Modulation of Serotonin Transporter Function during Fetal Development Causes Dilated Heart Cardiomyopathy and Lifelong Behavioral Abnormalities

Abstract

BackgroundWomen are at great risk for mood and anxiety disorders during their childbearing years and may become pregnant while taking antidepressant drugs. In the treatment of depression and anxiety disorders, selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed drugs, while it is largely unknown whether this medication affects the development of the central nervous system of the fetus. The possible effects are the product of placental transfer efficiency, time of administration and dose of the respective SSRI.Methodology/Principal FindingsIn order to attain this information we have setup a study in which these parameters were measured and the consequences in terms of physiology and behavior are mapped. The placental transfer of fluoxetine and fluvoxamine, two commonly used SSRIs, was similar between mouse and human, indicating that the fetal exposure of these SSRIs in mice is comparable with the human situation. Fluvoxamine displayed a relatively low placental transfer, while fluoxetine showed a relatively high placental transfer. Using clinical doses of fluoxetine the mortality of the offspring increased dramatically, whereas the mortality was unaffected after fluvoxamine exposure. The majority of the fluoxetine-exposed offspring died postnatally of severe heart failure caused by dilated cardiomyopathy. Molecular analysis of fluoxetine-exposed offspring showed long-term alterations in serotonin transporter levels in the raphe nucleus. Furthermore, prenatal fluoxetine exposure resulted in depressive- and anxiety-related behavior in adult mice. In contrast, fluvoxamine-exposed mice did not show alterations in behavior and serotonin transporter levels. Decreasing the dose of fluoxetine resulted in higher survival rates and less dramatic effects on the long-term behavior in the offspring.ConclusionsThese results indicate that prenatal fluoxetine exposure affects fetal development, resulting in cardiomyopathy and a higher vulnerability to affective disorders in a dose-dependent manner.

Prenatal Antidepressant Exposure: Clinical and Preclinical Findings

“…Continuous infusion of fluoxetine in sheep via maternal femoral vein catheter yielded concentrations in maternal and fetal serum of ;150 and ;60 ng/ml, respectively; no measurements of norfluoxetine were obtained (Morrison et al, 2004). Similar results were found in mice: placental transfer of fluoxetine was 69%, whereas human placental transfer is 73% (Noorlander et al, 2008). Placental transfer comparing rodents and humans is also reported for fluvoxamine (30% in mice, 35% in humans).…”

“…These findings were noted to be strongly indicative of pulmonary hypertension (Fornaro et al, 2007). Noorlander et al (2008) also reported that mice prenatally exposed to fluoxetine manifested decreased left ventricle wall thickness, a measure of dilated cardiomyopathy, on PND20 and 90. These findings provide some concordant data regarding persistent pulmonary hypertension reported in the clinical population.…”

“…The serum concentrations of fluoxetine and norfluoxetine were not determined in this study, but our experience suggests that this may be a clinically relevant exposure. A similar study examining prenatal fluvoxamine exposure reported decreased SERT immunoreactivity in the raphe on PND20 and 90 (Noorlander et al, 2008). Only one study has investigated nonserotonergic receptors and reported no changes in D 1 or D 2 receptor binding in the striatum on PND20 after prenatal fluoxetine exposure (Stewart et al, 1998).…”

“…Several animal studies examined these properties in the context of prenatal SSRI exposure with conflicting results. Impaired weight gain, low birth weight, or small litter size after prenatal SSRI exposure has been reported in several studies (da-Silva et al, 1999;Bairy et al, 2007;Pereira et al, 2007;Cagiano et al, 2008;Favaro et al, 2008;Forcelli and Heinrichs, 2008;Noorlander et al, 2008;Van den Hove et al, 2008;Bauer et al, 2010), whereas other studies observe no differences in weight gain or birth weight (Byrd and Markham, 1994;Stewart et al, 1998;Vartazarmian et al, 2005;Lisboa et al, 2007). Congenital malformations are reported in the clinical literature but have only been reported in the animal literature by extracting and exposing mouse embryos in vitro to 20 times the clinically observed serum concentration of sertraline for 48 hours (Shuey et al, 1992).…”

Fetal Effects of Selective Serotonin Reuptake Inhibitor Treatment During Pregnancy: Immediate and Longer Term Child Outcomes

“…In the UK antidepressant prescribing during pregnancy increased fourfold from 1992 to 2006, with Selective Serotonin Reuptake Inhibitors (SSRIs) most often chosen 5 . SSRIs cross the human placenta, with fetal levels varying according to treatment type 6,7 and are found in amniotic fluid 8 . The significance of prenatal exposure to SSRIs and outcomes in terms of the physical health and the neurodevelopment of the infant and child remain unclear.…”