Demonstration of a ‘leapfrog’ randomized controlled trial as a method to accelerate the development and optimization of psychological interventions

Abstract

Background The scale of the global mental health burden indicates the inadequacy not only of current treatment options, but also the pace of the standard treatment development process. The ‘leapfrog’ trial design is a newly-developed simple Bayesian adaptive trial design with potential to accelerate treatment development. A first leapfrog trial was conducted to provide a demonstration and test feasibility, applying the method to a low-intensity internet-delivered intervention targeting anhedonia. Methods At the start of this online, single-blind leapfrog trial, participants self-reporting depression were randomized to an initial control arm comprising four weeks of weekly questionnaires, or one of two versions of a four-week cognitive training intervention, imagery cognitive bias modification (imagery CBM). Intervention arms were compared to control on an ongoing basis via sequential Bayesian analyses, based on a primary outcome of anhedonia at post-intervention. Results were used to eliminate and replace arms, or to promote them to become the control condition based on pre-specified Bayes factor and sample size thresholds. Two further intervention arms (variants of imagery CBM) were added into the trial as it progressed. Results N = 188 participants were randomized across the five trial arms. The leapfrog methodology was successfully implemented to identify a ‘winning’ version of the imagery CBM, i.e. the version most successful in reducing anhedonia, following sequential elimination of the other arms. Conclusions The study demonstrates feasibility of the leapfrog design and provides a foundation for its adoption as a method to accelerate treatment development in mental health. Registration: clinicaltrials.gov, NCT04791137.

The Effect of Positive Mental Imagery versus Positive Verbal Thoughts on Anhedonia

“…Interestingly, there was no between-group difference in reduction in overall symptoms of depression, with participants in both groups showing improvements from pretraining to post-training and follow-up. This supports the idea that the effect of imagery on anhedonia as measured by the DARS was a specific, relatively direct, effect rather than caused by general improvements in depressive symptoms, and fits with similar patterns of results from other studies (Bibi et al, 2020;Blackwell et al, 2015Blackwell et al, , 2023Westermann et al, 2021). It is also interesting to note that while participants in the verbal condition did show reductions in symptoms of depression, they showed no change in anhedonia or positive affect (except briefly from pre to mid-training), consistent with these being relatively challenging targets for treatment even when depression symptoms in general are reduced (e.g., Alsayednasser et al, 2022;Dunn et al, 2020).…”

“…This is consistent with the theoretical importance of imagery in the anticipation of future events as a driver of interest or desire to engage in the activities and thus motivation (Renner et al, 2019). Further, it supports the role of positive imagery as a means to target anhedonia in clinical interventions, whether this is via simple computerized training programs (e.g., Blackwell et al, 2023) or as part of more complex interventions (e.g., Craske et al, 2019Craske et al, , 2023. Further work optimizing how positive imagery can be best applied to reduce anhedonia could bring significant clinical benefits in tackling this challenging symptom of depression.…”

“…For example, Pictet et al (2016) and Williams et al (2015) found a greater reduction in anhedonia, as measured via the anhedonia items from the BDI-II, following a one-week imagery CBM training schedule compared to a one-week sham training. Other studies with a variety of different training schedules and control conditions have found reductions in anhedonia on a dedicated anhedonia questionnaire (Bibi et al, 2020;Blackwell et al, 2023;Westermann et al, 2021).…”

“…Ambiguous Picture Rating Task (APRT). As per previous experimental studies using the picture-word paradigm (Holmes, Mathews, et al, 2008;Pictet et al, 2011) with 5 positive and 5 negative items (as per Blackwell et al, 2023;Westermann et al, 2021).…”

“…This study could therefore not test directly whether it was the generation of imagery specifically that resulted in the reductions in anhedonia observed; plausibly the generation of consistently positive resolutions (regardless of whether imagery-based or not) could in itself have been responsible for this effect. Other studies have also not addresssed this issue directly: Some have used control conditions in which only the training contingency or some other aspects of the intervention was changed, but the requirement to generate imagery remained (Blackwell et al, 2023;Pictet et al, 2016;Williams et al, 2015), whereas others have used a control condition that differed in too many aspects to draw conclusions about any specific component of the imagery CBM (Bibi et al, 2020;Westermann et al, 2021).…”