There is little doubt that serotonin influences bone biology. Bone loss in elderly patients on long-term selective serotonin receptor inhibitor (SSRI) or tricyclic (TCA) anti-depressant (AD) medication is considered to be secondary to a more sedentary lifestyle. However, a recent report suggested that in mice treated with SSRIs or TCAs the disturbances in normal bone mass was unrelated to the activity levels of the animal (Warden 2010). This could imply that psychoactive agents have a direct effect on normal bone cell metabolism. We have tested this hypothesis in vitro. Two SSRIs (fluoxetine hydrochloride (FLU) and citalopram hydrobromide (CIT)) and two TCAs (amitriptyline hydrochloride (AMI) and clomipramine hydrochloride (CLO)) in various doses at, above and below serum levels in treated patients (0.06μM–10μM) were added to rat osteoblast-like UMR106 cells and the effect on cell proliferation (DNA content per well) and alkaline phosphatase (AlkP) activity (soluble reaction product) assessed. After 72 hours treatment with SSRI or TCA (0.6μM), there was significant reduction in AlkP activity. DNA content was significantly reduced in all cases, except FLU. These data demonstrate a direct effect of ADs on bone cell behaviour.