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

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Psychosis; Schizophrenia Disorder
• Intervention / Treatment: Device: Accelerated iTBS; Device: High-Frequency rTMS; Device: Sham rTMS

Detailed Description

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

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Debadatta Mohapatra, MD; Phone Number: +91 9437658251; Email: psych_debadatta@aiimsbhubaneswar.edu.in

Study Locations

• India
  • Odisha
    • Bhubaneswar, Odisha, India, 751019
      • AIIMS Bhubaneswar
      • Contact: Exucutive Director, MD; Phone Number: +91 0674-2476083; Email: director@aiimsbhubaneswar.edu.in

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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	Device: 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	Device: 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	Device: 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Brief Cognitive Assessment Tool for Schizophrenia (B-CATS)	Assessment of cognitive function in multiple domains	Baseline, 2 weeks, 4 weeks, 12 weeks

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: All India Institute of Medical Sciences, Bhubaneswar
• Collaborators: Indian Council of Medical Research

Study record dates

Study Major Dates

• Study Start (Estimated): February 15, 2026
• Primary Completion (Estimated): February 14, 2029
• Study Completion (Estimated): December 14, 2029

Study Registration Dates

• First Submitted: February 23, 2026
• First Submitted That Met QC Criteria: February 27, 2026
• First Posted (Actual): March 3, 2026

Study Record Updates

• Last Update Posted (Actual): March 3, 2026
• Last Update Submitted That Met QC Criteria: February 27, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: rTMS; Cognitive deficit
• Additional Relevant MeSH Terms: Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Neurocognitive Disorders; Schizophrenia; Psychotic Disorders; Cognition Disorders
• Other Study ID Numbers: T/EMF/Psych/2023-24/282

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No