This randomized, double-blind, sham-controlled trial compares three brain stimulation approaches-accelerated intermittent theta burst stimulation (aITBS), high-frequency repetitive transcranial magnetic stimulation (HF-rTMS), and sham stimulation-for treating cognitive deficits in treatment-resistant schizophrenia. Ninety patients receiving clozapine will be randomized 1:1:1 to receive 20 sessions over 4 weeks targeting the dorsolateral prefrontal cortex. The primary outcome is change in cognitive function measured by B-CATS score at 2, 4, and 12 weeks. Secondary outcomes include social cognition, symptom severity, brain metabolism (FDG-PET), and inflammatory biomarkers.

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

Inclusion Criteria:

• Diagnosed with treatment-resistant schizophrenia according to TRIIP Consensus criteria
• Age: 18-60 years
• Currently receiving clozapine treatment for at least 6 months
• Attending psychiatry outpatient department at AIIMS Bhubaneswar

Exclusion Criteria:

• Currently receiving or recently received ECT/rTMS/tDCS
• Co-morbid psychiatric, major medical, or neurological disorders
• History of withdrawal seizures, delirium tremens, or significant head injury
• Presence of pacemaker or metal in any part of body (excluding mouth)
• Pregnant or lactating women