Profiling of lipidomics before and after antipsychotic treatment in first-episode psychosis.

Alterations in complex lipids may be involved in pathophysiology of schizophrenia spectrum disorders. Previously, we demonstrated importance of detecting lipid metabolism dysregulation by acylcarnitine (ACs) profile analysis in patients with first-episode psychosis (FEP). The aim of this study was to adopt lipidomics to identify serum glycerophospholipids (GPLs) and sphingomyelins (SMs) for describing FEP status before and after 7-month antipsychotic treatment. Using mass spectrometry and liquid chromatography technique, we profiled 105 individual lipids [14 lysophosphatidylcholines (LysoPCs), 76 phosphatidylcholines (PCs) and 15 SMs] in serum samples from 53 antipsychotic-naïve FEP patients, 44 of them were studied longitudinally and from 37 control subjects (CSs). Among the identified and quantified metabolites one LysoPC was elevated, and contrary the levels of 16 PCs as well as the level of one SM were significantly (p ≤ 0.0005) reduced in antipsychotic-naïve FEP patients compared to CSs. Comparison of serum lipids profiles of FEP patients before and after 7-month antipsychotic treatment revealed that 11 GPLs (2 LysoPCs, 9 PCs), and 2 SMs were found to be significantly changed (p ≤ 0.0005) in which GPLs were up-regulated, and SMs were down-regulated. However, no significant differences were noted when treated patient's serum lipid profiles were compared with CSs. Our findings suggest that complex lipid profile abnormalities are specifically associated with FEP and these discrepancies reflect two different disease-related pathways. Our findings provide insight into lipidomic information that may be used for monitoring FEP status and impact of the treatment in the early stage of the schizophrenia spectrum disorder.

Profiling of Acylcarnitines in First Episode Psychosis before and after Antipsychotic Treatment.

Acylcarnitines (ACs) have been shown to have a potential to activate pro-inflammatory signaling pathways and to foster the development of insulin resistance. The first task of the current study was to study the full list of ACs (from C2 to C18) in first episode psychosis (FEP) patients before and after antipsychotic treatment. The second task was to relate ACs to inflammatory and metabolic biomarkers established in the same patient cohort as in our previous studies. Serum levels of ACs were determined with the AbsoluteIDQ p180 kit (BIOCRATES Life Sciences AG, Innsbruck, Austria) using the flow injection analysis tandem mass spectrometry ([FIA]-MS/MS) as well as liquid chromatography ([LC]-MS/MS) technique. Identification and quantification of the metabolites was achieved using multiple reactions monitoring along with internal standards. The comparison of ACs in antipsychotic-naïve first-episode psychosis (FEP) patients (N = 38) and control subjects (CSs, N = 37) revealed significantly increased levels of long-chain ACs (LCACs) C14:1 (p = 0.0001), C16 (p = 0.00002), and C18:1 (p = 0.000001) in the patient group. These changes of LCACs were associated with augmented levels of CARN palmitoyltransferase 1 (CPT-1) (p = 0.006). By contrast, the level of short-chain AC (SCAC) C3 was significantly reduced (p = 0.00003) in FEP patients. Seven months of antipsychotic drug treatment ameliorated clinical symptoms in patients (N = 36) but increased significantly their body mass index (BMI, p = 0.001). These changes were accompanied by significantly reduced levels of C18:1 (p = 0.00003) and C18:2 (p = 0.0008) as well as increased level of C3 (p = 0.01). General linear model revealed the relation of LCACs (C16, C16:1, and C18:1) to the inflammatory markers (epidermal growth factor, IL-2, IL-4, IL-6), whereas SCAC C3 was linked to the metabolic markers (leptin, C-peptide) and BMI. FEP was associated with an imbalance of ACs in patients because the levels of several LCACs were significantly higher and the levels of several SCACs were significantly reduced compared with CSs. This imbalance was modified by 7 months of antipsychotic drug treatment, reversing the levels of both LCACs and SCACs to that established for CSs. This study supports the view that ACs have an impact on both inflammatory and metabolic alterations inherent for FEP.

Lack of guidelines and translational knowledge is hindering the implementation of psychiatric genetic counseling and testing within Europe - A multi-professional survey study.

Genetic research has identified a large number of genetic variants, both rare and common, underlying neurodevelopmental disorders (NDD) and major psychiatric disorders. Currently, these findings are being translated into clinical practice. However, there is a lack of knowledge and guidelines for psychiatric genetic testing (PsychGT) and genetic counseling (PsychGC). The European Union-funded COST action EnGagE (CA17130) network was started to investigate the current implementation status of PsychGT and PsychGC across 35 participating European countries. Here, we present the results of a pan-European online survey in which we gathered the opinions, knowledge, and practices of a self-selected sample of professionals involved/interested in the field. We received answers from 181 respondents. The three main occupational categories were genetic counselor (21.0%), clinical geneticist (24.9%), and researcher (25.4%). Of all 181 respondents, 106 provide GC for any psychiatric disorder or NDD, corresponding to 58.6% of the whole group ranging from 43.2% in Central Eastern Europe to 66.1% in Western Europe. Overall, 65.2% of the respondents reported that genetic testing is offered to individuals with NDD, and 26.5% indicated the same for individuals with major psychiatric disorders. Only 22.1% of the respondents indicated that they have guidelines for PsychGT. Pharmacogenetic testing actionable for psychiatric disorders was offered by 15%. Interestingly, when genetic tests are fully covered by national health insurance, more genetic testing is provided for individuals with NDD but not those with major psychiatric disorders. Our qualitative analyses of responses highlight the lack of guidelines and knowledge on utilizing and using genetic tests and education and training as the major obstacles to implementation. Indeed, the existence of psychiatric genetic training courses was confirmed by only 11.6% of respondents. The question on the relevance of up-to-date education and training in psychiatric genetics on everyday related practice was highly relevant. We provide evidence that PsychGC and PsychGT are already in use across European countries, but there is a lack of guidelines and education. Harmonization of practice and development of guidelines for genetic counseling, testing, and training professionals would improve equality and access to quality care for individuals with psychiatric disorders within Europe.

Antipsychotic treatment is associated with inflammatory and metabolic biomarkers alterations among first-episode psychosis patients: A 7-month follow-up study.

AIM: Second-generation antipsychotics are commonly used to treat schizophrenia, but may cause metabolic syndrome (MetS) in a subset of patients. The mechanisms of antipsychotic-related metabolic changes remain to be established, especially in first-episode psychosis (FEP) patients. METHODS: In the present study, we used a chip technology to measure metabolic (C-peptide, insulin, leptin, adiponectin and resistin) and inflammatory biomarkers (ferritin, interleukin-6, interleukin-1α, tumour necrosis factor-α and plasminogen activator inhibitor-1) in the serum samples of a population of FEP patients before and after 7 months of antipsychotic drug treatment, compared to control subjects (CS). RESULTS: The comparison of these markers in antipsychotic-naïve FEP patients (N = 38) and CS (N = 37) revealed significantly higher levels of ferritin (P = .004), and resistin (P = .03) and lower level of leptin (P = .03) among FEP patients group. Seven months of antipsychotic drug treatment in patients (N = 36) ameliorated clinical symptoms, but increased significantly body mass index (BMI; P = .002) and these changes were accompanied by increased levels of C-peptide (P = .03) and leptin (P = .02), as well as decreased level of adiponectin (P = .01). CONCLUSIONS: Seven months of antipsychotic drug treatment suppressed the clinical symptoms of psychosis whereas caused imbalance in metabolic biomarkers and increased BMI. These findings provide insight into antipsychotic-induced MetS and refer to problems in insulin processing already present in the early stage of the chronic psychotic disorder.

Polymorphisms in the interleukin-10 gene cluster are possibly involved in the increased risk for major depressive disorder.

BACKGROUND: Innate immune inflammatory response is suggested to have a role in the pathogenesis of major depressive disorder (MDD). Interleukin (IL)-10 family cytokines IL-10, IL-19, IL-20, and IL-24 are all implicated in the inflammatory processes and polymorphisms in respective genes have been associated with various immunopathological conditions. This study was carried out to investigate whether single-nucleotide polymorphisms (SNPs) in these genes are also associated with MDD. METHODS: Case-control association study was performed with seven SNPs from the IL10 gene cluster. 153 patients with MDD and 277 healthy control individuals were recruited. RESULTS: None of the selected SNPs were individually associated with MDD. The linkage disequilibrium (LD) analysis indicated the existence of two recombination sites in the IL10 gene cluster, thus confirming the formerly established LD pattern of this genomic region. This also created two haplotype blocks, both consisting of three SNPs. Additionally, the haplotype analysis detected a significantly higher frequency of block 2 (IL20 and IL24 genes) haplotype TGC in the patients group compared to healthy control individuals (P = 0.0097). CONCLUSION: Our study established increased risk for MDD related to the IL20 and IL24 haplotype and suggests that cytokines may contribute to the pathogenesis of MDD. Since none of the block 2 SNPs were individually associated with MDD, it is possible that other polymorphisms linked to them contribute to the disease susceptibility. Future studies are needed to confirm the results and to find the possible functional explanation.

Profiling of Amino Acids and Their Derivatives Biogenic Amines Before and After Antipsychotic Treatment in First-Episode Psychosis.

Schizophrenia (SCH) is a heterogeneous disorder, deriving from a potential multitude of etiopathogenetic factors. During the past few years there has been an increasing interest in the role of circulating amino acids (AAs) and biogenic amines (BAs) in the pathophysiology of SCH. In the present study, we aimed to provide an insight into the potential role of alterations in levels of AAs and BAs as well as examine their more specific metabolic shifts in relation to early stage of SCH. We measured 21 AAs and 17 BAs in serum samples of patients with first-episode psychosis (FEP) before and after 7-month antipsychotic treatment in comparison to control subjects (CSs). According to multivariate analysis, antipsychotic-naïve FEP patients had significantly higher levels of taurine and spermine, whereas values of proline (Pro), alpha-aminoadipic acid (alpha-AAA), kynurenine (Kyn), valine (Val), tyrosine (Tyr), citrulline (Citr), tryptophan (Trp), and histidine (His) were diminished compared to CSs. Increased levels of taurine and spermine, as well as reduced levels of alpha-AAA and Kyn probably reflect the compromised function of N-methyl-D-aspartate (NMDA) receptors in patients. The decreased levels of Pro (AA modulating the function of glutamate decarboxylase) likely reflect the imbalanced function of gamma-aminobutyric acid (GABA) system in the brain of FEP patients. The alterations in ratio between Tyr and phenylalanine (Phe) can be taken as a sign of compromised function of dopaminergic system. These metabolic shifts were reinstated by 7-month antipsychotic treatment. Serum metabolic profiles can be regarded as important indicators to investigate clinical course of SCH and treatment response.

Taurine and Epidermal Growth Factor Belong to the Signature of First-Episode Psychosis.

This study evaluated the levels of two amino acid derivatives taurine and spermine in first-episode psychosis (FEP) patients and their response to antipsychotic treatment. The levels of taurine and spermine were significantly up-regulated in antipsychotic-naïve FEP patients compared to control subjects (CS). Treatment of FEP patients with antipsychotic drugs significantly reduced the positive symptoms of schizophrenia. This positive effect was accompanied by a significant reduction of taurine and spermine to the levels measured in CS. General linear model was used to establish associations of taurine and spermine with the levels of cytokines and growth factors, measured in our previous experiments using the same study sample. There was a strong association between taurine and epidermal growth factor (EGF). Both biomarkers significantly correlated with the disease symptoms as well as with the effectiveness of antipsychotic treatment. Accordingly one can conclude that taurine and EGF belong to the signature of FEP. Most probably they reflect altered oxidative stress and corrupted function of N-methyl-D-aspartate (NMDA) receptors in FEP.

Antipsychotic Treatment Reduces Indices of Oxidative Stress in First-Episode Psychosis Patients.

38 first-episode psychosis (FEP) patients and 37 control subjects were recruited for the study of indices of oxidative stress (OxS). The main purpose of the study was to compare the OxS statuses (serum total antioxidant capacity (TAC), total level of peroxides (TPX), oxidative stress index (OSI), and ratio oxidized methionine (Met-SO) to methionine (Met)) between antipsychotic-naïve FEP patients and individuals without a history of psychiatric disorders. Subsequently, the impact of 7-month antipsychotic treatment was evaluated on the OxS status in FEP patients. An attempt was made to assess links between OxS signature and inflammation markers. The oxidative stress indices remained generally unchanged in antipsychotic-naïve FEP patients compared to control subjects. Despite that, there was a significant correlation between the levels of TPX and EGF (endothelial growth factor) in FEP patients. This correlation disappeared after antipsychotic treatment of FEP patients. Moreover, antipsychotic treatment was associated with a significant reduction in OxS indices, including TPX, OSI, and ratio between Met-SO and Met. By contrast, in chronic SCZ patients we established a significant high-grade OxS. In conclusion, the markers of total antioxidative capacity, lipid peroxidation, and protein oxidation revealed no high-grade OxS in FEP patients. Nevertheless, antipsychotic treatment induced a considerable anti-inflammatory effect. OxS levels were also significantly decreased if compared in FEP patients before and after antipsychotic treatment.

Association study of 90 candidate gene polymorphisms in panic disorder.

OBJECTIVE: In the present investigation we screened a large number of single nucleotide polymorphisms in the genes relevant to the neurobiology of anxiety for their association with panic disorder (PD). METHODS: The study sample included 127 patients with PD and 146 healthy control subjects. Using Arrayed Primer Extension technology we genotyped 90 polymorphisms in 21 candidate genes of serotonin, cholecystokinin, dopamine and opioid neurotransmitter systems. The association and haplotype analyses were performed in the whole group (PD-all) and in the subgroups of PD comorbid with major depression (PD-comorbid, n = 60) and without any comorbidity (PD-pure, n = 42). RESULTS: From the set of 90 polymorphisms, eight single nucleotide polymorphism markers in eight genes displayed at least a nominal association with any of the studied PD phenotype subgroups. Several polymorphisms of cholecystokinin, serotonin and dopamine systems were associated with PD-all and/or PD-comorbid phenotypes, while pure PD was associated only with HTR2A receptor 102T-C (P = 0.01) and DRD1 receptor -94G-A (P = 0.02) polymorphisms. Haplotype analysis supported an association of the cholecystokinin gene TG haplotype with the PD-all group (P = 0.04), whereas DRD1 receptor CAA and HTR2A receptor AT haplotypes were associated with a lower risk for PD-pure phenotype (P = 0.03 and P = 0.04, respectively). CONCLUSIONS: The study results suggest that genetic variants of several candidate genes of neurotransmitter systems, each of a minor individual effect, may contribute to the susceptibility to PD. Our data also indicate that genetic variability may have a distinctive influence on pure and comorbid phenotypes of PD.

Antipsychotic treatment reduces psychotic symptoms and markers of low-grade inflammation in first episode psychosis patients, but increases their body mass index.

OBJECTIVE: The main goal of the present study was to analyze levels of cytokines of the interleukin family (IL-1α, IL-1ß, IL-2, IL-4, IL-6, IL-8 and IL-10), interferon-gamma (IFN-γ), monocyte chemoattractant protein-1 (MCP1), tumor necrosis factor-alpha (TNF-α), and vascular endothelial and endothelial growth factors (VEGF and EGF), in the blood samples of first-episode psychosis (FEP) patients before and seven months after the start of antipsychotic medication use. METHOD: 38 anti-psychotic medication-naïve FEP patients and 37 healthy controls (HC) were recruited. Biochip array technology was used to measure cytokines and growth factors. RESULTS: The comparison of these markers in FEP patients and HC revealed significantly higher levels of EGF, IL-4 and IL-6 and significantly lower level of IL-1ß in FEP patients before the antipsychotic treatment. Multiple regression analysis demonstrated significant correlations between FEP and EGF, IL-1ß and smoking. Treatment with antipsychotic drugs resulted in a statistically significant amelioration of the symptoms of psychosis, but caused a significant increase in the body mass index (BMI) of patients. Levels of EGF, IL-2, VEGF, IL-6, IFN-γ, IL-4, IL-8 and IL-1α were significantly lower in treated FEP patients compared to premedication levels. CONCLUSIONS: According to the present study, EGF and IL-1ß are markers of FEP. Antipsychotic drug treatment resulted in a significant clinical improvement of FEP patients and the suppression of positive symptoms was correlated with the decreased levels of EGF, IL-2 and IL-4. EGF was the strongest marker of FEP and treatment efficiency among the measured cytokines and growth factors.

Polymorphisms of IKBKE gene are associated with major depressive disorder and panic disorder.

BACKGROUND: The immune system has been increasingly implicated in the development of mood and anxiety disorders. Inhibitor of kappa light polypeptide gene enhancer in B cells, kinase epsilon (IKBKE) gene encodes IKKε protein that is involved in innate immunity, predominantly antiviral response generation. It also bears pro-inflammatory properties that could affect psychiatric outcomes. In order to investigate the possible role of IKBKE gene in major depressive disorder (MDD) and panic disorder (PD), we conducted a case-control genetic association study concerning these disorders. METHODS: In all, 14 SNPs of IKBKE gene were genotyped in groups of 391 patients with MDD and 190 patients with PD together with respective 389 and 371 healthy control individuals. The given groups were further divided by gender for additional analyses. RESULTS: Substantial genetic associations were revealed between IKBKE SNPs and MDD (multiple testing adjusted P < 0.05) and suggestive associations in case of PD (P(adj) > 0.05). In addition, two SNPs that were only associated with PD among males, also displayed significantly different allele frequencies compared to PD females. This may indicate a specific role of these SNPs in male PD, but caution should be applied here due to the small size of the studied PD males group. CONCLUSIONS: The results of this study confirm our initial findings and indicate a possible role of IKBKE gene in mood and anxiety disorders.

Associations between polymorphisms of LSAMP gene and schizophrenia.

The purpose of this study was to explore relationships between single-nucleotide polymorphisms (SNPs) in the limbic system-associated membrane protein (LSAMP) gene and schizophrenia. Twenty-two SNPs were analysed in 127 unrelated schizophrenic patients and in 171 healthy controls. The results showed significant allelic and haplotypic associations between LSAMP gene and schizophrenia.

Limbic system associated membrane protein as a potential target for neuropsychiatric disorders.

The studies performed in laboratory animals and psychiatric patients suggest a possible role of limbic system-associated membrane protein (LAMP) in the mechanisms of psychiatric disorders. Stressful manipulations and genetic invalidation have revealed a role of the Lsamp gene in the regulation of anxiety in rodents. Besides that, Lsamp-deficient mice display reduced aggressiveness and impaired adaptation in novel and stressful environments. The behavioral effects of amphetamine were blunted in genetically modified mice. Recent pharmacological and biochemical studies point toward altered function of GABA-, 5-hydroxytryptamine-, and dopaminergic systems in Lsamp-deficient mice. Moreover, we found an association between the gene polymorphisms of LSAMP and major depressive disorder (MDD). Patients suffering from MDD had significantly increased ratio between risk and protective haplotypes of the LSAMP gene compared to healthy volunteers. However, the impact of these haplotypes for the function of LAMP is not clear and remains to be elucidated in future studies.

Interleukin 10 family gene polymorphisms are not associated with major depressive disorder and panic disorder phenotypes.

Genetic regulation of immune system and inflammatory response may be related to the pathogenesis and manifestations of mood and anxiety disorders. In the present study we examined a range of single-nucleotide polymorphisms (SNP) in chromosomal region 1q32, the locus of interleukin 10 (IL10) gene, in patients with major depressive disorder (n=312) and panic disorder (n=210), and matched healthy controls (n=356). We found no significant associations of the SNPs in IL10 family genes with either diagnostic group. Haplotype analysis revealed seven haplotype blocks, but their frequencies did not differ between patients and controls. Significant associations were detected for SNP rs1539243 in IKBKE (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase epsilon) gene showing different allelic and genotypic distributions in the total as well as in separate diagnostic groups as compared to controls. IKBKE emerged as a candidate for further studies of genetic factors associated with panic disorder and major depressive disorder.

Analysis of SNP profiles in patients with major depressive disorder.

The present study focused on 91 single-nucleotide polymorphisms (SNPs) in 21 candidate genes to find associations with major depressive disorder (MDD). In total, 160 healthy controls and 177 patients with MDD were studied. We applied arrayed primer extension (APEX) based genotyping technology followed by association and haplotype analysis. SNPs in CCKAR, DRD1, DRD2, and HTR2C genes showed nominally significant associations with MDD. None of these associations remained significant after adjustment for multiple testing. Haplotype analysis revealed CCKAR haplotypes to be associated with MDD (global p=0.004). More precisely, we found the GAGT haplotype to be associated with increased risk for MDD (OR 7.42, 95% CI 2.13-25.85, p=0.002). This haplotype effect remained significant after Bonferroni correction (p=0.04 after Bonferroni's adjustment). Altogether we were able to find some nominal associations, but due to small sample size these results should be taken as exploratory. However, the effect of GAGT haplotype on the CCKAR gene may be considered as increasing the risk for MDD.

Polymorphisms in wolframin (WFS1) gene are possibly related to increased risk for mood disorders.

Wolfram syndrome gene (WFS1) has been suggested to have a role in the susceptibility for mood disorders. A 26-fold increased risk for psychiatric disorders in WFS1 mutation carriers has been suggested. In this study we tested the hypothesis that the WFS1 gene is related to the risk for mood disorders. We analysed 28 single-nucleotide polymorphisms (SNPs) of the WFS1 gene in 224 unrelated patients with major depressive disorder and bipolar disorder and in 160 healthy control subjects. Patients were further stratified according to their comorbidity with anxiety disorders. We applied arrayed primer extension (APEX)-based genotyping technology followed by association and haplotype analysis. Five SNPs in the WFS1 gene were associated with major depressive disorder, and three SNPs with bipolar disorder. Haplotype analysis revealed a common GTA haplotype, formed by SNPs 684C/G, 1185C/T and 1832G/A, conferring risk for affective disorders. Specifically, for major depression the GTA haplotype has an OR of 1.59 (p = 0.01) and for bipolar disorder an OR of 1.89 (p = 0.03). These results support the hypothesis that the WFS1 gene is involved in the genetic predisposition for mood disorders.