In this study, researchers hypothesized that antidepressants have a class- and dose-dependent effect on mesenchymal stem cell (MSC) differentiation, which may affect bone metabolism. Use of antidepressant medications has been linked to detrimental bone mineral density and osteoporosis; However, the cellular basis behind these observations remains poorly understood.

The effect does not appear to be homogeneous across the whole class of drugs and may be linked to the serotonin transporter system. Maintenance of the human skeleton is dependent on the balance between bone deposition and bone resorption, which are mediated by osteoblasts and osteoclasts, respectively.

Failure to maintain bone mass can lead to an architectural decline in bone structure, which results in osteoporosis and a predisposition to fractures. Mesenchymal stem cells (MSC) within the bone marrow differentiate into osteoblasts and thus play an important role in bone integrity.

There is an increase in the volume of adipose tissue and a decrease in bone formation in osteoporotic bone, suggesting an inverse relationship between imbalanced adipogenesis and osteoblastogenesis, and the lipotoxic effect of marrow adipocytes on other bone cells. 

The differentiation process of MSC in bone marrow is regulated by an intricate set of interactions between numerous molecular factors. A disruption in the balance of this mechanism results in a change in differentiation outcomes.  In this study, they examined the effect of antidepressants with different mechanisms of action on the differentiation of hMSC into osteoblasts and adipocytes using mineralization.

Interestingly, while fluoxetine had a strong inhibitory effect on both mineralization and abiogenesis, amitriptyline and venlafaxine had only modest effects on adipogenesis and negligible effect on mineralization.differentiation of hMSC into osteoblasts and adipocytes using mineralization, alkaline phosphatase activity, and lipid staining as surrogate markers for these processes.

Interestingly, while fluoxetine had a strong inhibitory effect on both mineralization and abiogenesis, amitriptyline and venlafaxine had only modest effects on adipogenesis and negligible effect on mineralization. A novel observation of this study is the effect of antidepressants on adipogenesis, which has been partially explored in the past.

It would be expected that inhibition of osteoblastogenesis would be associated with higher adipogenesis, however, this was not the case. The observation that this antidepressant affected adipogenesis suggest that this effect is also associated with the serotonin-regulated pathways.

However, this effect occurred under most treatment conditions, indicating that even low levels of serotonin activity could be a strong inhibitor of adipogenesis.  The direct effect of serotonin on adipogenic pathways of hMSC should be a subject of future studies.however, this was not the case.

The observation that all our tested antidepressants affected adipogenesis suggests that this effect is also associated with the serotonin-regulated pathways. However, this effect occurred under most treatment conditions thus indicating that even low levels of serotonin activity could be a strong inhibitor of adipogenesis.

In conclusion, the data presented here support our hypothesis that antidepressants affect differentiation of hMSC to osteoblasts and adipocytes and that each class of antidepressant has a varying influence on MSC differentiation, which was previously unknown, and seems to be dependent on their affinity for the 5-HTT-a hypothesis that deserves further exploration.

The direct effect of serotonin on adipogenic pathways of hMSC should be a subject of future studies. The use of antidepressants in clinical practice has dramatically increased in recent years, how these drugs are associated with osteoporosis and fracture risk is pivotal and this may influence our prescribing practices as our knowledge increases.