Repetitive Transcranial Magnetic Stimulation (rTMS) Self-Referential Processing (rTMS-SRP) (rTMS-SRP)

Effects of Precuneus Repetitive Transcranial Magnetic Stimulation (rTMS) on Self-Referential Processing and Default Mode Network Functional Connectivity in Early Phase Psychosis

This will be a single site pilot study. 16 subjects with early phase psychosis (EPP), defined as medical record documentation of the onset of clinically significant psychotic symptoms within the past ten years, will be randomized 1:1 to double-blind treatment with 5 sessions of rTMS or sham stimulation directed at the bilateral precuneus over the course of 1 week. Subjects will undergo functional magnetic resonance imaging (fMRI) procedures, behavioral and cognitive assessments, and self-referential memory paradigm (SRMP) at baseline and immediately following the final rTMS or sham session. Contact with subjects will be conducted at two weeks after the end of study intervention for adverse event assessments. In the event new adverse events felt to be related to the study intervention have occurred following the termination of study procedures, subjects will be brought in for further safety assessments.

Study Overview

• Status: Withdrawn
• Conditions: Schizophrenia; Schizo Affective Disorder
• Intervention / Treatment: Device: rTMS

Detailed Description

A number of studies have investigated the therapeutic potential of rTMS in schizophrenia, noting improvements in treatment refractory auditory hallucinations as well as negative symptoms and cognitive dysfunction. However, no previous studies have examined the effects of precuneus directed rTMS on SRP deficits in schizophrenia. It is also important to note that the vast majority of studies using rTMS in schizophrenia have examined chronic populations where confounds associated with prolonged duration of illness may be present. Early phase psychosis (EPP) is a desirable population to study because these patients tend to have fewer psychiatric and physical comorbidities and less antipsychotic drug exposure, all of which are factors that may confound investigations of new treatment interventions for this illness. In light of the significant unmet medical need associated with schizophrenia and the grave clinical effect of disrupted SRP in the illness, rTMS modulating precuneus, and potentially DMN circuitry, represents an unexplored and potentially novel potential treatment option.

This study proposes to examine the application of rTMS targeting the precuneus for the treatment of disrupted SRP in EPP. This is an important population for study because if effective, rTMS may represent a preventative treatment for the development of poor outcomes and functioning associated with SRP deficits in in schizophrenia. This study will also seek to refine the understanding of the brain circuitry that mediates the potential pro-SRP effects of rTMS through the use of fMRI at baseline and following the course of rTMS administration.

• Study Type: Interventional
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Prevention and Recovery Center for Early Psychosis
    • Indianapolis, Indiana, United States, 46202
      • IU Center for Neuroimaging

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Between 18 and 45 years of age
2. Within 10 years of illness onset as defined by entry into treatment for psychotic symptoms
3. Able to give informed consent
4. Willing and able to adhere to the study schedule
5. Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (SCID-5) diagnosis of schizophrenia or schizoaffective disorder

6. Clinical stability as defined by:

   • Clinical Global Impression scale - Severity (CGI-S) score of less than or equal to 4 (moderately ill) at baseline AND
   • No exacerbation of their illness within 4 weeks prior to randomization, leading to an intensification of psychiatric care in the opinion of the investigator. Examples of intensification of care include, but are not limited to: inpatient hospitalization, day/partial hospitalization, outpatient crisis management, or psychiatric treatment in an emergency room AND
   • Antipsychotic treatment stability for at least 4 weeks prior to randomization (no change in antipsychotic dosing or addition of any new antipsychotic medication).

Exclusion Criteria:

1. Lifetime history of a seizure, excluding febrile seizures and those induced by substance withdrawal
2. First degree relative (that is, biological father, mother, brother, sister, or child) with idiopathic epilepsy or other seizure disorder
3. History of significant neurological illness (including stroke, central nervous system (CNS) infection with persistent neurologic deficit, or other event deemed significant by PI)
4. History of head trauma as defined by a loss of consciousness or a post-concussive syndrome
5. Pregnant or breast feeding
6. Known intelligence quotient (IQ) < 70 based on subject report
7. Subjects with current acute, serious, or unstable medical conditions, including, but not limited to: inadequately controlled diabetes, asthma, chronic obstructive pulmonary disease (COPD), severe hypertriglyceridemia, recent cerebrovascular accidents, acute systemic infection or immunologic disease, unstable cardiovascular disorders, malnutrition, or hepatic, renal gastroenterological, respiratory, endocrine, neurologic, hematologic, or infectious diseases based on medical history or physical examination
8. Metallic objects planted in or near the head, including implanted pacemaker, medication pump, vagal stimulator, deep brain stimulator, transcutaneous electrical nerve stimulation (TENS) unit, ventriculoperitoneal shunt, or cochlear implants
9. Contraindications to MRI or otherwise unable to tolerate MRI procedures
10. History of electroconvulsive therapy
11. Subjects taking clozapine
12. Subjects who have participated in a clinical trial with any pharmacological treatment intervention for which they received study-related medication in the 4 weeks prior to randomization
13. Subjects considered a high risk for suicidal acts - active suicidal ideation as determined by clinical interview OR any suicide attempt in 90 days prior to screening
14. Current SCID-5 diagnosis of substance use disorder (excluding nicotine or caffeine)
15. Subjects who require concomitant treatment with prohibited medication, as specified in Attachment 2

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
SHAM_COMPARATOR: Sham	Device: rTMS; Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique that received FDA clearance for use in treatment resistant major depressive disorder in 2008 and has become commonly used in clinical practice. rTMS utilizes the application of a repetitively pulsed magnetic field over the scalp to induce an electric field within a discrete area of the cerebral cortex. This electric field results in altered ion flow across the neuronal cellular membrane and ultimately changes in neuronal polarization. rTMS enables investigators to manipulate brain activity in a targeted cortical region as well as downstream connectivity within an associated neuronal circuit. High frequency (HF) rTMS leads to facilitatory effects on brain excitability. Previous studies have demonstrated that administration of as little as a single train or a small number of trains are able to produce an immediate increase in cortical excitability.
EXPERIMENTAL: rTMS	Device: rTMS; Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique that received FDA clearance for use in treatment resistant major depressive disorder in 2008 and has become commonly used in clinical practice. rTMS utilizes the application of a repetitively pulsed magnetic field over the scalp to induce an electric field within a discrete area of the cerebral cortex. This electric field results in altered ion flow across the neuronal cellular membrane and ultimately changes in neuronal polarization. rTMS enables investigators to manipulate brain activity in a targeted cortical region as well as downstream connectivity within an associated neuronal circuit. High frequency (HF) rTMS leads to facilitatory effects on brain excitability. Previous studies have demonstrated that administration of as little as a single train or a small number of trains are able to produce an immediate increase in cortical excitability.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SRMP	To determine the effects of HF rTMS targeting the bilateral precuneus on SRP as measured by a self-referential memory paradigm (SRMP)	1 week
Default mode network functional connectivity (DMN FC)	To assess the effects of HF rTMS targeting the bilateral precuneus on DMN FC at rest	1 week

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation between SRMP and DMN FC	Assessing the correlation between SRMP performance and DMN FC	1 week
SRMP and Scale to Assess Unawareness of Mental Disorder (SUM-D)	Assessing the correlation between SRMP performance and the SUM-D scale	1 week
SRMP and Beck Cognitive Insight Scale (BCIS)	Assessing the correlation between SRMP performance and the BCIS scale	1 week
SRMP and Birchwood Insight Scale	Assessing the correlation between SRMP performance and the Birchwood Insight Scale	1 week

Collaborators and Investigators

• Sponsor: Indiana University

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): September 1, 2019
• Primary Completion (ANTICIPATED): December 1, 2020
• Study Completion (ANTICIPATED): December 1, 2020

Study Registration Dates

• First Submitted: August 21, 2019
• First Submitted That Met QC Criteria: August 22, 2019
• First Posted (ACTUAL): August 28, 2019

Study Record Updates

• Last Update Posted (ACTUAL): November 21, 2019
• Last Update Submitted That Met QC Criteria: November 19, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: schizophrenia; schizoaffective disorder; psychosis; early phase
• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; Psychotic Disorders; Mood Disorders
• Other Study ID Numbers: 1904511224

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: Yes
• product manufactured in and exported from the U.S.: No