Clinical trial NCT05259306: Low-Intensity Focused Ultrasound Neuromodulation of the Mediodorsal Thalamus for Treatment-Resistant Schizophrenia
Official title: Low-Intensity Focused Ultrasound of the Mediodorsal Thalamus for Treatment-resistant Schizophrenia: Circuit Interrogation and Symptom Assessment
Study type: INTERVENTIONAL
Overall status: SUSPENDED
Phase: NA
Conditions: Treatment-resistant Schizophrenia
Lead sponsor: NYU Langone Health
Sponsor class: OTHER
First posted: 2022-02-28
Enrollment: 3
Sex: ALL
Minimum age (years): 21
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This pilot study aims to investigate the use of MRI-guided low-intensity focused ultrasound (LIFU) to modulate neuronal activity within the thalamus in human subjects with treatment-resistant schizophrenia.

Detailed description: Approximately 30% of patients with schizophrenia have symptoms that persist despite multiple antipsychotic medication trials including clozapine, and there is currently no evidence-based treatment option for this population. These patients often suffer psychological distress related to their psychotic symptoms, become chronically disabled, and are unable to lead meaningful lives. Several promising new treatment modalities are being explored including deep brain stimulation (DBS) in subjects with treatment-resistant schizophrenia. A pilot study at another institution is using DBS of the substantia nigra pars reticulata (SNr) to modulate circuitry in the thalamus by disinhibiting the mediodorsal (MD) nucleus of the thalamus. This approach follows evidence from multiple structural and functional studies implicating hypofunction of the MD thalamus in the pathophysiology of schizophrenia. This includes an association between MD hypofunction and both positive and cognitive symptoms of schizophrenia including auditory hallucinations and working memory, respectively. As DBS is an invasive neurosurgical procedure with small but definable risks of neurologic injury, a minimally invasive screening method to optimize patient selection for DBS would be optimal.

This pilot study aims to investigate the use of MRI-guided low-intensity focused ultrasound (LIFU) to modulate neuronal activity within the thalamus in human subjects with treatment-resistant schizophrenia. Focused ultrasound itself is a safe, incisionless technology with high spatial resolution and depth penetration that has been shown to stimulate and inhibit neuronal activity. At high intensities, focused ultrasound can be used to thermally ablate a specific region of brain tissue and has been FDA-approved for the treatment of essential tremor and tremor in Parkinson's disease via thermal ablation of the ventral intermediate (VIM) thalamus. In contrast, LIFU is non-ablative and thus can be used for transient neuromodulation with high spatial precision due to direct real-time MRI targeting. This pilot study aims to use non-ablative LIFU to target the MD thalamus noninvasively and specifically, with the aim of interrogating and modulating the neuronal circuitry involved in symptoms of schizophrenia.

Eligibility criteria: Inclusion Criteria:

* Subject has an age greater or equal to 21 years old.
* Subject has a diagnosis of schizophrenia as determined by a review of medical records, discussion with referring psychiatrist, as well as the Structured Clinical Interview for DSM-5 (SCID-5).
* Subject is determined to be treatment-resistant for at least one year prior to Visit 1 as demonstrated by clinical evidence (determined via medical records and referring psychiatrist) of persistent auditory hallucinations and/or delusions that have not responded to treatment with three adequate trials/regimens of antipsychotic medication, as follows:

  a. Adequate trials of any two different antipsychotic medications, belonging to different classes of at least 12 weeks equivalent to at least 500 mg/day of chlorpromazine within the previous five years.
* Subject has a score of at least moderate (4) on two of the three BPRS positive symptoms (conceptual disorganization, hallucinatory behavior, and unusual thought content) at all three Baseline Visits.
* Subject must be ambulatory.
* Female subjects must be practicing an acceptable method of contraception, postmenopausal, physically incapable of childbearing, or; if practicing an acceptable method of contraception, a negative urine pregnancy test must be confirmed at all three Baseline Visits
* Subject has decision-making capacity to provide informed consent, as determined by an independent psychiatrist.

Exclusion Criteria:

* Subject has a positive urine toxicology screen at any of the three Baseline Visits.
* Subject has medical contraindications to the procedure as determined by an internist or primary care physician.
* Subject is pregnant or breast-feeding.
* Subject has a history of alcohol or substance abuse within the past 6 months.
* Subject has a medical illness, comorbid psychiatric illness, and/or abnormal diagnostic finding that would interfere with the completion of the study, confound the results of the study, or pose risk to the patient.
* Subject has participated in another investigational drug trial or therapeutic trial within 30 days of Baseline Visit 1.
* Subject has a neurologic condition or history of traumatic brain injury associated with loss of consciousness and/or intracranial bleeding.
* Subject is considered high suicide risk as screened by the Columbia-Suicide Severity Rating Scale (C-SSRS).
* Subject has a defibrillator, pacemaker, or other implants that would interfere with MRI
* Subject has significant social factors that greatly interfere with consistent follow up and/or support.

Primary outcomes:
measure: Number of Patients who Complete All Visits Related to the Study
timeFrame: Up to Month 3
Secondary outcomes:
measure: Change in Brief Psychiatric Rating Scale (BPRS) Score from Baseline
timeFrame: Baseline, Month 3
measure: Change in Positive and Negative Syndrome Scale (PANSS) Score from Baseline
timeFrame: Baseline, Month 3
measure: Change in Montreal Cognitive Assessment (MoCA) Score from Baseline
timeFrame: Baseline, Month 3
Other outcomes:
Locations:
city: New York
country: United States
facility: NYU Langone Health
state: New York
Study officials:
affiliation: NYU Langone Health
name: Alon Mogliner, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: