BACKGROUND:Perimenopause is characterized by ovarian hormone fluctuation and associated with elevated risk for depression. Perimenopausal-onset major depression (PO-MDD) can be alleviated with estrogen treatment. However, due to potential risk for breast and uterine cancer, traditional hormone treatments may not be suitable for some. Conjugated estrogen combined with the selective estrogen receptor modulator (SERM) bazedoxifene (CEB) is a tissue selective estrogen complex (TSEC) used to target hot flashes and postmenopausal osteoporosis. CEB's effect on mood during perimenopause remains understudied. METHODS:In this open-label pilot clinical trial, CEB was administered to perimenopausal women (N = 10) for three weeks with weekly symptom assessments and estradiol measurements. Mixed effects models were used to examine changes in affective and menopausal symptoms. RESULTS:Menopausal symptoms were significantly reduced over the course of treatment, and several depression symptom domains were also reduced (e.g., dysphoria, anhedonia, ill temper, insomnia; all pFDRs < 0.05). DISCUSSION:The current findings suggest that CEB reduces mood and menopausal symptoms without the concurrent risk profile of standard hormonal treatments. Further research is needed to understand potential links with estradiol variability and implications for the further development of treatments.

Task-sharing and telemedicine can increase access to effective psychotherapies. Scaling Up Maternal Mental healthcare by Increasing access to Treatment (SUMMIT) is pragmatic, multisite, noninferiority, four-arm trial that tested the non-inferiority of provider (non-specialist vs. specialist providers) and modality (telemedicine vs. in-person) in delivering psychotherapy for perinatal depressive symptoms. Across three university-affiliated networks in the United States and Canada, pregnant and postpartum adult participants were randomized 1:1:1:1 to each arm (472 nonspecialist telemedicine, 145 nonspecialist in-person, 469 specialist telemedicine and 144 specialist in-person) and offered weekly behavioral activation treatment sessions. The primary outcome was depressive symptoms (Edinburgh Postnatal Depression Scale (EPDS)) and the secondary outcome was anxiety (Generalized Anxiety Disorder (GAD-7)) symptoms at 3 months post-randomization. Between 8 January 2020 and 4 October 2023, 1,230 participants were recruited. Noninferiority was met for the primary outcome comparing provider (EPDS: nonspecialist 9.27 (95% CI 8.85-9.70) versus specialist 8.91 (95% CI 8.49-9.33)) and modality (EPDS: telemedicine 9.15 (95% CI 8.79-9.50) versus in-person 8.92 (95% CI 8.39-9.45)) for both intention-to-treat and per protocol analyses. Noninferiority was also met for anxiety symptoms in both comparisons. There were no serious or adverse events related to the trial. This trial suggests compelling evidence for task-sharing and telemedicine to improve access to psychotherapies for perinatal depressive and anxiety symptoms. ClinicalTrials.gov NCT04153864.

BACKGROUND:Perimenopause is associated with increases in depressive and vasomotor symptoms (VMS), which can be alleviated with transdermal estradiol (TE2) administration. Subcortical brain regions are commonly implicated in depression, are dense with E2 receptors and are susceptible to volumetric changes resulting from E2 regulation of synaptic density. No studies have examined linkages among TE2 administration, perimenopausal-onset major depression (PO-MDD) and subcortical brain volumes. METHODS:This is an exploratory data analysis of change in subcortical brain volumes measured via 3 T MRI before and after three-weeks of TE2 administration in 14 women with PO-MDD and 17 euthymic controls. Regions of interest were the hippocampus, amygdala, putamen, thalamus, and caudate nucleus. Multilevel models examined relations between baseline volumes and volumetric changes with symptom trajectories in the PO-MDD group. RESULTS:In the PO-MDD group, anhedonia (p < 0.004) and VMS (p < 0.001) significantly reduced following TE2 administration. There was a significant Group X Time interaction in the right hippocampus (p < 0.01), driven by volume increases in the control group (p < 0.001). In the PO-MDD group, change in right hippocampal volumes significantly predicted decreases in anhedonia trajectories from baseline to week 2 and week 3 (p's < 0.001) and decreases in VMS across all timepoints (p's < 0.001). DISCUSSION:Women with PO-MDD, who presented with more severe baseline anhedonia and VMS, experienced greater reductions in anhedonia, VMS, and hippocampal volumes, demonstrating a greater response to E2. Hippocampal volume change may be a candidate for predicting treatment response to E2 for anhedonia and vasomotor symptoms in women with PO-MDD. These findings should be validated with a placebo-controlled trial.

The perimenopausal transition is marked by an increased risk for affective dysregulation and major depressive disorder (MDD), with hormone replacement therapy using estradiol (E2) showing promise for alleviating symptoms of perimenopausal-onset MDD (PO-MDD). Although E2's effectiveness is recognized, its mechanisms underlying mood symptom modulation remain to be fully elucidated. Building on previous research suggesting that E2 may influence mood by altering cortico-subcortical connectivity, this study investigated the effects of transdermal E2 on resting-state functional connectivity (rsFC) in perimenopausal women with and without PO-MDD, focusing on rsFC changes using seed regions within reward and emotion processing networks. In this pharmaco-fMRI study, 16 participants with PO-MDD and 18 controls underwent rsFC analysis before and after three weeks of transdermal E2 administration. Pre-E2 results showed that the PO-MDD group, compared to controls, exhibited increased connectivity between the right amygdala (seed) and medial prefrontal cortex and anterior cingulate cortex, and decreased connectivity with the supplementary motor area. Comparing groups on change from pre-E2 to post-E2 revealed several significant E2-induced changes in connectivity between the PO-MDD and control groups: PO-MDD showed increased connectivity between the right caudate nucleus (seed) and left insula, and decreased connectivity between the right putamen (seed) and left hippocampus, and the right amygdala (seed) and left ventromedial prefrontal cortex. Notably, changes in connectivity were predictive of symptom trajectories across anhedonia, depressive mood, somatic, and vasomotor domains in the PO-MDD group. These findings enrich our understanding of PO-MDD by highlighting distinct rsFC patterns characteristic of the disorder and their shifts in response to E2 treatment, suggesting potential neural mechanisms underlying E2's mood-modulating effects.

Single-session behavioral activation (BA) and transcranial alternating current stimulation (tACS) are promising interventions for major depressive disorder (MDD). However, the synergy of combined single-session BA and tACS has not yet been evaluated. This pilot study assessed whether tACS augments the efficacy of single-session BA in individuals with MDD. N = 30 (M age=36, SD=15; 70 % female) participants with MDD were randomized to receive either: 1) tACS with BA or 2) sham tACS with BA. Change in depression and anhedonia symptoms were assessed (preregistration: NCT05693922). Clinician-rated depression and anhedonia showed significant effects of time, but no significant differences between conditions, with the exception of dysphoria. Specifically, between baseline and two-week follow-up, those in the verum condition demonstrated significantly less dysphoria than those in the sham condition; however, these significant differences did not maintain at one-month follow-up. While preliminary, this is the first study to assess the augmentation of psychotherapy with tACS for MDD and it further serves as a template for future studies using combined interventions to treat depression.

Background: Half of perimenopausal women experience depressive symptoms, including anhedonia. Anhedonia is associated with dysregulation of the frontostriatal circuit. Both the frontrostriatal circuit and depression may be regulated by the reproductive hormone estradiol (E2). Here, we present data from a pharmaco-fMRI trial investigating E2 effects on brain activation and anhedonia in those with perimenopause-onset major depression (PO-MDD). Methods: Participants with PO-MDD (n = 16) and those without depression (i.e., Controls; n = 19) received transdermal E2 for three weeks and completed two fMRI sessions (Pre- and Post-E2), and weekly anhedonia assessments. During each fMRI session, neural responses to anticipation and outcomes of monetary rewards were measured. Results: The PO-MDD group exhibited steeper declines in anhedonia following E2 administration (t(101.95) = -8.7, pFDR < 0.001). Contrary to a priori hypotheses, there were no group differences in striatal activation at baseline nor did striatal activation significantly change with E2 administration in either group. However, exploratory whole-brain analyses revealed a significant Group*Time interaction in a cluster spanning the right inferior, middle, and precentral gyri during reward anticipation (Z = 2.58 and pFWE < 0.05). From Pre-E2 to Post-E2, PO-MDD showed decreased activation within this cluster (t = 3.0, p < 0.009), whereas the Controls did not (t = 1.89, p = 0.08). Further, following E2 administration, both PO-MDD and Control groups exhibited reduced activation in the cerebellum, inferior and medial frontal gyri, and occipital pole during reward anticipation (Z = 2.58, pFWE < 0.05). Conclusions: While both anhedonia and right prefrontal activation during anticipatory reward processing were reduced in PO-MDD after three weeks of E2 administration, further research investigating the antidepressant effects of E2 is needed.

Introduction:Perinatal depression affects up to 30% of pregnant and postpartum women, which has increased since the COVID-19 pandemic, making rapidly identifying affected women a high clinical priority. While screening tools like the Edinburgh Postnatal Depression Scale (EPDS) are widely used, brevity is important for busy clinical practice to reduce administration time and patient burden. Current methods to shorten assessments rely on traditional psychometric approaches, rather than machine learning (ML) methods that could optimize predictive accuracy. Methods:We developed a ML framework using National Clinical Cohort Collaborative (N3C) data to predict full 10-item EPDS scores from shortened question subsets (n=22,924). We evaluated all 2-5 item combinations using linear regression, validating performance across multiple cohorts including postpartum women (n=7,750) and an external non-N3C pregnancy population (n=1,217). For additional validation, we applied our approach to the PHQ-9 (n=398,606) to test generalizability. Binary classification models using clinical thresholds (≥13) determined EPDS screening accuracy. Decision curve analysis was performed to assess the clinical utility of our ML method. Results:The optimal 2-question EPDS combinations Q4+Q8 (anxiety/sadness) and Q5+Q8 (scared/sadness) both achieved R2=0.70. Binary classification demonstrated strong performance (sensitivity=0.68-0.72, specificity=0.98-0.99). The framework generalized across postpartum subsets, external pregnancy cohorts, and PHQ-9 validation (R2=0.64-0.73). Adding covariates did not improve performance. Decision curve analysis showed our ML approach had superior clinical benefit (0.01-0.03) versus traditional additive scoring. Conclusion/Implications:Our ML framework suggests a reduced assessment burden with two EPDS questions maintains predictive accuracy as the full-item EPDS. With ~3.6 million annual U.S. births, this approach could identify additional positive perinatal depression screens, enhancing screening implementation across clinical settings.