Accessing Gene Expression in Treatment-Resistant Schizophrenia.

Schizophrenia (SCZ) is a mental disorder arising from a complex interaction of genetic and environmental factors. It has been suggested that treatment-resistant schizophrenia (TRS) is a distinct, more severe, and homogenous subgroup of schizophrenia that could present specific biological markers. Our aim was to characterize expression of target genes in blood of TRS patients compared with non-TRS (NTRS) patients and healthy controls (HC). TRS has been defined using failure to respond to two previous antipsychotic trials. We hypothesized that genes involved in neurodevelopment, myelination, neuroplasticity, neurotransmission, and miRNA processing could be involved in treatment resistance; then, we investigated 13 genes related to those processes in 256 subjects, being 94 healthy controls and 162 schizophrenia patients treated with antipsychotics. Of those, 78 were TRS patients and 84 were NTRS patients. Peripheral blood samples were collected from all subjects and RNA was isolated. Gene expression analysis was performed using the TaqMan low-density array (TLDA) technology. To verify the influence of expression quantitative trait loci (eQTLs), we evaluated single-nucleotide polymorphism (SNP) of all genes using data from GTEx Project. SNP genotypes were obtained from HumanOmniExpress BeadChip. We did not detect gene expression differences between TRS and NTRS subjects, indicating candidate genes specific to treatment resistance. We detected an upregulation of CNR1 and UFD1L gene expression in patients (TRS and NTRS groups) when compared to controls, that may be associated with the release of neurotransmitters, which can influence neuronal plasticity, or with a stress response-activating protein degradation. DICER1 and AKT1 expression increased slightly across the groups and could differentiate only the extreme opposite groups, HC and TRS. Both genes act in heterogeneous pathways, such as cell signaling and miRNA processing, and seem to have an increased demand in the TRS group. We did not detect any eQTLs in our sample that could explain differences in mRNA levels, suggesting a possible regulation by other mechanism, not driven by genotypes. Our data strengthen the importance of several biological pathways involved in the schizophrenia refractoriness and severity, adding knowledge to develop more effective treatments in the future.

Leukocyte telomere length variation in different stages of schizophrenia.

Recent research has demonstrated that telomere maintenance might be a key integrating point for the cumulative effect of genetic and environmental factors in patients with first-episode psychosis (FEP) and schizophrenia (SCZ). Eighty-one participants with antipsychotic-naïve FEP, 173 with SCZ and 438 HC were enrolled in this study. Psychiatric diagnosis was assessed using the Semi-Structured Clinical Interview for DSM-IV Axis-I (SCID-I). The Positive and Negative Syndrome Scale (PANSS), Young Mania Rating Scale (YMRS) and Calgary Depression Scale for Schizophrenia (CDSS) were used to measure symptoms severity. Telomere length (TL) was determined using a multiplex qPCR assay. After adjustment for age, years of education, and smoking status, we found that patients with SCZ had longer TL (relative ratio (RR) = 1.08) than the HC group (RR = 1.00, Wald χ2 = 12.48, p = 0.002). Further, non-remitted SCZ patients presented longer TL (RR = 1.00) compared to remitted SCZ (RR = 0.88, Wald χ2 = 7.20, p = 0.007). TL in patients also correlated to psychopathology assessment in terms of total (p = 0.003) and positive PANSS scores (p = 0.001). No correlation with negative PANSS, YMRS, and CDSS or effects of medication was found on TL. Although the exact pathways underlying longer TL in SCZ patients remain unclear, these findings raise more questions than answers and suggest that TL may be of immense value on SCZ progression. Further studies are required to investigate the association of TL in FEP and SCZ.

The role of the CNR1 gene in schizophrenia: a systematic review including unpublished data

Objective: Schizophrenia is a multifactorial disorder. It is known that a combination of extensive multiple common alleles may be involved in its etiology, each contributing with a small to moderate effect, and, possibly, some rare alleles with a much larger effect size. We aimed to perform a systematic review of association studies between schizophrenia (and its subphenotypes) and polymorphisms in the CNR1 gene, which encodes cannabinoid receptors classically implicated in schizophrenia pathophysiology, as well as to present unpublished results of an association study in a Brazilian population. Methods: Two reviewers independently searched for eligible studies and extracted outcome data using a structured form. Papers were retrieved from PubMed and ISI Web of Knowledge using the search term schizophrenia in combination with CNR1 or CB1 or cannabinoid receptor. Twenty-four articles met our inclusion criteria. We additionally present data from a study of our own comparing 182 patients with schizophrenia and 244 healthy controls. Results: No consistent evidence is demonstrated. Conclusion: Some seemingly positive association studies stress the need for further investigations of the possible role of endocannabinoid genetics in schizophrenia.

The role of the CNR1 gene in schizophrenia: a systematic review including unpublished data.

OBJECTIVE:: Schizophrenia is a multifactorial disorder. It is known that a combination of extensive multiple common alleles may be involved in its etiology, each contributing with a small to moderate effect, and, possibly, some rare alleles with a much larger effect size. We aimed to perform a systematic review of association studies between schizophrenia (and its subphenotypes) and polymorphisms in the CNR1 gene, which encodes cannabinoid receptors classically implicated in schizophrenia pathophysiology, as well as to present unpublished results of an association study in a Brazilian population. METHODS:: Two reviewers independently searched for eligible studies and extracted outcome data using a structured form. Papers were retrieved from PubMed and ISI Web of Knowledge using the search term schizophrenia in combination with CNR1 or CB1 or cannabinoid receptor. Twenty-four articles met our inclusion criteria. We additionally present data from a study of our own comparing 182 patients with schizophrenia and 244 healthy controls. RESULTS:: No consistent evidence is demonstrated. CONCLUSION:: Some seemingly positive association studies stress the need for further investigations of the possible role of endocannabinoid genetics in schizophrenia.

Bipolar disorder course, impaired glucose metabolism and antioxidant enzymes activities: A preliminary report.

This study aimed to examine the role of oxidative stress in bipolar disorder (BD) by evaluating the relationship among antioxidant enzymes activities, impaired glucose metabolism (IGM) and illness course. We measured the activities of plasma superoxide dismutase (SOD) and glutathione peroxidase (GPx) in individuals with BD (N = 55) and healthy controls (N = 28). Information related to current and past psychiatric/medical history, as well as prescription of any pharmacological treatments was captured. Impaired glucose metabolism was operationalized as pre-diabetes or type 2 diabetes mellitus. Our results showed that, after adjustment for age, gender, alcohol use, smoking and current medication, both BD (p < 0.001) and IGM (p = 0.019) were associated with increased GPx activity, whereas only BD was associated with decreased SOD activity (p = 0.008). We also observed an interaction between BD and IGM on SOD activity (p = 0.017), whereas the difference between BD and controls was only significant in individuals with IGM (p = 0.009). IGM, GPx and SOD activity were independently associated with variables of illness course. Moreover, IGM moderated the association between SOD activity and number of mood episodes (p < 0.001), as a positive correlation between SOD activity and mood episodes was observed only in participants with IGM. In conclusion, BD and IGM are associated with independent and synergistic effects on markers of oxidative stress. The foregoing observations suggest that the heterogeneity observed in previous studies evaluating antioxidant enzymes in BD may be a function of concurrent IGM; and that imbalances in the oxidative system may subserve the association between BD and IGM, as well as its relationship with illness course.

Effects of risperidone on cytokine profile in drug-naïve first-episode psychosis.

BACKGROUND: There is robust evidence that schizophrenia is characterized by immune-inflammatory abnormalities, including variations on cytokine levels. The results of previous studies, however, are heterogeneous due to several confounding factors, such as the effects of antipsychotic drugs. Therefore, research on drug-naïve first-episode psychosis (FEP) patients is essential to elucidate the role of immune processes in that disorder. METHODS: The aim of this study is to compare cytokine levels (IL-2, IL-10, IL-4, IL-6, IFN-γ, TNF-α, and IL-17) in drug-naïve FEP patients both before and after treatment with risperidone for 10 weeks, and to investigate possible associations between cytokine levels and clinical responses to treatment and presence of depressive symptoms. It this study, we included 55 drug-naïve FEP patients who had repeated measurements of cytokine levels and 57 healthy controls. RESULTS: We found that FEP patients had significantly higher IL-6, IL-10 and TNF-α levels than healthy controls. After risperidone treatment, these three cytokines and additionally IL-4 decreased significantly. No significant difference was found between the post-treatment cytokine levels in FEP patients and in healthy controls, suggesting that these alterations in cytokine profiles are a state marker of FEP. No significant association was found between risperidone-induced changes in cytokines and the clinical response to treatment or the presence of depression. There was a significant inverse association between the risperidone-induced changes in IL-10 and the negative symptoms. CONCLUSIONS: In conclusion, our results show a specific cytokine profile in FEP patients (monocytic and regulatory T-cell activation) and suggest immunoregulatory effects of risperidone treatment, characterized by suppressant effects on monocytic, Th2, and T-regulatory functions.