Histone Deacetylase 5 (HDAC5) in Major Depressive Disorder: Analyzing Current Gaps on Bridging Epigenetic Mechanisms to Clinical Translation

Major depressive disorder (MDD) is a widespread psychiatric disorder that affects over 163 million people globally. Current treatments for MDD include pharmacological agents, such as selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs), electroconvulsive therapy (ECT), and more. Each treatment has the potential to provide symptom relief; however, they also have limitations. Recently there’s been an interest in epigenetic regulators within the field of depression research; more specifically, researchers are focusing on histone deacetylases (HDACs) for their roles in regulating gene expression by modifying the structure of chromatin. Among the HDAC isoforms, one of the most intriguing is the class IIa isoform, HDAC5. HDAC5 overexpression increases stress vulnerability, linking HDAC5 to molecular signaling processes underlying depressive behaviors. Researchers do not yet fully understand the mechanistic pathways connecting HDAC5 to synaptic plasticity, the effects of HDAC5 modulation on brain penetration and potential off-target effects, and much more. To fill these gaps, future studies might wish to look into CRISPR-based gene editing for mapping HDAC5, PET imaging tracers, and more peripheral assays in vivo. Altogether these approaches will allow the field to work towards bridging preclinical and clinical findings. Bridging these translational gaps creates new opportunities to develop individualized therapies to treat depression, while addressing ongoing unmet needs in psychiatric medicine.