Virtual Reality-Based Mindfulness as an Adjunct to Treatment as Usual in Treatment-Resistant Depression

Major Depressive Disorder (MDD) is a highly prevalent condition and one of the leading causes of disability worldwide. It is associated with increased mortality, higher risk of suicidal behaviour, and frequent comorbidity with somatic conditions such as obesity, cardiovascular disease, and cognitive impairment. Despite its clinical impact, available psychopharmacological treatments are suboptimal, with a substantial proportion of patients showing an inadequate response to first-line antidepressant therapies. This has led to the concept of treatment-resistant depression (TRD), generally understood as the failure to achieve response or remission after treatment with at least two antidepressants with different mechanisms of action.

At present, there is no standardised treatment algorithm for TRD. Commonly used strategies include combinations of antidepressants, pharmacological augmentation, and physical treatment approaches; however, none of these options is specifically indicated for TRD, and the evidence supporting their effectiveness remains limited. Esketamine, the S-enantiomer of racemic ketamine, is an antidepressant that acts as an N-methyl-D-aspartate (NMDA) receptor antagonist and enhances glutamatergic neurotransmission. This mechanism of action has demonstrated efficacy in patients with TRD, leading to its approval for this indication. Esketamine is administered intranasally using a treatment schedule that includes an induction phase followed by a maintenance phase and is considered part of routine pharmacological care for TRD in the study setting.

For a comprehensive approach to TRD, psychological treatment options should also be considered. When combined with pharmacological treatment, psychotherapy has been shown to provide additional benefit for patients with TRD by facilitating learning, coping, and resilience processes that may act synergistically with the biological mechanisms of antidepressant treatments. Among the psychological approaches studied in depression, mindfulness-based interventions focus on practices that promote acceptance of the present moment and the development of effective self-care and coping skills and have shown promising effects in depressive disorders.

In recent years, the combination of mindfulness-based interventions with virtual reality (VR) has been promoted. VR allows individuals to interact with computer-generated environments within a simulated scenario and offers the possibility of creating immersive and aesthetically engaging settings adapted to therapeutic needs. Similar to traditional mindfulness-based interventions, VR-based approaches provide guided meditative experiences, with audio guidance supporting standardisation and consistency of intervention delivery. An additional advantage of VR-based mindfulness interventions is their potential sustainability, as they do not require additional personnel resources.

Given the limitations of current treatment options for TRD, it is important to explore innovative interventions that may improve therapeutic outcomes. The combination of pharmacological treatment with mindfulness therapy delivered through VR represents a promising approach due to its potential to foster present-moment acceptance and effective coping skills. In addition, TRD has been repeatedly associated with altered immune cellular function and elevated circulating pro-inflammatory markers, making it relevant to examine biological parameters alongside clinical improvement.

In summary, this study aims to explore the potential value of adding a mindfulness-based intervention delivered through virtual reality to standard pharmacological treatment in patients with treatment-resistant depression. By building on existing clinical practice within a specialised programme, this pilot study seeks to generate preliminary evidence to inform future research and the development of integrated treatment approaches for TRD.

• Clinical Global Impressions - Improvement (CGI-I) and Severity (CGI-S) [Time frame: Baseline (Week 0), Week 4 (end of induction), Week 30 (end of maintenance), and Week 54 (follow-up)]
• Self-reported depressive symptoms as assessed by the Beck Depression Inventory (BDI) [Time frame: Baseline (Week 0), Week 4 (end of induction), Week 30 (end of maintenance), and Week 54 (follow-up)]
• Global functioning as assessed by Global Assessment of Functioning (GAF) [Time frame: Baseline (Week 0), Week 4 (end of induction), Week 30 (end of maintenance), and Week 54 (follow-up)]
• Functional impairment as assessed by Sheehan Disability Scale (SDS) [Time frame: Baseline (Week 0), Week 4 (end of induction), Week 30 (end of maintenance), and Week 54 (follow-up)]
• Dissociative symptoms as assessed by the Clinician-Administered Dissociative States Scale (CADSS) [Time frame: During the induction phase, approximately 1.5 hours after each dose, through Week 4 (end of induction phase).]
• Mindfulness trait levels as assessed by Five Facet Mindfulness Questionnaire - Short Form (FFMQ-SF) [Time frame: Baseline (Week 0), Week 4 (end of the induction phase)]
• The incidence of adverse events [Time frame: Throughout the study period (up to Week 30)]