In vitro and in vivo reproduction toxicology of 12 monoaminergic reuptake inhibitors: Possible mechanisms of infrequent cardiovascular anomalies

The rat Whole Embryo Culture (WEC) has been used to predict the potential teratogenicity of 12 selective/mixed monoaminergic reuptake inhibitors (MRUI). WEC results were compared with in vivo animal and human epidemiological teratogenicity data. In vitro, paroxetine and the positive control retinol were the only compounds identified as a clear teratogen, but developmental morphological indicators suggestive of a teratogenic potential were observed for most other MRUIs, including fluoxetine, citalopram and venlafaxine. No clear evidence of teratogenic potential was observed for three compounds, however, all compounds assessed showed a dose-dependent general embryotoxicity.In vivo testing of nine MRUIs for teratogenicity was limited by maternal toxicity (e.g. anorexia) without showing overt embryotoxicity (e.g. implantation loss). Next to complete absence, the cardiovascular (CV) anomalies observed (mostly) in rabbits ranged from a low incidence (e.g. above historical background of 0.35%) to a clear incidence (mean 4.1%).It is suggested that observed specific malformations in vitro (e.g. branchial bars deformed, displaced or additional otic system), not noted in any (historical) controls, may be early ontogenetic indicators for infrequent CV-anomalies observed in vivo. Despite the low incidence of anomalies in vitro or in vivo, they may yet be clinically relevant as in the case of paroxetine. Possible mechanisms are discussed, e.g. perturbed neural crest cell migration.