Virtual reality-assessment of social interactions and prognosis in depression

Importance Stratification of depression for personalised treatment is urgently needed to improve poor outcomes. Excessive self-blame-related motivations such as self-punishing tendencies have been proposed to play a key role in the onset and maintenance of depression. Their prognostic role, however, remains elusive. Objective Use Virtual Reality (VR) to determine whether maladaptive self-blame-related action tendencies are associated with a poor prognosis for depression when treated as usual in primary care (pre-registered: NCT04593537). Design Remote prospective cohort study (6/2020-6/2021) with four months follow-up. Settings Online recruitment from primary care and self-report. Participants n=879 pre-screened, n=164 eligible, n=101 completed baseline (age:18-66 years, mean=32.05±12.32, n=89 female), n=98 the VR-task, and n=93 the follow-up. Main inclusion criteria: at least one antidepressant medication trial and Patient Health Questionnaire-9≥15 at screening; main exclusion criteria: screening above threshold on validated self-report instruments for bipolar or alcohol/substance use disorders. Exposure(s) All participants completed a VR assessment via headsets sent to their homes, as well as online questionnaires to measure their clinical characteristics. Main outcomes and Measures Primary: Quick Inventory of Depressive Symptomatology self-reported-16 score after four months. Hypotheses in the study were formulated before the data collection and pre-registered. Results Contrary to our specific prediction, neither feeling like hiding nor creating a distance from oneself was associated with prognosis of depression during the follow-up period in the pre-registered regression model. Using a data-driven principal components analysis of all pre-registered continuous measures, a factor most strongly loading on punishing oneself for other people’s wrongdoings (β=.23, p=.01), a baseline symptom factor (β=.30, p=.006) and Maudsley Staging Method treatment-resistance scores (β=.28, p=.009) at baseline predicted higher depressive symptoms after four months. This relationship was confirmed by a significant interaction between feeling like punishing oneself for others’ wrongdoings and time of monthly follow-up which was driven by higher depressive symptoms at last follow-up [F(1,84)=6.45, p=.01, partial Eta Squared=0.07] in the subgroup who had reported feeling like punishing themselves at baseline. Our pre-registered statistical learning model prospectively predicted a cross-validated 19% of variance in depressive symptoms. Conclusions and Relevance Feeling like punishing oneself is a relevant prognostic factor and should therefore be assessed and tackled in personalised care pathways for difficult-to-treat depression. Question Can remote virtual-reality (VR)-based measures of social interactions be used to identify risk factors of poor prognosis in depression? Findings In this pre-registered remote prospective cohort study in 101 participants with depression and follow-up over four months, the VR-assessed feeling like punishing oneself for other people’s wrongdoing was the sole prognostic risk factor apart from known clinical variables such as symptom severity and previous treatment-resistance. Meaning Feeling like punishing oneself is a relevant prognostic factor and should therefore be assessed and targeted in difficult-to-treat depression. ### Competing Interest Statement RZ is a private psychiatrist service provider at The London Depression Institute and co-investigator on a Livanova-funded observational study of Vagus Nerve Stimulation for Depression. RZ has received honoraria for talks at medical symposia sponsored by Lundbeck as well as Janssen. He has collaborated with EMOTRA, EMIS PLC and Depsee Ltd. He is affiliated with the Dprime or minuteOr Institute of Research and Education, Rio de Janeiro and advises the Scients Institute, USA. The other authors have no conflicts of interests to declare. ### Funding Statement This study was funded by a Scients Institute Catalyst Award to SD who is also partly funded by a Henry Lester Trust Award and the Great Britain-China Educational Trust Chinese Student Award. DF was funded by the Medical Research Council Doctoral Training Partnership (ref: 2064430). AW, RZ, LV and the VR Lab were partly funded by the National Institute for Health and Care Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the King's College London PNM Research Ethics Subcommittee (Project Reference:HR-19/20-17589) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors