TGF-ß1 is associated with deficits in cognition and cerebral cortical thickness in first-episode schizophrenia.

BACKGROUND: Evidence indicates that cytokines are associated with cognitive deficits in schizophrenia; however, the underlying brain-behaviour mechanisms remain unclear. We hypothesized that aberrations in brain structural connectivity mediate the cytokine effect in schizophrenia. METHODS: In this study, we recruited patients with first-episode schizophrenia (n = 75, average illness duration 12.3 months, average medication period 0.6 days) and healthy controls (n = 44) of both sexes. We first conducted whole-blood RNA sequencing to detect differentially expressed genes. We also explored transcriptomic data on the dorsal lateral prefrontal cortices (dlPFC) retrieved from the CommonMind Consortium for gene functional clustering; we measured plasma transforming growth factor ß1 (TGF-ß1) levels by enzyme-linked immunosorbent assay; we acquired high-resolution T 1-weighted MRI data on cortical thickness MRI; and we assessed cognitive function using the validated Chinese version of the MATRICS Consensus Cognitive Battery. We compared these parameters in patients with schizophrenia and controls, and analyzed their associations. RESULTS: Patients with schizophrenia had higher TGF-ß1 at both the mRNA level (log2 fold change = 0.24; adjusted p = 0.026) and the protein level (12.85 ± 6.01 µg/mL v. 8.46 ± 5.15 µg/mL, adjusted p < 0.001) compared to controls. Genes coexpressed with TGFB1 in the dlPFC were less abundant in patients with schizophrenia compared to healthy controls. In patients with schizophrenia, TGF-ß1 protein levels were inversely correlated with cortical thickness, especially of the lateral occipital cortex (r = -0.47, adjusted p = 0.001), and with the MATRICS Consensus Cognitive Battery visual learning and memory domain (r = -0.50, adjusted p < 0.001). We found a complete mediation effect of the thickness of the lateral occipital cortex on the negative relationship between TGF-ß1 and visual cognition (p < 0.05). LIMITATIONS: We did not explore the effect of other blood cytokines on neurocognitive performance and cortical thickness. Participants from the CommonMind Consortium did not all have first-episode schizophrenia and they were not all antipsychotic-naive, so we could not exclude an effect of antipsychotics on TGF-ß1 signalling in the dlPFC. The sample size and cross-sectional design of our study were additional limitations. CONCLUSION: These findings highlighted an association between upregulated blood levels of TGF-ß1 and impairments in brain structure and function in schizophrenia.

Microglial regional heterogeneity and its role in the brain.

Microglia have been recently shown to manifest a very interesting phenotypical heterogeneity across different regions in the mammalian central nervous system (CNS). However, the underlying mechanism and functional meaning of this phenomenon are currently unclear. Baseline diversities of adult microglia in their cell number, cellular and subcellular structures, molecular signature as well as relevant functions have been discovered. But recent transcriptomic studies using bulk RNAseq and single-cell RNAseq have produced conflicting results on region-specific signatures of microglia. It is highly speculative whether such spatial heterogeneity contributes to varying sensitivities of individual microglia to the same physiological and pathological signals in different CNS regions, and hence underlie their functional relevance for CNS disease development. This review aims to thoroughly summarize up-to-date knowledge on this specific topic and provide some insights on the potential underlying mechanisms, starting from microgliogenesis. Understanding regional heterogeneity of microglia in the context of their diverse neighboring neurons and other glia may provide an important clue for future development of innovative therapies for neuropsychiatric disorders.

Association of serum uric acid levels with suicide risk in female patients with major depressive disorder: a comparative cross-sectional study.

BACKGROUND: Individuals with major depressive disorder (MDD) have a high suicide risk. Some evidence suggests that uric acid (UA) may be involved in the pathophysiology of MDD. The purpose of this study was to evaluate whether serum UA levels were associated with suicide risk in MDD patients. METHODS: One hundred four female patients with MDD (52 patients with suicide risk and 52 patients without suicide risk) and 52 healthy individuals were included in this study. The suicide risk was evaluated by Mini International Neuropsychiatric Interview (M.I.N.I.). Fasting serum levels of UA, as well as glucose, lipid and renal function indicators were measured. RESULTS: Serum UA levels in MDD patients with suicide risk (245.01 ± 55.44 µmol/L) were significantly lower than those in MDD patients without suicide risk (274.17 ± 72.65 µmol/L) (p = 0.017) and healthy controls (271.42 ± 55.25 µmol/L) (p = 0.030). There was no difference in serum UA levels between the MDD patients without suicide risk and healthy controls (p = 0.821). Binary logistic regression analysis revealed a significant relationship between suicide risk and decreased serum UA levels (OR = 0.989, p = 0.010) in MDD patients. CONCLUSION: Decreased serum UA levels were associated with suicide risk in MDD patients. Purinergic system dysfunction may be involved in the neurobiological basis of suicide risk in these patients.

The Effect of Cognitive Impairment on the Prognosis of Major Depressive Disorder.

The study recruited 168 patients diagnosed with major depressive disorder (MDD). The nine-item Patient Health Questionnaire (PHQ-9) and Perceived Deficits Questionnaire for Depression (PDQ-D) were lower and the Digit Symbol Substitution Test (DSST) was higher in the community volunteers than those in MDD patients. Depression-related scores (17-item Hamilton Depression Rating Scale [HAMD-17], Clinical Global Impressions-Severity of Illness Scale [CGI-S], and PHQ-9), functioning-related scores (Sheehan Disability Scale [SDS]), and Work Efficiency and Activity Damage-Specific Health Problems questionnaire work productivity loss were decreased, and the quality of life-related scores (European Quality of life-5 Dimensions [EQ-5D] utility score) were increased in the MDD patients. PDQ-D was decreased and DSST was increased with the increase of follow-up time. Linear regression indicated that cognitive symptoms (PDQ-D and DSST) improved more slowly than depressive symptoms (PHQ-9). At baseline, PDQ-D was related with functioning (SDS and work productivity loss). PDQ-D and DSST were related with EQ-5D utility score. In addition, at month 6, PDQ-D was related with functioning (SDS and work productivity loss) and EQ-5D utility score. Cognitive impairment might be a risk for MDD and MDD-related changes in the functioning and quality of life.

Brain Abnormalities in Different Phases of Working Memory in Schizophrenia: An Integrative Multi-Modal MRI Study.

The current study aimed to examine both gray matter and functional activity changes in schizophrenia by combing both structural and task-related functional magnetic resonance imaging (fMRI). Nineteen patients with schizophrenia and 17 controls were recruited. The fMRI scan was performed while performing a working memory (WM) task. In terms of task performance, accuracy did not differ between groups, but there were significant differences in reaction time. Compared with controls, patients exhibited decreased functional activation in prefrontal areas, insula, lingual gyrus, and superior temporal gyrus during different phases of WM. The subcallosal cortex showed increased activation. Intriguingly, a structural-functional correlation was found in the left dorsolateral prefrontal cortex, anterior cingulate cortex, and subcallosal cortex in patients when performing high-load WM task. This study demonstrated both impaired gray matter volume and functional activation during WM in schizophrenia, suggesting structural and functional impairments. The structural-functional correlation in schizophrenia suggested that structural damage in schizophrenia might induce a decreased ability to modulate functional response in accordance with increasing task difficulty.

Fluoxetine induces lipid metabolism abnormalities by acting on the liver in patients and mice with depression.

Depressive disorders are frequently managed with long-term use of antidepressant medication. Fluoxetine (FLX) is the first selective serotonin reuptake inhibitor to be widely available for the treatment of depression. The present study focuses on the effects and mechanisms of the lipid metabolism abnormalities caused by FLX in patients and in a mouse model of depression. Depression severity was assessed by the Hamilton Depression Scale (HAMD). Triglyceride (TG), cholesterol (TC) and low-density lipoprotein (LDL) serum levels were assessed in 28 patients with depression, aged 31.2±3.3 years, treated with FLX (20 to 60 mg/day) for 8 weeks. Meanwhile, the serum levels of other lipid metabolism-related parameters, such as high-density lipoprotein (HDL), apolipoprotein A1 (APOA1) and apolipoprotein B (ApoB), were also determined. The infiuence of FLX on the hepatic lipid profile and hepatic gene expression of both lipogenic and lipolytic enzymes was evaluated in a mouse model of depression treated with FLX (10 mg·kg-1·d-1, ip) for 4 weeks. We showed that the serum TG, TC and LDL levels were significantly increased in patients with depression after FLX treatment. The elevation in serum TG levels in the patients was not affected by gender or family history. FLX treatment did not significantly alter serum HDL, APOA1 or APOB levels in the patients. We further demonstrated in mice with depression that FLX treatment increased the hepatic TG level by increasing the expression of lipogenic enzymes and decreasing the expression of lipolytic enzymes in the liver. Antidepressive therapy with FLX is associated with lipid metabolism abnormalities, which are in part mediated by disturbances in hepatic lipid metabolism homeostasis. The findings contribute to the uncovering of metabolic adverse reactions in the pharmacological therapy of depression.

Tumor necrosis factor-alpha -1031T/C polymorphism is associated with cognitive deficits in chronic schizophrenia patients versus healthy controls.

Recent compelling research has demonstrated a pathophysiologic role for proinflammatory cytokines of microglial origin in decreasing neurocognitive function. Psychiatric diseases are already known to have reduced cognitive function and are also associated with increased inflammation. To elaborate on these data, our study aims to investigate how a particular polymorphism of the tumor necrosis factor gene, TNF-α -1031T/C, affects neurocognitive performance in patients with schizophrenia. We recruited 905 patients with schizophrenia and 571 healthy control subjects. We employed the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) to test for neurocognitive function and the positive and negative syndrome scale to evaluate schizophrenia severity. The -1031T/C polymorphism was genotyped in both healthy controls and schizophrenic patients. Our results demonstrate that patients with the C allele (either T/C or C/C) possessed increased immediate memory index, visuospatial/constructional index, and RBANS total scores as compared to patients without it (p < .05). In healthy controls, there was no significant difference across genotypes (p > .05). Our findings demonstrate that the TNF-α -1031T/C polymorphism may not play a role in the susceptibility of schizophrenia itself, but may be involved in the cognitive deficits of schizophrenia. This suggests an important role for cytokine signaling in mediating the severity of cognitive dysfunction in schizophrenia.

Interaction of BDNF with cytokines in chronic schizophrenia.

Brain-derived neurotrophic factor (BDNF) interacts with cytokines. Although both BDNF and cytokines occur at abnormal levels in schizophrenia patients, their interactions have not yet been examined. We therefore compared serum BDNF, TNF-α, interleukin (IL)-2, IL-6, and IL-8 levels in 92 chronically medicated schizophrenia patients and 60 healthy controls. We correlated these serum levels within these subject groups with each other and with clinical symptoms assessed according to the Positive and Negative Syndrome Scale (PANSS). Compared to the control group, the schizophrenia patients had significantly lower BDNF and TNF-α levels, and higher IL-2, IL-6, and IL-8 levels. The patients also showed a significant positive correlation between BDNF and both IL-2 and IL-8 levels, and low BDNF and TNF-α levels together were associated with poor performance on the PANSS cognitive factor. Thus, an interaction between cytokines and neurotrophic factors may be implicated in the pathophysiology of chronic schizophrenia. In particular, the cytokine TNF-α may interact with BNDF causing cognitive impairment.

Contribution of IL-10 and its -592 A/C polymorphism to cognitive functions in first-episode drug-naive schizophrenia.

Numerous studies have shown that proinflammatory cytokines produced by immune cells in the brain have deleterious effects on cognitive functions. In contrast, IL-10, an anti-inflammatory cytokine, can be neuroprotective and prevent neuronal dysfunction. However, few studies have linked the role of IL-10 to cognitive deficits in schizophrenia. In this study, serum IL-10 levels and genotypes for the IL10 -592 A/C promoter polymorphism were measured in a cohort of first-episode drug-naïve schizophrenic patients (FEDN-S) (n=256) and healthy control subjects (HC) (n=540). All participants were assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and psychopathology was assessed by the Positive and Negative Syndrome Scale (PANSS). In a separate transcriptomic data set containing 577 healthy human brain samples, we analyzed IL-10 and IL-10 RA/B-associated genetic networks in order to ascertain potential functions for IL-10 in the brain. We found a significant difference in allelic frequency between FEDN-S and HC subjects. The A allelic variant was associated with reduced serum IL-10 levels and worse attentional performance in FEDN-S but not in HC subjects. Moreover, serum IL-10 levels were correlated with the extent of cognitive impairment, especially attentional performance in the schizophrenic A-allele carriers. In human brain transcriptomic coexpression analysis, we found that genes most significantly co-expressed with IL10 were associated with synaptic vesicle transportation, and both IL10RA and IL10RB were most significantly co-expressed not only with genes that regulate inflammation but also with those that participate in synaptic formation. The IL10-592 A/C genetic variant was more common in schizophrenic patients than HC and was associated with lower IL-10 serum levels and worse attentional performance in these patients. Furthermore, the IL10 gene and its receptors in the healthy human brain appear to regulate inflammation and synaptic functions that are important for cognition, and hence its deficiency in schizophrenia may contribute to cognitive impairment.

ZNF804A variants confer risk for heroin addiction and affect decision making and gray matter volume in heroin abusers.

Drug addiction shares common neurobiological pathways and risk genes with other psychiatric diseases, including psychosis. One of the commonly identified risk genes associated with broad psychosis has been ZNF804A. We sought to test whether psychosis risk variants in ZNF804A increase the risk of heroin addiction by modulating neurocognitive performance and gray matter volume (GMV) in heroin addiction. Using case-control genetic analysis, we compared the distribution of ZNF804A variants (genotype and haplotype) in 1035 heroin abusers and 2887 healthy subjects. We also compared neurocognitive performance (impulsivity, global cognitive ability and decision-making ability) in 224 subjects and GMV in 154 subjects based on the ZNF804A variants. We found significant differences in the distribution of ZNF804A intronic variants (rs1344706 and rs7597593) allele and haplotype frequencies between the heroin and control groups. Decision-making impairment was worse in heroin abusers who carried the ZNF804A risk allele and haplotype. Subjects who carried more risk alleles and haplotypes of ZNF804A had greater GMV in the bilateral insular cortex, right temporal cortex and superior parietal cortex. The interaction between heroin addiction and ZNF804A variants affected GMV in the left sensorimotor cortex. Our findings revealed several ZNF804A variants that were significantly associated with the risk of heroin addiction, and these variants affected decision making and GMV in heroin abusers compared with controls. The precise neural mechanisms that underlie these associations are unknown, which requires future investigations of the effects of ZNF804A on both dopamine neurotransmission and the relative increases in the volume of various brain areas.

Association of the manganese superoxide dismutase gene Ala-9Val polymorphism with age of smoking initiation in male schizophrenia smokers.

Schizophrenia patients exhibit higher smoking rates than the general population. A growing body of evidence suggests that cigarette smoke impairs the antioxidant defense mechanisms, leading to oxidative damage. Manganese superoxide dismutase (MnSOD) is the major antioxidant in the mitochondria, catalyzing the metabolism of superoxide radicals to form hydrogen peroxide. Since the identification of a well-characterized functional polymorphism, Ala-9Val of MnSOD, a number of studies have evaluated the association between Val-9Ala and schizophrenia or cancer. In this study, we hypothesized that the functional polymorphism of MnSOD Ala-9Val was associated with smoking in patients with schizophrenia. This polymorphism was genotyped in 666 chronic male schizophrenia patients (smoker/never-smoker = 507/159) and 660 male controls (smoker/never-smoker = 360/300) using a case-control design. The cigarettes smoked per day (CPD) and smoking behaviors were evaluated by clinician-administered questionnaires and the Fagerstrom Test for Nicotine Dependence (FTND). The results showed no significant differences in MnSOD Ala-9Val genotype and allele distributions between the patients and healthy controls or between smokers and never-smokers in either patients or healthy controls alone. The smokers with the Ala allele started smoking significantly earlier (19.9 ± 5.8 vs. 21.7 ± 6.5 years, P = 0.005) only in patients. These results suggest that the MnSOD Ala-9Val polymorphism may not influence smoking status in a Chinese male schizophrenia population, but may influence the age at which smoking is started among schizophrenia smokers.

Mn-superoxide dismutase activity is associated with orofacial involuntary movements in schizophrenia patients with tardive dyskinesia.

BACKGROUND: Oxidative stress-induced damage may be involved in tardive dyskinesia (TD) development. Superoxide dismutase (SOD), the key antioxidant enzyme, was found abnormal in TD. OBJECTIVE: We examined the role of oxidative stress in relation to TD and TD subtypes in schizophrenia using manganese SOD (MnSOD) as the biomarker. METHODS: We recruited 152 male chronic patients with (n = 76) and without TD (n = 76) meeting Diagnostic and Statistical Manual of Mental Disorders-IV criteria for schizophrenia and 75 male control subjects. We examined the MnSOD activity for all subjects. Positive and Negative Syndrome Scale and the Abnormal Involuntary Movement Scale (AIMS) were assessed in the patients. RESULTS: Manganese SOD activity was lower in patients with TD than non-TD (p < 0.05). In the patients with TD, orofacial and total scores of AIMS were positively associated with MnSOD levels (both p < 0.05). Multiple regression analysis further confirmed that MnSOD was an independent contributor to both the orofacial and the total scores of AIMS (both p < 0.05). CONCLUSIONS: Oxidative stress reflected by compromised oxidative defense may play a role in the development and severity of TD. There may be an etiologic relationship between increased SOD level and dyskinetic movements associated with TD. In particular, MnSOD activity may have a specific role in orofacial TD.

Gender differences in cognitive deficits in schizophrenia with and without diabetes.

This study investigated gender differences in cognition in schizophrenia with and without diabetes. Cognition was assessed in 263 individuals with schizophrenia with age range (40-68): 67 males and 34 females with schizophrenia with diabetes; and 125 males and 37 females with schizophrenia without diabetes according to the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Fasting glucose, hemoglobin A1c (HbA1c) and lipid levels were measured. Results showed that male individuals performed worse on most cognitive tasks, especially attention, in schizophrenia with than without diabetes. This result was not observed in female individuals. Also, individuals of both genders showed higher fasting glucose and HbA1c in schizophrenia with than without diabetes. In schizophrenia with diabetes, males had significantly worse cognition than females in all cognitive domains. Higher HbA1c, lower high-density lipoprotein, and an earlier age of onset of schizophrenia were found in males compared with female individuals. HbA1c was negatively associated with attention and the RBANS total score for males but not for females. In schizophrenia without diabetes, males showed worse performance in immediate and delayed memory than females. This study support cognition was worse for males with schizophrenia irrespective of whether they have diabetes. However, diabetes exemplified the gender differences, especially in attention.

Interleukin 18 and cognitive impairment in first episode and drug naïve schizophrenia versus healthy controls.

Alterations in the inflammatory and immune systems have been documented to occur from the earliest stages of schizophrenia, and have been associated with neurodevelopmental changes. Cognitive impairment is a core feature in the pathology of schizophrenia, and recent studies showed a significant increase in serum IL-18 in schizophrenia, and a putative role of IL-18 in neuroprogression and thus neurocognitive defects. The purpose of this study was to examine the association of IL-18 with cognitive deficits in schizophrenia. We recruited 77 first episode and drug naïve schizophrenic patients and 75 healthy control subjects and examined the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and serum IL-18 in both groups. Schizophrenic symptoms were assessed using the positive and negative syndrome scale (PANSS). We found that IL-18 levels were non-significantly higher in patients than controls (206.0±92.9 pg/ml vs 193.2±41.8 pg/ml, p=0.28). Cognitive scores on the RBANS and nearly all of its five subscales (all p<0.05) except for the Visuospatial/Constructional index (p>0.05) were significantly lower in schizophrenic patients than normal controls. For the patients, IL-18 was positively associated with the Visuospatial/Constructional domain of cognitive deficits in schizophrenia. Our findings suggest that cognitive deficits occur during the acute stage of a schizophrenic episode, and IL-18 may be involved in Visuospatial/Constructional deficits of these patients.

Extract of Ginkgo biloba is equivalent to vitamin E in attenuating and preventing vacuous chewing movements in a rat model of tardive dyskinesia.

Free radical-mediated abnormalities may contribute toward the pathogenesis of tardive dyskinesia (TD). Many studies have reported the protective antioxidant and free radical-scavenging activities of extract of Ginkgo biloba (EGb761) against free radical-induced cell damage and dysfunction. This study aimed to compare the efficacy of EGb761 with that of vitamin E for the prevention and treatment of TD in a rat model. We carried out two studies. First, rats were injected with haloperidol (2 mg/kg intraperitoneally) daily for 5 weeks. EGb761 (50 mg/kg/day) or vitamin E (20 mg/kg/day) were then administered for another 5 weeks, and their effects on vacuous chewing movements (VCMs) were compared. Second, we compared 10 weeks of haloperidol alone with 10 weeks of haloperidol plus EGb761 or vitamin E. The administration of haloperidol led to a progressive increase in VCMs, which peaked at week 5. In study one, EGb761 and vitamin E, administered by an oral gavage for 5 weeks during withdrawal from chronic haloperidol treatment, decreased VCMs significantly, showing 83.8 and 91.0% reduction, respectively, compared with the haloperidol-alone group. In study two, the concomitant administration of EGb761 and vitamin E led to significantly fewer VCMs, by 64.4 and 73.9%, respectively, compared with the haloperidol-alone group. There was no significant difference in either study between EGb761 and vitamin E treatment. EGb761 shows promise for the prevention and treatment of TD in a rat model with a magnitude that was similar to that of vitamin E.

Measuring Sleep Stages and Screening for Obstructive Sleep Apnea with a Wearable Multi-Sensor System in Comparison to Polysomnography.

Objective: To assess the performance of a wearable multi-sensor system (SensEcho) in comparison to polysomnography (PSG) in measuring sleep stages and searching for obstructive sleep apnea (OSA). Methods: Participants underwent overnight simultaneous monitoring using SensEcho and PSG in a sleep laboratory. SensEcho analyzed the recordings spontaneously, and PSG was assessed as per standard guidelines. The degree of snoring was evaluated according to the guidelines for the diagnosis and treatment of OSA hypopnea syndrome (2011 revision). The Epworth Sleepiness Scale (ESS) was used to assess general daytime sleepiness. Results: This study included 103 Han Chinese, 91 of whom (age 39.02 ± 13.84 years, body mass index 27.28 ± 5.12 kg/m2, 61.54% male) completed the assessments. The measures of total sleep time (P = 0.198); total wake time (P = 0.182); shallow sleep (P = 0.297), deep sleep (P = 0.422), rapid eye movement sleep (P = 0.570), and awake (P = 0.336) proportions were similar between SensEcho and PSG. Using an apnea-hypopnea index (AHI) cutoff of ≥ 5 events/h, the SensEcho had 82.69% sensitivity and 89.74% specificity. Almost the same results were obtained at an AHI threshold of ≥ 15 events/h. Although the specificity increased to 94.67%, it decreased to 43.75% at an AHI cutoff of ≥ 30 events/h. Conclusion: This study demonstrated that SensEcho can be used to evaluate sleep status and screen for OSA. Nevertheless, improving the accuracy of its assessment of severe OSA and further testing its effectiveness in community and home environments is necessary.

Changes in Inflammatory Biomarkers in Patients with Schizophrenia: A 3-Year Retrospective Study.

Objective: Accumulating evidence suggested that immune system activation might be involved in the pathophysiology of schizophrenia. The neutrophil/lymphocyte ratio (NLR), monocyte/lymphocyte ratio (MLR), platelet/lymphocyte ratio (PLR) and systemic immune-inflammation index (SII) can measure inflammation. This study aimed to investigate the inflammatory state in patients with schizophrenia by using these indicators. Methods: In this study, the complete blood count data for 187 continuing hospitalized patients with schizophrenia and 187 age- and sex-matched healthy participants was collected annually from 2017 to 2019. Platelet (PLT), lymphocyte (LYM), monocyte (MON) and neutrophil (NEU) counts were aggregated and NLR, MLR, PLR, and SII were calculated. Using a generalized linear mixed model, we assessed the impact of age, sex, diagnosis, and sampling year on the above indicators and evaluated the interaction between the factors. Results: According to the estimation results of the generalized linear mixed model, the NLR increased by 0.319 (p = 0.004), the MLR increased by 0.037 (p < 0.001), and the SII increased by 57.858 (p = 0.018) in patients with schizophrenia. Data after two years of continuous antipsychotic treatment showed that the NLR and MLR were higher in patients with schizophrenia than those in healthy controls, while the PLT and LYM counts were decreased in patients with schizophrenia. The schizophrenia diagnosis was correlated to the MON and LYM count, NLR, MLR, and SII (p < 0.05). Conclusion: The differences in these markers were stable and cannot be eliminated by a full course of treatment. This study provides impetus for the inflammatory hypothesis of schizophrenia.

Prediction of treatment response to antipsychotic drugs for precision medicine approach to schizophrenia: randomized trials and multiomics analysis.

BACKGROUND: Choosing the appropriate antipsychotic drug (APD) treatment for patients with schizophrenia (SCZ) can be challenging, as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers. Previous studies have indicated the association between treatment response and genetic and epigenetic factors, but no effective biomarkers have been identified. Hence, further research is imperative to enhance precision medicine in SCZ treatment. METHODS: Participants with SCZ were recruited from two randomized trials. The discovery cohort was recruited from the CAPOC trial (n = 2307) involved 6 weeks of treatment and equally randomized the participants to the Olanzapine, Risperidone, Quetiapine, Aripiprazole, Ziprasidone, and Haloperidol/Perphenazine (subsequently equally assigned to one or the other) groups. The external validation cohort was recruited from the CAPEC trial (n = 1379), which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine, Risperidone, and Aripiprazole groups. Additionally, healthy controls (n = 275) from the local community were utilized as a genetic/epigenetic reference. The genetic and epigenetic (DNA methylation) risks of SCZ were assessed using the polygenic risk score (PRS) and polymethylation score, respectively. The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis, methylation quantitative trait loci, colocalization, and promoter-anchored chromatin interaction. Machine learning was used to develop a prediction model for treatment response, which was evaluated for accuracy and clinical benefit using the area under curve (AUC) for classification, R2 for regression, and decision curve analysis. RESULTS: Six risk genes for SCZ (LINC01795, DDHD2, SBNO1, KCNG2, SEMA7A, and RUFY1) involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response. The developed and externally validated prediction model, which incorporated clinical information, PRS, genetic risk score (GRS), and proxy methylation level (proxyDNAm), demonstrated positive benefits for a wide range of patients receiving different APDs, regardless of sex [discovery cohort: AUC = 0.874 (95% CI 0.867-0.881), R2 = 0.478; external validation cohort: AUC = 0.851 (95% CI 0.841-0.861), R2 = 0.507]. CONCLUSIONS: This study presents a promising precision medicine approach to evaluate treatment response, which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ. Trial registration Chinese Clinical Trial Registry ( https://www.chictr.org.cn/ ), 18. Aug 2009 retrospectively registered: CAPOC-ChiCTR-RNC-09000521 ( https://www.chictr.org.cn/showproj.aspx?proj=9014 ), CAPEC-ChiCTR-RNC-09000522 ( https://www.chictr.org.cn/showproj.aspx?proj=9013 ).

Vocal Acoustic Features as Potential Biomarkers for Identifying/Diagnosing Depression: A Cross-Sectional Study.

Background: At present, there is no established biomarker for the diagnosis of depression. Meanwhile, studies show that acoustic features convey emotional information. Therefore, this study explored differences in acoustic characteristics between depressed patients and healthy individuals to investigate whether these characteristics can identify depression. Methods: Participants included 71 patients diagnosed with depression from a regional hospital in Beijing, China, and 62 normal controls from within the greater community. We assessed the clinical symptoms of depression of all participants using the Hamilton Depression Scale (HAMD), Hamilton Anxiety Scale (HAMA), and Patient Health Questionnaire (PHQ-9), and recorded the voice of each participant as they read positive, neutral, and negative texts. OpenSMILE was used to analyze their voice acoustics and extract acoustic characteristics from the recordings. Results: There were significant differences between the depression and control groups in all acoustic characteristics (p < 0.05). Several mel-frequency cepstral coefficients (MFCCs), including MFCC2, MFCC3, MFCC8, and MFCC9, differed significantly between different emotion tasks; MFCC4 and MFCC7 correlated positively with PHQ-9 scores, and correlations were stable in all emotion tasks. The zero-crossing rate in positive emotion correlated positively with HAMA total score and HAMA somatic anxiety score (r = 0.31, r = 0.34, respectively), and MFCC9 of neutral emotion correlated negatively with HAMD anxiety/somatization scores (r = -0.34). Linear regression showed that the MFCC7-negative was predictive on the PHQ-9 score (ß = 0.90, p = 0.01) and MFCC9-neutral was predictive on HAMD anxiety/somatization score (ß = -0.45, p = 0.049). Logistic regression showed a superior discriminant effect, with a discrimination accuracy of 89.66%. Conclusion: The acoustic expression of emotion among patients with depression differs from that of normal controls. Some acoustic characteristics are related to the severity of depressive symptoms and may be objective biomarkers of depression. A systematic method of assessing vocal acoustic characteristics could provide an accurate and discreet means of screening for depression; this method may be used instead of-or in conjunction with-traditional screening methods, as it is not subject to the limitations associated with self-reported assessments wherein subjects may be inclined to provide socially acceptable responses rather than being truthful.

Vocal acoustic features may be objective biomarkers of negative symptoms in schizophrenia: A cross-sectional study.

BACKGROUND: There are currently no objective biomarkers that allow the quantification of negative symptoms of schizophrenia. This study therefore explored the use of acoustic features in identifying the severity of negative symptoms in patients with schizophrenia. METHODS: We recruited 79 inpatients who were diagnosed with schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (the schizophrenia group) at the Huilongguan Hospital in Beijing, China, and 79 healthy controls from the surrounding community (the control group). We assessed the clinical symptoms of the patients with schizophrenia using the Positive and Negative Syndrome Scale (PANSS) and the Brief Negative Symptom Scale (BNSS) and recorded the voice of each participant as they read emotionally positive, neutral, and negative texts. The Praat software was used to analyse and extract acoustic characteristics from the recordings, such as jitter, shimmer, and pitch. The acoustic differences between the two groups of participants and the relationship between acoustic characteristics and clinical symptoms in the patient group were analysed. RESULTS: There were significant differences between the schizophrenia and control groups in pitch, voice breaks, jitter, shimmer, and the mean harmonics-to-noise ratio (p < 0.05). Jitter was negatively correlated with the blunted affect and alogia subscale scores of the BNSS, both in the positive and neutral emotion conditions, but the correlation disappeared in the negative emotion condition. However, shimmer exhibited a stable negative correlation with the blunted affect and alogia subscale scores of the BNSS in all three emotion conditions. A linear regression analysis showed that pitch, jitter, shimmer, and age were statistically significant predictors of BNSS subscale scores. CONCLUSIONS: Acoustic emotional expression differs between patients with schizophrenia and healthy controls. Some acoustic characteristics are related to the severity of negative symptoms, regardless of semantic emotions, and may therefore be objective biomarkers of negative symptoms. A systematic method for assessing vocal acoustic characteristics could provide an accurate and feasible means of assessing negative symptoms in schizophrenia. TWEET: Acoustic emotional expression differs between patients with schizophrenia and healthy controls. A systematic method for assessing vocal acoustics could provide an accurate and feasible means of assessing negative symptoms in schizophrenia.