Hypothalamic–pituitary–adrenal (HPA) axis function in 3-month old infants with prenatal selective serotonin reuptake inhibitor (SSRI) antidepressant exposure

Abstract

Background

Prenatal exposure to stress and selective serotonin reuptake inhibitors (SSRIs) alter hypothalamic–pituitary–adrenal (HPA) stress reactivity in offspring, however, the effects of combined exposure to HPA activity in human infants is unknown.

Objective

To examine HPA basal levels and stress responsiveness in 3-month olds with prenatal exposure to SSRIs.

Methods

Salivary cortisol levels in infants of SSRI treated mothers (n = 31, mean exposure 230.2 ± 72.2 days) were compared with non-SSRI exposed (n = 45) infants in response to a challenge (infant-controlled habituation task) and under basal conditions in the late afternoon/early evening. Mode of feeding, to account for possible postnatal drug exposure via breast milk, as well as measures of pre and postnatal maternal mood, were included as covariates.

Results

Lower post-stress cortisol levels were observed in non-SSRI exposed/non-breastfed infants compared with non-SSRI exposed infants who were breastfed at 3 months of age. Stress reactivity patterns among SSRI exposed infants did not differ with mode of feeding. The cortisol reactivity slope (CRS) was significantly lower among non-SSRI exposed non-breastfed infants compared with non-SSRI exposed breastfed infants. Early evening basal cortisol levels were lower in SSRI exposed infants than in non-SSRI exposed infants, controlling for maternal mood and mode of feeding. Postnatal SSRI exposure (infant SSRI drug levels) via breast milk was not associated with stress or basal cortisol levels. Total cortisol, reflected by the AUC measure, did not differ significantly between exposure groups.

Conclusions

Prenatal SSRI exposure altered HPA stress response patterns and reduced early evening basal cortisol levels. Stress challenge HPA response differences only became apparent when the moderating effect of method of feeding was accounted for. These findings suggest an early “programming” effect of antenatal maternal mood, prenatal SSRI exposure and postnatal maternal care giving on the HPA system.

Introduction

The development and function of the hypothalamic–pituitary–adrenal (HPA) and the serotonergic (5HT) regulatory systems are highly interrelated [1] and are exquisitely sensitive to the effects of early adverse experience [2]. Among the earliest adverse experiences is exposure to maternal depression during pregnancy, which alters HPA and 5-HT function and potentially sets a life course of vulnerability to illness [3], [4], [5]. While, antenatal exposure to stress in animal models and to maternal mood disorders in humans might not constitute similar etiological or phenomenological adverse experiences, they both appear to share a final common pathway that affects HPA function in offspring, possibly via altered 5HT levels. In animals, prenatal and early postnatal stress is associated with increased corticosterone responses to mild stressors in adulthood [6], mediated by altered 5HT and 5HT receptors [7]. In humans, offspring of depressed and anxious mothers may have an increased risk for neonatal neurobehavioral [4] and physiological disturbances, such as increased cortisol and norepinephrine levels and lower dopamine and 5-HT levels [8]. Central 5HT plays a key role in regulating the HPA system, and in turn, HPA hormones modulate 5-HT function [9], [10]. Importantly, prenatal stress in animal models lowers plasma and hippocampal serotonergic activity [11], [12] leading to reduced HPA adaptation to stressors [13].

Increasingly, the use of selective (and non-selective) serotonin reuptake inhibitor (SSRI) antidepressants which act by blocking the reuptake of 5HT, thereby increasing levels of central 5HT, are used to manage maternal mood disorders during pregnancy [14], raising concerns that such exposure may alter HPA development and function in offspring. Depression has been characterized by increased HPA activity and resistance to suppression of cortisol by dexamethasone [15] and SSRI antidepressants, which potentiate central 5HT activity, are thought to “normalized” HPA function [16]. In an animal model, Ishiwata et al. [17] observed that early postnatal SSRI (fluoxetine) treatment of prenatally stressed mice “normalized” corticosterone responses to a subsequent stressor, increased 5HT turnover in the hippocampus and restored the ability to learn spatial information compared with the effects of exposure to prenatal stress alone. This might be analogous to a “normalized” HPA activity that may following SSRI antidepressant treatment secondary to increased glucocorticoid receptor (GR) and GR mRNA levels [16]. To date, such effects have not been examined in humans following gestational antidepressant exposure. However, given serotonin's role as a trophic developmental signal [18], mediating hippocampal GR expression and subsequent HPA stress reactivity, changes in basal or stress HPA function following prenatal exposure to maternal depression alone or together with SSRI medication may occur.

Given the highly interrelated nature of the serotonergic and HPA systems, it is conceivable that prenatal SSRI exposure will lead to altered HPA regulation in human infants. The following study was undertaken to examine the effects of prenatal SSRI exposure on HPA activity, indexed by salivary cortisol levels, at 3 months of age in two settings: first, during a stress challenge (infant-controlled habituation and novelty response procedure) and second, under basal conditions in the late afternoon/early evening. Further, as some infants at 3 months also received postnatal SSRI exposure via breastfeeding, we examined the potential influence of mode of feeding and related infant drug levels as possible confounding variables. We hypothesized that prenatal SSRI exposure would have long term effects on HPA basal function and stress reactivity, even when accounting for SSRI drug levels at 3 months (i.e. via postnatal exposure in breastfeeding infants) and depressed maternal mood.