The goal of this clinical trial is to learn whether transcranial temporal interference stimulation (tTIS) can help treat major depressive disorder (MDD) in adults. The study will also learn about the safety of tTIS and explore how it may affect brain structure and brain function. The main questions it aims to answer are whether active tTIS lowers depression symptom scores more than sham stimulation after treatment, and what medical problems or side effects participants have during or after tTIS. Researchers will compare active tTIS targeting the left anterior limb of the internal capsule, active tTIS targeting the left subgenual anterior cingulate cortex, and sham stimulation. Sham stimulation is designed to feel similar to real stimulation but does not provide the same active treatment. Participants with MDD will be randomly assigned to one of the three groups. They will receive two 20-minute treatment sessions each day for 5 days. They will complete depression, anxiety, pleasure, psychosomatic symptom, and safety assessments before treatment, after treatment, and during follow-up. They will also have brain magnetic resonance imaging scans before and after treatment.
Major depressive disorder (MDD) is a common and disabling mental disorder. Although medication, psychotherapy, and established brain stimulation methods can help many people with MDD, some participants still have insufficient improvement. Transcranial temporal interference stimulation (tTIS) is a non-invasive brain stimulation technique that may allow modulation of deeper brain regions or pathways. This study is designed to evaluate whether tTIS can improve depressive symptoms in adults with MDD, assess its safety, and explore potential neuroimaging mechanisms. This is a single-center, randomized, double-blind, sham-controlled clinical trial conducted at Zhongda Hospital, Southeast University. Eligible participants with MDD will be randomly assigned in a 1:1:1 ratio to one of three groups: active tTIS targeting the left anterior limb of the internal capsule (ALIC), active tTIS targeting the left subgenual anterior cingulate cortex (sgACC), or sham tTIS. The sham stimulation will be designed to provide sensory feedback similar to active stimulation while maintaining blinding. Participants with MDD will receive 10 treatment sessions over 5 consecutive days, with two 20-minute sessions each day. Clinical symptoms and safety will be assessed at baseline, after treatment, and during follow-up. The main clinical outcome is the change in the 24-item Hamilton Depression Rating Scale (HAMD-24) total score from baseline to after treatment. Secondary outcomes include follow-up changes in depressive symptoms, response and remission rates, anxiety symptoms, anhedonia, psychosomatic symptoms, side effects, and adverse events. Multimodal 5.0T brain magnetic resonance imaging (MRI) will be collected from participants with MDD before and after treatment. MRI measures will include structural imaging, resting-state functional imaging, and diffusion imaging. These data will be used to explore changes in brain structure, functional connectivity, and diffusion-related measures after tTIS, and to identify potential imaging biomarkers related to treatment response.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
60
Participants in this arm will receive active transcranial temporal interference stimulation (tTIS) targeting the left anterior limb of the internal capsule (ALIC). The stimulation target will be individualized based on each participant's magnetic resonance imaging data. The difference frequency will be 130 Hz. Each session will last 20 minutes, twice daily for 5 consecutive days, with a 30-minute interval between sessions.
Participants in this arm will receive active transcranial temporal interference stimulation (tTIS) targeting the left subgenual anterior cingulate cortex (sgACC). The stimulation target will be individualized based on each participant's magnetic resonance imaging data. The difference frequency will be 130 Hz. Each session will last 20 minutes, twice daily for 5 consecutive days, with a 30-minute interval between sessions.
Participants in this arm will receive sham transcranial temporal interference stimulation (tTIS) using the same type of device as active stimulation. Sham stimulation will provide sensory feedback similar to active stimulation to help maintain masking, but it will not deliver the same active treatment dose. Each session will last 20 minutes, twice daily for 5 consecutive days, with a 30-minute interval between sessions.
Zhongda Hospital Southeast University
Nanjing, Jiangsu, China
Change in 24-item Hamilton Depression Rating Scale (HAMD-24) Total Score From Baseline to Week 1
The 24-item Hamilton Depression Rating Scale (HAMD-24) will be used to assess the severity of depressive symptoms. The total score ranges from 0 to 76, with higher scores indicating more severe depressive symptoms. The primary outcome is the change in HAMD-24 total score from baseline to Week 1.
Time frame: Baseline and Week 1
Change in 24-item Hamilton Depression Rating Scale (HAMD-24) Total Score From Baseline to Week 2
The 24-item Hamilton Depression Rating Scale (HAMD-24) will be used to assess depressive symptoms. The total score ranges from 0 to 76, with higher scores indicating more severe depressive symptoms. This outcome measures the change in HAMD-24 total score from baseline to Week 2.
Time frame: Baseline and Week 2
Change in 24-item Hamilton Depression Rating Scale (HAMD-24) Total Score From Baseline to Week 6
The 24-item Hamilton Depression Rating Scale (HAMD-24) will be used to assess depressive symptoms. The total score ranges from 0 to 76, with higher scores indicating more severe depressive symptoms. This outcome measures the change in HAMD-24 total score from baseline to Week 6.
Time frame: Baseline and Week 6
Remission Rate Based on the 24-item Hamilton Depression Rating Scale (HAMD-24) at Week 1
Remission is defined as a 24-item Hamilton Depression Rating Scale (HAMD-24) total score of 9 or lower. This outcome measures the proportion of participants who meet the remission criterion at Week 1.
Time frame: Week 1
Remission Rate Based on the 24-item Hamilton Depression Rating Scale (HAMD-24) at Week 2
Remission is defined as a 24-item Hamilton Depression Rating Scale (HAMD-24) total score of 9 or lower. This outcome measures the proportion of participants who meet the remission criterion at Week 2.
Time frame: Week 2
Remission Rate Based on the 24-item Hamilton Depression Rating Scale (HAMD-24) at Week 6
Remission is defined as a 24-item Hamilton Depression Rating Scale (HAMD-24) total score of 9 or lower. This outcome measures the proportion of participants who meet the remission criterion at Week 6.
Time frame: Week 6
Response Rate Based on the 24-item Hamilton Depression Rating Scale (HAMD-24) at Week 1
Response is defined as a reduction of at least 50% in the 24-item Hamilton Depression Rating Scale (HAMD-24) total score from baseline. This outcome measures the proportion of participants who meet the response criterion at Week 1.
Time frame: Baseline and Week 1
Response Rate Based on the 24-item Hamilton Depression Rating Scale (HAMD-24) at Week 2
Response is defined as a reduction of at least 50% in the 24-item Hamilton Depression Rating Scale (HAMD-24) total score from baseline. This outcome measures the proportion of participants who meet the response criterion at Week 2.
Time frame: Baseline and Week 2
Response Rate Based on the 24-item Hamilton Depression Rating Scale (HAMD-24) at Week 6
Response is defined as a reduction of at least 50% in the 24-item Hamilton Depression Rating Scale (HAMD-24) total score from baseline. This outcome measures the proportion of participants who meet the response criterion at Week 6.
Time frame: Baseline and Week 6
Change in Hamilton Anxiety Rating Scale (HAMA) Total Score From Baseline to Week 1
The Hamilton Anxiety Rating Scale (HAMA) will be used to assess anxiety symptoms. The total score ranges from 0 to 56, with higher scores indicating more severe anxiety symptoms. This outcome measures the change in HAMA total score from baseline to Week 1.
Time frame: Baseline and Week 1
Change in Hamilton Anxiety Rating Scale (HAMA) Total Score From Baseline to Week 2
The Hamilton Anxiety Rating Scale (HAMA) will be used to assess anxiety symptoms. The total score ranges from 0 to 56, with higher scores indicating more severe anxiety symptoms. This outcome measures the change in HAMA total score from baseline to Week 2.
Time frame: Baseline and Week 2
Change in Hamilton Anxiety Rating Scale (HAMA) Total Score From Baseline to Week 6
The Hamilton Anxiety Rating Scale (HAMA) will be used to assess anxiety symptoms. The total score ranges from 0 to 56, with higher scores indicating more severe anxiety symptoms. This outcome measures the change in HAMA total score from baseline to Week 6.
Time frame: Baseline and Week 6
Change in Snaith-Hamilton Pleasure Scale (SHAPS) Total Score From Baseline to Week 1
The Snaith-Hamilton Pleasure Scale (SHAPS) will be used to assess anhedonia. The total score ranges from 0 to 14, with higher scores indicating more severe anhedonia. This outcome measures the change in SHAPS total score from baseline to Week 1.
Time frame: Baseline and Week 1
Change in Snaith-Hamilton Pleasure Scale (SHAPS) Total Score From Baseline to Week 2
The Snaith-Hamilton Pleasure Scale (SHAPS) will be used to assess anhedonia. The total score ranges from 0 to 14, with higher scores indicating more severe anhedonia. This outcome measures the change in SHAPS total score from baseline to Week 2.
Time frame: Baseline and Week 2
Change in Snaith-Hamilton Pleasure Scale (SHAPS) Total Score From Baseline to Week 6
The Snaith-Hamilton Pleasure Scale (SHAPS) will be used to assess anhedonia. The total score ranges from 0 to 14, with higher scores indicating more severe anhedonia. This outcome measures the change in SHAPS total score from baseline to Week 6.
Time frame: Baseline and Week 6
Change in Psychosomatic Symptoms Scale (PSSS) Total Score From Baseline to Week 1
The Psychosomatic Symptoms Scale (PSSS) will be used to assess psychosomatic symptoms. Higher scores indicate more severe psychosomatic symptoms. This outcome measures the change in PSSS total score from baseline to Week 1.
Time frame: Baseline and Week 1
Change in Psychosomatic Symptoms Scale (PSSS) Total Score From Baseline to Week 2
The Psychosomatic Symptoms Scale (PSSS) will be used to assess psychosomatic symptoms. Higher scores indicate more severe psychosomatic symptoms. This outcome measures the change in PSSS total score from baseline to Week 2.
Time frame: Baseline and Week 2
Change in Psychosomatic Symptoms Scale (PSSS) Total Score From Baseline to Week 6
The Psychosomatic Symptoms Scale (PSSS) will be used to assess psychosomatic symptoms. Higher scores indicate more severe psychosomatic symptoms. This outcome measures the change in PSSS total score from baseline to Week 6.
Time frame: Baseline and Week 6
Incidence of Adverse Events
Adverse events will be recorded throughout the treatment and follow-up period. The number and proportion of participants experiencing adverse events will be summarized. The type, severity, duration, outcome, and relationship of adverse events to the intervention will be recorded.
Time frame: From Day 1 through Week 6
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