Treatment of Auditory Hallucinations in Schizophrenia With Bilateral Theta Burst Stimulation

Study Overview
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Brief Summary
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This randomized, sham-controlled, double blind, multicentre clinical trial aims at providing evidence for the efficacy and safety of continuous theta burst stimulation (cTBS) in the treatment of auditory hallucinations in patients with schizophrenia. Overall, the study will include 137 patients. Because of the adaptive study design, an interim analysis was performed after half of the originally planned patients (43/86), according to which the sample size was increased by 51 patients). Each patient will receive a three weeks course of daily (5/week) treatment; 50% of the patients will be treated with cTBS (1200 impulses daily), the other half with a sham stimulation to the left and right temporoparietal cortex. Sham stimulation will be applied by an active sham-coil that allows for a double-blind treatment. Follow-up assessments 1, 3 and 6 months after treatment will investigate the stability of treatment effects.

Detailed Description
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Auditory verbal hallucinations (AH), a cardinal feature of schizophrenia, are often severely distressing and increase the risk for violence and suicide. Although antipsychotic medication mostly exerts rapid beneficial effects on this symptom particularly in first-episode patients who continue on taking their medication (Sommer et al. 2012), in up to 25%-30% of all patients, such hallucinations persist (Shergill et al. 1998). The often progressive course of the disease and insufficient treatment adherence due to unwanted side effects significantly limit the treatment response. In turn, this lack of treatment efficacy also contributes to low treatment adherence which is generally associated with an unfavorable course of schizophrenia and increased relapse and readmission rate. New and effective treatments are therefore essential to reduce the massive individual burden and psychosocial costs associated with schizophrenia. Nevertheless, in the last decades, the hopes for new pharmacological treatment options have been disappointed and the pharmaceutical industry has apparently withdrawn from the development of new compounds for this disorder. Accordingly, the development of non-pharmacological approaches based on an increasing body of patho-physiological knowledge is even more needed to pave new ways for the treatment of this frequently detrimental symptom of schizophrenia. The main objective of the present study is to provide high-level evidence for efficacy and safety of continuous theta burst stimulation (cTBS) in the treatment of auditory hallucination (AH) by this first full-size multicenter (3 centers) controlled clinical trial. This is a double blind (actually triple blind, i.e. patient, clinical investigator, and person who will administer cTBS), randomized, sham-controlled clinical trial to test the efficacy and safety of bilateral (successively applied) daily cTBS to the temporoparietal cortex on the severity of AH. The study will be conducted in a two-armed parallel design in which 50 % of the patients will be treated with the verum stimulation and the other half of patients will receive the placebo / sham stimulation. The cTBS protocol follows the method by Huang et al. (2005) and our pilot study (Plewnia et al. 2014a) to achieve a lasting reduction of cortical excitability. Accordingly, each stimulation train (40 s) of cTBS consists of 600 stimuli applied in bursts of 3 pulses at 50 Hz given every 200 ms (5 Hz). Stimulation intensity is standardized at 80% of the resting motor threshold (RMT) and applied successively to each hemisphere. For the first session, the order of right and left hemisphere will be determined by randomization and will alternate in each following session to preclude order effects.The RMT will be determined using EMG recordings from the left and right abductor pollicis brevis and defined as the minimal stimulation intensity needed to elicit at least 10 out of 20 motor-evoked-potentials of ≥ 50µV. RMT will be determined once, i.e. before the beginning of treatment period. The cTBS or sham treatment will be targeted both temporoparietal cortices halfway between T3/P3 and T4/P4 (EEG 10/20 system). The treatment (active cTBS or sham cTBS) will be administered over a period of 3 consecutive weeks at each workday (Monday to Friday), resulting in a total of 15 treatment sessions. Ratings will be performed after the last treatment of each week by an independent rater. Follow-up visits are planned 1, 3 and 6 months after end of treatment phase to control for sustainability of cTBS treatment effects.

Official Title
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Treatment of Auditory Hallucinations in Schizophrenia With Bilateral Theta Burst Stimulation

Conditions
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Schizophrenia, Auditory Hallucinations

Intervention / Treatment
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* Device: MagPro Cool-B65A/P, Magventure
* Device: MagPro Cool-B65A/P, Magventure


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women, age 18-65 years Schizophrenia (DSM-5 295.90), schizophreniform disorder (DSM-5, 295.40), or schizoaffective disorder (DSM-5 295.70) Auditory hallucinations (AH) present at least once a week, for at least 3 months No sufficient effect of at least one adequate antipsychotic treatment Severity according to PANSS hallucination score (Item P3) of 3 or more Fluent German language Stable antipsychotic medication 2 weeks before and 3 weeks during the treatment Exclusion Criteria: Suicidality History/evidence of brain surgery Significant brain malformation or neoplasm Head injury Cerebral vascular events Neurodegenerative disorder Deep brain stimulation Intracranial metallic particles History of seizures Diagnose of substance dependence or abuse as primary clinical problem Severe somatic comorbidity Cardiac pacemakers Pregnancy

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: active cTBS<br>Determination of resting motor threshold (RMT); Coil position: temporoparietal cortices halfway between T3/P3 and T4/P4 (EEG 10/20 system); active cTBS (80% of RMT); | Device: MagPro Cool-B65A/P, Magventure<br>* combined active and sham coil<br>|
| Sham Comparator: Sham cTBS<br>Determination of resting motor threshold (RMT); Coil position: temporoparietal cortices halfway between T3/P3 and T4/P4 (EEG 10/20 system); sham cTBS; | Device: MagPro Cool-B65A/P, Magventure<br>* combined active and sham coil<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of Psychotic Symptom Rating Scales - Auditory Hallucinations subscale (PSYRATS-AH) | Group comparison (active vs. sham cTBS) regarding the change of the auditory hallucination subscale of the Psychotic Symptom Rating Scales (PSYRATS-AH) score from baseline to end of treatment period. | 3 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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auditory hallucinations, schizophrenia, cTBS, noninvasive brain stimulation