Decreased serum IGFBP-7 level is associated with cognitive impairment in first-episode drug-naïve adolescent-onset schizophrenia

Abstract

Background

Adolescent-onset schizophrenia (AOS) is characterized by severe cognitive impairment. Insulin-like growth factor binding protein-7 (IGFBP-7), a biomarker of vascular aging and neuroinflammation, and hepatocyte growth factor (HGF), involved in neurodevelopment, have been linked to cognitive decline, but their roles in AOS remain unexplored.

Methods

This case–control study enrolled 91 first-episode drug-naïve AOS patients and 40 healthy controls. Clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) and its five-factor model, and cognitive function was evaluated using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).

Results

AOS patients exhibited significantly lower serum IGFBP-7 levels compared to healthy controls (10.15 ± 3.62 vs. 11.75 ± 3.41 ng/mL, t = -2.377, P = 0.019), while HGF levels showed no significant difference (P > 0.05). IGFBP-7 levels were negatively correlated with PANSS cognitive factor scores (r = -0.308, P = 0.003) and positively correlated with RBANS total scores (r = 0.353, P = 0.001). IGFBP-7 was independently associated with RBANS total score (β = 0.284, P = 0.002) after controlling for confounding factors. Sex (β = 0.467, t = 5.325, P < 0.001) was identified as a confounder but did not moderate the IGFBP-7-cognition relationship (P > 0.05). Modified Poisson regression revealed that low IGFBP-7 levels independently predicted AOS risk (RR = 1.298, 95% CI: 1.037–1.624, P = 0.023), with attributable fractions of 23.0% in exposed individuals and 12.7% in the overall population.

Conclusions

Decreased serum IGFBP-7 levels are associated with cognitive impairment in AOS and represent a significant risk factor, suggesting IGFBP-7 as a potential biomarker for cognitive dysfunction in AOS.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12991-026-00672-3.

Introduction

Schizophrenia is a severe mental disorder affecting approximately 1% of the global population, characterized by hallucinations, delusions, thought disorders, and significant cognitive dysfunction [1, 2]. Adolescent-onset schizophrenia (AOS), typically defined as illness onset before the age of 18, which affects roughly 0.3% of the population, is associated with more severe premorbid neurodevelopmental abnormalities, poorer long-term prognosis, and more profound cognitive impairments [3, 4]. Studies have demonstrated that cognitive dysfunction exists years before the emergence of psychotic symptoms, and cognitive deficits may share common pathological mechanisms with clinical symptoms [5, 6]. Despite extensive research exploring the neurobiological underpinnings of schizophrenia [7, 8], the pathophysiological mechanisms of AOS remain incompletely understood [9].

Insulin-like growth factor binding protein-7 (IGFBP-7) is an important extracellular matrix protein that plays critical roles in various physiological and pathological processes [10, 11]. Studies have shown that elevated plasma IGFBP-7 levels are associated with chronic inflammatory states and are significantly increased in aging- and obesity-related diseases [12, 13]. IGFBP-7 regulates the senescence-associated secretory phenotype and may play important roles in cerebrovascular aging and neuroinflammation [14]. IGFBP-7 has been recognized as closely associated with cognitive function. In animal studies, decreased IGFBP-7 levels in the cerebrospinal fluid of adult male rats have been found to be associated with cognitive impairment [15]. In clinical research, peripheral circulating IGFBP-7 levels have been correlated with postoperative cognitive dysfunction [16]. In the field of psychiatric disorders, significantly elevated plasma IGFBP-7 levels have been found in patients with major depressive disorder, and elevated IGFBP-7 shows a negative correlation with cognitive function [17]. In contrast, studies in schizophrenia patients have revealed that serum IGFBP-7 levels are lower in drug-naïve first-episode patients compared to healthy controls [18], but increase after antipsychotic treatment [19]; however, no associations between IGFBP-7 and clinical symptoms or cognitive function have been observed in either first-episode or multiple-episode patients [18, 19].

Hepatocyte growth factor (HGF) is another important neuroprotective factor that exerts critical functions in preventing neuronal death and promoting neuronal survival through pro-angiogenic, anti-inflammatory, and immunomodulatory mechanisms [20, 21]. Dysfunction of HGF may contribute to neurodevelopmental disorders [22]. Genetic studies have identified HGF gene variants associated with schizophrenia risk [23], and animal experiments have demonstrated that mice with abnormal HGF signaling exhibit not only impaired interneuron development but also behavioral abnormalities related to neurodevelopmental disorders [24].

However, no studies have yet explored the characteristics of IGFBP-7 and HGF alterations in AOS patients, nor their relationships with cognitive function and clinical symptoms. Based on the above background, we hypothesized that IGFBP-7 and HGF may play important roles in the pathophysiology of AOS and be associated with cognitive impairment. Therefore, the present study aimed to: (1) investigate the alterations of serum IGFBP-7 and HGF levels in first-episode drug-naïve AOS patients; (2) examine the correlations between these biomarkers and clinical symptom severity as well as cognitive function; and (3) evaluate whether IGFBP-7 and HGF levels serve as risk factors for AOS.

Materials and methods

Subjects

This study enrolled first-episode drug-naïve adolescent-onset schizophrenia (AOS) patients who were hospitalized in the Department of Psychiatry at the Fourth People’s Hospital of Lianyungang between September 2021 and June 2024. Inclusion criteria were: (1) aged 13–18 years; (2) met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for schizophrenia; (3) first episode with no previous treatment with antipsychotic medication; (4) presence of clear psychotic symptoms and ability to cooperate with clinical assessment and cognitive function testing; (5) voluntary participation with informed consent signed by both the patient and their guardian. Exclusion criteria were: (1) comorbidities of other psychiatric disorders or neurological diseases; (2) comorbidities of severe physical diseases (e.g., cardiac, hepatic, renal, or endocrine system diseases); (3) history of substance abuse; (4) pregnancy or lactation; (5) use of medications that could affect metabolism or cognitive function within the past 3 months.

During the same period, healthy controls matched for age, sex, and years of education were recruited. Healthy controls with a personal or family history of psychiatric disorders, neurological diseases, severe physical diseases, or substance abuse were excluded.

All participants and their guardians were fully informed of the study objectives, procedures, and potential risks prior to participation and voluntarily signed informed consent forms. This study was approved by the Ethics Committee of the Fourth People’s Hospital of Lianyungang (approval number: 2021LSYYXLL-P11).

Assessment of clinical and cognitive functions

All AOS patients underwent clinical symptom and cognitive function assessments at enrollment by two trained attending psychiatrists. The Positive and Negative Syndrome Scale (PANSS) was used to assess the severity of psychotic symptoms [25]. The PANSS consists of 30 items, each rated on a 7-point scale ranging from 1 to 7, with a total score ranging from 30 to 210. This study employed the PANSS five-factor model for symptom dimension assessment: positive factor (P1, P3, P5, P6, G9), negative factor (N1, N2, N3, N4, N6, G7), cognitive factor (P2, N5, G5, G10, G11), excitement/hostility factor (P4, P7, G8, G14), and anxiety/depression factor (G1, G2, G3, G6) [9, 25, 26].

The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was used to assess cognitive function in patients [27, 28]. RBANS is a standardized neuropsychological test battery comprising 12 subtests that evaluate five cognitive domains: (1) immediate memory (list learning, story memory); (2) visuospatial/constructional (figure copy, line orientation); (3) language (picture naming, semantic fluency); (4) attention (digit span, coding); and (5) delayed memory (list recognition, list recall, story recall, figure recall). All cognitive function tests were conducted in a quiet, distraction-free environment, with a testing duration of approximately 30–45 min.

Blood sampling and biochemical assays

Fasting venous blood samples (5 mL) were collected from all participants between 7:00 and 9:00 AM following enrollment after at least 8 h of fasting. Blood samples were collected in vacuum tubes containing clot activator, allowed to stand at room temperature for 30 min, and centrifuged at 3,000 rpm for 15 min to separate serum. Serum samples were aliquoted and immediately stored at -80 °C until batch analysis. Serum IGFBP-7 and HGF levels were measured using Luminex liquid suspension array technology with a human IGFBP-7 and HGF assay kit (R&D Systems, Minneapolis, MN, USA), performed strictly according to the manufacturer’s instructions. All samples were analyzed in duplicate within the same batch. The coefficient of variation for quality control samples was less than 10%.

Statistical analysis

All statistical analyses were performed using SPSS 25.0 software (IBM Corporation, Armonk, NY, USA). Normally distributed continuous variables were presented as mean ± standard deviation and compared between groups using independent samples t-tests. Non-normally distributed continuous variables were presented as median (interquartile range) and compared using Mann-Whitney U tests. Categorical variables were presented as number (percentage) and compared using chi-square tests. Analysis of covariance (ANCOVA) was used to compare serum IGFBP-7 levels between groups after controlling for age. Pearson or Spearman correlation analysis was used to examine the correlations between serum IGFBP-7 and HGF levels and PANSS five-factor scores in AOS patients, as well as between these biomarkers and RBANS scores in healthy controls. Prior to Pearson correlation analysis, normality of serum IGFBP-7 levels, PANSS five-factor scores, and RBANS scores was confirmed using the Shapiro-Wilk test. Stepwise multiple linear regression analysis was conducted to explore the independent associations of IGFBP-7 with clinical symptoms and cognitive function, with PANSS cognitive factor score, RBANS total score, and delayed memory score as dependent variables, IGFBP-7 level as the independent variable, and age, sex, BMI, years of education, illness duration, and age of onset as covariates. Multiple linear regression models were constructed to explore the moderating effect of sex on the relationship between IGFBP-7 and cognitive function, including the IGFBP-7 × sex interaction term.

All participants were divided into a low IGFBP-7 group and a high IGFBP-7 group based on the median IGFBP-7 level. Modified Poisson regression analysis was used to evaluate the predictive value of low IGFBP-7 levels for AOS, controlling for age, sex, years of education, and BMI, and relative risk (RR), attributable fraction (AF), and population attributable fraction (PAF) were calculated. All statistical tests were two-tailed, and P < 0.05 was considered statistically significant.

Results

Comparisons of demographic and clinical data of AOS patients and healthy controls

As shown in Table 1, there were no significant differences in sex, education level, or BMI between AOS patients and healthy controls (all P > 0.05); however, the average age of the patient group was higher than that of the healthy controls (P = 0.010). Among AOS patients, the average age of onset was 14 years, with an average duration of illness of 12 months, and 10 patients had a family history of mental disorders. Cognitive function assessments indicated that AOS patients scored significantly lower than healthy controls on the RBANS total score and its subscale scores (all P < 0.001).

Table 1.

Demographic and clinical characteristics of adolescent-onset schizophrenia patients and healthy controls (HC)

Variables	Patients (n = 91)	HC (n = 40)	t/Z/χ2	P
Age, years	15.64 ± 1.58	14.88 ± 1.42	2.620a	0.010
Sex, n (Male/female)	37/54	13/27	0.784b	0.376
Education levels, years	9.0 (8.0, 11.0)	9.0 (8.0, 10.0)	-1.569c	0.117
BMI, kg/m2	21.04 ± 3.69	21.21 ± 3.33	-0.254a	0.800
Family history of mental disorders, n (yes/no)	10/81	-	-	-
Age of onset, years	14.0 (13.0, 16.0)	-	-	-
Duration of illness, months	12.0 (3.0, 26.0)	-	-	-
PANSS total score	81.12 ± 15.85	-	-	-
Positive factor	18.98 ± 6.83	-	-	-
Negative factor	13.79 ± 3.63	-	-	-
Cognitive factor	13.14 ± 3.18	-	-	-
Excitement/hostility factor	12.59 ± 4.58	-	-	-
Anxiety/depression factor	8.63 ± 2.59	-	-	-
Immediate memory	68.92 ± 21.52	89.35 ± 11.58	-5.647a	< 0.001
Visuospatial/constructional	82.01 ± 16.64	95.85 ± 13.86	-4.601a	< 0.001
Language	86.40 ± 13.62	99.78 ± 10.74	-5.504a	< 0.001
Attention	92.15 ± 14.29	111.15 ± 8.65	-7.793a	< 0.001
Delayed memory	72.81 ± 21.57	88.95 ± 16.94	-4.194a	< 0.001
RBANS	75.44 ± 16.26	94.88 ± 8.65	-7.119a	< 0.001

BMI, body mass index; PANSS, Positive and Negative Syndrome Scale; RBANS, Repeatable Battery for the Assessment of Neuropsychological Statue. a independent samples t-test; b χ2 test; c Mann-Whitney U test

Serum IGFBP-7 and HGF levels of AOS patients and healthy controls

Non-normally distributed HGF levels were log-transformed to achieve normality. Compared to healthy controls, the serum IGFBP-7 levels in AOS patients were significantly lower (10.15 ± 3.62 vs. 11.75 ± 3.41 ng/mL, t = -2.377, P = 0.019, Fig. 1A), while there was no significant difference in HGF levels between the two groups [124.44 (89.05, 168.51) vs. 122.77 (104.59, 168.18) pg/mL, Z = − 0.447, P = 0.655, Fig. 1B].

Fig. 1.

Comparison of serum IGFBP-7 and HGF levels between adolescent-onset schizophrenia patients and healthy controls (HC). (A) Serum IGFBP-7 levels followed a normal distribution and are presented as mean ± standard deviation (SD). (B) Serum HGF levels exhibited a skewed distribution and are presented as median with interquartile range (IQR)

Considering the age difference between the two groups, ANCOVA revealed that there remained a significant difference in IGFBP-7 levels between AOS patients and healthy controls after controlling for age (F = 6.845, P = 0.010).

Correlation of serum IGFBP-7 concentrations with clinical symptoms in AOS patients

Pearson correlation analysis revealed a significant negative correlation between serum IGFBP-7 levels and the PANSS cognitive factor score (r = -0.308, P = 0.003, Fig. 2). No significant correlations were observed between serum IGFBP-7 concentrations and the PANSS total score or other factor scores (all P > 0.05).

Fig. 2.

Correlation between serum IGFBP-7 levels and PANSS cognitive factor scores in AOS patients

Stepwise multiple linear regression analysis was conducted with the PANSS cognitive factor score as the dependent variable, serum IGFBP-7 level as the independent variable, and age, sex, BMI, years of education, duration of illness, and age of onset as covariates. Serum IGFBP-7 level remained significantly negatively correlated with the PANSS cognitive factor score (B = -0.303, β = -0.345, t = -3.491, P = 0.001). Additionally, sex was a significant confounder (B = 1.634, β = 0.254, t = 2.568, P = 0.012).

Correlations of serum IGFBP-7 concentrations with cognitive impairments

Pearson correlation analysis showed that serum IGFBP-7 levels were significantly positively correlated with delayed memory scores (r = 0.218, P = 0.037, Fig. 3A) and RBANS total scores (r = 0.353, P = 0.001, Fig. 3B), but not with other RBANS subscale scores (all P > 0.05).

Fig. 3.

Correlations between serum IGFBP-7 levels and cognitive impairments in AOS patients. (A) Serum IGFBP-7 levels were significantly positively correlated with delayed memory scores. (B) Serum IGFBP-7 levels were significantly positively correlated with RBANS total scores

Subsequently, stepwise multiple linear regression analyses were performed with RBANS total score or delayed memory score as dependent variables, serum IGFBP-7 level as the independent variable, and age, sex, BMI, years of education, duration of illness, and age of onset as covariates. The results demonstrated that serum IGFBP-7 level remained significantly positively correlated with RBANS total score (B = 1.275, β = 0.284, t = 3.238, P = 0.002), with sex as a significant confounder (B = 15.375, β = 0.467, t = 5.325, P < 0.001). However, no significant correlation was observed between serum IGFBP-7 level and delayed memory score (P > 0.05), with sex (B = 25.404, β = 0.582, t = 6.911, P < 0.001) and age (B = 2.296, β = 0.168, t = 1.999, P = 0.049) identified as significant confounders.

Correlations of serum HGF concentrations with clinical symptoms and cognitive function

Correlation analysis revealed no significant associations between HGF levels and any PANSS five-factor scores or PANSS total score in AOS patients (all P > 0.05), nor between HGF levels and RBANS total score or subscale scores in healthy controls (all P > 0.05).

Moderating effect of sex on the relationship between IGFBP-7 and cognitive impairment

Given that sex emerged as a significant confounder in the above regression analyses, while serum IGFBP-7 levels showed no significant difference between male and female AOS patients (P = 0.165), we further explored whether sex moderates the relationship between IGFBP-7 and cognitive impairment. A multiple linear regression model was constructed with RBANS total score as the dependent variable, IGFBP-7, sex, and the IGFBP-7 ⋅ sex interaction term as independent variables, and age, years of education, BMI, illness duration, and age of onset as covariates. The results revealed that the sex × IGFBP-7 interaction term was not statistically significant (B = 0.061, β = 0.022, t = 0.074, P = 0.941).

Furthermore, serum IGFBP-7 levels showed no significant correlation with age in the total sample, AOS group, or HC group (all P > 0.05; see Supplementary Table S1). Detailed IGFBP-7 levels stratified by sex in AOS patients are presented in Supplementary Table S2. Sex-stratified comparisons of serum IGFBP-7 and HGF levels between AOS patients and HC are further illustrated in Supplementary Figure S1 and Supplementary Table S3.

Independent variables predictive of AOS

All participants were categorized into low IGFBP-7 (coded as 1) and high IGFBP-7 (coded as 0) groups based on the median serum IGFBP-7 level. Modified Poisson regression analysis was performed with AOS diagnostic status as the dependent variable, IGFBP-7 grouping as the independent variable, and age, sex, years of education, and BMI as covariates. The results demonstrated that low IGFBP-7 level was an independent risk factor for AOS (B = 0.261, P = 0.023, RR = 1.298, 95% CI: 1.037–1.624). The AF and PAF were 23.0% and 12.7%, respectively, indicating that low IGFBP-7 levels accounted for 23.0% of AOS cases in exposed individuals and 12.7% of cases in the overall population.

Discussion

The main findings of this study were: (1) compared to healthy controls, AOS patients exhibited significantly lower serum IGFBP-7 levels; (2) in AOS patients, serum IGFBP-7 levels were significantly negatively correlated with the PANSS cognitive factor score; (3) serum IGFBP-7 levels were significantly positively correlated with RBANS total score, and this correlation persisted after controlling for confounding factors; (4) sex was a confounder in the relationship between IGFBP-7 and RBANS total score, but the sex × IGFBP-7 interaction term was not statistically significant; (5) low IGFBP-7 level was an independent risk factor for AOS, with a population attributable risk percentage of 23.0% in the exposed group and 12.7% in the total population.

This study is the first to report that serum IGFBP-7 levels in first-episode drug-naïve AOS patients were significantly lower than those in healthy controls, consistent with Fernández-Pereira et al. [19]. Fernández-Pereira et al. found that plasma IGFBP-7 levels were lower in first-episode drug-naïve schizophrenia patients compared to healthy controls, but increased after antipsychotic treatment, suggesting that the reduction of IGFBP-7 may be a pathological feature of schizophrenia itself rather than a consequence of medication. Yang et al. reported similar reductions in a cohort including patients who were either drug-naïve or medication-free for at least 3 months, suggesting directional consistency albeit with differences in patient characterization [29]. Adolescence represents a critical period for cerebrovascular system development and maturation. Reduced IGFBP-7 levels may potentially contribute to alterations in this developmental process, which could be associated with cerebrovascular and neuronal functional changes [30]. Recent studies have demonstrated that IGFBP-7 also functions as a neuroimmune regulatory molecule, with its expression being modulated by neuronal signals such as GABAergic neurotransmission [31], suggesting that IGFBP-7 may serve as a bridge between neurodevelopment and immune homeostasis. IGFBP-7 may participate in the pathogenesis of AOS by regulating angiogenesis and neurotrophic support during critical neurodevelopmental periods. The peripheral IGF system comprises IGF-1, IGF-2, and six classical high-affinity IGF-binding proteins (IGFBP-1 to IGFBP-6) that regulate IGF bioavailability and signaling [14, 32]. Although IGFBP-7 is structurally related to this family, it exhibits approximately 100-fold lower binding affinity for IGF-1 and IGF-2 compared to IGFBP-1 through IGFBP-6, and is uniquely characterized by its higher binding affinity for insulin than for IGFs [11]; nevertheless, IGFBP-7 may still contribute to neurotrophic regulation in part through modulation of IGF-1 and IGF-2 signaling, alongside its IGF-independent functions in cellular senescence and neuroinflammation [14].

IGFBP-7 levels were negatively correlated with PANSS cognitive factor scores, suggesting that reduced IGFBP-7 is associated with more severe cognitive symptoms. This finding differs from the findings of Yang et al. [29], which did not reveal significant correlations between IGFBP-7 and PANSS scores. This discrepancy may reflect both differences in neurobiological mechanisms between adolescent-onset and adult-onset illness, and differences in patient characterization, as Yang et al.’s cohort included patients who were either drug-naïve or had undergone a minimum 3-month antipsychotic washout period. IGFBP-7 regulates the IGF system and participates in neuronal survival and synaptic plasticity [33–35], and its reduction may affect these neurobiological processes, manifesting as cognitive symptoms.

IGFBP-7 levels were positively correlated with RBANS total scores, and this correlation persisted after controlling for confounding factors. This is the first report of a significant association between IGFBP-7 and cognitive assessment in AOS patients. This finding supports the hypothesis that IGFBP-7 may influence cognitive function through multiple mechanisms: as an angiogenesis regulator, IGFBP-7 maintains cerebrovascular integrity and cerebral perfusion [10, 30, 36]; it affects synaptic plasticity through IGF system regulation [37]; and it protects neural function through neuroimmune modulation [31]. Furthermore, IGFBP-7 has been shown to be up-regulated in brain tissue and amyloid precursor protein transgenic mouse models of Alzheimer’s disease (AD) [38], with convergent evidence from peripheral samples also indicating its association with cognitive impairment in AD [39]; this contrasts with the reduced IGFBP-7 observed in AOS patients in this study, which may reflect different pathological mechanisms between neurodevelopmental disorders and neurodegenerative diseases. The association between IGFBP-7 and overall cognitive performance across multiple domains suggests it may serve as a potential biological indicator of cognitive function in AOS patients.

This study showed that sex was a significant confounder in the relationship between IGFBP-7 and RBANS total score, but interaction analysis revealed that sex did not moderate the relationship between IGFBP-7 and cognitive function, suggesting that the association between IGFBP-7 and cognitive deficits is consistent across male and female AOS patients and does not vary by sex. A 4-year follow-up study demonstrated sex differences in cognitive performance in schizophrenia, with males showing more pronounced impairment in verbal learning, while females exhibited more significant impairment in reasoning/problem-solving [40]. In first-episode schizophrenia patients, females outperformed males in processing speed and verbal learning, whereas males demonstrated superiority in working memory and reasoning/problem-solving [41]. These differences may be related to sex hormones, oxidative stress, neurosteroids, brain structural differences, neurodevelopmental trajectories, or associated psychosocial factors [42–44]. The association observed in this study may reflect a sex-independent biological process.

This study found that low IGFBP-7 levels were an independent risk factor for AOS. Among individuals exposed to low IGFBP-7 levels, 23.0% of AOS cases were associated with low IGFBP-7 levels; in the entire population, 12.7% of AOS cases were associated with low IGFBP-7 levels. Adolescence is a crucial period for synaptic pruning and myelination [45], during which the fine-tuning of neural circuits requires precise regulation by neurotrophic and immunoregulatory factors [46]. IGFBP-7 influences neuronal survival and synaptic plasticity through IGF system regulation [32, 47], while also participating in the balance of inflammatory responses as a neuroimmune regulatory factor [31]. Its insufficiency may lead to dysregulation of these critical developmental processes, increasing the risk of psychotic symptom emergence, which aligns with the neurodevelopmental hypothesis of schizophrenia [48, 49]. These findings suggest that IGFBP-7 reduction may play a role in the pathogenesis of AOS, but its precise causal relationship and potential clinical application value require further validation through prospective studies.

This study has the following limitations. First, as a cross-sectional case–control study, this investigation cannot establish a causal relationship between IGFBP-7 and AOS, nor can it determine whether decreased IGFBP-7 levels are a cause or consequence of AOS. Second, the relatively small sample size of the healthy control group may affect the statistical power and stability of the results, and may also limit the power of sex-stratified analyses in AOS patients. Third, this was a single-center study with relatively homogeneous sample source, and participants were primarily recruited from a specific geographic region and medical institution. Future multi-center, large-sample prospective longitudinal studies are needed to further validate the findings of this study. Fourth, additional factors such as differences in analytical platforms (e.g., Luminex versus ELISA) and ethnic backgrounds across studies may also contribute to variability in peripheral IGFBP-7 levels and limit direct cross-study comparability [50]. Finally, peripheral IGFBP-7 levels may not accurately reflect central alterations, and metabolic parameters related to insulin signaling (e.g., glucose homeostasis) may also influence circulating IGFBP-7 levels, representing potential sources of residual confounding.

Conclusions

In summary, this study showed that serum IGFBP-7 levels were significantly decreased in first-episode drug-naïve AOS patients, and IGFBP-7 levels were significantly positively correlated with cognitive function. Low IGFBP-7 levels were identified as an independent risk factor for AOS, suggesting that IGFBP-7 may play a role in the pathogenesis of AOS. Future prospective longitudinal studies with larger sample sizes are needed to further validate the predictive value of IGFBP-7 and explore its potential clinical utility in early identification of AOS.

Supplementary Information

Below is the link to the electronic supplementary material.

Author contributions

Haidong Yang and Jie Hou wrote the manuscript; Xiaobin Zhang and Qing Tian were responsible for the study design; Haidong Yang and Yubing Han performed the statistical analysis; Yubing Han, Man Yang, and Lingshu Luan performed the clinical ratings, recruited the patients, and collected the samples. All authors have contributed to and approved the final manuscript.

Funding

The study was financially supported by the Suzhou Clinical Medical Center for Mood Disorders (grant no. Szlcyxzx202109), Suzhou Key Laboratory (grant no. SZS2024016), Suzhou Multicenter Clinical Research Project on Major Diseases (grant no. DZXYJ202413), Guidance Project of Jiangsu Provincial Health Commission (grant no. Z2023074), Lianyungang Science and Technology Bureau of Social Development Key R&D Projects (grant no. SF2532), and Lianyungang National Natural Science Foundation Reserved Project (General Program) (grant no. K82504). The funding sources of this study had no role in the study design, data collection and analysis, decision to publish, or preparation of the article.

Data availability

The data supporting the results of this study are available from the corresponding author upon reasonable request.

Declarations

Ethical approval and consent to participate

We declare that all human experimentation was conducted in accordance with the Declaration of Helsinki and that all procedures were carried out with the adequate understanding and written consent of the subjects. All experimental protocols were approved by the Ethics Committee of Lianyungang Fourth People’s Hospital (approval number: 2021LSYYXLL-P11). Informed consent was obtained from all participants and/or their legal guardians. All methods were carried out in accordance with relevant guidelines and regulations.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Declaration of generative AI and AI-assisted techniques

Artificial intelligence (AI) tools were used only for minor language editing (e.g., grammar and style checks). All scientific content, interpretations, and conclusions were generated by the authors.