Citalopram and sertraline exposure compromises embryonic bone development.
Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed treatments for depression and, as a class of drugs, are among the most used medications in the world. Concern regarding possible effects of SSRI treatment on fetal development has arisen recently as studies have suggested a link between maternal SSRI use and an increase in birth defects such as persistent pulmonary hypertension, seizures and craniosynostosis. Furthermore, SSRI exposure in adults is associated with decreased bone mineral density and increased fracture risk, and serotonin receptors are expressed in human osteoblasts and osteoclasts. To determine possible effects of SSRI exposure on developing bone, we treated both zebrafish, during embryonic development, and human mesenchymal stem cells (MSCs), during differentiation into osteoblasts, with the two most prescribed SSRIs, citalopram and sertraline. SSRI treatment in zebrafish decreased bone mineralization, visualized by alizarin red staining and decreased the expression of mature osteoblast-specific markers during embryogenesis. Furthermore, we showed that this inhibition was not associated with increased apoptosis. In differentiating human MSCs, we observed a decrease in osteoblast activity that was associated with a decrease in expression of the osteoblast-specific genes Runx2, Sparc and Spp1, measured with quantitative real-time PCR (qRT-PCR). Similar to the developing zebrafish, no increase in expression of the apoptotic marker Caspase 3 was observed. Therefore, we propose that SSRIs inhibit bone development by affecting osteoblast maturation during embryonic development and MSC differentiation. These results highlight the need to further investigate the risks of SSRI use during pregnancy in exposing unborn babies to potential skeletal abnormalities.
Metabolic Genetic Diseases Laboratory, Metabolic Research Unit, School of Medicine, Deakin University, Geelong, VIC, Australia.|IMPACT and MMR Strategic Research Centres, School of Medicine, Deakin University, Geelong, VIC, Australia.
D
D
Fraher
IMPACT and MMR Strategic Research Centres, School of Medicine, Deakin University, Geelong, VIC, Australia.|Barwon Biomedical Research, University Hospital, Geelong, VIC, Australia.
J M
JM
Hodge
IMPACT and MMR Strategic Research Centres, School of Medicine, Deakin University, Geelong, VIC, Australia.
F M
FM
Collier
Barwon Biomedical Research, University Hospital, Geelong, VIC, Australia.
J S
JS
McMillan
Barwon Biomedical Research, University Hospital, Geelong, VIC, Australia.
R L
RL
Kennedy
Metabolic Genetic Diseases Laboratory, Metabolic Research Unit, School of Medicine, Deakin University, Geelong, VIC, Australia.|IMPACT and MMR Strategic Research Centres, School of Medicine, Deakin University, Geelong, VIC, Australia.
M
M
Ellis
Barwon Biomedical Research, University Hospital, Geelong, VIC, Australia.
G C
GC
Nicholson
Metabolic Genetic Diseases Laboratory, Metabolic Research Unit, School of Medicine, Deakin University, Geelong, VIC, Australia.|IMPACT and MMR Strategic Research Centres, School of Medicine, Deakin University, Geelong, VIC, Australia.
K
K
Walder
IMPACT and MMR Strategic Research Centres, School of Medicine, Deakin University, Geelong, VIC, Australia.
S
S
Dodd
IMPACT and MMR Strategic Research Centres, School of Medicine, Deakin University, Geelong, VIC, Australia.|Orygen, The National Centre of Excellence in Youth Mental Health and the Centre for Youth Mental Health, Department of Psychiatry, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC, Australia.
M
M
Berk
IMPACT and MMR Strategic Research Centres, School of Medicine, Deakin University, Geelong, VIC, Australia.|Department of Medicine, Northwest Academic Centre, The University of Melbourne, St Albans, VIC, Australia.
J A
JA
Pasco
IMPACT and MMR Strategic Research Centres, School of Medicine, Deakin University, Geelong, VIC, Australia.
L J
LJ
Williams
Metabolic Genetic Diseases Laboratory, Metabolic Research Unit, School of Medicine, Deakin University, Geelong, VIC, Australia.|IMPACT and MMR Strategic Research Centres, School of Medicine, Deakin University, Geelong, VIC, Australia.
Y
Y
Gibert
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001842:Bone and Bones / Q000187:drug effects* / Q000196:embryology*; D002113:Calcification, Physiologic / Q000187:drug effects / Q000502:physiology; D002356:Cartilage / Q000187:drug effects / Q000196:embryology; D002478:Cells, Cultured; D015283:Citalopram / Q000633:toxicity*; D004195:Disease Models, Animal; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000502:physiology; D010006:Osteoblasts / Q000187:drug effects / Q000502:physiology; D010012:Osteogenesis / Q000187:drug effects / Q000502:physiology; D017367:Selective Serotonin Reuptake Inhibitors / Q000633:toxicity*; D020280:Sertraline / Q000633:toxicity*; D015027:Zebrafish
D015283:Citalopram; D017367:Selective Serotonin Reuptake Inhibitors; D020280:Sertraline