Accessing Gene Expression in Treatment-Resistant Schizophrenia

Abstract

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.

Haplotypic and Genotypic Association of Catechol-O-Methyltransferase rs4680 and rs4818 Polymorphisms and Treatment Resistance in Schizophrenia

“…In our study, both male and female patients with TRS had significantly higher PANSS total, positive, negative, and general psychopathology scores, as well as higher chlorpromazine equivalent doses in comparison to male and female patients in non-TRS group. This is in agreement with previous studies reporting that patients with TRS had more severe symptomatology as measured by PANSS ( Moretti et al, 2018 ) and received higher total antipsychotic dose presented as chlorpromazine equivalents, compared to patients with non-TRS ( Hotta et al, 2011 ; de Bartolomeis et al, 2018 ; Moretti et al, 2018 ). In the present study, the concentration of antipsychotics in plasma was not measured.…”

“…et al, 2011 ). Moreover, there were no differences between patients with and without TRS in the whole-blood gene expression of 13 genes, including COMT gene ( Moretti et al, 2018 ).…”

Distinguishing Between Treatment-Resistant and Non-Treatment-Resistant Schizophrenia Using Regional Homogeneity

“…By contrast, increased ReHo was found in the left postcentral gyrus in TRS compared with NTRS, and decreased ReHo was observed in the left postcentral gyrus in NTRS relative to HCs. In line with our findings, Gong et al ( 30 ) revealed that Disrupted in Schizophrenia Gene 1 (DISC1) was related to the postcentral gyrus, suggesting that TRS may have distinct heredity as a special subgroup ( 4 ). Moreover, by using positron emission tomography, Monika et al ( 25 ) discovered that the bilateral postcentral gyrus in patients with auditory hallucination showed increased metabolism, indicating that this region is a cue for explaining the increased ReHo values and symptoms.…”

“…Treatment-resistant schizophrenia (TRS) is characterized by the lack of response to two kinds of antipsychotics at doses ≥ 400 mg/day equivalents of chlorpromazine for a minimum period of 4–6 weeks, and with continuing moderate to severe psychopathology (especially positive symptoms) ( 3 ). TRS has been regarded as a severe and homogenous subgroup of schizophrenia that presents specific biological markers ( 4 ).…”

The neurobiology of treatment-resistant schizophrenia: paths to antipsychotic resistance and a roadmap for future research

“…62 A study comparing gene expression among patients with TRS, patients with treatment-responsive schizophrenia, and healthy controls found no difference between the groups with schizophrenia in the expression of 13 candidate genes, including COMT. 63 Although there are inconsistencies and variability among the results of some of these highlighted studies, several candidates for the biological mechanisms or subtypes of TRS require further research. Additional studies are needed to further characterize these candidate biological mechanisms and to identify new treatment targets.…”