Hippocampal volume changes in a pharmacological sex-hormone manipulation risk model for depression in women.

Hormone transition phases may trigger depression in some women, yet the underlying mechanisms remain elusive. In a pharmacological sex-hormone manipulation model, we previously reported that estradiol reductions, induced with a gonadotropin-releasing hormone agonist (GnRHa), provoked subclinical depressive symptoms in healthy women, especially if neocortical serotonin transporter (SERT) binding also increased. Within this model, we here evaluated if GnRHa, compared to placebo, reduced hippocampal volume, in a manner that depended on the magnitude of the estradiol decrease and SERT binding, and if this decrease translated to the emergence of subclinical depressive symptoms. Sixty-three healthy, naturally cycling women were included in a randomized, double-blind, placebo-controlled GnRHa-intervention study. We quantified the change from baseline to follow-up (n = 60) in serum estradiol (ΔEstradiol), neocortical SERT binding ([11C] DASB positron emission tomography; ΔSERT), subclinical depressive symptoms (Hamilton depression rating scale; ΔHAMD-17), and hippocampal volume (magnetic resonance imaging data analyzed in Freesurfer 7.1, ΔHippocampus). Group differences in ΔHippocampus were evaluated in a t-test. Within the GnRHa group, associations between ΔEstradiol, ΔHippocampus, and ΔHAMD-17, in addition to ΔSERT-by-ΔEstradiol interaction effects on ΔHippocampus, were evaluated with linear regression models. Mean ΔHippocampus was not significantly different between the GnRHa and placebo group. Within the GnRHa group, hippocampal volume reductions were associated with the magnitude of estradiol decrease (p = 0.04, Cohen's f2 = 0.18), controlled for baseline SERT binding, but not subclinical depressive symptoms. There was no ΔSERT-by-ΔEstradiol interaction effects on ΔHippocampus. If replicated, our data highlight a possible association between estradiol fluctuations and hippocampal plasticity, adjusted for serotonergic contributions.

The role of central serotonergic markers and estradiol changes in perinatal mental health.

OBJECTIVE: Women have an increased risk for mental distress and depressive symptoms in relation to pregnancy and birth. The serotonin transporter (SERT) may be involved in the emergence of depressive symptoms postpartum and during other sex-hormone transitions. It may be associated with cerebrospinal fluid (CSF) levels of the main serotonin metabolite 5-hydroxyindolacetic acid (5-HIAA). In 100 healthy pregnant women, who were scheduled to deliver by cesarean section (C-section), we evaluated 5-HIAA and estradiol contributions to mental distress 5 weeks postpartum. METHODS: Eighty-two women completed the study. CSF collected at C-section was analyzed for 5-HIAA, with high performance liquid chromatography. Serum estradiol concentrations were quantified by liquid chromatography tandem mass spectrometry before C-section and postpartum. Postpartum mental distress was evaluated with the Edinburgh Postnatal Depression Scale (EPDS). Associations between EPDS, 5-HIAA, and Δestradiol were evaluated in linear regression models adjusted for age, parity and SERT genotype. RESULTS: Higher levels of postpartum mental distress symptoms were negatively associated with a large decrease in estradiol concentrations (ßΔE2  = 0.73, p = 0.007) and, on a trend level, positively associated with high antepartum 5-HIAA levels (ß5-HIAA  = 0.002, p = 0.06). CONCLUSION: In a cohort of healthy pregnant women, postpartum mental distress was higher in women with high antepartum 5-HIAA (trend) and lower in women with a large perinatal estradiol decrease. We speculate that high antepartum 5-HIAA is a proxy of SERT levels, that carry over to the postpartum period and convey susceptibility to mental distress. In healthy women, the postpartum return to lower estradiol concentrations may promote mental well-being.

The cortisol awakening response is blunted in healthy women early postpartum.

INTRODUCTION: The dynamic capacity of the hypothalamic-pituitary-adrenal (HPA) axis supports healthy adaptions to stress and play a key role in maintaining mental health. Perinatal adaptations in the HPA-axis dynamics in terms of the Cortisol Awakening Response (CAR), may be involved in dysregulation of perinatal mental health. We aimed to determine if CAR and absolute evening cortisol early postpartum differed from non-perinatal women and evaluate the association between the CAR and maternal mental well-being. METHODS: The CAR was computed as the area under the curve with respect to increase from baseline from serial home-sampling of saliva across 0-60 minutes from awakening. We evaluated differences in CAR and absolute evening cortisol between postpartum women (N=50, mean postpartum days: 38, SD: ±11) and non-perinatal women (N=91) in a multiple linear regression model. We also evaluated the association between CAR and maternal mental well-being in a multiple linear regression model. RESULTS: We found that healthy postpartum women had a blunted CAR (p<0.001) corresponding to 84% reduction and 80% lower absolute evening cortisol (p<0.001) relative to non-perinatal healthy women. In the postpartum group, there was a trend-level association between lower CAR and higher scores on the WHO Well-Being Index (WHO-5) (p=0.048) and lower Edinburgh Postnatal Depression Scale (EPDS) scores (p=0.04). CONCLUSION: Our data emphasize the unique hormonal landscape during the postpartum period in terms of blunted CAR and lower absolute evening cortisol in healthy women early postpartum compared to non-perinatal. Our findings show a potential association between a reduced CAR and improved mental well-being during early motherhood, which suggests that reduced CAR might reflect healthy adjustment to early motherhood.

Chronic escitalopram in healthy volunteers has specific effects on reinforcement sensitivity: a double-blind, placebo-controlled semi-randomised study.

Several studies of the effects on cognition of selective serotonin reuptake inhibitors (SSRI), administered either acutely or sub-chronically in healthy volunteers, have found changes in learning and reinforcement outcomes. In contrast, to our knowledge, there have been no studies of chronic effects of escitalopram on cognition in healthy volunteers. This is important in view of its clinical use in major depressive disorder (MDD) and obsessive-compulsive disorder (OCD). Consequently, we aimed to investigate the chronic effect of the SSRI, escitalopram, on measures of 'cold' cognition (including inhibition, cognitive flexibility, memory) and 'hot cognition' including decision-making and particularly reinforcement learning. The study, conducted at the University of Copenhagen between May 2020 and October 2021, used a double-blind placebo-controlled design with 66 healthy volunteers, semi-randomised to receive either 20 mg of escitalopram (n = 32) or placebo (n = 34), balanced for age, sex and intelligence quotient (IQ) for at least 21 days. Questionnaires, neuropsychological tests and serum escitalopram measures were taken. We analysed group differences on the cognitive measures using linear regression models as well as innovative hierarchical Bayesian modelling of the Probabilistic Reversal Learning (PRL) task. The novel and important finding was that escitalopram reduced reinforcement sensitivity compared to placebo on both the Sequential Model-Based/Model-Free task and the PRL task. We found no other significant group differences on 'cold' or 'hot' cognition. These findings demonstrate that serotonin reuptake inhibition is involved in reinforcement learning in healthy individuals. Lower reinforcement sensitivity in response to chronic SSRI administration may reflect the 'blunting' effect often reported by patients with MDD treated with SSRIs. Trial Registration: NCT04239339 .

Stress-Hormone Dynamics and Working Memory in Healthy Women Who Use Oral Contraceptives Versus Non-Users.

Background: Women who use oral contraceptives (OCs) may have a higher risk of developing a depression, which is associated with both vulnerability to stress and cognitive dysfunction. OCs disrupt the hypothalamic-pituitary-gonadal (HPG) axis by suppressing endogenous sex steroid production including estradiol. The HPG axis and the hypothalamic-pituitary-adrenal (HPA) axis are known to interact, possibly through modulations driven by estradiol. OCs may affect HPA regulation capacity, i.e., disturb cortisol dynamics such as the cortisol awakening response (CAR), and influence cognition such as working memory (WM). We hypothesize that OC use is associated with blunted cortisol dynamics and impaired WM performance relative to non-users. Methods: Data from 78 healthy women in the reproductive age were available from the CIMBI database. We evaluated if CAR and WM differed between OC users (n=25) and non-users (n=53) and if the level of estradiol modulated the OC use effect on CAR or WM in generalized least square models. Results: We found that OC users had a blunted CAR (p= 0.006) corresponding to a 61% reduction relative to non-users; however, no estradiol-BY-OC use interaction effect was observed on CAR. Also, OC users had higher cortisol levels at awakening compared to non-users (p = 0.03). We observed no effect of OC use or an estradiol-BY-OC use interaction effect on WM. Also, within the OC user group, neither CAR nor WM was associated with suppressed estradiol. CAR was not associated with WM. Conclusion: Healthy women who use OCs have blunted cortisol dynamics relative to non-users. However, we could not detect OC use effects on working memory in our sample size. We speculate that disrupted cortisol dynamics may be important for the emergence of depressive symptoms in OC users.

Short-term oestrogen as a strategy to prevent postpartum depression in high-risk women: protocol for the double-blind, randomised, placebo-controlled MAMA clinical trial.

INTRODUCTION: Postpartum depression affects 10%-15% of women and has a recurrence rate of 40% in subsequent pregnancies. Women who develop postpartum depression are suspected to be more sensitive to the rapid and large fluctuations in sex steroid hormones, particularly estradiol, during pregnancy and postpartum. This trial aims to evaluate the preventive effect of 3 weeks transdermal estradiol treatment immediately postpartum on depressive episodes in women at high risk for developing postpartum depression. METHODS AND ANALYSIS: The Maternal Mental Health Trial is a double-blind, randomised and placebo-controlled clinical trial. The trial involves three departments of obstetrics organised under Copenhagen University Hospital in Denmark. Women who are singleton pregnant with a history of perinatal depression are eligible to participate. Participants will be randomised to receive either transdermal estradiol patches (200 µg/day) or placebo patches for 3 weeks immediately postpartum. The primary outcome is clinical depression, according to the Diagnostic and Statistical Manual of Mental Disorders-V criteria of Major Depressive Disorder with onset at any time between 0 and 6 months postpartum. Secondary outcomes include, but are not limited to, symptoms of depression postpartum, exclusive breastfeeding, cortisol dynamics, maternal distress sensitivity and cognitive function. The primary statistical analysis will be performed based on the intention-to-treat principle. With the inclusion of 220 participants and a 20% expected dropout rate, we anticipate 80% power to detect a 50% reduction in postpartum depressive episodes while controlling the type 1 error at 5%. ETHICS AND DISSEMINATION: The study protocol is approved by the Regional Committees on Health Research Ethics in the Capital Region of Denmark, the Danish Medicines Agency and the Centre for Data Protection Compliance in the Capital Region of Denmark. We will present results at scientific meetings and in peer-reviewed journals and in other formats to engage policymakers and the public. TRIAL REGISTRATION NUMBER: NCT04685148.

Amygdala response to emotional faces in seasonal affective disorder.

BACKGROUND: Seasonal affective disorder (SAD) is characterized by seasonally recurring depression. Heightened amygdala activation to aversive stimuli is associated with major depressive disorder but its relation to SAD is unclear. We evaluated seasonal variation in amygdala activation in SAD and healthy controls (HC) using a longitudinal design targeting the asymptomatic/symptomatic phases of SAD. We hypothesized increased amygdala activation to aversive stimuli in the winter in SAD individuals (season-by-group interaction). METHODS: Seventeen SAD individuals and 15 HCs completed an implicit emotional faces BOLD-fMRI paradigm during summer and winter. We computed amygdala activation (SPM5) to an aversive contrast (angry & fearful minus neutral) and angry, fearful and neutral faces, separately. Season-by-group and main effects were evaluated using Generalized Least Squares. In SAD individuals, we correlated change in symptom severity, assessed with The Hamilton Rating Scale for Depression - Seasonal Affective Disorder version (SIGH-SAD), with change in amygdala activation. RESULTS: We found no season-by-group, season or group effect on our aversive contrast. Independent of season, SAD individuals showed significantly lower amygdala activation to all faces compared to healthy controls, with no evidence for a season-by-group interaction. Seasonal change in amygdala activation was unrelated to change in SIGH-SAD. LIMITATIONS: Small sample size, lack of positive valence stimuli. CONCLUSIONS: Amygdala activation to aversive faces is not increased in symptomatic SAD individuals. Instead, we observed decreased amygdala activation across faces, independent of season. Our findings suggest that amygdala activation to angry, fearful and neutral faces is altered in SAD individuals, independent of the presence of depressive symptoms.