Negative Symptoms in SchizophreniaNCT07680959

Combining HD-tDCS and iTBS in Treating Negative Symptoms of Schizophrenia

A study testing active iTBS followed by active HD-tDCS in people with Negative Symptoms in Schizophrenia and Brain Stimulation Intervention, run by Tri-Service General Hospital (TSGH) at 1 site in Taiwan.

Enrolling by invitation

Enrolling by invitation. The study team selects and invites participants, usually from an existing group of patients.

Sites and contacts

Official record

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Trial summary

Dysfunction of the dorsolateral prefrontal cortex (DLPFC) is central to the persistence of negative symptoms in schizophrenia. Both HD-tDCS and iTBS targeting the left DLPFC have shown therapeutic benefit. This trial will test the hypothesis that combining HD-tDCS with iTBS yields additive efficacy. Read more about this study

Who is it for?: Ages 18 to 65 years
Conditions the study is for: Negative Symptoms in Schizophrenia, Brain Stimulation Intervention
What is being tested?: active iTBS followed by active HD-tDCS
Type of treatment: Medical device
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 100 participants
Where: 1 siteTaiwan
Study dates: 6 May 2024to 1 Mar 2028
Phase: Interventional
Are there results?: Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 65 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

Subjects diagnosed with DSM-5 schizophrenia or schizoaffective disorder;
With a clinical presentation characterized by predominant negative symptoms, as determined by psychiatric assessment and a score of at least 20 on the Negative Symptoms Subscale of the Positive and Negative Syndrome Scale (PANSS);
Stable positive and negative symptoms for at least 4 weeks, as documented in medical records and confirmed by clinical judgment and psychiatric interview;

Who cannot join

Unstable medical conditions;
Current psychiatric comorbidity or active substance use disorder (except for tobacco use disorders);
Contraindications for MRI, tDCS or rTMS;
Pregnancy or breastfeeding at the time of enrollment;
History of meningitis, encephalitis, seizures, intracranial neoplasms or surgery, severe head injury or cerebrovascular disease, or a family history of seizures;
rTMS or tDCS treatment within the past 6 months as well as a history of electroconvulsive therapy (ECT);

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Any skin lesion at the stimulation sites;
Patients receiving medications that significantly change the seizure threshold;
A history of suicidal behavior within the past 6 months, or symptom worsening and emergence of suicidal ideation during the screening period.

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Taiwan1 site

Tri-service general hospital
Taipei, 114

Other trials in Taiwan

About this study

Official title: The Efficacy of Combined HD-tDCS and iTBS in Treating Negative Symptoms of Schizophrenia

Read the detailed description

Dysfunction of the left dorsolateral prefrontal cortex (DLPFC) is central to the persistence of negative symptoms in schizophrenia, an area of unmet therapeutic need. High-definition transcranial direct current stimulation (HD-tDCS) and intermittent theta burst stimulation (iTBS), an optimized form of repetitive transcranial magnetic stimulation (rTMS), have each demonstrated efficacy in alleviating negative symptoms when applied to the left DLPFC. However, meta-analyses indicate only moderate effect sizes for these interventions individually. Evidence suggests that combining iTBS with tDCS may enhance cortical plasticity beyond either technique alone, warranting trials to assess additive efficacy. This double-blind, randomized, sham-controlled study will test the hypothesis that combined HD-tDCS and iTBS produce superior therapeutic benefit for negative symptoms in schizophrenia.

Conditions: Negative Symptoms in Schizophrenia, Brain Stimulation Intervention
Being tested: active iTBS followed by active HD-tDCS, active iTBS followed by sham HD-tDCS, sham iTBS followed by active HD-tDCS, sham iTBS followed by sham HD-tDCS
Keywords: HD-tDCS, iTBS, negative symptoms, schizophrenia, neuroimaging
Medical subject headings: Schizophrenia

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

active iTBS followed by active HD-tDCSDevice
The active iTBS sessions will be delivered using the Magstim Rapid2 stimulator. The iTBS protocol consists of 3-pulse 50-Hz bursts given every 200 ms (at 5 Hz) for 2 s at 8-s intervals for 60 cycles. A 2-s train of iTBS will be repeated every 10 s for a total of 1800 pulses per session. The intensity of stimulation will be set at 80% resting motor threshold (RMT). The target will be the left DLPFC with the coil centered at the MNI coordinate [-38, 44, 26] calculated from T1-weighted MRI. The active HD-tDCS will be applied by NeuroConn DC Stimulator Plus. The central anode will be placed over the International 10-20 electrode position F3 and the return peripheral electrodes placed at Fp1, Fz, C3 and F7. Stimulation session will be applied at an intensity of 2 mA, 8-sec fade in and 5-sec fade out, for 20 min. During each session, the subject has to perform a computerized working memory task (i.e., 2-back task). The two times daily sessions will be separated by at least 2 hours.
active iTBS followed by sham HD-tDCSDevice
The active iTBS sessions will be delivered using the Magstim Rapid2 stimulator. The iTBS protocol consists of 3-pulse 50-Hz bursts given every 200 ms (at 5 Hz) for 2 s at 8-s intervals for 60 cycles. A 2-s train of iTBS will be repeated every 10 s for a total of 1800 pulses per session. The intensity of stimulation will be set at 80% resting motor threshold (RMT). The target is the left DLPFC with the coil centered at the MNI coordinate [-38, 44, 26] calculated from T1-weighted MRI. In the sham HD-tDCS stimulation, short continuous currents without neuromodulatory effects will be applied to mimic real-stimulation sensations. Specifically, sham stimulation will deliver 40-sec, 2 mA normal-like stimulation, followed by a tiny current pulse (110 μA over 15 ms) for impedance control taking place every 550 ms for the remaining time. The other procedure is the same as the active HD-tDCS stimulation.
sham iTBS followed by active HD-tDCSDevice
In the sham iTBS condition, the patients receive the same iTBS regimen and exact positioning of the coil but stimulations will be delivered using a commercial identical looking figure 8 sham coil (Magstim D70 Air film sham coil) that can produce a similar sound and sensation. In the active HD-tDCS condition, stimulation will be applied by a battery-operated device (NeuroConn DC Stimulator Plus) via 5 carbon rubber electrodes (1 cm radius, high-definition 4 × 1 rings configuration). To target the left DLPFC, the central electrode (anode) will be placed over International 10-20 electrode position F3, with return peripheral electrodes at Fp1, Fz, C3 and F7. Stimulation will be applied at an intensity of 2 milliamp (mA), 8-sec fade in and 5-sec fade out, for 20 min. During each session, the subject has to perform a computerized working memory task (i.e., 2-back task). The two times daily sessions will be separated by at least 2 hours.
sham iTBS followed by sham HD-tDCSDevice
In the sham iTBS condition, patients receive the same iTBS regimen and exact positioning of the coil but stimulations will be delivered using a commercial identical looking figure 8 sham coil (Magstim D70 Air film sham coil) that can produce a similar sound and sensation. In the sham HD-tDCS condition, short continuous currents without neuromodulatory effects will be applied to mimic real-stimulation sensations. Specifically, sham stimulation will deliver 40-sec, 2 mA normal-like stimulation, followed by a tiny current pulse (110 μA over 15 ms) for impedance control taking place every 550 ms for the remaining time. The other procedure is the same as the active HD-tDCS stimulation.

Study groups in NCT07680959
Study group	Role	What they receive
active iTBS followed by active HD-tDCS	Experimental	During the 3-week intervention phase, patients in this group will receive 2 sessions of active iTBS per working day for 2 weeks (totaling 20 sessions), followed by 2 sessions of active HD-tDCS per working day for 1 week (totaling 10 sessions). Receives: Device: active iTBS followed by active HD-tDCS
sham iTBS followed by active HD-tDCS	Experimental	During the 3-week intervention phase, patients in this group will receive 2 sessions of sham iTBS per working day for 2 weeks (totaling 20 sessions), followed by 2 sessions of active HD-tDCS per working day for 1 week (totaling 10 sessions). Receives: Device: sham iTBS followed by active HD-tDCS
active iTBS followed by sham HD-tDCS	Experimental	During the 3-week intervention phase, patients in this group will receive 2 sessions of active iTBS per working day for 2 weeks (totaling 20 sessions), followed by 2 sessions of sham HD-tDCS per working day for 1 week (totaling 10 sessions). Receives: Device: active iTBS followed by sham HD-tDCS
sham iTBS followed by sham HD-tDCS	Sham comparator	During the 3-week intervention phase, patients in this group will receive 2 sessions of sham iTBS per working day for 2 weeks (totaling 20 sessions), followed by 2 sessions of sham HD-tDCS per working day for 1 week (totaling 10 sessions). Receives: Device: sham iTBS followed by sham HD-tDCS

What is being measured

The primary outcome is the main question the study is designed to answer.

The change in Positive and Negative Syndrome Scale (PANSS) negative subscale score
PANSS is a clinician-administered rating scale to measure the severity of psychopathological symptoms of the patients with schizophrenia spectrum disorder. The patient is rated from 1 to 7 on 30 different symptom items. All items scores are summed up to yield a total PANSS score, which ranges from 30 to 210. A higher score indicates greater psychopathological symptom severity.
PANSS negative subscale has 7 items with its score ranging from 7 to 49. The changes in the PANSS negative subscale score immediately after the 3-week intervention (primary endpoint), as well as at one-month and three-month follow-ups, will be collected as the primary outcome.
Measured: Fifteen weeks

Secondary outcomes (12)

The change in score of the Scale for the Assessment of Negative Symptoms (SANS)
The Scale for the Assessment of Negative Symptoms (SANS) is used to assess negative symptoms in schizophrenia on a 25 item, 6-point scale. The SANS measures five domains of the negative symptoms including affective flattening or blunting, alogia, avolition - apathy, anhedonia - Asociality, Attention. In each domain, separate symptoms are rated from 0 (absent) to 5 (severe). A total SANS score ranges from 0 to 125. The changes in the SANS score immediately after the 3-week intervention, as well as at one-month and three-month follow-ups, will be collected as the secondary outcome.
Measured: Fifteen weeks
The change in score of Calgary Depression Rating Scale for Schizophrenia (CDSS)
The participants' depressive symptoms will be measured by Calgary Depression Rating Scale for Schizophrenia (CDSS). The changes in the CDSS score immediately after the 3-week intervention, as well as at one-month and three-month follow-ups, will be collected as the secondary outcome.
Measured: Fifteen weeks
The change in the Personal and Social Performance scale (PSP) score
PSP is a clinician-administered rating scale for measuring the psychosocial functioning of the patients with schizophrenia spectrum disorder. The PSP scale measures psychosocial functioning within four domains: socially useful activities, personal and social relationships, self-care, and disturbing and aggressive behavior.The patient is rated from 1 to 6 on each item of the four domains. A higher score indicates greater psychosocial functioning in any of the four domains.
The final global score is defined according to a summary instruction table. This scale provides a single, overall rating from 1 to 100, where a higher score represents better personal and social function. The changes in the Personal and Social Performance scale (PSP) score immediately after the 3-week intervention, as well as at one-month and three-month follow-ups, will be collected as the secondary outcome.
Measured: Fifteen weeks
The change in the score of the Beck Cognitive Insight Scale (BCIS)
Cognitive insight was measured by the Taiwanese version of the Beck Cognitive Insight Scale (BCIS), a self-reported instrument comprising 15 items.The Taiwanese BCIS is composed of 2 subscales including reflective attitude (9 items) and certain attitude (6 items). We obtained a R-C (reflective attitude minus certain attitude) index of the Taiwanese BCIS, representing the measurement of cognitive insight by subtracting the score of the certain attitude subscale from that of the reflective attitude subscale. Lower R-C index scores indicate poorer cognitive insight. The changes in the score of the Beck Cognitive Insight Scale (BCIS) immediately after the 3-week intervention, as well as at one-month and three-month follow-ups, will be collected as the secondary outcome.
Measured: Fifteen weeks
The change in the score of Schizophrenia Quality of Life Scale Revision Four (SQOLR4)
The Chinese version of the Schizophrenia Quality of Life Scale Revision Four (SQOLR4) is a self-administered questionnaire of 33 items in two domains: psychosocial and vitality. All but four items are coded on a scale of 0-4 according to the frequency of occurrence during the previous 7 days (0 = always, 4 = never; the four exceptions are coded 0 = never, 4
= always). A higher score indicates higher health-related QoL. The changes in the score of Schizophrenia Quality of Life Scale Revision Four (SQOLR4) immediately after the 3-week intervention, as well as at one-month and three-month follow-ups, will be collected as the secondary outcome.
Measured: Fifteen weeks
The changes in the results of the Tower of London Drexel University Test 2nd Edition
The Tower of London Drexel University Test 2nd Edition is a neuropsychological test for the assessment of executive functioning specifically to detect deficits in planning, which may occur due to a variety of medical and neuropsychiatric conditions. The changes in the results of the Tower of London Drexel University Test 2nd Edition immediately after the 3-week intervention will be collected as the secondary outcome.
Measured: Three weeks
The changes in the results of the Color Trails Test (CTT)
The CTT, a culture-neutral version of the Trail Making Test, was selected to measure sustained visual attention. The CTT consists of two parts (CTT-1 and CTT-2). The CTT-1 requires participants to connect a series of numbered circles that are randomly printed on a sheet of paper. In the CTT-2, numbered circles of 1 to 25 are shown twice (printed in pink and in yellow) randomly on a sheet of paper. Participants are asked to connect the numbers from 1 to 25 alternating between the two colors. The changes in the results of the Color Trails Test (CTT) immediately after the 3-week intervention will be collected as the secondary outcome.
Measured: Three weeks
The changes in the results of the Stroop Color Word Test (SCWT)
Stroop Color Word Test (SCWT) will be administered to measure selective attention and cognitive flexibility. SCWT is composed of three parts, each lasting for 45 seconds. The changes in the results of the Stroop Color Word Test (SCWT) immediately after the 3-week intervention will be collected as the secondary outcome.
Measured: Three weeks
The changes in indices of heart rate variability (HRV) derived from R-R intervals of ECG signals
HRV indices represent autonomic functioning. ECG electrodes will be placed on bilateral arms just below the elbows, with a ground electrode placed just above the right wrist bone. Lead I electrocardiogram of each patient will be taken for 5 min after sitting and having a rest for 20 min in a soundproof, dim-lighted room with thermostatic control.
The ECG signals will be acquired, stored, pre-processed according to the recommended procedures and processed by an HRV analyser. The time domain of HRV is obtained: Standard deviation of NN intervals (SDNN). Power spectrum of HRV is quantified into the standard frequency-domain measurements including low-frequency power (LF, 0.04-0.15 Hz), high-frequency power (HF, 0.15- 0.40 Hz). The changes in indices of heart rate variability (HRV) derived from R-R intervals of ECG signals immediately after the 3-week intervention will be collected as the secondary outcome.
Measured: Three weeks
The changes in resting-state EEG features
In a dimly lit, electrically shielded room, patients' electroencephalogram (EEG) will be recorded. Resting-state EEG will be collected with eye opened (5min) and closed (5min). Signals will be amplified by using EEG amplifiers and stored for offline analyses. The changes in resting-state EEG features (power, coherence, and microstates within different frequency bands including delta, theta, alpha and beta) immediately after the 3-week intervention will be collected as the secondary outcome.
Measured: Three weeks
The changes in fNIRS features
Functional near infrared spectroscopy (fNIRS) system is used to measure the relative changes in oxyhemoglobin (Hb) of the frontal regions. Resting-state fNIRS fo 180s and verbal fluency task (VFT)-based fNIRS for 160s will be collected in a quiet room. The changes in fNIRS features immediately after the 3-week intervention will be collected as the secondary outcome.
Measured: Three weeks
The changes in resting-state fMRI features
Magnetic Resonance Imaging (MRI) scans will be performed on the hybrid 3.0T PET-MR imaging unit (GE Healthcare, Waukesha, WI). MRI scans will be carried out using the same imaging protocol, including T1-weighted images and resting-state functional MRI (rs-fMRIs).The changes in resting-state fMRI features immediately after the 3-week intervention will be collected as the secondary outcome.
Measured: Three weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

6 May 20241 Mar 2028

First posted2 Jul 2026
Study start6 May 2024
Primary completion31 Dec 2027 (estimated)
Study completion1 Mar 2028 (estimated)

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (6)Papers the sponsor has linked to this study.
Other trials for Negative Symptoms in SchizophreniaStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase N/A
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Triple blind
Who is masked: Participant, Care provider, Outcomes assessor
Enrolment: 100 participants (estimated)

IDs, dates and publications

ClinicalTrials.gov ID: NCT07680959
Sponsor's protocol ID: B202303001
Status last verified: Jul 2026
First submitted: 26 Jun 2026
Last updated: 9 Jul 2026
Results posted: No
Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: No
Individual data sharing: No: Individual participant data (IPD) will not be shared, as required by the local ethics committee to protect patient privacy.

Publications

Kishi T, Ikuta T, Sakuma K, Hamanaka S, Nishii Y, Hatano M, Kito S, Iwata N. Theta Burst Stimulation Protocols for Schizophrenia: A Systematic Review and Network Meta-Analysis. JAMA Netw Open. 2024 Oct 1;7(10):e2441159. doi: 10.1001/jamanetworkopen.2024.41159.
PubMed 39446321
Tong S, Chen S, Chen J, Tong Z, Li W, Liu S, Shi H, Yao L, Zhang C, Zhang X. Efficacy and long-term effects of intermittent theta burst stimulation on negative symptoms in schizophrenia: a systematic review and meta-analysis. Brain Commun. 2026 Jan 29;8(1):fcag027. doi: 10.1093/braincomms/fcag027. eCollection 2026.
PubMed 41704822
Gupta R, Sharma A, Goyal N. Breaking the Negative Symptom Barrier: A Novel Neuromodulation Strategy Using HD-tDCS Primed iTBS in Schizophrenia. J ECT. 2026 Jan 20. doi: 10.1097/YCT.0000000000001224. Online ahead of print.
PubMed 41575458
Ma CC, Lin YY, Chung YA, Park SY, Huang CC, Chang WC, Chang HA. The two-back task leads to activity in the left dorsolateral prefrontal cortex in schizophrenia patients with predominant negative symptoms: a fNIRS study and its implication for tDCS. Exp Brain Res. 2024 Mar;242(3):585-597. doi: 10.1007/s00221-023-06769-5. Epub 2024 Jan 16.
PubMed 38227007
Yeh TC, Lin YY, Tzeng NS, Kao YC, Chung YA, Chang CC, Fang HW, Chang HA. Effects of online high-definition transcranial direct current stimulation over left dorsolateral prefrontal cortex on predominant negative symptoms and EEG functional connectivity in patients with schizophrenia: a randomized, double-blind, controlled trial. Psychiatry Clin Neurosci. 2025 Jan;79(1):2-11. doi: 10.1111/pcn.13745. Epub 2024 Sep 24.
PubMed 39317963
Lin CE, Chen LF, Sack AT, Chang HA. Task-based fNIRS biomarkers of HD-tDCS treatment for negative symptoms in schizophrenia. Schizophr Res. 2026 Aug;294:35-43. doi: 10.1016/j.schres.2026.04.010. Epub 2026 Apr 17.
PubMed 42000633

Interested in taking part?

The sponsor has not listed a contact. The official record may have more details.

Talk to your doctor first and take this page with you. Only the study team can confirm whether you can join.

Questions to ask the study team

What is the study trying to find out?
What would I need to do, and how often would I visit?
Could I receive a placebo instead of the treatment?
What are the possible risks and benefits for me?
Will it cost me anything? Are travel or time paid for?
Can I keep seeing my own doctor during the study?
What happens when the study ends?

See sites and contacts

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All Negative Symptoms in Schizophrenia trials

Study at a glance

From the registry record, last updated by the sponsor on 9 Jul 2026. Recruitment status is as the sponsor reported it: confirm with the study team.

Official title: The Efficacy of Combined HD-tDCS and iTBS in Treating Negative Symptoms of Schizophrenia
ClinicalTrials.gov ID: NCT07680959
Acronym / sponsor ID: B202303001
Conditions: Negative Symptoms in Schizophrenia, Brain Stimulation Intervention
Keywords: HD-tDCS, iTBS, negative symptoms, schizophrenia, neuroimaging
Study type: Interventional
Recruitment status: Enrolling by invitation
Enrolment: 100 participants (estimated)
Lead sponsor: Tri-Service General Hospital (TSGH)University, hospital or other
Collaborators: National Science and Technology Council, Taiwan
Study start: 6 May 2024 (actual)
Primary completion: 31 Dec 2027 (estimated)
Study completion: 1 Mar 2028 (estimated)
First posted: 2 Jul 2026 (actual)
Results: Not posted in the source record

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

Detailed description

Study design

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Triple blind (participant, care provider, outcomes assessor)
Number of arms: 4

Arm	Type	Receives
active iTBS followed by active HD-tDCS	Experimental	Device: active iTBS followed by active HD-tDCSDuring the 3-week intervention phase, patients in this group will receive 2 sessions of active iTBS per working day for 2 weeks (totaling 20 sessions), followed by 2 sessions of active HD-tDCS per working day for 1 week (totaling 10 sessions).
sham iTBS followed by active HD-tDCS	Experimental	Device: sham iTBS followed by active HD-tDCSDuring the 3-week intervention phase, patients in this group will receive 2 sessions of sham iTBS per working day for 2 weeks (totaling 20 sessions), followed by 2 sessions of active HD-tDCS per working day for 1 week (totaling 10 sessions).
active iTBS followed by sham HD-tDCS	Experimental	Device: active iTBS followed by sham HD-tDCSDuring the 3-week intervention phase, patients in this group will receive 2 sessions of active iTBS per working day for 2 weeks (totaling 20 sessions), followed by 2 sessions of sham HD-tDCS per working day for 1 week (totaling 10 sessions).
sham iTBS followed by sham HD-tDCS	Sham comparator	Device: sham iTBS followed by sham HD-tDCSDuring the 3-week intervention phase, patients in this group will receive 2 sessions of sham iTBS per working day for 2 weeks (totaling 20 sessions), followed by 2 sessions of sham HD-tDCS per working day for 1 week (totaling 10 sessions).

Who may qualify

Ages: 18 to 65 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (3 listed)

Subjects diagnosed with DSM-5 schizophrenia or schizoaffective disorder;
With a clinical presentation characterized by predominant negative symptoms, as determined by psychiatric assessment and a score of at least 20 on the Negative Symptoms Subscale of the Positive and Negative Syndrome Scale (PANSS);
Stable positive and negative symptoms for at least 4 weeks, as documented in medical records and confirmed by clinical judgment and psychiatric interview;

Key exclusion criteria (9 listed)

Unstable medical conditions;
Current psychiatric comorbidity or active substance use disorder (except for tobacco use disorders);
Contraindications for MRI, tDCS or rTMS;
Pregnancy or breastfeeding at the time of enrollment;
History of meningitis, encephalitis, seizures, intracranial neoplasms or surgery, severe head injury or cerebrovascular disease, or a family history of seizures;

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
active iTBS followed by active HD-tDCSThe active iTBS sessions will be delivered using the Magstim Rapid2 stimulator. The iTBS protocol consists of 3-pulse 50-Hz bursts given every 200 ms (at 5 Hz) for 2 s at 8-s intervals for 60 cycles. A 2-s train of iTBS will be repeated every 10 s for a total of 1800 pulses per session. The intensity of stimulation will be set at 80% resting motor threshold (RMT). The target will be the left DLPFC with the coil centered at the MNI coordinate [-38, 44, 26] calculated from T1-weighted MRI. The active HD-tDCS will be applied by NeuroConn DC Stimulator Plus. The central anode will be placed over the International 10-20 electrode position F3 and the return peripheral electrodes placed at Fp1, Fz, C3 and F7. Stimulation session will be applied at an intensity of 2 mA, 8-sec fade in and 5-sec fade out, for 20 min. During each session, the subject has to perform a computerized working memory task (i.e., 2-back task). The two times daily sessions will be separated by at least 2 hours.	Device	active iTBS followed by active HD-tDCS
active iTBS followed by sham HD-tDCSThe active iTBS sessions will be delivered using the Magstim Rapid2 stimulator. The iTBS protocol consists of 3-pulse 50-Hz bursts given every 200 ms (at 5 Hz) for 2 s at 8-s intervals for 60 cycles. A 2-s train of iTBS will be repeated every 10 s for a total of 1800 pulses per session. The intensity of stimulation will be set at 80% resting motor threshold (RMT). The target is the left DLPFC with the coil centered at the MNI coordinate [-38, 44, 26] calculated from T1-weighted MRI. In the sham HD-tDCS stimulation, short continuous currents without neuromodulatory effects will be applied to mimic real-stimulation sensations. Specifically, sham stimulation will deliver 40-sec, 2 mA normal-like stimulation, followed by a tiny current pulse (110 μA over 15 ms) for impedance control taking place every 550 ms for the remaining time. The other procedure is the same as the active HD-tDCS stimulation.	Device	active iTBS followed by sham HD-tDCS
sham iTBS followed by active HD-tDCSIn the sham iTBS condition, the patients receive the same iTBS regimen and exact positioning of the coil but stimulations will be delivered using a commercial identical looking figure 8 sham coil (Magstim D70 Air film sham coil) that can produce a similar sound and sensation. In the active HD-tDCS condition, stimulation will be applied by a battery-operated device (NeuroConn DC Stimulator Plus) via 5 carbon rubber electrodes (1 cm radius, high-definition 4 × 1 rings configuration). To target the left DLPFC, the central electrode (anode) will be placed over International 10-20 electrode position F3, with return peripheral electrodes at Fp1, Fz, C3 and F7. Stimulation will be applied at an intensity of 2 milliamp (mA), 8-sec fade in and 5-sec fade out, for 20 min. During each session, the subject has to perform a computerized working memory task (i.e., 2-back task). The two times daily sessions will be separated by at least 2 hours.	Device	sham iTBS followed by active HD-tDCS
sham iTBS followed by sham HD-tDCSIn the sham iTBS condition, patients receive the same iTBS regimen and exact positioning of the coil but stimulations will be delivered using a commercial identical looking figure 8 sham coil (Magstim D70 Air film sham coil) that can produce a similar sound and sensation. In the sham HD-tDCS condition, short continuous currents without neuromodulatory effects will be applied to mimic real-stimulation sensations. Specifically, sham stimulation will deliver 40-sec, 2 mA normal-like stimulation, followed by a tiny current pulse (110 μA over 15 ms) for impedance control taking place every 550 ms for the remaining time. The other procedure is the same as the active HD-tDCS stimulation.	Device	sham iTBS followed by sham HD-tDCS

Primary outcome

The change in Positive and Negative Syndrome Scale (PANSS) negative subscale score
Time frame: Fifteen weeks
PANSS is a clinician-administered rating scale to measure the severity of psychopathological symptoms of the patients with schizophrenia spectrum disorder. The patient is rated from 1 to 7 on 30 different symptom items. All items scores are summed up to yield a total PANSS score, which ranges from 30 to 210. A higher score indicates greater psychopathological symptom severity. PANSS negative subscale has 7 items with its score ranging from 7 to 49. The changes in the PANSS negative subscale score immediately after the 3-week intervention (primary endpoint), as well as at one-month and three-month follow-ups, will be collected as the primary outcome.

12 secondary outcomes

The change in score of the Scale for the Assessment of Negative Symptoms (SANS)
Time frame: Fifteen weeks
The change in score of Calgary Depression Rating Scale for Schizophrenia (CDSS)
Time frame: Fifteen weeks
The change in the Personal and Social Performance scale (PSP) score
Time frame: Fifteen weeks
The change in the score of the Beck Cognitive Insight Scale (BCIS)
Time frame: Fifteen weeks
The change in the score of Schizophrenia Quality of Life Scale Revision Four (SQOLR4)
Time frame: Fifteen weeks
The changes in the results of the Tower of London Drexel University Test 2nd Edition
Time frame: Three weeks
The changes in the results of the Color Trails Test (CTT)
Time frame: Three weeks
The changes in the results of the Stroop Color Word Test (SCWT)
Time frame: Three weeks
The changes in indices of heart rate variability (HRV) derived from R-R intervals of ECG signals
Time frame: Three weeks
The changes in resting-state EEG features
Time frame: Three weeks
The changes in fNIRS features
Time frame: Three weeks
The changes in resting-state fMRI features
Time frame: Three weeks

Results and safety

This study is still under way. Results are not available in the source record yet.

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 9 Jul 2026.
Background: PubMed 39446321Kishi T, Ikuta T, Sakuma K, Hamanaka S, Nishii Y, Hatano M, Kito S, Iwata N. Theta Burst Stimulation Protocols for Schizophrenia: A Systematic Review and Network Meta-Analysis. JAMA Netw Open. 2024 Oct 1;7(10):e2441159. doi: 10.1001/jamanetworkopen.2024.41159.
Background: PubMed 41704822Tong S, Chen S, Chen J, Tong Z, Li W, Liu S, Shi H, Yao L, Zhang C, Zhang X. Efficacy and long-term effects of intermittent theta burst stimulation on negative symptoms in schizophrenia: a systematic review and meta-analysis. Brain Commun. 2026 Jan 29;8(1):fcag027. doi: 10.1093/braincomms/fcag027. eCollection 2026.
Background: PubMed 41575458Gupta R, Sharma A, Goyal N. Breaking the Negative Symptom Barrier: A Novel Neuromodulation Strategy Using HD-tDCS Primed iTBS in Schizophrenia. J ECT. 2026 Jan 20. doi: 10.1097/YCT.0000000000001224. Online ahead of print.
Background: PubMed 38227007Ma CC, Lin YY, Chung YA, Park SY, Huang CC, Chang WC, Chang HA. The two-back task leads to activity in the left dorsolateral prefrontal cortex in schizophrenia patients with predominant negative symptoms: a fNIRS study and its implication for tDCS. Exp Brain Res. 2024 Mar;242(3):585-597. doi: 10.1007/s00221-023-06769-5. Epub 2024 Jan 16.
Background: PubMed 39317963Yeh TC, Lin YY, Tzeng NS, Kao YC, Chung YA, Chang CC, Fang HW, Chang HA. Effects of online high-definition transcranial direct current stimulation over left dorsolateral prefrontal cortex on predominant negative symptoms and EEG functional connectivity in patients with schizophrenia: a randomized, double-blind, controlled trial. Psychiatry Clin Neurosci. 2025 Jan;79(1):2-11. doi: 10.1111/pcn.13745. Epub 2024 Sep 24.
Background: PubMed 42000633Lin CE, Chen LF, Sack AT, Chang HA. Task-based fNIRS biomarkers of HD-tDCS treatment for negative symptoms in schizophrenia. Schizophr Res. 2026 Aug;294:35-43. doi: 10.1016/j.schres.2026.04.010. Epub 2026 Apr 17.
Individual participant dataSharing planned: No. Individual participant data (IPD) will not be shared, as required by the local ethics committee to protect patient privacy.

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Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.

Hsin-An Chang, M.D. principal investigator

Tri-Service General Hospital (TSGH)

1 site in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: enrolling by invitation, as of the sponsor's last update on 9 Jul 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Taiwan. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

The change in Positive and Negative Syndrome Scale (PANSS) negative subscale score (time frame: Fifteen weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT07680959, which also lists 6 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Jul 2026.