Search Results (114)

Sex differences are increasingly recognized as key determinants of vulnerability, clinical presentation, and treatment response in depression. Rather than arising from a single mechanism, these differences emerge from the interplay of multiple biological and non-biological factors. Converging evidence points to the hippocampus as a central region where these processes intersect, with adult neurogenesis and astrogliogenesis representing a potential mechanistic link between sex-specific biological factors and behavioral outcomes in depression. In this review, we integrate findings from human studies and preclinical models to examine how sex impacts depression while considering the multiple origins of sexual differentiation in the central nervous system. We discuss the importance of studying sex as a biological variable and acknowledge current limitations in the field. Finally, we highlight how cytogenic processes in the adult hippocampus are modulated in a sex-dependent manner, how their disruption may contribute to the pathophysiology of depression, and their potential role in precision psychiatry. Adult cytogenesis provides a promising target for developing therapeutic strategies aimed at promoting the integration of these cells in neural circuits, which may counterbalance the cellular impairments observed in stress-induced depression, representing a therapeutic avenue for this disorder. Full article

Background/Objectives: Parents of children with autism spectrum disorder (ASD) often face sustained emotional, practical, and social demands. However, evidence from Romania remains limited, particularly regarding the combined assessment of caregiver burden, emotional distress, and coping strategies of parents. This exploratory study compared these outcomes between parents of children/adolescents with ASD and parents of typically developing children and examined whether coping patterns varied according to selected sociodemographic characteristics. Methods: We conducted a cross-sectional comparative study in Târgu-Mureș, Romania, between 2024 and 2025. The sample included 92 parents: 46 parents of children/adolescents with clinician-confirmed ASD and 46 parents of typically developing children. Participants completed a demographic questionnaire, the Caregiver Burden Inventory (CBI), the Depression Anxiety Stress Scales-21 (DASS-21), and the Strategic Approach to Coping Scale (SACS). DASS-21 data were available for 44 ASD caregivers and 46 controls. Between-group comparisons were performed using t-tests, Mann–Whitney U tests, chi-square tests, or Fisher’s exact tests, as appropriate. Results: The groups were comparable in sex, age, residence, number of children, and household size, but differed significantly in marital status and educational level. Clinically relevant caregiver burden (CBI ≥ 36) was more frequent among parents of children with ASD than among controls (30% vs. 17%), although this difference was not statistically significant. Parents of children with ASD showed trend-level higher depressive and anxiety symptoms, with small effect sizes, whereas stress scores were similar between groups. Coping patterns varied according to sociodemographic characteristics. Marital status was associated with aggressive coping, urban residence was associated with indirect and aggressive coping, and number of children was associated with seeking social support. Conclusions: Parents of children with ASD showed a higher proportion of clinically relevant caregiver burden and trend-level elevations in depressive and anxiety symptoms, while stress scores were comparable between groups. Exploratory adjusted analyses suggested that ASD caregiver status remained associated with caregiver burden and depressive symptoms after controlling for educational level and marital status. Coping strategies appeared heterogeneous and context-dependent. Given the exploratory design, modest sample size, and multiple comparisons, these findings should be interpreted as preliminary and hypothesis-generating. Full article

Background: Testosterone is the most abundant biologically active sex steroid in women, yet the therapeutic implications of its age-related decline remain undercharacterized. Published trials have focused predominantly on sexual function, leaving gaps in understanding how testosterone replacement therapy (TRT) affects broader symptom domains and metabolic biomarkers in women. Objective: To investigate whether individualized, biomarker-guided TRT in women is associated with improvements across multiple symptom domains and favorable hormonal, hematologic, and cardiometabolic biomarker changes, and to examine whether symptomatic benefit varies with treatment duration. Methods: In this retrospective observational study, women (n = 332; ages 27 to 78; mean 45.7 ± 7.1 years) receiving TRT as part of routine clinical care through a telehealth-based platform completed a structured survey at a single post-treatment time point assessing eight symptom domains: energy/fatigue, memory, concentration, irritability, depression, anhedonia, sexual interest, and relationship satisfaction. Respondents were stratified by TRT duration (1 month to >12 months) and a subset (n = 120) underwent paired biomarker assessment at baseline and 12 weeks for total testosterone, free testosterone, SHBG, hemoglobin, and triglycerides. Results: Improvement was reported across all eight domains, with energy/fatigue showing the strongest response (84.3% improved). Depression, irritability, anhedonia, and sexual interest each exceeded 65% improvement. Cognitive domains showed a delayed trajectory, with meaningful gains emerging at 4 to 6 months. Quality of life improvement was reported by 89.7%, with significant improvement rising from 5.4% at 1 month to 51.5% at greater than 12 months. Energy/fatigue (64.2%) and mood (49.7%) ranked above sexual desire (41.3%) as self-identified areas of greatest benefit. All five biomarkers changed favorably: total testosterone +151.8% (d = 3.60), free testosterone +216.7% (d = 3.01), hemoglobin +5.5% (d = 2.03), SHBG −13.3% (d = 1.57), and triglycerides −12.6% (d = 1.28). Conclusions: Individualized TRT in women was associated with broad symptomatic improvement spanning energy/fatigue, depression, irritability, anhedonia, cognitive function, and sexual interest, with duration-dependent gains and favorable biomarker changes across all five markers assessed. These findings suggest that the value of testosterone in women extends beyond sexual function and supports the need for larger controlled trials with extended follow-up. Full article

The role of the endocannabinoid system (ECS) in the development of depression and anxiety is being actively studied, with evidence suggesting that elevation of ECS signaling can have anxiolytic and antidepressant properties. The current study explored the therapeutic potential of Oleoyl Serine (OS), an endocannabinoid-like lipid, and HU-910, a synthetic selective Cannabinoid type 2 (CB2) receptors agonist, in depression and anxiety, using both sexes of the depressive-like genetic model: Wistar Kyoto (WKY) rats. The aim was to investigate behavioral and molecular mechanisms associated with acute and sub-chronic intraperitoneal administration of these compounds. We showed that, in females, acutely administered OS yielded antidepressant-like and anxiolytic-like effects in the Forced Swim Test (FST) and Open Field Test (OFT), respectively. In males, OS yielded acute and sub-chronic anxiolytic-like effects. HU-910 yielded an acute anxiolytic-like effect in females and an acute antidepressant-like effect in males. Sub-chronic administration of imipramine (IMI), used as a positive control, yielded an antidepressant-like effect in both sexes but an anxiogenic-like effect in females. Sub-chronic administration of all the treatments increased hippocampal Cannabinoid Receptor 1 (CNR1) mRNA expression (but not Fatty Acid Amide Hydrolase (FAAH)) in males. Exploratory in silico absorption, distribution, metabolism, and excretion (ADME) profiling suggests that sex-dependent pharmacokinetic variability may partly underlie the observed behavioral differences, in addition to possible pharmacodynamic factors. Our study provides a lead towards unraveling the putative sex differences in response to both conventional antidepressants (e.g., IMI) and emerging pharmacological agents (e.g., OS, HU-910). Further, our study helps advance the field of neuropharmacology by elucidating the anxiolytic-like and antidepressant-like effects of OS and HU-910. Full article

Fibromyalgia is a chronic nociplastic pain condition frequently accompanied by affective disturbances, particularly depression, for which effective treatments remain limited. Increasing evidence implicates central oxidative stress, maladaptive synaptic plasticity, and neuroinflammatory alterations in its pathophysiology. This study investigated the therapeutic effects of molecular hydrogen (H₂) in a reserpine-induced murine model of fibromyalgia, with emphasis on sex-dependent and region-specific mechanisms. Male and female C57BL/6 mice received repeated reserpine injections to induce fibromyalgia-like symptoms. Mechanical allodynia, thermal hyperalgesia, cold allodynia, and depressive-like behaviors were assessed, followed by molecular analyses in the spinal cord and amygdala. Reserpine induced persistent nociceptive hypersensitivity and depressive-like behaviors in both sexes, with earlier cold allodynia in females. Hydrogen-rich water (HRW) progressively reversed mechanical and thermal hypersensitivity and rapidly abolished cold allodynia, showing greater efficacy in females. HRW also normalized depressive-like behaviors in both sexes. At the molecular level, HRW reduced spinal oxidative stress and ERK-dependent plasticity without altering spinal NLRP3 expression, whereas it fully reversed NLRP3 upregulation and HO-1 downregulation in the amygdala. HRW additionally engaged sex-dependent antioxidant pathways in the spinal cord. These findings indicate that H₂ alleviates sensory and affective alterations through region- and sex-dependent central mechanisms, supporting HRW as a promising therapeutic strategy for nociplastic pain and its affective comorbidities. Full article

Global forced displacement has reached unprecedented levels, with more than 123 million people uprooted by the end of 2024. Although older adults represent a growing proportion of refugee populations, their mental health needs remain overlooked. This scoping review synthesized current evidence on depression among older adult refugees aged 50 years and older. Guided by the Joanna Briggs Institute methodology and reported using PRISMA-ScR standards, searches were conducted in CINAHL, PsycINFO, AgeLine, and Medline for English-language publications from 2015 to 2025. A total of 1971 records were identified, with nine studies (N = 1370 participants) meeting eligibility criteria. Most studies employed cross-sectional designs and were conducted in high-income countries. Depression prevalence was consistently elevated, with rates ranging from 22% to over 70%, depending on population and measurement tools. Risk factors included female sex, widowhood, low socioeconomic status, chronic illness, functional impairment, trauma exposure, language barriers, social isolation, and limited access to care. Protective influences such as family support, higher socioeconomic status, and improved living conditions were identified but inconsistently reported. Findings indicate that older refugees are at high risk of depression, often shaped by intersecting aging- and displacement-related vulnerabilities. Findings highlight the need for culturally specific tools and longitudinal research to inform culturally safe care for older refugees. Full article

Background/Objectives: The increasing consumption of ultra-processed foods (UPFs) has been associated in recent years with negative effects on both physical and mental health. Ultra-processed products have been increasingly linked with poorer mental health outcomes, with research suggesting associations with higher rates of depression, anxiety, and cognitive difficulties. The aim of this systematic review was to determine whether and to what extent UPF intake is linked to metal health in children and adolescents. Methods: The methodological approach involved a systematic review of 20 recent epidemiological studies, identified through the PubMed and EBSCO databases using MeSH and TIAB search terms. The selected articles were evaluated in terms of sample characteristics, assessment tools, results and methodological quality. Results: Most findings revealed a positive association between high UPF consumption and mental health problems such as anxiety, depression, irritability or nervousness, sleep disturbances and suicidal ideation. However, variations were observed depending on the country, sex and the assessment tools used. Conclusions: In conclusion, the results of this review support the hypothesis that increased consumption of UPFs may be a risk factor for mental health in children and adolescents. Further longitudinal and interventional research is needed, alongside the promotion of healthy dietary policies targeting the pediatric and adolescent populations. Full article

Background/Objectives: An increasing proportion of patients with Type 2 diabetes mellitus (T2DM) are classified as high risk, often presenting with multimorbidity, functional vulnerability, and complex treatments. This study compared the sociodemographic, functional, clinical, therapeutic, and healthcare utilization profiles of high-risk chronic patients with and without T2DM in primary health care. Methods: A cross-sectional study included adults classified as high-risk chronic patients in primary health care electronic health records in the Madrid Region (30 April 2021). Sociodemographic, functional, clinical, lifestyle, pharmacological variables, and primary health care services utilization were analyzed. Multivariate logistic regression identified factors independently associated with T2DM. Results: Among 163,188 high-risk chronic patients, 41.5% had T2DM. Patients with T2DM were older, more often male, and had a comparable deprivation index values to non-diabetic patients. They showed higher functional dependency and greater need for informal caregiving. Clinically, patients with T2DM had a higher burden of chronic conditions and a predominance of cardiometabolic, hematological and renal comorbidities, whereas non-diabetic patients exhibited more neuropsychiatric, chronic infectious, oncological and respiratory profiles. Polypharmacy was more frequent in T2DM patients, who also showed lower medication adherence. In the explanatory model, older age (OR 1.02/year), cardiometabolic comorbidities (ORs ~1.2–1.6), highest quartile of morbidity complexity (OR 1.27), polypharmacy (OR 1.34), and concern about medications (OR 1.08) were associated with T2DM, while female sex (OR 0.660), depression (OR 0.888), COPD (0.704), neoplasms (0.688), and higher medication adherence (OR 0.53) were associated with not having T2DM. Conclusions: High-risk chronic patients with T2DM exhibit distinct sociodemographic, functional, and clinical profiles compared with those without T2DM, characterized by greater complexity, cardiometabolic burden, therapeutic intensity and use of healthcare services, supporting the need for tailored, integrated primary health care strategies. Full article

Sex differences in stress-induced alcohol-seeking are well documented. The overarching goal of this study is to examine how sex may moderate the relationship between depression and anxiety symptoms and stress-induced alcohol-seeking and to identify mechanisms of this relationship. We explore subjective alcohol responses and the resting-state functional connectivity of the amygdala and the hippocampus, regions implicated in anxiety and depression, as potential sex-dependent mediators. This secondary analysis draws from a recently published trial of 84 adults aged 21 to 55 (54.8% female, mean age = 32, SD = 10.68; 58.3% White, 88.1% non-Hispanic/Latino) who endorsed moderate-to-heavy alcohol use. All participants completed two counterbalanced intravenous alcohol administration sessions, and 54 completed optional neuroimaging. Generalized anxiety symptoms were significantly associated with greater stress-induced alcohol-seeking in women but not in men. Depression symptoms showed a similar pattern, though the results did not reach statistical significance. Across men and women, blunted state stimulation, but not state anxiety, in response to alcohol was associated with greater stress-induced alcohol-seeking. In men, anxiety symptoms were linked with heightened state stimulation effects, which appeared to buffer against stress-induced alcohol-seeking. State stimulation findings may suggest a possible mechanism for sex differences concerning anxiety pathways to alcohol-seeking. Subjective alcohol responses did not mediate the relationship between depression symptoms and stress-induced alcohol-seeking. Resting-state network connectivity findings identified several potential sex-dependent neural mechanisms that warrant further investigation. Although this study was not originally designed as a direct test of competing subjective response and low-level response to alcohol theoretical models, our findings are consistent with Schuckit’s low level of response to alcohol theory. Our findings showed that blunted stimulation may contribute to stress-induced alcohol-seeking among men. Identifying mechanisms that underlie sex-specific relationships with stress-induced alcohol-seeking can inform the development of tailored intervention approaches, ultimately enhancing treatment efficacy for both men and women. Full article

Heart rate variability (HRV) reflects autonomic nervous system (ANS) activity and provides insight into physiological and emotional regulation. Evaluating HRV during postural and emotional challenges may help characterize autonomic adaptability in healthy individuals. HRV was recorded in 24 young medical residents (17 females, 7 males; mean age 27.04 ± 1.97 years) during four conditions: rest, orthostatic standing, and exposure to positive and negative emotional images. Each session lasted five minutes. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale. Heart rate increased significantly only during standing, consistent with sympathetic activation with postural change. Spectral and normalized HRV parameters (nLF, nlf, LF/HF, and normalized coherence) were lowest at rest and increased during standing and emotional image exposure, particularly in males. Parasympathetic indices showed opposite trends. Emotional image exposure did not produce significant differences between positive and negative valence at the group level; however, sex- and anxiety-related patterns emerged. Females with anxiety showed increased heart rate during positive image exposure, whereas non-anxious females exhibited higher heart rate responses to negative images. Orthostatic challenge elicited the strongest autonomic response, whereas emotional visual stimuli induced subtler, sex- and anxiety-dependent autonomic modulation without overall changes in heart rate. These preliminary observations suggest that anxiety and sex may be associated with differences in cardiac autonomic regulation in young healthy adults. These results should be interpreted cautiously, given the pilot design, the small sample size (N = 24), the imbalance between sexes, the exclusion of the depression subgroup from inferential analyses, and the use of non-validated emotional visual stimuli Full article

Background/Objectives: Physical activity (PA) has been associated with better inhibitory control (IC), which may support self-regulatory processes related to eating. However, whether regular PA is related to food-specific IC and its neural correlates remains insufficiently understood. This cross-sectional study aimed to examine the relationship between regular PA, behavioral performance, and neural correlates of IC, with a focus on high-reward food-related contexts. Methods: Sixty-one healthy right-handed young Chinese adults were classified into a regular physical activity group (RPG; n = 30, 24 males) or an inactive group (IAG; n = 31, 17 males) based on self-reported frequency and volume of PA. Stop-signal tasks performed during functional MRI under high-calorie food and neutral image conditions were used to assess IC. Stop-signal reaction time (SSRT) indexed IC performance. Neural correlates of IC were examined using whole-brain and region-of-interest analyses, with brain activation values derived from general linear models including age, sex, body mass index, depressive scores, and subjective appetite ratings as covariates. Given the relatively small sample size and unbalanced distribution of sex and body mass index, sensitivity analyses were performed by varying covariate adjustments to assess the robustness of the primary results. Results: RPG demonstrated significantly shorter SSRT than IAG across both high-calorie food and neutral stimulus conditions. In contrast to successful-stop trials relative to baseline, IAG showed lower activation in the bilateral precuneus than RPG under the high-calorie food condition. In comparison, RPG showed lower activation than IAG under the neutral condition. In contrast to failed-stop trials relative to successful-go trials, IAG exhibited greater activation in the left caudate than RPG under the high-calorie food condition. These behavioral and neural patterns were generally robust across sensitivity analyses. Conclusions: Regular PA was associated with superior general IC, and this advantage was maintained in the presence of high-calorie food cues. At the neural level, regular PA was associated with stimulus-dependent neural responses in the bilateral precuneus and left caudate. Future studies using larger, more representative samples, objective measures of PA, and stratification by sex or BMI are warranted. Full article

Women exhibit a higher prevalence of depression, anxiety, stress-related disorders, and autoimmune conditions compared to men, yet the biological mechanisms underlying this sex difference remain incompletely understood. Growing evidence identifies neuroinflammation as a central mediator of psychiatric vulnerability in women, shaped by interactions between sex hormones, immune activation, and neural circuit regulation. Throughout the female lifespan, fluctuations in estrogen and progesterone, such as those occurring during puberty, the menstrual cycle, pregnancy, postpartum, and perimenopause, modulate microglial activity, cytokine release, and neuroimmune signaling. These hormonal transitions create windows of heightened sensitivity in key brain regions involved in affect regulation, including the amygdala, hippocampus, and prefrontal cortex. Parallel variations in systemic inflammation, mitochondrial function, and hypothalamic–pituitary–adrenal (HPA) axis responsivity amplify stress reactivity and autonomic imbalance, contributing to increased risk for mood and anxiety disorders in women. Emerging data also highlight sex-specific interactions between the immune system and monoaminergic neurotransmission, gut–brain pathways, endothelial function, and neuroplasticity. This review synthesizes current neuroscientific evidence on the sex-dependent neuroinflammatory mechanisms that bridge hormonal dynamics, brain function, and psychiatric outcomes in women. We identify critical periods of vulnerability, summarize converging molecular pathways, and discuss novel therapeutic targets including anti-inflammatory strategies, estrogen-modulating treatments, lifestyle interventions, and biomarkers for personalized psychiatry. Understanding neuroinflammation as a sex-specific process offers a transformative perspective for improving diagnosis, prevention, and treatment of psychiatric disorders in women. Full article

Background/Objectives. Chronic benzodiazepine (BDZ) use is frequently maintained beyond recommended durations due to neuroadaptation, psychological dependence, and withdrawal-related issues. Passiflora incarnata L., herba (P. incarnata) has shown anxiolytic and GABAergic activity that may mitigate withdrawal symptoms, while cognitive-behavioural therapy (CBT) targets maladaptive beliefs and behaviours sustaining BDZ misuse. This study investigates the independent and interactive effects of P. incarnata and CBT on BDZ dose reduction during a three-month tapering program. Methods. This retrospective observational study included 186 outpatients with anxiety or depressive disorders in clinical remission undergoing BDZ tapering, of whom 93 received a dry extract of P. incarnata as adjunctive treatment and 93, matched for diagnosis, age and sex, followed a standard tapering protocol. BDZ doses were assessed at baseline and three months. CBT was recorded as a binary variable based on the information documented in the medical records. An ANCOVA was performed to assess the impact of CBT and P. incarnata on BDZ reduction (change in mg diazepam equivalents), adjusting for sex, age, education, baseline anxiety and depression scores, initial BDZ and antidepressant dosage. A subgroup analysis was conducted to investigate the role of P. incarnata dosage in BDZ reduction. Results. Both CBT and P. incarnata were associated with significantly greater reductions in BDZ dosage at three months (CBT: p = 0.005, effect size: 0.032; P. incarnata: p < 0.001, effect size: 0.128). A significant interaction between CBT and P. incarnata was also observed (p = 0.037, effect size: 0.018), indicating a synergistic effect when both interventions were combined. Baseline sociodemographic characteristics, BDZ and antidepressant dosage and symptom severity did not differ significantly between groups. Patients taking 400–600 mg of P. incarnata dry extract showed a higher BDZ reduction compared to those taking 200 mg. Conclusions. These findings suggest that P. incarnata and CBT exert independent yet complementary effects in supporting BDZ tapering. Their combination appears to enhance dose reduction beyond either intervention alone, supporting a multimodal approach that addresses both neurobiological and psychological components of BDZ addiction. Prospective controlled studies are needed to confirm these results and to clarify their impact on long-term discontinuation outcomes. Full article

Introduction: Sarcoidosis is a systemic granulomatous disorder classified among interstitial lung diseases (ILDs). While the lungs and intrathoracic lymph nodes are most affected, the disease can involve multiple organs. The heterogeneity of clinical presentation arises from complex interactions between environmental exposures and immune responses in genetically susceptible individuals. Sex-dependent genetic variations are associated with differences in phenotype and organ localization. Gender-related factors also influence the impact of sarcoidosis on quality of life and health perception, contributing to variability in disease burden and outcomes. Aim of the study: to provide an overview of sex- and gender-related differences in sarcoidosis, focusing on pathophysiological and clinical implications. Material and Methods: The systematic search was conducted on Medline database through Pubmed search engine. We included all clinical studies from 1992 to the present, and imposed language restrictions, accepting only English publications. Case reports, reviews, and pre-print studies were excluded. Results: A total of 35 studies were included. Sex differences significantly influenced both age of onset and clinical presentation of the disease. Women received a diagnosis of sarcoidosis at an older age and exhibited more frequently extrapulmonary localizations, with predominant involvement of the eyes, skin, and extra-thoracic lymph nodes. In contrast, men more commonly presented with limited pulmonary forms. Löfgren syndrome was more prevalent among women and appeared to be associated with sex-specific genetic variations, particularly within the MHC region. Gender differences also impacted quality of life and disease perception: women reported a lower quality of life and were more susceptible to anxiety and depression throughout the disease course. Conclusions: This report confirms that clinical presentation of sarcoidosis is significantly influenced by sex and gender. The identification of sex- and gender-specific clinical patterns supports a personalized medicine framework, in which diagnostic assessment, monitoring strategies, and therapeutic approaches may be tailored according to individual biological and gender-related characteristics. Full article

Serotonin reuptake inhibitors (SSRIs) are commonly prescribed to pregnant women experiencing depression. Such drugs, however, might adversely affect placenta and fetal brain development. Parietal trophoblast giant cells (pTGCs) in the mouse placenta are postulated to internalize maternal serotonin (5-HT) via transport through SERT, encoded by Slc6a4, and to provide the initial source of 5-HT to the emerging brain via the placental–brain axis. Genetic deletion of Slc6a4 in pTGCs has been hypothesized to impact placental and fetal brain development. A transgenic mouse line with high-affinity SERT, encoded by Slc6a4, was selectively deleted by pairing mice with Cre recombinase linked to Prl2c2, with LoxP sites flanking the Slc6a4 gene. PRL2C2 is solely expressed by pTGCs and other giant cells of the placenta. To compare placental and fetal brain development in selective Slc6a4 KO and WT mice, 5-HT content in the placenta and fetal brains of conceptuses was measured. No significant differences in 5-HT content were evident between knockout (KO) and wild-type (WT) placentas or fetal brains. However, there were significantly fewer pTGCs in KO placentas compared to WT (p ≤ 0.05). Sexually dimorphic differences in gene expression were evident in the placenta and fetal brain between KO and WT counterparts, with female conceptuses showing the most dramatic responses, including decrease in Prl7a2, Prl5a1, Prl3a1, Slc28a3, and Ceacam 15 in female placental samples. These findings suggest that ablation of Slc6a4 in pTGC disrupts the placenta–brain axis in a sex-dependent manner. The results might have important clinical ramifications for pregnant women being treated with SSRIs. Full article