MicroRNAs as Biomarkers in First Episode Schizophrenia (MIRFEST)

MicroRNAs in Neural-Derived Extracellular Vesicles as Biomarkers in First Episode Schizophrenia

This study investigates whether tiny molecules called microRNAs (miRNAs), found in special brain-derived "packages" (neural-derived extracellular vesicles, or NDEs) that travel from the brain into the blood, can serve as helpful indicators (biomarkers) for schizophrenia. Currently, doctors diagnose schizophrenia and monitor treatment primarily through clinical interviews, which can be slow and imprecise. This study will work with 80 individuals recently diagnosed with first-episode schizophrenia who are beginning treatment with either aripiprazole or risperidone, along with 80 healthy volunteers. Blood samples will be collected from all participants. For individuals with schizophrenia, blood will be drawn at the beginning of treatment and again after 12 weeks. By comparing patterns of brain-derived miRNAs in the blood of patients versus healthy volunteers, and by observing changes in these miRNAs during treatment, the researchers hope to discover whether these molecules can help diagnose schizophrenia more quickly and predict how well a treatment will work. If successful, this study will provide initial evidence that these miRNAs could become valuable new tools leading to earlier, more accurate diagnoses and more personalized treatment selection.

Study Overview

• Status: Recruiting
• Conditions: Schizoaffective Disorder; Schizophreniform Disorder; Psychosis Not Otherwise Specified (NOS); Schizophrenia Disorder
• Intervention / Treatment: Diagnostic test: Plasma NDE miRNA Sequencing; Genetic: Whole Genome Sequencing

Detailed Description

Schizophrenia is a significant psychiatric illness characterized by psychosis, social withdrawal, and cognitive difficulties leading to impaired daily functioning. Diagnosis and treatment assessment remain heavily reliant on clinical interviews, which are subjective and lack objective biological indicators. Previous research has established evidence of miRNA dysregulation in schizophrenia through genome-wide association studies, post-mortem brain tissue analysis, and biological fluid studies. A more recent and promising approach involves measuring miRNAs specifically contained within neural-derived extracellular vesicles (NDEs) isolated from plasma. These NDEs carry brain-specific miRNA cargo and can be identified in peripheral blood, offering a less invasive approach compared to cerebrospinal fluid or brain tissue.

This study addresses the identified knowledge gap by investigating plasma NDE miRNAs as novel diagnostic and treatment response biomarkers specifically in first-episode schizophrenia (FES). The focus on FES participants minimizes confounding effects associated with long-term medication use and extended illness duration. The study employs a 12-week mechanistic clinical trial design with clinical assessments, neurocognitive testing (MATRICS), and blood collection for NDE miRNA sequencing at baseline and 12 weeks. MiRNA sequencing will be performed using Illumina NovaSeq6000 following NDE isolation via L1/NCAM antibody immunoprecipitation. Statistical analysis includes differential expression analysis using DESeq, Binary Elastic Net Regression for feature selection, and machine learning models (random forests, gradient boosting, SVM) for predictive performance assessment.

• Study Type: Interventional
• Enrollment (Estimated): 160
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Nicole Montgomery, MD; Phone Number: 949-486-9390; Email: nmontgomery@northwell.edu
• Study Contact Backup: Name: Juan Gallego, MD, MS; Phone Number: 718-470-4588; Email: NMontgomery@northwell.edu

Study Locations

• United States
  • New York
    • Glen Oaks, New York, United States, 11004
      • Recruiting
      • Zucker Hillside Hospital
      • Contact: Nicole Montgomery; Phone Number: 9494869390; Email: NMontgomery@northwell.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Acute first episode of psychosis with DSM-5 diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder, or psychosis Not Otherwise Specified (NOS)
2. Current positive symptoms rated ≥4 (moderate) on one or more of these BPRS items: hallucinatory behavior, unusual thought content, grandiosity, conceptual disorganization
3. Early phase of illness as defined by having taken antipsychotic drugs for a cumulative lifetime period ≤2 weeks
4. Age 15 to 40
5. Receiving or about to start naturalistic treatment with either aripiprazole or risperidone
6. Full capacity to consent

Exclusion Criteria:

• Participant voluntarily withdraws consent at any given time during the study
• Loss of capacity to consent during the study
• Treating psychiatrist determines that the participant requires an antipsychotic medication other than aripiprazole or risperidone due to adverse effects, poor tolerability, poor response, or any other reason
• The investigator, sponsor, independent safety monitor, or DSMB determines discontinuation is necessary to protect the participant
• Pregnancy is discovered during the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: First-Episode Schizophrenia - Aripiprazole/Risperidone; FES participants receiving naturalistic treatment with aripiprazole or risperidone as prescribed by their treating psychiatrist. Blood samples collected at baseline and week 12 for NDE miRNA analysis.	Diagnostic test: Plasma NDE miRNA Sequencing; Blood samples collected at baseline and week 12 for isolation of neural-derived extracellular vesicles (NDEs) from plasma using L1/NCAM antibody immunoprecipitation, followed by small RNA sequencing on Illumina NovaSeq6000 to identify differentially expressed miRNAs.; Genetic: Whole Genome Sequencing; Single baseline blood sample collected for DNA extraction and whole genome sequencing to analyze genetic variation associated with psychosis and treatment response.
Active Comparator: Healthy volunteers; Healthy volunteers providing a single baseline blood sample for NDE miRNA analysis comparison.	Diagnostic test: Plasma NDE miRNA Sequencing; Blood samples collected at baseline and week 12 for isolation of neural-derived extracellular vesicles (NDEs) from plasma using L1/NCAM antibody immunoprecipitation, followed by small RNA sequencing on Illumina NovaSeq6000 to identify differentially expressed miRNAs.; Genetic: Whole Genome Sequencing; Single baseline blood sample collected for DNA extraction and whole genome sequencing to analyze genetic variation associated with psychosis and treatment response.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnostic performance of plasma NDE miRNA panel	Sensitivity, specificity, and Area Under the Curve (AUC) of a panel of plasma NDE miRNAs in differentiating acutely psychotic First-Episode Schizophrenia (FES) participants from Healthy Volunteers (HV), assessed using Binary Elastic Net Regression and machine learning models.	Baseline (Week 0)
Predictive performance of baseline plasma NDE miRNA levels for treatment response	Predictive performance (AUC, accuracy, sensitivity, specificity) of baseline plasma NDE miRNA levels for clinical response to antipsychotic treatment (aripiprazole or risperidone). Treatment response defined as all 4 BPRS Thought Disturbance factor items below psychotic level (<4) for 2 consecutive ratings with concomitant CGI ratings of much/very much improved.	Baseline NDE miRNAs predicting response at Week 12

Collaborators and Investigators

• Sponsor: Northwell Health
• Investigators: Principal Investigator: Juan Gallego, MD, Northwell Health

Study record dates

Study Major Dates

• Study Start (Estimated): July 1, 2026
• Primary Completion (Estimated): May 1, 2031
• Study Completion (Estimated): May 1, 2031

Study Registration Dates

• First Submitted: June 4, 2026
• First Submitted That Met QC Criteria: July 10, 2026
• First Posted (Actual): July 14, 2026

Study Record Updates

• Last Update Posted (Actual): July 14, 2026
• Last Update Submitted That Met QC Criteria: July 10, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: biomarkers; miRNA; exosomes; first episode; neural derived extracellular vesicles
• Additional Relevant MeSH Terms: Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders; Schizophrenia; Psychotic Disorders; Investigative Techniques; Genetic Techniques; Sequence Analysis; Sequence Analysis, DNA; Whole Genome Sequencing
• Other Study ID Numbers: R01MH143042 (U.S. NIH Grant/Contract)

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