Efficacy and Safety of Individualized Sequential Accelerated Theta Burst Stimulation in Improving Cognitive Function in Schizophrenia

N/ANot Yet RecruitingNCT07806877

Central South University60 enrolled

Overview

The goal of this clinical trial is to learn if sequential dual-site accelerated theta burst stimulation (SD-aTBS) targeting the frontoparietal network and default mode network works to improve cognitive function in adults with schizophrenia. It will also learn about the safety of SD-aTBS. The main questions it aims to answer are: Does SD-aTBS improve cognitive function in participants with schizophrenia? What are the neurobiological mechanisms (brain network and synaptic plasticity changes) underlying the effects of SD-aTBS? Researchers will compare real SD-aTBS to sham stimulation to see if SD-aTBS is effective and safe for treating cognitive impairment in schizophrenia. Participants will: Receive real SD-aTBS or sham stimulation for 10 consecutive working days Complete clinical symptom assessments, cognitive function tests, MRI scans, and EEG recordings at baseline, after treatment, and 1 month after treatment Undergo SV2A-PET scans at baseline and 1 month after treatment

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

Conditions

Schizophrenia / Schizoaffective Disorder TMS Cognitive

Eligibility

Sex: ALLMin age: 18 YearsMax age: 35 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Age 18-35 years. 2. Meets the diagnostic criteria for schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), confirmed by the Structured Clinical Interview for DSM-5 (SCID-5). 3. Duration of illness ≤ 8 years. 4. Taking no more than 2 antipsychotic medications, with a stable antipsychotic dose for at least 4 weeks prior to enrollment, and no expected change in the medication regimen throughout the treatment and follow-up period. （4）Presence of significant cognitive impairment (overall deficit score of MCCB plus supplementary tests ≥ 0.5). （5）The participant and their guardian agree to participate in the study and provide written informed consent. Exclusion Criteria: 1. Current or lifetime co-occurrence of any other DSM-5 psychiatric disorder. 2. Concurrent use of mood stabilizers, antidepressants, or excessive benzodiazepines (lorazepam equivalent \> 2 mg/day). 3. Presence of severe or acute physical illness, including a history of epilepsy, traumatic brain injury, intracranial space-occupying or infectious disease, acute cardiovascular or cerebrovascular disease, acute respiratory disease, or acute hematologic disease. 4. Any contraindication to transcranial magnetic stimulation (TMS), PET scanning, or magnetic resonance imaging (MRI). 5. Receipt of any other electrical or stimulation therapy within 3 months prior to enrollment. 6. Current use of medications known to interact with SV2A (e.g., levetiracetam, loratadine, quinine). Withdrawal Criteria 1. Occurrence of a serious adverse event possibly related to the intervention (e.g., seizure, symptom relapse requiring immediate hospitalization). 2. Onset of a new severe illness during the study (e.g., cardiovascular event, severe infection, severe hepatic or renal dysfunction). 3. A change in the antipsychotic medication regimen during the study - including a dose adjustment of ≥ 25%, or a switch to a different antipsychotic medication. 4. Poor adherence, inability to complete the full intervention, failure to return for follow-up as required, or inability to cooperate with the examinations and assessments. 5. Pregnancy. 6. Voluntary withdrawal of informed consent by the participant. 7. Any other condition judged by the investigator to render the participant unable to complete the study or likely to affect the study results.

Outcomes

Primary Outcomes

Change in Global Cognitive Function as Measured by the Mean Composite T-Score Derived from 14 Neuropsychological Tests

Global cognitive function will be assessed using the mean of the standardized T-scores from 14 neuropsychological tests: the MATRICS Consensus Cognitive Battery (MCCB; 9 subtests) plus 5 supplementary tests - the Wisconsin Card Sorting Test 64-Item Version (WCST-64), the Color Trails Test I and II, the Stroop Color-Word Test, and the Paced Auditory Serial Addition Task (PASAT). Raw scores from all 14 tests will be converted to standardized T-scores (population mean of 50, standard deviation of 10), adjusted for age, sex, education, and city of childhood and current residence. A single composite T-score will be calculated as the mean of the 14 test T-scores. Higher scores indicate better cognitive function.

Time frame: Baseline, immediately after the intervention (Day 10), and at Follow-up (Day 40 ± 3)

Change in Synaptic Density as Measured by [18F]SV2A-PET Standardized Uptake Value Ratio (SUVR)

Synaptic density will be assessed using \[18F\]SV2A positron emission tomography (SV2A-PET). The outcome is the change in the standardized uptake value ratio (SUVR), calculated with the centrum semiovale (white matter) as the reference region. Higher SUVR values indicate greater synaptic density.

Time frame: Baseline and Follow-up (Day 40 ± 3)

Secondary Outcomes

Change in Psychotic Symptom Severity as Measured by the Positive and Negative Syndrome Scale (PANSS) Total Score

Psychiatric symptom severity will be assessed using the Positive and Negative Syndrome Scale (PANSS). The PANSS total score ranges from 30 to 210, with higher scores indicating more severe symptoms.

Time frame: Baseline, immediately after the intervention (Day 10), and at Follow-up (Day 40 ± 3)

Change in Negative Symptom Severity as Measured by the Scale for the Assessment of Negative Symptoms (SANS) Total Score

Negative symptoms will be assessed using the Scale for the Assessment of Negative Symptoms (SANS). The SANS total score ranges from 0 to 125, with higher scores indicating more severe negative symptoms

Time frame: Baseline, immediately after the intervention (Day 10), and at Follow-up (Day 40 ± 3)

Change in Treatment-Emergent Adverse Event Severity as Measured by the Treatment Emergent Symptom Scale (TESS) Total Score

Treatment-emergent adverse events will be assessed using the Treatment Emergent Symptom Scale (TESS), a 35-item clinician-rated scale. Each item is rated for severity on a 0-4 scale (0 = absent/not applicable, 4 = severe). The outcome is the change in TESS total severity score, with higher scores indicating greater adverse event burden.

Time frame: Baseline, immediately after the intervention (Day 10), and at Follow-up (Day 40 ± 3)

Brain MRI Measures (High-Resolution T1-Weighted, Resting-State fMRI, Task-Based fMRI [n-back]，DTI)

Change in structural and functional MRI measures.

Time frame: Baseline, post-intervention, and Follow-up (Day 40 ± 3)

Change in Resting-State EEG Spectral Power

Resting-state electroencephalography (EEG) will be recorded with eyes closed. The outcome is the change in absolute spectral power (in μV²) in the delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta (12-30 Hz), and gamma (30-48 Hz) frequency bands.

Time frame: Baseline, immediately after the intervention (Day 10), and at Follow-up (Day 40 ± 3)

Change in Peripheral Blood Biomarker Concentrations

Peripheral blood samples will be collected for exploratory biomarker assessment. The outcome is the change in the concentration of selected peripheral blood biomarkers (e.g., inflammatory cytokines, neurotrophic factors, and other candidate analytes), reported in their respective units (e.g., pg/mL). Specific analytes will be determined and described in the results publication.

Time frame: Baseline, immediately after the intervention (Day 10), and at Follow-up (Day 40 ± 3)

Incidence of Adverse Events Related to SD-aTBS

Adverse events recorded daily through spontaneous reporting and post-treatment inquiries during the intervention period

Time frame: Daily during the 10-day intervention period

Change in 40 Hz Auditory Steady-State Response (ASSR)

The auditory steady-state response (ASSR) will be elicited by 40 Hz click trains. The outcome is the change in phase-locking factor (inter-trial coherence) and evoked power at 40 Hz. Higher values indicate stronger 40 Hz neural synchronization.

Time frame: Baseline, immediately after the intervention (Day 10), and at Follow-up (Day 40 ± 3)

Change in Mismatch Negativity (MMN) Amplitude

Mismatch negativity (MMN) will be recorded during an auditory oddball paradigm. The outcome is the change in MMN amplitude (in microvolts) at fronto-central electrodes (e.g., Fz). Larger (more negative) MMN amplitude indicates greater pre-attentive change detection.

Time frame: Baseline, immediately after the intervention (Day 10), and at Follow-up (Day 40 ± 3)

Change in P300 Event-Related Potential Amplitude

The P300 event-related potential will be recorded during an auditory oddball paradigm. The outcome is the change in P300 amplitude (in microvolts) at midline electrodes (e.g., Cz, Pz). Larger P300 amplitude indicates better attentional/cognitive processing.

Time frame: Baseline, immediately after the intervention (Day 10), and at Follow-up (Day 40 ± 3)

Efficacy and Safety of Individualized Sequential Accelerated Theta Burst Stimulation in Improving Cognitive Function in Schizophrenia

Overview

Conditions

Interventions

Eligibility

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts