Efficacy of Maintenance Repetitive Transcranial Magnetic Stimulation (rTMS) in Auditory Verbal Hallucinations

Study Overview
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Brief Summary
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Repetitive transcranial magnetic stimulation (rTMS) can alleviate persistent auditory verbal hallucinations (AVH) in schizophrenic patients, but the classical procedure with low-frequency stimulation for several weeks upon the left temporoparietal junction have shown modest therapeutic effects, and there is currently no robust predictive factor to the response of the treatment. In a previous multicentric, randomized, and double-blind controlled study, it has been demonstrated that a high-frequency rTMS over an anatomical target can rapidly affect AVHs. Moreover, an intensification of the classical procedure delivering 20-Hz rTMS over a 2-day period was used in addition to a personalized anatomical stimulation target and neuronavigation guidance. Besides the significant efficacy of the procedure, the efficacy was maximal at two weeks after the end of the treatment. In this project, the hypothesis is that the two-day cure could benefit from maintenance rTMS sessions every week for one month and then every two weeks for 3 months to provide an optimal strategy for a long-lasting AVH reduction. This has for now never been tested. Predictive factors to the response of the treatment are also investigated.

Detailed Description
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To investigate the clinical efficacy of a 4-month maintenance procedure of rTMS in AVH reduction, a multicenter, controlled, double-blind study enrolling 120 patients randomly assigned in two groups is proposed. The active group will receive active rTMS with a two-day intense procedure (consisting in 4 20-Hz rTMS sessions within two days) and a maintenance phase with a two- rTMS session every week for one month and then every two weeks the next 3 months (i.e. 24 rTMS sessions). The individual target will be personalized and guided by neuronavigation. The placebo group will benefit from the exact same procedure but with sham rTMS instead of active rTMS. Patients will be carried out during 5 months and what distinguishes responders from non-responders will be studied. Among other variables, BDNF serum levels as a reflect of the individual neural plasticity and the measurement of the scalp-to-cortex distance to the target as a reflect of the cerebral morphological interindividual variations will be investigated.

Official Title
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Efficacy of Maintenance Repetitive Transcranial Magnetic Stimulation (rTMS) Treatment in Reducing Auditory Verbal Hallucinations (AVH) With High Frequency and Neuronavigation Guidance: A Double-blind, Randomized and Multicentric Study

Conditions
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Schizophrenia; Psychosis

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female; Age ≥ 18 years ≤ 65 years Diagnosis of schizophrenia or schizoaffective disorders according to DSM 5.0 criteria Patients treated with at least one antipsychotic medication Presence of auditory verbal hallucinations despite the optimization of the antipsychotic dosage for at least 6 weeks. This will be operationalized by a minimum AHRS score > 10 Stable medication dosage for at least 6 weeks before the rTMS treatment Patient who understands the French language The agreement of the curatorship or tutorship in the case of a protected adult Willing to comply with scheduled visits, as outlined in the protocol Covered by, or having the right to Social Security or European cover Informed and written consent Exclusion Criteria: Women who are pregnant Patients with contraindications for rTMS (history of epilepsy, neurologic stimulator, pacemaker, cardiac defibrillator, cardiac prosthesis, vascular prosthesis, intracranial clips or clamps, cerebrospinal fluid derivation, metallic splinters in the eyes) Patients included or planning to be included in another medical research protocol Patients unable to complete the protocol follow-up Any brain pathological abnormality known or diagnosed by the cerebral MRI Contre-indication for cerebral MRI (metallic fix tooth prosthesis, neurologic stimulator, pacemaker, cardiac defibrillator, cardiac prosthesis, vascular prosthesis, intracranial clips or clamps, cerebrospinal fluid derivation, metallic splinters in the eyes, severe claustrophobia)

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Sham Comparator: sham rTMS<br>The sham treatment, following the group assignment, will be maintained during the two successive phases of the evaluated protocol. One initial sham rTMS phase will consist of four sham stimulation sessions (20 Hz sham) within two consecutive days. One sham rTMS maintenance phase will consist of two sham stimulation sessions on one day every week for one month and then every two weeks for three months. Clinical data will be assessed by an investigator blind to group assignment until the end of the study. Patients will also be blind to stimulation. A questionnaire will assess the investigator physician and patient beliefs about what group the patient was involved in (placebo group or active group) at the end of the treatment initial phase and at the end of the treatment maintenance phase | Device: Sham Repetitive Transcranial Magnetic Stimulation (rTMS)<br>* a 4-month maintenance procedure of sham rTMS<br>|
| Experimental: active rTMS<br>The active treatment, following the group assignment, will be maintained during the two successive phases of the evaluated protocol. One initial active rTMS phase will consist of four stimulation sessions (20 Hz) within two consecutive days. One active rTMS maintenance phase will consist of two active stimulation sessions on one day every week for one month and then every two weeks for three months. | Device: Repetitive Transcranial Magnetic Stimulation (rTMS) Treatment<br>* a 4-month maintenance procedure of active rTMS<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the number of times a patient is assessed as a responder | the number of times a patient is assessed as a responder in the active versus the sham group during their follow-up between baseline (D1) and at the end of the maintenance treatment (M5), i.e. the month after the last maintenance session. | between baseline and month 5 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Transcranial Magnetic Stimulation, Auditory verbal Hallucination, Neuronavigation