Perinatal selective serotonin reuptake inhibitor exposure and behavioral outcomes: a systematic review and meta-analyses of animal studies

Abstract

<jats:title>Abstract</jats:title><jats:p>In the Western world, 2-5% of pregnant women use selective serotonin reuptake inhibitor (SSRI) antidepressants. There is no consensus on the potential long-term neurodevelopmental outcomes of early SSRI exposure. Our aim was to determine whether there is an overall effect of perinatal SSRI exposure in animals on a spectrum of behavioral domains. After a comprehensive database search in PubMed, PsycINFO, and Web of Science, we included 99 publications. We performed nine meta-analyses and two qualitative syntheses corresponding to different behavioral categories, aggregating data from thousands of animals. We found evidence for reduced activity and exploration behavior (standardized mean difference (SMD) −0.28 [-0.38, −0.18]), more passive stress coping (SMD −0.37 [-0.52, −0.23]), and less efficient sensory processing (SMD −0.37 [-0.69, −0.06]) in SSRI-versus vehicle-exposed animals. No differences were found for anxiety (p=0.06), social behavior, learning and memory, ingestive- and reward behavior, motoric behavior, or reflex and pain sensitivity. Exposure in the period equivalent to the human third trimester was associated with the strongest effects.</jats:p><jats:sec><jats:title>Highlights</jats:title><jats:p><jats:list list-type="bullet"><jats:list-item><jats:p>Perinatal SSRI exposure in rodents alters outcomes in three behavioral domains.</jats:p></jats:list-item><jats:list-item><jats:p>It leads to reduced activity, passive stress coping, and weaker sensory processing.</jats:p></jats:list-item><jats:list-item><jats:p>Females are understudied but seem to be less vulnerable than males.</jats:p></jats:list-item><jats:list-item><jats:p>Early postnatal exposure in rodents leads to the largest effects on behavior.</jats:p></jats:list-item><jats:list-item><jats:p>This is equivalent to the third trimester of pregnancy in humans.</jats:p></jats:list-item></jats:list></jats:p></jats:sec>

Perinatal selective serotonin reuptake inhibitor (SSRI) and other antidepressant exposure effects on anxiety and depressive behaviors in offspring: A review of findings in humans and rodent models

“…Rodent studies suggest that perinatal SSRIs, and other types of antidepressant medications to treat maternal stress-related disorders, are not consistently associated with changes in offspring anxiety as the majority of tasks administered report null results (n = 75, 56%, see Figure 2). These conclusions are consistent with a recent meta-analyses that found no significant differences between animals with and without perinatal SSRI exposure in relation to anxiety behaviors (p = .06; Ramsteijn et al, 2020). However, our conclusion diverges from Grieb and Ragan (2019) who suggest that perinatal SSRI treatment modifies anxiety behaviors as our count of null results (n = 75) exceed the count of tasks demonstrating increased and decreased anxiety behaviors (total n = 45, 14, respectively).…”

“…Recent reviews have reported the effects of perinatal SSRI exposure on offspring social behaviors, neurodevelopmental disorders, anxious behavior, and cognition (Gemmel et al, 2018;Grieb & Ragan, 2019;Millard et al, 2017;Ramsteijn et al, 2020). This review focuses on the effects of perinatal SSRI exposure on both anxiety and depression in offspring as there is considerable overlap between these two affective behaviors, possibly reflecting a common stressrelated origin (Smoller, 2016).…”

Perinatal exposure to fluoxetine and maternal adversity affect myelin-related gene expression and epigenetic regulation in the corticolimbic circuit of juvenile rats

“…Preclinical evidence in rodents suggests that males are more vulnerable to develop long-term behavioral effects after perinatal SSRI exposure than females 87 . For example, our lab has identified stronger effects of perinatal fluoxetine exposure on social behavior in males than in females 63 .…”

“…First, we investigated both the PFC and BLA, which revealed a clear brain region-dependent effect on myelin-related gene expression after exposure to perinatal fluoxetine exposure and maternal adversity. Second, we studied both sexes, whereas this is still surprisingly uncommon in animal research 87 as well as human imaging studies 84 , despite strong indications for sex-specificity. Third, we used the same tissue punches for transcriptomic analyses and targeted DNA methylation analyses, enabling direct correlations.…”

“…Neurodevelopmental patterns 37 , including serotonin system-specific ones [38][39][40] , are remarkably conserved between rodents and humans, with the first postnatal weeks in rodents corresponding to the third trimester of pregnancy in humans 41 . In a metaanalysis of rodent behavioral outcomes, we showed that perinatal SSRI exposure is associated with reduced activity and exploration behavior, a more passive stress-coping style, and less efficient sensory processing 42 .…”