencephalography (EEG)	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).
Behavioral Activation therapy	Surveys and Interviews	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).
Exposure-based therapy	Magnetic resonance imaging (MRI)	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).
Behavioral Activation therapy	Electroencephalography (EEG)	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).
Behavioral Activation therapy	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).
Behavioral Activation therapy	Magnetic resonance imaging (MRI)	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).

Primary Outcome Measures

Name	Time	Method
For Aim1: Baseline Generalized Anxiety Disorder Symptoms as Measured by the Generalized Anxiety Disorder - 7 Item Scale (GAD-7).	Baseline assessment (one time point)	Test the relationship between imaging and behavioral factors and the level of symptoms at baseline assessment. Scores on the Generalized Anxiety Disorder - 7 item scale (GAD-7) range from 0 to 21, higher scores reflect greater symptom severity.
For Aims 2 and 3: Change in Generalized Anxiety Disorder Symptoms as Measured by the Generalized Anxiety Disorder - 7 Item Scale (GAD-7).	Trajectory of change from pre- to post- treatment; last time point assessed within 6 weeks following last treatment session, on average at 16 weeks after baseline assessment.	Test the predictive effects of imaging and behavioral factors on change in symptoms at baseline compared to within 6 weeks after completing treatment. Scores on the Generalized Anxiety Disorder - 7 item scale (GAD-7) range from 0 to 21, higher scores reflect greater symptom severity.

Secondary Outcome Measures

Name	Time	Method
Change in Anxiety Symptoms as Measured by the Patient Reported Outcomes Measurement Information System (PROMIS) Anxiety Scale.	Trajectory of change from pre- to post- treatment; last time point assessed within 6 weeks following last treatment session, on average at 16 weeks after baseline assessment	Test the predictive effects of imaging and behavioral factors on change in symptoms at baseline compared to within 6 weeks after completing treatment. The PROMIS Anxiety Scale yields t-scores, higher scores indicate greater symptom severity, with 50 indicating the population mean and a standard deviation of 10.
Depressive Symptoms as Measured by the Beck Depression Inventory - II.	Post- treatment; last time point assessed within 6 weeks following last treatment session, on average at 16 weeks after baseline assessment	Test the predictive effects of imaging and behavioral factors on symptoms at post-treatment (within 6 weeks after completing treatment), covarying for baseline symptom severity. The BDI-II is a 21-item questionnaire, with each individual item being rated from 0-3 in a list of four statements arranged in increasing severity about a particular symptom of depression. The outcome measure is the total score on the BDI-II, which is the sum of all 21 items. Higher scores equate to greater severity of depression symptoms. Total score of 0-13 is considered minimal range, 14-19 is mild, 20-28 is moderate, and 29-63 is severe.
Change in Depressive Symptoms as Measured by the Patient Reported Outcomes Measurement Information System (PROMIS) Depression Scale.	Trajectory of change from pre- to post- treatment; last time point assessed within 6 weeks following last treatment session, on average at 16 weeks after baseline assessment	Test the predictive effects of imaging and behavioral factors on change in symptoms at baseline compared to within 6 weeks after completing treatment. The PROMIS Depression scale yields t-scores; higher scores indicate greater symptom severity, with population mean being 50 and standard deviation of 10.
Change in Level of Disability as Measured by the Sheehan Disability Scale	Trajectory of change from pre- to post- treatment; last time point assessed within 6 weeks following last treatment session, on average at 16 weeks after baseline assessment	Test the predictive effects of imaging and behavioral factors on change in symptoms at baseline compared to within 6 weeks after completing treatment. The Sheehan Disability Scale assesses functional impairment in the domains of work/school, social life, and family life. Participants are provided with a 0-10 visual analog scale with spatiovisual, numeric, and descriptive anchors and asked to rate the extent to which their symptoms have interfered with their functioning on each item for total score ranges of 0-30. Higher scores indicate greater impairment.
Worry Symptoms as Measured by the Penn State Worry Questionnaire	Post- treatment; last time point assessed within 6 weeks following last treatment session, on average at 16 weeks after baseline assessment	Test the predictive effects of imaging and behavioral factors on post-treatment symptoms (within 6 weeks after completing treatment), covarying for baseline symptom severity. The PSWQ is a 16-item self-report scale designed to measure the trait of worry in adults. Scores range from 16 to 80 with higher scores indicative of higher levels of trait worry. Scores of 66 or greater are thought to indicate clinically significant worry.