Suicide is the 2nd leading cause of death in adolescents. Unfortunately, our ability to accurately predict suicidal
ideation (SI) and suicide attempts (SA) among adolescents remains remarkably limited. Thus, there is an urgent
need for biomarkers that can identify risk for SI and SA. There is also a need to identify novel molecular pathways
that may underlie suicide risk. There is growing interest in microRNAs (miRNAs), a subclass of non-coding RNAs
that regulate mRNA expression via post-transcriptional mechanisms, as potential mediators of disease
pathologies and in the development of targeted novel therapeutics. Earlier, we reported that specific miRNAs
were markedly altered in the brain of adults who died by suicide independent of psychiatric illnesses, suggesting
that miRNAs can distinguish suicidality separately from psychopathology. Using a specific neural marker, we
isolated neural-derived exosomes (NDEs) from blood plasma and found that these exosomes are highly enriched
with miRNAs that are expressed in the brain. In preliminary studies, we also found remarkable resemblance in
brain and NDE miRNA changes among adult and adolescent suicide populations. Differences in many miRNAs
were common in adults and adolescents with SI or SA; however, a distinct set of miRNAs was associated
exclusively with adolescent suicide. In addition, differentially expressed NDE miRNAs changed significantly in
adults treated with ketamine. Our novel approach thus provides a unique opportunity to detect NDE miRNAs in
plasma, which can be used as biomarkers for suicidality and treatment response. Based on our pilot data, we
propose an overarching hypothesis that a subset of NDE miRNAs will be differentially expressed in adolescents
with MDD and SI or SA compared with non-suicidal adolescents with MDD and healthy controls. There will be
unique subsets of miRNAs specifically associated with MDD, SI, and SA. These miRNAs will have specific mRNA
targets and biological pathways that may be associated with SI, SA, and MDD risk. To test these, we will examine
genome-wide expression of NDE miRNAs and mRNAs in the following groups of adolescent subjects (11-19 y;
n=240): 1) MDD with serious SI and a recent SA (MDD+SA), 2) MDD+SI without recent SA, 3) MDD without
recent SI or SA (MDD-SI/SA), and 4) healthy controls without a history of mental disorder. We will also test if
expression of NDE miRNAs will change across six weeks of antidepressant treatment (AD). With this, we will
examine if: 1) specific subset(s) of NDE miRNAs are associated with SI and SA among adolescents, 2) specific
miRNA/mRNA-regulatory pathway is associated with SI, SA, and MDD, and 3) response to AD treatment impacts
differences in NDE miRNAs associated with MDD and SI/SA. Using our existing NDE miRNA datasets in 240
adults ages 20-65 y across the same groups proposed for this study, we will also examine if miRNA biosignatures
are common in MDD and SI/SA groups for adolescents and adults, or if they differ by age. Altogether, our study
will provide novel avenues to identify miRNAs as ‘‘molecular tools’’ for the development of a biomarker for
suicidality across age group and eventually new molecular-based therapies to treat or prevent this disorder.
