Protocol for a randomized controlled trial examining multilevel prediction of response to behavioral activation and exposure-based therapy for generalized anxiety disorder

Abstract

Background: Only 40-60% of patients with generalized anxiety disorder experience long-lasting improvement with gold standard psychosocial interventions. Identifying neurobehavioral factors that predict treatment success might provide specific targets for more individualized interventions, fostering more optimal outcomes and bringing us closer to the goal of "personalized medicine." Research suggests that reward and threat processing (approach/avoidance behavior) and cognitive control may be important for understanding anxiety and comorbid depressive disorders and may have relevance to treatment outcomes. This study was designed to determine whether approach-avoidance behaviors and associated neural responses moderate treatment response to exposure-based versus behavioral activation therapy for generalized anxiety disorder.

Methods/design: We are conducting a randomized controlled trial involving two 10-week group-based interventions: exposure-based therapy or behavioral activation therapy. These interventions focus on specific and unique aspects of threat and reward processing, respectively. Prior to and after treatment, participants are interviewed and undergo behavioral, biomarker, and neuroimaging assessments, with a focus on approach and avoidance processing and decision-making. Primary analyses will use mixed models to examine whether hypothesized approach, avoidance, and conflict arbitration behaviors and associated neural responses at baseline moderate symptom change with treatment, as assessed using the Generalized Anxiety Disorder-7 item scale. Exploratory analyses will examine additional potential treatment moderators and use data reduction and machine learning methods.

Discussion: This protocol provides a framework for how studies may be designed to move the field toward neuroscience-informed and personalized psychosocial treatments. The results of this trial will have implications for approach-avoidance processing in generalized anxiety disorder, relationships between levels of analysis (i.e., behavioral, neural), and predictors of behavioral therapy outcome.

Trial registration: The study was retrospectively registered within 21 days of first participant enrollment in accordance with FDAAA 801 with ClinicalTrials.gov, NCT02807480. Registered on June 21, 2016, before results.

Keywords: Behavioral activation; Cognitive behavioral therapy; Depression; Exposure therapy; Functional magnetic resonance imaging; Generalized anxiety disorder.

Conflict of interest statement

Jessica Santiago, Elisabeth Akeman, Kelly Cosgrove, Bailey Mathis, Timothy McDermott, and Drs. James Abelson and Wes Thompson have no conflicts of interest to declare. Drs. Namik Kirlic and Jerzy Bodurka report receiving grants from the National Institute for General Medical Sciences. Dr. Ashley Clausen is funded by the Department of Veterans Affairs Office of Academic Affiliations Advanced Fellowship Program in Mental Illness Research and Treatment; the Medical Research Service of the Durham VA Health Care System; and the Department of Veterans Affairs Mid-Atlantic Mental Illness Research, Education, and Clinical Center (MIRECC). Dr. Michelle Craske reports receiving grants from the National Institute of Mental Health. Dr. Christopher Martell reports receiving royalties for four books on the topic of behavioral activation. Dr. Kathryn Wolitzky-Taylor reports receiving grants from the National Institute on Alcohol Abuse and Alcoholism and the National Institute on Drug Abuse. Dr. Martin Paulus has received royalties for an article about methamphetamine published in UpToDate and grants from the National Institute of General Medical Sciences and the National Institute of Mental Health. Dr. Robin Aupperle reports receiving grants from the National Institute of Mental Health, the National Institute of General Medical Sciences, and Oklahoma Science and Technology Research and Development. The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the U.S. government.

Figures

Fig. 1

Approach-avoidance conflict model that provided the bases for the current study protocol, aims, and hypotheses. As illustrated, both the fear or avoidance system and the reward/approach system are considered important in eliciting conflict and anxiety. Conflict arbitration requires appropriate balancing of both approach and avoidance drives. In the current protocol, approach and avoidance behaviors are defined by approach-avoidance test (AAT) bias scores; conflict arbitration is defined by reaction time during the approach-avoidance conflict (AAC) trials. For brain responses, we focus on the AAC task and extract percentage signal change (PSC) from a priori regions of interest: (1) approach: left caudate (reward versus no-reward outcome), (2) avoidance: right amygdala (negative versus positive affective outcome), and (3) conflict: right dorsolateral prefrontal cortex (dlPFC; conflict versus nonconflict decisions). Exposure-based therapy was included as a treatment that primarily targets avoidance or threat processes, whereas behavioral activation was included as a treatment that primarily targets approach or reward systems

Fig. 2

Schedule of enrollment, interventions, and assessments. This figure displays the assessments or interventions completed for screening, pretreatment, weekly during completion of therapy, posttreatment, and 3- and 6-month follow-up. Participants are randomized in groups of 8–10 to complete either behavioral activation or exposure-based therapy and are blinded to which intervention they will receive until after completion of all pretreatment assessments. Tx treatment, BDI-II SI Beck Depression Inventory suicidal ideation item, GAD-7 Generalized Anxiety Disorder 7-item scale, PROMIS Anx & Dep Patient-Reported Outcomes Measurement Information System anxiety and depression scales, BADS-SF Behavioral Activation for Depression Scale–Short Form, SDS Sheehan Disability Scale, HRS Homework Rating Scale, OASIS Overall Anxiety Severity and Impairment Scale, PSWQ Penn State Worry Questionnaire, LSAS Liebowitz Social Anxiety Scale, PDSS Panic Disorder Severity Scale, WAI Working Alliance Inventory, CEQ Credibility/Expectancy Questionnaire

Fig. 3

Approach-avoidance conflict (AAC) task. This figure displays (1) example decision screens displayed during the task for each of the five conditions: avoid-threat, approach-reward, and conflict with 2, 4, or 6 cents offered and (2) the sequence of screens presented for each AAC trial, including a decision phase followed by presentation of the affective image and sound pair (e.g., from International Affective Picture System and International Affective Digitized Sounds system [72, 73]), display of the number of cents received, and then a fixation cross until the next trial begins