Objective To investigate the effects and mechanisms of antidepressants on TNF-α- induced neuronal survival and apoptosis. Methods Mouse hippocampal neuronal cells HT22 were divided into 5 groups： control group， TNF-α group， mianserin group， mirtazapine group and amitriptyline group. The last three groups were first treated with the assigned antidepressant for 30 min. All groups except the control group were then treated with TNF-α for 24 h. The neuronal survival rate of each group was detected by the MTT method. The neuronal apoptosis rate was detected by the Annexin V-FITC/PI double staining method. Expressions of related proteins were detected by the Western Blot. Results Antidepressants increased TNF- α-induced neuronal survival rate， reduced TNF-α-induced cell apoptosis rate， TNF-α-induced cytochrome c release， activities of caspase-9， caspase-3， and Cleaved PARP. However， antidepressants had no significant effect on the activity of caspase-8 in any group. Antidepressants also had no significant effect on the expressions of TNFR1 and TNFR2 or the activity of IKBα and NF-κB p65. Antidepressants increased TNF-α-induced LPA1 and FGFR expression as well as JNK and ERK1/2 activity. Conclusions Antidepressants can promote TNF-α-induced neuronal survival， reduce TNF-α-induced neuronal apoptosis， enhancing the TNF-α- induced expression of LPA1/FGFR pathway and activating JNK and ERK1/2 pathways.