Selective Serotonin Reuptake Inhibitors (SSRIs) are the most frequently prescribed class of drugs worldwide and are implemented in the treatment of depression and other psychiatric disorders. SSRIs relieve depressive symptoms by modulating levels of the neurotransmitter serotonin in the brain. SSRIs block the function of the serotonin transporter, thereby increasing concentrations of extracellular serotonin. However, serotonin levels in the neurons of the brain only account for 5% while the remaining 95% is present outside the brain. Serotonin receptors and transporter are located on bone resident cells (mesenchymal stem cells (MSCs)), osteoblasts and osteoclasts, and serotonergic activity is believed to affect bone homeostasis. Consequently, alterations in serotonin levels by SSRI treatment have the potential to alter bone formation and remodeling. Clinical reports correlate increase risk of bone fractures and delayed bone healing with SSRI use. Metallic implants are commonly used as orthopedic and dental implants to fix bony defects. Surface modifications have been used to increase the level of bone to implant contact by controlling the differentiation of MSCs into an osteoblastic linage and facilitate bone production. However, it is not known if SSRIs can affect MSCs osteoblastic differentiation and bone remodeling signaling in response to microstructured biomaterials. The aims of this study were: 1) Investigate the effects of SSRIs on MSCs differentiation on microstructured titanium (Ti), 2) Determine the effects of SSRIs on bone remodeling signaling and osteoclast activation, and 3) Elucidate the effects of SSRIs on serotonin receptors and their effect on bone remodeling. To investigate this, human MSCs were grown on tissue culture polystyrene (TCPS), smooth Ti (PT) or microstructured Ti (SLA) surfaces under exposure to therapeutic concentrations of commonly prescribed antidepressants (SSRIs (fluoxetine, sertraline, paroxetine), Selective Norepinephrine Reuptake Inhibitor (SNRI) (duloxetine) and other regularly prescribed antidepressants (bupropion)) during differentiation toward osteoblasts. Osteoblastic differentiation was assessed in MSCs after treatment with the drugs (0.1μM, 1μM, 10μM) by alkaline phosphatase activity and osteocalcin levels. Antidepressant treatment decreased levels of MSC differentiation markers on microstructured Ti surfaces. Furthermore, treatment dose-dependently decreased protein levels secreted by MSCs which are important for bone formation (BMP2, VEGF, Osteoprotegerin), and increased those involved in bone resorption (RANKL). To determine the effect of SSRIs on bone remodeling signaling and osteoclast activation, human osteoclasts were either directly exposed to antidepressants or conditioned media obtained from MSCs treated with antidepressants on Ti surfaces, after which, enzymatic tartrate-resistant acid phosphatase (TRAP) activity was assessed. Antidepressants increased TRAP activity both directly and through treated MSCs, with the highest levels evident after treatment with conditioned media from MSCs on microstructured Ti surfaces. To elucidate the effects of serotonin receptors and their effect on bone remodeling, receptors were pharmacologically inhibited. Surface roughness decreased gene expression of HTR2A, HTR1B, and HTR2B, and antidepressant treatment increased their expression. Inhibition of HTR2A decreased RANKL protein levels, while inhibition of other serotonin receptors had no effect on RANKL or OPG levels. These studies suggest that antidepressants inhibit MSCs differentiation on microstructured Ti surfaces and increase levels of proteins associated with bone resorption. Additionally, our results showed that RANKL is regulated by serotonin receptor HTR2A. Taken together, our results suggest that antidepressants have a negative effect on osteoblastic differentiation, compromising bone formation and enhancing bone resorption, which can be detrimental to patients under orthopedic and dental treatment.