Activated immune-inflammatory pathways play an important role in the pathophysiology of schizophr... more Activated immune-inflammatory pathways play an important role in the pathophysiology of schizophrenia. Paraoxonase 1 (PON1) activity is inversely associated with inflammatory responses in numerous clinical conditions. The aims of this study were to delineate serum arylesterase PON1 activity in drug-naïve first episode psychosis (FEP) patients and a healthy control group, and to assess whether there are inverse relationships between PON1 activity and cytokine levels. A total of 51 drug-naïve FEP patients and 61 healthy controls were enrolled in this study. Levels of interleukin (IL)-4, IL-10, IL-6, tumor necrosis factor (TNF)-α and activity of PON1 were quantified. Compared to healthy controls, FEP patients showed lower serum PON1 activity and higher levels of IL-4, IL-10 and TNF-α. A significant inverse relationship between PON1 activity and IL-4, IL-6 and IL-10 levels was detected, but not for TNF-α. Subjects with very low PON1 activity (25th quartile) presented significantly highe...
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 2014
There is robust evidence that schizophrenia is characterized by immune-inflammatory abnormalities... more 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. 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. We found that FEP patients had significantly higher IL-6, IL-10 and TNF-α levels than healthy controls. After ri...
Schizophrenia is accompanied by alterations in immuno-inflammatory pathways, including abnormalit... more Schizophrenia is accompanied by alterations in immuno-inflammatory pathways, including abnormalities in cytokine profile. The immune assessment of patients in a first episode of psychosis (FEP) and particularly in drug naïve patients is very important to further elucidate this association. The objectives of this study are to delineate the cytokine profile (IL-2, IL-10, IL-4, IL-6, IFNγ, TNFα and IL-17) in FEP patients (n = 55) versus healthy controls (n = 57) and to examine whether the presence of depressive symptoms in FEP is accompanied by a specific cytokine profile. We found increased levels of IL-6, IL-10 and TNFα in FEP patients when compared to healthy controls. FEP patients with depression showed higher IL-4 and TNFα levels versus those without depression. Cytokine levels were not correlated to the total PANSS and the positive or negative subscale scores. Our results suggest that FEP is accompanied by a cytokine profile indicative of monocytic and T regulatory cell (Treg) activation. Depression in FEP is accompanied by monocytic and Th-2 activation, whereas FEP without depression is characterized by Treg activation only. In conclusion, depression emerged as a key component explaining the cytokines imbalance in FEP that is responsible for a large part of the immune-inflammatory abnormalities described.
Angiotensin-I converting enzyme (ACE) is a key component of the renin-angiotensin system (RAS). A... more Angiotensin-I converting enzyme (ACE) is a key component of the renin-angiotensin system (RAS). Although the several contradictory data, ACE has been associated with schizophrenia (SCZ) pathophysiology. Here the ACE activity of SCZ patients and healthy controls (HCs), and its possible correlations with the ACE polymorphism genotype and symptomatic dimensions, was investigated. ACE activity of 86 SCZ patients and 100 HCs paired by age, gender and educational level was measured, using the FRET peptide substrate and the specific inhibitor lisinopril. The ACE insertion/deletion (I/D) genotypes were assessed by the restriction fragment length polymorphism (RFLP) technique. Significantly higher ACE activity was observed in SCZ patients compared to HCs (t=-5.09; p<0.001). The area under the receiver operating characteristic (ROC) curve was 0.701. Mean ACE activity levels were higher for the D-allele carriers (F=5.570; p=0.005), but no significant difference was found among SCZ patients and HCs for genotypes frequencies (Chi-squared=2.08; df=2; p=0.35). Interestingly, we found that the difference between the measured ACE activity for each SCZ patient and the expected average mean value for each respective genotype group (for control subjects) was a better predictor of SCZ than the ACE dichotomized values (high/low) or ACE I/D. Our results suggest that higher levels of ACE activity are associated with SCZ with stronger impact when the genetic background of each individual is considered. This may explain the heterogeneity of the results on ACE previously reported.
Schizophrenia is a neurodevelopmental disorder with high heritability. Several lines of evidence ... more Schizophrenia is a neurodevelopmental disorder with high heritability. Several lines of evidence indicate that the PRODH gene may be related to the disorder. Therefore, our study investigates the effects of 12 polymorphisms of PRODH on schizophrenia and its phenotypes. To further evaluate the roles of the associated variants in the disorder, we have conducted magnetic resonance imaging (MRI) scans to assess cortical volumes and thicknesses. A total of 192 patients were evaluated using the Structured Clinical Interview for DSM-IV (SCID), Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale, Global Assessment of Functioning (GAF) and Clinical Global Impression (CGI) instruments. The study included 179 controls paired by age and gender. The samples were genotyped using the real-time polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP)-PCR and Sanger sequencing methods. A sample of 138 patients and 34 healthy controls underwent MRI scans. One polymorphism was associated with schizophrenia (rs2904552),
Schizophrenia is a severe mental health disorder with high heritability. The investigation of ind... more Schizophrenia is a severe mental health disorder with high heritability. The investigation of individuals during their first-episode psychosis (FEP), before the progression of psychotic disorders and especially before treatment with antipsychotic medications, is particularly helpful for understanding this complex disease and for the identification of potential biomarkers. In this study, we compared the expression of genes that are involved in neurotransmission and neurodevelopment of antipsychotic-naive FEP in the peripheral blood of patients (n=51) and healthy controls (n=51). In addition, we investigated the differentially expressed genes with respect to a) DNA methylation, b) the correlation between gene expression and clinical variables (PANSS), and c) gene expression changes after risperidone treatment. Expression levels of 11 genes were quantified with SYBR Green. For methylation analysis, bisulfite sequencing was performed. A significant decrease in GCH1 mRNA levels was obser...
drugs (APDs) are the standard treatment for schizophrenia. The therapeutic effect of these drugs ... more drugs (APDs) are the standard treatment for schizophrenia. The therapeutic effect of these drugs is dependent upon the dopaminergic D2 blockade, but they also modulate other neurotransmitter pathways. The exact mechanisms underlying the clinical response to APDs are not fully understood. In this study, we compared three groups of animals for the expression of 84 neurotransmitter genes in the prefrontal cortex (PFC) and nucleus accumbens (NAcc). Each group was treated with a different APD (risperidone, clozapine or haloperidol), and with a non-treated group of spontaneously hypertensive rats (SHRs), which is an animal model for schizophrenia. This study also explored whether or not differential expression was regulated by DNA methylation in the promoter region (PR). In the clozapine group, we found that Chrng was downregulated in the NAcc and six genes were downregulated in the PFC. In the haloperidol group, Brs3 and Glra1 were downregulated, as was Drd2 in the clozapine group and Drd3, Galr3 and Gabrr1 in the clozapine and haloperidol groups. We also encountered four hypermethylated CG sites in the Glra1 PR, as well as three in the risperidone group and another in the haloperidol group, when compared to non-treated rats. Following the APD treatment, the gene expression results revealed the involvement of genes that had not previously been described, in addition to the activity of established genes. The investigation of the involvement of these novel genes can lead to better understanding about the specific mechanisms of action of the individual APDs studied.
The spontaneously hypertensive rat (SHR) strain was shown to be a useful animal model to study se... more The spontaneously hypertensive rat (SHR) strain was shown to be a useful animal model to study several behavioral, pathophysiological and pharmacological aspects of schizophrenia and attention-deficit/ hyperactivity disorder. To further understand the genetic underpinnings of this model, our primary goal in this study was to compare the gene expression profile of neurotransmitter receptors and regulators in the prefrontal cortex (PFC) and nucleus accumbens (NAcc) of SHR and Wistar rats (control group). In addition, we investigated DNA methylation pattern of promoter region of the genes differentially expressed. We performed gene expression analysis using a PCRarray technology, which simultaneously measures the expression of 84 genes related to neurotransmission. Four genes were significantly downregulated in the PFC of SHR compared to Wistar rats (Gad2, Chrnb4, Slc5a7, and Qrfpr) and none in nucleus accumbens. Gad2 and Qrfpr have CpG islands in their promoter region. For both, the promoter region was hypomethylated in SHR group, and probably this mechanism is not related with the downregulation of these genes. In summary, we identified genes that are downregulated in the PFC of SHR, and might be related to the behavioral abnormalities exhibited by this strain.
A study of the gene expression levels in the blood of individuals with schizophrenia in the begin... more A study of the gene expression levels in the blood of individuals with schizophrenia in the beginning of the disease, such as first-episode psychosis (FEP), is useful to detect gene expression changes in this disorder in response to treatment. Although a large number of genetic studies on schizophrenia have been conducted, little is known about the effects of antipsychotic treatment on gene expression. The aim of the present study was to examine differences in the gene expression in the blood of antipsychoticnaïve FEP patients before and after risperidone treatment (N ¼ 44) and also to verify the correlation with treatment response. In addition, we determined the correlations between differentially expressed genes and clinical variables. The expression of 40 neurotransmitter and neurodevelopment-associated genes was assessed using the RT 2 Profiler™ PCR Array. The results indicated that the GABRR2 gene was downregulated after risperidone treatment, but no genes were associated with response to treatment and clinical variables after Bonferroni correction. GABRR2 downregulation after treatment can both suggest an effect of risperidone treatment or processes related to disease progression, either not necessarily associated with the improvement of symptoms. Despite this change was observed in blood, this decrease in GABRR2 mRNA levels might be an effect of changes in GABA concentrations or other systems interplay consequently to D2 blockage induced by risperidone, for example. Thus, it is important
Child maltreatment is associated with an increased risk of psychiatric disorders, and a range of ... more Child maltreatment is associated with an increased risk of psychiatric disorders, and a range of health problems later in life. Research suggests that adverse events early in life can lead to changes in gene expression through epigenetic mechanisms that alter stress reactivity, brain function, and behaviour. Although epigenetic changes are often long lasting, they can be reversed with pharmacological and environmental manipulations. The complexity of the epigenome is not fully understood. The aim of this Review is to assess emerging data for the role of epigenetic mechanisms in stress-related psychiatric disorders with a focus on future research. We describe the epigenetic processes, key fi ndings in this specialty, clinical implications of research, and methodological issues. Studies are needed to investigate new epigenetic processes other than methylation and assess the effi cacy of interventions to reverse epigenetic processes associated with the eff ects of early life adversity. Lancet Psychiatry 2014; 2: 461-66 McGill Group for Suicide Studies,
Little is known about how genes expressed in blood relate to schizophrenia or antipsychotic use. ... more Little is known about how genes expressed in blood relate to schizophrenia or antipsychotic use. We analyzed gene expression in 10 first-episode psychosis patients and nine controls using PCR Arrays. GABRR2 and CHRNA3 were found to be differentially expressed after risperidone treatment. These genes may be regulated by antipsychotic use.
We investigated the association of dopamine receptor D1 gene (DRD1) rs4532 polymorphism with anti... more We investigated the association of dopamine receptor D1 gene (DRD1) rs4532 polymorphism with antipsychotic treatment response in schizophrenia. We have analyzed 124 patients with schizophrenia, consisting of 59 treatment resistant (TR) and 65 non-TR. We found an association between G-allele and TR schizophrenia (p = 0.001; adjusted OR= 2.71). Setting the common AA-genotype as reference, the GG-homozygous presented a five-fold risk compared to AA-homozygous (p = 0.010; OR= 5.56) with an intermediate result for AG-genotype (p = 0.030; adjusted OR= 2.64). The DRD1 rs4532 polymorphism showed a dose-response gradient with increased risk for treatment resistance and may be a potential pharmacogenetic marker for antipsychotic drug treatment response.
Background: Treatment resistance affects up to one third of patients with schizophrenia (SCZ). A ... more Background: Treatment resistance affects up to one third of patients with schizophrenia (SCZ). A better understanding of its biological underlying processes could improve treatment. The aim of this study was to compare cortical thickness between non-resistant SCZ (NR-SCZ), treatment-resistant SCZ (TR-SCZ) patients and healthy controls (HC). Methodology: Structural MRI scans were obtained from 3 groups of individuals: 61 treatment resistant SCZ individuals, 67 non-resistant SCZ and 80 healthy controls. Images were analyzed using cortical surface modelling (implemented in freesurfer package) to identify group differences in cortical thickness. Statistical significant differences were identified using Monte-Carlo simulation method with a corrected p-cluster b 0.01. Results: Patients in the TR-SCZ group showed a widespread reduction in cortical thickness in frontal, parietal, temporal and occipital regions bilaterally. NR-SCZ group had reduced cortex in two regions (left superior frontal cortex and left caudal middle frontal cortex). TR-SCZ group also showed decreased thickness in the left dorsolateral prefrontal cortex (DLPFC) when compared with patients from NR-SCZ group. Conclusions: The reduction in cortical thickness in DLPFC indicates a more severe form of the disease or a specific finding for this group. Alterations in this region should be explored as a putative marker for treatment resistance. Prospective studies, with individuals being followed from first episode psychosis until refractoriness is diagnosed, are needed to clarify these hypotheses.
Activated immune-inflammatory pathways play an important role in the pathophysiology of schizophr... more Activated immune-inflammatory pathways play an important role in the pathophysiology of schizophrenia. Paraoxonase 1 (PON1) activity is inversely associated with inflammatory responses in numerous clinical conditions. The aims of this study were to delineate serum arylesterase PON1 activity in drug-naïve first episode psychosis (FEP) patients and a healthy control group, and to assess whether there are inverse relationships between PON1 activity and cytokine levels. A total of 51 drug-naïve FEP patients and 61 healthy controls were enrolled in this study. Levels of interleukin (IL)-4, IL-10, IL-6, tumor necrosis factor (TNF)-α and activity of PON1 were quantified. Compared to healthy controls, FEP patients showed lower serum PON1 activity and higher levels of IL-4, IL-10 and TNF-α. A significant inverse relationship between PON1 activity and IL-4, IL-6 and IL-10 levels was detected, but not for TNF-α. Subjects with very low PON1 activity (25th quartile) presented significantly highe...
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 2014
There is robust evidence that schizophrenia is characterized by immune-inflammatory abnormalities... more 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. 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. We found that FEP patients had significantly higher IL-6, IL-10 and TNF-α levels than healthy controls. After ri...
Schizophrenia is accompanied by alterations in immuno-inflammatory pathways, including abnormalit... more Schizophrenia is accompanied by alterations in immuno-inflammatory pathways, including abnormalities in cytokine profile. The immune assessment of patients in a first episode of psychosis (FEP) and particularly in drug naïve patients is very important to further elucidate this association. The objectives of this study are to delineate the cytokine profile (IL-2, IL-10, IL-4, IL-6, IFNγ, TNFα and IL-17) in FEP patients (n = 55) versus healthy controls (n = 57) and to examine whether the presence of depressive symptoms in FEP is accompanied by a specific cytokine profile. We found increased levels of IL-6, IL-10 and TNFα in FEP patients when compared to healthy controls. FEP patients with depression showed higher IL-4 and TNFα levels versus those without depression. Cytokine levels were not correlated to the total PANSS and the positive or negative subscale scores. Our results suggest that FEP is accompanied by a cytokine profile indicative of monocytic and T regulatory cell (Treg) activation. Depression in FEP is accompanied by monocytic and Th-2 activation, whereas FEP without depression is characterized by Treg activation only. In conclusion, depression emerged as a key component explaining the cytokines imbalance in FEP that is responsible for a large part of the immune-inflammatory abnormalities described.
Angiotensin-I converting enzyme (ACE) is a key component of the renin-angiotensin system (RAS). A... more Angiotensin-I converting enzyme (ACE) is a key component of the renin-angiotensin system (RAS). Although the several contradictory data, ACE has been associated with schizophrenia (SCZ) pathophysiology. Here the ACE activity of SCZ patients and healthy controls (HCs), and its possible correlations with the ACE polymorphism genotype and symptomatic dimensions, was investigated. ACE activity of 86 SCZ patients and 100 HCs paired by age, gender and educational level was measured, using the FRET peptide substrate and the specific inhibitor lisinopril. The ACE insertion/deletion (I/D) genotypes were assessed by the restriction fragment length polymorphism (RFLP) technique. Significantly higher ACE activity was observed in SCZ patients compared to HCs (t=-5.09; p<0.001). The area under the receiver operating characteristic (ROC) curve was 0.701. Mean ACE activity levels were higher for the D-allele carriers (F=5.570; p=0.005), but no significant difference was found among SCZ patients and HCs for genotypes frequencies (Chi-squared=2.08; df=2; p=0.35). Interestingly, we found that the difference between the measured ACE activity for each SCZ patient and the expected average mean value for each respective genotype group (for control subjects) was a better predictor of SCZ than the ACE dichotomized values (high/low) or ACE I/D. Our results suggest that higher levels of ACE activity are associated with SCZ with stronger impact when the genetic background of each individual is considered. This may explain the heterogeneity of the results on ACE previously reported.
Schizophrenia is a neurodevelopmental disorder with high heritability. Several lines of evidence ... more Schizophrenia is a neurodevelopmental disorder with high heritability. Several lines of evidence indicate that the PRODH gene may be related to the disorder. Therefore, our study investigates the effects of 12 polymorphisms of PRODH on schizophrenia and its phenotypes. To further evaluate the roles of the associated variants in the disorder, we have conducted magnetic resonance imaging (MRI) scans to assess cortical volumes and thicknesses. A total of 192 patients were evaluated using the Structured Clinical Interview for DSM-IV (SCID), Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale, Global Assessment of Functioning (GAF) and Clinical Global Impression (CGI) instruments. The study included 179 controls paired by age and gender. The samples were genotyped using the real-time polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP)-PCR and Sanger sequencing methods. A sample of 138 patients and 34 healthy controls underwent MRI scans. One polymorphism was associated with schizophrenia (rs2904552),
Schizophrenia is a severe mental health disorder with high heritability. The investigation of ind... more Schizophrenia is a severe mental health disorder with high heritability. The investigation of individuals during their first-episode psychosis (FEP), before the progression of psychotic disorders and especially before treatment with antipsychotic medications, is particularly helpful for understanding this complex disease and for the identification of potential biomarkers. In this study, we compared the expression of genes that are involved in neurotransmission and neurodevelopment of antipsychotic-naive FEP in the peripheral blood of patients (n=51) and healthy controls (n=51). In addition, we investigated the differentially expressed genes with respect to a) DNA methylation, b) the correlation between gene expression and clinical variables (PANSS), and c) gene expression changes after risperidone treatment. Expression levels of 11 genes were quantified with SYBR Green. For methylation analysis, bisulfite sequencing was performed. A significant decrease in GCH1 mRNA levels was obser...
drugs (APDs) are the standard treatment for schizophrenia. The therapeutic effect of these drugs ... more drugs (APDs) are the standard treatment for schizophrenia. The therapeutic effect of these drugs is dependent upon the dopaminergic D2 blockade, but they also modulate other neurotransmitter pathways. The exact mechanisms underlying the clinical response to APDs are not fully understood. In this study, we compared three groups of animals for the expression of 84 neurotransmitter genes in the prefrontal cortex (PFC) and nucleus accumbens (NAcc). Each group was treated with a different APD (risperidone, clozapine or haloperidol), and with a non-treated group of spontaneously hypertensive rats (SHRs), which is an animal model for schizophrenia. This study also explored whether or not differential expression was regulated by DNA methylation in the promoter region (PR). In the clozapine group, we found that Chrng was downregulated in the NAcc and six genes were downregulated in the PFC. In the haloperidol group, Brs3 and Glra1 were downregulated, as was Drd2 in the clozapine group and Drd3, Galr3 and Gabrr1 in the clozapine and haloperidol groups. We also encountered four hypermethylated CG sites in the Glra1 PR, as well as three in the risperidone group and another in the haloperidol group, when compared to non-treated rats. Following the APD treatment, the gene expression results revealed the involvement of genes that had not previously been described, in addition to the activity of established genes. The investigation of the involvement of these novel genes can lead to better understanding about the specific mechanisms of action of the individual APDs studied.
The spontaneously hypertensive rat (SHR) strain was shown to be a useful animal model to study se... more The spontaneously hypertensive rat (SHR) strain was shown to be a useful animal model to study several behavioral, pathophysiological and pharmacological aspects of schizophrenia and attention-deficit/ hyperactivity disorder. To further understand the genetic underpinnings of this model, our primary goal in this study was to compare the gene expression profile of neurotransmitter receptors and regulators in the prefrontal cortex (PFC) and nucleus accumbens (NAcc) of SHR and Wistar rats (control group). In addition, we investigated DNA methylation pattern of promoter region of the genes differentially expressed. We performed gene expression analysis using a PCRarray technology, which simultaneously measures the expression of 84 genes related to neurotransmission. Four genes were significantly downregulated in the PFC of SHR compared to Wistar rats (Gad2, Chrnb4, Slc5a7, and Qrfpr) and none in nucleus accumbens. Gad2 and Qrfpr have CpG islands in their promoter region. For both, the promoter region was hypomethylated in SHR group, and probably this mechanism is not related with the downregulation of these genes. In summary, we identified genes that are downregulated in the PFC of SHR, and might be related to the behavioral abnormalities exhibited by this strain.
A study of the gene expression levels in the blood of individuals with schizophrenia in the begin... more A study of the gene expression levels in the blood of individuals with schizophrenia in the beginning of the disease, such as first-episode psychosis (FEP), is useful to detect gene expression changes in this disorder in response to treatment. Although a large number of genetic studies on schizophrenia have been conducted, little is known about the effects of antipsychotic treatment on gene expression. The aim of the present study was to examine differences in the gene expression in the blood of antipsychoticnaïve FEP patients before and after risperidone treatment (N ¼ 44) and also to verify the correlation with treatment response. In addition, we determined the correlations between differentially expressed genes and clinical variables. The expression of 40 neurotransmitter and neurodevelopment-associated genes was assessed using the RT 2 Profiler™ PCR Array. The results indicated that the GABRR2 gene was downregulated after risperidone treatment, but no genes were associated with response to treatment and clinical variables after Bonferroni correction. GABRR2 downregulation after treatment can both suggest an effect of risperidone treatment or processes related to disease progression, either not necessarily associated with the improvement of symptoms. Despite this change was observed in blood, this decrease in GABRR2 mRNA levels might be an effect of changes in GABA concentrations or other systems interplay consequently to D2 blockage induced by risperidone, for example. Thus, it is important
Child maltreatment is associated with an increased risk of psychiatric disorders, and a range of ... more Child maltreatment is associated with an increased risk of psychiatric disorders, and a range of health problems later in life. Research suggests that adverse events early in life can lead to changes in gene expression through epigenetic mechanisms that alter stress reactivity, brain function, and behaviour. Although epigenetic changes are often long lasting, they can be reversed with pharmacological and environmental manipulations. The complexity of the epigenome is not fully understood. The aim of this Review is to assess emerging data for the role of epigenetic mechanisms in stress-related psychiatric disorders with a focus on future research. We describe the epigenetic processes, key fi ndings in this specialty, clinical implications of research, and methodological issues. Studies are needed to investigate new epigenetic processes other than methylation and assess the effi cacy of interventions to reverse epigenetic processes associated with the eff ects of early life adversity. Lancet Psychiatry 2014; 2: 461-66 McGill Group for Suicide Studies,
Little is known about how genes expressed in blood relate to schizophrenia or antipsychotic use. ... more Little is known about how genes expressed in blood relate to schizophrenia or antipsychotic use. We analyzed gene expression in 10 first-episode psychosis patients and nine controls using PCR Arrays. GABRR2 and CHRNA3 were found to be differentially expressed after risperidone treatment. These genes may be regulated by antipsychotic use.
We investigated the association of dopamine receptor D1 gene (DRD1) rs4532 polymorphism with anti... more We investigated the association of dopamine receptor D1 gene (DRD1) rs4532 polymorphism with antipsychotic treatment response in schizophrenia. We have analyzed 124 patients with schizophrenia, consisting of 59 treatment resistant (TR) and 65 non-TR. We found an association between G-allele and TR schizophrenia (p = 0.001; adjusted OR= 2.71). Setting the common AA-genotype as reference, the GG-homozygous presented a five-fold risk compared to AA-homozygous (p = 0.010; OR= 5.56) with an intermediate result for AG-genotype (p = 0.030; adjusted OR= 2.64). The DRD1 rs4532 polymorphism showed a dose-response gradient with increased risk for treatment resistance and may be a potential pharmacogenetic marker for antipsychotic drug treatment response.
Background: Treatment resistance affects up to one third of patients with schizophrenia (SCZ). A ... more Background: Treatment resistance affects up to one third of patients with schizophrenia (SCZ). A better understanding of its biological underlying processes could improve treatment. The aim of this study was to compare cortical thickness between non-resistant SCZ (NR-SCZ), treatment-resistant SCZ (TR-SCZ) patients and healthy controls (HC). Methodology: Structural MRI scans were obtained from 3 groups of individuals: 61 treatment resistant SCZ individuals, 67 non-resistant SCZ and 80 healthy controls. Images were analyzed using cortical surface modelling (implemented in freesurfer package) to identify group differences in cortical thickness. Statistical significant differences were identified using Monte-Carlo simulation method with a corrected p-cluster b 0.01. Results: Patients in the TR-SCZ group showed a widespread reduction in cortical thickness in frontal, parietal, temporal and occipital regions bilaterally. NR-SCZ group had reduced cortex in two regions (left superior frontal cortex and left caudal middle frontal cortex). TR-SCZ group also showed decreased thickness in the left dorsolateral prefrontal cortex (DLPFC) when compared with patients from NR-SCZ group. Conclusions: The reduction in cortical thickness in DLPFC indicates a more severe form of the disease or a specific finding for this group. Alterations in this region should be explored as a putative marker for treatment resistance. Prospective studies, with individuals being followed from first episode psychosis until refractoriness is diagnosed, are needed to clarify these hypotheses.
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