Plans for assessment and collection of outcomes

Participants will complete demographic information, symptom evaluation, cognitive function assessment, social function assessment, and fMRI at baseline and the end of sixth week.

Demographic information

A self-made general information questionnaire was used to collect demographic information such as gender, age, occupation, education years, and disease-related information.

Symptom evaluation

The CDS [35] was used to evaluate depersonalization symptoms in patients with DPD; the Hamilton Anxiety Scale (HAMA) [36] and Hamilton Depression Scale (HAMD) [37] were used to assess anxiety and depression symptoms in patients with DPD. The Chinese version of CDS demonstrates moderate test–retest reliability (r = 0.651) and excellent internal consistency and split-half reliability (Cronbach’s α = 0.938, Guttman split-half coefficient = 0.957). The criterion-related validity is satisfactory (Mann–Whitney Z = − 6.059, p < 0.001). The item-total correlation coefficients range from 0.321 to 0.777, all reaching statistical significance, indicating acceptable construct validity [38]. The reliability coefficient for total scores, as evaluated by a collaborative group from 14 psychiatric departments in China, ranges from 0.88 to 0.99 (p < 0.01). In terms of validity, the empirical authenticity coefficient for clinical symptom severity is 0.92 [39]. The HAMA shows a total score reliability of 0.93, with reliability coefficients for individual symptom assessments ranging from 0.83 to 1.00. Furthermore, it effectively reflects the severity of anxiety states (coefficient = 0.36) [40].

Cognitive function assessment

The assessment employs the MATRICS Consensus Cognitive Battery [41]. The Trail Making Test A and Symbol Coding Test evaluate information processing speed, while the Hopkins Verbal Learning Test-Revised assesses word learning ability. The Brief Visuospatial Memory Test-Revised evaluates visual memory, and the Continuous Performance Test measures attention/alertness, with the Stroop Color-Word Test assessing attention inhibition. The test–retest reliability coefficients for the 10 MCCB tests range from 0.73 to 0.94, with a composite score reliability of 0.95 [42].

Social function assessment

The Global Assessment Function (GAF) [43] and the Short Form of Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-QSF) [44] are used to assess the social function, happiness, life quality, and satisfaction of patients with DPD. In contrast, the World Health Organization Quality of Life – BREF (WHOQOL-BREF) [45] is used to evaluate their quality of life and satisfaction comprehensively. The Chinese version of Q-LES-QSF and WHOQOL-BREF demonstrates satisfactory psychometric properties, with good internal consistency (overall α = 0.89) and acceptable reliability across domains (α = 0.67–0.78), while confirmatory factor analysis supported its four-factor structure (χ2 (244) = 1836, RMSEA = 0.088, CFI = 0.909) and showed good discriminant validity between healthy individuals and those with chronic illness [46]. Internal consistency data revealed a high reliability evidenced by internal consistency Cronbach’s α (0.87) for the Chinese Q-LES-Q-SF [47].

Safety assessment

Safety assessment involves collecting various indicators, including physical examination, vital signs, blood routine, urine routine, biochemistry, electrocardiogram, and other relevant measures. This assessment mainly focuses on measuring different health parameters to ensure an individual’s safety and well-being. These indicators have been proven reliable in assessing an individual’s health status and detecting potential health risks. Thus, it is crucial to conduct a comprehensive safety assessment using these various indicators to ensure the accuracy and reliability of the results. The trial will be terminated if the following conditions occur:

(1)

If significant safety issues arise during the trial, the clinical study should be promptly halted

(2)

If the trial reveals insufficient or negligible therapeutic effects of the investigational drug, rendering it clinically nonviable

(3)

Challenges in assessing treatment efficacy may arise due to critical errors in the clinical trial protocol or substantial deviations in implementation, hindering the evaluation of treatment outcomes

(4)

The applicant or regulatory authority may request the experiment’s termination

(5)

Upon early termination or upon study completion, the investigator will discontinue free transauricular vagus nerve stimulation treatment for participants. Patients will then be scheduled for an outpatient consultation to devise a future treatment plan

MRI

MRI was conducted using a Siemens Magnetom Trio 3.0 TMR scanner. To minimize noise and head movement, participants lay flat on the scanning bed with a foam pad on their heads.

Resting-state functional magnetic resonance imaging (rs-fMRI) was utilized to extract the brain’s spontaneous activity, static and dynamic functional connections, and functional network properties that reflect the brain’s functional state. Data acquisition used a multi-layer, simultaneously acquired gradient echo planar imaging sequence. The reference scanning parameters were axial, with TR/TE = 600/30 ms, flip angle = 90°, matrix = 80 × 80, FOV = 240 × 240 mm, slice thickness = 3 mm, no gap, number of layers = 50, number of frequency bands = 6, and parallel acceleration factor = 2. The resting state scan ended after a continuous scan of 8 min and 10 s. The high-resolution structural scan was acquired with the following parameters: voxel size = 1 mm3, TR = 2530 ms, TE = 3.39 ms, flip angle = 90°, matrix = 256 × 256, field of view = 256 × 256 mm, slice thickness = 1 mm.

Plans to promote participant retention and complete follow-up

The assessors will contact participants who cancel or do not show up at appointments by phone and, if no contact is made, send the participant a letter according to established clinical routines.

Data management Prior to commencing participant enrollment

Research personnel will undergo comprehensive training on the completion of case report forms (CRFs) and scale scoring. This training aims to clarify the operational procedures outlined in the protocol, ultimately enhancing the consistency and reliability of the data.

Throughout the participant enrollment phase

Rigorous measures will be taken to verify the accuracy and completeness of all data records and reports. All forms will be meticulously filled out, ensuring alignment with the original data. Pertinent information for each subject, encompassing treatment modifications, concurrent medication, instances of loss to follow-up or withdrawals, and missed assessments, will be duly confirmed and documented.

Upon the culmination of participant enrollment

An exhaustive examination of the CRF records will be conducted to confirm the rectification of all errors or omissions. Corrections or annotations will be endorsed with the investigator’s signature and date. Any inquiries arising from identified discrepancies will be promptly addressed, either through supplementation, correction, or explanation by the investigator. Furthermore, a dedicated data manager will undertake a secondary review of the scrutinized CRFs, with the objective of identifying any latent issues that may have previously evaded detection. This review process will facilitate subsequent supplementation or correction efforts.

During the data entry phase

Thorough data validation procedures will be applied, encompassing the detection and resolution of logical and other potential issues using established software programs. To ensure data accuracy, a dual data entry approach utilizing EpiData software will be implemented.

Confidentiality

Each participant will be given a code upon enrollment. The statistics team will only see patient codes, and real information will not be disclosed. The statistics team will have access only to de-identified patient codes, and no real identifying information will be disclosed to them. Participant details will be securely stored on EpiData accessible only to authorized members of the trial team, including individuals from the Sponsor organization or relevant center sites where required for the trial. Access rights to the dataset will be limited to qualified personnel who are essential to the trial’s conduct and oversight.

Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in this trial/future use

Blood samples collected in this study will be stored in the biobank of Beijing Anding Hospital for future safety and mechanistic analyses.