Personalized Non-invasive Neuromodulation by rTMS for Chronic and Treatment Resistant Catatonia (RETONIC)

Personalized Non-invasive Neuromodulation by rTMS for Chronic and Treatment Resistant Catatonia - A Proof of Concept Study

Investigators hypothesize that personalizing rTMS targets using functional MRI will allow to improve symptoms of patients suffering from chronic catatonia.

Study Overview

• Status: Active, not recruiting
• Conditions: Schizophreniform Catatonia; Treatment Resistant
• Intervention / Treatment: Device: Individualized rTMS on VERUM 1's region or network; Procedure: Individualized rTMS on VERUM 1's region or network; Device: Individualized rTMS on VERUM 2's region or network; Procedure: Individualized rTMS on VERUM 2's region or network; Device: Individualized rTMS on PLACEBO region; Procedure: Individualized rTMS on PLACEBO region

Detailed Description

Two dysfunctional networks or regions will be chosen (verum 1 and 2) based on their abnormal rCBF. In line with the symptoms, dorso-lateral prefrontal and premotor regions are expected to be chiefly concerned. A normal region regarding its rCBF will be used as placebo. Targets will be stimulated using intermittent or continuous theta-burst according to the rCBF anomaly as an attempt to "normalize" their activity. The coil will be positioned using a robotic device under the control of a neuronavigation system in order to deliver a homogeneous stimulation. Using a balanced blinded randomized cross-over design, patients will be stimulated on 5 consecutive days (4 sessions per day) and evaluated pre-, post-stimulation and 1 month after. In this pilot study the primary outcome measures will be the clinical global impression scale whereas MRI will insure that stimulations achieved the correction of the rCBF anomalies. Secondary outcome measures will include personalized target symptom scales, and scales for catatonic, apathic and obsessive-compulsive symptoms.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Not Applicable

Contacts and Locations

Study Locations

• France
  • Strasbourg, France, 67091
    • CEMNIS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 66 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• Aged from 18 to 70 Y
• Affiliated to the health insurance
• Having signed an informed consent
• Suffering from catatonia according to the DSM5, unremitted since > 2Y
• Unresponsive or incomplete remission after at least one trial of benzodiazepine and/or Electroconvulsivotherapy
• Treatment stable for > 6 weeks

Exclusion criteria:

• Contraindication for MRI, rTMS or tDCS: non-removable ferromagnetic body, prosthesis, pacemaker, medication delivered by an implanted pump clip or vascular stent, heart valve or ventricular shunt, seizure disorders, skin pathology in the region of tDCS electrode placement.
• Pregnancy
• Severe and non-stabilized somatic pathology
• Patients deprived of liberty or hospitalized without their consent
• Patients unable to give informed consent.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Verum 1 - Premotor; The target region will be defined by comparing the rCBF scan of the patient to a control population (n = 38). rCBF will be measured using the QUIPS2 arterial spin labeling sequence on a Siemens 3T Verio. The network including the premotor region will be targeted. The therapeutic protocol will be design to correct the rCBF anomaly.	Device: Individualized rTMS on VERUM 1's region or network; To increase cortical rCBF, iTB (intermittent theta burst) will be used: triplet at 50 Hz repeated at 5 Hz in trains of 2 sec with an inter-train interval of 8 sec. To decrease cortical rCBF, cTB (continuous theta burst) will be used: triplet at 50 Hz repeated at 5 Hz in trains of 40 sec. Intensity 120% of passive threshold (or 150% of active threshold). Stimulation protocol will be used up to 5 times per session to allow a reasonable regional or network coverage. Patients will have 4 sessions per day on 5 successive days per arm.; Other Names: Putative premotor region or network; Procedure: Individualized rTMS on VERUM 1's region or network; To increase cortical rCBF, iTB (intermittent theta burst) will be used: triplet at 50 Hz repeated at 5 Hz in trains of 2 sec with an inter-train interval of 8 sec. To decrease cortical rCBF, cTB (continuous theta burst) will be used: triplet at 50 Hz repeated at 5 Hz in trains of 40 sec. Intensity 120% of passive threshold (or 150% of active threshold). Stimulation protocol will be used up to 5 times per session to allow a reasonable regional or network coverage. Patients will have 4 sessions per day on 5 successive days per arm.; Other Names: Putative premotor region or network
Experimental: Verum 2 - Prefrontal; The target region will be defined by comparing the rCBF scan of the patient to a control population (n = 38). rCBF will be measured using the QUIPS2 arterial spin labeling sequence on a Siemens 3T Verio. The network including the prefrontal region will be targeted. The therapeutic protocol will be design to correct the rCBF anomaly.	Device: Individualized rTMS on VERUM 2's region or network; To increase cortical rCBF, iTB (intermittent theta burst) will be used: triplet at 50 Hz repeated at 5 Hz in trains of 2 sec with an inter-train interval of 8 sec. To decrease cortical rCBF, cTB (continuous theta burst) will be used: triplet at 50 Hz repeated at 5 Hz in trains of 40 sec. Intensity 120% of passive threshold (or 150% of active threshold). Stimulation protocol will be used up to 5 times per session to allow a reasonable regional or network coverage. Patients will have 4 sessions per day on 5 successive days per arm.; Other Names: Putative prefrontal region or network; Procedure: Individualized rTMS on VERUM 2's region or network; To increase cortical rCBF, iTB (intermittent theta burst) will be used: triplet at 50 Hz repeated at 5 Hz in trains of 2 sec with an inter-train interval of 8 sec. To decrease cortical rCBF, cTB (continuous theta burst) will be used: triplet at 50 Hz repeated at 5 Hz in trains of 40 sec. Intensity 120% of passive threshold (or 150% of active threshold). Stimulation protocol will be used up to 5 times per session to allow a reasonable regional or network coverage. Patients will have 4 sessions per day on 5 successive days per arm.; Other Names: Putative prefrontal region or network
Active Comparator: Placebo; Stimulation of a region with normal rCBF and putatively unrelated to catatonic symptoms (parietal cortex).	Device: Individualized rTMS on PLACEBO region; Region will be modulated up or down according to the stimulation protocol used in VERUM 1 and 2 conditions. Stimulation will be replicated up to 5 times per session. Patients will have 4 sessions per day on 5 successive days per arm.; Other Names: (One per line); Procedure: Individualized rTMS on PLACEBO region; Region will be modulated up or down according to the stimulation protocol used in VERUM 1 and 2 conditions. Stimulation will be replicated up to 5 times per session. Patients will have 4 sessions per day on 5 successive days per arm.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical global impression (change in severity and improvement)	Clinical Global Impression - Severity scale (CGI-S) is a 7-point scale that requires the clinician to rate the severity of the patient's illness at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis. Clinical Global Impression - Improvement scale (CGI-I) is a 7 point scale that requires the clinician to assess how much the patient's illness has improved or worsened relative to a baseline state at the beginning of the intervention	In term of percentage reduction in symptoms, difference between before (assessed on D1) and after (assessed on D5 to 7) and at 1 month after each therapeutic protocol (D = day of the beginning of the protocol)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in personalized daily visual analogical scales assessing the core symptoms.	This scale has been validated	Points results will be averaged over the 4 days before and after each therapeutic arm.
Change in Bush and Francis Catatonia Rating Scale.	This scale has been validated.	Points involvement in scale between before (assessed on D1) and after (assessed on D5 to 7) and at 1 month after each therapeutic protocol (D = day of the beginning of the protocol)
Change in psychosis: PANSS.	This scale has been validated.	Points involvement in scale between before (assessed on D1) and after (assessed on D5 to 7) and at 1 month after each therapeutic protocol (D = day of the beginning of the protocol)
Change in depression: Calgary Depression Scale.	This scale has been validated.	Points involvement in scale between before (assessed on D1) and after (assessed on D5 to 7) and at 1 month after each therapeutic protocol (D = day of the beginning of the protocol)
Change in apathy: actimetry, apathy inventory and apathy evaluation scale.	This scale has been validated.	Points involvement in scale between before (assessed on D1) and after (assessed on D5 to 7) and at 1 month after each therapeutic protocol (D = day of the beginning of the protocol)
Change in obsessive compulsive symptoms: Brief Obsessive Compulsive Scale	This scale has been validated.	Points involvement in scale between before (assessed on D1) and after (assessed on D5 to 7) and at 1 month after each therapeutic protocol (D = day of the beginning of the protocol)
Change in obsessive compulsive symptoms: Cambridge-Exeter Repetitive Thought Scale.	This scale has been validated.	Points involvement in scale between before (assessed on D1) and after (assessed on D5 to 7) and at 1 month after each therapeutic protocol (D = day of the beginning of the protocol)
Change in quality of life for the patient (SF36)	All these scales have been validated.	Points involvement in scale between before (assessed on D1) and after (assessed on D5 to 7) and at 1 month after each therapeutic protocol (D = day of the beginning of the protocol)
Change in the helping person ("Zarit scale")	This scale has been validated.	Points involvement in scale between before (assessed on D1) and after (assessed on D5 to 7) and at 1 month after each therapeutic protocol (D = day of the beginning of the protocol)
Change in functioning: Global Assessment of Functioning (GAF scale)	This scale has been validated.	Points involvement in scale between before (assessed on D1) and after (assessed on D5 to 7) and at 1 month after each therapeutic protocol (D = day of the beginning of the protocol)
Change in functioning: WHODAS 2.0.	This scale has been validated.	Points involvement in scale between before (assessed on D1) and after (assessed on D5 to 7) and at 1 month after each therapeutic protocol (D = day of the beginning of the protocol)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change of rCBF anomalies	The target region will be defined by comparing the rCBF scan of the patient to a control population (n = 38). rCBF will be measured using the average of 2 ∙ 3 (=6) measures of rCBF using QUIPS2 arterial spin labeling sequence on a Siemens 3T Verio. We will compare the rCBF change of the target region before and after the therapeutic protocol between the different procedures (ANOVA).	Points involvement in scale between before (assessed once between D-7 to -1) and after (assessed once between D+15 to +21) each therapeutic protocol (D = day of the beginning of the protocol).

Collaborators and Investigators

• Sponsor: University Hospital, Strasbourg, France
• Investigators: Principal Investigator: Jack FOUCHER, MD, Hôpitaux Universitaires de Strasbourg

Study record dates

Study Major Dates

• Study Start (Actual): April 24, 2017
• Primary Completion (Anticipated): June 1, 2022
• Study Completion (Anticipated): June 1, 2022

Study Registration Dates

• First Submitted: March 22, 2017
• First Submitted That Met QC Criteria: April 11, 2017
• First Posted (Actual): April 17, 2017

Study Record Updates

• Last Update Posted (Actual): April 20, 2022
• Last Update Submitted That Met QC Criteria: April 19, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Transcranial Direct Current Stimulation; Functional Neuroimaging; Precision Medicine; Transcranial Magnetic Stimulation, Repetitive; Monocentric; Comparative balanced, randomized; double-blind cross-over 3 Arms Study
• Additional Relevant MeSH Terms: Behavioral Symptoms; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Catatonia; Physiological Effects of Drugs; Micronutrients; Vitamins; Vitamin B Complex; Pantothenic Acid
• Other Study ID Numbers: 6441

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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