Butyrylcholinesterase as a potential depression biomarker: Insights from a translational study

Major depressive disorder, a prevalent psychiatric disorder, significantly impacts quality of life. Although several biological pathways and related biomarker candidates try to explain its complex pathomechanism and assess objectively its diagnosis and onset, biomarker research in depression is still in infancy. Recent studies showed that depression may be influenced by dysregulation of cholinergic transmission. Within these findings, while the role of acetylcholinesterase is commonly studied in depression pathomechanism, the role of butyrylcholinesterase (BChE) remains unclear. Recently, we developed a BChE-activatable chemiluminescent molecular sensor (BCC) for real-time visualization of BChE activity, demonstrating efficiency in vitro and in tumor-bearing mice. In this translational study, we employed BCC to investigate the association between BChE activity and depression. We first assessed BChE activity in patients with depression (32 unipolar depression, 20 bipolar disorders with depressive episodes) compared to healthy controls (n=48) and reassessed changes with respect to remission (n=15). Second, we evaluated BChE activity in rats exposed to chronic unpredictable mild stress (CUMS), CUMS with concurrent fluoxetine treatment, and controls. Lastly, we established cell models for psychological stress by mimicking the hypothalamic-pituitary-adrenal (HPA) axis outcomes with 200µM corticosterone for 24 hours and the sympatho-adrenomedullary (SAM) system outcomes with 1mM norepinephrine treatments for 24 hours and assessed their BChE activity compared to controls in PC-12 Adh cell. Results indicated that individuals with depression exhibited significantly lower BChE activity compared to controls (p<.001), with increased activity correlating with remission (p<.001). Rats exposed to CUMS showed a significant decrease in BChE levels (p=.011), while fluoxetine treatment showed an increasing trend but could not achieve significance (p=.345). Additionally, BChE activity significantly decreased with corticosterone exposure (p=.002) and increased with norepinephrine exposure (p=.002). Subsequent, 5µM fluoxetine treatment cell exposed to those psychological stresses showed increased BChE activity (p=.002 for both). This translational study demonstrates a decrease in BChE activity in both clinical populations and chronic stress animal models, and psychological stress model established cell models, with levels reversing upon symptom alleviation. Our findings ultimately suggest that BChE activity can be a promising biomarker for depression diagnosis and treatment outcome.