Depression is a common and severe mental illness with limited effectiveness of current treatments. New insights into the neurobiology of stress and mood disorders have revealed mechanisms underlying depression vulnerability and identified novel antidepressants. Environmental factors and stress disrupt neuronal function and connectivity, leading to dysfunction in mood and cognitive circuits. New antidepressants show rapid improvement in mood and reverse stress-induced synaptic deficits. Stress and glucocorticoids disrupt synaptic plasticity, while neurotrophic factors like BDNF are crucial for synaptic function. Genetic and environmental factors influence depression susceptibility, with BDNF polymorphisms playing a role. Stress and depression reduce BDNF expression, while antidepressants increase it. Sex differences in depression susceptibility are influenced by gonadal hormones. Metabolic disorders like obesity and diabetes are linked to depression and share risk factors. Inflammatory cytokines and the innate immune system contribute to depression pathophysiology. Rapid-acting antidepressants like ketamine and scopolamine act through mTORC1 signaling, increasing synaptic plasticity and reversing stress-induced deficits. These agents offer a promising approach for treating depression, with ongoing research exploring their mechanisms and broader applications. The discovery of rapid-acting antidepressants highlights the importance of synaptic plasticity in depression treatment and provides new therapeutic targets.Depression is a common and severe mental illness with limited effectiveness of current treatments. New insights into the neurobiology of stress and mood disorders have revealed mechanisms underlying depression vulnerability and identified novel antidepressants. Environmental factors and stress disrupt neuronal function and connectivity, leading to dysfunction in mood and cognitive circuits. New antidepressants show rapid improvement in mood and reverse stress-induced synaptic deficits. Stress and glucocorticoids disrupt synaptic plasticity, while neurotrophic factors like BDNF are crucial for synaptic function. Genetic and environmental factors influence depression susceptibility, with BDNF polymorphisms playing a role. Stress and depression reduce BDNF expression, while antidepressants increase it. Sex differences in depression susceptibility are influenced by gonadal hormones. Metabolic disorders like obesity and diabetes are linked to depression and share risk factors. Inflammatory cytokines and the innate immune system contribute to depression pathophysiology. Rapid-acting antidepressants like ketamine and scopolamine act through mTORC1 signaling, increasing synaptic plasticity and reversing stress-induced deficits. These agents offer a promising approach for treating depression, with ongoing research exploring their mechanisms and broader applications. The discovery of rapid-acting antidepressants highlights the importance of synaptic plasticity in depression treatment and provides new therapeutic targets.