Disturbed development of the enteric nervous system after in utero exposure of selective serotonin re-uptake inhibitors and tricyclic antidepressants. Part 1: Literature review

The increase in selective serotonin re-uptake inhibitor (SSRI) use during pregnancy, questions concerning abnormal development of the enteric nervous system (ENS), increase in laxative use in children and the association of fluoxetine with infantile hypertrophic pyloric stenosis (IHPS) gave rise to this pharmacological literature review. The role of 5-HT and the NE uptake in ontogeny of the ENS and the effects SSRIs and TCAs might have on the development of the ENS were investigated. The literature study showed that SSRIs may influence the development of the ENS in two ways. Blockage of the serotonin re-uptake transporter (SERT) during foetal development could influence migration, differentiation and survival of cells. This could lead to abnormal development in the first trimester of pregnancy. The other way is that 5-HT seems to be a growth factor in the primitive ENS. This growth factor like action is mediated through the 5-HT(2B) receptor and stimulation of this receptor by SSRIs influences the fate of late-developing enteric neurons. This could lead to abnormal development in the second and third trimester. TCAs could influence the development of the ENS, besides through inhibition of the SERT, through inhibition of the norepinephrine transporter (NET). Expression of the NET seems to be essential for a full development of enteric neurons and especially for serotonergic neurons. In addition the NET was detected early in ontogeny and precedes neuronal differentiation, which suggests that TCAs might influence development of the ENS when exposed early in pregnancy. The insights of this study gave rise to hypotheses which will be tested in an epidemiological cohort study.