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

NCT07680959 | Enrolling By Invitation

• 1 other identifier: B202303001
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Negative Symptoms in Schizophrenia; Brain Stimulation Intervention

Keywords

HD-tDCS; iTBS; negative symptoms; schizophrenia; neuroimaging

Outcome Measures

Primary Outcomes (1)

• 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.

  Fifteen weeks

Secondary Outcomes (12)

• The change in score of the Scale for the Assessment of Negative Symptoms (SANS)

  Fifteen weeks

• The change in score of Calgary Depression Rating Scale for Schizophrenia (CDSS)

  Fifteen weeks

• The change in the Personal and Social Performance scale (PSP) score

  Fifteen weeks

• The change in the score of the Beck Cognitive Insight Scale (BCIS)

  Fifteen weeks

• The change in the score of Schizophrenia Quality of Life Scale Revision Four (SQOLR4)

  Fifteen weeks

Study Arms (4)

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).

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).

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).

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).

Device: sham iTBS followed by sham HD-tDCS

Interventions

active iTBS followed by active HD-tDCS DEVICE

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 active HD-tDCS

active iTBS followed by sham HD-tDCS DEVICE

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.

active iTBS followed by sham HD-tDCS

sham iTBS followed by active HD-tDCS DEVICE

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 active HD-tDCS

sham iTBS followed by sham HD-tDCS DEVICE

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.

sham iTBS followed by sham HD-tDCS

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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;

You may not qualify if:

• 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);
• 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.

Sponsors & Collaborators

• Tri-Service General Hospital (TSGH): lead
• National Science and Technology Council, Taiwan: collaborator

Study Sites (1)

Tri-service general hospital

Taipei, 114, Taiwan

Location

Related Publications (6)

• 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.

  PMID: 39446321 BACKGROUND

• 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.

  PMID: 41704822 BACKGROUND

• 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.

  PMID: 41575458 BACKGROUND

• 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.

  PMID: 38227007 BACKGROUND

• 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.

  PMID: 39317963 BACKGROUND

• 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.

  PMID: 42000633 BACKGROUND

MeSH Terms

Conditions

Schizophrenia

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders

Study Officials

• Hsin-An Chang, M.D.

  Tri-Service General Hospital (TSGH)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Attending psychiatrist

Study Record Dates

• First Submitted: June 26, 2026
• First Posted: July 2, 2026
• Study Start: May 6, 2024
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): March 1, 2028
• Last Updated: July 9, 2026

Record last verified: 2026-07

Data Sharing

• IPD Sharing: Will not share

Locations

TW (1)