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.
Acute first episode of psychosis with DSM-5 diagnosis of schizophrenia, schizoaffective disorder, schizophreniform disorder, or psychosis Not Otherwise Specified (NOS)
Current positive symptoms rated ≥4 (moderate) on one or more of these BPRS items: hallucinatory behavior, unusual thought content, grandiosity, conceptual disorganization
Early phase of illness as defined by having taken antipsychotic drugs for a cumulative lifetime period ≤2 weeks
Age 15 to 40
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
Parallel
Plasma NDE miRNA Sequencing
Diagnostic testBlood 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.
Whole Genome Sequencing
GeneticSingle baseline blood sample collected for DNA extraction and whole genome sequencing to analyze genetic variation associated with psychosis and treatment response.
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.
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.
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