NCT07422519

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

A Pilot Randomised Controlled Study Evaluating the Efficacy and Tolerability of Virtual Reality-Based Mindfulness as an Adjunct to Treatment as Usual in Treatment-Resistant Depression

• Status: Recruiting
• Phase: N/A
• Study type: Interventional
• Enrollment: 30 (estimated)
• Sponsor: Hospital Universitari Vall d'Hebron Research Institute · Academic / Other
• Sex: All
• Age: 18 Years – 74 Years
• Healthy volunteers: Not accepted

Summary

The primary aim of this study is to evaluate the efficacy and tolerability of a combined Virtual Reality (VR)-based mindfulness intervention and pharmacological treatment compared with pharmacological treatment alone in reducing depressive symptoms in patients with Treatment-Resistant Depression (TRD). Secondary questions this study aims to address include: 1. Does the combined intervention lead to changes in inflammatory blood parameters compared with pharmacological treatment alone? 2. Does the addition of a VR-based mindfulness intervention prolong remission of depressive symptoms six months after treatment completion? 3. Is the combined treatment with mindfulness and esketamine well-tolerated, and how does its adverse effect profile compare with esketamine treatment alone? 4. Is there an association between changes in mindfulness trait levels, assessed using the FFMQ-SF, and reductions in depressive symptom severity? Participants will be recruited from a Treatment-Resistant Depression Programme and randomly assigned to receive either VR-based mindfulness intervention in addition to treatment as usual or treatment as usual alone. The mindfulness intervention will last one month and include a total of 8 sessions. All participants will undergo comprehensive assessments at baseline and at predefined follow-up time points to evaluate clinical outcomes, inflammatory markers, tolerability, and remission duration.

Detailed description

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.

Conditions

• Depression - Major Depressive Disorder
• Depression Disorder
• Depression Chronic
• Treatment-Resistant Major Depressive Disorder

Interventions

Type	Name	Description
BEHAVIORAL	Virtual-Reality-based mindfulness intervention	The mindfulness-based intervention will be delivered using a virtual reality (VR) platform (Sunrise Serenity) developed by XRHealth. The intervention consists of a 10-minute guided mindfulness meditation presented in a 360-degree immersive virtual environment depicting a seaside scene at sunrise. Participants will use a Pico Neo 2 VR headset with handheld controllers. The intervention software will be pre-installed on the device to ensure standardised delivery. Prior to the first intervention session, participants will complete a 5-minute familiarisation period with the VR equipment to ensure comfort and proper use. The VR-based mindfulness session will be administered immediately before each intranasal esketamine treatment during the induction phase (weeks 1-4; 8 sessions in total). The software used is patented and certified for medical use, with regulatory approval from the U.S. Food and Drug Administration (FDA) and CE marking.
DRUG	Esketamine Treatment as Usual (ESK)	The treatment with intranasal esketamine for treatment-resistant depression includes two phases. Induction Phase (Weeks 1-4): Following diagnosis of treatment-resistant depression, participants will receive intranasal esketamine twice weekly for four weeks. At the first treatment session, a total dose of 56 mg (two 28 mg devices) will be administered. In subsequent sessions, the dose may be adjusted according to individual tolerability and clinical judgement. Maintenance Phase (Weeks 5-30): After completion of the induction phase, participants will enter a maintenance phase in which esketamine will be administered once weekly for four weeks, followed by administration once every two weeks until the end of the treatment period. Doses of 56 mg or 84 mg will be administered based on clinical response and tolerability, with dose adjustments made according to clinical evolution.

Timeline

• Start date: 2025-09-18
• Primary completion: 2026-12-15
• Completion: 2026-12-15
• First posted: 2026-02-20
• Last updated: 2026-02-27

Locations

1 site across 1 country: Spain