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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:
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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Control Arm: Esketamine Treatment as Usual (ESK) | Other | Participants allocated to the control arm will receive conventional pharmacological treatment with intranasal esketamine for treatment-resistant depression. |
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| Experimental Arm: Esketamine Plus Mindfulness (ESK-MIND) | Experimental | Participants allocated to the experimental arm will receive intranasal esketamine in combination with a mindfulness-based intervention delivered via virtual reality. Induction Phase (Weeks 1-4): Participants will receive the same intranasal esketamine induction regimen as the control arm. In addition, participants will receive a 10-minute session of virtual reality-based mindfulness therapy immediately prior to each esketamine administration during the induction phase. The mindfulness intervention will be standardised and delivered using immersive virtual environments with guided audio content. Maintenance Phase (Weeks 5-30): Following the induction phase, participants will continue with the same esketamine maintenance regimen as the control arm: once-weekly administration for four weeks, followed by once every two weeks until treatment completion. Doses of 56 mg or 84 mg will be administered according to clinical response and tolerability, with adjustments based on clinical course. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Virtual-Reality-based mindfulness intervention | Behavioral | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Severity in depressive symptoms as assessed by Montgomery-Åsberg Depression Rating Scale (MADRS) | The Montgomery-Åsberg Depression Rating Scale (MADRS) is a clinician-rated, 10-item scale used to evaluate the severity of depressive symptoms. Each item is scored from 0 to 6, yielding a total score ranging from 0 to 60, with higher scores indicating greater depression severity. | Baseline (Week 0), Week 4 (end of the induction phase), Week 30 (end of the maintenance phase), and Week 54 (follow-up) |
| Measure | Description | Time Frame |
|---|---|---|
| Clinical Global Impressions - Improvement (CGI-I) and Severity (CGI-S) | The CGI-S is a single-item, clinician-rated measure of the clinician's assessment of the patient's current illness severity relative to the clinician's total experience with patients with the same condition. The CGI-S is rated on the following seven-point scale: 1=normal, not at all ill; 2=borderline mentally ill; 3=mildly ill; 4=moderately ill; 5=markedly ill; 6=severely ill; 7=among the most extremely ill patients. The CGI-I is a single-item, clinician-rated measure evaluating change in the patient's condition relative to baseline. The CGI-I is rated on a 7-point scale ranging from 1 = very much improved to 7 = very much worse. Lower scores indicate greater improvement. |
| Measure | Description | Time Frame |
|---|---|---|
| Treatment resistance severity assessed by Maudsley Staging Method (MSM) | The Maudsley Staging Method (MSM) is a clinician-rated instrument used to quantify the degree of treatment resistance in major depressive disorder. The scale incorporates three domains: (1) duration of the current depressive episode, (2) symptom severity, and (3) history of antidepressant treatment failures, including adequacy of dose and duration. Domain scores are combined to generate a total score, with higher scores indicating greater treatment resistance. |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Dr. J. Antoni Ramos-Quiroga | Contact | +3493 274 6087 | antoni.ramos@vallhebron.cat | |
| Júlia Vendrell-Serres | Contact | +3493 274 60 87 | julia.vendrell@vallhebron.cat |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Hospital Universitari Vall d'Hebron | Recruiting | Barcelona | 08035 | Spain |
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| Esketamine Treatment as Usual (ESK) | Drug | 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. |
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| 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) | The Beck Depression Inventory (BDI) is a 21-item self-report questionnaire designed to measure the severity of depressive symptoms, with total scores ranging from 0 to 63. Scores are calculated by summing the 0-3 ratings for each item, where higher scores indicate greater severity. | 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) | The Global Assessment of Functioning (GAF) scale is a 0-100 numerical rating assessing a person's overall psychological, social, and occupational functioning. It measures how symptoms affect daily life, with higher scores indicating better functioning and lower scores indicating severe impairment. | 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) | The Sheehan Disability Scale (SDS) is a self-rated, 3-item questionnaire assessing functional impairment across three domains: work/school, social life, and family life/home responsibilities. Each domain is rated on a 10-point visual analogue scale ranging from 0 = no impairment to 10 = extreme impairment, yielding a total score ranging from 0 to 30, with higher scores indicating greater functional impairment. | 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) | The Clinician-Administered Dissociative States Scale (CADSS) is a clinician-administered scale designed to measure present-state dissociative symptoms. The scale includes 23 items, each rated from 0 = not at all to 4 = extremely. Item scores are summed to yield a total score ranging from 0 to 92, with higher scores indicating greater dissociative symptom severity. | 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) | The FFMQ-SF is a self-report instrument that assesses five domains of mindfulness: Observing, Describing, Acting with Awareness, Nonjudging of Inner Experience, and Nonreactivity to Inner Experience. The short form consists of 24 items, each rated on a 5-point Likert scale ranging from 1 = never or very rarely true to 5 = very often or always true. Item scores are summed to yield a total score, with higher scores indicating greater levels of trait mindfulness. | Baseline (Week 0), Week 4 (end of the induction phase) |
| The incidence of adverse events | Treatment tolerability and safety as assessed by the incidence, nature, and severity of adverse events, including treatment-emergent adverse events (TEAEs). | Throughout the study period (up to Week 30) |
| Baseline (Week 0) |
| ID | Term |
|---|---|
| D061218 | Depressive Disorder, Treatment-Resistant |
| D003865 | Depressive Disorder, Major |
| ID | Term |
|---|---|
| D003866 | Depressive Disorder |
| D019964 | Mood Disorders |
| D001523 | Mental Disorders |
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