Multiomics Analyses Reveal Microbiome-Gut-Brain Crosstalk Centered on Aberrant Gamma-Aminobutyric Acid and Tryptophan Metabolism in Drug-Naïve Patients with First-Episode Schizophrenia.

BACKGROUND AND HYPOTHESIS: Schizophrenia (SCZ) is associated with complex crosstalk between the gut microbiota and host metabolism, but the underlying mechanism remains elusive. Investigating the aberrant neurotransmitter processes reflected by alterations identified using multiomics analysis is valuable to fully explain the pathogenesis of SCZ. STUDY DESIGN: We conducted an integrative analysis of multiomics data, including the serum metabolome, fecal metagenome, single nucleotide polymorphism data, and neuroimaging data obtained from a cohort of 127 drug-naïve, first-episode SCZ patients and 92 healthy controls to characterize the microbiome-gut-brain axis in SCZ patients. We used pathway-based polygenic risk score (PRS) analyses to determine the biological pathways contributing to genetic risk and mediation effect analyses to determine the important neuroimaging features. Additionally, a random forest model was generated for effective SCZ diagnosis. STUDY RESULTS: We found that the altered metabolome and dysregulated microbiome were associated with neuroactive metabolites, including gamma-aminobutyric acid (GABA), tryptophan, and short-chain fatty acids. Further structural and functional magnetic resonance imaging analyses highlighted that gray matter volume and functional connectivity disturbances mediate the relationships between Ruminococcus_torgues and Collinsella_aerofaciens and symptom severity and the relationships between species Lactobacillus_ruminis and differential metabolites l-2,4-diaminobutyric acid and N-acetylserotonin and cognitive function. Moreover, analyses of the Polygenic Risk Score (PRS) support that alterations in GABA and tryptophan neurotransmitter pathways are associated with SCZ risk, and GABA might be a more dominant contributor. CONCLUSIONS: This study provides new insights into systematic relationships among genes, metabolism, and the gut microbiota that affect brain functional connectivity, thereby affecting SCZ pathogenesis.

Exploring Zentangle as a virtual mindfulness-based art intervention for people with serious mental illness.

Introduction: Zentangle is an emerging art intervention that incorporates mindfulness into creative drawing. This pilot study explored Zentangle as a novel adjunct treatment for people with serious mental illness (SMI). Methods: Six participants with SMI completed an 8-week Zentangle program. Psychiatric outcomes were evaluated using the Brief Psychiatric Rating Scale (BPRS), Mindful Attention Awareness Scale (MAAS), Perceived Stress Scale (PSS), and Quality of Life Enjoyment and Satisfaction Scale (Q-LES-Q-SF). A focus group was conducted to better understand the experiences of the participants. Results: A significant reduction in psychiatric symptoms was observed as measured by the total score on the BPRS between baseline and 5-week post-intervention (40.7 ± 9.1 vs. 33.7 ± 8.9, mean ± SD, p = 0.02). Participants also showed a significant increase in mindful attention using the average score on the MAAS between 1- and 5-week post-intervention (3.5 ± 0.4 vs. 4.2 ± 0.7, mean ± SD, p = 0.04). Four themes were generated from the focus group: (1) approaching mindfulness through Zentangle; (2) power of uncomplicated art creation; (3) understanding the value of self-appreciation; and (4) fostering a positive environment. Discussion: Our preliminary data suggest that the use of Zentangle for participants with SMI may have a positive impact on overall psychiatric symptoms and mindfulness. Moreover, the Zentangle Method encourages positive emotions like gratitude and self-accomplishment to counteract negative feelings of self-criticism and failure in participants.

Gut mycobiota dysbiosis in drug-naïve, first-episode schizophrenia.

Bacterial dysbiosis has been demonstrated in patients with schizophrenia (SCH). The aim of the present study was to investigate alterations in mycobiota composition and fungi-bacteria correlation network in drug-naïve, first episode SCH. We recruited 205 SCH patients and 125 healthy controls (HCs), whose gut bacterial and fungal compositions were characterized by 16S and 18S ribosomal RNA gene amplicon sequencing, respectively. Fungal-bacterial relative correlation network analysis was performed using the Spearman's test and distance correlation. We also computed relative networks connectedness, which represents the ratio of significant interactions (edges) and taxa (nodes) in the network. SCH patients showed lower fungal α-diversity compared with that of HCs. Furthermore, we identified 29 differential fungal markers at multiple taxonomies between SCH patients and HCs. SCH patients also showed a significantly lower fungi-to-bacteria α-diversity ratio compared with that of HCs (p = 1.81 × 10-8). In risk prediction models, we observed that combining bacterial and fungal markers achieved higher accuracy than that of bacterial markers alone (AUC = 0.847 vs AUC = 0.739; p = 0.043). Fungal-bacterial correlation network was denser in HCs than in SCH patients and was characterized by a high number of neighbors (p < 0.05). In addition, an increased abundance of Purpureocillium was associated with more severe psychiatric symptoms and poorer cognitive function in SCH patients (p < 0.05). Our study demonstrated a disrupted and weakened fungi-bacteria network in SCH patients, which might be associated with their clinical manifestations. Future research on fungal-bacterial correlation network is warranted to advance our understanding about the role of mycobiota in the etiology of SCH and to explore novel intervention approaches.

The effect of serum lipids and short-chain fatty acids on cognitive functioning in drug-naïve, first episode schizophrenia patients.

OBJECTIVE: Many studies have reported the important role of serum levels of short-chain fatty acids (SCFAs) in lipid metabolism and cognitive dysfunction. This study investigated the role of plasma lipids and SCFAs on cognitive functioning in drug- naïve first episode schizophrenia. METHODS: This study recruited 44 schizophrenia inpatients and 35 healthy controls. Plasma lipid metabolism was characterized using standard enzymatic methods and an automated analyzer. Serum levels of SCFAs were measured by Gas chromatography mass spectrometry (GC-MS). Cognitive performance was evaluated by the MATRICS Consensus Cognitive Battery (MCCB). RESULTS: The patient group showed significantly higher serum levels of total SCFAs, acetic acid, acetic acid/ propionic acid ratio, and poorer cognitive scores compared with the control group (p's < 0.05). Within the patient group, the lipid levels were positively associated with acetic acid/ propionic acid ratio (p's < 0.05). Furthermore, multiple regression analysis revealed that the interactions of LDL level × acetic acid/ propionic acid ratio was a significant predictor of the MCCB working memory, and processing speed subscale scores within the patient group. CONCLUSIONS: Cognitive dysfunction and abnormal serum levels of SCFAs occur in the early phase of schizophrenia. Lipid metabolism and serum levels of SCFAs might be, both independently or interactively, associated with cognitive dysfunction in schizophrenia.

A Pilot Remote Drama Therapy Program Using the Co-active Therapeutic Theater Model in People with Serious Mental Illness.

The impact of drama therapy on mental health recovery remains poorly understood. We examined the effects of a pilot remote drama therapy program for community members living with serious mental illness. The entire intervention was delivered remotely. Participants with serious mental illness completed a 12-week drama therapy program which included an online performance open to the public. Four quantitative scales were administered pre- and post-program. A focus group was conducted 1 week after the performance. Six participants completed the program and crafted a public performance themed around hope. No significant differences were identified in the quantitative measures. Five themes were identified in the post-performance focus group. Drama therapy presents an opportunity for individuals with serious mental illness to process and share their journeys with their diagnoses and re-create a healthy sense of self with increased community awareness.

Improvement of adjunctive berberine treatment on negative symptoms in patients with schizophrenia.

The upregulation of immune and inflammatory response may play a role in the negative symptoms of schizophrenia. Berberine is an effective drug with anti-inflammatory property, and may be beneficial for the treatment of negative symptoms. The aim of this study is to test this hypothesis through a randomized, double-blind, placebo-controlled, clinical trial. Eligible patients with schizophrenia were randomized to receive placebo or berberine (900 mg/day) for 8 weeks as adjunctive treatment to single atypical antipsychotic drug. The Positive and Negative Syndrome Scale (PANSS) was used to evaluate clinical symptoms at three time points (baseline, 4th and 8th week). Blood samples were collected at the above three time points to determine the concentrations of inflammatory markers including interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP). 59 patients with intention-to-treat were analyzed, 32 in the berberine group and 27 in the placebo group. From the baseline to the 8th week, berberine treatment significantly improved the negative symptom subscale of PANSS (F = 18.981; p < 0.001). From the baseline to the 8th week, the plasma CRP concentration decreased in the berberine group, while increased in the placebo group (F = 5.373; p = 0.024). Furthermore, in the berberine group, the change of CRP concentration was significantly positively correlated with the change of PANSS negative symptom subscale within 8 weeks (r = 0.56; p = 0.002). There was no significant difference in adverse events between the two groups (p's > 0.05). Our study suggests that berberine treatment is well tolerated in patients with schizophrenia. Berberine may improve negative symptoms through anti-inflammatory effect.Trial registration: Clinicaltrials.gov identifier: NCT03548155.

The role of white matter abnormality in the left anterior corona radiata: In relation to formal thought disorder in patients with schizophrenia.

White matter abnormality has been widely reported in patients with schizophrenia (Sz). However, few studies have focused on the relationship between the white matter deficit and formal thought disorder (FTD). Moreover, the role of genetic high risk in FTD-related white matter deficit remains unclear. The present study recruited 46 Sz patients, 18 unaffected first-degree relatives of Sz patients, and 29 healthy controls. There was a widespread fractional anisotropy (FA) reduction in Sz. In addition, reduced FA in the left anterior corona radiata was related to more severe FTD symptoms in Sz. However, the genetic high-risk group only showed lower mean FA in the left anterior limb of the internal capsule than healthy controls. Our findings suggest that abnormality in the left anterior corona radiata may only occur in Sz but not in the genetic high-risk group. Such an abnormality might be associated with the severity of FTD symptoms. Meanwhile, genetic vulnerability may contribute to the abnormality in the left anterior limb of the internal capsule. Better analytical methods are needed to validate our results.

The Role of Butyric Acid in Treatment Response in Drug-Naïve First Episode Schizophrenia.

Background: Butyric acid, a major short-chain fatty acid (SCFA), has an important role in the microbiota-gut-brain axis and brain function. This study investigated the role of butyric acid in treatment response in drug-naïve first episode schizophrenia. Methods: The study recruited 56 Chinese Han schizophrenia inpatients with normal body weight and 35 healthy controls. Serum levels of butyric acid were measured using Gas Chromatography-Mass Spectrometer (GC-MS) analysis at baseline (for all participants) and 24 weeks after risperidone treatment (for patients). Clinical symptoms were measured using the Positive and Negative Syndrome Scale (PANSS) for patients at both time points. Results: At baseline, there was no significant difference in serum levels of butyric acid between patients and healthy controls (p = 0.206). However, there was a significant increase in serum levels of butyric acid in schizophrenia patients after 24-week risperidone treatment (p = 0.030). The PANSS total and subscale scores were decreased significantly after 24-week risperidone treatment (p's < 0.001). There were positive associations between baseline serum levels of butyric acid and the reduction ratio of the PANSS total and subscale scores after controlling for age, sex, education, and duration of illness (p's < 0.05). Further, there was a positive association between the increase in serum levels of butyric acid and the reduction of the PANSS positive symptoms subscale scores (r = 0.38, p = 0.019) after controlling for potential confounding factors. Conclusions: Increased serum levels of butyric acid might be associated with a favorable treatment response in drug-naïve, first episode schizophrenia. The clinical implications of our findings were discussed.

Gut microbial biomarkers for the treatment response in first-episode, drug-naïve schizophrenia: a 24-week follow-up study.

Preclinical studies have shown that the gut microbiota can play a role in schizophrenia (SCH) pathogenesis via the gut-brain axis. However, its role in the antipsychotic treatment response is unclear. Here, we present a 24-week follow-up study to identify gut microbial biomarkers for SCH diagnosis and treatment response, using a sample of 107 first-episode, drug-naïve SCH patients, and 107 healthy controls (HCs). We collected biological samples at baseline (all participants) and follow-up time points after risperidone treatment (SCH patients). Treatment response was assessed using the Positive and Negative Symptoms Scale total (PANSS-T) score. False discovery rate was used to correct for multiple testing. We found that SCH patients showed lower α-diversity (the Shannon and Simpson's indices) compared to HCs at baseline (p = 1.21 × 10-9, 1.23 × 10-8, respectively). We also found a significant difference in ß-diversity between SCH patients and HCs (p = 0.001). At baseline, using microbes that showed different abundance between patients and controls as predictors, a prediction model can distinguish patients from HCs with an area under the curve (AUC) of 0.867. In SCH patients, after 24 weeks of risperidone treatment, we observed an increase of α-diversity toward the basal level of HCs. At the genus level, we observed decreased abundance of Lachnoclostridium (p = 0.019) and increased abundance Romboutsia (p = 0.067). Moreover, the treatment response in SCH patients was significantly associated with the basal levels of Lachnoclostridium and Romboutsia (p = 0.005 and 0.006, respectively). Our results suggest that SCH patients may present characteristic microbiota, and certain microbiota biomarkers may predict treatment response in this patient population.

Association of Aripiprazole With Reduced Hippocampal Atrophy During Maintenance Treatment of First-Episode Schizophrenia.

PURPOSE/BACKGROUND: Hippocampal volume loss in early schizophrenia has been linked with markers of inflammation and oxidative stress, and with less response of negative symptoms. Aripiprazole has been reported to preserve hippocampal volume and to reduce inflammation. METHODS/PROCEDURES: Study 1 was a 12-month multicenter randomized placebo-controlled trial of citalopram added to clinician-determined second-generation antipsychotic medication in 95 patients with first-episode schizophrenia (FES), 19 of whom received aripiprazole. We compared participants taking aripiprazole with those on other antipsychotics to determine whether those on aripiprazole had less hippocampal volume loss. We also examined peripheral biomarker data from medication-naive patients with schizophrenia receiving 8 weeks of antipsychotic treatment (n = 24) to see whether markers of inflammation and oxidative stress that previously predicted hippocampal volume differed between aripiprazole (n = 9) and other antipsychotics (study 2). FINDINGS/RESULTS: Aripiprazole was associated with a mean increase in hippocampal volume of 0.35% (SD, 0.80%) compared with a 0.53% decrease (SD, 1.2%) with other antipsychotics during the first year of maintenance treatment in patients with FES. This difference was significant after adjusting for age, sex, citalopram treatment, and baseline Brief Psychiatric Rating Scale score (B = 0.0079, P = 0.03). Aripiprazole was also associated with reduced concentrations of the inflammatory cytokines interleukin-8 and tumor necrosis factor (P < 0.01) during the first 8 weeks of treatment in medication-naive patients with FES. IMPLICATIONS/CONCLUSIONS: These results suggest that aripiprazole may protect against hippocampal atrophy via an anti-inflammatory mechanism, but these results require replication in larger, randomized trials, and the clinical relevance of hippocampal volume loss is not established.

Effect of citalopram on hippocampal volume in first-episode schizophrenia: Structural MRI results from the DECIFER trial.

Hippocampal volume loss is prominent in first episode schizophrenia (FES) and has been associated with poor clinical outcomes and with BDNF genotype; antidepressants are believed to reverse hippocampal volume loss via release of BDNF. In a 12-month, placebo-controlled add-on trial of the antidepressant, citalopram, during the maintenance phase of FES, negative symptoms were improved with citalopram. We now report results of structural brain imaging at baseline and 6 months in 63 FES patients (34 in citalopram group) from the trial to assess whether protection against hippocampal volume loss contributed to improved negative symptoms with citalopram. Hippocampal volumetric integrity (HVI) did not change significantly in the citalopram or placebo group and did not differ between treatment groups, whereas citalopram was associated with greater volume loss of the right CA1 subfield. Change in cortical thickness was associated with SANS change in 4 regions (left rostral anterior cingulate, right frontal pole, right cuneus, and right transverse temporal) but none differed between treatment groups. Our findings suggest that minimal hippocampal volume loss occurs after stabilization on antipsychotic treatment and that citalopram's potential benefit for negative symptoms is unlikely to result from protection against hippocampal volume loss or cortical thinning.

A narrative review of mindfulness-based therapy for schizophrenia, co-occurring substance use and comorbid cardiometabolic problems.

Mindfulness-based therapy (MBT) has gained attention in recent years as a promising treatment for patients with schizophrenia for whom traditional interventions are not effective. Research demonstrates improvements in psychotic symptoms, emotion regulation, and other areas including re-hospitalization rates and insight into illness following MBT interventions. Yet MBT studies have not carefully reported results in patients with schizophrenia and co-occurring substance use or comorbid medical problems, bringing into question the generalizability of these findings. This narrative review explores the literature regarding the use of mindfulness-based interventions for patients with schizophrenia as well as for patients with substance use disorder, cardiovascular disease, obesity, and diabetes. Findings suggest that MBTs can improve craving in substance use disorder, eating related behaviors in obesity, diabetes-related distress, and metabolic regulation in patients with diabetes. Increased insula and anterior cingulate cortex volumes and activities following MBTs might be associated with the potential benefit of MBTs in patients with schizophrenia. Our review provides a foundational basis in support of the need for future studies evaluating the safety and efficacy of MBTs for schizophrenia with co-occurring substance use disorder and/or comorbid cardiometabolic problems.

Sequential Multiple-Assignment Randomized Trials to Compare Antipsychotic Treatments (SMART-CAT) in first-episode schizophrenia patients: Rationale and trial design.

Accumulated studies have investigated pharmacological interventions for first-episode schizophrenia (FES) patients. However, studies on subsequent treatment steps, which are essential to guide clinicians, are largely missing. This Sequential Multiple-Assignment Randomized Trials comparing Antipsychotic Treatments (SMART-CAT) program intends to evaluate the effectiveness of commonly used antipsychotic drugs in FES patients. The major goals of this study are to examine: 1) what would be the optimal subsequent sequential treatment if the first antipsychotic drug failed; 2) whether clozapine could be used in those first-trial failed and have superior efficacy compared to other atypical antipsychotics. In this article we will report the detail protocol of SMART-CAT. The SMART-CAT is a randomized controlled clinical multicenter trial in which 9 institutions in China will participate. A total of 720 FES patients will be enrolled and followed up for 12 months in this study. The trial includes three treatment phases (each phase lasting for 8 weeks) and a naturalistic follow-up phase; participants who do well on an assigned treatment will remain on that treatment for the duration of the 12-month treatment period, while non-responders will move to the next phase of the study to receive a new treatment. Phase 1 is a randomized controlled trial; patients will be randomly assigned to one of the treatments with oral olanzapine, risperidone, amisulpride, aripiprazole or perphenazine. Subjects who fail to respond after 8 weeks will enter the phase 2 randomization. Phase 2 is an equipoise-stratified randomization trial, and patients will be randomly assigned to oral olanzapine, amisulpride or clozapine for 8 weeks. Subjects who fail to respond after phase 2 will enter an open label trial (phase 3); patients who receive clozapine in phase 2 and fail to respond will be assigned to an extended clozapine treatment or modified electroconvulsive therapy add-on therapy (Phase 3A). Patients who were not assigned to clozapine in phase 2 will be assigned to treatment with clozapine or another SGAs not previously used in phase 1 and 2 (Phase 3B). The primary outcome for the treatment phase is the treatment efficacy rate, which is defined as at least 40% reduction in Positive and Negative Syndrome Scale (PANSS) total score. We hypothesize that clozapine is more therapeutically effective than any other SGAs to patients who failed to meet efficacy criteria in Phase 1, and earlier treatment with clozapine can improve the functional outcomes of schizophrenia patients. As for the naturalistic follow-up phase, time to all-cause treatment failure, marked by its discontinuation is selected as the primary outcome, since it reflects both efficacy and side effects. The all-cause discontinuation is defined as discontinuing for any reasons, including poor efficacy, intolerance of adverse reactions, poor compliance and other reasons. The results of the SMART-CAT trial will provide evidence for the selection of antipsychotics in FES patients who fail to respond to the first trial of an antipsychotic drug. It will also provide evidence for the efficacy and safety of using clozapine in the early phase of schizophrenia treatment by comparing with other SGAs. The study is based on the combination of sequential therapy and dynamic therapy, which can be more suitable to assess the effectiveness of treatment options in the real-world clinical setting. As a result, we hope that this study can provide guidance for an optimal treatment algorithm in first-episode schizophrenia patients. Trial registration: ID NCT03510325 in ClinicalTrials.gov.

Insulin Resistance and Oxidative Stress: In Relation to Cognitive Function and Psychopathology in Drug-Naïve, First-Episode Drug-Free Schizophrenia.

Objective: The present study aimed to examine whether insulin resistance and oxidative stress are associated with cognitive impairment in first-episode drug-free schizophrenia (SZ) patients. Methods: Ninety first-episode SZ patients and 70 healthy controls were enrolled. Fasting insulin (FINS) and markers of oxidative stress [oxidized glutathione (GSSG), superoxide dismutase (SOD), nitric oxide (NO) and uric acid (UA) levels] were measured in serum before pharmacological treatment was initiated. Psychiatric symptoms and cognitive function were assessed with the Positive and Negative Syndrome Scale (PANSS) and MATRICS Consensus Cognitive Battery (MCCB), respectively. In addition, the homeostatic model assessment of insulin resistance (HOMA-IR) was also studied. Results: HOMA-IR and serum levels of GSSG and NO were significantly higher in SZ patients than in healthy controls (P < 0.001), while the serum levels of SOD were significantly lower than in healthy controls (P < 0.001). HOMA-IR, GSSG and NO levels were significantly correlated to the total cognitive function scores of the patient group (r = -0.345,-0.369,-0.444, respectively, P < 0.05). But these factors were not co-related to the cognitive functions in the healthy control group. And, levels of SOD, UA were not associated with the total cognitive function scores in both the patient and the healthy control groups. NO was positively correlated with general pathological and the total score in the PANSS, and was negatively correlated with six cognitive domains (r = -0.316 to -0.553, P < 0.05). Conclusions: The levels of insulin resistance and oxidative stress are elevated, and correlated with the severity of cognitive impairment in drug-naïve, first-episode SZ patients. Treatment approaches targeting on reducing insulin resistance and oxidative stress may improve cognitive function in SZ patients.

Solute Carrier Family 1 (SLC1A1) Contributes to Susceptibility and Psychopathology Symptoms of Schizophrenia in the Han Chinese Population.

OBJECTIVE: Schizophrenia (SZ) is a common and complex psychiatric disorder that has a significant genetic component. The glutamate hypothesis describes one possible pathogenesis of SZ. The solute carrier family 1 gene (SLC1A1) is one of several genes thought to play a critical role in regulating the glutamatergic system and is strongly implicated in the pathophysiology of SZ. In this study, we identify polymorphisms of the SLC1A1 gene that may confer susceptibility to SZ in the Han Chinese population. METHODS: We genotyped 36 single-nucleotide polymorphisms (SNPs) using Illumina GoldenGate assays on a BeadStation 500G Genotyping System in 528 paranoid SZ patients and 528 healthy controls. Psychopathology was rated by the Positive and Negative Symptom Scale. RESULTS: Significant associations were found in genotype and allele frequencies for SNPs rs10815017 (p = 0.002, 0.030, respectively) and rs2026828 (p = 0.020, 0.005, respectively) between SZ and healthy controls. There were significant associations in genotype frequency at rs6476875 (p = 0.020) and rs7024664 (p = 0.021) and allele frequency at rs3780412 (p = 0.026) and rs10974573 (p = 0.047) between SZ and healthy controls. Meanwhile, significant differences were found in genotype frequency at rs10815017 (p = 0.015), rs2026828 (p = 0.011), and rs3780411 (p = 0.040) in males, and rs7021569 in females (p = 0.020) between cases and controls when subdivided by gender. Also, significant differences were found in allele frequency at rs2026828 (p = 0.003), and rs7021569 (p = 0.045) in males, and rs10974619 in females (p = 0.044). However, those associations disappeared after Bonferroni's correction (p's > 0.05). Significant associations were found in the frequencies of four haplotypes (AA, CA, AGA, and GG) between SZ and healthy controls (χ 2 = 3.974, 7.433, 4.699, 4.526, p = 0.046, 0.006, 0.030, 0.033, respectively). There were significant associations between rs7032326 genotypes and PANSS total, positive symptoms, negative symptoms, and general psychopathology in SZ (p = 0.002, 0.011, 0.028, 0.008, respectively). CONCLUSION: The present study provides further evidence that SLC1A1 may be not a susceptibility gene for SZ. However, the genetic variations of SLC1A1 may affect psychopathology symptoms.

Association of DTNBP1 With Schizophrenia: Findings From Two Independent Samples of Han Chinese Population.

OBJECTIVES: Schizophrenia (SZ) is a complex psychiatric disorder that has a strong genetic basis. Dystrobrevin-binding protein 1 (DTNBP1) is one of the genes thought to be pivotal in regulating the glutamatergic system. Studies have suggested that variations in DTNBP1 confer susceptibility to SZ and clinical symptoms. Here, we performed a two-stage independent verification study to identify polymorphisms of the DTNBP1 gene that might be associated with SZ in the Han Chinese population. METHODS: In stage 1, 14 single nucleotide polymorphisms (SNPs) were genotyped in 528 paranoid SZ patients and 528 healthy controls (HCs) using the Illumina GoldenGate assays on a BeadStation 500G Genotyping System. In stage 2, ten SNPs were genotyped in an independent sample of 1,031 SZ patients and 621 HCs using the Illumina 660k Genotyping System. Clinical symptoms were assessed using the Positive and Negative Syndrome Scale. RESULTS: There was a significant association related to allele frequency, and a trend association in relation to genotype between SZ patients and HCs at rs4712253 (p = 0.03 and 0.05, respectively). These associations were not evident following Bonferroni correction (p > 0.05 for both). Haplotype association analysis revealed that only two haplotypes (GAG and GAA; rs16876575-rs9464793-rs4712253) were significantly different between SZ patients and HCs (χ2 = 4.24, 6.37, p = 0.04 and 0.01, respectively). In addition, in SZ patients there was a significant association in the rs4964793 genotype for positive symptoms, and in the rs1011313 genotype for excitement/hostility symptoms (p = 0.01 and 0.002, respectively). We found a significant association in the baseline symbol digital modalities test (SDMT), forward-digital span (DS), backward-DS, and semantic fluency between SZ patients and HCs (p < 0.05 for all). Finally, the SNP rs1011313 genotypes were associated with SDMT in SZ patients (p = 0.04). CONCLUSION: This study provides further evidence that SNP rs4712253 of DTNBP1 has a nominal association with SZ in the Han Chinese population. Such a genotype variation may play a role in psychopathology and cognitive function.