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.
Highlights
Mood and anxiety disorders such as depression, panic disorder and obsessive-compulsive disorder are common in women during their childbearing years [1,2]
These results indicate that prenatal fluoxetine exposure affects fetal development, resulting in cardiomyopathy and a higher vulnerability to affective disorders in a dose-dependent manner
Several studies have reported no associations between congenital malformations and prenatal selective serotonin reuptake inhibitors (SSRIs) exposure, it has been recently shown that fetal exposure to SSRIs results in an increased risk of adverse neonatal effects, including neurological abnormalities, cardiac malformations and persistent pulmonary hypertension [5,6,7,8,9,10,11]
Summary
Mood and anxiety disorders such as depression, panic disorder and obsessive-compulsive disorder are common in women during their childbearing years [1,2]. In the treatment of depression and anxiety disorders during pregnancy, selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed drugs nowadays. Lower birth weight and an increased risk of preterm birth have been observed after prenatal SSRI treatment [12,13]. It is unknown whether this medication affects the development of the central nervous system of the fetus. 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
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