Genetic predisposition and antipsychotic treatment effect on metabolic syndrome in schizophrenia: a ten-year follow-up study using the Estonian Biobank.

Background: Schizophrenia (SCZ) patients exhibit 30% higher prevalence of metabolic syndrome (MetS) compared to the general population with its suboptimal management contributing to increased mortality. Large-scale studies providing real-world evidence of the underlying causes remain limited. Methods: To address this gap, we used real-world health data from the Estonian Biobank, spanning a median follow-up of ten years, to investigate the impact of genetic predisposition and antipsychotic treatment on the development of MetS in SCZ patients. Specifically, we set out to characterize antipsychotic treatment patterns, genetic predisposition of MetS traits, MetS prognosis, and body mass index (BMI) trajectories, comparing SCZ cases (n = 677) to age- and sex-matched controls (n = 2708). Findings: SCZ cases exhibited higher genetic predisposition to SCZ (OR = 1.75, 95% CI 1.58-1.94), but lower polygenic burden for increased BMI (OR = 0.88, 95% CI 0.88-0.96) and C-reactive protein (OR = 0.88, 95% CI 0.81-0.97) compared to controls. While SCZ cases showed worse prognosis of MetS (HR 1.95, 95% CI 1.54-2.46), higher antipsychotic adherence within the first treatment year was associated with reduced long-term MetS incidence. Linear mixed modelling, incorporating multiple BMI timepoints, underscored the significant contribution of both, antipsychotic medication, and genetic predisposition to higher BMI, driving the substantially upward trajectory of BMI in SCZ cases. Interpretation: These findings contribute to refining clinical risk prediction and prevention strategies for MetS among SCZ patients and emphasize the significance of incorporating genetic information, long-term patient tracking, and employing diverse perspectives when analyzing real-world health data. Funding: EU Horizon 2020, Swedish Research Council, Estonian Research Council, Estonian Ministry of Education and Research, University of Tartu.

Adapting the early recognition inventory ERIraos to Estonian: A validation study.

AIM: Validated assessment tools are needed to identify clinically high risk for psychosis. This study aimed to validate the early recognition inventory ERIraos, which consists of the ERIraos Checklist for risk screening and the ERIraos Symptom List for a more thorough risk assessment in the Estonian language to detect psychotic prodromal symptoms. METHODS: A prospective cohort study provided an opportunity to evaluate the characteristics of the ERIraos instrument in predicting the increased risk of a psychotic disorder in the future. The 177 study participants, aged 13-42 years old, were divided into groups without an increased risk and three risk groups with different risk severity levels based on the ERIraos Symptom List assessment. RESULTS: The results indicated excellent inter-rater reliability for the ERIraos Symptom List total score. The ability of the ERIraos checklist to screen persons with an elevated psychosis risk was very good (ROC-AUC = 0.86). The capability of the ERIraos Symptom List scores to predict the probability of transitioning to psychosis within 2 years was very good (ROC-AUC = 0.83). Brief limited intermittent psychotic symptoms and observable behavioural and affective symptoms were statistically significant predictors of transition to psychosis. There were strong and statistically significant correlations between the ERIraos Symptom List scores and other clinical measures assessing functioning and psychopathology. CONCLUSIONS: The results of this study demonstrate the reliability and validity of the Estonian version of the ERIraos instrument and support the usability of ERIraos as a two-step tool for the early recognition of psychosis risk.

The risk assessment of imminent inpatient aggression: A cross-cultural validation study of the dynamic appraisal of situational aggression in Estonia.

INTRODUCTION: The reason for this study was void of a data-driven imminent risk assessment instrument for aggression in psychiatry clinics in Estonia. The predictive accuracy of the observer-rated Dynamic Assessment of Situational Aggression (DASA) has been repeatedly demonstrated. However, the research gap remains regarding a deeper conceptual understanding of the underlying latent structure of the DASA. AIM: Comprehensively evaluate the psychometric properties of the Estonian DASA version for cross-cultural clinical use. METHOD: We used a prospective repeated measure design and collected 6097 risk evaluations from 381 adult inpatients, 151 of whom committed 1013 aggressive incidents during the study. RESULTS: The Estonian DASA version has acceptable inter-rater reliability (Kendall's τ = 0.74) and is a useful instrument with excellent predictive validity (AUC = 0.86) for identifying potentially aggressive inpatients. In our sample, the DASA has a bi-factorial structure which explains 83% of the total variance. DISCUSSION: The adapted DASA has acceptable validity and reliability indices for measuring imminent aggression risk in adult inpatient units. IMPLICATIONS FOR PRACTICE: Evidence-based risk assessment of aggression in psychiatric clinics enhances recognition of the signs of potentially aggressive behaviour in order to apply preventive actions and reduce aggression, thereby improving the quality of the care provided.

Multivariate analyses of immune markers reveal increases in plasma EN-RAGE in first-episode psychosis patients.

Immune cells and cytokines are largely recognized as significant factors in the pathophysiology of neuropsychiatric disorders. The possible role of other blood cells such as leukocytes in events of acute psychosis is in contrast only emerging. To study blood-born markers in acute psychosis we here evaluated plasma proteins in drug-naive first-episode psychosis (FEP) patients and healthy controls using a multiplex proximity extension assay technique. We analyzed a panel of 92 immune markers and plasma samples from 60 FEP patients and 50 controls and evaluated the changes obtained using multivariate statistical methods followed by protein pathway analyses. Data showed that 11 proteins are significantly different between FEP patients and healthy controls We observed increases in pro-inflammatory proteins such as interleukin-6, oncostatin-M, and transforming growth factor-alpha in FEP patients compared with controls. Likewise, the extracellular newly identified RAGE-binding protein (EN-RAGE) that regulates the expression of various cytokines was also elevated in the plasma of FEP patients. The results indicate that neutrophil-derived EN-RAGE could play an important role during the early phase of acute psychosis by stimulating cytokines and the immune response targeting thereby likely also the brain vasculature.

Kynurenine pathway dynamics in patients with schizophrenia spectrum disorders across the disease trajectory.

The aim of this study was to evaluate how schizophrenia spectrum disorders (SSD) and applied long-term (5.1 years) antipsychotic (AP) treatment affect the serum levels of tryptophan (Trp) metabolites. A total of 112 adults (54 first-episode psychosis [FEP] patients and 58 control subjects [CSs]) participated in the study. The investigated changes in the metabolite levels appeared against a background of persistent increase in BMI and waist circumference among the patients. Regarding the kynurenine (KYN) pathway, the strongest changes were seen in AP-naïve FEP patients. Trp, KYN, kynurenic acid (KYNA), and anthranilic acid (ANT) levels were significantly reduced in blood samples from patients in the early stage of the disease. Furthermore, 3-OH-kynurenine (3-HK) and quinolinic acid (QUIN) levels were somewhat lower in these patients. Most of these changes in the KYN pathway became weaker with AP treatment. The levels of serotonin and its metabolite 5-HIAA tended to be higher at 5.1 years in patients showing the relation of elevated serotonin turnover to increased BMI and waist circumference. The similar trend was evident for the ratio between xanthurenic acid (XA) and KYNA with strong link to the elevated BMI. Altogether, the present study supports the role of Trp-metabolites in the development of obesity and metabolic syndrome in SSD patients.

Investigating general and specific psychopathology factors with nuance-level personality traits.

Mental health disorders share substantial variance, prompting researchers to develop structural models that can capture both generalised psychopathology risk and disorder/symptom-specific variation. This study investigated the associations of the general and specific psychopathology factors with multiple personality trait hierarchy levels: broad domains, their facets and nuances (N = 1839 Estonian adults). A bi-factor model with a general 'p' factor and specific factors for internalising problems, thought disorders and substance use best represented psychopathology structure. Although traits' predictive accuracy varied across psychopathology factors, nuances (the lowest level personality units) provided higher predictive accuracy and higher discriminant validity than domains. For example, traits related to high vulnerability, depression and immoderation and low friendliness and achievement striving were most strongly associated with the p factor. Nuances may prove useful for predicting and understanding general and specific psychopathology forms.

Differential patterns of cross-reactive antibody response against SARS-CoV-2 spike protein detected for chronically ill and healthy COVID-19 naïve individuals.

Immunity to previously encountered viruses can alter response to unrelated pathogens. We reasoned that similar mechanism may also involve SARS-CoV-2 and thereby affect the specificity and the quality of the immune response against the virus. Here, we employed high-throughput next generation phage display method to explore the link between antibody immune response to previously encountered antigens and spike (S) glycoprotein. By profiling the antibody response in COVID-19 naïve individuals with a diverse clinical history (including cardiovascular, neurological, or oncological diseases), we identified 15 highly antigenic epitopes on spike protein that showed cross-reactivity with antigens of seasonal, persistent, latent or chronic infections from common human viruses. We observed varying degrees of cross-reactivity of different viral antigens with S in an epitope-specific manner. The data show that pre-existing SARS-CoV-2 S1 and S2 cross-reactive serum antibody is readily detectable in pre-pandemic cohort. In the severe COVID-19 cases, we found differential antibody response to the 15 defined antigenic and cross-reactive epitopes on spike. We also noted that despite the high mutation rates of Omicron (B.1.1.529) variants of SARS-CoV-2, some of the epitopes overlapped with the described mutations. Finally, we propose that the resolved epitopes on spike if targeted by re-called antibody response from SARS-CoV-2 infections or vaccinations can function in chronically ill COVID-19 naïve/unvaccinated individuals as immunogenic targets to boost antibodies augmenting the chronic conditions. Understanding the relationships between prior antigen exposure at the antibody epitope level and the immune response to subsequent infections with viruses from a different strain is paramount to guiding strategies to exit the COVID-19 pandemic.

A Marked Low-Grade Inflammation and a Significant Deterioration in Metabolic Status in First-Episode Schizophrenia: A Five-Year Follow-Up Study.

The objective of this study was to evaluate how schizophrenia spectrum disorders and applied long-term (5.1 years) antipsychotic (AP) treatment affect the serum level of acylcarnitines (ACs), cytokines and metabolic biomarkers and to characterize the dynamics of inflammatory and metabolic changes in the early course of the disorder. A total of 112 adults participated in the study (54 patients with first-episode psychosis (FEP) and 58 control subjects). Biomolecule profiles were measured at the onset of first-episode psychosis and 0.6 years and 5.1 years after the initiation of APs. The results of the present study confirmed that specific metabolic-inflammatory imbalance characterizes AP-naïve patients. Short-term (0.6-years) AP treatment has a favourable effect on psychotic symptoms, as well as the recovery of metabolic flexibility and resolution of low-level inflammation. However, 5.1 years of AP treatment resulted in weight gain and increased serum levels of interleukin (IL)-2, IL-4, IL-6, IL-10, interferon-γ, hexoses, acetylcarnitine, short-chain ACs (C3, C4) and long-chain ACs (C16:2, C18:1, C18:2). In conclusion, despite the improvement in psychotic symptoms, 5.1 years of AP treatment was accompanied by a pronounced metabolic-inflammatory imbalance, which was confirmed by the presence of enhanced pro-inflammatory activity and increased obesity with changes in the metabolism of carbohydrates, lipids, and their metabolites.

The Expanded Endocannabinoid System Contributes to Metabolic and Body Mass Shifts in First-Episode Schizophrenia: A 5-Year Follow-Up Study.

Alterations in the expanded endocannabinoid system (eECS) and cell membrane composition have been implicated in the pathophysiology of schizophrenia spectrum disorders. We enrolled 54 antipsychotic (AP)-naïve first-episode psychosis (FEP) patients and 58 controls and applied a targeted metabolomics approach followed by multivariate data analysis to investigate the profile changes in the serum levels of endocannabinoids: 2-arachidonoylglycerol (2-AG) and anandamide, endocannabinoids-like N-acylethanolamines (NAEs: linoleoylethanolamide, oleoylethanolamide, and palmitoylethanolamide), and their dominating lipid precursor's phosphatidylcholines. Biomolecule profiles were measured at the onset of first-episode psychosis (FEP) and 0.6 years and 5.1 years after the initiation of AP treatment. The results indicated that FEP might be characterized by elevated concentrations of NAEs and by decreased 2-AG levels. At this stage of the disease, the NAE-mediated upregulation of peroxisome proliferator-activated receptors (PPARs) manifested themselves in energy expenditure. A 5-year disease progression and AP treatment adverse effects led to a robust increase in 2-AG levels, which contributed to strengthened cannabinoid (CB1) receptor-mediated effects, which manifested in obesity. Dynamic 2-AG, NAEs, and their precursors in terms of phosphatidylcholines are relevant to the description of the metabolic shifts resulting from the altered eECS function during and after FEP.

Healthcare professionals' and patients' attitudes toward the causes and management of aggression in Estonian psychiatric clinics: a quantitative cross-sectional comparative study.

BACKGROUND: To enhance patient aggression management efficacy and to reduce the use of coercive interventions in inpatient psychiatric care, it is important to know the attitudes of all involved parties towards the aggression and its management. AIMS: This study aimed to explore attitudes of the psychiatrists, nurses and inpatients toward the causes and management of patient aggression in Estonian psychiatric clinics. A frequency of aggressive behaviour experienced by professionals, the relationships between the attitudes, participation in coercion, and a frequency of aggression, were also identified. METHODS: To assess attitudes towards the causes and management of patient aggression, the Management of Aggression and Violence Attitude Scale was implemented. RESULTS: The survey comprised of 63 psychiatrists, 197 nurses and 199 inpatients. The patients and the professionals had similar as well as different attitudes toward aggression and its management. Patients expected professionals to take a more personal approach when aggression occurs; in some cases, allowing the patients to deal with negative emotions on their own but, if necessary, isolating or restraining the violent people. CONCLUSIONS: There is a need of training programs that focus on dealing patient aggression to foster a culture of safe, patient-centred care and to reduce aggression in psychiatric clinics.

Metabolomics approach revealed robust changes in amino acid and biogenic amine signatures in patients with schizophrenia in the early course of the disease.

The primary objective of this study was to evaluate how schizophrenia (SCH) spectrum disorders and applied antipsychotic (AP) treatment affect serum level of amino acids (AAs) and biogenic amines (BAs) in the early course of the disorder. We measured 21 different AAs and 10 BAs in a sample of antipsychotic (AP)-naïve first-episode psychosis (FEP) patients (n = 52) at baseline, after 0.6-year as well as after 5.1-year treatment compared to control subjects (CSs, n = 37). Serum levels of metabolites were determined with AbsoluteIDQ p180 kit using flow injection analysis tandem mass spectrometry and liquid chromatography technique. Elevated level of taurine and reduced level of proline and alpha-aminoadipic acid (alpha-AAA) were established as metabolites with significant change in AP-naïve FEP patients compared to CSs. The following 0.6-year treatment restored these alterations. However, further continuous 5.1-year AP treatment changed the metabolic profile substantially. Significantly elevated levels of asparagine, glutamine, methionine, ornithine and taurine, alongside with decreased levels of aspartate, glutamate and alpha-AAA were observed in the patient group compared to CSs. These biomolecule profile alterations provide further insights into the pathophysiology of SCH spectrum disorders and broaden our understanding of the impact of AP treatment in the early stages of the disease.

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.

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.

Repeated Administration of D-Amphetamine Induces Distinct Alterations in Behavior and Metabolite Levels in 129Sv and Bl6 Mouse Strains.

The main goal of the study was to characterize the behavioral and metabolomic profiles of repeated administration (for 11 days) of d-amphetamine (AMPH, 3 mg/kg i. p.), indirect agonist of dopamine (DA), in widely used 129S6/SvEvTac (129Sv) and C57BL/6NTac (Bl6) mouse strains. Acute administration of AMPH (acute AMPH) induced significantly stronger motor stimulation in Bl6. However, repeated administration of AMPH (repeated AMPH) caused stronger motor sensitization in 129Sv compared acute AMPH. Body weight of 129Sv was reduced after repeated saline and AMPH, whereas no change occurred in Bl6. In the metabolomic study, acute AMPH induced an elevation of isoleucine and leucine, branched chain amino acids (BCAA), whereas the level of hexoses was reduced in Bl6. Both BCAAs and hexoses remained on level of acute AMPH after repeated AMPH in Bl6. Three biogenic amines [asymmetric dimethylarginine (ADMA), alpha-aminoadipic acid (alpha-AAA), kynurenine] were significantly reduced after repeated AMPH. Acute AMPH caused in 129Sv a significant reduction of valine, lysophosphatidylcholines (lysoPC a C16:0, lysoPC a C18:2, lysoPC a C20:4), phosphatidylcholine (PC) diacyls (PC aa C34:2, PC aa C36:2, PC aa C36:3, PC aa C36:4) and alkyl-acyls (PC ae C38:4, PC ae C40:4). However, repeated AMPH increased the levels of valine and isoleucine, long-chain acylcarnitines (C14, C14:1-OH, C16, C18:1), PC diacyls (PC aa C38:4, PC aa C38:6, PC aa C42:6), PC acyl-alkyls (PC ae C38:4, PC ae C40:4, PC ae C40:5, PC ae C40:6, PC ae C42:1, PC ae C42:3) and sphingolipids [SM(OH)C22:1, SM C24:0] compared to acute AMPH in 129Sv. Hexoses and kynurenine were reduced after repeated AMPH compared to saline in 129Sv. The established changes probably reflect a shift in energy metabolism toward lipid molecules in 129Sv because of reduced level of hexoses. Pooled data from both strains showed that the elevation of isoleucine and leucine was a prominent biomarker of AMPH-induced behavioral sensitization. Simultaneously a significant decline of hexoses, citrulline, ADMA, and kynurenine occurred. The reduced levels of kynurenine, ADMA, and citrulline likely reflect altered function of N-methyl-D-aspartate (NMDA) and NO systems caused by repeated AMPH. Altogether, 129Sv strain displays stronger sensitization toward AMPH and larger variance in metabolite levels than Bl6.

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.

Metabolic profile associated with distinct behavioral coping strategies of 129Sv and Bl6 mice in repeated motility test.

We investigated the metabolic outcome of different coping strategies in 129S6/SvEvTac (129Sv) and C57BL/6Ntac (Bl6) strains. Two different batches of male 129Sv and Bl6 mice were used. One batch was not subjected to any behavioral manipulations (home cage control; HCC), whereas the other batch was treated with saline for 11 days and exposed after every treatment to the motor activity measurement (repeated motility tested; RMT). Bl6 RMT mice displayed a robust increase in number of rearings during repeated testing. 129Sv RMT mice experienced significant loss of body weight, but showed enhanced weight gain in HCC batch compared to Bl6. Serum metabolites (acylcarnitines, amino acids, biogenic amines, hexoses, glycerophospholipids and sphingolipids) were determined with AbsoluteIDQ p180 kit. Results of the metabolomic study revealed prominent peculiarities between strains in two different conditions. Comparison of both batches of mice demonstrated that in Bl6 biogenic amines (acetyl-ornithine, alpha-amionadipic acid, carnosine) and lysophosphatidylcholine PC(16:1/0:0) dominated. However in 129Sv acylcarnitine C5 clearly dominated, indicating shift towards short-chain acylcarnitines. Stable strain-specific ratios also emerged for both lines, ratio of glycine/PC ae C38:2 for Bl6 and ratios of C5/C0 as well as PC(16:0/0:0)/PC(16:1/0:0) for 129Sv. The described metabolic changes probably reflect different behavioral coping strategies of 129Sv and Bl6 mice.

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.

The course of cognitive functioning after first-episode of psychosis: A six month follow-up study.

Our aim with the present study was to evaluate rank-order and mean-level cognitive functioning stability among first-episode psychosis (FEP) patients, measured using the Cambridge Neuropsychological Test Automated Battery (CANTAB), over a six month period. We also aimed to examine longitudinal measurement invariance and identify factors-such as age, gender, educational level, treatment and psychopathological change scores-potentially linked to cognitive change among patients. In addition, correlations between objectively measured and subjectively evaluated cognitive functioning were estimated. Neuropsychological assessments were administered to 85 patients after the initial stabilisation of their psychosis; 82 of the patients were retested. Subjectively perceived cognitive functioning was measured using a subscale derived from the Estonian version of the Subjective Well-Being Under Neuroleptic Scale (SWN-K-E). On average, executive functioning and processing speed improved significantly, while memory test scores decreased significantly, over time. Very high rank-order stability (r=0.80 to 0.94, p<0.001) was observed with all measured ability scores. Confirmatory factor analysis revealed the loadings of a single (broad ability) factor model were equal across both measurement occasions, but the lack of intercept invariance suggested that mean-level comparisons are more appropriately carried out at a subtest level. On average psychopathology scores and antipsychotics doses declined over time, with the latter also significantly correlating with better executive functioning. Gender was a significant moderator of some domains of cognitive performance, and decline tended to be somewhat more pronounced for women. The results also indicated the lack of any relationship between objective and subjective measurements of cognitive functioning.

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.

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.