Background: Major Depressive Disorder (MDD) exhibits significant gender disparities in prevalence. Previous studies have indicated that differential patterns of sympathetic nervous system activation in different gender may contribute to varying cardiovascular/cerebrovascular risks in MDD, though underlying factors remain unclear. In this study, we aim to investigate the association between subjective sleep alterations, blood pressure, emotional state, and gender specific sympathetic activation in MDD.

Methods: We collected and analyzed ECG data from 50 female and 25 male age-matched, first-episode, drug-naive MDD patients. Autonomic nerve function was assessed using Heart Rate Variability (HRV). Subjective sleep indicators of SE, SOL, short sleep, and poor sleep quality were evaluated utilizing the Pittsburgh Sleep Quality Index (PSQI). Emotional characteristics were quantified via the Hamilton Depression Scale-17 (HAMD-17) and Hamilton Anxiety Scale (HAMA). Resting systolic (SBP) and Diastolic Blood Pressure (DBP) were also measured upon arrival. Results: In male MDD patients, each 1% reduction in SE was associated with a 0.350ms decrease in SDNN. In females, each 1-minute reduction in SOL was associated with a 0.004-unit increase in LF/HF ratio; while short sleep (< 6h) was associated with increased RMSSD and pNN50 (all p ≤ 0.048). Reduced DBP in males correlated with different patterns (decreased pNN50 and HF (nu); increased LF (nu) and LF/HF ratio) (all p ≤ 0.033). In females, only reduced SBP was associated with each 1-mmHg decrease linked to a 0.040-unit increase in LF/HF ratio.

Conclusion: Subjective sleep disturbances exhibit disparity in gender-specific patterns of sympathetic-vagal balance in MDD. However, blood pressure reduction consistently correlated with sympathetic activation across both genders, revealing distinct autonomic-mediated pathophysiological pathways that may underlie differential cardiovascular susceptibility in MDD.

• Major Depressive Disorder

• Gender Difference

• Subjective Sleep Disturbances

• Blood Pressure

• Autonomic Nerve Dysfunction

• Heart Rate Variability

Ban W, Wu F, Li H, Zhou S, Feng S, et al. (2026) Effect of Subjective Sleep Impairment and Decreased Blood Pressure on Gender-Specific HRV in First-Episode and Drug-Naive Patients with Major Depressive Disorder. J Sleep Med Disord 10(1): 1150.

Major Depressive Disorder (MDD), a highly prevalent and debilitating psychiatric condition defined by altered regulation of mood, behavior and affect [1], leading to a range of adverse health outcomes [2,3]. Within the DSM 5 diagnostic criteria for MDD, sleep disorders constitute specific sub-items, notably requiring reports of insomnia or hypersomnia occurring nearly daily. Clinically, sleep dysfunction is a frequent manifestation in MDD patients [4]. Supporting this, the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study revealed that 87.4% of individuals with MDD exhibited concurrent insomnia symptoms, predominantly characterized by prolonged sleep latency and frequent nocturnal awakenings [5]. Furthermore, alterations in key sleep parameters— including duration, quality, and circadian rhythm are related to detrimental clinical sequelae [6]. Several studies have reported distinct changes in sleep patterns among depressed patients, encompassing both reduced and extended sleep duration, as well as diminished sleep quality [7]. Critically, these sleep pattern alterations are closely linked to an increased risk of subsequent Cardiovascular Disease (CVD). Cross-sectional evidence also indicates that insomnia correlates with metabolic diseases, including hypertriglyceridemia and insulin resistance, particularly in individuals with severe mental disorders [8]. Additionally, sleep disorders are implicated in dementia risk. A prospective study of cognitively intact male patients demonstrated that alterations in five specific sleep characteristics were significantly associated with accelerated long-term cognitive decline and heightened risk of developing Alzheimer’s disease dementia [9]. Finally, a meta-analysis published in 2023 synthesized evidence suggesting that nsomnia acts as a potential etiological or exacerbating factor for subsequent mental disorders, including depression [10]. This evidence supports a pernicious bidirectional relationship wherein sleep pathology and depressive illness mutually reinforce each other, thereby complicating clinical trajectories and presenting substantial therapeutic challenges. Collectively, these findings indicate that sleep disorders not only contribute to chronic cardiovascular and cerebrovascular diseases but also may exacerbate MDD symptomatology, which further underscores the necessity and importance of vigilant monitoring and clinical attention to sleep characteristics in the management of MDD patients. Patients with MDD face a substantially elevated risk of cardiovascular morbidity and mortality. Previous studies have demonstrated that MDD patients exhibit significantly higher susceptibility to developing CVD and experience greater mortality rates compared to healthy controls [11], with a demonstrable dose-response relationship between depression severity and subsequent cardiovascular mortality/events [12]. A parallel trend was observed in patients with comorbid MDD and chronic insomnia. Data from the China Health and Retirement Longitudinal Study indicated that both depression and subjective short sleep duration independently increase cardiovascular disease risk [13]. Furthermore, the analysis revealed that subjective short sleep duration mediates 38.6% of the association between depression and hypertension. Additionally, clinical studies [14] show that the pathogenesis of cardiovascular events involves multiple interrelated physiological and pathological mechanisms, including inflammatory factors release [15], dysregulation of the HPA axis [16], excessive the sympathetic nervous system activation [17], and endothelial dysfunction [18], among others. Another study [19] suggests that short sleep duration increases the risk of subsequent cardiovascular and cerebrovascular diseases, such as hypertension, potentially linked to excessive activation of sympathetic nerve [17]. Moreover, research [20] posits that sympathetic nerve activation represents a common pathway integrating various pathophysiological mechanisms and may play a particularly significant role. Prior investigations into cardiovascular comorbidity in MDD patients suggest that autonomic dysfunction represents one underlying mechanism [21]. Specifically, depressive symptoms severity has been associated with sympathetic-vagal imbalance [22]. Similar parasympathetic down regulation is also evident in MDD patients with comorbid anxiety disorders [23,24]. In clinical and scientific settings, sympathetic nerve activity can be assessed using various methods. Common tools for evaluating sympathetic-vagal balance include Heart Rate Variability (HRV) [25], bar reflex sensitivity (BRS) [26], micron urography (MSNA) [27], and sympathetic skin response [28]. Among these, HRV offers the advantages of non-invasiveness and suitability for continuous monitoring, making it widely applicable in population studies, including those involving mental disorders [29,30]. Notably, a pronounced gender disparity exists in depression epidemiology, with women exhibiting a twofold higher lifetime incidence than men. Studies [31] further suggest that gender-related differences in sympathetic activation contribute to the differential cardiovascular risk observed in MDD patients. Consequently, we aim to elucidate whether subjective sleep indicators correlate with gender-specific sympathetic activation in depression. Furthermore, several studies [32,34] highlight a potential paradoxical sexual dimorphism: within the context of depression, women, despite exhibiting relatively greater vagal tone, face a significantly elevated risk of adverse cardiovascular events compared to their male counterparts. However, the determinants—such as sleep disorder, anxiety severity, and depression severity— underlying these gender-specific sympathetic activation in MDD remain inadequately investigated. Sustained sympathetic activation is frequently implicated as a potential mechanism increasing cardiovascular diseases [35], including hypertension, and has been documented in MDD patients [36,37]. Nevertheless, research examining the association between sympathetic nerve changes, blood pressure and gender specifically in MDD patients is lacking. Therefore, this study also seeks to explore the relationship between blood pressure level and sympathetic-vagal balance in MDD patients stratified by gender. In summary, the established comorbidity between MDD and sleep disturbances holds significant clinical relevance. Accumulating evidence suggests that “subjective sleep impairment” and “co-occurring affective symptomatology” (depressive-anxious load) may synergistically elevate cardiovascular risk profiles, particularly hypertension susceptibility. Crucially, the gender-specific modulation of sympathetic-vagal balance, manifesting as differential sympathetic activation patterns between genders, remains underexplored as a potential mediator in this pathophysiological triad. Therefore, we hypothesized that poorer subjective sleep indicators, worse emotional states (higher depressive-anxious load), and elevated blood pressure in MDD patients are associated with increased gender-specific sympathetic nerve system activity.

Participants and Study Design

A cross-sectional study was conducted at the Department of Psychiatry, Affiliated Brain Hospital of Guangzhou Medical University between February 2022 and July 2024. The cohort comprises 50 female patients with first-episode, unmedicated MDD and 25 male patients with first-episode, drug-naive MDD. Diagnoses were independently confirmed by two board-certified psychiatrists according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM 5) [1]. The study protocol received ethical approval from the Affiliated Brain Hospital Guangzhou Medical University and complied with Helsinki Declaration guidelines (2013). Written informed consent was obtained from all participants following a comprehensive procedural briefing. All participants underwent centralized assessment including: demographic data collection, standard scale assessment, blood pressure measurement and ECG data acquisition. Inclusion criteria required: (1) DSM-5 diagnostic criteria of MDD; (2) first-episode presentation (duration ≤2 years); (3) lifetime absence of psychopharmacological treatment; (4) age ≥ 18 years. Exclusion criteria encompassed: (1) Significant physical comorbidities potentially affect sympathetic nerve activity (e.g., coronary heart disease, hypertension, diabetes) or severe arrhythmias (e.g., advanced atrioventricular block, frequent ventricular premature contractions) documented by ECG; (2) Coexisting serious psychiatric disorders per DSM-5 (e.g., bipolar disorder, schizophrenia, delusional disorder); (3) History of chronic ethanol abuse or illicit psychostimulant use; (4) pregnancy or lactation; (5) Use of β-blockers (e.g., propranolol) or other drugs that may affect the sympathetic nerve within 3 months; (6) Inability to cooperate with ECG acquisition.

Clinical Data Collection

Systematically documented parameters included: (1) Demographic parameters (chronological age, biological sex, marital status, occupational classification, geographic residency); (2) Longitudinal medical histories (via clinician-administered structured interviews). Subjective sleep dice were evaluated using the Pittsburgh Sleep Quality Scale (PSQI) [38]. From the PSQI, we derived four key indicators: (1) Short sleep duration, defined as < 6 hours per night based on Question 4:: “During the past month, how many hours of actual sleep did you get at night?”; (1) Poor sleep quality, categorized as “Poor” or “Extremely poor” responses to Question 6: “During the past month, what do you think of your sleep quality?”; (3) Sleep Onset Latency (SOL), determined from Question 2: “How many hours did you fell asleep after you stay at bed during the night in the past 1 month?”; (4) Sleep Efficiency (SE), calculated as Total Sleep Time (TST) divided by Time In Bed (TIB) using responses to PSQI Questions 1-4. Depressive symptom severity was assessed using the Hamilton depression rating scale-17 (HAMD-17) [39], while anxiety symptoms were quantified with the Hamilton anxiety rating scale (HAMA) [40]. All clinical evaluators completed standardized training and demonstrated inter rater reliability in HAMD-17 administration. Resting blood pressure was measured in triplicate recordings at 5-minute intervals following 10 minutes of seated rest using an electronic sphygmomanometer (Omron, HEM-7136, measurement accuracy ± 3 mmHg), which underwent monthly calibration against a mercury sphygmomanometer. The mean values of Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) in the tests were utilized for statistical analyses. Anthropometric measurements (height, weight, waist circumference, hip circumference), electrocardiogram, heart rate, and substance use histories (smoking status, alcohol consumption patterns) were obtained by qualified technicians.

Evaluation of Heart Rate Variability (HRV)

HRV metrics were employed to delineate Autonomic Nervous System (ANS) function in the MDD cohorts. Participants maintained 24-hour pre-assessment abstinence from psychostimulants (caffeine ≥ 200mg/ day), ethanol consumption, and vigorous physical activity. Continuous 10-minute Electrocardiographic (ECG) recordings were acquired at a sampling frequency of 10000 Hz. HRV indices were processed using NeuroKit2 [41], an open-source Python package for neurophysiological signal analysis (installation details accessible at https:// neurokit2.readthedocs.io/en/latest/installation.html, accessed 3 May 2021). Both time-domain parameters (SDNN, RMSSD, pNN50) and frequency-domain parameters (normalized low-frequency power LF(nu), normalized high-frequency power HF(nu), LF/HF ratio) were computed according to established standards by Phyllis K. Stein [42]. ECG recordings were segmented into consecutive 5-minute epochs, with HRV indices averaged across all segments for final statistical analysis.

Statistical Analysis

All data underwent dual-entry verification via EpiData 3.1 (EpiData Association, Odense, Denmark) with cross checked validation protocols. Statistical analyses were performed using IBM SPSS Statistics version 26.0 (IBM Corp, Armonk, NY). The analytical sequence comprised three phases. First, the age-matching procedure was completed. Demographic equivalence between male and female groups was established through statistical matching. Second, general demographic characteristics, subjective sleep parameters, clinical features, and emotional assessment scores (HAMD-17, HAMA) were compared between male and female MDD groups. Third, multiple linear regression models were constructed to examine relationships between HRV parameters (dependent variables) and subjective sleep characteristics, clinical characteristics, and emotional assessment scores (independent variables). Covariates with established biological relevance to HRV (age, BMI, smoking status, alcohol consumption status) were incorporated into all models using forced entry methodology. Statistical significance was defined as a two-tailed p-value ≤ 0.05. 

Participant Characteristics and Group Comparisons

A total of 25 male MDD patients and 50 MDD female patients were included in this study. Demographic and clinical characteristics are presented in (Table 1). Age pre-assessment distributions were matched between groups. Compared to their male counterparts, female MDD patients exhibited significantly lower BMI (t = -2.458, p < 0.001), reduced smoking prevalence (χ2 = 9.232, p = 0.002), and lower alcohol consumption rates (χ2 = 4.751, p = 0.029). Clinical assessment revealed significantly lower systolic blood pressure (t = -4.042, p < 0.001) in MDD female patients versus males. Emotional scales assessment demonstrated higher HAMD-17 scores in MDD female patients (Z = -2.427, p = 0.015), indicating greater depressive symptoms.

Table 1: Demographic, Clinical, and Sleep Characteristics of Depressed Patientsa.

Notes: Data are presented as mean ± standard deviation for continuous variables, and sample size (percentage) for categorical variables. *There are 75 depressed patients enrolled, including 25 males and 50 females; p-values in bold indicate P < 0.05.

aBased on the Major Depressive Disorder diagnostic criteria of the Diagnostic Statistical

Mental Disorder-V.

bAll of the subjects under Psychotropic medications (Antipsychotics, Antidepressants,

Mood stabilizers, Hypnotic drugs) were excluded.

cSubjective sleep characteristic is based on PSQI’s fourth question.

Abbreviations: MDD: Major Depressive Disorder; BMI: Body Mass Index; SOL: Sleep Onset Latency; SE: Sleep Efficiency; HAMD-17: Hamilton Depression Rating Scale-17; HAMA: Hamilton Anxiety Rating Scale; SBP: Systolic Blood Pressure; DBP: Diastolic Blood Pressure; HR: Heart rate; SDNN: Standard deviation of all NN intervals; RMSSD: Square root of the mean squared difference of successive NN intervals; pNN50: Percent of NN intervals > 50 ms different from previous (NN) for period of interest; LFnu: [LF/ (TP-VLF)] for the measured period (5-min or less). Some calculate LF/ (LF+HF). HFnu: [HF/ (TP-VLF)] for the measured period (5-min or less). Some calculate HF/ (LF+HF); LF/HF: LF/HF average over 5-min periods or less; * means P < 0.05.

HRV analysis showed significant between-group differences in frequency-domain parameters: Male patients exhibited higher LF (Z = -2.585, p = 0.010) and LF/ HF (Z = -2.304, p = 0.021), and lower HF (t = 2.979, p = 0.004). These findings suggest heightened sympathetic nerve activation in male MDD patients. No significant statistical gender-based differences were detected in any of the subjective sleep parameters or in the time-domain HRV indices.

Sleep Parameters and HRV Associations

The results of the multiple linear regression analyses examining the relationship between subjective sleep indicators, blood pressure, and emotional scales with HRV of male and female MDD patients, are detailed in (Table 2-4) and selectively illustrated in (Figure 1).

Table 2: Linear Regression of Subjective sleep indicators with HRV in Different gender of MDD.

Note: 1 means group of Male MDD patients. 2 means group of Female MDD patients.

All of the subjects under Psychotropic medications (Antipsychotics, Antidepressants, Mood stabilizers, Hypnotic drugs) were excluded. The liner regression was adjusted for age, body mass index, smoking, and alcohol. Short sleep duration was defined less than 6 hours according to question 2 in the Pittsburgh Sleep Quality Index: “During the past month, how many hours of actual sleep did you get at night”. Poor sleep quality was defined as “Poor or Extremely poor” according to question 6 in the Pittsburgh Sleep Quality Index: “During the past month, what do you think of your sleep quality”. SOL: Sleep Onset Latency. SE: Sleep Efficiency. HR: Heart rate; SDNN: Standard deviation of all NN intervals; RMSSD: Square root of the mean squared difference of successive NN intervals; pNN50: Percent of NN intervals > 50 ms different from previous (NN) for period of interest; LFnu: [LF/ (TP-VLF)] for the measured period (5-min or less). Some calculate LF/ (LF+HF). HFnu: [HF/ (TP-VLF)] for the measured period (5-min or less). Some calculate HF/ (LF+HF); LF/HF: LF/HF average over 5-min periods or less; B: Non-standardized regression coefficient; β: standardized regression coefficient; CI, confidence interval. * means P < 0.05.

Figure 1 

Table 3: Linear Regression of Blood pressure with HRV in Different gender of MDD.

Note: 1 means group of Male MDD patients. 2 means group of Female MDD patients.

The liner regression was adjusted for age, body mass index, smoking, and alcohol. SBP: Systolic Blood Pressure. DBP: Diastolic Blood Pressure. HR: Heart rate; SDNN: Standard deviation of all NN intervals; RMSSD: Square root of the mean squared difference of successive NN intervals; pNN50: Percent of NN intervals>50 ms different from previous (NN) for period of interest; LFnu: [LF/ (TP-VLF)] for the measured period (5-min or less). Some calculate LF/ (LF+HF). HFnu: [HF/ (TP-VLF)] for the measured period (5-min or less). Some calculate HF/ (LF+HF); LF/HF: LF/HF average over 5-min periods or less; B: Non-standardized regression coefficient; β: standardized regression coefficient; CI, confidence interval. * means P < 0.05.

Table 4: Linear Regression of Emotional scales with HRV in Different gender of MDD.

Note: 1 means group of Male MDD patients. 2 means group of Female MDD patients.

The liner regression was adjusted for age, body mass index, smoking, and alcohol. HAMD-17: Hamilton Depression Rating Scale-17. HAMA: Hamilton Anxiety Rating Scale. HR: Heart rate; SDNN: Standard deviation of all NN intervals; RMSSD: Square root of the mean squared difference of successive NN intervals; pNN50: Percent of NN intervals>50 ms different from previous (NN) for period of interest; LFnu: [LF/ (TP-VLF)] for the measured period (5-min or less). Some calculate LF/ (LF+HF). HFnu: [HF/ (TP-VLF)] for the measured period (5-min or less). Some calculate HF/ (LF+HF); LF/HF: LF/HF average over 5-min periods or less; B: Non-standardized regression coefficient; β: Standardized Regression Coefficient; CI: Confidence Interval. * means P < 0.05.

Among male patients, higher SE was significantly correlated with a greater SDNN (B = 0.35 ms per 1% SE increase; Model A; 95% CI = 0.00 ~ 0.09, β = 0.49, p = 0.049), In female MDD patients, SOL positively predicted LF/HF ratio (B = 0.004 units per 1-min SOL increase; Model F; 95% CI = 0.00 ~ 0.01, β = 0.26, p = 0.038), while short sleep duration (<6 hrs) was associated with increased RMSSD (B = 7.75 ms; Model G; 95% CI = 0.08 ~ 15.42, β = 0.29, p = 0.048) and pNN50 (B = 7.21%; Model H; 95% CI = 0.25 ~ 14.17, β = 0.30, p = 0.043). Additionally, gender-divergent autonomic responses to subjective sleep disturbances were observed. Male patients with MDD exhibited sympathetic activation related to subjective sleep disorders, whereas female patients demonstrated bidirectional alterations in sympathetic regulation—prolonged sleep onset latency associated with sympathetic excitation, while subjective sleep duration less than 6h paradoxically corresponded to sympathetic inhibition with concomitant vagal predominance.

Blood Pressure and HRV Relationships

Furthermore, our detailed investigation into the correlations between systolic/diastolic blood pressure (SBP/DBP) and HRV parameters revealed significant inverse associations with sympathetic activation, as visualized in Figure 1. In the MDD male group (model B-E), each 1 mmHg increase in DBP corresponded to statistically significant alterations in multiple HRV indices - specifically, 0.80% (95% CI = 0.18 ~ 1.42, β = 0.59, p = 0.014) increase in pNN50, a 0.01% (95% CI = 0.00 ~ 0.01, β = 0.47, p = 0.033) increase in HF(nu), a 0.01% (95% CI = -0.01 ~ -0.00, β = -0.50, p = 0.024) decrease in LF(nu), and a 0.07-unit (9 CI = -1.12 ~ -0.01, β = -0.48, p = 0.033) reduction in the LF/ HF ratio. Similarly, in female MDD patients (Model I), we observed parallel but quantitatively distinct relationships, where every 1 mmHg increase in SBP predicted a 0.04 unit (95% CI = -0.06 ~ -0.01, β = -0.28, p = 0.024) decrease in the LF/HF ratio, indicating consistent blood pressure dependent attenuation of sympathetic dominance across both genders despite differential hemodynamic and autonomic regulatory mechanisms.

Our study elucidates the complex interplay between sleep disturbances, blood pressure fluctuations, and gender-specific sympathetic activation patterns in MDD. To our knowledge, this represents the first investigation examining the relationships among subjective sleep indicators, emotional state, blood pressure, and gender- dimorphic autonomic nervous system activity in MDD. The principal findings reveal three key patterns: (1) Male MDD patients demonstrated impaired HRV regulation relative to female counterparts, particularly evident in frequency-domain parameters; (2) Gender-stratified analysis revealed distinct sleep-HRV interactions patterns: increased HRV in males correlated specifically with SE, while female patients displayed inverse HRV associations with both shortened SOL and curtailed sleep duration (<6h); (3) blood pressure profiles showed gender-specific HRV correlations by gender—diastolic hypertension accompanied by concomitant HRV reduction characterized males, while females displayed systolic hypertension concurrent with HRV attenuation. These findings demonstrate gender-dimorphic autonomic regulation in MDD, with female patients exhibiting superior HRV modulation compared to males, suggesting heightened sympathetic activation in depressed males. This pathophysiological pattern aligns with prior evidence of gender-specific autonomic dysfunction in MDD. While gender differences in HRV remain underexplored in current depression research, emerging evidence from MDD-comorbid conditions like Somatic Symptom Disorder (SSD) reveals distinct autonomic patterns. Notably, studies of elderly SSD patients report significantly reduced Low-Frequency to High-Frequency HRV ratios (LF/HF) in females compared to males [44].This gender-specific sympathetic pattern contrasts with the stability observed in parasympathetic measures, evidenced by comparably high-frequency HRV (HF-HRV) values across genders. However, contradictory evidence exists. Pediatric research [45] by Shvartz and colleagues involving children aged 5.5-12.5 years found consistently reduced HRV in females across developmental stages, indicating heightened sympathetic activation despite comparable LF%, HF%, and LF/HF ratios between genders. These paradoxical observations may reflect multifactorial interactions encompassing MDD diagnostic heterogeneity, clinical characteristics, illness duration variability, ethnic diversity, and gender-specific antidepressant treatment responses. We further identified an independent correlation between subjective sleep disorder severity and gender related HRV modulation in MDD, with progressive sympathetic predominance accompanying worsening SE in male patients and prolonged SOL in females, contrastingly, female patients manifested restrained sympathetic activities associated with shorten sleep duration (< 6h). This pathophysiological cascade in males of MDD, consistent with prior neurocardiac investigations the [4,8], suggests sleep architecture disruption may critically impair Hypothalamic-Pituitary-Adrenal axis function, thereby exacerbating sympathetic-vagal imbalance through excessive noradrenergic activation. Concurrently, sleep disturbances may elevate subsequent cardiovascular/cerebrovascular risk [7] and potential cognitive impairment [46] in MDD, compounding physical comorbidities and socioeconomic burdens. Crucially, we observed gender-specific patterns: Male MDD patients showed reduced sleep efficiency primarily associated with decreased SDNN, indicating compromised overall HRV. In contrast, female MDD patients exhibited more complex patterns, where prolonged sleep onset latency was correlated with an increased LF/HF ratio, while shortened sleep duration was related to increased RMSSD and pNN50. These findings partial align with established gender differences in depressive sleep architecture and autonomic regulation [47]. Silverstein [48] previously reported that female MDD patients typically experience greater somatic depression, including more pronounced sleep disturbances than males. Our findings extend this understanding by revealing the gender specific autonomic correlates, suggesting that distinct pathophysiological mechanisms underlie sleep disruption in MDD. Methodologically, time-domain indices RMSSD and PNN50 demonstrate greater stability against heart rate fluctuations and temporal variations than SDNN and frequency-domain metrics [41,49,50], rendering them sensitive indicators of sympathetic modulation. The association between short sleep duration and HRV increase (indicating sympathetic nerve suppression) in female MDD patients may reflect women’s degenerative feedback in sympathetic-vagal regulatory capacity [31]. These findings further emphasize the necessity of gender-specific considerations when developing sleep interventions for MDD patients. Specifically, male patients might derive greater benefit from interventions targeting sleep efficiency improvement. Conversely, females exhibit bidirectional autonomic dysregulation—prolonged sleep onset latency exacerbates sympathetic predominance while curtailed sleep duration (<6 h) induces sympathetic attenuation. This divergence likely originates from distinct neurobiological pathways (e.g., immune inflammatory response, hormone regulation) mediating differential autonomic responses to specific sleep parameters. This gender-dimorphic pattern corresponds with emerging evidence on neurophysiological differences in sleep regulation. As highlighted in a Sleep Medicine Reviews systematic assessment [51], combining light therapy with behavioral strategies may provide scientific rationale for gender-specific interventions. Such integrated approaches (HPA) could address persistent sympathetic nervous system hyperactivation observed in chronic MDD cases, thereby mitigating associated long-term health consequences. Additionally, our findings offer novel evidence-based guidance for gender-specific antidepressant selection in MDD management. Pharmacodynamic analyses reveal clinically significant temporal variations in treatment responses. For instance, unlike traditional SSRIs whose initial administration may exacerbate insomnia, mirtazapine demonstrates superior 5-hydroxytryptamine receptor 2 (5-HT2) blockade that enhances sleep architecture through reduced sleep latency, extended total sleep time, and improved sleep efficiency [52], Optimal management requires gender-specific pharmacotherapy targeting differential sleep dysregulation: female patients benefit from agents that reduce shorten SOL and modulate total sleep time characteristics; while male patients with depression require interventions prioritizing sleep efficiency enhancement. Such studies supporting the need for gender- adapted dosing regimens and pretreatment counseling. Blood pressure-autonomic function also exhibited notable gender differences. Unlike previous studies [53], we specifically examined blood pressure on gender related sympathetic regulation in MDD patients. Male patients showed comprehensive autonomic alterations with diastolic blood pressure reduction, including decreased pNN50 and HF power alongside increased LF power and the LF/HF ratio. Given that LF/HF ratio serves as a sensitive indicator of sympathetic-vagal balance [41], these findings suggest a more pronounced sympathetic predominance with lower blood pressure in male MDD patients. Conversely, female MDD patients exhibited a varied pattern where only systolic blood pressure reduction correlated with increased LF/HF ratio. This observation may indicate a blood pressure-sympathetic negative feedback mechanism in MDD, whereby blood pressure elevation reduces sympathetic regulation— consistent with the previous research results in other populations [54]. Estrogen-enhanced endothelium mediated vasodilation in the female population [53,55] may explain the greater relevance of blood pressure with HRV-LF/HF ratio in female MDD patients than males. Notably, our analysis did not reveal a direct correlation between the severity of affective symptoms (as measured by HAMD-17 and HAMA) and HRV indices in either gender, contradicting previous reports [13,23]. This suggests autonomic dysfunction-emotional state (including the severity of depression and anxiety) relationships may be mediated through alternative physiological pathways [56], such as the hypothalamic-pituitary-adrenal axis function, chronic systemic inflammation, or other mechanisms, rather than direct associations with gender-specific sympathetic nerve activation.

Methodological constraints warrant consideration. First, the limited sample size (particularly male subgroup underrepresentation, n=25) may restrict statistical power for detecting subtle effect sizes. Second, the cross sectional design of our study precludes causal inferences between sleep disturbances, blood pressure changes, and autonomic dysfunction. Third, reliance on subjective sleep measures rather than objective polysomnographic measures introduces potential reporting bias. Future studies should incorporate larger sample sizes, longitudinal designs, and objective sleep monitoring to validate and extend our findings. Additionally, investigating the role of sex hormones and other potential mediating factors would further elucidate the mechanisms underlying observed gender differences.

This study demonstrates that MDD manifests gender specific patterns in sleep architecture, blood pressure alterations, and sympathetic activation. Male patients exhibit sympathetic hyperactivity primarily associated with reduced sleep efficiency, whereas females show abhorrent autonomic alterations correlated with both prolonged sleep onset latency and shortened sleep duration. Crucially, we identified divergent blood pressure autonomic relationships: in males, diastolic hypotension corresponded with sympathetic predominance evidenced by depressed parasympathetic indices (pNN50, HF power) and elevated sympathetic markers (LF power, LF/HF ratio). Conversely, females showed selective sensitivity to systolic blood pressure reductions, which specifically correlated with increased LF/HF ratios. These differential integration pathophysiological patterns suggest that gender modulates the of sleep-cardiovascular-autonomic pathways in MDD, likely through complex regulatory mechanisms involving sex hormones, inflammatory pathways, and adrenal cortex pathways. Our findings underscore the necessity for gender-stratified approaches in managing autonomic dysfunction in depression, with therapeutic strategies requiring tailored consideration of sleep parameters, blood pressure profiles, and autonomic biomarkers specific to each gender.

Authorship Contribution Statement

Wenli Ban: Writing – original draft, Visualization, Investigation, Formal analysis, Data curation, Conceptualization. Fengchun Wu: Writing – review & editing, Methodology, Funding acquisition. Hehua Li: Writing – review & editing, Visualization, Formal analysis, Data curation. Sumiao Zhou: Writing: Validation, Methodology. Shixuan Feng: Visualization, Software. Chenyu Liu: Resources. Zhendong Zhang: Data curation. Yuanyuan Huang: Writing – review & editing, Supervision, Conceptualization, Project administration, Funding acquisition.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

1. National Key Research and Development Program of China (2025YFC3410000, 2025YFC3410005).
2. Key-Area Research and Development Program of Guangdong Province (2023B0303020001).National Natural Science Foundation of China (82301688).
3. Natural Science Foundation of Guangdong (2025A1515010507, 2023A1515011383),
4. Science and Technology Program of Guangzhou (2025A03J3357, 202206060005, 2023A03J0856, 2023A03J0839).
5. Guangzhou Key Clinical Specialty (Clinical Medical Research Institute).

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