rTMS Add on Value for Amelioration of Negative Symptoms of Schizophrenia

Study Overview
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Brief Summary
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Treatment of depression with repetitive transcranial magnetic stimulation (rTMS) has shown high evidence using high-frequency left dorsolateral prefrontal cortex (DLPFC) stimulation. The treatment of negative symptoms with the same protocol in schizophrenia is considered as possible effective. Theta burst stimulation is a new protocol which is characterized by shorter sessions showing first evidence that it's efficacy is comparable to the high-frequency rTMS. In this randomized placebo-controlled study the efficacy of high-frequency rTMS and TBS are evaluated.

Detailed Description
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In this randomized placebo-controlled study the efficacy of high-frequency rTMS and TBS are evaluated. The active study arms are high-frequency rTMS and iTBS of the left dorsolateral prefrontal cortex to treat negative symptoms in schizophrenia. The control arm will include the same number of patients as each active arm and includes both sham rTMS and sham iTBS in the same proportion as the active treatments. Standards of the trial will be harmonized across four clinical centers with the aim to pool data for analysis. Each center is responsible for ethical approval and adherence to good clinical practice by itself (Sponsor). Interim analysis: Several meta-analyses of the effect of rTMS/iTBS on negative symptoms in schizophrenia showing heterogeneous effect sizes have been published since begin of the trial. Thefore, we added an interim analysis after inclusion of at least 15 patients in each arm to the protocol. In case of null findings and low effect sizes (no differences of either rTMS or TBS vs. sham in the primary outcome), we would terminate the trial.

Official Title
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rTMS Add on Value for Amelioration of Negative Symptoms of Schizophrenia

Conditions
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Negative Symptoms With Primary Psychotic Disorder, Schizophrenia

Intervention / Treatment
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* Device: high-frequency rTMS
* Device: TBS
* Device: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ICD-10: schizophrenia with primarily negative symptoms Age: 18-75 years at least 35 Points at the composite score of the SANS stabe medication during the last 2 weeks (at the investigator's discretion) written informed consent (by the patient or guardian) Exclusion Criteria: clinically relevant unstable concomitant somatic diseases previous treatment by rTMS conditions in which TMS may not be applicated, as e.g., cardiac pacemakers or ferromagnetic implants history of epileptic seizures current substance or alcohol abuse, or clinically relevant comorbidity (according to M.I.N.I. interview) unacceptable concomitant medication (benzodiazepines in higher doses, e.g., Lorazepam > 2 mg/d, Diazepam > 10 mg/d) insufficient knowledge of the language of the country of the treatment site pregnancy and nursing period current statutory hospitalisation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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
Interventional Model Description: randomized controlled trial with two active and one placebo arm
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: high-frequency repetitive transcranial magnetic stimulation<br>repetitive transcranial magnetic stimulation over left dorsolateral prefrontal cortex using 3000 pulses applied with 10Hz and 120% resting motor threshold | Device: high-frequency rTMS<br>* repetitive transcranial magnetic stimulation<br>|
| Experimental: theta burst stimulation<br>intermittent theta burst stimulation over left dorsolateral prefrontal cortex using 600 pulses applied in trains of 10 triplets/bursts (50Hz) with 8s intertrain-interval and 120% resting motor threshold | Device: TBS<br>* theta burst stimulation<br>|
| Placebo Comparator: sham rTMS<br>half of the patients with high-frequency repetitive transcranial magnetic stimulation and half of the patients with theta burst Stimulation with angled coil (45 degree) or sham coil | Device: placebo<br>* placebo transcranial magnetic stimulation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Scale for the Assessement of Negative Symptoms (SANS) | negative symptoms in schizophrenia with 25 items and a range 0-125 with higher score representing more symptoms | 4 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Scale for the Assessement of Negative Symptoms (SANS) | negative symptoms in schizophrenia with 25 items and a range 0-125 with higher score representing more symptoms | 2 weeks, 4 weeks, 12 weeks | 
| Positive and Negative syndrome scale (PANSS) | positive and negative symptoms in schizophrenia with 30 items and a range 30-210 with higher scores representing more symptoms (total score, score for positive, negative symptoms and for general psychopathology) | 2 weeks, 4 weeks, 12 weeks | 
| Calgary Depression Scale for Schizophrenia (CDSS) | Calgary Depression Scale for Schizophrenia | 2 weeks, 4 weeks, 12 weeks | 
| Clinical global impression (CGI) | measure of overall symptom severity and treatment response on a scale 1-7 with higher scores presenting more symptoms | 2 weeks, 4 weeks, 12 weeks | 
| Major Depression Inventory (MDI) | measurment of depressivity: 10 items with a range 0-50 and higher values indicating higher scores | 2 weeks, 4 weeks, 12 weeks | 
| Hamilton depression rating scale (HDRS) | measurment of depressivity: 21 items with a range 0-65 and higher values indicating higher scores | 2 weeks, 4 weeks, 12 weeks | 
| Memory span test (digit span) | test for short-term and working memory | 4 weeks, 12 weeks | 
| test of attention (d2) | test of attention for measurement of concentration | 4 weeks, 12 weeks | 
| Resting state electroencephalogram (EEG) | measurement of resting state electrophysiologic activity as indicated by frequency analysis and rTMS-evoked activity | 4 weeks | 
| magnetic resonance imaging (MRI) | structural, anatomical, diffusion weighted magnetic resonance imaging | 4 weeks | 
| cigarettes | number of smoked cigarettes per week | 4 weeks, 12 weeks |