Depression is associated with reduced brain regions regulating mood and cognition, including the prefrontal cortex and hippocampus, and decreased neuronal synapses. Antidepressants can reverse these deficits, but they are slow-acting and have limited efficacy. Ketamine, an NMDA receptor antagonist, rapidly alleviates depressive symptoms in treatment-resistant patients, likely by inducing synaptogenesis and reversing stress-induced synaptic deficits. This highlights the importance of synaptic homeostasis in depression and treatment response. Chronic stress causes neuronal atrophy and synaptic loss, as shown in rodent models. Stress reduces dendrite complexity, spine density, and neurogenesis in the hippocampus and prefrontal cortex. Postmortem studies of depression show reduced pyramidal neurons and GABAergic interneurons in the prefrontal cortex, along with decreased glial cells and synaptic proteins. Stress also decreases BDNF levels, which is crucial for neuronal survival and synaptic plasticity. Chronic antidepressants increase BDNF expression, but their effects are slow and limited. Ketamine rapidly increases synaptic connections and spine density, reversing stress-induced synaptic deficits. This is associated with activation of the mTOR pathway and increased glutamate transmission. Ketamine also enhances BDNF release and synaptogenesis, which may explain its rapid and effective antidepressant actions. However, its effects are temporary, and relapse can occur after 7-10 days, possibly due to failure of synaptic homeostasis. The synaptogenic hypothesis suggests that depression results from disruption of homeostatic mechanisms controlling synaptic plasticity, leading to synaptic destabilization and loss. Ketamine's rapid action highlights the importance of synaptogenesis in treatment response. New therapeutic targets, such as NMDA receptor antagonists and mGluR2/3 blockers, are being explored for their potential to enhance synaptic plasticity and antidepressant effects. Further research is needed to understand the role of synaptic alterations in depression and to develop more effective treatments.Depression is associated with reduced brain regions regulating mood and cognition, including the prefrontal cortex and hippocampus, and decreased neuronal synapses. Antidepressants can reverse these deficits, but they are slow-acting and have limited efficacy. Ketamine, an NMDA receptor antagonist, rapidly alleviates depressive symptoms in treatment-resistant patients, likely by inducing synaptogenesis and reversing stress-induced synaptic deficits. This highlights the importance of synaptic homeostasis in depression and treatment response. Chronic stress causes neuronal atrophy and synaptic loss, as shown in rodent models. Stress reduces dendrite complexity, spine density, and neurogenesis in the hippocampus and prefrontal cortex. Postmortem studies of depression show reduced pyramidal neurons and GABAergic interneurons in the prefrontal cortex, along with decreased glial cells and synaptic proteins. Stress also decreases BDNF levels, which is crucial for neuronal survival and synaptic plasticity. Chronic antidepressants increase BDNF expression, but their effects are slow and limited. Ketamine rapidly increases synaptic connections and spine density, reversing stress-induced synaptic deficits. This is associated with activation of the mTOR pathway and increased glutamate transmission. Ketamine also enhances BDNF release and synaptogenesis, which may explain its rapid and effective antidepressant actions. However, its effects are temporary, and relapse can occur after 7-10 days, possibly due to failure of synaptic homeostasis. The synaptogenic hypothesis suggests that depression results from disruption of homeostatic mechanisms controlling synaptic plasticity, leading to synaptic destabilization and loss. Ketamine's rapid action highlights the importance of synaptogenesis in treatment response. New therapeutic targets, such as NMDA receptor antagonists and mGluR2/3 blockers, are being explored for their potential to enhance synaptic plasticity and antidepressant effects. Further research is needed to understand the role of synaptic alterations in depression and to develop more effective treatments.