Antidepressant use during pregnancy and the neurodevelopmental effects on the offspring

Depressive symptoms frequently occur during pregnancy and can tremendously affect the developing child. The number of women suffering from depression during pregnancy in Norway doubled in the last 15 years. Over the last years, antidepressants have gained acceptance as medication during pregnancy, which resulted in an increase in the prescription rate in pregnant women. However, antidepressants can cross the placenta and thereby affect the development of the fetus and newborn. Moreover, the potential effect of the drugs on the progeny may be mediated also by a change in the dynamic of the mother-infant relationship. Unfortunately, the developmental effects of antidepressant exposure during pregnancy on the fetus and mother-infant interaction are poorly documented. This project aims to investigate the biological mechanisms and behavioral effects of AD treatment on the offspring throughout lifetime: in juvenile ages, adolescent ages, and at adulthood including maternal behavior. We evaluate the effects on depressive-, anxiety-, and social-emotional behavior. In addition, the project aims to study the influences of multiple life-events on the behavioral outcomes in the offspring. The first part of this project uses a seminatural environmental approach in which rats live in groups and can freely express their full repertoire of behavior, thereby mimicking the real-life environment of children. The effects of AD use during pregnancy on the offspring are investigated in a social context, in which the consequences of environmental influences and life-events can be determined. In the second part, more traditional test set-ups are used to study the effects on social behavior in more detail. Additionally, we will monitor the circulating levels of the AD along time in order to evaluate the administration efficacy and calculate the level of AD passively delivered to the offspring. Ultimately, the results of this project will be beneficial for human health by opening up new strategies for biomedical research and therapeutic applications. This project will need a maximum of 1059 Wistar rats (522 males and 537 females, from which 113 mothers, 98 fathers, and 848 offspring), which is carefully calculated with a power analysis. The severity category in this proposal is expected to be moderate. This kind of experiments cannot be replaced by other models. First of all, there are no methods to study brain mechanisms in humans at such a detailed level. Second, computer simulations or in vitro studies are too simplified compared to the reality. Finally, only in living animals it is possible to study these complex behavioral systems.

The Norwegian Food Safety Authority can ask for retrospectively assessment for experiments. You must therefore submit necessary information making it possible for us to evaluate 1) whether the objectives of the project were achieved, 2) the harm inflicted on the animals, and 3) any elements that may contribute to further implementation of 3 R in future studies. This information must be submitted via FOTS.

The main aim of the project was to investigate the biological mechanisms and behavioral effects of Selective serotonin reuptake inhibitors (SSRIs, in this study fluoxetine, FLX) treatment during pregnancy on the offspring throughout lifetime, with a special focus on the influences of multiple life-events on the behavioral outcomes in the offspring. Although not all planned studies have been conducted due to lack of time, the main objectives of the study have been achieved. While not all planned studies were completed due to time constraints, the main goals of the study were achieved. Our findings thus far suggest that SSRI treatment during pregnancy may increase the risk of social impairments and non-social behaviors in offspring, underscoring its potential impact on child development. These findings have implications for biomedical research and therapeutic interventions, offering insights into potential avenues for improving human health outcomes.
The study has used fewer animals than initially intended due to the omission of some planned experiments. As these omitted studies involved procedures categorized as moderately severe, the overall severity of the project was reduced from the original plan. Furthermore, transitioning to naturally cycling females instead of ovariectomized ones contributed to lowering the project's severity to a mild level.
Our study was designed such to prioritize the principles of the 3Rs from the start (appropriate design and power analysis). We implemented strategies to minimize the use of animals, refine procedures to reduce any potential discomfort or distress, and explore alternatives where feasible. As such we have attempted (but were unfortunately unsuccessful) to replace the oral gavage FLX administration, and changed the procedures from ovariectomized to naturally cycling females. Given our proactive approach to adhering to these principles, we believe that further enhancements will be difficult for studies of this nature.