The article discusses the role of synaptic dysfunction in depression and the potential therapeutic targets for treating this condition. It highlights that depression is associated with reduced brain regions involved in mood and cognition, such as the prefrontal cortex and hippocampus, and decreased neuronal synapses in these areas. Traditional antidepressants can block or reverse these deficits but have limited efficacy and delayed response times. A recent discovery shows that ketamine, a N-methyl-D-aspartate receptor antagonist, produces rapid antidepressant responses in patients resistant to typical antidepressants. Basic studies show that ketamine rapidly induces synaptogenesis and reverses synaptic deficits caused by chronic stress. The authors propose a hypothesis that depression is caused by disruptions in homeostatic mechanisms controlling synaptic plasticity, leading to destabilization and loss of synaptic connections in mood and emotion circuits. They compare the mechanisms underlying typical antidepressants and ketamine, particularly the induction of synaptogenesis. The article also reviews the neurobiological mechanisms of neuronal atrophy and synaptic loss in depression, the role of stress in these processes, and the impact of neurotrophic factors like brain-derived neurotrophic factor (BDNF) on synaptic function. Finally, it discusses the rapid-acting effects of ketamine and potential new therapeutic targets, such as selective NMDA receptor subtype 2B antagonists and agents that enhance glutamate signaling.The article discusses the role of synaptic dysfunction in depression and the potential therapeutic targets for treating this condition. It highlights that depression is associated with reduced brain regions involved in mood and cognition, such as the prefrontal cortex and hippocampus, and decreased neuronal synapses in these areas. Traditional antidepressants can block or reverse these deficits but have limited efficacy and delayed response times. A recent discovery shows that ketamine, a N-methyl-D-aspartate receptor antagonist, produces rapid antidepressant responses in patients resistant to typical antidepressants. Basic studies show that ketamine rapidly induces synaptogenesis and reverses synaptic deficits caused by chronic stress. The authors propose a hypothesis that depression is caused by disruptions in homeostatic mechanisms controlling synaptic plasticity, leading to destabilization and loss of synaptic connections in mood and emotion circuits. They compare the mechanisms underlying typical antidepressants and ketamine, particularly the induction of synaptogenesis. The article also reviews the neurobiological mechanisms of neuronal atrophy and synaptic loss in depression, the role of stress in these processes, and the impact of neurotrophic factors like brain-derived neurotrophic factor (BDNF) on synaptic function. Finally, it discusses the rapid-acting effects of ketamine and potential new therapeutic targets, such as selective NMDA receptor subtype 2B antagonists and agents that enhance glutamate signaling.