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.
Age between 18 and 74 years, inclusive
Diagnosis of treatment-resistant Major Depressive Disorder (MDD), single or recurrent episode, in accordance with DSM-5 diagnostic criteria.
Inadequate response to two or more oral antidepressants during the current depressive episode
Inadequate response to at least one pharmacological combination or augmentation strategy
Presence of any contraindication to esketamine administration according to the approved product label
Current participation in another interventional clinical study involving antidepressant medication
Any medical, psychiatric, or other condition that, in the opinion of the investigator, could: (a) compromise participant safety or well-being, or (b) interfere with, limit, or confound study assessments or outcomes
Parallel
Virtual-Reality-based mindfulness intervention
BehavioralThe 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.
Esketamine Treatment as Usual (ESK)
DrugThe 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.
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.
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.
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.
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.
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.
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.
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