Comparison of Accelerated Intermittent Theta Burst Stimulation vs High Frequency Transcranial Magnetic Stimulation (Hf-rTMS) on Cognitivesymptoms in Treatment-resistant Schizophrenia

Objectives: This randomized controlled trial will compare the efficacy of aITBS, high-frequency rTMS, and sham TMS on cognition, social cognition, cerebral metabolism (via FDG PET), and inflammatory biomarkers (neurogranin and neurofilament light chain protein) in patients with TRS.

Study Design: This is a three-arm, parallel-group, randomized, sham-controlled, double-blind trial. Participants will be randomized 1:1:1 to receive either aITBS, high-frequency rTMS, or sham rTMS.

Intervention Details:

* Group 1 (aITBS): 3 pulses at 50 Hz bursts, 2 seconds on/10 seconds off for 3 minutes (600 pulses per session), 3 rounds per day separated by 15 minutes (1800 pulses/day), 5 sessions/week for 4 weeks (20 sessions total) * Group 2 (HF-rTMS): 20 Hz pulses for 20 minutes, 4 seconds per second, intertrain interval 20 seconds, 110% resting motor threshold (RMT), 5 sessions/week for 4 weeks (20 sessions total) * Group 3 (Sham): Sham stimulation using identical-appearing coil, same schedule as active groups * Target: Dorsolateral prefrontal cortex for all groups Population: 90 patients (30 per group) with treatment-resistant schizophrenia according to TRIIP Consensus criteria, aged 18-60 years, receiving clozapine treatment for at least 6 months.

Primary Outcome: Change in Brief Cognitive Assessment Tool for Schizophrenia (B-CATS) score from baseline to 2 weeks, 4 weeks, and 12 weeks.

Secondary Outcomes:

* Change in Social Cognition Rating Tool in Indian Setting (SOCRATIS) score * Change in Positive and Negative Syndrome Scale (PANSS) score * Change in cerebral metabolic rate measured by FDG-PET * Change in inflammatory biomarkers (neurogranin and NFLP levels) Assessment Timeline: Baseline, 2 weeks, 4 weeks (end of treatment), and 12 weeks (follow-up) Expected Outcome: If aITBS demonstrates superior improvement in cognitive deficits compared to high-frequency rTMS and sham, this study will provide evidence for a novel treatment protocol to enhance patient functionality and reduce healthcare burden in treatment-resistant schizophrenia.

Study Details Study Type Interventional (Clinical Trial) Study Phase Phase 2/Phase 3 Study Design

* Allocation: Randomized * Intervention Model: Parallel Assignment (3 arms) * Masking: Double Blind (Participant, Outcomes Assessor) * Primary Purpose: Treatment Condition Treatment-Resistant Schizophrenia Intervention * Device: Accelerated Intermittent Theta Burst Stimulation (aITBS) * Device: High-Frequency Repetitive Transcranial Magnetic Stimulation (HF-rTMS) * Device: Sham Transcranial Magnetic Stimulation Arms and Interventions Experimental: Accelerated iTBS * Participants will receive aITBS using 100X transcranial magnetic stimulator with 70 mm active cooled figure-of-eight coil * Parameters: 3 pulses at 50 Hz bursts, 2 sec on/10 sec off, 3 minutes per session * Dosage: 1800 pulses per day (3 rounds separated by 15 min), 5 days/week for 4 weeks Active Comparator: High-Frequency rTMS * Participants will receive HF-rTMS using 100X transcranial magnetic stimulator with 70 mm active cooled figure-of-eight coil * Parameters: 20 Hz pulses, 20 minutes, 4 sec per second, intertrain interval 20 sec, 110% RMT * Dosage: 5 sessions per week for 4 weeks Sham Comparator: Sham rTMS * Participants will receive sham stimulation using identical-appearing sham coil * Same session schedule and positioning as active groups but without therapeutic magnetic field Outcome Measures

Primary Outcome Measures:

1\. Change in Brief Cognitive Assessment Tool for Schizophrenia (B-CATS) Score

* Time Frame: Baseline, 2 weeks, 4 weeks, 12 weeks * Description: Assessment of cognitive function in multiple domains

Secondary Outcome Measures:

1\. Change in Social Cognition Rating Tool in Indian Setting (SOCRATIS)

* Time Frame: Baseline, 2 weeks, 4 weeks, 12 weeks 2. Change in Positive and Negative Syndrome Scale (PANSS) * Time Frame: Baseline, 2 weeks, 4 weeks, 12 weeks 3. Change in cerebral metabolic rate (FDG-PET) * Time Frame: Baseline, 4 weeks, 12 weeks 4. Change in biomarkers (Neurogranin and NFLP levels) * Time Frame: Baseline, 4 weeks, 12 weeks

• Change in Social Cognition Rating Tool in Indian Setting (SOCRATIS) [Time frame: Baseline, 2 weeks, 4 weeks, 12 weeks]
• Change in Positive and Negative Syndrome Scale (PANSS) [Time frame: Baseline, 2 weeks, 4 weeks, 12 weeks]
• Change in cerebral metabolic rate (FDG-PET) [Time frame: Baseline, 4 weeks, 12 weeks]
• Change in biomarkers (Neurogranin and NFLP levels) [Time frame: Baseline, 4 weeks, 12 weeks]