Impact of body mass index elevation, Vitamin D receptor polymorphisms and antipsychotics on the risk of Vitamin D deficiency in schizophrenia patients.

Antipsychotics with weight gain as side effect and vitamin D receptor dysfunction associated with single nucleotide polymorphisms (VDR SNPs) may have different effects on vitamin D status. Hence, present study aimed to investigate the relationship between vitamin D with body mass index (BMI), antipsychotics and VDR SNPs (rs2228570, rs1544410, rs7975232 and rs731236) in Malaysian patients with schizophrenia. Serum vitamin D level was measured using competitive enzyme-linked immunosorbent assay kit. VDR SNPs were analyzed using polymerase chain reaction-restriction fragment length polymorphism. We found significantly lower serum vitamin D level in patients with schizophrenia (p < 0.01), especially those taking atypical antipsychotics (p = 0.02) and combined antipsychotics (p = 0.02) and obese (BMI ≥27.5 kg/m2) patients (p = 0.04) after adjustment for covariates. For VDR SNPs, the CT genotype of rs1544410, CA genotype of rs7975232, and AA and AG genotypes of rs731236 may contribute to the significant decreased serum vitamin D level in patients (p < 0.05). Nevertheless, these relationships may differ by populations or medical conditions. The hypotheses of volumetric dilution and sequestration of vitamin D may explain the lower vitamin D level in obese patients. In addition, lifestyle factors such as poor diet and lack of physical activity with less sunlight exposure may cause reduced vitamin D level among patients. As patients in present study were prescribed with various antipsychotics, the effect of each antipsychotic on vitamin D level could not be determined. Thus, future studies should investigate the effect of different types of antipsychotics and obesity on vitamin D level in schizophrenia.

Meta-analysis of soluble tumour necrosis factor receptors in severe mental illnesses.

Tumour necrosis factor (TNF), as an innate immune defense molecule, functions through binding to TNF receptor 1 (TNFR1) or TNF receptor 2 (TNFR2). Peripheral levels of soluble TNFR1 (sTNFR1) and soluble TNFR2 (sTNFR2) were widely measured in severe mental illnesses (SMIs) including schizophrenia (SCZ), bipolar disorder (BD) and major depressive disorder (MDD) but inconsistencies existed. Hence, the present meta-analysis was conducted to identify the overall association between plasma/serum sTNFR1 and sTNFR2 levels and SMIs. Published studies were searched using Pubmed and Scopus. Data were analysed using Comprehensive Meta-Analysis version 2. Hedges's g effect sizes and 95% confidence intervals were pooled using fixed-effect or random-effects models. Heterogeneity, publication bias and study quality were assessed. Sensitivity analysis and subgroup analysis were performed. Our findings revealed that sTNFR1 level was significantly higher in SMI, particularly in BD. The sTNFR2 level significantly elevated in SMI but with smaller effect size. These findings further support the association between altered immune system and inflammatory abnormalities in SMI, especially in patients with BD. Subgroup analysis showed that younger age of onset, longer illness duration and psychotropic medication raised both sTNFR levels, especially sTNFR1, as these factors may contribute to the activation of inflammation. Future studies were suggested to identify the causality between TNFR pathway and SCZ, BD and MDD respectively using homogenous group of each SMI, and to determine the longitudinal effect of each psychotropic medication on TNFR pathway.

Integrative Roles of Dopamine Pathway and Calcium Channels Reveal a Link between Schizophrenia and Opioid Use Disorder.

Several theories have been proposed to explain the mechanisms of substance use in schizophrenia. Brain neurons pose a potential to provide novel insights into the association between opioid addiction, withdrawal, and schizophrenia. Thus, we exposed zebrafish larvae at 2 days post-fertilization (dpf) to domperidone (DPM) and morphine, followed by morphine withdrawal. Drug-induced locomotion and social preference were assessed, while the level of dopamine and the number of dopaminergic neurons were quantified. In the brain tissue, the expression levels of genes associated with schizophrenia were measured. The effects of DMP and morphine were compared to vehicle control and MK-801, a positive control to mimic schizophrenia. Gene expression analysis revealed that α1C, α1Sa, α1Aa, drd2a, and th1 were up-regulated after 10 days of exposure to DMP and morphine, while th2 was down-regulated. These two drugs also increased the number of positive dopaminergic neurons and the total dopamine level but reduced the locomotion and social preference. The termination of morphine exposure led to the up-regulation of th2, drd2a, and c-fos during the withdrawal phase. Our integrated data implicate that the dopamine system plays a key role in the deficits in social behavior and locomotion that are common in the schizophrenia-like symptoms and opioid dependence.

Receptor-Mediated AKT/PI3K Signalling and Behavioural Alterations in Zebrafish Larvae Reveal Association between Schizophrenia and Opioid Use Disorder.

The link between substance abuse and the development of schizophrenia remains elusive. In this study, we assessed the molecular and behavioural alterations associated with schizophrenia, opioid addiction, and opioid withdrawal using zebrafish as a biological model. Larvae of 2 days post fertilization (dpf) were exposed to domperidone (DMP), a dopamine-D2 dopamine D2 receptor antagonist, and morphine for 3 days and 10 days, respectively. MK801, an N-methyl-D-aspartate (NMDA) receptor antagonist, served as a positive control to mimic schizophrenia-like behaviour. The withdrawal syndrome was assessed 5 days after the termination of morphine treatment. The expressions of schizophrenia susceptibility genes, i.e., pi3k, akt1, slc6a4, creb1 and adamts2, in brains were quantified, and the levels of whole-body cyclic adenosine monophosphate (cAMP), serotonin and cortisol were measured. The aggressiveness of larvae was observed using the mirror biting test. After the short-term treatment with DMP and morphine, all studied genes were not differentially expressed. As for the long-term exposure, akt1 was downregulated by DMP and morphine. Downregulation of pi3k and slc6a4 was observed in the morphine-treated larvae, whereas creb1 and adamts2 were upregulated by DMP. The levels of cAMP and cortisol were elevated after 3 days, whereas significant increases were observed in all of the biochemical tests after 10 days. Compared to controls, increased aggression was observed in the DMP-, but not morphine-, treated group. These two groups showed reduction in aggressiveness when drug exposure was prolonged. Both the short- and long-term morphine withdrawal groups showed downregulation in all genes examined except creb1, suggesting dysregulated reward circuitry function. These results suggest that biochemical and behavioural alterations in schizophrenia-like symptoms and opioid dependence could be controlled by common mechanisms.

Effects of antipsychotics on antioxidant defence system in patients with schizophrenia: A meta-analysis.

Theory of oxidative stress is suggested in the pathophysiology of schizophrenia. To determine the cause of impaired antioxidant defense system in schizophrenia, a meta-analysis was performed by selecting studies published from 1964 to 2021 from Pubmed and Scopus databases. Data were analysed using Comprehensive Meta-Analysis version 2 and calculated effect sizes were compared between unmedicated and medicated patients with schizophrenia and healthy controls. Heterogeneity, publication bias assessments and subgroup analyses of drug-free and drug-naïve patients, and patients treated with atypical and typical antipsychotics were conducted. Subgroup analysis of confounding factors including age, gender, illness duration and patient status was also conducted. We found that glutathione peroxidase (GPx) was significantly decreased in all patients. Significantly lower catalase (CAT), glutathione (GSH) and albumin (ALB) were found in unmedicated patients only. Both groups showed significantly weakened non-enzymatic antioxidant capacity. Subgroup analyses indicated that weakened non-enzymatic antioxidant capacity may be associated with schizophrenia. Antioxidant status was more impaired in drug-free patients compared with other subgroups. This indicated that antipsychotics may improve antioxidant defense system. Although effect sizes were smaller, future studies may focus on the effect of antipsychotic discontinuation. In overall, schizophrenia was associated with impaired antioxidant defense system especially the non-enzymatic antioxidant system.

Blood-based oxidation markers in medicated and unmedicated schizophrenia patients: A meta-analysis.

Increased reactive species due to the effect of antipsychotics on oxidative stress may be involved in the development of schizophrenia. However, antipsychotics may have different direct antioxidant effects due to their chemical structures. The present meta-analysis aimed to investigate whether the cause increased oxidant status in schizophrenia patients is due to the illness or induction by antipsychotics. Studies published from 1964 to 2021 were selected from Pubmed and Scopus databases. Data were analysed using Comprehensive Meta-Analysis version 2. Effect sizes were calculated and compared between unmedicated and medicated patients and healthy controls. Heterogeneity and publication bias were assessed. Subgroup analyses were conducted on drug-free and drug-naïve patients, and patients treated with atypical and typical antipsychotics. We found that medicated patients had significantly higher malondialdehyde (MDA), thiobarbituric acid reactive substances (TBARS) and total oxidant status (TOS). Meanwhile, significantly increased plasma/serum MDA and nitric oxide (NO) were observed in unmedicated patients only. Higher lipid peroxidation in the drug-naïve group may be associated schizophrenia. However, both atypical and typical antipsychotics may worsen lipid peroxidation. Antipsychotic discontinuation in the drug-free group led to significantly increased plasma/serum NO, with larger effect size than the atypical antipsychotic group. In conclusion, medicated schizophrenia patients were more suffered from increased oxidative stress. Therefore, future study may focus on the mechanism of action of specific antipsychotic on oxidative stress.

8-Hydroxy-2'-Deoxyguanosine and Reactive Oxygen Species as Biomarkers of Oxidative Stress in Mental Illnesses: A Meta-Analysis.

OBJECTIVE: Mental illnesses may be caused by genetic and environmental factors. Recent studies reported that mental illnesses were accompanied by higher oxidative stress level. However, the results were inconsistent. Thus, present meta-analysis aimed to analyse the association between oxidative DNA damage indicated by 8-hydroxy-2'-deoxyguanosine (8-OHdG) or 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), which has been widely used as biomarker of oxidative stress, and mental illnesses, including schizophrenia, bipolar disorder and depression. As oxidative DNA damage is caused by reactive oxygen species (ROS), systematic review and meta-analysis were also conducted to analyse the relationship between ROS and these three mental illnesses. METHODS: Studies from 1964 to 2020 (for oxidative DNA damage) and from 1907 to 2021 (for ROS) in Pubmed and Scopus databases were selected and analysed using Comprehensive Meta-Analysis version 2 respectively. Data were subjected to meta-analysis for examining the effect sizes of the results. Publication bias assessments, heterogeneity assessments and subgroup analyses based on biological specimens, patient status, illness duration and medication history were also conducted. RESULTS: This meta-analysis revealed that oxidative DNA damage was significantly higher in patients with schizophrenia and bipolar disorder based on random-effects models whereas in depressed patients, the level was not significant. Since heterogeneity was present, results based on random-effects model was preferred. Our results also showed that oxidative DNA damage level was significantly higher in lymphocyte and urine of patients with schizophrenia and bipolar disorder respectively. Besides, larger effect size was observed in inpatients and those with longer illness duration and medication history. Significant higher ROS was also observed in schizophrenic patients but not in depressive patients. CONCLUSION: The present meta-analysis found that oxidative DNA damage was significantly higher in schizophrenia and bipolar disorder but not in depression. The significant association between deoxyguanosines and mental illnesses suggested the possibility of using 8-OHdG or 8-oxodG as biomarker in measurement of oxidative DNA damage and oxidative stress. Higher ROS level indicated the involvement of oxidative stress in schizophrenia. The information from this study may provide better understanding on pathophysiology of mental illnesses.

Traditional Chinese Medicine Body Constitutions and Psychological Determinants of Depression among University Students in Malaysia: A Pilot Study.

Depression is commonly observed in university students, who are a high risk group for developing psychiatric disorders during adulthood. This study aimed to determine the prevalence of depression and its traditional Chinese medicine body constitutions and psychological determinants among university students in Malaysia. A cross-sectional pilot study was conducted between 9 and 28 September 2020 among 80 university students in Malaysia. Participants completed online survey questionnaires, including the validated Patient Health Questionnaire (PHQ-9), Constitution in Chinese Medicine Questionnaire (CMCQ), Dysfunctional Attitude Scale (DAS), Depression Anxiety Stress Scale (DASS-21) stress subscale, Perceived Stress Scale (PSS-10), and Rosenberg Self-Esteem Scale (RSES), which assess depression, body constitution, dysfunctional attitude, stress, perceived stress, and self-esteem. Multiple linear regression analyses were performed to determine the associated risk factors for depression. The overall prevalence of depression among university students was 33.8%. The multiple regression analysis showed a significant relationship between depression and qi-stagnation constitution (B = 0.089, p = 0.011), balanced constitution (B = -0.077, p = 0.049), and self-esteem (B = -0.325, p = 0.001). Our findings suggest that some traditional Chinese medicine body constitutions and self-esteem are significant risk factors affecting depression among university students. Identifying risk factors of depression is vital to aid in the early detection of depression among university students.

Functional characterization of two variants in the 3'-untranslated region (UTR) of transcription factor 4 gene and their association with schizophrenia in sib-pairs from multiplex families.

Transcription factor 4 (TCF4) gene plays an important role in nervous system development and it always associated with the risk of schizophrenia. Since miRNAs regulate targetgenes by binding to 3'UTRs of target mRNAs, the functional variants located in 3'UTR of TCF4 are highly suggested to affect the gene expressions in schizophrenia. To test the hypothesis regarding the effects of the variants located in 3'UTR of TCF4, we conducted an in silico analysis to identify the functional variants and their predicted functions. In this study, we sequenced the 3'UTR of TCF4 in 13 multiplex schizophrenia families and 14 control families. We found two functional variants carried by three unrelated patients. We determined that the C allele of rs1272363 and the TC insert of rs373174214 might suppress post- transcriptional expression. Secondly, we cloned the region that flanked these two variants into a dual luciferase reporter system and compared the luciferase activities between the pmirGLO-TCF4 (control), pmirGLO-TCF4-rs373174214 and pmirGLO-TCF4-rs1273263. Both pmirGLO-TCF4-rs373174214 and pmirGLO-TCF4-rs1273263 caused lower reporter gene activities, as compared to the control. However, only the C allele of rs1272363 reduced the luciferase activity significantly (p = 0.0231). Our results suggested that rs1273263 is a potential regulator of TCF4 expression, and might be associated with schizophrenia.

Assessment of Cognition in Schizophrenia Using Trail Making Test: A Meta-Analysis.

OBJECTIVE: The present meta-analysis aimed to analyze the cognitive performance of schizophrenia patients measured by Trail Making Tests (TMT) and the contribution of socio-demographic factors to cognitive impairments. METHODS: PubMed and PsycARTICLES databases were searched for the studies published between January 1985 and November 2017. Data were drawn from 19 studies encompassing 1095 patients and 324 controls. The effect size and heterogeneity were assessed with Comprehensive Meta-Analysis version 2 using random-effect model. RESULTS: Overall, the results showed that the schizophrenia patients performed significantly (p<0.001) worse than healthy controls in both TMT-A and B. However, concurrent substance abuse, clinical status (inpatient or outpatient), duration of education and duration of illness were not associated with cognitive impairment among the schizophrenia patients. CONCLUSION: The present meta-analysis confirmed the cognitive processing speed and flexibility of schizophrenia patients were impaired. However, their duration of education, duration of illness and clinical status (inpatient or outpatient) were not the risk factors.

Genetic Association of TCF4 and AKT1 Gene Variants with the Age at Onset of Schizophrenia.

BACKGROUND: Age at onset (AAO) is a known prognostic indicator for schizophrenia and is hypothesized to correlate with cognition and symptom severity. TCF4 and AKT1 are schizophrenia risk genes involved in cognitive functions. The current study examined the interactive effects of TCF4 and AKT1 variants with gender, family history of psychiatric disorders and ethnicity on the AAO of schizophrenia. METHODS: This study consisted of 322 patients with schizophrenia meeting the DSM-IV criteria. Six single nucleotide polymorphisms (SNPs) of TCF4 (rs12966547, rs8766, rs2958182, rs9960767, rs10401120 and rs17512836) and seven AKT1 SNPs (rs2498804, rs3803304, rs2494732, rs3730358, rs1130214, rs2498784 and rs3803300) were genotyped using the TaqMan® SNP genotyping-based assays method. The relationship of AAO with each variant was investigated using analyses of covariance. RESULTS: Among the TCF4 variants, rs12966547 (p = 0.024) and rs8766 (p = 0.021) were significantly associated with earlier AAO. We found a lower average AAO in patients with the AA genotype of rs12966547, while the CT genotype of rs8766 was demonstrated to have a protective effect on AAO. For rs8766, there was significant gene × gender interaction (p = 0.012) in influencing AAO. However, these results were not significant after false discovery rate correction. Significant gene × ethnicity interactions were observed to influence AAO (p < 0.05). The Kaplan-Meier curve of the minor AA genotype of rs12966547 displayed a significant trend (p = 0.008) for onset after 19 years of age. Similarly, the minor CC genotype of rs8766 showed a significantly (p = 0.034) lower AAO compared to the TT genotype. CONCLUSION: Our analyses suggest that individual risk genotypes may influence the risk of schizophrenia in an age-specific manner.

Genetic association of single nucleotide polymorphisms in dystrobrevin binding protein 1 gene with schizophrenia in a Malaysian population.

Dystrobrevin binding protein 1 (DTNBP1) gene is pivotal in regulating the glutamatergic system. Genetic variants of the DTNBP1 affect cognition and thus may be particularly relevant to schizophrenia. We therefore evaluated the association of six single nucleotide polymorphisms (SNPs) with schizophrenia in a Malaysian population (171 cases; 171 controls). Associations between these six SNPs and schizophrenia were tested in two stages. Association signals with p < 0.05 and minor allele frequency > 0.05 in stage 1 were followed by genotyping the SNPs in a replication phase (stage 2). Genotyping was performed with sequenced specific primer (PCR-SSP) and restriction fragment length polymorphism (PCR-RFLP). In our sample, we found significant associations between rs2619522 (allele p = 0.002, OR = 1.902, 95%CI = 1.266 - 2.859; genotype p = 0.002) and rs2619528 (allele p = 0.008, OR = 1.606, 95%CI = 1.130 - 2.281; genotype p = 6.18 × 10(-5)) and schizophrenia. Given that these two SNPs may be associated with the pathophysiology of schizophrenia, further studies on the other DTNBP1 variants are warranted.

No association between AKT1 gene variants and schizophrenia: a Malaysian case-control study and meta-analysis.

We aim to replicate AKT1 gene variants studies using Malaysian samples. Seven AKT1 single nucleotide polymorphisms (SNPs) were studied in 417 patients and 429 controls. Haplotype showed significant association (p=0.036) with schizophrenia, especially in Malays and Indians. Meta-analysis of rs2494732 showed significant association worldwide (p=0.018) and in Asians (p=0.023).

Neuregulin-1 (NRG-1) and its susceptibility to schizophrenia: a case-control study and meta-analysis.

Neuregulin-1 is widely investigated due to its hypothesised association with schizophrenia. Single-nucleotide polymorphisms rs764059, rs2954041 and rs3924999 were investigated (417 patients with schizophrenia and 429 controls). We failed to demonstrate a significant association between rs2954041 and rs3924999 with schizophrenia in the three ethnic groups studied (Malay, Chinese, and Indian), while rs764059 was found to be monomorphic.

COMT haplotype analyses in Malaysians with schizophrenia.

The present study included a total 261 patients with schizophrenia and 261 healthy controls to replicate the genetic association between the cathechol-o-methyltransferase gene and schizophrenia using a haplotype block-based gene-tagging. The G-G-G haplotype was found to show a highly significant association with schizophrenia.