Depressive symptoms and impulsive behavior in schizophrenia patients are seen in multiple periods of the disorder. It has been demonstrated that BDNF levels (16) are decreased in the peripheral blood of schizophrenia patients; low PI3K expression (32, 33) is seen in animal and cellular models of schizophrenia studies, PI3K mRNA expression is downregulated and AKT mRNA expression is elevated in the peripheral blood of schizophrenia patients (34, 35), and AKT3 gene deletion mice exist with increased susceptibility to schizophrenia-related symptoms (36); CREB is lowly expressed in schizophrenia model mice, while it negatively regulates BDNF when it is overexpressed (37). Our results suggest that BDNF, PI3K, and CREB plasma levels were lower in the patient group than in the control group, while AKT plasma levels were higher than control group, which is partially consistent with the results of previous related studies. BDNF has a trophic effect on nerve cells. The reduced BDNF concentration and down-regulated gene expression in the peripheral blood of schizophrenia patients suggest that there may be a neurotrophic defect in the pathogenesis of schizophrenia, leading to impaired brain(38). AKT is a serine/threonine kinase, and the balance of kinase activity is closely related to cell growth, proliferation, survival and differentiation, which plays an important role in maintaining normal brain function. PI3K/AKT is an intracellular signal downstream of BDNF, and it has been shown that BDNF can promote AKT phosphorylation and thus play a neuroprotective role against ischemic brain injury (39). Phosphorylation of PI3K and its effector AKT stimulates the activation of CREB. CREB is one of the major regulators of BDNF response, the phosphorylated CREB binds to specific sequences in the BDNF promoter and regulates its transcription, which can upregulate BDNF expression (37). In the results of this study, the decrease in PI3K concentration may be associated with a decrease in upstream BDNF, and the increase in AKT concentration may be related to its reduced phosphorylation, followed by diminished CREB activation and decreased expression in peripheral serum. It further suggests a disruption of the BDNF/PI3K/AKT/CREB pathway in schizophrenic patients. There are abnormal manifestations related to neurotrophy, synaptic transmission and cell signaling. See Fig. 1. However, there are also previous inconsistencies with the results of the present study, for example, one study found reduced AKT protein concentrations in the dorsolateral prefrontal cortex of schizophrenic patients (40). We think the difference in protein concentration in schizophrenic patients may be related to the course and severity of the disease, and that the nervous system may adopt a "compensatory response" and "decompensatory response" mechanism. The results showed that AKT levels were elevated in the early stages of stress, and persistently deficient in the later stages, followed by clinical symptoms of varying degrees.
Depressive symptoms are considered an important dimension of psychiatric symptoms (41), however, this symptom is often underappreciated in schizophrenia patients for other reasons such as similarity to negative symptoms (42). In the present study, the prevalence of depressive symptoms among first-episode drug-naive schizophrenia patients was 55.56%, a result within the range of 30–70% reported in previous studies assessing depressive symptoms in schizophrenia using the CDSS (43, 44). It also consistent with the idea that the prevalence of depression is higher in patients with first-episode schizophrenia than in patients with chronic schizophrenia (45). It is worth mentioning that we included patients with first-episode schizophrenia who had not taken psychotropic medications, which prevented drugs from interfering with biological mechanisms and covering up depressive symptoms. Thus, our study reports for the first time the prevalence of depressive symptoms in first-episode drug-naive schizophrenia patients. Many studies have shown that peripheral blood BDNF concentrations are reduced in patients with schizophrenia (43, 46) or major depressive disorder (47). In the present study, serum BDNF expression was lower in first-episode drug-naive schizophrenia patients than in healthy controls, and in the patient group, the depressed group was lower than the non-depressed group. Our findings suggest that BDNF levels were significantly correlated with CDSS scores in the case group, suggesting that BDNF may be related to the pathological mechanisms of schizophrenia and the occurrence of depression in schizophrenic patients. The PI3K-AKT signaling pathway is one of the many pathways shared by schizophrenia and major depressive disorder (48). To date, no study has been conducted to explore the serum PI3K and AKT levels and their relationship with depressive symptoms in first-episode drug-naive schizophrenia patients. We found that serum protein PI3K levels were significantly lower in the patient group than in healthy controls, which is partially consistent with previous studies finding that serum PI3K mRNA was lower and AKT mRNA was higher in schizophrenia patients than in healthy controls (34). In addition, PI3K concentrations were lower in patients with significant depressive mood than in those with insignificant depressive mood. And AKT had the opposite result with PI3K. We also found that depressed mood was negatively correlated with the expression level of PI3K and negatively correlated with the expression level of AKT. In the study of depressed-like mice, CREB/BDNF expression was restored by anti-inflammatory treatment, followed by remission of depressive symptoms (49), which is roughly consistent with the CREB results in our study, suggesting that CREB may be involved in the development of depressive symptoms in schizophrenic patients through similar inflammatory responses and neuroplasticity.
Our study also showed significant impulsive behavior in schizophrenic patients. In previous mouse studies of dopamine receptor knockout and drug-induced cognitive impairment and impulsive behavior, phosphorylated CREB in the brain increased (50), indicating that CREB participated in the regulation of impulsive behavior in different pathways. In this work, a significant correlation between BDNF, PI3K, AKT, and CREB expression levels and S-UPPS-P scores was showed, suggesting that BDNF, PI3K, AKT, and CREB are not only involved in schizophrenia pathogenesis. Hence, we hypothesized that PI3K-AKT signaling pathway expression levels can be used as status indicators in schizophrenia patients. Interestingly, our results showed that BDNF, PI3K, and CREB were positively correlated with each other, and AKT was negatively correlated with all the first three. These four serum proteins interacted significantly to further function on CDSS and S-UPPS-P scores in schizophrenic patients.
Our study also has some limitations. Case-control studies cannot yield a causal relationship between serum protein factor indicators and depressive symptoms and impulsive behavior in schizophrenia patients. Although the included patient groups were all first-episode drug-naive schizophrenia patients, there was still heterogeneity in the course of the disease. So reasonable stratification of patients according to the course of the disease could be considered in the future. The number of cases included in our study was limited and only cross-sectional data were used for analysis. In future studies, we will enlarge the sample size, conduct further longitudinal studies, appropriately increase the measures to reduce experimental error, and track the improvement of patients' depressive mood and impulsive behavior.