Theta-burst rTMS in Schizophrenia to Ameliorate Negative and Cognitive Symptoms

Study Overview
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Brief Summary
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The major target of the study is to confirm the safety and efficacy of our augmented protocol of theta-burst TMS in schizophrenia. Our aim is to confirm the beneficial effects of rTMS treatment on multiple aspects of the disorder such as (1) clinical aspect in terms of PANSS, (2) cognitive aspect such as emotion recognition (ER) and working memory (WM) / distractor filtering (DF) performance, and (3) neurobiology in terms of electrophysiology correlates of ER, WM and DF such as event related theta synchronization, resting state theta power, and network connectivity. Response prediction to (theta-burst) TB-rTMS will be the exploratory part of the study.

Official Title
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Theta-burst rTMS in Schizophrenia to Ameliorate Negative and Cognitive Symptoms: a Double-blind, Randomized Clinical Trial

Conditions
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Transcranial Magnetic Stimulation Repetitive, Schizophrenia

Intervention / Treatment
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* Device: repetitive Transcranial Magnetic Stimulation (rTMS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: diagnosis of schizophrenia or schizoaffective disorder; clinically stabilized on antipsychotic: a stable dose of antipsychotic medication for >4 weeks; age 18-55 years, and presence of negative symptoms (based on PANSS): a negative subscore ≥16 points and [one of items N1-N7 scoring ≥4 or two items N1-N7 scoring ≥3] Exclusion Criteria: any significant neurological illness; mental retardation history of head injury with loss of consciousness for more than 1 hour history of epileptic seizures or epileptic activity on the baseline EEG (evaluated by an expert in clinical EEG and epilepsy), alcohol or drug abuse within the past 3 months, and depressive episode or antidepressant treatment in the past 4 weeks. Severe positive symptoms inferfere with cognitive tests ECT in the medical history Implanted pacemaker, implanted drug pump, cochlear implant, implanted defibrillator, implanted neurostimulator or any other TMS incompatible implanted metal device Skin surface is severly injured in the stimulated region of the skull Sclerosis multiplex Pregnancy Severe sleep deprivation Severe heart failure Increased intracranial pressure Untreated migrain

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Theta-burst rTMS<br>Theta-burst repetitive transcranial magnetic stimulation | Device: repetitive Transcranial Magnetic Stimulation (rTMS)<br>* Theta-burst stimulation<br>|
| Sham Comparator: Sham stimulation<br>Sham stimulation of the same location | Device: repetitive Transcranial Magnetic Stimulation (rTMS)<br>* Theta-burst stimulation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Positive and Negative Syndrome Scale, Negative subscore | The Positive and Negative Syndrome Scale (PANSS) is a medical scale used for measuring symptom severity of patients with schizophrenia. It is the gold standard in the treatment monitoring of schizophrenia.The scale has three subscales : positive, negatve and general symptom score. We use the negative subscore as primary outcome. Its minimum and maximum scores are 7 and 49 respectively. Higher values indicate worse outcome. | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cognitive functioning/Short-Term Memory - The Digit Span Forward and Backward tests | They will be used to assess working memory. Digits Recalled is the primary outcome measure ranging between 2 and 10. Lower values indicate worse outcome. | 4 weeks | 
| Cognitive functioning/Executive functioning - Wisconsin Card Sorting test | The test will be used to measure cognitive flexibility/Executive functioning. Number of persevarative errors is the major outcome variable of the test, its minimum is 0, while it has no theroretical maximum value. Higher values indicate worse outcome. Punishment sensitivity (P) from the reinforcement learning model of WCST will also be used as outcome variable. Its minimum value is 0 and it has no theoretical maximum value. Lower values indicate worse outcome. | 4 weeks | 
| Social cognition 1 - The Baron-Cohen 'Reading the Mind in the Eyes Test ' | The total score is the primary outcome, which ranges between 0 and 37 points. Lower values indicate worse outcome. | 4 weeks | 
| Social cognition 2 - The 'Faux Pas' test. | Measures Theory of Mind (ToM), and the primary outcome measure is the total score, which ranges between 0 and 1. Lower values indicate worse outcome. | 4 weeks | 
| Facial Emotion Recogniton - Karolinska Directed Emotional Face set | Facial expression recognition task. Subject have to identify emotional expressions from photographs of 8 male and 8 female subjects. The pictures are chosen from Karolinska Directed Emotional Face set. There are 3 photographs from each faces (happy, neutral, and sad). Hit rate is the primary outcome measure, which ranges from 0% to 100%, and lower values indicate worse outcome. | 4 weeks | 
| Safety in terms of adverse events | Safety in terms of the number of serious adverse events (SAE). A Serious Adverse Event is any untoward medical occurrence that: Results in death Is life-threatening or Requires in-patient confinement or prolongation of existing confinement or Results in persistent or significant disability/incapacity or Is a congenital anomaly/birth defect. | 4 weeks |