Depression is a global health concern, affecting 3.8% of the population. Current pharmacological treatments can cause serious side effects, such as increased suicidal ideation, and fail to adequately treat the patient population, with up to 50% of individuals with major depressive disorder (MDD) experiencing treatment-resistant depression. Most antidepressants increase monoamine concentrations, but their precise therapeutic mechanism remains unclear. Glial cell loss has been linked to MDD in humans, and experimentally induced glial loss in animal models induces depressive behaviours. Astrocytes, the most abundant type of glial cell, exhibit altered function upon antidepressant application including increased lactate release. Newest hypotheses of depression pathology propose the importance of synaptic regulation, a process modulated by lactate. This study aimed to optimise media conditions for measuring astrocytic lactate release, and explore the effects of antidepressant application on lactate release and cellular metabolism. Dulbecco's Modified Eagle Medium containing 0.5mM glucose was found to be the most suitable medium for 4-hour astrocytic incubation. Seven antidepressants from four different classes increased lactate release. No relationship was identified that applied to all antidepressants, however findings suggest that increased lactate release upon application of fluoxetine, citalopram, paroxetine and amitriptyline may result from a cellular shift towards glycolysis. While this study did not identify a specific target or mechanism underlying antidepressant-induced astrocytic lactate release, it supports the involvement of astrocytic lactate in a novel antidepressant mechanism. Further investigation to identify the precise pathways underlying astrocytic lactate release may enhance our understanding of antidepressant action and inform the development of more effective antidepressant medications.
Do Antidepressants Alter Astrocytic Lactate Release?
Clements, L. A. (Author). 10 Dec 2024
Student thesis: Master's Thesis › Master of Science by Research (MScR)