Essentially, all antidepressant drugs increase the expression and signaling of brain-derived neurotrophic factor (BDNF). These drugs act through tyrosine kinase receptor 2 (TRKB), the receptor for BDNF, to regulate neuronal plasticity. Casarotto et al. investigated the potential interactions among TRKB, cholesterol, and antidepressants. The authors found that a dimer of TRKB forms a binding pocket, where several antidepressants from different drug classes bind with a low but physiologically meaningful affinity. This low-level binding depends on membrane cholesterol to stabilize the TRKB structure in synaptic membranes and thereby promotes BDNF signaling. Such direct binding to TRKB and promotion of BDNF-mediated plasticity may therefore be a common mechanism of action for anti-depressant drugs.
Cell, 184, 1299 (2021).
