Intermittent Theta-Burst Stimulation to Improve Negative Symptoms and Cognition in Schizophrenia (ITBS-NKS-2024)

Intermittierende Theta-Burst-Stimulation Zur Verbesserung Von Negativsymptomatik Und Kognition Bei Schizophrenie

The planned randomized, sham-controlled, double-blind, monocentric study aims to evaluate the effectiveness of intermittent Theta-Burst Stimulation (iTBS) on negative symptoms and cognitive deficits in schizophrenia. Both the cerebellar vermis and the left dorsolateral prefrontal cortex will be stimulated successively within the same session.

The goal of this trial is to learn if intermittent theta-burst stimulation (iTBS) of the cerebellum and the left dorsolateral prefrontal cortext (DLPFC) can treat negative symptoms and improve cognition in patients with schizophrenia. The main question it aims to answer is:

Does iTBS of the cerebellum and the left DLPFC improve negative symptoms in patients with schizophrenia? Researchers will compare iTBS to sham stimulation to see if iTBS improves negative symptoms.

Participants will:

• Receive 10 sessions of iTBS over the course of 2 weeks
• Undergo extensive examination before iTBS treatment, immediately after iTBS treatment and 4 weeks after iTBS treatment. The examination includes assessment of negative symptoms; psychometric assessment of cognition, social cognition, depressive symptoms; functional magnetic resonance imaging; assessment of eye movements; blood and saliva sampling; assessment of adverse events and stimulation associated sensations.

The study thus seeks to determine whether iTBS of the fronto-cerebellar network might improve negative symptoms and cognition by altering the network's functional activity. Additionally, it will investigate whether a pro-inflammatory cytokine profile could affect iTBS outcomes and whether inflammatory markers could be affected by iTBS.

Study Overview

• Status: Recruiting
• Conditions: Schizophrenia Patients
• Intervention / Treatment: Device: Intermittent theta-burst stimulation; Device: Sham intermittent theta-burst stimulation

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Rasmus Schülke, MD (Dr. med.); Phone Number: +49 511 532 2039; Email: schuelke.rasmus@mh-hannover.de

Study Locations

• Germany
  • Niedersachsen
    • Hannover, Niedersachsen, Germany, 30625
      • Recruiting
      • Hannover Medical School
      • Contact: Rasmus Schülke, MD (Dr. med.); Phone Number: +49 511 532 2039; Email: schuelke.rasmus@mh-hannover.de
      • Principal Investigator: Rasmus Schülke, MD (Dr. med.)

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Diagnosis of schizophrenia (ICD-10: F20.-)
• Age: 18-65 years
• Ability to give informed consent
• Signed informed consent form

Exclusion Criteria:

• Any electronic implants
• Non-MRI-compatible metal implants (e.g., pacemaker, cochlear implant, insulin pump, metal fragment injuries, work in the metal-processing industry)
• Non-TMS-compatible metal implants (compatible items include: earrings, piercings, dental fillings, crowns, implants)
• Claustrophobia
• Epilepsy
• History of traumatic brain injury within the last 3 months
• History of stroke
• Active central nervous system (CNS) infection
• History of CNS infection within the last 3 months
• Pregnancy
• Current drug, medication, or alcohol abuse
• Simultaneous participation in another clinical trial
• Planned changes in psychopharmacological medication within the next 2 weeks
• Severe physical illnesses that could endanger the patient, affect the examinations or make the MRI scanning cause additional burden

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: iTBS; Active intermittent theta-burst stimulation of the cerebellar vermis and the left dorsolateral prefrontal cortex	Device: Intermittent theta-burst stimulation; Intermittent theta-burst stimulation, applied sequentially to the cerebellar vermis and the left dorsolateral prefrontal cortex
Sham Comparator: Sham iTBS; Sham intermittent theta-burst stimulation of the cerebellar vermis and the left dorsolateral prefrontal cortex	Device: Sham intermittent theta-burst stimulation; Sham intermittent theta-burst stimulation, applied sequentially to the cerebellar vermis and the left dorsolateral prefrontal cortex

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in negative symptoms	Change in negative symptoms, measured with the Clinical Assessment Interview for Negative Symptoms (CAINS). Higher CAINS scores correspond to more negative symptoms. The minimum total score is 0 points, the maximum total score is 52 points.	From enrollment to the end of iTBS treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Speech-gesture rating task	Accuracy and speed of evaluations in the Speech-Gesture Rating Task.	From enrollment to the end of iTBS treatment
Speech-gesture rating task at 4-week follow-up	Accuracy and speed of evaluations in the Speech-Gesture Rating Task at 4-week follow-up.	From enrollment to follow-up 4 weeks after the end of iTBS treatment
Eye-Tracking Task	Changes in eye movements in the Eye-Tracking Task.	From enrollment to the end of iTBS treatment
Eye-Tracking Task at 4-week follow-up	Changes in eye movements in the Eye-Tracking Task at 4-week follow-up.	From enrollment to 4 weeks after the end of iTBS treatment
Reading the Mind in the Eyes Test	Reading the Mind in the Eyes Test.	From enrollment to 4 weeks after the end of iTBS treatment
Reading the Mind in the Eyes Test at 4-week follow-up	Reading the Mind in the Eyes Test at 4-week follow-up.	From enrollment to 4 weeks after the end of iTBS treatment
N-Back Test	Working memory performance in the N-Back Test (sensitivity index).	From enrollment to the end of iTBS treatment
N-Back Test at 4-week follow-up	Working memory performance in the N-Back Test (sensitivity index) 4 weeks after the end of iTBS treatment.	From enrollment to the end of iTBS treatment
FMRI: Resting-state functional connectivity	Changes in resting-state functional connectivity in functional magnetic resonance imaging. Focus on connectivity between cerebellar vermis and DLPFC.	From enrollment to the end of iTBS treatment
FMRI: Resting-state functional connectivity at 4-week follow-up	Changes in resting-state functional connectivity in functional magnetic resonance imaging. Focus on connectivity between cerebellar vermis and DLPFC.	From enrollment to 4 weeks after the end of iTBS treatment
FMRI: Task-related functional connectivity	Changes in task-related functional connectivity in functional magnetic resonance imaging, for the N-Back-task and the speech-gesture rating task.	From enrollment to the end of iTBS treatment
FMRI: Task-related functional connectivity at 4-week follow-up	Changes in task-related functional connectivity in functional magnetic resonance imaging, for the N-Back-task and the speech-gesture rating task.	From enrollment to 4 weeks after the end of iTBS treatment
Inflammatory cytokines	Concentrations of inflammatory cytokines (especially IL-6 and TNF-α) in serum and saliva.	From enrollment to the end of iTBS treatment
Inflammatory cytokines at 4-week follow-up	Concentrations of inflammatory cytokines (especially IL-6 and TNF-α) in serum and saliva.	From enrollment to 4 weeks after the end of iTBS treatment
Stimulation-associated perceptions	Stimulation-associated perceptions, measured using the TMS Adverse Events and Associated Sensations Questionnaire (TMSensQ, Section IV), after each iTBS session.	From the beginning of each iTBS stimulation to after the end of each iTBS stimulation
Therapy dropout rate	Therapy dropout rate (i.e. study termination).	From the beginning of iTBS treatment to the end of iTBS treatment
Serious Adverse Events (SAEs)	Serious Adverse Events (SAEs), measured using TMSensQ (Section V).	From the beginning of iTBS treatment to the end of iTBS treatment
Epigenetic changes of neurotrophic and immunological factors	Exploratory molecular biological investigations focusing on neurotrophic (e.g., BDNF, VEGF, GDNF) and immunological (e.g., TNF-alpha, IL-6, t-PA, S100A10) factors.	From enrollment to the end of iTBS treatment
Epigenetic changes of neurotrophic and immunological factors at 4-week follow-up	Exploratory molecular biological investigations focusing on neurotrophic (e.g., BDNF, VEGF, GDNF) and immunological (e.g., TNF-alpha, IL-6, t-PA, S100A10) factors.	From enrollment to 4 weeks after the end of iTBS treatment
Concentrations of markers of neuronal damage	Concentrations of markers of neuronal damage (e.g., NSE, S100-β) in serum.	From enrollment to the end of iTBS treatment
Concentrations of markers of neuronal damage at 4-week follow-up	Concentrations of markers of neuronal damage (e.g., NSE, S100-β) in serum.	From enrollment to 4 weeks after the end of iTBS treatment
Change in negative symptoms at 4-week follow-up	Change in negative symptoms, measured with the Clinical Assessment Interview for Negative Symptoms (CAINS). Higher CAINS scores correspond to more negative symptoms. The minimum total score is 0 points, the maximum total score is 52 points.	From enrollment to follow-up 4 weeks after the end of iTBS treatment
Self-reported depression: BDI-II	Self-reported depression, measured using the Beck Depression Inventory-II (BDI-II). Higher scores correspond to more depressive symptoms. The minimum total score is 0 points, the maximum total score is 63 points.	From enrollment to the end of iTBS-treatment
Self-reported depression at 4-week follow-up: BDI-II	Self-reported depression, measured using the Beck Depression Inventory-II (BDI-II). Higher scores correspond to more depressive symptoms. The minimum total score is 0 points, the maximum total score is 63 points.	From enrollment to 4 weeks after the end of iTBS-treatment
Self-rated gesture perception and production: BAG	Change in self-rated gesture perception and production, measured using the Brief Assessment of Gestures (BAG) questionnaire. Higher BAG scores correspond to greater engagement with or reliance on gestures in communication and indicate stronger tendencies to produce or perceive gestures effectively in different contexts. The minimum total score is 12 points, the maximum total score is 60 points.	From enrollment to the end of iTBS-treatment
Self-rated gesture perception and production at 4-week follow-up: BAG	Change in self-rated gesture perception and production, measured using the Brief Assessment of Gestures (BAG) questionnaire. Higher BAG scores correspond to greater engagement with or reliance on gestures in communication and indicate stronger tendencies to produce or perceive gestures effectively in different contexts. The minimum total score is 12 points, the maximum total score is 60 points.	From enrollment to 4 weeks after the end of iTBS-treatment

Collaborators and Investigators

• Sponsor: Hannover Medical School
• Investigators: Principal Investigator: Rasmus Schülke, MD (Dr. med.), Hannover Medical School

Study record dates

Study Major Dates

• Study Start (Actual): April 8, 2025
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: December 14, 2024
• First Submitted That Met QC Criteria: December 14, 2024
• First Posted (Actual): December 18, 2024

Study Record Updates

• Last Update Posted (Actual): July 20, 2025
• Last Update Submitted That Met QC Criteria: July 16, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: cognition; schizophrenia; negative symptoms; iTBS; intermittent theta-burst stimulation
• Additional Relevant MeSH Terms: Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Schizophrenia
• Other Study ID Numbers: 11473_BO_S_2024

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Whether IPD may be shared has not yet been decided. IPD might not be shared due to data protection laws.

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