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

Hutchison, Sarah M; Mâsse, Louise C.; Pawluski, Jodi L.; Oberlander, Tim F.

doi:10.1016/j.reprotox.2020.11.013

Cited by 29 publications

(31 citation statements)

References 173 publications

(223 reference statements)

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“…Maternal prenatal depressed mood has been associated with preterm birth (< 37 weeks of gestation), growth and developmental delays, and increased postnatal infant stress 8 , 9 . Additionally, the literature suggests that the presence of maternal depressive symptoms independent of SSRI therapy is associated with increases in offspring childhood internalizing behaviours and affective disorders, though these exposures are hard to separate in human studies 10 . Animal studies have permitted further investigation into the effect of maternal depressed mood on offspring outcomes by enabling the randomization of SSRI treatment.…”

Section: Introductionmentioning

confidence: 99%

“…Animal studies have permitted further investigation into the effect of maternal depressed mood on offspring outcomes by enabling the randomization of SSRI treatment. Rodent models have confirmed that associations identified between maternal depressed mood and offspring anxiety disorders are not mediated by SSRI exposure, and that SSRI treatment does not protect offspring from these outcomes; this topic is reviewed in 10 .…”

Section: Introductionmentioning

confidence: 99%

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Profiling placental DNA methylation associated with maternal SSRI treatment during pregnancy

Inkster

Konwar

Peñaherrera

et al. 2022

Sci Rep

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Selective serotonin reuptake inhibitors (SSRIs) for treatment of prenatal maternal depression have been associated with neonatal neurobehavioral disturbances, though the molecular mechanisms remain poorly understood. In utero exposure to SSRIs may affect DNA methylation (DNAme) in the human placenta, an epigenetic mark that is established during development and is associated with gene expression. Chorionic villus samples from 64 human placentas were profiled with the Illumina MethylationEPIC BeadChip; clinical assessments of maternal mood and SSRI treatment records were collected at multiple time points during pregnancy. Case distribution was 20 SSRI-exposed cases and 44 SSRI non-exposed cases. Maternal depression was defined using a mean maternal Hamilton Depression score > 8 to indicate symptomatic depressed mood (“maternally-depressed”), and we further classified cases into SSRI-exposed, maternally-depressed (n = 14); SSRI-exposed, not maternally-depressed (n = 6); SSRI non-exposed, maternally-depressed (n = 20); and SSRI non-exposed, not maternally-depressed (n = 24). For replication, Illumina 450K DNAme profiles were obtained from 34 additional cases from an independent cohort (n = 17 SSRI-exposed, n = 17 SSRI non-exposed). No CpGs were differentially methylated at FDR < 0.05 comparing SSRI-exposed to non-exposed placentas, in a model adjusted for mean maternal Hamilton Depression score, or in a model restricted to maternally-depressed cases with and without SSRI exposure. However, at a relaxed threshold of FDR < 0.25, five CpGs were differentially methylated (|Δβ| > 0.03) by SSRI exposure status. Four were covered by the replication cohort measured by the 450K array, but none replicated. No CpGs were differentially methylated (FDR < 0.25) comparing maternally depressed to not depressed cases. In sex-stratified analyses for SSRI-exposed versus non-exposed cases (females n = 31; males n = 33), three additional CpGs in females, but none in males, were differentially methylated at the relaxed FDR < 0.25 cut-off. We did not observe large-scale alterations of DNAme in placentas exposed to maternal SSRI treatment, as compared to placentas with no SSRI exposure. We also found no evidence for altered DNAme in maternal depression-exposed versus depression non-exposed placentas. This novel work in a prospectively-recruited cohort with clinician-ascertained SSRI exposure and mood assessments would benefit from future replication.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Profiling placental DNA methylation associated with maternal SSRI treatment during pregnancy

Inkster

Konwar

Peñaherrera

et al. 2022

Sci Rep

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“…Changes in anxiety-like behavior, due to maternal stress, were previously described by several research groups [ 41 , 70 ]. Although there are controversial results regarding effect of chronic pregestational stress on anxiety-like behavior of offspring, possibly due to the different stress paradigm strategies, a great proportion of studies postulate that male offspring whose mothers were submitted to stress before or during pregnancy are more reluctant to enter and spent time in the open arm of the elevated plus maze [ 71 – 73 ]. Effect of perinatal mirtazapine treatment on anxiety-like behavior of offspring, in our study present only in females, may be due to the antagonism that mirtazapine exerts on noradrenergic autoreceptors that in turn enhances the noradrenergic transmission opposing the stress-related response [ 74 ].…”

Section: Discussionmentioning

confidence: 99%

Sex- and age- dependent effect of pre-gestational chronic stress and mirtazapine treatment on neurobehavioral development of Wistar rat offspring

et al. 2022

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Hormonal fluctuations, such as the perinatal period, may increase susceptibility of women to depression, which in turn exert a negative impact on child’s neurodevelopment, becoming a risk factor in development of neuropsychiatric disorders. Moreover, the use of antidepressants during this critical period presents a serious health concern for both the mother and the child, due to the consequences of treatment in terms of the reliability and safety for the proper neurodevelopment of the organism being not well known. Atypical antidepressants, such as mirtazapine, that targets both serotonergic and noradrenergic systems in the central nervous system (CNS), represent a novel focus of research due to its unique pharmacological profile. The aim of this work was to study the effects of maternal depression and/or perinatal antidepressant mirtazapine treatment on the neurobehavioral development of the offspring. Pre-gestationally chronically stressed or non-stressed Wistar rat dams were treated with either mirtazapine (10 mg/kg/day) or vehicle during pregnancy and lactation followed by analysis of offspring’s behavior at juvenile and adolescent age. We found mirtazapine induced significant alterations of nursing behavior. In offspring, pregestational stress (PS) had an anxiogenic effect on adolescent males (p≤0.05) and increased their active behavior in forced swim test (p≤0.01). Interaction between pregestational stress and mirtazapine treatment variously induced anxiolytic changes of juvenile (p≤0.05) and adolescent (p≤0.05) females and impairment of spatial memory (p≤0.01) in adolescent females as well. Hippocampal density of synaptophysin, pre-synaptic protein marker, was decreased mainly by mirtazapine treatment. In conclusion, our results show mirtazapine induced significant alterations in maternal behavior and several sex- and age-dependent changes in neurobehavioral development of offspring caused by both prenatal mirtazapine treatment and/or chronic pregestational stress.

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“…Changes in anxiety-like behavior, due to maternal stress, were previously described by several research groups (28,56). Although there are controversial results regarding effect of chronic pregestational stress on anxiety-like behavior of offspring, possibly due to the different stress paradigm strategies, a great proportion of studies postulate that male offspring whose mothers were submitted to stress before or during pregnancy are more reluctant to enter and spent time in the open arm of the elevated plus maze (57–59). This effect of perinatal mirtazapine treatment on anxiety-like behavior of offspring may be due to the antagonism that mirtazapine exerts on noradrenergic autoreceptors that in turn enhances the noradrenergic transmission opposing the stress-related response (60).…”

Section: Discussionmentioning

confidence: 99%

Sex- and age- dependent effect of pre-gestational chronic stress and mirtazapine treatment on neurobehavioral development of offspring

Viñas-Noguera

Csatlósová

Šimončičová

et al. 2021

Preprint

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Hormonal fluctuations, such as the perinatal period, may increase susceptibility of women to depression, which in turn exert a negative impact on child’s neurodevelopment, becoming a risk factor in development of neuropsychiatric disorders. Moreover, the use of antidepressants during this critical period presents a serious health concern for both the mother and the child, due to the consequences of treatment in terms of the reliability and safety for the proper neurodevelopment of the organism being not well known. Atypical antidepressants, such as mirtazapine, that targets both serotonergic and noradrenergic systems in the central nervous system (CNS), represent a novel focus of research due to its unique pharmacological profile. The aim of this work was to study the effects of maternal depression and/or perinatal antidepressant mirtazapine treatment on the neurobehavioral development of the offspring. Pre-gestationally chronically stressed or non-stressed Wistar rat dams were treated with either mirtazapine (10 mg/kg/day) or vehicle during pregnancy and lactation followed by analysis of offspring’s behavior at juvenile and adolescent age. We found mirtazapine induced alterations of nursing behavior. In offspring, pregestational stress (PS) had an anxiogenic effect on adolescent males and increased their active behavior in forced swim test. Interaction between pregestational stress and mirtazapine treatment variously induced anxiolytic changes of juvenile and adolescent females and impairment of spatial memory in adolescent females as well. Hippocampal density of synaptophysin, pre-synaptic protein marker, was decreased mainly by mirtazapine treatment. In conclusion, our results show mirtazapine induced alterations in maternal behavior and several sex- and age-dependent changes in neurobehavioral development of offspring caused by both prenatal mirtazapine treatment and/or chronic pregestational stress.

show abstract

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

Cited by 29 publications

References 173 publications

Profiling placental DNA methylation associated with maternal SSRI treatment during pregnancy

Profiling placental DNA methylation associated with maternal SSRI treatment during pregnancy

Sex- and age- dependent effect of pre-gestational chronic stress and mirtazapine treatment on neurobehavioral development of Wistar rat offspring

Sex- and age- dependent effect of pre-gestational chronic stress and mirtazapine treatment on neurobehavioral development of offspring

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