Assessment of the consequences of gestational SSRI antidepressant exposure in the rat

Although the most common psychotropic drugs prescribed in pregnancy are selective serotonin reuptake inhibitor (SSRI) antidepressants, their health impact on the resultant offspring is largely unknown due to the ethical challenges of assessment clinically. Fluoxetine, paroxetine, sertraline, and citalopram are members of the SSRI class, which alter serotonin, a key neurotransmitter dysregulated in many psychiatric disorders and a fundamental guide for embryogenesis and the formations of brain structure and function. As all SSRIs cross the placental barrier, there is the potential for them to affect the developing foetus. The incidence of perinatal depression has increased, and pharmacological intervention is deemed necessary to reduce the risks of miscarriage and harm to the pregnant woman that may manifest if the depression is untreated. Current preclinical models are lacking as many are focused on fluoxetine, however, recent clinical birth-outcome data suggests that different teratogenic risks are dependent on the particular SSRI exposed. The current work aims to individually evaluate gestational exposure in Sprague-Dawley rats from gestational day (GD) 7-21 via oral gavage to a range of doses (1.25, 2.5, 5, or 10 mg/kg depending on the SSRI) of the four aforementioned SSRIs in a longitudinal study; examining parameters of maternal wellbeing as well as male and female progeny measurements of neonatal development, behaviour in adolescence and adulthood, and behavioural response to anxiolytic and acute antidepressant drug treatment in adulthood. Fluoxetine, paroxetine, and sertraline caused profound effects on maternal wellbeing and neonatal mortality. Neonatal advances, in regards to somatic and behavioural development, were induced by fluoxetine and sertraline exposure, with fluoxetine increasing male ano-genital distance and sertraline promoting successful forelimb grip behaviours in males when compared to respective controls. Most notably, citalopram induced no effects on the parameters measured; further, no enduring consequences were found in adulthood on the specific parameters assessed after any of the SSRI exposures. Additionally, paroxetine treatment accentuated existing differences in sex by increasing male and decreasing female ambulation during adolescence. Furthermore, this model confirms a novel automated approach to assessing behavioural despair after antidepressant treatment and highlights that traditional behavioural models developed for male rodents may not be adequate in measuring female behaviour. Overall, this research highlights factors of offspring sex and age and more importantly emphasizes the differences in dose-dependent findings attributed to distinct SSRIs. Interestingly, while citalopram had no significant effects on maternal wellbeing or offspring development, this drug was also tolerated at a higher dose range than fluoxetine or paroxetine. Moreover, the work also provides a model for assessing perinatal exposure to psychotropic drugs which acknowledges important maternal and offspring parameters in a manner that is transferable to the clinical scenario. Thus, the current results applied to the clinical scenario could inform physicians in prescribing SSRIs to treatment-naïve pregnant women which commonly face depression during pregnancy, presenting citalopram as the best treatment option of the four SSRIs for both the mothers and progeny, based on the parameters assessed here. Lastly, this longitudinal study has the potential to inform physicians of critical periods of risk for the individuals exposed to the SSRIs, thus anticipating that additional care may be required during these early life periods, while also concluding that many offspring behaviours are normalized by adulthood.2021-10-0