An interventional study of Active transcranial temporal interference stimulation and Sham transcranial temporal interference stimulation in Schizophrenia, sponsored by Anhui Medical University. Not yet recruiting at 1 site in China. Open to participants aged 18 Years to 60 Years. Per ClinicalTrials.gov, last updated 2026-10-22.
Sponsored by Anhui Medical University · Not applicable, Interventional, and Treatment
This study will evaluate whether temporal interference (TI) stimulation, added to usual clinical treatment, improves symptoms of schizophrenia and is safe and tolerable. Approximately 100 adults aged 18 to 60 years with schizophrenia will be randomly assigned in equal numbers to active TI or sham TI. Participants and researchers assessing treatment outcomes will not know which treatment has been assigned.
Participants will continue usual clinical treatment and receive two 30-minute stimulation sessions daily for 14 consecutive days, for a total of 28 sessions. Symptoms will be assessed before treatment and on Days 7, 15, and 45. Magnetic resonance imaging (MRI) scans will be obtained before treatment and on Day 15. Side effects will be monitored throughout participation.
The main question is whether active TI produces a greater improvement in overall schizophrenia symptoms from baseline to Day 15 than sham TI. The study will also assess symptom improvement at other time points, changes in other symptoms, treatment completion, safety, and changes in brain imaging measures.
This multicenter, randomized, double-blind, parallel-group, sham-controlled trial will evaluate individualized temporal interference (TI) stimulation targeting the left insula as an adjunct to usual clinical treatment for schizophrenia.
Randomization will be stratified by study center with a 1:1 allocation ratio. An independent statistician will generate the randomization sequence, which will be implemented through a central randomization system after eligibility confirmation and baseline assessment. Access to treatment allocation codes will be restricted to authorized unblinded personnel who are not involved in outcome assessment or data analysis.
Baseline high-resolution three-dimensional T1-weighted magnetic resonance imaging (MRI) will be used to construct an individualized finite-element head model. The positions and channel configuration of two pairs of scalp electrodes will be optimized to enhance the modeled modulation field within the predefined left-insula target while reducing electric-field exposure in superficial cortical and other nontarget regions. Active TI will use carrier frequencies of 2000 Hz and 2005 Hz to produce a 5-Hz modulation frequency. Sham TI will use the same electrode setup, session duration, and device interface and simulate brief scalp sensations, without sustained treatment current during the middle of each session.
Both groups will continue usual clinical treatment. Clinically necessary adjustments to antipsychotic medication will be permitted and documented, including medication names, doses, timing and reasons for adjustments, and concomitant medication use. Other neuromodulation interventions that could affect study outcomes will be prohibited during participation.
The primary efficacy analysis will use a mixed model for repeated measures in the modified intention-to-treat population. The model will include treatment group, visit, treatment-by-visit interaction, study center, and prespecified baseline covariates. The primary treatment comparison will be the between-group difference in change from baseline to Day 15 in Positive and Negative Syndrome Scale (PANSS) total score. Per-protocol analyses and analyses addressing missing data and medication adjustments will serve as sensitivity analyses to support interpretation of the primary results.
Exploratory analyses of structural and resting-state functional MRI will examine treatment-related imaging changes, their associations with symptom improvement, and the potential predictive value of baseline imaging and individualized electric-field measures. An independent data and safety monitoring board will oversee participant safety and study conduct.
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Participants will receive individualized temporal interference stimulation targeting the left insula in addition to usual clinical treatment. Electrode placement will be optimized using a finite-element head model derived from baseline structural MRI. Treatment will consist of two 30-minute sessions per day for 14 consecutive days, for a total of 28 sessions, with at least 60 minutes between sessions.
Device: Active transcranial temporal interference stimulation
Participants will receive sham temporal interference stimulation in addition to usual clinical treatment. Electrode placement, fixation, device interface, treatment environment, and session duration will match those used for active stimulation. Brief current will be delivered at the beginning and end of each session to simulate scalp sensations, with no sustained treatment current during the middle of the session. Two 30-minute sessions will be administered daily for 14 consecutive days, with at least 60 minutes between sessions, for 28 sessions in total.
Device: Sham transcranial temporal interference stimulation
Two pairs of scalp electrodes will deliver sinusoidal alternating currents at carrier frequencies of 2000 Hz and 2005 Hz, producing a 5-Hz modulation frequency at the modeled left-insula target. Electrode positions, channel configuration, and current amplitudes will be individualized using MRI-based finite-element modeling. The current amplitudes and their ratio will be set according to the individualized electric-field modeling results, allowing unequal amplitudes between channels. Current settings and actual outputs will be recorded for each session. Each session will last 30 minutes, with 30-second ramp-up and ramp-down periods at the beginning and end, respectively. Two sessions will be administered daily for 14 consecutive days, with at least 60 minutes between sessions, for a total of 28 sessions.
Sham stimulation will use the same individualized electrode locations and channel configuration as active stimulation. The device will provide brief current at the beginning and end of each session, using 30-second ramping procedures to mimic scalp sensations, but will not deliver sustained treatment current during the middle of the session. Session duration, treatment schedule, monitoring, device displays, and communication procedures will match those used in the active arm.
Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Day 15
The Positive and Negative Syndrome Scale (PANSS) is a clinician-rated instrument used to assess positive symptoms, negative symptoms, and general psychopathology in schizophrenia. The PANSS total score ranges from 30 to 210, with higher scores indicating greater schizophrenia symptom severity. The primary outcome is the change in PANSS total score from baseline to Day 15, compared between the active TI and sham groups. Change is calculated as the Day 15 total score minus the baseline total score, with negative values indicating improvement.
Time frame: Baseline (Day 0) and Day 15
Change From Baseline in PANSS Total Score at Days 7 and 45
The PANSS total score ranges from 30 to 210, with higher scores indicating greater schizophrenia symptom severity. Change at each visit will be calculated as the visit total score minus the baseline total score. Negative changes indicate improvement. Day 7 and Day 45 will be evaluated separately.
Time frame: Baseline (Day 0), Day 7, and Day 45
Change From Baseline in PANSS Positive Subscale Score
The PANSS positive subscale comprises 7 items, each scored from 1 to 7, yielding a total score from 7 to 49. Higher scores indicate more severe positive symptoms. Change at each visit will be calculated as the visit score minus the baseline score; a negative value indicates improvement.
Time frame: Baseline (Day 0), Day 7, Day 15, and Day 45
Change From Baseline in PANSS Negative Subscale Score
The PANSS negative subscale comprises 7 items, each scored from 1 to 7, yielding a total score from 7 to 49. Higher scores indicate more severe negative symptoms. Change at each visit will be calculated as the visit score minus the baseline score; a negative value indicates improvement.
Time frame: Baseline (Day 0), Day 7, Day 15, and Day 45
Change From Baseline in PANSS General Psychopathology Subscale Score
The PANSS general psychopathology subscale comprises 16 items, each scored from 1 to 7, yielding a total score from 16 to 112. Higher scores indicate more severe general psychopathology. Change at each visit will be calculated as the visit score minus the baseline score; a negative value indicates improvement.
Time frame: Baseline (Day 0), Day 7, Day 15, and Day 45
Change From Baseline in Auditory Hallucination Rating Scale (AHRS) Total Score
The AHRS assesses the severity of auditory hallucinations across seven dimensions. As specified in the protocol, the total score ranges from 0 to 41, with higher scores indicating more severe auditory hallucinations. Change at each visit will be calculated as the visit total score minus the baseline total score; a negative value indicates improvement.
Time frame: Baseline (Day 0), Day 7, Day 15, and Day 45
Change From Baseline in 17-Item Hamilton Depression Rating Scale (HAMD-17) Total Score
The HAMD-17 is a 17-item clinician-rated measure of depressive symptom severity. Total scores range from 0 to 52, with higher scores indicating more severe depressive symptoms. Changes from baseline to Days 7, 15, and 45 will be compared between the active TI and sham groups. Change is calculated as the total score at each follow-up visit minus the baseline total score, with negative values indicating improvement.
Time frame: Baseline (Day 0), Day 7, Day 15, and Day 45
Change From Baseline in 14-Item Hamilton Anxiety Rating Scale (HAMA-14) Total Score
The HAMA-14 is a 14-item clinician-rated measure of anxiety symptom severity. Total scores range from 0 to 56, with higher scores indicating more severe anxiety symptoms. Changes from baseline to Days 7, 15, and 45 will be compared between the active TI and sham groups. Change is calculated as the total score at each follow-up visit minus the baseline total score, with negative values indicating improvement.
Time frame: Baseline (Day 0), Day 7, Day 15, and Day 45
Change From Baseline in Insomnia Severity Index (ISI) Total Score
The ISI is a seven-item self-report measure of insomnia severity. Total scores range from 0 to 28, with higher scores indicating more severe insomnia. Changes from baseline to Days 7, 15, and 45 will be compared between the active TI and sham groups. Change is calculated as the total score at each follow-up visit minus the baseline total score, with negative values indicating improvement.
Time frame: Baseline (Day 0), Day 7, Day 15, and Day 45
Change From Baseline in Patient Health Questionnaire-15 (PHQ-15) Total Score
The PHQ-15 is a 15-item self-report measure of somatic symptom burden. Total scores range from 0 to 30, with higher scores indicating greater somatic symptom burden. Changes from baseline to Days 7, 15, and 45 will be compared between the active TI and sham groups. Change is calculated as the total score at each follow-up visit minus the baseline total score, with negative values indicating improvement.
Time frame: Baseline (Day 0), Day 7, Day 15, and Day 45
Percentage of Participants With a Treatment Response Based on PANSS Total Score
Treatment response is defined as a reduction of at least 30% in PANSS total score from baseline after correction for the scale minimum of 30 points. Percentage reduction is calculated as 100 × (baseline total score - follow-up total score) / (baseline total score - 30). Response rates at Days 7, 15, and 45 will be compared between the active TI and sham groups. Percentages will be based on all randomized participants in each group, with missing assessments classified as nonresponse in the main responder analysis. Observed-case and multiple-imputation analyses will assess the sensitivity of the results.
Time frame: Baseline (Day 0), Day 7, Day 15, and Day 45
Percentage of Participants Completing the Full Treatment Course
Treatment completion is defined as completion of all 28 scheduled stimulation sessions during the 14-day treatment period. Each completed session must include the full programmed 30-minute stimulation procedure, as documented in the device log. Completion rates will be compared between the active TI and sham groups using all randomized participants in each group as the denominator. Participants who complete fewer than 28 sessions, including those who do not initiate treatment, will be classified as not completing the treatment course.
Time frame: Day 1 through Day 14
Percentage of Correct Treatment-Allocation Guesses by Participants and Outcome Assessors
Blinding will be assessed on Day 15. Participants and independent clinical outcome assessors will separately indicate whether they believe the assigned treatment was active TI, sham TI, or do not know. Treatment allocation will not be disclosed as part of this assessment, and masking will be maintained through the Day 45 follow-up and until protocol-specified unblinding, except when emergency unblinding is necessary for participant safety. The percentage of correct guesses will be calculated separately for participants and assessors in each treatment group, using completed questionnaires as the denominator. Do not know responses will remain in the denominator and will not count as correct. Missing questionnaires will be reported separately. Confidence in the guesses and reasons for the responses will be summarized descriptively.
Time frame: Day 15, after completion of the 14-day treatment course
Change From Baseline in Clinical Global Impression-Severity (CGI-S) Score
The Clinical Global Impression-Severity (CGI-S) scale is a clinician-rated measure of overall illness severity, scored from 1 (normal, not at all ill) to 7 (among the most extremely ill). Higher scores indicate greater illness severity. Changes from baseline to Days 7, 15, and 45 will be compared between the active TI and sham groups. Change is calculated as the score at each follow-up visit minus the baseline score, with negative values indicating improvement.
Time frame: Baseline (Day 0), Day 7, Day 15, and Day 45
Clinical Global Impression-Improvement (CGI-I) Score
The Clinical Global Impression-Improvement (CGI-I) scale is a clinician-rated assessment of overall clinical change relative to baseline. Scores range from 1 (very much improved) to 7 (very much worse), with 4 indicating no change. Lower scores indicate greater improvement. CGI-I scores at Days 7, 15, and 45 will be compared between the active TI and sham groups. Because each rating already reflects change relative to baseline, no baseline CGI-I score or change-from-baseline score will be calculated.
Time frame: Day 7, Day 15, and Day 45
Percentage of Participants Experiencing Adverse Events
The percentage of participants experiencing at least one treatment-emergent adverse event will be summarized for the active TI and sham groups. Treatment-emergent adverse events are defined as new events or worsening of pre-existing conditions occurring from the first stimulation session through Day 45, regardless of their relationship to study procedures. Events will be characterized by severity, seriousness, relatedness, management, and outcome. Percentages will be calculated using participants who receive at least one stimulation session as the denominator, according to treatment received.
Time frame: From the first stimulation session on Day 1 through the Day 45 follow-up visit
Percentage of Participants Experiencing Serious Adverse Events
The percentage of participants experiencing at least one treatment-emergent serious adverse event from the first stimulation session through Day 45 will be summarized for the active TI and sham groups. Serious adverse events will be identified according to the protocol-defined criteria, including death, life-threatening events, hospitalization or prolonged hospitalization, and persistent or significant disability. Events will be recorded regardless of their relationship to study procedures. Percentages will be calculated using participants who receive at least one stimulation session as the denominator, according to treatment received.
Time frame: From the first stimulation session on Day 1 through the Day 45 follow-up visit
Changes From Baseline in Left Insular Gray Matter Volume and Related Functional Connectivity
Structural and resting-state functional MRI data will be acquired at baseline and Day 15 to assess changes in left insular gray matter volume and related functional connectivity. Differences between the active TI and sham groups will be examined, along with associations between imaging changes and symptom improvement and the potential predictive value of baseline imaging and individualized electric-field measures.
Time frame: Baseline (Day 0) and Day 15
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