The article reviews the neurobiological mechanisms underlying depression, focusing on the role of synaptic plasticity and the impact of stress. It highlights the limitations of current antidepressants, such as their delayed onset and partial efficacy, and introduces novel rapid-acting antidepressants that show promise in reversing synaptic deficits caused by stress. The authors discuss the importance of neurotrophic factors like BDNF, the role of the HPA axis and glucocorticoids, and the impact of metabolic imbalances and inflammatory cytokines on synaptic function. They also explore the potential of ketamine and scopolamine as rapid-acting antidepressants, emphasizing their ability to increase mTORC1 signaling and synaptogenesis. The review concludes by emphasizing the need for further research to identify novel therapeutic targets and strategies to enhance synaptic connectivity in depression circuits.The article reviews the neurobiological mechanisms underlying depression, focusing on the role of synaptic plasticity and the impact of stress. It highlights the limitations of current antidepressants, such as their delayed onset and partial efficacy, and introduces novel rapid-acting antidepressants that show promise in reversing synaptic deficits caused by stress. The authors discuss the importance of neurotrophic factors like BDNF, the role of the HPA axis and glucocorticoids, and the impact of metabolic imbalances and inflammatory cytokines on synaptic function. They also explore the potential of ketamine and scopolamine as rapid-acting antidepressants, emphasizing their ability to increase mTORC1 signaling and synaptogenesis. The review concludes by emphasizing the need for further research to identify novel therapeutic targets and strategies to enhance synaptic connectivity in depression circuits.