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Objective Antidepressants modulate neuronal plasticity. Tianeptine, an atypical antidepressant, might be involved in the restoration of neuronal plasticity; it primarily enhances the synaptic reuptake of serotonin. NCAM140 is involved in neuronal development processes, synaptogenesis and synaptic plasticity. We investigated the effect of tianeptine on the expression of NCAM140 and its downstream signaling molecule in the human neuroblastoma cell line SH-SY5Y. Methods NCAM protein expression was measured in human neuroblastoma SH-SY5Y cells that were cultivated in serum-free media and treated with 0, 10, or 20 μM tianeptine for 6, 24, or 72 hours. NCAM140 expression in the tianeptine treatment group was confirmed by Western blot, and quantified through measurement of band intensity by absorbance. CREB and pCREB expression was identified after treatment with 20 μM tianeptine for 6, 24, and 72 hours by Western blot. Results Compared to cells treated for 6 hours, cells treated with 0 or 10 μM tianeptine for 72 hours showed a significant increase in NCAM140 expression and cells treated with 20 μM tianeptine showed a significant increase after 24 and 72 hours. The pCREB level in cells treated with 20 μM tianeptine increased in time-dependent manner. Conclusion Our findings indicated that the tianeptine antidepressant effect may occur by induction of NCAM140 expression and CREB phosphorylation.