Techniques in Understanding the Causes, Progression, Diagnosis, Prevention, and Intervention Surrounding Psychiatric Conditions

There is an urgent need for improved techniques in understanding the causes, progression, diagnosis, prevention, and intervention surrounding psychiatric conditions. A relatively new field of extracellular vesicle biology offers a promising approach. Extracellular vesicles (EVs) refer to vesicles that are derived from the lipid membranes in cells, which contain exosomes and microvesicles from the endosomal system or plasma membrane (Figure 1). EVs are secreted by a host of cells in the body under normal and pathological conditions, providing information regarding the physiological state of an organism. EVs contain a variety of molecules such as RNAs (non-coding RNA, mRNA and miRNA), proteins, lipids and metabolites. These molecular cargos are representative of their cellular origin and navigate between their donor and recipient cell, making them essential regulators of physiological processes in the body as well as a communication apparatus to alert and respond to changes in the environment. An important feature of EVs is that they are able to cross the blood-brain barrier (BBB), which makes them able to execute communication between the central nervous system (CNS) and other peripheral organ systems as well as position EVs as potential good candidates for drug delivery to address various diseases of the CNS (Rao et al 2018).

Because EVs shuttle molecules between tissues and cells, they have emerged as important mediators of cellular communication across the body, including normal functioning such as orchestrating immune responses, facilitating lactation and mediating cognition. In addition, EVs have been shown to play a pivotal role in the development and progression of diseases. For example, EVs faclilitate the formation of tumor metastesesy conditioning distal tissues to accept the metastatic cells, or neuroally enriched EVs have been shown to contain coagoes that play a role in the progression of Alzheimer’s disease up to ten years prior to the onst of the illness. So far, all classes of molecular cargo: RNA, protein, lipid and metabolites have been shown to have potential biomarker utility. However, while proteins, lipids and metabolites have been found to have biomarker utility in CNS disorders, in psychiatry specifically, the sole focus up until now has been on studying miRNA EV cargos, which, have emerged in recent years as a promising tool for biomarker discovery in the field.

EV research has already identified miRNA biomarkers in schizophrenia, bipolar disorder, and depression. In a study on schizophrenia, miR-497 was found to be expressed significantly higher in comparison to the control group (Raghavan et al 2017). In patients with bipolar disorder, reduced miR-134 levels were associated with more frequent manic symptoms. It was and miR-134 levels increased after patients were treated with mood-stabilizing agents. The finding that miRNA expression levels increase with treatment suggests that miRNAs could serve as targets for pharmaceutical interventions (i.e. deliver synthesized exosomes with miR-134 to the brain). Similarly, a study on depression showed that EV miR-16 was identified to be the a posttranscriptional repressor of the serotonin transporter. Decreased levels of EV miR-16 were found to decrease serotonin signaling at the synapse, contributing to depressive symptoms (Narahari et al 2017). Additionally, other plasma EV miRNAs such as miR‐21, miR22, miR‐26b, miR‐32, miR‐132, miR‐186, and miR‐107 have been shown to be expressed differently in patients with major depression disorder versus healthy controls. Because EVs shuttle these miRNA cargos to recipient cells, this may serve as a mechanism by which a neurons and glia regulate and signal each other. Thus, miRNAs could potentially induce as well as inhibit CNS processes related to depression such as neurogenesis and neuroplasticity, which could potentially worsen or ameliorate the disease (Tavakolizadeh et al 2014). Hence, EV miRNA can serve as diagnostic markers for schizophrenia, bipolar disorder and major depression to improve accuracy, aid large-scale screening, as well as potentially guide treatment decisions.

RNA is a notoriously unstable molecule that can degrade quite quickly and easily in the bloodstream (Fleshner and Crane 2017), leading to decreased utility of RNAs as biomarkers in clinical practice. An advantage of studying miRNA in EVs is that unlike free-floating RNA, EV miRNAs are particularly stable molecular messages that can withstand storage, handling and extraction methods. EV miRNAs are able to withstand RNase degradation and sustain stability for 5 years at -20 °C, short-term storage at 4 °C, and can handle freeze-thaw cycles (Thind et al 2016). Thus, EV miRNAs are an effective clinical tool for diagnosing and identifying disease progression, especially for cancer (Thind et al, 2016). Moreover, EV miRNAs are specifically showing promise as a diagnostic tool for psychiatric disorders and have some advantageous features such as stability during handling and extraction, compared to plasma free floating RNA (Khalyfa and Goza 2014).

Beyond miRNA, research on EVs in patients with psychiatric conditions should also be expanded to protein, lipids and metabolites. There has been some research on the EV proteome from human cerebrospinal fluid, which has collected data on exosome markers, heat shock proteins, and brain-derived proteins (Pegtel et al 2014). Yet, more research is needed to provide evidence that these cargos prove to be promising in identifying biomarkers of many different types of diseases, including those involving the central nervous system. Plasma EV interrogation has already provided clues to biomarkers in patients with schizophrenia, bipolar disorder, and major depressive disorder. Because cargos from EVs are influenced by stressors in the body and provide genetic and epigenetic information about the physiological state of an organism, analyzing this information can be beneficial towards developing a greater understanding of the biological functioning of patients with a variety of psychiatric conditions. Finding EV biomarkers for psychiatric diseases would also improve clinicians’ diagnostic accuracy, ensuring the patients of the biological bases of their disorder. In turn, the stigma surrounding psychiatric disorders could decrease as more and more biological markers become identified to legitimize their expression. Thus to further understand diagnosis, prevention, progression, and intervention efforts of psychiatric conditions, EVs may provide key biological insights and should be invested in future research efforts.