Schizophrenia is a chronic psychiatric disease with high disability rate. The manifestations of schizophrenia include positive symptoms such as delusion, hallucination, disorganized speech and behavior, and negative symptoms containing social withdrawal, emotional dullness and avolition, while cognitive function is also affected such as memory, executive function, and processing speed (1). In fact, schizophrenia affects about 1% of the global population and is one of the top ten disabling diseases (2). However, with countless patients and their families suffering from schizophrenia, we still have a long way in exploring the pathogenesis of schizophrenia. At present, it is generally believed that the etiology of schizophrenia is related to various factors, which involve genes, neurodevelopment, environmental factors together with social and psychological factors. There are also many hypotheses about the pathogenesis. The mainstream is the neurobiological hypothesis, which suggesting that the schizophrenia mainly originates from the dysfunction of neurotransmitters in the brain, such as dopamine, serotonin, glutamatergic and other neurotransmitters, and this hypothesis has also been confirmed by the evidence of psychopharmacology.

Neuropeptide Y(NPY) was first discovered by Tatemoto in 1982 (3), which is a polypeptide chain composed of 36 amino acids with tyrosine amide group at the C-termina (4). NPY acts on 6 receptors, namely Y1, Y2, Y3, Y4, Y5 and Y6. However, Y3 receptor is not expressed in mammals, while Y6 receptor is not expressed in primates (5). These receptors are distributed in the cortex, amygdala, hypothalamus, hippocampus and striatum in the central nervous system, and are also widely distributed in the heart, kidney, liver, pancreas and intestine (6). Among them, Y4 receptor is mainly distributed in the intestine and less in the central nervous system. In other words, the central system mainly distributes Y1, Y2 and Y5 receptors (7). Through these receptors above, NPY can increase food intake, promote energy to be converted into fat, alleviate anxiety and pain, and also affects biological rhythms (8).

Previous studies have suggested that there were associations between Neuropeptide Y and schizophrenia. For example, in the DISC1(disrupted-in-schizophrenia 1) model, which is the candidate gene locus first described in a large Scottish family (9), NPY-immunoreactive neurons expressions in the prefrontal lobes of DISC1-knockout mice were decreased compared to wild type (10). The study on the brain of schizophrenia patients indicated that, compared with healthy controls, the proportion of NPY neurons in the upper layers of cortex was lower while the expression was abnormally increased in the deep white matter (11). Researchers also found reduced expression of NPY in the prefrontal cortex of schizophrenia patients (12). NPY levels of medication-naïve chronic schizophrenia patients was higher than controls (13).

Antipsychotics can alter the expression of NPY. Mice fed with risperidone for 4 weeks showed decreased NPY mRNA levels in the hypothalamus, but no difference was found in NPY levels in cerebrospinal fluid or peripheral blood (14). The olanzapine would raise the NPY expression in the arcuate nucleus of rats (15), and it was possibly through the NPY pathway that betahistine reversed the weight gain induced by olanzapine (16). The plasma concentrations of clozapine (17) and olanzapine (18) are both negatively correlated with NPY levels.

Some studies have reported that sex heterogeneity was found in many aspects of schizophrenia, including the age of onset, psychiatric symptoms, cognitive function, and treatment efficiency (19). For instance, chronic male patients had an earlier onset of schizophrenia and more severe cognitive impairment and negative symptoms (20). It has been suggested that in many clinical, epidemiological, and fundamental researches that oestradiol could have protective effects in schizophrenic psychoses (21). More interestingly, NPY seemed to be different in males and females. Serum NPY levels were higher in women than in men in chronic patients treated with clozapine (22). Previous studies on stress-related diseases also showed that there were different changes in NPY levels between males and females under acute or chronic stress stimuli (23). NPY in mice showed sexual dimorphism under chronic stress. Social isolation would indicate the decreasing of NPY mRNA levels in the hippocampus of females (24). In prefrontal cortex, NPY mRNA levels were elevated under chronic stress in female mice but not in males (25).

The relationship between schizophrenia and stress can be understood from several perspectives: A characteristic of schizophrenia is subcortical hyperdopaminergia, which has been found to be associated with chronic psychological stress (26). Physiological stress, as measured by allostatic load (AL), is elevated in patients with first-episode schizophrenia and shows a direct correlation with the severity of positive symptoms (27).Schizophrenia patients show heightened anticipation and negative affect in response to stress, indicating difficulties in cognitive stress regulation (28). This impaired ability to manage stress, in turn, intensifies their reliance on negative coping strategies, creating a feedback loop that further deteriorates cognitive performance under stress and amplifies negative outcomes (29).

We speculate that there may be a relationship between sex and NPY in schizophrenia, but there is a dearth of studies related to this field, indicating that we need more efforts to make it clear. Because of the restrictions of medical ethics, it is difficult to collect the samples of cerebrospinal fluid. Fortunately, the NPY cerebrospinal fluid/plasma concentration was basically stable at the level of 20%~40% (30), which means the plasma NPY, to some degree, can reflect the NPY level in the central nervous system.

Therefore, the objective of our study was to investigate relationships between the serum NPY levels and severity of psychiatric symptoms in schizophrenia patients, especially to explore the sexual heterogeneity, which would help explore what role NPY may play in schizophrenia.

To the best of our knowledge, this is the first study to explore the role that NPY plays in first-episode schizophrenia. 1) We found that serum NPY levels were significantly higher in patients with first-episode schizophrenia than in controls. 2) We found that in male patients, there is a positive correlation between the severity of symptoms and the level of NPY, and the change trend of NPY after treatment can reflect the improvement of clinical symptoms. However, the correlations and predictive effects above were not found in female patients.

Serum NPY levels were significantly higher in patients with first-episode schizophrenia. This result also corroborate the findings of prior work that the NPY levels in cerebrospinal fluid of chronic drug-free schizophrenia patients were higher than healthy controls (13). There were also studies that contradicted our findings. In a study in clozapine-treated chronic schizophrenia patients, no difference for NPY was found between the patients and healthy controls (22). However, the included subjects of Wysokiński’s study were all chronic patients treated with clozapine, while it have been proved that clozapine can influence the plasma concentrations of NPY (17). As the first study in first-episode schizophrenia, our study excludes possible interference from antipsychotics, and definitely obtained more reliable results.

The most important finding of our study is that NPY may be used as a predictor of the severity of schizophrenia symptoms. In male patients, NPY is positively correlated with severity of symptoms, and changes in NPY following treatment can reflect improvements in clinical symptoms. Similar findings have been reported by several previous studies. For instance, there was a negative correlation between CSF NPY levels and social function in schizophrenia patients. The higher the NPY at baseline, the worse the social function at the end point of the cohort (33). There were also some studies that contrast with our findings. In a randomized controlled trials of chronic schizophrenia patients with treatment augmented by sarcosine, no relationship between NPY levels and PANSS scores was found, whether at baseline or change (34). After treatment of quetiapine, the NPY level in cerebrospinal fluid (CSF) of schizophrenia patient increased. Further, as defined by more than 20% PANSS reduction, the responder group had higher CSF NPY levels compared to the nonresponders (35). However, these researches included both first-episode and long-term hospitalized patients as subjects, so compared to our study, the results obtained were not reliable enough on account of difficulty in controlling for confounding factors.

We speculate that the relationship of NPY and severity of symptoms may be mediated by dopamine (DA). Previous studies have suggested that NPY can regulate the secretion of dopamine in neurons. For instance, intraventricular injection of NPY agonists can increase the concentration of DA in the nucleus accumbens (36). Y1 and Y5 receptors on the striatum neurons decreased dopamine release, while Y2 receptors played the opposite role (37). A mouse experiment further confirms the idea that NPY indicate changes related to schizophrenia through the dopamine pathway. Peptide tyrosine-tyrosineis 3-36(PYY3-36) is a selective Y2 receptor agonist (38). In mice, administration of PYY3-36 would cause schizophrenia-related behavioral changes, such as impairment in the PPI (paradigm of prepulse inhibition) and water maze test (39). Furthermore, the PPI impairment was reversed by first-generation antipsychotics, but not by clozapine. We speculate that when NPY stimulates the Y2 receptors of neurons, it may cause an abnormal increase in DA, which may explain that the concentration of NPY is proportional to the severity of symptoms. And also, the impairment would be relieved when DA receptors were blocked.

Of course, except for DA, there is also research examining the interactions between neuropeptide Y (NPY) and other neurotransmitters. In mice, NPY has been found to inhibit the activity of serotonergic (5-HT) neurons in the dorsal raphe nucleus (DRN) via activation of Y1 receptors (40). Additionally, NPY increases extracellular glutamate concentration through activation of Y1 receptors in the hippocampus, which has been shown to mitigate seizure-like neuronal activity (41). Furthermore, by modulating 5-HT receptors, NPY may facilitate adaptive coping responses, thereby enhancing resilience in extreme environments (42). However, the results of these studies remain inconclusive, and much work is needed to fully elucidate the underlying mechanisms.

Another significant finding of our study is sexual heterogeneity in the effect of NPY on schizophrenia. The above-mentioned relationships between NPY and severity of symptoms were only found in male patients. Previous experimental studies indicated that the function of Y2 receptor seems to be different between male and female mouse. Male NPY Y2 receptor knockout mice, compared to wild-type, performed better in social interaction, Y-maze and PPI experiments, while the improvements not seen in females (43). In another study of Y1 receptor knockout mice (44), whose subjects were all males, Y1 receptor influenced the acoustic startle response.

We conjecture that the sexual heterogeneity may result from the influence of sexual hormone. The NPY-knockout mice showed sexual dimorphism, and the HPA axis of male mice was abnormally activated when compared to the wild-type (45). Furthermore, NPY-knockout female mice were divided into the ovariectomized group and the normal cycling group, and the ovariectomized also showed metabolic status similar to the male mice (46). It is supposed that NPY can promote the release of GnRH, while NPY itself is regulated by estrogen (47). However, there are many contradictory conclusions about the effect of estrogen on NPY. On the one hand, in NPY knockout mice, the luteinizing hormone(LH) peak stimulated by estrogen was blunted, suggesting that estrogen may increase the expression of NPY (48). On the other hand, there were also studies on the regulation of feeding indicated that estrogen can inhibit the expression of NPY (49). It is also clear that estradiol has a corresponding inhibitory receptor in the regulatory region of the NPY gene (50). The contradictory results of NPY in different brain regions of different sexes may be related to the characteristics of estrogen receptors on neurons (51). As reviewed (23), some studies have identified that aged males had less NPY gene expression compared with young animals in both arcuate nucleus and hypothalamic nuclei, while serum NPY levels would increase with age in females. Therefore, further studies are needed to explore the possible mechanisms in the sexual heterogeneity of NPY.

A few limitations need to be noted regarding the present study. First, only serum NPY levels were measured in this study, though peripheral levels can reflect the concentration in CSF. Evaluation of NPY gene expression and detection of NPY variants could be the next step, which would be more helpful to study the pathogenesis of schizophrenia. Second, after 10 weeks of risperidone treatment, NPY levels did not show significant changes, suggesting a potential lag in NPY response relative to symptom improvement, in future studies, the sample size should be increased, and the follow-up time needs to be prolonged to obtain conclusive results. Additionally, monitoring changes in estrogen and NPY levels across the menstrual cycle could provide further insights into the sex differences.

NPY plays a significant role in the pathogenesis of schizophrenia. Higher NPY levels were observed in patients with first-episode schizophrenia. Moreover, there is sexual dimorphism of the NPY in schizophrenia. In male patients, NPY levels were positively correlated with the severity of schizophrenia, while this relationship was not observed in female patients. Further researches are needed to ascertain the possible mechanisms underlying this sexual heterogeneity.