Serotonin Transporter Occupancy in Rats Exposed to Serotonin Reuptake Inhibitors In Utero or via Breast Milk

Abstract

Rigorous data regarding fetal central nervous system (CNS) exposure after antidepressant exposure are sparse. The magnitude of serotonin reuptake inhibitor (SRI) CNS exposure was measured in three groups of rats using ex vivo autoradiography of the serotonin transporter (SERT): 1) in utero, 2) postnatal clearance after birth, and 3) exposure through lactation. Rats were exposed to one of five SRI-type antidepressants (escitalopram, fluoxetine, paroxetine, sertraline, and venlafaxine) administered continuously via osmotic minipumps to pregnant or nursing dams. Dam dosing was adjusted to reflect the 50th and 85th percentiles of serum concentrations observed in pregnant women. Embryonic day 21 rat pups exposed in utero exhibited Ͼ80% SERT occupancy in brain tissue, which is equivalent to that of the pregnant dam and similar to that reported for human pharmacotherapy. Venlafaxine was the exception with occupancies ranging from 61 to 92% across different litters. The magnitude of SERT occupancy is essentially equivalent between dams and fetuses. By postnatal day 4, high SERT occupancy was observed only in fluoxetine-exposed pups (41-92% occupancy). Significantly less, but measurable, exposure occurred via breast milk exposure even in the absence of detectable drug concentrations in nursing pup sera. Pups exposed to SRIs via breast milk for 3 or 7 days exhibited varying SERT occupancies (0 -57% depending on the individual medication and dam dose). These data highlight the need for animal modeling of fetal and nursing infant drug exposure using clinically meaningful dosing strategies and appropriate CNS measures to develop rational treatment guidelines that systematically minimize fetal and neonatal medication exposure in humans.

Prenatal Antidepressant Exposure: Clinical and Preclinical Findings

“…2). Although we observed variable placental transfer, fetal CNS exposure is similar to that of the pregnant dam (Capello et al, 2011). Direct measurement of monoamine Fig.…”

“…Postnatally, SERT occupancy rapidly dropped after parturition as predicted from the pharmacokinetics of the drugs in rodents. Exposure via breast milk resulted in measurable but generally low SERT occupancy (Capello et al, 2011). This was demonstrated independently for escitalopram, fluoxetine, paroxetine, sertraline, and venlafaxine (Fig.…”

“…Placental transfer comparing rodents and humans is also reported for fluvoxamine (30% in mice, 35% in humans). Comparing maternal serum concentrations and amniotic fluid concentrations, our group observed variable placental transfer depending on the antidepressant used (Capello et al, 2011).…”

“…Notably, the increasing milk: plasma ratios roughly correlate with the degree of protein binding for individual medications. Our previous work utilizing octanol partition coefficients as an index of lipophilicity of antidepressants (Capello et al, 2011) suggests that venlafaxine should have the lowest transfer into breast milk if driven primarily by lipophilicity.…”

Genome-wide DNA methylation in neonates exposed to maternal depression, anxiety, or SSRI medication during pregnancy

“…However, a number of studies have in fact recently found the same relative patterns of inter-individual variability in methylation levels across brain and blood, despite large tissue-specific differences within individuals. 35 Furthermore, stress hormones, such as cortisol, and SSRI medications can cross the placental barrier and have been detected in cord blood, 36,37 and thus these cells may be directly affected by these exposures.…”