Accelerated Transcranial Magnetic Stimulation for People With Schizophrenia Treated With Clozapine

Study Overview
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Brief Summary
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In this study, the investigators will examine whether a type of repetitive transcranial magnetic stimulation called accelerated intermittent theta burst stimulation (iTBS) can augment neurocognition in individuals who receive treatment with clozapine. Following a baseline evaluation and magnetic resonance imaging (MRI), participants will undergo a session of iTBS +MRI and session of sham delivery + MRI. The order for these sessions will be blinded and randomized. The investigators predict that accelerated iTBS will enhance neurocognition relative to sham delivery.

Official Title
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Accelerated Neuromodulation of Prefrontal Circuitry During Clozapine Treatment

Conditions
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Schizophrenia, Schizoaffective Disorder

Intervention / Treatment
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* Device: sham stimulation
* Device: transcranial magnetic stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A current Diagnostic and Statistical Manual of Mental Disorders 5 (DSM 5)-defined diagnosis of schizophrenia or schizoaffective disorder age 18-50 years at least 4 months of clozapine treatment history of at least 2 failed antipsychotic trials competency and willingness to sign informed consent A clinically optimized dosage of clozapine, unchanged for at least 1 month, with a minimum of 150 mg/day Exclusion Criteria: Serious neurologic or medical condition/treatment that impacts the brain a significant risk of suicidal or homicidal behavior cognitive or language limitations, or any other factor that would preclude subjects providing informed consent pregnancy or postpartum (<6 weeks after delivery or miscarriage) history of treatment with electroconvulsive therapy contraindications for magnetic resonance imaging (e.g., a pacemaker) Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders 5 (DSM 5)-verified moderate or severe substance use disorder, including alcohol use disorder seizure disorder or prior history of seizures on clozapine patients taking both bupropion and clozapine prior issues with intermittent theta burst stimulation/transcranial magnetic stimulation administration Concomitant treatment with serotonin and norepinephrine reuptake inhibitors will be examined on a case-by-case basis.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: iTBS, then Sham<br> | Device: sham stimulation<br>* sham delivery of transcranial magnetic stimulation<br>Device: transcranial magnetic stimulation<br>* accelerated intermittent theta burst stimulation<br>|
| Experimental: Sham, then iTBS<br> | Device: sham stimulation<br>* sham delivery of transcranial magnetic stimulation<br>Device: transcranial magnetic stimulation<br>* accelerated intermittent theta burst stimulation<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| change in brain functional connectivity within the prefrontal cortex | Examine changes in left dorsolateral prefrontal cortex-basal forebrain functional connectivity following adjunctive accelerated intermittent theta burst stimulation (iTBS) | 1 hour | 
| change in activation of the working memory network | Examine whether accelerated intermittent theta burst stimulation (iTBS) is associated with functional magnetic resonance imaging (fMRI)-based changes in activation of the working memory network during AX-continuous performance task engagement | 1 hour | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| explore change in functional magnetic resonance imaging (fMRI) measures versus plasma n-desmethylclozapine/clozapine ratios | In exploratory analyses we will compare change in dorsolateral prefrontal cortex-basal forebrain functional connectivity and change in working memory network activation in relation to plasma n-desmethylclozapine/clozapine ratios. | 1 month |