Anxiety is the most common mental health problem in children and adolescents. This two-phased study will test the effects of an experimental computerized intervention aimed at reducing threat-based thinking (i.e., interpretation bias) in anxious youth. Participants in both the R61 (N=46) and R33 (N=72) trials will be youth ages 10 to 17 with a primary anxiety disorder (Separation, Social, Generalized). In the R61 trial, youth will be randomly assigned to receive 16 sessions over 4 weeks of either a personalized cognitive bias modification program for interpretation bias (CBM-I) or a computerized control condition (ICC). If CBM-I reduces interpretation bias significantly more than the ICC, the R33 trial will commence. In the R33, youth will be randomly assigned to either CBM-I or an equal amount of time in a cognitive restructuring intervention, which also aims to reduce threat-based thinking in anxiety. Please note that only the R61 phase of the trial has been completed and currently this record summary only reflects the R61 phase.

Anxiety is the most common mental health problem in youth, affecting one in four children and adolescents. Unfortunately, evidence-based treatments (pharmacotherapy, cognitive-behavioral therapy) are costly, not widely available, and ineffective for a substantial proportion of youth. In response, experts have called for novel treatments that directly target mechanisms underlying youth anxiety while simultaneously addressing barriers to care (i.e., cost, accessibility). One such promising mechanism is interpretation bias - the inaccurate interpretation of threat from ambiguity. The investigators have previously demonstrated that interpretation bias occurs in over 90% of anxious youth, is predictive of anxiety severity in clinical samples of youth, and differentiates between anxious and non-anxious youth. These data indicate that interpretation bias may be a ubiquitous phenomenon underlying anxiety expression in children and adolescents and therefore may be an ideal intervention target. Cognitive bias modification for interpretation bias (CBM-I) is a computerized intervention that attempts to reduce anxiety by directly modifying interpretation bias. CBM-I has demonstrated preliminary efficacy for reducing anxiety symptoms in adults. Yet extant CBM-I data in anxious youth are sparse, with little work addressing whether CBM-I significantly reduces interpretation bias, and whether this in turn reduces anxiety symptoms, as well as the dose necessary to reduce both bias and anxiety. This two-phased study tests personalized CBM-I in youth ages 10 to 17 who meet diagnostic criteria for a primary anxiety disorder (Separation, Social, Generalized). In the R61 Phase (N=46), a randomized clinical trial (RCT) examines whether CBM-I personalized to youth anxiety symptoms significantly reduces interpretation bias compared to a computerized interpretation control condition (ICC). The interpretation target will be measured at multiple time points (4, 8, 12, 16 sessions) to identify the optimal dose for reduction in interpretation bias. If the R61 trial results indicate that CBM-I outperforms ICC on interpretation bias reduction, the R33 phase will commence. In the R33 Phase, an RCT (N=72) will validate whether CBM-I significantly reduces interpretation bias, and conducts a mechanism test (i.e., does bias reduction precede and predict anxiety reduction?), by comparing CBM-I to cognitive restructuring, a clinically relevant psychosocial intervention that also targets anxious cognition. Please note that only the R61 phase of the trial has been completed and currently this record summary only reflects the R61 phase. If the R33 phase is funded, it will be registered as a separate NCT.

Inclusion Criteria:

• youth aged 10 to 17
• diagnosed at study baseline with a primary "big three" anxiety disorder (Separation, Social, Generalized)
• standard score greater than or equal to 85 on the Wide Range Achievement Test - Word Reading Subtest (to ensure ability to read stimuli during interpretation bias assessment and CBM-I/ICC), and estimated IQ standard score of at least 80 on the Wechsler Abbreviated Scale of Intelligence
• youth and consenting parent/legal guardian speak sufficient English to complete consent/assent and study procedures
• no concurrent psychosocial services during study participation to reduce likelihood that other interventions are responsible for change in primary or secondary outcomes
• no psychotropic medications with no plans to start medications during study, or six weeks stable on SSRI or psychostimulant medication and dose with no plans to change medication/dose during study

Exclusion Criteria:

• severe anxiety indicting that youth requires higher level of care (e.g., intensive treatment such as psychiatric hospitalization), significant diagnostic comorbidity (e.g., presence of psychosis or significant mood disorder), or another primary diagnosis that warrants alternate intervention
• significant uncorrected vision impairment (e.g., uncorrected blindness) that precludes participation in CBM-I/ICC
• safety concerns due to recent or acute suicidality with plan, intent, and/or attempt that warrants alternate intervention

Data resulting from this project will be de-identified and uploaded in a timely manner to the National Database for Clinical Trials Related to Mental Illness, including de-identified youth demographic and clinical characteristics, and summary scores from outcome measures, along with a data dictionary that provides variable definitions, value labels, and scoring of measures. The study protocol and dataset may be made available to other investigators based on successful completion of a data request form, following the conclusion of this study and publication of primary outcome papers.

Data will become available following conclusion of the study and publication of primary outcome papers.

Researchers will be required to complete a request form that includes: research identifying information and institutional affiliation, description of research objectives, and IRB approval. Completed request forms will be reviewed by the PI and Co-Is to ensure that the research request will not duplicate work being conducted by the study team. The requesting researcher must provide signed data sharing agreements from all users on their team outlining the details of how information will be kept secure, consistent with NIMH and University of Denver data sharing guidelines. Requesting researchers will also provide the University of Denver's IRB with an IRB approval from their institution. The data will only be released after the proposed study has been completed and primary outcomes have been accepted for publication.

Adverse event data were collected from study visit 2 (post-randomization and post-eligibility determination at Visit 1), and weekly through week 6 of study participation.

Adverse events were queried at each study visit starting study visit 2 after participants were enrolled. The independent evaluator queried youth and caregiver separately about potential adverse events using a table provided by the NIMH CREST program. Nearly all adverse events were either COVID related (e.g., participant was exposed to or had COVID transmission from their daily life activities) or cold/flu related.

The trial was funded in January 2020, and recruitment scheduled to begin in April 2020. COVID shutdowns in March 2020 led to delays in initiating recruitment, continued delays in recruitment, and COVID-related illnesses that led to enrolled participants rescheduling their in-person study visits beyond the initially scheduled 6 weeks of study participation for the first 2.5 years of recruitment. Our analytic method allows for controlling for number of days in study to address this.

Both participants and outcome assessors will be blind to condition. Unblinding occurs following all post-intervention assessment (i.e., after 16 CBM-I or ICC sessions).