Reduction of Auditory-Verbal Hallucinations in Schizophrenia Through Cortical Neuromodulation (HALLUSTIM)

Reduction of Auditory-Verbal Hallucinations in Schizophrenia Through Cortical Neuromodulation: Towards a Closed-loop System

Approximately 1% of the general population will be affected by schizophrenia over the course of their lives, with life expectancy being reduced by 20 years on average and quality of life being severely diminished in affected individuals. One third of patients suffering from schizophrenia will evolve towards a resistant form of the disease, amongst which many will suffer from auditory-verbal hallucinations (AVH) that current therapeutic approaches struggle to alleviate. Previous work from our team has demonstrated the possibility of robustly inferring the periods of occurrence of AVH from fMRI data, paving the way for the development of a closed-loop neuromodulation system comprised of an electrode array positioned in Broca's area, which would detect AVH in real time, and effector electrodes which would stimulate the temporo-parietal cortex to interrupt them. The aim of this project is to assess the feasibility of this system. To do so, we will first test the ability of transcranial magnetic stimulation of the "continuous theta burst" (cTBS) type, applied at the time of AVH onset, to reduce their duration and intensity, and assess whether this is associated with therapeutic response to the current gold standard rTMS protocol for AVH reduction through neuroplasticity induction. Demonstrating the feasibility of acute suppression of AVH by cortical neurostimulation is an essential element in the feasibility of a closed-loop reactive neuromodulation system.

The research project comprises two phases:

-Phase 1: randomized controlled clinical trial (1 weekly session per patient over 12 weeks: 6 active stimulation sessions and 6 sham sessions) evaluating the phasic effects of rTMS on AVHs as they appear during the sessions.

Phase 2: open-label study offering patients a routine rTMS protocol which has demonstrated its effects on AVH (10 TMS sessions over one workweek - twice daily with 1-hour intervals, MULTIMODHAL study, NCT01373866).

Study Overview

• Status: Not yet recruiting
• Conditions: Treatment Resistant Schizophrenia
• Intervention / Treatment: Device: Active Transcranial Magnetic Stimulation (TMS); Device: Sham Transcranial Magnetic Stimulation (TMS)

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Philippe Domenech, MD, PhD; Phone Number: +(33) (0)1 49 81 22 01; Email: philippe.domenech@ghu-paris.fr
• Study Contact Backup: Name: Fabien Vinckier, MD, PhD; Phone Number: +(33) (0) 1 45 65 84 52; Email: f.vinckier@ghu-paris.fr

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Age > 18 years old
• Schizophrenic Disorder (Diagnostic and statistical manual of mental disorders, DSM-5-TR, American Psychiatric Association, 2013)
• AVHs that have resisted to at least two properly conducted antipsychotic therapies at an effective dose for at least 8 weeks (criteria of Kinon et al., 1993)
• Frequent AVHs (at least 10 times per hour) (Fovet et al., 2022)
• Unmodified antipsychotic dosage for 30 days prior to inclusion in the protocol
• AVH are the main residual symptom of schizophrenia.
• Consent to participate in the study

Exclusion Criteria:

• Pregnancy (based on date of last menstrual period with possibility of urine test if in doubt)
• Anticonvulsant therapy
• Neurological disorder (e.g., multiple sclerosis, epilepsy)
• Current addictive behavior (except tobacco and cannabis, widely used in this clinical population; Fovet et al., 2022)
• Contraindication to MRI (i.e., presence of ferromagnetic material or implanted neurostimulation devices due to the risk of displacement or dysfunction such as cochlear implants, cardiac pacemakers, metal splinters in the body following an accident, permanent makeup applied less than 6 months ago, neurosurgical clips, deep brain or vagus nerve stimulation devices, baclofen pumps) (Lefaucheur et al., 2011)
• Morphological criteria: weight > 130 Kg, abdominal circumference conditioned by the opening of the magnet, shoulder width
• Lack of coverage by the social security system
• Current participation in another interventional research protocol or being in the exclusion period of a previous research protocol
• Refusal to be informed of an brain anomaly detected in the MRI
• Person under guardianship or curatorship
• Behavioral disorders or delusions likely to prevent the MRI or rTMS from being performed under good conditions (left to the discretion of the investigator at baseline).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active TMS sessions; For a given patient, the 6 sessions (out of 12) in which the TMS is active.	Device: Active Transcranial Magnetic Stimulation (TMS); Active rTMS (continuous theta burst, cTBS) applied to the temporo-parietal junction (TPJ) at the onset of the Auditory Verbal Hallucinations (AVH).; Other Names: Active TMS
Sham Comparator: Sham TMS sessions; For a given patient, the 6 sessions (out of 12) in which the TMS is a sham.	Device: Sham Transcranial Magnetic Stimulation (TMS); Sham rTMS (continuous theta burst, cTBS) applied to the temporo-parietal junction (TPJ) during the onset of the Auditory Verbal Hallucinations (AVH). An electrical stimulator is synchronised with the magnetic stimulation to recreate the tactile sensation and the coils emits the same noise during sham stimulation as in the active configuration, making it impossible to distinguish between active and placebo magnetic stimulation.; Other Names: Sham TMS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of auditory-verbal hallucinations	The primary endpoint is the reduction in the duration of AVH (in seconds) during active phasic stimulation sessions compared to sham sessions. Participants will press a button when an AVH occurs (starting the intervention) and press another when the AVH disappears. This allows for the recording of the duration of the AVHs.	During the intervention of Phase 1 (for each active or sham TMS session)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical scales scores	An evaluation of the following clinical measures will take place : AHRS, CGI, Visual analog scale for AVH intensity and frequency, GAF and PANSS.	At baseline (before Phase 1), before the intervention of Phase 2 (Day 0, two weeks after the end of Phase 1), after the intervention of Phase 2 (Day 15, Month 1, Month 3, Month 6, Month 12)
Measure of the duration and/or intensity of HAV (in seconds) during active phasic stimulation sessions compared to sham sessions (phase 1) among TMS responders and non-responders in phase 2	Reduction in duration and/or intensity of HAV (in seconds) during active phasic stimulation sessions compared to sham sessions (phase 1) among TMS responders and non-responders in phase 2 (response: decrease in pre/post AHRS score >25%).	Through study completion, an average of 2 years
Intensity of auditory-verbal hallucinations	Phase 1 At the end of each active or sham cTBS train, the computer screen will display an 5-point Likert Scale, through which the patient will have to report AVH-intensity before the session can continue.	During the intervention of Phase 1 (for each active or sham TMS session)

Collaborators and Investigators

• Sponsor: Centre Hospitalier St Anne
• Investigators: Principal Investigator: Philippe Domenech, MD, PhD, GHU Paris Psychiatrie & Neurosciences

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2024
• Primary Completion (Estimated): April 1, 2026
• Study Completion (Estimated): April 1, 2026

Study Registration Dates

• First Submitted: March 29, 2024
• First Submitted That Met QC Criteria: April 8, 2024
• First Posted (Actual): April 11, 2024

Study Record Updates

• Last Update Posted (Actual): April 11, 2024
• Last Update Submitted That Met QC Criteria: April 8, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Transcranial Magnetic Stimulation (TMS); Treatment Resistant Schizophrenia
• Additional Relevant MeSH Terms: Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Schizophrenia Spectrum and Other Psychotic Disorders; Perceptual Disorders; Schizophrenia; Hallucinations; Schizophrenia, Treatment-Resistant
• Other Study ID Numbers: D23-P037

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No