Modulation of serotonin transporter function during fetal development causes dilated heart cardiomyopathy and lifelong behavioral abnormalities.
BACKGROUND
Women 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.


RESULTS
In 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.


CONCLUSIONS
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.
Noorlander
Cornelle W
CW
Rudolf Magnus Institute of Neuroscience, Department of Neuroscience and Pharmacology, University Medical Center Utrecht, Utrecht, The Netherlands.
Ververs
Frederique F T
FF
Nikkels
Peter G J
PG
van Echteld
Cees J A
CJ
Visser
Gerard H A
GH
Smidt
Marten P
MP
D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy; D001522:Behavior, Animal; D002311:Cardiomyopathy, Dilated / Q000378:metabolism*; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology; D008279:Magnetic Resonance Imaging; D018811:Maternal Exposure; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011248:Pregnancy Complications; D011270:Pregnancy, Animal; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism / Q000502:physiology*; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use
D000928:Antidepressive Agents; D005473:Fluoxetine; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors