Neural signaling mechanisms in depression: bridging classical monoamine hypotheses, animal models, and emerging antidepressant strategies
Frontiers in Cell and Developmental Biology March 25, 2026 Mizuki Yamamoto, Haruka Hirakata, Koji Toda 5 citations
Major depressive disorder affects many people across their lives, but its biological causes are still not fully understood. Older theories focused on imbalances in monoamine neurotransmitters like serotonin, leading to common antidepressants such as selective serotonin reuptake inhibitors. These drugs can take weeks to work, must be taken continuously, and fail to help about one-third of patients, while also carrying risks like increased suicidal thoughts in some groups. Newer findings show that ketamine and psychedelic compounds can produce rapid antidepressant effects by acting on glutamate signaling, synaptic plasticity, and immune-brain interactions, challenging the older models. This review covers both historical and emerging views on antidepressant development, describes major animal models of depression, and discusses recent translational research that is reshaping treatment approaches.