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NCT Number: NCT07829575

Amygdala-Targeted Transcranial Temporal Interference Stimulation for Major Depressive Disorder: A Randomized Sham-Controlled Trial of Clinical Efficacy and Neurobiological Mechanisms

This randomized, sham-controlled clinical trial aims to evaluate the efficacy and safety of amygdala-targeted transcranial temporal interference stimulation (tTIS) in adults with major depressive disorder (MDD) and to explore its potential neurobiological mechanisms.

The main questions this study aims to answer are:

Whether active amygdala-targeted tTIS reduces depressive symptoms compared with sham stimulation.

Whether tTIS produces changes in amygdala-related neural activity and functional brain networks that are associated with clinical improvement.

Participants will be randomly assigned to receive either active tTIS or sham stimulation. They will complete a course of stimulation sessions and undergo clinical assessments before and after the intervention. Neuroimaging assessments will also be performed to investigate treatment-related changes in the amygdala and associated brain networks.

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Key information

Conditions

Major Depressive Disorder (MDD Depressive Disorder Depressive Disorder, Major Mental Disorders Mood Disorders

Age range

18 year–55 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Shanghai Pudong New Area Mental Health Center

Shanghai, Shanghai Municipality, 201204, China

Location contact

Jingjing Huang

CONTACT

[email protected]

021-68306699*1222

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Aged 18 to 55 years, inclusive, with no restriction on sex.
  • Diagnosed with Major Depressive Disorder (MDD) according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), as determined by a study physician.
  • A 17-item Hamilton Depression Rating Scale (HAMD-17) score ≥17 at screening/baseline.
  • The antidepressant medication regimen must remain stable from at least 30 days before signing the informed consent form through the study period.
  • In the judgment of the investigator, the participant or their legally authorized representative is able to understand the purpose and procedures of the study, comply with the study protocol, and provide written informed consent.

Exclusion criteria

  • A history of other psychiatric disorders, neurological disorders, or substance abuse that, in the investigator's judgment, may interfere with the assessment of treatment efficacy.
  • A history of epilepsy, seizures, or convulsive episodes.
  • Presence of intracranial metallic foreign bodies or metallic implants in or near the heart.
  • Presence of organic brain disease, or a history of severe head injury or cranial surgery.
  • Receipt of electroconvulsive therapy (ECT) or other physical treatments, such as transcranial magnetic stimulation (TMS), within the 30 days before enrollment.
  • An unstable psychiatric condition or significant suicide risk, as assessed by the investigator.
  • Women who are pregnant or breastfeeding.
  • Current participation in another interventional clinical trial.
  • Any other condition that, in the investigator's judgment, makes the participant unsuitable for participation in this study.

Treatment and study plan

Transcranial temporal interference stimulation

Device

Active transcranial temporal interference stimulation (tTIS) will be delivered using two pairs of scalp electrodes. Two high-frequency alternating currents with slightly different carrier frequencies will be applied to generate a low-frequency temporal interference envelope within the targeted amygdala region. Electrode placement and stimulation parameters will be determined according to the study protocol and individualized electric-field modeling when applicable. Participants assigned to the active group will receive 10 stimulation sessions, with each session lasting 30 minutes, according to the predefined treatment schedule.

Sham Transcranial Temporal Interference Stimulation

Device

Participants assigned to the sham group will undergo the same electrode placement and treatment procedures as the active stimulation group. Sham stimulation will include brief ramp-up and ramp-down periods to mimic the initial sensory experience of active stimulation, without delivering continuous therapeutic stimulation during the remainder of the session.

Primary outcomes

  1. Change in 17-item Hamilton Depression Rating Scale (HAMD-17) Total Score

    Time frame: Baseline; after 10 stimulation sessions (30 minutes per session; end of Week 2)

    The 17-item Hamilton Depression Rating Scale (HAMD-17) is a clinician-rated scale used to assess the severity of depressive symptoms. Total scores range from 0 to 52, with higher scores indicating greater depressive symptom severity. The primary outcome is the change in HAMD-17 total score from baseline to the end of the 10-session intervention.

Secondary outcomes

  1. Change in Montgomery-Åsberg Depression Rating Scale (MADRS) Total Score

    Time frame: Baseline,after 5 stimulation sessions (30 minutes per session; end of Week 1); after 10 stimulation sessions (30 minutes per session; end of Week 2); and at 1 week and 4 weeks after completion of the 10-session intervention.

    The Montgomery-Åsberg Depression Rating Scale (MADRS) is a clinician-rated scale used to assess the severity of depressive symptoms. Total scores range from 0 to 60, with higher scores indicating greater depressive symptom severity. Changes in MADRS total score from baseline will be assessed following treatment and during follow-up.

  2. Change in 17-item Hamilton Depression Rating Scale (HAMD-17) Total Score Across Treatment and Follow-up

    Time frame: Baseline,after 5 stimulation sessions (30 minutes per session; end of Week 1); after 10 stimulation sessions (30 minutes per session; end of Week 2); and at 1 week and 4 weeks after completion of the 10-session intervention.

  3. Change in Hamilton Anxiety Rating Scale (HAMA) Total Score

    Time frame: Baseline,after 5 stimulation sessions (30 minutes per session; end of Week 1); after 10 stimulation sessions (30 minutes per session; end of Week 2); and at 1 week and 4 weeks after completion of the 10-session intervention.

    The Hamilton Anxiety Rating Scale (HAMA) is a clinician-rated scale used to assess the severity of anxiety symptoms. Total scores range from 0 to 56, with higher scores indicating greater anxiety severity. Changes in HAMA total score from baseline will be assessed following treatment and during follow-up.

  4. Change in Snaith-Hamilton Pleasure Scale (SHAPS) Score

    Time frame: Baseline,after 5 stimulation sessions (30 minutes per session; end of Week 1); after 10 stimulation sessions (30 minutes per session; end of Week 2); and at 4 weeks after completion of the 10-session intervention.

    The Snaith-Hamilton Pleasure Scale (SHAPS) is used to assess anhedonia and reduced capacity to experience pleasure. Changes in SHAPS score from baseline will be used to evaluate treatment-related changes in hedonic functioning.

  5. Change in Pittsburgh Sleep Quality Index (PSQI) Global Score

    Time frame: Baseline,after 5 stimulation sessions (30 minutes per session; end of Week 1); after 10 stimulation sessions (30 minutes per session; end of Week 2); and at 1 week and 4 weeks after completion of the 10-session intervention.

    The Pittsburgh Sleep Quality Index (PSQI) is a self-reported measure of sleep quality and sleep disturbances. The global score ranges from 0 to 21, with higher scores indicating poorer sleep quality. Changes in PSQI global score from baseline will be assessed following treatment and during follow-up.

  6. Change in World Health Organization Quality of Life-BREF (WHOQOL-BREF) Domain Scores

    Time frame: Baseline,after 10 stimulation sessions (30 minutes per session; end of Week 2); and at 4 weeks after completion of the 10-session intervention.

    The WHOQOL-BREF is a self-reported measure of quality of life across physical health, psychological health, social relationships, and environmental domains. Higher domain scores indicate better perceived quality of life. Changes in domain scores from baseline will be assessed after treatment and during follow-up.

  7. Change in Generalized Anxiety Disorder-7 (GAD-7) Score

    Time frame: Baseline,after 5 stimulation sessions (30 minutes per session; end of Week 1); after 10 stimulation sessions (30 minutes per session; end of Week 2); and at 1 week and 4 weeks after completion of the 10-session intervention.

    The Generalized Anxiety Disorder-7 (GAD-7) is a self-reported measure of anxiety symptoms. Total scores range from 0 to 21, with higher scores indicating greater anxiety symptom severity. Changes in GAD-7 score from baseline will be assessed following treatment and during follow-up.

  8. Change in Patient Health Questionnaire-9 (PHQ-9) Total Score

    Time frame: Baseline,after 5 stimulation sessions (30 minutes per session; end of Week 1); after 10 stimulation sessions (30 minutes per session; end of Week 2); and at 1 week and 4 weeks after completion of the 10-session intervention.

    The Patient Health Questionnaire-9 (PHQ-9) is a 9-item self-reported measure used to assess the severity of depressive symptoms. Total scores range from 0 to 27, with higher scores indicating greater depressive symptom severity. Changes in PHQ-9 total score from baseline will be assessed following treatment and during follow-up.

  9. Change in Cognitive Performance Assessed by the THINC-integrated Tool (THINC-it)

    Time frame: Baseline,after 5 stimulation sessions (30 minutes per session; end of Week 1); after 10 stimulation sessions (30 minutes per session; end of Week 2); and at 4 weeks after completion of the 10-session intervention.

    The THINC-integrated Tool (THINC-it) is a computerized cognitive assessment designed to evaluate subjective and objective cognitive functioning, including attention, processing speed, working memory, and executive function. Changes in THINC-it performance from baseline will be assessed following treatment and during follow-up.

  10. Change in Temporal Experience of Pleasure Scale (TEPS) Score

    Time frame: Baseline,after 10 stimulation sessions (30 minutes per session; end of Week 2); and at 4 weeks after completion of the 10-session intervention.

    The Temporal Experience of Pleasure Scale (TEPS) is a self-reported measure of anticipatory and consummatory pleasure. Changes in TEPS scores from baseline will be explored to assess treatment-related changes in reward-related emotional experience.

  11. Change in Emotion Regulation Questionnaire (ERQ) Score

    Time frame: Baseline,after 10 stimulation sessions (30 minutes per session; end of Week 2); and at 4 weeks after completion of the 10-session intervention.

    The Emotion Regulation Questionnaire (ERQ) assesses habitual use of cognitive reappraisal and expressive suppression as emotion regulation strategies. Changes in ERQ scores from baseline will be explored following treatment and during follow-up.

Other outcomes

  1. DTI

    Time frame: Baseline,after 10 stimulation sessions (30 minutes per session; end of Week 2); and at 4 weeks after completion of the 10-session intervention.

    Diffusion tensor imaging (DTI) will be used to explore treatment-related changes in white matter microstructural measures within neural pathways associated with the amygdala and emotion-regulation networks.

  2. fMRI

    Time frame: Baseline,after 10 stimulation sessions (30 minutes per session; end of Week 2); and at 4 weeks after completion of the 10-session intervention.

    Functional magnetic resonance imaging (fMRI) will be used to assess treatment-related changes in functional connectivity involving the amygdala and brain regions associated with emotional processing and regulation. Amygdala-based functional connectivity measures will be compared across study time points.

  3. Incidence of Treatment-Emergent Adverse Events

    Time frame: From the first stimulation session through the 4-week follow-up

Study contacts

Contact information is provided by the study sponsor or research team.

Jingjing Huang

CONTACT

[email protected]

021-68306699*1222

Sponsors and collaborators

Lead sponsor

Shanghai Pudong New Area Mental Health Center, School of Medicine, Tongji University

Other

Registry information

Official study title

Amygdala-targeted Temporal Interference Stimulation for Major Depressive Disorder。

Important dates

Study start
2026
Primary completion
2027
Study completion
2027
First posted
Sep 21, 2026
Registry last updated
Sep 21, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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