Sex-specific associations between Neutrophil-Percentage-to-Albumin Ratio(NPAR) and Neutrophil-to-Lymphocyte Ratio (NLR) with positive and negative symptoms in schizophrenia

Abstract

Background

Inflammatory markers such as the Neutrophil-Percentage-to-Albumin Ratio (NPAR) and Neutrophil-to-Lymphocyte Ratio (NLR) have been associated with psychiatric disorders. However, the role of sex differences in the association between these markers and symptoms severity in schizophrenia remains largely unexplored. Given that sex differences in immune response may influence the relationship between systemic inflammation and clinical symptoms, understanding these differences is crucial. This study aims to evaluate sex differences in the associations of NPAR and NLR with the severity of positive and negative symptoms in patients with schizophrenia.

Methods

This study retrospectively included 108 male and 109 female patients with schizophrenia of Han Chinese ethnicity who were admitted to our hospital between January 2023 and March 2025. Clinical data were collected and analyzed retrospectively. Venous blood samples were obtained to determine the neutrophil percentage, absolute neutrophil count, absolute lymphocyte count and albumin level. Based on these parameters, NPAR and NLR were calculated. We further examined the relationships between these inflammatory markers and symptom severity, assessed via the Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of Negative Symptoms (SANS).

Results

Male and female patients with schizophrenia exhibited differences in the severity of positive and negative symptoms. In male patients, NLR was positively associated with positive symptoms (B = 2.53; p < 0.001), while in female patients, NPAR was positively associated with negative symptoms (B = 2.58; p < 0.001). Furthermore, significant interaction effects were observed between sex and inflammatory markers (NPAR and NLR), which influenced the severity of both positive and negative symptoms.

Conclusions

Our study suggests that NPAR and NLR are associated with the severity of schizophrenia symptoms and vary by sex, highlighting the importance of considering sex differences in clinical practice.

Clinical trial number

Not applicable.

Introduction

Schizophrenia is a chronic and disabling psychiatric disorder characterized by a broad range of clinical symptoms, including positive symptoms (such as delusions and hallucinations), negative symptoms (such as emotional blunting and social withdrawal), and cognitive impairments [1, 2]. It affects approximately 1% of the global population, with a rising incidence, particularly among adolescents and young adults [3]. Increasing evidence suggests that immune system dysregulation and persistent low-grade inflammation play a crucial role in the pathophysiology of schizophrenia [4].

There are significant physiological differences in immune responses between males and females, driven by sex hormones, genetic expression, and immune cell functions [5, 6]. In schizophrenia, females may exhibit heightened immune reactivity, such as elevated C-reactive protein levels, higher secretion of interleukin-6 (IL-6), and increased release of other pro-inflammatory cytokines, which are often associated with symptom exacerbation [7–9]. In contrast, male patients display distinct immune response characteristics, with more pronounced activation of innate immune pathways (such as TLR4 signaling) and relatively diminished anti-inflammatory regulation (such as IL-10 secretion), potentially contributing to clinical symptoms progression and treatment resistance [10, 11].

Among various peripheral inflammatory markers, NPAR and NLR have emerged as convenient and reliable indicators for assessing systemic inflammation and immune-nutritional status [12]. Both biomarkers have already been established as important inflammatory indicators in diseases such as cancer and cardiovascular diseases [13]. NLR reflects the balance between innate and adaptive immune responses [14]. Elevated NLR suggests a pro-inflammatory state and immune imbalance, which may lead to blood-brain barrier dysfunction, microglial activation, and increased oxidative stress—all of which are associated with altered brain function [15–17]. NPAR, which combines neutrophil percentage and serum albumin levels, provides a composite measure of inflammation intensity and antioxidant capacity [18].

Although other markers, such as CRP and IL-6, are widely used in schizophrenia research, NLR and NPAR, as novel composite markers, have not been widely applied in clinical practice. They offer a more detailed perspective on immune and nutritional status, providing a more comprehensive assessment compared to single inflammatory markers [19].

Given that sex-specific immune responses may influence disease progression and treatment response, this suggests that a one-size-fits-all treatment approach may not be sufficient for all patients. Understanding the role of sex in immune responses, particularly in how inflammatory markers such as NLR and NPAR relate to symptoms, could provide a basis for developing personalized treatment strategies and drive the development of more targeted clinical treatments. Therefore, this study aims to explore the sex-specific associations between NPAR, NLR, and the severity of schizophrenia symptoms.

Methods

Participants

This study was approved by the Ethics Committee of the Affiliated Xiaoshan Hospital, Hangzhou Normal University. Demographic information and data from routine physical examinations were collected from patients who visited the Department of Psychiatry at the Affiliated Xiaoshan Hospital between January 2023 and March 2025.

Participants were eligible for inclusion if they satisfied these conditions: (1) a diagnosis of schizophrenia according to the 10th edition of the International Classification of Diseases (ICD-10); (2) age between 18 and 65 years; (3) duration of illness of at least one year; (4) receiving a stable antipsychotic treatment regimen for a minimum of two consecutive weeks. (5) patients with complete clinical and demographic data. Exclusion criteria were as follows: (1) a current diagnosis of depression, bipolar disorder, or any other psychiatric disorder based on ICD-10 criteria; (2) presence of serious neurological conditions such as epilepsy, Parkinson’s disease, or Alzheimer’s disease; (3) use of immunomodulatory medications, including corticosteroids or immunosuppressants; (4) evidence of acute infection at the time of recruitment; (5) pregnancy or lactation.

Clinical interview and assessment

The severity of positive and negative symptoms was assessed via the Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of Negative Symptoms (SANS), respectively [20]. All assessments were conducted by psychiatrists who had received standardized training and possessed substantial clinical experience in administering these instruments.

Measurement of indicators of NPAR and NLR

Complete blood count data were obtained using the SYSMEX XN-3000 automated hematology analyzer, along with its corresponding reagents and quality control materials. All procedures, including quality control and sample analysis, were carried out in strict accordance with the manufacturer’s instructions.

The NPAR was determined as follows: the neutrophil percentage (relative to total white blood cell count, %) multiplied by 100, then divided by albumin level (g/dL) [21].

The NLR was derived by dividing the neutrophil count by the lymphocyte count [22].

Covariates

The covariates included age, marital status, education level, smoking behavior, drinking behavior, body mass index (BMI), medication (antipsychotic medication), olanzapine equivalent milligrams, and duration of illness.

The inclusion of these covariates is essential for several reasons. First, age-related immune senescence can contribute to systemic low-grade inflammation and reduced immunoregulatory function, both of which may influence symptom progression [23]. Second, lower education levels and non-marital status are often associated with weaker social support networks, which are known environmental risk factors for negative symptoms [24]. These factors may indirectly affect inflammation and symptom expression by increasing chronic stress [25]. Moreover, smoking activates immune cells, such as neutrophils, thereby raising systemic inflammation, while alcohol abuse compromises the gut barrier, allowing endotoxins to enter the bloodstream and trigger a potent inflammatory response [26, 27]. Regarding nutritional status, we used BMI to assess obesity, which alters the secretion of adipokines, promoting a chronic, low-grade systemic inflammatory state [28]. Antipsychotic medications also have complex effects on the immune system, influencing lymphocyte populations and cytokine levels, with varying effects depending on the drug type and dosage [29]. Finally, the duration of the illness itself contributes to immune dysregulation, as prolonged disease duration may exacerbate chronic inflammation and accelerate immune senescence, leading to worsening symptom severity, chronicity, and treatment response [30].

By controlling for these factors, we can more accurately identify biological associations between inflammatory markers and clinical symptoms in schizophrenia.

Statistical analysis

All statistical analyses were performed using SPSS software (version 27.0). To examine the associations between inflammatory markers and psychiatric symptoms, participants were stratified by sex into male and female groups, followed by descriptive statistical analysis. For continuous variables that were normally distributed, independent samples t-tests were used, and results were expressed as mean ± standard deviation (M ± SD). Categorical variables were analyzed using the chi-square (χ²) test, and results are presented as frequencies and percentages [n (%)]. Pearson correlation analysis was conducted separately for males and females to evaluate the associations among NPAR, NLR, and positive and negative symptoms. Interaction effects of sex with NPAR and NLR on both positive and negative symptoms were first examined in the multiple linear regression model. Then, Multiple linear regression stratified by sex was performed to assess the independent factors associated with symptoms severity.

Results

Demographic and clinical features

This study included 217 patients diagnosed with schizophrenia, comprising 108 males and 109 females, all of Han Chinese ethnicity. Table 1 details the participants’ primary demographic and clinical characteristics. Notably, compared to female patients, males exhibited significantly higher rates of being unmarried and smoking, along with more severe positive and negative symptoms. Conversely, females demonstrated elevated NPAR values. A significant sex-based difference in educational distribution was observed. No other demographic or clinical variables showed statistically significant differences between the cohorts (Table 1).

Table 1.

Demographic and clinical characteristics of male and female participants with schizophrenia

Variable	Male participants (n = 108)	Female participants (n = 109)	p-value
Age, years	39.11 ± 13.66	39.17 ± 11.34	0.970
Marital status, n (%)			< 0.001
Single	94 (87.04%)	65 (59.63%)
Married	14 (12.96%)	44 (40.37%)
Education, n (%)			0.023
No education	1 (0.93%)	1 (0.92%)
Primary School	2 (1.85%)	13 (11.93%)
Middle School	33 (30.56%)	20 (18.35%)
High School	32 (29.63%)	34 (31.19%)
College	40 (37.04%)	41 (37.61%)
Smoking behavior, n (%)			< 0.001
Yes	22 (20.37%)	1 (0.92%)
No	86 (79.63%)	108 (99.08%)
Drinking behavior, n (%)			0.095
Yes	5 (4.63%)	1 (0.92%)
No	103 (95.37%)	108 (99.08%)
BMI, kg/m2	24.79 ± 4.88	24.29 ± 4.33	0.422
NPAR	13.26 ± 2.48	14.64 ± 2.32	< 0.001
NLR	3.15 ± 2.68	3.38 ± 4.57	0.651
Medication, n(%)			0.062
Single atypical AP	69 (63.89%)	56 (51.38%)
Multiple atypical APs	39 (36.11%)	53 (48.62%)
Olanzapine equivalent milligrams, mg/day	13.51 ± 4.05	12.99 ± 3.53	0.315
Duration of illness, years	15.84 ± 11.00	14.01 ± 9.66	0.193
SAPS	22.78 ± 10.91	17.72 ± 5.79	< 0.001
SANS	41.49 ± 18.62	30.80 ± 12.62	< 0.001

Single atypical AP: Single atypical antipsychotic medication; Multiple atypical APs: Multiple atypical antipsychotic medications

Correlation analysis of NPAR, NLR with positive and negative symptoms in male and female schizophrenia patients

Bonferroni correction was applied to control the family-wise error rate (FWER) for bivariate correlations within each sex group, with an adjusted threshold of α = 0.0125 (0.05/4 tests per group).

In male patients, NLR showed a strong positive correlation with SAPS scores (r = 0.60, p < 0.001), suggesting that elevated NLR correlates with more severe positive symptoms. In contrast, NPAR showed no significant correlation with SAPS (r = 0.19, p = 0.055) or SANS scores (r = −0.07, p = 0.448).(Table 2).

Table 2.

Analysis of related variables in male patients

	SAPS		SANS
	r	p	r	p
NPAR	0.19	0.055	−0.07	0.448
NLR	0.60	< 0.001	−0.05	0.647

In female patients, NPAR levels demonstrated a significant positive correlation with SANS scores (r = 0.40, P < 0.001), indicating that higher NPAR correlates with more severe negative symptoms. Notably, NLR showed no significant correlation with either SAPS (r = −0.10, p = 0.292) or SANS scores (r = 0.15, p = 0.124) in this group (Table 3).

Table 3.

Analysis of related variables in female patients

	SAPS		SANS
	r	p	r	p
NPAR	−0.03	0.736	0.40	< 0.001
NLR	−0.10	0.292	0.15	0.124

Sex differences in the interaction effects of NPAR and NLR on positive and negative symptoms in schizophrenia

To formally examine the sex differences in the associations between NPAR and NLR with positive and negative symptoms, we constructed a multiple linear regression model that includes interaction terms between sex and biomarkers. All relevant covariates were controlled for in the analysis. Additionally, Bonferroni correction controlled FWER for the four primary interaction effects (sex * NPAR/NLR on SAPS/SANS), with significance threshold set at α = 0.0125.

The results show that sex significantly moderates the effect of NPAR and NLR on both positive and negative symptoms. Specifically, the interaction effect of sex * NPAR on negative symptoms was significantly negative (B = −2.89, p = 0.006), indicating that the association between higher NPAR and increased SANS is stronger in females than in males, with the effect being 2.89 units stronger in females. The interaction effect of sex * NLR on positive symptoms was significantly positive (B = 2.68, p < 0.001), suggesting that the relationship between higher NLR and increased SAPS is stronger in males than in females, with the effect being 2.68 units stronger in males. However, the interaction effect of sex * NPAR on positive symptoms (p = 0.352) and the interaction effect of sex * NLR on negative symptoms (p = 0.629) were not statistically significant(Table 4).

Table 4.

Interaction effects of NPAR and NLR with sex on positive and negative symptoms

	SAPSa						SANSb
	B	SE	Beta	t	p	VIF	B	SE	Beta	t	p	VIF
Sex	6.09	1.33	0.34	4.59	< 0.001	1.78	10.53	2.79	0.32	3.77	< 0.001	1.78
NRAP	0.09	0.36	0.02	0.24	0.812	3.32	2.42	0.77	0.36	3.15	0.002	3.32
NLR	−0.13	0.19	−0.05	−0.67	0.504	1.96	−0.31	0.39	−0.07	−0.79	0.429	1.96
Sex * NPAR	−0.46	0.49	−0.09	−0.93	0.352	3.08	−2.89	1.03	−0.31	−2.79	0.006	3.08
Sex * NLR	2.68	0.35	0.56	7.67	< 0.001	1.75	0.36	0.74	0.04	0.48	0.629	1.75

^a R² = 0.39; Adjusted R² = 0.35; F = 9.21

^b R² = 0.21; Adjusted R² = 0.15; F = 3.77

Predictive relationship between NPAR, NLR and positive and negative symptoms in male and female patients with schizophrenia

We performed multiple linear regression stratified by sex to examine the associations between NPAR, NLR, and positive and negative symptoms in male and female patients, adjusting for all relevant covariates. Bonferroni correction was applied per sex group to control the FWER for four comparisons (NPAR and NLR tested against SAPS and SANS) with an adjusted threshold of α = 0.0125.

In male patients, NLR showed a significant positive association with positive symptom severity (B = 2.53, p < 0.001), indicating that higher NLR levels are associated with more severe positive symptoms. However, neither NPAR nor NLR showed a significant association with negative symptoms (NPAR: B = −0.55, p = 0.519; NLR: B = 0.08, p = 0.921). This suggests that while NLR is associated with positive symptoms in males, it does not have a significant effect on negative symptoms(Table 5).

Table 5.

Association between NPAR and NLR with positive and negative symptoms in male patients

	SAPSc						SANSd
	B	SE	Beta	t	p	VIF	B	SE	Beta	t	p	VIF
NPAR	−0.37	0.39	−0.08	−0.93	0.354	1.36	−0.55	0.85	−0.07	−0.65	0.519	1.36
NLR	2.53	0.36	0.62	7.10	< 0.001	1.30	0.08	0.77	0.01	0.10	0.921	1.30

^c R² = 0.43; Adjusted R² = 0.37; F = 28.15

^d R² = 0.09; Adjusted R² = 0.01; F = 1.06

In female patients, NPAR showed a significant positive association with negative symptom severity (B = 2.58, p < 0.001), suggesting that higher NPAR levels are linked to more severe negative symptoms. However, neither NPAR nor NLR showed a significant association with positive symptoms (NPAR: B = 0.02, p = 0.954; NLR: B = −0.13, p = 0.386)(Table 6).

Table 6.

Association between NPAR and NLR with positive and negative symptoms in female patients

	SAPSe						SANSf
	B	SE	Beta	t	p	VIF	B	SE	Beta	t	p	VIF
NPAR	0.02	0.30	0.01	0.06	0.954	1.49	2.58	0.58	0.48	4.43	< 0.001	1.49
NLR	−0.13	0.15	−0.10	−0.87	0.386	1.49	−0.28	0.30	−0.10	−0.95	0.343	1.49

^e R² = 0.09; Adjusted R² = 0.01; F = 0.50

^f R² = 0.25; Adjusted R² = 0.16; F = 11.27

Discussion

To the best of our knowledge, this is the first study specifically designed to investigate the potential associations between NPAR and NLR and the severity of positive and negative symptoms in schizophrenia patients, with a focus on sex differences. In this study, we assessed positive and negative symptom scores in 108 male and 109 female patients, while measuring relevant inflammatory markers. The results indicated that in male patients, NLR was significantly associated with the severity of positive symptoms, whereas in female patients, NPAR was positively associated with the severity of negative symptoms. These findings suggest that NPAR and NLR may serve as valuable biological markers for predicting the severity of positive and negative symptoms in individuals of different sexes with schizophrenia.

In immunological research on schizophrenia, sex differences are not only reflected in the intensity of immune responses but are also closely linked to disease pathophysiology, symptom expression, and treatment responses [31, 32]. The immune systems of males and females differ significantly in terms of immune cell composition, cytokine secretion, and immune regulation [33]. Studies have shown that females generally exhibit a stronger immune response and have a certain advantage in terms of inflammatory response and antioxidant capacity [34]. This sex difference is likely attributed to sex hormones, particularly estrogen, which plays a crucial role in regulating immune system functions [35]. Estrogen not only inhibits the release of pro-inflammatory cytokines but also modulates microglial activation and oxidative stress responses, thereby alleviating the impact of inflammation on the central nervous system (CNS) [36, 37]. In contrast, males tend to exhibit overactivation of innate immune pathways and relatively weaker anti-inflammatory regulation, which may lead to immune imbalance and a chronic pro-inflammatory state [38, 39].

In our study, the elevated NLR in male patients was significantly associated with the severity of positive symptoms in schizophrenia, which is consistent with existing literature linking increased NLR with psychiatric symptoms. An elevated NLR typically reflects an imbalance in the immune system, characterized by an increase in neutrophils and a decrease in lymphocytes, indicating a pro-inflammatory state [40]. This immune imbalance may contribute to blood-brain barrier disruption and microglial activation, further promoting neuroinflammation and impairing CNS function [41]. Research has also shown that chronic low-grade inflammation can enhance dopaminergic activity in the mesolimbic pathways, potentially exacerbating positive symptoms such as hallucinations and delusions [42, 43]. Thus, the positive association between NLR and positive symptoms in male patients in our study may reflect heightened sensitivity to immune imbalance and neuroinflammation, thus intensifying the expression of positive symptoms.

Additionally, our study found a significant positive correlation between NPAR and the severity of negative symptoms in female patients, suggesting that inflammation-metabolism interactions may play a more significant role in the pathophysiology of negative symptoms in females [44]. As a composite index, NPAR combines the neutrophil percentage and serum albumin levels, providing a comprehensive measure of systemic inflammation and antioxidant capacity [45]. Albumin, beyond its role as a nutritional marker, is crucial for antioxidant defense, maintaining endothelial integrity, and regulating vascular permeability [46]. Under chronic inflammatory or oxidative stress conditions, albumin synthesis is often suppressed, weakening the body’s ability to neutralize free radicals and increasing the vulnerability of neural tissue to damage [47]. Long-term inflammation-metabolism imbalance may lead to the manifestation of more negative symptoms in females, potentially linked to the lower antioxidant capacity and the insufficient ability to neutralize free radicals due to decreased albumin synthesis [48, 49]. Moreover, estrogen has been shown to exert protective effects on the immune and antioxidant systems, mitigating the impact of chronic inflammation on the CNS [50]. However, in the context of chronic inflammation, albumin synthesis is reduced, leading to weakened antioxidant functions and increased neural tissue vulnerability [51]. Due to differences in immune and metabolic systems, females are more likely to experience immune-metabolic imbalance in a prolonged inflammatory state, which may exacerbate neuroinflammation, impair neuroplasticity, and contribute to more prominent negative symptoms [52]. This sex-specific mechanism likely reflects a greater tendency for females to experience immune-metabolic imbalance when facing chronic inflammation, whereas males, due to their pro-inflammatory immune response, are more likely to exhibit positive symptoms (such as hallucinations and delusions) [53, 54]. Therefore, as a comprehensive index, NPAR more accurately reflects the neurobiological disturbances in females under conditions of inflammation and antioxidant imbalance, and consequently, shows a stronger correlation with the severity of negative symptoms.

This study has several limitations. Firstly, due to its cross-sectional design, causal relationships between inflammatory markers and symptom severity should be inferred. Longitudinal studies are needed to investigate the temporal dynamics and potential causal pathways. Secondly, the single-center recruitment approach could limit the generalizability of the results. Future multi-center studies with more diverse populations would help to enhance the applicability of these findings. Thirdly, although we focused on sex differences, the analysis did not account for direct measures of sex hormones, which are known to play a crucial role in regulating immune responses. Future research that directly measures sex hormone levels could provide more precise insights into how hormonal fluctuations might influence immune dysfunction and symptom manifestation, particularly regarding the immune-metabolic imbalance observed in female patients. Lastly, the use of peripheral inflammatory markers might not fully capture the role of central nervous system (CNS) inflammation, which could affect the interpretation of how neuroinflammation contributes to psychiatric symptoms. Incorporating neuroimaging or cerebrospinal fluid (CSF) biomarkers in future work would allow for a more accurate assessment.

Conclusions

Our findings indicate that elevated NPAR and NLR levels may be associated with symptom severity in schizophrenia, with apparent sex-specific differences. These preliminary results suggest that peripheral inflammatory markers could potentially aid in clinical assessment and inform personalized treatment planning. Monitoring systemic inflammation might help to elucidate sex-related mechanisms underlying symptom expression. Further studies are needed to confirm these associations and explore their role in precision psychiatry.

Author contributions

YTZ designed the research. YTZ, JJR and ZCF collected and analyzed the data. YTZ and JJR wrote the initial draft, and ZCF revised it. All authors contributed to and approved the final version of the manuscript.

Funding

This study received no funding.

Data availability

The datasets used and/or analyzed in this study are available upon reasonable request from the corresponding author.

Declarations

Competing interests

The authors declare no competing interests.

Consent to publish

Not applicable.

Human ethics and consent to participate declarations

All methods were performed in compliance with the relevant guidelines and regulations, in accordance with the Declaration of Helsinki.The study was approved by the Ethics Committee of the Affiliated Xiaoshan Hospital, Hangzhou Normal University(Approval number:2025-012). This study used secondary data that does not contain any information that could identify individual participants. Therefore, the requirement for informed consent was waived by the ethics committee.