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Despite extensive research, the neurobiology of major depressive disorder (MDD) remains poorly understood. A significant number of patients with depression do not respond to currently available medications, such as selective serotonin reuptake inhibitors, and even in cases of successful treatment, these compounds typically take weeks or months to trigger an antidepressant response. This delay in onset is a major drawback to current antidepressant therapies, leaving a crucial need for the development of faster-acting antidepressants, especially in patients at risk of suicide. There are consistent reports of decreased size of brain regions implicated in depression, as well as neuronal atrophy, including loss of synapses in MDD. Accumulating evidence suggests that the glutamatergic system plays an important role in the neuropathology and treatment of MDD. Antidepressant drugs promote many forms of neuronal plasticity, including neurogenesis, synaptogenesis and neuronal maturation in hippocampus. Recent evidences indicate that neurotrophic factors may regulate neuronal plasticity bidirectionally, meaning they may play role in pathophysiology and treatment of depression. Recently it has been shown that ketamine has a rapid and long lasting antidepressant activity after a single dose. Ketamine has been used as a human and animal anesthetic. It acts on the human brain by blocking the N-methyl-D-aspartate receptors (NMDARs), which receive nerve signals carried by glutamate; the exact mechanism of ketamine’s action has been identified. In studies with rats, basic researchers demonstrated that ketamine rapidly activates the so called “mammalian target of rapamycin” (mTOR) pathway, one of many such pathways that perform signal transduction in neurons. The involvement of mTOR signaling in dendritic protein synthesis has been recently characterized. Several components of this pathway are present in dendrites and are enriched at postsynaptic sites. mTOR function is inşuenced by the activity of neuronal surface receptors including NMDAR, mGluR5, and neurotrophic tyrosine kinase receptors (TrkB) which are vital for the induction of synaptic plasticity. It is generally accepted that mTOR acts as a node of convergence downstream of the aforementioned receptors and several signaling pathways, including phosphoinositide dependent kinase-1 (PDK1), phosphoinositide-3-kinase (PI3K), and Akt/protein kinase-B (Akt/PKB). This new approach may be a revolutionary break-through in the treatment of depression and it might lead to novel therapeutic targets for antidepressant drug development. The main hypothesis is depression caused by disruption of homeostatic mechanisms that control synaptic plasticity, resulting in destabilization and loss of synaptic connections in mood and emotion circuitry. A major thrust of future drug discovery in MDD will enhance efforts to identify the molecular basis of rapid and sustained antidepressant actions, thereby minimizing disorder morbidity and mortality during the critical weeks between initial symptom expression and drug efficacy.