Introduction: Antipsychotics are a class of psychotropic medication used in the treatment of psychosis. Given the potential harm of not treating psychosis, administration is recommended during pregnancy; however, resultant congenital abnormalities and preterm birth have been described. To date there is no clear evidence on the effects of antipsychotics on fetal bone development. Therefore, we aimed to investigate the effects of antipsychotics on embryonic bone formation in-vivo using zebrafish as a model.
Methods: The effect of first- (haloperidol; FGA), second- (olanzapine; SGA) and third- (aripiprazole; TGA) generation antipsychotics on early zebrafish bone development was measured using alizarin red staining. Osteoblast development marker expression (runx2b, col10a1, spp1) was measured using whole mount in-situ hybridization, with the total area of staining measured in pixel/µM. Embryos were treated from 36-50 hpf for runx2b and 36-72 hpf for col10a1 and spp1. Dopamine (drd1b and drd2a), serotonin (htr2b) and adrenergic receptor (adrb2b) expression profiles were measured along with a marker of apoptosis (casp3a).
Results: Each antipsychotic inhibited zebrafish bone formation in a dose-dependent manner, where haloperidol was the most potent inhibitor, followed by aripiprazole and then olanzapine. Expression of osteoblast genes were decreased with treatment of 10µM for haloperidol and aripiprazole, whereas olanzapine reduced bone development at 30µM. There was no effect on casp3a expression upon antipsychotic exposure, or on dopamine or serotonin receptor expression. However, higher concentration of olanzapine increased adrb2b expression, while lower concentrations had no effect.
Conclusion: Each antipsychotic dose dependently inhibited bone development, with haloperidol and aripiprazole being the most potent inhibitors compared to olanzapine. Haloperidol- and aripiprazole-induced bone loss was not due to apoptosis nor did antipsychotic exposure effect dopamine, serotonin or adrenergic receptor expression, while olanzapine-induced bone loss could be due to increased adrb2b expression. Further work into the potential signalling pathways is needed to understand the mechanisms involved in antipsychotic induced bone loss.