In a 2011 study by Lai et al. [25], a comparative analysis of miRNA expression in peripheral blood mononuclear leukocytes was performed with Taqman low-density arrays. Seven miRNAs (miR-34a, miR-449a, miR-564, miR-432, miR-548d, miR-572, and miR-652) were differentially expressed between SCZ patients and healthy controls (CTL), with the most significant difference being in expression of miR-34a. A support vector machine was used to assess the predictive accuracy of the 7-miRNA signature in differentiating SCZ from CTL. The area under the receiver operating characteristic (ROC) curve of its diagnostic prediction model was 93% and the area under the curve (AUC) in the test set was 85%, with good diagnostic performance. Diagnostic prediction models for SCZ serve as an essential approach to distinguish SCZ cases from CTL and to predict whether SCZ will occur. It has become widely accepted to employ machine learning methods to construct diagnostic prediction models, where combining different variables for SCZ prediction may improve the accuracy of prediction. With the help of diagnostic prediction models, clinicians and SCZ patients can make better joint decisions, researchers can screen suitable SCZ study subjects more accurately, and governments can allocate medical resources accordingly.

Their subsequent study in 2016 [26] revealed that hospitalization did not influence expression of these seven miRNAs above that in peripheral blood, leading them to suggest that miRNAs may as trait-dependent markers. Moreover, their study revealed a corresponding correlation between the expression levels of miR-34a in the blood and in cortical Brodmann area 46. In a study conducted by Horai et al. [27] in 2020, miR-19b, which is highly expressed in neural progenitor cells in the hippocampus of SCZ patients, also had increased expression in peripheral blood. The high expression of miR-19b likely increases the vulnerability of SCZ by attenuating the proliferation of neural progenitor cells in the hippocampus. It is possible that these studies may provide further support for the use of miRNAs in peripheral blood as diagnostic biomarkers of SCZ. Sun et al. [28] detected that the expression of miR-132, miR-195, miR-30e, and miR-7 were significantly upregulated in blood plasma and miR-212, miR-34a, and miR-30e were upregulated in peripheral blood mononuclear cells (PBMC). Differences in the tissue microenvironment in which miRNAs function may explain the differences in their expression levels in different tissues. Interestingly, the expression of miR-30e in both plasma and PBMC was significantly different in patients with SCZ compared to CTL. Further logistic regression analysis demonstrated that miR-30e in plasma has greater diagnostic value for SCZ, which further suggests that miR-30e may be considered as a plasma biomarker for the diagnoses of SCZ. Meanwhile, in their other study [29], the combination of miR-30e, miR-181b, miR-34a, miR-346, and miR-7 in plasma was found to be a potential biomarker for SCZ diagnosis. He et al. [30] detected that miR-34a-5p, miR-432-5p, and miR-449a were aberrantly expressed in the serum of SCZ patients. Accordingly, it could be suggested that miR-34a, miR-449a, and miR-432 are performing relatively important roles in the pathogenesis of SCZ and that it is feasible to look for miRNAs in peripheral blood that can reflect aberrant alterations in brain tissue.

Shi et al. [31] detected that miR-181b, miR-219-2-3p, miR-195, miR-1308, and let-7g could act as potential diagnostic biomarkers of SCZ. In an attempt to explore miRNAs relevant to SCZ in non-neural tissues, Gardiner et al. [32] performed an analysis of miRNA expression profiles and discovered that certain miRNAs that are differentially expressed in the brain are also differentially expressed in peripheral blood, such as miR-134, miR-128, and miR-181b. Additionally, from their study, seven miRNAs (miR-31, miR-431, miR-433, miR-107, miR-134, miR-99b, miR-487b) were identified as being differentially expressed in the peripheral blood of patients with SCZ. Aberrant expression of miR-181b in the plasma of SCZ patients was also identified in a study by Sun et al. [29]. Hence, miR-181b may also be potentially valuable for the diagnosis of SCZ.

A study by Wu et al. [33] revealed upregulation of the expression of miR-148b-3p in the peripheral blood of patients with SCZ during their first-episode and predicted that ZNF804A may be the target gene where miR-148b-3p exerts its effect in the pathological mechanism of SCZ. In another study conducted by Wu et al. [34] 2016, the expression of miR-137 was upregulated in the peripheral blood of SCZ patients compared to CTL. The diagnostic ROC curve for distinguishing SCZ from CTL with the utilization of miR-137 showed an area under the curve(AUC) value of 0.795. Furthermore, this study also revealed that miR-137 may target genetic variants impacting the RNA binding site of the EFNB2 gene, causing its down-regulation. Accordingly, they suggested that miR-137 may be a meaningful biomarker for SCZ. Two years later, Ma et al. [15]explored miRNAs in peripheral blood that are potential diagnostic biomarkers for SCZ with second-generation sequencing in combination with RT-qPCR and detected that the combination of three miRNAs, miR-137, miR-22-3p, and miR-92a-3p, may be meaningful diagnostic biomarkers for SCZ. Additionally, a study by Yu et al. [35] identified miR-132 as a promising biomarker in peripheral blood for differentiating SCZ from CTL. Sun et al. [28] have also demonstrated the value of miR-132 in the diagnosis of SCZ. As such, miR-137 and miR-132, may serve as potential diagnostic biomarkers of SCZ that are intimately associated with regulating the expression of SCZ-related mRNAs.

As previously described, Shi et al. [31] identified nine miRNAs, including miR-195, as candidate biomarkers for the diagnosis of SCZ back in 2011. Another study by Sun et al. [28] subsequently revealed significant upregulation of miR-195 expression in the plasma of SCZ. In 2021, Pan et al. [36] also identified significantly elevated levels of miR-195 in peripheral blood of SCZ patients. Additionally, their study demonstrated that in SCZ patients, high expression of miR-195 was associated with a decrease in levels of brain-derived neurotrophic factor (BDNF), where low levels of BDNF protein is associated with cognitive dysfunction. Consequently, the upregulation of miR-195 in peripheral blood likely influences cognitive function in SCZ by modulating the expression of BDNF.

In 2016, Camkurt et al. [37] detected five miRNAs, miR9-5p, miR29a-3p, miR106b-5p, miR125a-3p, and miR125b-3p, significantly upregulated in SCZ. Interestingly, in 2022, Jin et al. [38] revealed that the expression of miR-4467 was significantly upregulated in SCZ, while miR-9-5p expression was significantly down-regulated. The predicted AUC value was 0.709 by combining miR-4467 and miR-9-5p for the diagnosis of SCZ. Notably, miR-9-5p expression appeared to be in opposite directions in different studies although they were all aberrantly expressed; therefore, further exploration is necessary to clarify the diagnostic value of miR-9-5p in peripheral blood for SCZ.

As mentioned previously, a study by Shi et al. [31] identified let-7g as a potential diagnostic biomarker in the serum of SCZ patients. It was also detected by Rizos et al. [39], that the expression of let-7g-5p, miR-98-5p, and miR-183-5p were significantly down-regulated in the blood of patients with cancer and SCZ. Additionally, Geaghan et al. [40], revealed that miRNAs of the let-7 family, miR-1271-5p, and miR-221-5p performed essential functions in regulating the expression of genes in immune cells in the peripheral blood of SCZ patients. It has been determined that the let-7 family of miRNAs are tumor suppressors that modulate the response of macrophages as well as the production of B-cell antibodies, both of which play essential roles in regulating the immune system [48]. Hence, further exploration of the aberrantly expressed let-7 family miRNAs in peripheral blood may be of significance for understanding the pathogenesis of SCZ.

In addition, several studies have detected other miRNAs in peripheral blood that might serve as diagnostic markers for SCZ. In 2015, Wei et al. [41] conducted validation of eight miRNAs (miR-130a, miR-130b, miR-122, miR-193a-3p, miR-193b, miR-502-3p, miR-652, and miR-886-5p) differentially expressed between SCZ patients and CTL by utilizing RT-qPCR. They determined that two of these miRNAs (miR-130b and miR-193a-3p) may have significance for the diagnosis of SCZ. Zhao et al. [42] identified that the expression of miR-223 in plasma of SCZ patients was upregulated both during the first episode and its later stages compared to CTL. This abnormal expression of miR-223 may affect the expression levels of its targeted genes involved in cell migration. An investigation by Wang et al. [43] revealed that the expression of miR-320a-3p and miR-320b was significantly downregulated in the serum of SCZ patients. Pala et al. [44] identified miR-373-5p and miR-199a-3p as potential biomarkers for SCZ diagnosis by analyzing the microRNA expression profile GSE54578. You et al. [45] discovered that the expression of miR-218-5p and miR-1262 were notably upregulated in PBMC of treatment-resistant SCZ patients. The target genes of these two miRNAs, CBX5, NF165, and CACUL1, are intimately associated with brain function and the nervous system. As a result, they proposed that miR-218-5p and miR-1262 might be biomarkers for early diagnosis of treatment-resistant SCZ. Davarinejad et al. [46] identified miR-574-5P, miR-4429, and miR-1827 as potential blood diagnostic biomarkers for SCZ. Sabaie et al. [47] identified down-regulation of miR-185-5p in the peripheral blood in SCZ patients, which could be relatively well differentiated from that of CTLs (AUC = 0.722), but larger samples for validation are still necessary.

It is evident that there have been multiple studies which have detected miRNAs in peripheral blood that can serve as diagnostic biomarkers for SCZ. Interestingly, some of the aberrantly expressed miRNAs detected in peripheral blood are also present at abnormal levels in brain tissue of SCZ patients. Therefore, the use of peripheral blood is promising as a means for the detection of diagnostic miRNAs in SCZ. Additionally, it is noteworthy that several studies have found the same miRNAs in peripheral blood to be of diagnostic value for SCZ, such as miR-34a, miR-181b, miR-137, miR-132, miR-195, miR9-5p, miR-432, miR-7, miR-30e, miR-548d, miR-432, miR-449a, and let-7. Thus, these miRNAs are promising as reliable diagnostic biomarkers for SCZ. However, the accuracy of diagnostic prediction of SCZ using a single miRNA may be low and an attempt should be made to combine multiple miRNAs that are abnormally expressed in peripheral blood for the prediction of SCZ, thus further improving the accuracy of diagnostic results. Consequently, miRNAs differentially expressed in the peripheral blood of SCZ patients may be novel biomarkers that provide non-invasive and accurate diagnosis of SCZ.

lncRNAs are RNA transcripts that encode proteins less than 200 nucleotides in length. They play vital roles in an array of biological functions and cellular processes, such as metabolism, cell differentiation, cell cycle, and have been implicated in multiple diseases [49]. Qian et al. [50] investigated the mechanism and functional role of lncRNAs in regulating RNA metabolism and expression of genes by using high-throughput sequencing, bioinformatics, and automated capillary approaches. They identified that lncRNAs are essential modulators of the function and expression of almost all genes.

Previous studies have revealed the expression of numerous lncRNAs in the brain that are predominantly engaged in the development and function of the nervous system [51]. It is widely accepted that SCZ is a caused by multiple factors with sophisticated genetic constituents. Rusconi et al. [52] demonstrated that the characteristic mutations of numerous psychiatric disorders, including SCZ, occurred in non-coding parts of genes. There has been an accumulation of studies demonstrating the relevance of lncRNAs to the pathogenesis of SCZ [53, 54]. It has been suggested that most genes expressed in the brain and peripheral blood share common regulation pathways. For instance, Rao et al. [55] demonstrated that LINC00461, which is downregulated in the hippocampus of SCZ patients, was also downregulated in peripheral blood. Hence, lncRNAs aberrantly expressed in the brain of SCZ patients may also have abnormal expression in the peripheral blood and it is therefore feasible to detect lncRNAs aberrantly expressed in peripheral blood of SCZ patients [54]. Table 2 (Ref. [8, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72]) presents potential lncRNAs biomarkers in peripheral blood of SCZ patients.

To investigate the potential regulatory effects of lncRNAs on the expression of genes and the pathogenesis in SCZ, Ren et al. [56] performed a Weighted Gene Co-expression Network Analysis (WGCNA) which identified two modules that are relevant to SCZ, the blue and brown modules. It is possible that these two modules are engaged in the pathogenesis of SCZ by causing dysfunction of mitochondria through the regulation of their targeted mRNAs. In 2020, to explore lncRNAs associated with the prodromal stage of SCZ, which is known to be ultra-high risk for psychosis, they conducted an additional WGCNA and detected that the expression of ASHG19A3A011462 and ASHG19A3A026335 was upregulated, while the expression of ASHG19A3A049471, ASHG19A3A044112, and ASHG19A3A049556 was downregulated. Subsequently, by analyzing the function of mRNAs with corresponding expression patterns with these five lncRNAs, the study observed that these mRNAs appeared to be notably abundant in functional pathways associated with immunity and inflammation. Consequently, they suggested that lncRNAs may participate in immune and inflammatory abnormalities in the pathogenesis of ultra-high-risk psychosis, which may have great implications for further exploration of the pathogenesis of SCZ.

To explore the regulatory role of IFNG-AS1 on the gene locus of IFNG in SCZ, Ghafelehbashi et al. [57] compared the expression levels of IFNG-AS1, IFNG, and IL-1B in the blood cells of SCZ patients and CTL. They detected that the expression level of IFNG-AS1 was significantly downregulated in the blood cells of SCZ patients when compared to CTLs and there was a positive correlation with expression levels of IFNG and IL-1B. IFNG and IL-1B are known to be of significance in the regulation of inflammation, so it was hypothesized in this study that IFNG-AS1 is intimately involved in inflammation and immunity, and may be one of the essential inflammatory regulators in the pathogenesis of SCZ. Additionally, a study by Melbourne et al. [58] demonstrated a positive correlation between the expression of lncRNA TMEVPG1, NRON, and the expression of IL-6 and IFN-$\gamma$ mRNA in blood cells of SCZ patients. IL-6 and TNF-$\alpha$ have been confirmed to be elevated in SCZ [73], in which IL-6 is closely related to positive symptoms of SCZ and TNF- $\alpha$is a crucial pro-inflammatory factor in the development of SCZ. Furthermore, TMEVPG1 showed some modulatory effect on the expression of IFN-$\gamma$. Therefore, both TMEVPG1 and NRON may participate in the regulation of pro-inflammatory cytokine-related gene expression in SCZ. In a study by Ni et al. [59], a SCZ-associated lncRNA, AC006129.1, which mainly participates in the inflammatory response by augmenting the expression of SOCS3 and CASP1, was detected by the sequencing of peripheral blood lncRNAs in SCZ patients. This finding may further enhance the understanding of the epigenetic mechanism of SCZ.

By analyzing lncRNAs microarray data from SCZ patients and CTL, Chen et al. [60] determined that NONHSAT089447, NONHSAT021545, and NONHSAT041499 were significantly upregulated in peripheral blood of SCZ. These three lncRNAs were co-expressed with various mRNAs involved in regulating biological processes such as memory, cognition, neuronal apoptosis, and Ras protein signaling. Additionally, the down-regulated expression of NONHSAT041499 was correlated with the alleviation of positive symptoms in SCZ patients following drug treatment, indicating that NONHSAT041499 may be a potential prognostic factor for the outcome of SCZ treatment. Subsequently, Chen et al. [61] carried out a study to further examine the associations between these lncRNAs and SCZ. They found that the expression of NONHSAT089447 was higher than NONHSAT041499 in SCZ patients and showed either activation or regulation of the dopamine signaling pathway. The expression level of NONHSAT089447 may regulate downstream dopamine signaling, thus affecting the occurrence and development of SCZ. Consequently, NONHSAT089447 may be a potentially valuable diagnostic biomarker of SCZ.

To investigate the relations between NEAT1, NEAT2, MEG3 and MIAT, and SCZ, Li et al. [67] evaluated the levels of these lncRNAs in peripheral blood. What they identified was that the expression levels of NEAT1 and NEAT2 were markedly downregulated but were elevated in SCZ after treatment. However, MIAT and MEG3 were at lower expression levels. Furthermore, they investigated the distribution of these lncRNAs in the body and identified that MIAT was abundantly expressed in the brain, while NEAT1, NEAT2, and MEG3 were abundantly expressed in both the brain and peripheral tissues. Fallah et al. [62] identified differences in the expression levels of HOXA-AS2, Linc-ROR, MEG3, SPRY4-IT1, and UCA1 between female SCZ patients and CTL. However, there were no differences in the expression levels of lncRNAs between male SCZ patients and CTL, suggesting a potential sex difference. Moreover, they suggested that MEG3 may affect SCZ by impacting the glutamatergic, dopaminergic, and GABA ergic pathways. Sudhalkar et al. [63] revealed that the expression levels of MEG3 were upregulated in PBMCs of SCZ patients, while that of PITT and GAS5 were downregulated, and the ROC curve analysis showed strong diagnostic predictive capability of MEG3 for SCZ. Furthermore, this study also detected an association between MEG3 and PITT. This may be attributed to the fact that MEG3 is a lncRNA which could regulate the binding specificity of transcription factor P53. P53 exerts a regulatory and activating effect on the expression of PINT, whereas GAS5 is involved in the mechanism of the development of SCZ by serving as the decoy nucleotide-binding site for the glucocorticoid receptor. Subsequently, in 2019, Safari et al. [64] demonstrated that the expression levels of FAS-AS1, PVT1, and TUG1 were down-regulated and THRIL expression was up-regulated in the peripheral blood of SCZ patients compared to CTL. While the expression of GAS5, NEAT1, and OIP5-AS1 did not differ significantly between SCZ and CTL, there were notable differences in the expression of GAS5, NEAT1, and OIP5-AS1 in female subjects. There was 86.96% specificity and 100% sensitivity of GAS5 for the prediction of the diagnosis of SCZ in females and the level of GAS5 exhibited negative correlation with the other six lncRNAs. Thus, it is speculated that there may be sex differences in certain lncRNAs in peripheral blood of SCZ patients.

Jia et al. [65] attempted to explore prospective diagnostic biomarkers for SCZ and detected that the expression levels of Gomafu and uc011dma.1 were markedly upregulated in plasma of those with SCZ. Meanwhile, AK096174, AK123097, DB340248, ENST00000509804-1, and ENST00000509804-2 were downregulated. The combination of seven lncRNAs for the diagnostic prediction of SCZ showed excellent predictive performance with the area under the ROC curve reaching 0.925. Additionally, the expression of AK123097 and ENST00000509804-1 in plasma were upregulated with the amelioration of patients’ symptoms after drug treatment, while that of uc011dma.1 was greatly reduced. Accordingly, AK123097, uc011dma.1, and ENST00000509804-1 may be promising therapeutic targets for SCZ.

Badrlou et al. [8] evaluated the diagnostic performance of four BDNF-related lncRNAs for SCZ with ROC curves. The diagnostic capabilities of MIAT, MIR137HG, BDNF-AS, and BDNF were 68%, 67%, 72%, and 71%, respectively. A study by Liu et al. [66] explored the expression levels of Gomafu in PBMC of SCZ patients before and after drug treatment. Gomafu was found to be significantly higher in PBMC of untreated SCZ patients compared to CTL. Subsequently, the expression level of Gomafu in PBMC of SCZ patients was markedly increased after 12 weeks of drug treatment. It is well-known that Gomafu, also named MIAT, is located on 22q12.1 and is intimately associated with SCZ. Although MIAT was principally distributed in the brain [67], it is also expressed in peripheral blood and several studies have detected upregulation of its expression level in peripheral blood of SCZ. Hence, Gomafu may be a promising diagnostic biomarker for peripheral blood of SCZ.

The NF-$\kappa$B signaling pathway exerts effects on the function of the nervous system and is implicated with the pathogenesis of SCZ, which in turn is regulated by lncRNAs. Safa et al. [68] explored the expression of nine NF-$\kappa$B-associated lncRNAs and revealed CHAST, CEBPA, DICER1-AS1, H19, and HNF1A-AS1 have excellent predictive performance in the diagnosis of SCZ. The signaling of the vitamin D receptor plays an essential role in the development of SCZ and the receptor signaling is functionally connected with numerous lncRNAs. A study by Ghafouri-Fard et al. [69] revealed that LINC00511, LINC00346, and SNHG6 were upregulated in SCZ and all are associated with the vitamin D receptor.

The oxytocin-related signaling pathway can interact with dopaminergic signaling, which is linked with the pathophysiology of SCZ. There are certain lncRNAs that mediate the activity of the oxytocin system and thus exert influence on the development of SCZ. Eghtedarian et al. [70] assessed the aberrant expression of nine oxytocin-related lncRNAs as well as mRNAs in the venous blood of SCZ patients, where the expression of LNC-FOXF1 was significantly upregulated. LNC-FOXF1 is an oxytocin system related lncRNA. There is also an association between LNC-FOXF1 and the immune response. There are common genetic mechanisms between SCZ and nicotine dependence. Chen et al. [71] identified multiple lncRNAs associated with these genetic mechanisms, including DA376252, BX089737, LOC101927273, LINC01029, LOC101928622, HY157071, and DA902558.

In summary, through comprehensive review and evaluation of the existing studies on relevant lncRNAs in peripheral blood of SCZ, it can be concluded that these lncRNAs may exert a certain influence on the pathogenesis of SCZ. They may do so through a variety of mechanisms, such as regulating the expression of genes associated with inflammatory cytokines and the function of signaling pathways that influence glutamatergic and dopaminergic signaling pathways. Additionally, there are studies that reveal the abnormal expression of lncRNAs in SCZ, such as NONHSAT089447, NEAT1, MEG3, GAS5, and Gomafu. Furthermore, a number of lncRNAs have been closely associated with immune and inflammatory responses in the SCZ, such as IFNG-AS1, TMEVPG1, and NRON. Moreover, certain signaling pathway-related lncRNAs have corresponding effects on the pathogenesis of SCZ, such as NF-$\kappa$B signaling pathway-related CHAST and HNF1A-AS1, VDR-related LINC00511, LINC00346, and SNHG6, and oxytocin-related LNC-FOXF1. Additionally, the expression levels of certain lncRNAs in peripheral blood of SCZ patients appear to be remarkably altered after receiving treatment, such as NONHSAT041499, NEAT1, NEAT2, AK123097, ENST00000509804-1, uc011dma.1, and Gomafu. These may serve as prospective therapeutic targets, or they may be used to assess the prognosis of patients based on their expression level. Thus, these lncRNAs could be instrumental for further comprehension of the pathogenesis of SCZ and have the potential to act as prospective diagnostic biomarkers and therapeutic targets. Nevertheless, the current application of lncRNAs as diagnostic biomarkers for SCZ remains at an introductory stage and further studies are warranted.

CircRNAs are a type of single-stranded, ncRNA molecule that perform diverse functions in cells. They are generated during retrosplicing of the precursor mRNA and are covalently enclosed with highly specific expression in the cells of numerous organisms [74]. For instance, circRNAs can regulate gene expression and chromatin modification, moderate transcription and splicing, act as molecular sponges by repressing the interaction of miRNA with mRNA or proteins, and serve as templates for translation in several biological and pathophysiological contexts [75]. Studies have also established that there are certain linkages between circRNAs interfering with cellular processes and signaling pathways, modulating immune responses, and the biological mechanisms of multiple conditions, such as tumors [76] and psychiatric disorders [77].

With the continued application of high-throughput sequencing technologies, several studies [78, 79] have recently been conducted to investigate the biologic functions of circRNAs in brain and peripheral nervous system. It has been shown that circRNAs are abundantly expressed in the nervous system, are remarkably hyperactive in synapses of neurons, and that the expression of certain genes in the nervous system are regulated by the expression levels of circRNAs. circRNAs serve critical roles in the maintenance of proper function of the brain and preventing the progression of neurological diseases. Accordingly, dysregulation of circRNA expression may be associated with neurological damage or neurodegenerative diseases [80]. In a study [81] that sequenced the RNA molecules in postmortem brain tissue from SCZ and CTL, it was revealed that the expression of numerous circRNAs was decreased in the brain of SCZ patients compared to CTLs. The stability of these circRNAs was also diminished, suggesting these circRNAs might be playing a vital role in the etiology of SCZ by regulating the expression of miRNAs or the translation of proteins. Table 3 (Ref. [13, 82, 83, 84]) lists circRNAs with potential as biomarkers in peripheral blood of SCZ.

While circRNAs are abundantly expressed in the brain, it is possible that shared pathway alterations or genetic variants that are involved in the etiology of SCZ are also manifested in the periphery, such as in peripheral blood. In an attempt to determine whether circRNAs in peripheral blood could function as diagnostic or therapeutic biomarkers of SCZ, Yao et al. [82] comparatively analyzed the expression of circRNAs in PBMCs of nine SCZ and nine CTL. They found nine differentially expressed circRNAs. RT-qPCR in 102 SCZ patients and 103 CTL further validated that the expression levels of circ_104597, circ_102101, and circ_101836 were remarkably down-regulated and circ_103102 and circ_103704 were notably up-regulated. The presence of a combination of the three downregulated circRNAs predicted a relatively high success rate in the diagnosis of SCZ with a ROC curve of 0.8967. Additionally, it was detected that circ_104597 was down-regulated before treatment but up-regulated following eight weeks of treatment. Thus, it was concluded that circ_104597 might serve as a potential therapeutic biomarker of SCZ.

In 2020, Mahmoudi’s team [13] conducted a study that analyzed circRNA expression in PBMC from 20 patients with SCZ, 19 patients with bipolar disorder (BD), and 20 CTL. It was revealed that circTMEM2, circEZH1, circKFBP8, and circRARS were downregulated and that there were interactions between these circRNAs and miRNAs related to SCZ, such as miR-564 and miR-572. To explore whether circRNAs in plasma could be potential diagnostic and therapeutic biomarkers for SCZ, Tan et al.’s [83] research recognized four up-regulated circRNAs, chr5_69175537_69174877_+660, chr3_196488683_196483770_-4913, chr6_130956499_130926605_-29894, and chr5_143057747_143054439_+3308. With the use of bioinformatic analysis, these circRNAs were found to play potential roles in the stress response, histone ubiquitination, metabolic processes, and other mechanisms associated with SCZ, suggesting they may have the potential to become diagnostic circRNAs for SCZ. circRNAs contain abundant binding sites for miRNAs, which can control gene expression by binding to miRNA, and could thereby be involved in the initiation and progression of SCZ. Liao et al. [84] investigated this potential mechanism of SCZ by constructing a circRNA-miRNA-mRNA network. They determined that circ_0006151/ miR-4685-3p/ZBTB16, circ_0007963/miR-3127-3p/UBE2K, and circ_0000008/miR-1976/ZBTB16 were the top three core competitive endogenous RNA (ceRNA) networks with essential roles in SCZ.

There are currently few studies on circRNAs in peripheral blood in SCZ. However, based on the existing studies, it can be concluded that circRNAs in peripheral blood may have significant implications for SCZ as they provide a basis for the molecular mechanisms involved in the development and pathogenesis of SCZ. As a result, circRNAs could be utilized for early diagnosis and treatment of SCZ.