Graziano Pinna

Women’s mental health remains underrepresented in biomedical research despite the substantial burden associated with postpartum depression, premenstrual dysphoric disorder, anxiety disorders, major depressive disorder, and related psychiatric conditions that are more common in women than men. Progress in biological characterization and biomarker development has been constrained by the limited availability of validated, standardized methods that account for reproductive stage, hormonal fluctuations, and sex-specific biology. Neuroactive steroids, including allopregnanolone, regulate neuronal excitability and stress responsivity through modulation of γ-aminobutyric acid type A (GABA-A) receptors. Alterations in neurosteroid biosynthesis, GABA-A receptor plasticity, and their coordinated regulation may therefore contribute to vulnerability across reproductive transitions and other periods of increased risk for mood disorders. Moreover, genes encoding neurosteroidogenic enzymes and GABA-A receptor subunits are susceptible to epigenetic regulation in response to hormonal, inflammatory, traumatic, and environmental exposures. This study aims to establish and validate a blood-based molecular platform for detecting and quantifying the expression of GABA-A receptor subunits; neurosteroidogenic enzymes, including 5α-reductase types 1 and 2, 5β-reductase, and 3α- and 3β-hydroxysteroid dehydrogenases; and epigenetic regulators from the ten-eleven translocation, histone deacetylase, and DNA methyltransferase. Whole blood provides a minimally invasive matrix suitable for repeated longitudinal assessment. Integrating these neurobiological signatures may provide a more comprehensive representation of the neurosteroid–GABAergic axis and its epigenetic regulation than examining individual markers alone. This methodological platform is intended to support future studies of biological vulnerability, disease progression, and treatment response, thereby facilitating the translation of experimental neurosteroid research into clinically relevant applications in women’s mental health and psychiatric populations more broadly.

In PTSD, microglia are more engaged in fear-related circuits, where they participate in fear memory processing responses. The reconsolidation-impairing effect of Δ⁹-tetrahydrocannabinol (THC), the primary psychoactive constituent of Cannabis, is typically linked to cannabinoid type-1 receptor (CB1) signaling. THC also engages peroxisome proliferator-activated receptor gamma (PPARγ), and both CB1 and PPARγ modulate neuroimmune processes, including microglial activity. This dual mechanism suggests that THC’s impact on fear memory reconsolidation may extend beyond classical cannabinoid signaling. We hypothesize that THC disrupts contextual fear memory reconsolidation via microglial recruitment in the dorsal hippocampus (DH) through a sex-specific engagement of CB1 and PPARγ. Adult male and female Wistar rats underwent contextual fear conditioning, followed by THC (0.002 mg/kg, i.p.) or vehicle administration immediately after memory retrieval. Microglial involvement was assessed using immunofluorescence and pharmacological and chemogenetic inhibition in DH. The role of CB1 and PPARγ receptors was assessed via intra-DH selective antagonist infusion. THC impaired reconsolidation in males and females. In males, fear memory retrieval increased microglial engagement in the DH CA1 subfield, which THC further enhanced. Pharmacological and chemogenetic inhibition of microglia, as well as selective CB1 and PPARγ antagonism, blocked THC’s effects in males. In females, THC-induced reconsolidation blockade was cycle-dependent, occurring at estrus and diestrus but not at proestrus, and was mediated exclusively through CB1 activation. These findings identified sex-specific neuroimmune pathways mediating THC’s reconsolidation impairment, offering a mechanistic basis for novel sex-tailored therapeutic opportunities.

Menstrual cycle affective change (MCAC), including conditions like Premenstrual Dysphoric Disorder (PMDD), is triggered by ovarian hormone fluctuations, but its neurobiological mechanisms remain poorly understood. A leading hypothesis implicates abnormal GABA-A receptor (GABA_AR) subunit regulation in altering sensitivity to neuroactive steroids, a theory difficult to test in humans. We examined peripheral mRNA expression of GABRD, GABRG2, and GABRA5 in a transdiagnostic sample of 112 participants (75 psychiatric outpatients with suicidality; 37 controls) to capture a dimensional range of MCAC severity. Participants provided daily affect ratings and five LH-timed blood samples using PAXgene tubes for RT-PCR analysis. Replicating preclinical findings, GABRG2 expression decreased during the midluteal phase. Critically, individual differences in both person-mean expression and perimenstrual change (AUCi) were correlated with cyclical symptom trajectories. Greater perimenstrual increases or higher average expression were associated with classic luteal-phase worsening of anxiety (GABRG2, GABRA5), irritability (GABRG2), and suicidal ideation (GABRG2, GABRA5, GABRD). However, relative to those with moderate or stable expression, perimenstrual decreases or lower average expression were also linked to cyclical worsening of anxiety and suicidal ideation that emerged around menses and persisted into the follicular phase. Overall, more stable subunit expression was associated with less cyclical symptom change. These findings could be consistent with a loss of homeostatic stability in GABAergic plasticity, rather than a simple unidirectional differences in levels or changes, as a potential correlate of MCAC. Peripheral GABAAR gene expression warrants further investigation, particularly in experimental studies, to determine whether there are causal associations between subunit gene expression and MCAC.

Perinatal psychiatry stands at the intersection of neurobiology, psychosocial dynamics, and public health. As the field evolves, it has become increasingly clear that the molecular mechanisms underpinning perinatal mental health are deeply entwined with social and environmental determinants, particularly the presence or absence of support systems during pregnancy and postpartum. Beyond psychosocial influences, recent advances in biomarker discovery have begun to unravel the complex neuroendocrine and immunological pathways that shape vulnerability and resilience to perinatal depression (1)(2)(3).At the molecular level, perinatal depression has been associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis (4), altered neurosteroid biosynthesis. especially deficits in allopregnanolone and related GABAergic modulators (5,6), and inflammatory activation that can perturb neurotransmitter signaling (7). These biological alterations interact dynamically with psychosocial stressors, forming a biopsychosocial network in which chronic stress, hormonal withdrawal, and insufficient social buffering converge to precipitate depressive symptomatology. Peripheral biomarkers, including neuroactive steroids, inflammatory cytokines (e.g., IL-6, TNF-α), cortisol rhythms, and epigenetic markers of stress-responsive genes (8)(9)(10), provide measurable frameworks into these mechanisms and may ultimately guide individualized risk prediction and intervention strategies.Against this backdrop, the integration of biological and psychosocial research has become essential to advancing perinatal psychiatry. This special feature brings together four pivotal studies that collectively deepen our understanding of how targeted psychosocial interventions can influence both the clinical course and the molecular correlates of perinatal depression. Together, they illustrate how bridging biomarker research and community-based preventive approaches can redefine the prevention and treatment of mood disorders during one of the most biologically and socially sensitive periods of a woman's life.A large-scale cross-sectional study by He and colleagues evaluated the prevalence and determinants of prenatal depression among 4,564 pregnant individuals in Beijing. The prevalence of perinatal depressive symptoms was 4.1% based on the Edinburgh Postnatal Depression Scale, reflecting a lower rate compared to global estimates. The study identified parity, weight gain as indicated by higher BMI, and occupational status as significant predictors of depressive symptoms. These findings highlight not only biological and sociodemographic risk factors but also underscore the need for nuanced screening frameworks that integrate metabolic vulnerability with psychosocial context.Complementing this epidemiological perspective, Wenzel and colleagues investigated variability in neuroactive steroid derivatives of progesterone across different clinical profiles of perinatal depression, accounting for pre-pregnancy history of major depressive disorder and timing of depression onset. By analyzing blood samples from 98 pregnant participants during the first and second trimesters, they found that allopregnanolone, isoallopregnanolone, and pregnanolone levels were significantly elevated in those with perinatal-emergent depression. This suggests distinct neurosteroid pathways underlying different depression subtypes observed during pregnancy.This pattern points to heterogeneous neurosteroid trajectories during pregnancy that may reflect dysfunction within the GABAergic stress-regulatory system. These findings lend neurobiological support to the notion that perinatal depression encompasses distinct phenotypes influenced by psychiatric vulnerability, hormonal transitions, and individual variability in neurosteroid biosynthetic capacity. Differential modulation of neurosteroids may underlie specific temporal and symptomatic subtypes of perinatal depression, offering potential biomarker targets for early risk stratification and tailored intervention.Moving from mechanisms to intervention, Tessema and colleagues conducted a clusterrandomized controlled trial across 32 health centers involving 550 pregnant women to investigate the impact of antenatal group-based psychoeducation on postnatal social support and postpartum depression. The intervention was grounded in a knowledgebased framework: by educating pregnant women and their caregivers about the multifaceted nature of postpartum depression (PPD) and its effects on mothers, infants, and families, the intervention aimed to strengthen awareness of social support needs and mobilize assistance.The psychoeducation was delivered to pregnant women with moderate to severe depressive symptoms based on PHQ-9 scores during early pregnancy by frontline clinicians, who were trained by experienced psychiatrists. Sessions emphasized strategies for improving social support among postnatal mothers, leveraging the early pregnancy window when women may be more receptive to intervention before depressive symptoms intensify. The findings revealed significant increases in postnatal social support among those receiving the intervention, with participants demonstrating a reduced risk of PPD. The underlying premise proved effective: the more informed care recipients and informal caregivers became aware of the consequences of poor social support, the greater the assistance mothers received during the critical postpartum period.In the second component of the trial, Tessema and colleagues examined factors that made the prenatal group-based psychoeducation intervention effective at preventing PPD. The intervention reduced PPD incidence from 28.9% in the control group to 7.6% in the intervention group. The study emphasized the protective role of multiple interconnected factors, including enhanced social support, partner's emotional support, PPD literacy, and improved self-esteem. Additionally, the research...

Sex and gender disparities have emerged as critical determinants of COVID-19 outcomes, with males exhibiting higher hospitalization and mortality rates than females. Sex steroids such as estradiol, progesterone, and testosterone have been proposed as modulators of these differences, given their known roles in inflammation, immune function, and vascular health. However, the precise hormonal mechanisms underlying COVID-19 severity, particularly among individuals with comorbid hypertension—a major risk factor for adverse outcomes—remain unclear. In this study, we investigated circulating levels of key sex hormones and their neuroactive metabolites in 116 hypertensive COVID-19 patients enrolled through an urban academic emergency department. Our findings revealed distinct sex-based hormonal profiles and associations with disease severity. Males exhibited higher serum estradiol and testosterone levels, while progesterone levels were significantly higher in postmenopausal females. Notably, hospitalized patients showed elevated estradiol and progesterone levels compared to non-hospitalized individuals, whereas ICU-admitted patients had significantly lower concentrations of all three hormones. A unique exception was ICU-admitted postmenopausal females, who exhibited increased serum testosterone levels relative to non-ICU females. Additionally, in males, elevated 3α-diol was associated with hospitalization and ICU admission, while lower allopregnanolone and estradiol levels correlated with hypoxia in males and females, respectively. These results highlight a dynamic, sex-specific hormonal response to COVID-19 progression in hypertensive individuals, suggesting early upregulation and late depletion of protective sex steroids. Understanding these patterns may improve clinical risk stratification and inform the development of sex-targeted therapeutic interventions for COVID-19 and related inflammatory conditions.

Sex and gender disparities have emerged as critical determinants of COVID-19 outcomes, with males exhibiting higher hospitalization and mortality rates than females. Sex steroids such as estradiol, progesterone, and testosterone have been proposed as modulators of these differences, given their known roles in inflammation, immune function, and vascular health. However, the precise hormonal mechanisms underlying COVID-19 severity, particularly among individuals with comorbid hypertension—a major risk factor for adverse outcomes—remain unclear. In this study, we investigated circulating levels of key sex hormones and their neuroactive metabolites in 116 hypertensive COVID-19 patients enrolled through an urban academic emergency department. Our findings revealed distinct sex-based hormonal profiles and associations with disease severity. Males exhibited higher serum estradiol and testosterone levels, while progesterone levels were significantly higher in postmenopausal females. Notably, hospitalized patients showed elevated estradiol and progesterone levels compared to non-hospitalized individuals, whereas ICU-admitted patients had significantly lower concentrations of all three hormones. A unique exception was ICU-admitted postmenopausal females, who exhibited increased serum testosterone levels relative to non-ICU females. Additionally, in males, elevated 3α-diol was associated with hospitalization and ICU admission, while lower allopregnanolone and estradiol levels correlated with hypoxia in males and females, respectively. These results highlight a dynamic, sex-specific hormonal response to COVID-19 progression in hypertensive individuals, suggesting early upregulation and late depletion of protective sex steroids. Understanding these patterns may improve clinical risk stratification and inform the development of sex-targeted therapeutic interventions for COVID-19 and related inflammatory conditions.