Differences in serum neuropeptide Y levels and appetite changes in patients with major depressive disorder stratified by sex and reproductive aging

Abstract

Objective

To examine serum neuropeptide Y (NPY) levels and appetite changes in major depressive disorder (MDD) patients by sex and reproductive aging.

Methods

A total of 210 MDD were divided into male (n = 65), premenopausal women (n = 80), and postmenopausal women (n = 65) groups. Serum NPY levels were measured using ELISA, appetite changes were assessed with a visual analog scale (VAS), and depression severity was evaluated with the 17-item Hamilton Depression Rating Scale (HDRS-17). One-way ANOVA with post-hoc tests and stratified regression models were used to compare NPY levels and analyze the association between NPY and appetite changes across groups.

Results

One-way ANOVA showed significant group differences in serum NPY levels. Premenopausal women’NPY levels (280.80±35.50 pg/mL) were significantly higher than those of men (Δ = 30.30, p = 0.007) and postmenopausal women (Δ = 28.70, p = 0.009), whereas there is no difference between postmenopausal women and males (Δ = 1.60, p = 0.989). Similar group differences were observed for VAS scores. NPY was positively correlated with VAS scores, and the strength of this association differed across sex and reproductive aging groups: in the overall population, NPY is positively correlated with the VAS score (r = 0.422→0.437 after controlling for depression severity, p < 0.001), with the strongest association in premenopausal women (β = 0.027, p < 0.001), followed by males (β = 0.012, p = 0.017), and the weakest in postmenopausal women (β = 0.007, p = 0.021).

Conclusion

Significant sex and reproductive aging differences exist in serum NPY levels, which are associated with appetite changes in MDD, particularly in premenopausal women, suggesting potential implications for individualized clinical consideration. However, without a healthy control group, it remains unclear whether these findings are specific to depression or reflect general population differences.

Clinical trial number

Not applicable.

Supplementary information

The online version contains supplementary material available at 10.1186/s12888-025-07753-9.

Introduction

Major depressive disorder (MDD), one of the most disabling mental disorders worldwide, is a major public health challenge. Epidemiological studies have clearly revealed significant sex differences in the prevalence of MDD, with women being approximately 1.5–2 times more likely to be affected than men. Understanding the sex differences in MDD is key to determining its cause and improving treatment [1, 2]. Changes in appetite are among the core symptoms of MDD, with approximately 70% of patients experiencing either decreased or increased appetite [3]. This symptom not only makes patients’ physical health worse (such as malnutrition and metabolic syndrome) but is also closely related to the severity of depressive symptoms and prognosis. Importantly, appetite changes vary significantly between sexes and different life stages: female patients are more likely to experience typical appetite reduction, whereas males may present atypical appetite increases [3, 4]. However, these patterns are derived primarily from mixed or unselected depressed populations, and subgroup differences related to reproductive status remain less explored. Additionally, the reproductive aging process in women (such as menopause) involves dramatic fluctuations in estrogen levels, further complicating appetite regulation. The incidence of depression in postmenopausal women increases significantly and is often accompanied by metabolic disorders (such as weight gain and insulin resistance), suggesting that reproductive aging may influence appetite regulation by altering the neuroendocrine system [5].

The differences in the sex distribution of MDD can be traced back to puberty, when the incidence in women begins to exceed that in males between the ages of 13 and 15, continuing throughout adulthood. This difference might be due to a mix of biological, psychological, and social factors [6]. At the biological level, the cyclical fluctuations of sex hormones (such as estrogen and progesterone) influence how neurotransmitter systems (such as serotonin and dopamine) function. For example, estrogen can upregulate the expression of serotonin transporters (SERTs), enhancing serotonin reuptake, whereas progesterone can modulate the sensitivity of gamma-aminobutyric acid (GABA) receptors, affecting mood stability [7]. Furthermore, the unique brain structure and connections in women (such as stronger connections between the limbic system and prefrontal cortex) may increase their sensitivity to emotional stimuli, increasing their susceptibility to depression. The various pressures faced by women in social roles (such as occupational discrimination and family responsibilities), emotional expression patterns (more inclined toward introspection and emotional immersion), and exposure to trauma (such as sexual assault and domestic violence) are associated with the onset of MDD [8, 9]. Notably, these factors do not act independently of biological mechanisms but produce synergistic effects through pathways such as epigenetic modifications (such as DNA methylation) and neuroinflammatory responses.

Neuropeptide Y (NPY), which is a key player in the hypothalamic appetite regulation network, is crucial for maintaining energy homeostasis. NPY consists of 36 amino acids and activates downstream signaling pathways (such as the PI3K-AKT and MAPK pathways) by binding to the Y1, Y2, and Y5 receptors, ultimately increasing appetite [10]. Animal experiments have shown that intracerebroventricular injection of NPY can induce binge eating behavior in rats, while blocking NPY receptors significantly inhibits food intake [11]. In addition to directly regulating appetite, NPY is involved in the negative feedback regulation of the hypothalamic-pituitary-adrenal (HPA) axis; under stress conditions, increased NPY release can inhibit the secretion of corticotropin-releasing hormone (CRH), alleviating excessive stress responses [11]. However, in chronic depressive states, this regulatory mechanism can become imbalanced, leading to sustained activation of the HPA axis, which in turn affects the synthesis and release of NPY. Clinical studies have indicated that NPY levels in the serum and cerebrospinal fluid of MDD patients exhibit complex changes [12]. Some studies report that NPY levels decrease during depressive episodes, possibly reflecting impaired hypothalamic neuron function, whereas in patients with atypical depression or increased appetite, NPY levels may be elevated, suggesting its differential role in various symptom subtypes [12; 13]. Additionally, polymorphisms in the NPY gene (such as rs16147) are associated with susceptibility to depression and treatment response, further emphasizing its importance in the pathological mechanisms of MDD.

Menopause, a hallmark event of women reproductive aging, is accompanied by a sharp decline in estrogen levels, triggering a series of physiological and psychological changes [14]. Epidemiological studies have shown that the incidence of MDD in postmenopausal women is approximately 40% greater than that in premenopausal women, which is often accompanied by changes in appetite and weight gain [15, 16]. Previous experimental studies have suggested that estrogen may influence the NPY system through multiple pathways, potentially including modulation of appetite-related signaling; however, these mechanisms have not been directly examined in the present study. on the other hand, it can indirectly affect energy homeostasis by regulating insulin sensitivity and fat metabolism. The lack of estrogen after menopause can interfere with these regulatory mechanisms, leading to abnormal NPY levels and appetite disorders [17, 18].

Although existing studies have explored the associations between MDD, NPY, and appetite changes, there are still large gaps in research. First, current studies often focus on a single sex or do not consider different reproductive aging stages, and systematic comparisons among men, premenopausal women, and postmenopausal women are lacking. Second, the dynamic changes in NPY in appetite regulation across different physiological stages are not well understood; in particular, how fluctuations in estrogen levels affect the NPY‒appetite axis remains unclear. Finally, the relationship between peripheral blood NPY levels and central nervous system function is controversial, and its clinical value as a biomarker still needs validation.

Therefore, this study aimed to systematically explore the differences and associations between serum NPY levels and appetite changes in MDD patients stratified by sex and reproductive aging. We propose the following a priori hypotheses based on prior literature: first, serum NPY levels are expected to differ across male, premenopausal female, and postmenopausal female MDD patients, with potentially lower levels in postmenopausal women; second, the association between NPY and appetite changes may be modulated by sex and reproductive aging status, with a stronger association anticipated in premenopausal women; third, biomarkers such as estrogen levels and inflammatory factors could partially mediate these differences.

Methods

Sample

This study is a cross-sectional study that continuously recruited 210 patients with MDD who were treated at the psychiatric department of Xiamen Xianyue Hospital from February 2024 to February 2025. The inclusion criteria were as follows: 1) met the diagnostic criteria for MDD according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), as established by experienced psychiatrists through a structured clinical interview [19 2]) aged 18–65 years; 3) signed an informed consent form; and 4) administered only selective serotonin reuptake inhibitors (SSRIs). The exclusion criteria included the following: 1) severe physical illnesses (such as liver or kidney failure or malignant tumors); 2) a history of substance abuse, including alcohol and drugs; 3) pregnant or breastfeeding women; and 4) the use of known NPY modulators (e.g., NPY receptor agonists or antagonists) or other medications that directly affect appetite in the past three months; 5) known obesity (BMI > 30), metabolic syndrome, diabetes, thyroid disorders, or other endocrine/metabolic conditions; 6) current regular smoking or alcohol consumption. The participants were divided into three groups according to sex and reproductive aging status: the male group (65 patients), the women group (80 patients who had regular menstrual cycles and were not receiving hormone replacement therapy), and the women group (65 patients who had been naturally menopausal for at least 12 months and had no hormonal treatment).

Clinical assessments

The study included demographic and clinical characteristics, specifically covering the subjects’ age, sex, education level, and total duration of the illness (the time from the first appearance of clinical symptoms to when the subjects were enrolled in the study). We measured the severity of depressive symptoms via the classic 17-item Hamilton Depression Rating Scale (HDRS-17) [20]. This scale consists of 17 items, each scored on a 0–2 or 0–4 scale depending on how severe the symptoms are (for example, some items, such as “depressed mood,” use a 0–4 scale, whereas items such as “insomnia” use a 0–2 scale). All item scores are summed to obtain a total score for the scale, ranging from 0 to 52, with higher scores indicating more severe depressive symptoms. The reliability of the Chinese version of the HDRS-17 used in this study has been validated, with internal consistency reliability measured by a Cronbach’s α of 0.714 [21]. The visual analog scale (VAS) is used to quantify appetite status, where subjects mark their current appetite intensity on a 10 cm horizontal line (0 points = no appetite, 10 points = the strongest appetite), and the score is based on the distance from the left end [22]. At the same time, communicate with the patient and record the types of appetite changes (decreased appetite: a reduction in food intake of 30% or more compared to before the onset; increased appetite: an increase in food intake of 30% or more compared to before the onset) (Supplementary file 1). All appetite assessments were conducted at a single time point.

The total duration of illness (time from first onset of clinical symptoms to study enrollment) was recorded for all patients (median 15 months, range 1–60 months). Age at onset of MDD was calculated as current age minus duration of illness and was also documented (median age at onset 38 years, IQR 28–48 years). All patients were treated exclusively with selective serotonin reuptake inhibitors (SSRIs) as monotherapy; commonly used agents included sertraline, escitalopram, and fluoxetine. No other psychotropic or appetite-modulating medications were permitted.

Blood collection and measurement of NPY

Peripheral venous blood (5 mL) was collected from all participants under fasting conditions in the morning (between 8:00 and 10:00 AM) to standardize timing and minimize potential circadian variation in NPY levels. The mixture was allowed to warm at room temperature for 30 min and then centrifuged at 3000 r/min for 10 min serum separation. Serum NPY levels were measured using a commercial human NPY ELISA kit (Jiangsu Enzyme Exemption Industry Co., Ltd., Jiangsu, China; catalog number [Cat#202303]). According to the manufacturer, the detection limit was 10 pg/mL, with intra-assay CV < 8% and inter-assay CV < 10%. NPY was measured in series via specific enzyme-linked immunosorbent assay (ELISA) kits as directed by the manufacturer, with the optical density at 450 nm.

Statistical analyses

Statistical analysis was performed via SPSS 24.0. The Kolmogorov‒Smirnov test was used to check for a normal distribution. Body mass index (BMI), which follows a normal distribution, is presented as the mean ± standard deviation (SD). Age, duration of illness, HDRS-17 scores, and other non-normally distributed variables were described via the median (lower quartile, upper quartile) [M (QL, QU)].

Demographic and clinical characteristics across the three groups, one-way ANOVA was used for normally distributed variables (e.g., BMI) and Kruskal-Wallis tests for non-normally distributed variables (e.g., age, duration of illness, HDRS-17), followed by post-hoc tests where appropriate.

To account for potential confounding by age and BMI (known to influence NPY levels, appetite regulation, and metabolic status), primary comparisons of serum NPY levels and VAS scores across the three groups (men, premenopausal women, postmenopausal women) were performed using one-way ANCOVA, with age and BMI as covariates (after confirming homogeneity of regression slopes). Adjusted means and Bonferroni-adjusted pairwise comparisons were reported. Effect sizes were reported as partial eta squared (η² _p) (small: 0.01; medium: 0.06; large: 0.14). For analyses examining reproductive aging effects within the female subsample, ANCOVA with age and BMI as covariates was similarly applied. Sensitivity analyses using non-parametric methods or multiple regression confirmed the robustness of the findings.

Associations between NPY levels and VAS scores were examined using partial correlations and multiple linear regression, controlling for HDRS-17 score, age, and BMI. Medication use was uniform across all patients (only selective serotonin reuptake inhibitors [SSRIs] as monotherapy; commonly used agents included sertraline, escitalopram, and fluoxetine), with no other psychotropic or appetite-modulating drugs permitted, precluding the need for further adjustment.

Results

Participant characteristics

This study collected general demographic data from 65 male participants and 145 women participants. The median duration of illness was 15 months (IQR 8–20 months), with no significant group differences (Kruskal-Wallis H (2) = 0.954, p = 0.621). The median age at onset of MDD was 38 years (IQR 28–48 years), and there were no significant group differences (Kruskal-Wallis H (2) = 1.28, p = 0.527). One-way ANOVA showed no significant difference in BMI among the three groups (F (2,207) = 0.312, p = 0.732). Kruskal-Wallis tests revealed no significant differences in duration of illness (H (2) = 0.954, p = 0.621) or HDRS-17 score (H (2) = 0.318, p = 0.853). The median ages were 42.31 (20.36, 65.47), 32.52 (18.48, 48.76) and 57.27 (49.36, 68.27) years for the male group, premenopausal group and postmenopausal group, respectively. As expected given the group definitions, a significant difference was found in age (Kruskal-Wallis H (2) = 14.732, p < 0.001) (Table 1). Age and BMI were included as covariates in all primary analyses of NPY levels and VAS scores.

Table 1.

Characteristics of the study participants (n = 210)

Characteristic	Male (65)	women (145)		Test statistic	P value
		Premenopausal (80)	Postmenopausal (65)
Age (years) M (QL, QU)	42.31(20.36,65.47)	32.52(18.48,48.76)	57.27(49.36,68.27)	14.732	< 0.001
BMI (kg/m2)	23.14±2.83	22.76±3.13	23.56±2.93	0.312	0.732
Duration of illness (months) M (QL, QU)	15.6(8.40,19.00)	14.8(5.80,21.20)	16.3(10.20,23.80)	0.954	0.621
HDRS-17 score M (QL, QU)	17.50(10.00,19.00)	17.00(8.00,20.00)	17.50(9.00,19.00)	0.318	0.853
Age at onset (years), M (QL, QU)	38.2 (28.5, 48.1)	31.7 (23.4, 40.2)	41.8 (32.6, 51.3)	1.28	0.527

BMI: body mass index; HDRS-17: 17-item Hamilton Depression Rating Scale. Group comparisons: BMI - one-way ANOVA; age, duration of illness, HDRS-17 score—Kruskal-Wallis test. Age and BMI were included as covariates in primary analyses of NPY levels and VAS scores

Serum NPY levels

One-way ANCOVA (covariates: age and BMI) revealed significant group differences in serum NPY levels after adjustment (F (2, 205) = 41.82, p < 0.001; partial η² = 0.29, large effect). Premenopausal women’s adjusted NPY levels (estimated marginal mean = 280.5 pg/mL; original raw mean 280.80 ± 35.50 pg/mL) were significantly greater than those of men (estimated marginal mean = 250.8 pg/mL; original raw mean 250.50 ± 30.20 pg/mL, adjusted p = 0.007) and postmenopausal women (estimated marginal mean = 251.8 pg/mL; original raw mean 252.10 ± 32.80 pg/mL, adjusted p = 0.008), while there was no significant difference between postmenopausal women and men (adjusted p = 0.989) (Fig. 1). These pairwise comparisons were Bonferroni-adjusted. Within the women subsample, ANCOVA (covariates: age and BMI) confirmed that premenopausal women had significantly higher NPY levels than postmenopausal women (p < 0.001). These results are robust after controlling for age and BMI, indicating clear group-specific differences in serum NPY levels (Table 2).

Fig. 1.

Serum NPY levels in men, premenopausal women, and postmenopausal women. NPY: neuropeptide Y; ^*** p < 0.001 (one-way ANCOVA adjusted for age and BMI)

Table 2.

Serum NPY levels across the three study groups (n = 210)

Group	n	Raw mean ± SD (pg/mL)	Adjusted mean (pg/mL) (95% CI)	Post-hoc comparisons (Bonferroni-adjusted p values)
Men	65	250.50 ± 30.20	250.8 (244.2–257.4)	-
Premenopausal women	80	280.80 ± 35.50	280.5 (274.6–286.4)	vs. Men: 0.007 vs. Postmenopausal: 0.008
Postmenopausal women	65	252.10 ± 32.80	251.8 (245.0–258.6)	vs. Men: 0.989

NPY: neuropeptide Y. Overall ANCOVA: F (2,205) = 41.82, p < 0.001; partial η² = 0.29 (large effect)

VAS appetite scores

age and BMI) revealed significant group differences in VAS scores among the three groups (F(2,207) = 45.38, p < 0.001; η² ≈ 0.30, large effect). The scores of premenopausal women (7.02±1.54) were significantly greater than those of male (5.48±1.82, Δ = 1.54, p < 0.001) and postmenopausal women (5.52±1.63, Δ = 1.50, p < 0.001), whereas there was no significant difference between postmenopausal women and men (Δ = 0.04, p = 0.912) (Fig. 2). These pairwise comparisons were obtained from Tukey’s post-hoc tests. Additionally, within the women subsample, premenopausal women had significantly higher VAS scores than postmenopausal women (independent t-test, p < 0.001). These findings indicate group-specific differences in appetite scores across sex and reproductive aging groups (Table 3).

Fig. 2.

VAS appetite scores in men, premenopausal women, and postmenopausal women. VAS: visual analog Scale; ^*** p < 0.001 (one-way ANCOVA adjusted for age and BMI)

Table 3.

VAS scale appetite scores across the three study groups (n = 210)

Group	n	VAS score	Post-hoc comparisons (Tukey’s test)
Men	65	5.48 ± 1.82	-
Premenopausal women	80	7.02 ± 1.54	vs. Men: p < 0.001 vs. Postmenopausal: p < 0.001
Postmenopausal women	65	5.52 ± 1.63	vs. Men: p = 0.912

VAS: Visual analog scale

Analysis of the associations between serum NPY levels and VAS scores

A correlation analysis of 210 MDD patients revealed that serum NPY levels were significantly positively correlated with VAS appetite scores (Pearson r = 0.422, p < 0.001). After controlling for depression severity (HDRS-17 score), the partial correlation coefficient was r = 0.437 (p < 0.001; Fig. 3). The scatter plots show greater dispersion without control for HDRS-17 (Fig. 3A) and tighter clustering around the trend line after adjustment (Fig. 3B).

Fig. 3.

Association between serum NPY and VAS scores in MDD. (a) correlation between serum NPY levels and vas scores in MDD patients. (b) After adjusting for the HDRS-17 scores, age, and BMI, correlation between serum NPY levels and vas scores in MDD patients. vas: visual analog Scale; NPY: neuropeptide Y; MDD: Major depressive disorder

Separate partial correlation and multiple linear regression analyses by group (controlling for HDRS-17 score, age, and BMI) showed consistent differences in the strength of the association between NPY levels and VAS scores. In males (n = 65), the partial correlation was r = 0.207 (p = 0.098; Fig. 4A). In women (n = 145), it was r = 0.386 (p < 0.001; Fig. 4B). Within women, premenopausal women (n = 80) showed a stronger partial correlation (r = 0.460, p < 0.001; Fig. 5A) than postmenopausal women (n = 65; r = 0.176, p = 0.162; Fig. 5B).

Fig. 4.

Correlation analysis of NPY levels and VAS scores by sex. (a) In males. (b) In women. VAS: visual analog Scale; NPY: neuropeptide Y. (partial correlations adjusted for HDRS-17, age, and BMI)

Fig. 5.

Correlation analysis of NPY levels and VAS scores by reproductive aging status in women. (a) in premenopausal women. (b) in postmenopausal women. VAS: visual analog Scale; NPY: neuropeptide Y. (partial correlations adjusted for HDRS-17, age, and BMI)

Multiple linear regression models in each group separately (controlling for HDRS-17, age, and BMI) yielded the following nonstandardized coefficients (β) for NPY predicting VAS scores: males: β = 0.012 (p = 0.017); premenopausal women: β = 0.027 (p < 0.001); postmenopausal women: β = 0.007 (p = 0.021). Results remained consistent after additionally controlling for age and BMI, with the strongest association in premenopausal women. Direct comparisons of these regression coefficients confirmed significantly stronger associations in premenopausal women compared to males (Z = 3.47, p = 0.001) and postmenopausal women (Z = 4.62, p < 0.001), with no difference between males and postmenopausal women (Z = 0.45, p = 0.652) (Tables 4 and 5).

Table 4.

Regression coefficients for NPY predicting VAS scores by group (controlling for HDRS-17, age, and BMI)

Group	Number	Nonstandardized coefficient (β)	β (95%CI)	P value
Male group	65	0.012	0.010–0.014	0.017
Premenopausal group	80	0.027	0.025–0.029	< 0.001
Postmenopausal group	65	0.007	0.005–0.009	0.021

Adjusted for HDRS-17 score, age, and BMI

Table 5.

Test of differences in association strength between groups

Group	Z value	P value
Premenopausal group vs. Male group	3.47	0.001
Postmenopausal group vs. Male group	0.45	0.652
Premenopausal group vs. Postmenopausal group	4.62	< 0.001

Regression coefficients used for comparisons were adjusted for HDRS-17 score, age, and BMI

Discussion

The present study systematically examined the associations of sex and reproductive aging status with serum NPY levels and appetite changes in 210 patients with MDD. Stratified analyses revealed significant group differences, providing novel insights into sex- and reproductive stage-specific biological mechanisms in depression and potential strategies for personalized clinical interventions. Serum NPY levels were significantly higher in premenopausal women than in men and postmenopausal women, with no difference between the latter two groups. This pattern—highest in premenopausal women and comparable in postmenopausal women and men—suggests a role for female reproductive aging. Premenopausal women also showed the highest VAS appetite scores, indicating relatively preserved or increased appetite. These findings remained robust after adjusting for chronological age, BMI, and HDRS-17 scores, strengthening evidence for reproductive stage-related effects despite the correlation between age and reproductive status.

Notably, the higher appetite scores in premenopausal women contrast with much of the literature reporting predominant appetite loss in depressed females [3]. Our finding of relatively preserved or increased appetite in this subgroup differs from the typical appetite reduction reported in mixed-sex or unselected female MDD samples, highlighting a potential protective or modulating role of premenopausal hormonal profiles. This discrepancy likely reflects subgroup-specific patterns modulated by reproductive stage, underscoring the importance of stratifying female MDD patients by reproductive status when evaluating appetite symptoms. Furthermore, while we hypothesized lower NPY levels in postmenopausal women, the observed similarity in NPY levels between this group and men partially supports but also refines our initial expectation. Specifically, these results suggest that reproductive aging effects may primarily manifest as a loss of the elevated NPY levels seen in premenopausal women, rather than a further reduction below the baseline levels observed in men.

The following mechanistic interpretations are speculative, as this study lacked direct measurements of sex hormones (e.g., estradiol, progesterone, testosterone), metabolic markers (e.g., insulin, leptin, ghrelin, GLP-1), or HPA-axis hormones (e.g., cortisol). Prior research suggests estrogen may influence hypothalamic NPY neurons [3, 23, 24] and upregulate NPY Y1/Y5 receptor expression [25], potentially enhancing NPY signaling via PLC-IP3 pathways and intracellular calcium mobilization [26, 27]. Androgens may play a similar role in males [28], while progesterone and thyroid hormones could interact with NPY, and cortisol may influence NPY via HPA-axis feedback mechanisms [29–31]. Neurotransmitter systems, including serotonin and dopamine, may also modulate NPY-related appetite regulation [32–36]. At the neural circuit level, hypothalamic NPY neurons interact with limbic regions (amygdala, hippocampus) and the prefrontal cortex [37–39], with connectivity potentially influenced by estrogen across reproductive stages [38, 39]. The stronger NPY-appetite association in premenopausal women may thus reflect enhanced estrogen-mediated receptor signaling and neural connectivity, while weaker associations in postmenopausal women and men could indicate reduced estrogen influence or dominance of other factors (e.g., androgens).

These findings have implications for clinical management of appetite disturbances in MDD, which are closely linked to symptom severity and prognosis. The strongest NPY-appetite association in premenopausal women suggests potential benefit from targeting the NPY pathway, such as with Y1 receptor antagonists shown to modulate appetite in preclinical models [40, 41]. Combining such agents with estrogen replacement therapy has been hypothesized to influence NPY and appetite, though risks (e.g., breast cancer, cardiovascular events) must be weighed. In postmenopausal women and men, where associations were weaker, multitarget approaches may be preferable, including selective estrogen receptor modulators (SERMs) with potential NPY effects [42], neurotransmitter-targeted drugs (5-HT, dopamine), or androgen modulation in males. Non-pharmacological interventions, including cognitive behavioral therapy and regular exercise, can positively affect appetite and mood [43–45]. Personalized dietary strategies tailored to sex and reproductive stage (e.g., high-fiber for premenopausal women, nutrient-focused for others) should also be considered.

Despite these insights, several limitations must be acknowledged. First, appetite was assessed using a single-timepoint VAS score and subjective ≥30% change estimates at a single time point, potentially introducing recall bias and missing day-to-day fluctuations; future studies should employ repeated objective measures or validated questionnaires. The absence of healthy controls limits determination of MDD-specificity. Lack of direct hormone, metabolic, or HPA-axis assessments restricts mechanistic conclusions, and residual confounding from subclinical conditions, smoking, or alcohol cannot be excluded. MDD diagnosis relied on clinical interview without standardized instruments, and male androgen variability was unassessed. This unmeasured heterogeneity in age-related gonadal decline (andropause) may contribute to the intermediate NPY-appetite association observed in males. The cross-sectional design precludes causality, while genetic [45–48], environmental [49, 50], and microbiota factors [51] were not evaluated. Only serum (not central) NPY was measured, and interactions with other appetite regulators (e.g., ghrelin, GLP-1) remain unexplored. Future longitudinal studies with comprehensive biomarker assessments, healthy controls, and advanced neuroimaging are needed to validate these findings and inform targeted interventions.

Conclusions

In summary, this cross-sectional study observed significant sex and reproductive aging differences in serum NPY levels and in the association between NPY and appetite in patients with MDD. These findings highlight potential sex- and reproductive stage-related variations in the NPY-appetite relationship and may provide insights into depression-specific mechanisms. However, the absence of a healthy control group limits determination of whether these differences and associations are specific to MDD or represent general population patterns related to sex and reproductive aging. Although the study has other limitations, including its cross-sectional design and lack of direct hormone measurements, the results may inform future research directions. In particular, studies incorporating healthy controls are needed to clarify the specificity of these observations to depression. We anticipate that further investigations could explore more precise and effective personalized approaches based on patients’ sex and reproductive aging status, potentially contributing to improved clinical outcomes and quality of life for individuals with depression, as well as advancing the field of depression research.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Author contributions

QF Y: Writing – review & editing, Methodology, Investigation, Conceptualization, Formal analysis. Y Q: Writing – review & editing, Investigation, Formal analysis Conceptualization and methodology. L W: Investigation, Methodology. Y Z: Investigation, Methodology. DD L: Investigation; Methodology; ZZ X: Methodology. CY W:Methodology. WC S: Methodology. ZY H: Methodology.

Funding

This work was supported by grants from the Xiamen Medical and Health Guidance Project (No.3502Z20199092), Fujian Provincial Health Youth Scientific Research Project (No.2019-2-54), and Medical and Health Guidance Project of Xiamen (No.3502Z20244ZD1304).

Data availability

All the data are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

This study strictly adheres to the principles of the Helsinki Declaration and has obtained consent from the Medical Ethics Committee of Xiamen Xianyue Hospital (No.2024-KY-012). After the study explanation, each participant signed a written informed consent form.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.