Association of Blood Metabolomics Biomarkers with Brain Metabolites and Patient-Reported Outcomes as a New Approach in Individualized Diagnosis of Schizophrenia.

Given its polygenic nature, there is a need for a personalized approach to schizophrenia. The aim of the study was to select laboratory biomarkers from blood, brain imaging, and clinical assessment, with an emphasis on patients' self-report questionnaires. Metabolomics studies of serum samples from 51 patients and 45 healthy volunteers, based on the liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS/MS), led to the identification of 3 biochemical indicators (cortisol, glutamate, lactate) of schizophrenia. These metabolites were sequentially correlated with laboratory tests results, imaging results, and clinical assessment outcomes, including patient self-report outcomes. The hierarchical cluster analysis on the principal components (HCPC) was performed to identify the most homogeneous clinical groups. Significant correlations were noted between blood lactates and 11 clinical and 10 neuroimaging parameters. The increase in lactate and cortisol were significantly associated with a decrease in immunological parameters, especially with the level of reactive lymphocytes. The strongest correlations with the level of blood lactate and cortisol were demonstrated by brain glutamate, N-acetylaspartate and the concentrations of glutamate and glutamine, creatine and phosphocreatine in the prefrontal cortex. Metabolomics studies and the search for associations with brain parameters and self-reported outcomes may provide new diagnostic evidence to specific schizophrenia phenotypes.

Benefits and Meaning of Lipids Profile in Relation to Oxidative Balance and Brain Morphology in Schizophrenia.

Schizophrenia is characterized by complex metabolic dysregulations and their consequences. Until now, numerous theories have explained its pathogenesis, using a spectrum of available technologies. We focused our interest on lipid profile-periphery high-density cholesterol level and lipoproteins in the human brain and compared magnetic resonance imaging (MRI) scans of patients with schizophrenia and the healthy group. Detailed analysis of biochemical parameters was performed using magnetic resonance spectroscopy. Our study aimed to reveal correlations between periphery high-density lipoproteins levels and lipoproteins in the brain, depicted in MRI scans, and parameters of peripheral oxidative stress expressed as paraoxonase. Patients with schizophrenia have decreased levels of high-density lipoproteins, low paraoxonase activity, and slightly raised sodium in the blood. Positive significant correlations between serum high-density cholesterol and anterior cingulate cortex, unique brain area for schizophrenia pathophysiology, MR spectroscopy signals, and diffusion have been revealed. To our knowledge, this is the first study to describe the effect of an anterior cingulate disorder on high-density cholesterol levels on the development of schizophrenia.

GDNF and miRNA-29a as biomarkers in the first episode of psychosis: uncovering associations with psychosocial factors.

Aim: Schizophrenia involves complex interactions between biological and environmental factors, including childhood trauma, cognitive impairments, and premorbid adjustment. Predicting its severity and progression remains challenging. Biomarkers like glial cell line-derived neurotrophic factor (GDNF) and miRNA-29a may bridge biological and environmental aspects. The goal was to explore the connections between miRNAs and neural proteins and cognitive functioning, childhood trauma, and premorbid adjustment in the first episode of psychosis (FEP). Method: This study included 19 FEP patients who underwent clinical evaluation with: the Childhood Trauma Questionnaire (CTQ), the Premorbid Adjustment Scale (PAS), the Positive and Negative Syndrome Scale (PANSS), and the Montreal Cognitive Assessment Scale (MoCA). Multiplex assays for plasma proteins were conducted with Luminex xMAP technology. Additionally, miRNA levels were quantitatively determined through RNA extraction, cDNA synthesis, and RT-qPCR on a 7500 Fast Real-Time PCR System. Results: Among miRNAs, only miR-29a-3p exhibited a significant correlation with PAS-C scores (r = -0.513, p = 0.025) and cognitive improvement (r = -0.505, p = 0.033). Among the analyzed proteins, only GDNF showed correlations with MoCA scores at the baseline and after 3 months (r = 0.533, p = 0.0189 and r = 0.598, p = 0.007), cognitive improvement (r = 0.511, p = 0.025), and CTQ subtests. MIF concentrations correlated with the PAS-C subscale (r = -0.5670, p = 0.011). Conclusion: GDNF and miR-29a-3p are promising as biomarkers for understanding and addressing cognitive deficits in psychosis. This study links miRNA and MIF to premorbid adjustment and reveals GDNF's unique role in connection with childhood trauma.

From periphery immunity to central domain through clinical interview as a new insight on schizophrenia.

Identifying disease predictors through advanced statistical models enables the discovery of treatment targets for schizophrenia. In this study, a multifaceted clinical and laboratory analysis was conducted, incorporating magnetic resonance spectroscopy with immunology markers, psychiatric scores, and biochemical data, on a cohort of 45 patients diagnosed with schizophrenia and 51 healthy controls. The aim was to delineate predictive markers for diagnosing schizophrenia. A logistic regression model was used, as utilized to analyze the impact of multivariate variables on the prevalence of schizophrenia. Utilization of a stepwise algorithm yielded a final model, optimized using Akaike's information criterion and a logit link function, which incorporated eight predictors (White Blood Cells, Reactive Lymphocytes, Red Blood Cells, Glucose, Insulin, Beck Depression score, Brain Taurine, Creatine and Phosphocreatine concentration). No single factor can reliably differentiate between healthy patients and those with schizophrenia. Therefore, it is valuable to simultaneously consider the values of multiple factors and classify patients using a multivariate model.

Questionnaire for the Perception of Psychotherapy Process by the Psychotherapist (QPPP) - a preliminary presentation of a research tool. / Kwestionariusz postrzegania procesu psychoterapii przez psychoterapeute (KPPP) ­ wstepna prezentacja narzedzia.

OBJECTIVES: The emotional reactions of therapist in the treatment process constitute the core of therapeutic work, but they are poorly represented in research area. The article presents the results of work on the creation of a new tool the Questionnaire for the Perception of Psychotherapy Process by the Psychotherapist (QPPP). METHODS: The Questionnaire containing 267 statements assessing cognitive, affective and behavioural reactions of psychotherapists in interaction with a specific patient was uploaded on the website. The link to the website, together with a request to complete the questionnaire, was sent to the members of the Psychotherapeutic Societies. The study involved 159 therapists, working mainly psychodynamically (91.95%). The analysis of basic descriptive statistics of test items and exploratory factor analysis by principal components method with varimax rotation were used. RESULTS: The work resulted in creating a tool consisting of 75 items grouped into 6 scales: Positive cooperation with the patient, Therapist burdened with commitment, Therapist in the centre of negative interest, Therapist with no room for intervention, The overwhelmed/overloaded therapist, The helpless/disengaged therapist. High alpha-Cronbach reliability of all distinguished factors was demonstrated at the level from 0.79 to 0.94. The data analysis also made it possible to create initial sten standards for therapists working in the psychodynamic approach. CONCLUSIONS: A tool was developed to assess emotions of therapist in relation to client. QPPP contains generally understandable terminology, independent of the therapist's dominant modality. The questionnaire can have many practical applications - both scientific and clinical.

Risk factors for weight gain in patients with first-episode psychosis. / Czynniki ryzyka przyrostu masy ciala u pacjentów z pierwszym epizodem psychozy.

OBJECTIVES: Assessment of the association between weight gain in patients with first-episode psychosis (FEP) and biopsychosocial and sociological factors. METHODS: 25 subjects with FEP aged 14-35 examined in week 1 (P1) and after three months of hospitalization (P3) were enrolled in the study. Within 3 months all patients were diagnosed with schizophrenia. The study used: a socio-demographic survey, Positive and Negative Syndrome Scale (PANSS), State-Trait Anxiety Inventory (STAI), Coping Inventory for Stressful Situations (CISS), Questionnaire Eating Behaviors (QEB), and routine biochemical test findings. For some variables, the differences (variable_D) between the values at P1 and P3 were calculated. RESULTS: Statistically significant correlations were shown between body weight_P1, _P3, _D, and healthy diet index_P1, _P3, severity of psychotic symptoms measured by the PANSS_P1 and _D, the CISS focused on emotions and task_P1, _P3 and _D, mother's body weight in youth and now, father's body weight in youth and now, and the number of the patient's siblings. In the linear regression analysis, body weight_P1 and the CISS focused on emotions_P1 turned out to be significant predictors of body weight_P3. CONCLUSIONS: Multifactorial influence of weight gain in FEP in schizophrenia was observed. Countermeasures against weight gain should refer not only to the diet, but also to the way the eating habits are related to psychopathology associated with psychosis and to the emotional functioning of the patient.

Immunological routine laboratory parameters at admission influence the improvement of positive symptoms in schizophrenia patients after pharmacological treatment.

Introduction: The standard care of schizophrenia patients is based on the assessment of their psychotic behavior, using interview-based, subjective scales that measure symptoms severity. We aimed at defining easily accessible and inexpensive blood-derived clinical diagnostic parameters that might serve as objective markers in the prediction of the effects of pharmacological treatment of schizophrenia patients. Methods: A total of 40 patients with schizophrenia diagnosis according to ICD 10 during psychotic decompensation were included in the study. Blood-based biochemical parameters, BMI and interview-based medical scales of symptom severity were determined - all at admission and after 12 weeks of standard pharmacological treatment. Results: The drops in scale values were correlated with clinical parameters. All scale changes after treatment were dependent on the value of the given scale at admission, with higher initial values leading to larger drops of the values after treatment. Models based on those correlations were significantly improved when immune and metabolism parameters were included. C4 complement and C-reactive protein (CRP) level at admission were predictive of changes in Positive and Negative Syndrome Scale (PANSS) subscales related to significant disruption of thought processes, reality testing and disorganization. The pharmacological treatment-driven changes in scales representing negative symptoms were correlated with markers of the patients' thyroid status and metabolism. Discussion: We show that objective markers can be obtained by testing immune and metabolic parameters from the patients' blood and may be added at a low cost to the standard care of schizophrenia patients in order to predict the outcome of pharmacological treatment.

The Association of the Oral Microbiota with the Effects of Acid Stress Induced by an Increase of Brain Lactate in Schizophrenia Patients.

The altered cerebral energy metabolism central to schizophrenia can be linked to lactate accumulation. Lactic acid is produced by gastrointestinal bacteria, among others, and readily crosses the blood-brain barrier, leading to the brain acidity. This study aimed to examine the association of the oral microbiota with the effects of acid stress induced by an increase of brain lactate in schizophrenia patients. The study included patients with a diagnosis of acute polyphasic psychotic disorder meeting criteria for schizophrenia at 3-month follow-up. Results: Individuals with a significantly higher total score on the Positive and Negative Syndrome Scale had statistically significantly lower lactate concentrations compared to those with a lower total score and higher brain lactate. We observed a positive correlation between Actinomyces and lactate levels in the anterior cingulate cap and a negative correlation between bacteria associated with lactate metabolism and some clinical assessment scales. Conclusions: Shifts in the oral microbiota in favour of lactate-utilising bacterial genera may represent a compensatory mechanism in response to increased lactate production in the brain. Assessment of neuronal function mediated by ALA-LAC-dependent NMDA regulatory mechanisms may, thus, support new therapies for schizophrenia, for which acidosis has become a differentiating feature of individuals with schizophrenia endophenotypes.

Redefining the Cut-Off Ranges for TSH Based on the Clinical Picture, Results of Neuroimaging and Laboratory Tests in Unsupervised Cluster Analysis as Individualized Diagnosis of Early Schizophrenia.

Thyroid abnormalities, including mild forms of hypothyroidism and hyperthyroidism, are reported as risk factors for the development of a number of neuropsychiatric disorders, including schizophrenia. The diagnostic process still takes into account the extreme ranges of the accepted reference values for serum TSH since the concentration of free thyroxine in the serum does not change by definition. TSH mU/L cut-off values in psychiatric patients are currently clinically considered in the case of extremely high serum TSH levels (>4.0 mU/L). The results obtained in this study suggest that the clinically significant value has a lower TSH cut-off point with an upper limit of 2-2.5 mU/L. The criteria for the differential diagnosis of patients with schizophrenia, however, mainly take into account statutory reference ranges without a background related to the history of thyroid diseases in the family. The results indicate the need to lower the upper cut-off values for TSH among patients with early psychosis, which is related to the potential clinical significance of the obtained values both in the field of clinical evaluation and neuroimaging and laboratory evaluation parameters. The cut-off points obtained with the prior available knowledge coincided with the values established in the unsupervised clustering method, which further confirms the legitimacy of their use in the individualized diagnosis strategy of schizophrenia.

Relationship of metabolic parameters with the course of the first episode of psychosis - preliminary research. / Zwiazek parametrów metabolicznych z przebiegiem pierwszego epizodu psychozy ­ badania wstepne.

OBJECTIVES: Cardiometabolic syndromes are the most common causes of complications shortening life expectancy in patients treated for mental disorders, especially schizophrenia. However, how much cardiometabolic risk is related to lifestyle, side-effects of treatment or psychosis is not clear. The aim of this study was a prospective assessment of metabolic changes in young, initially somatically healthy patients diagnosed with the first acute episode of psychosis with no prior pharmacological treatment. METHODS: The study involved 15 young patients (average age of 19.95 ± 6.88 years). Analyses (laboratory and clinical) were performed at the time of admission and after 3 and 12 weeks and included morphology, lipid profile, glucose, inflammation markers, blood pressure (BP), and body mass index (BMI). The severity of clinical symptoms was assessed using the Positive and Negative Syndrome Scale (PANSS), and the cognitive functioning was assessed using the Montreal Cognitive Assessment (MoCA). The duration of untreated psychosis (DUP) was also measured. RESULTS: There was a significant increase in BMI, dyslipidemia, inflammation, and systolic blood pressure after 12 weeks from the start of the treatment, while cortisol level decreased. A negative correlation was observed between PANSS-P (PANSS positivescale) measurements and total cholesterol, PANSS total and low-density lipoprotein, as well as DUPand MoCA. High-density lipoprotein (HDL) correlated positively with DUP, cortisol, monocytes, and white blood cells in the first week. CONCLUSIONS: The results of the study indicate a relationship between the development and treatment of the first acute episode of psychosis and the results of laboratory tests that are indicators of the development of metabolic stress in patients.

Improvement in clinical symptoms in patients with the first episode of psychosis is associated with a decrease in systemic nitric oxide availability. A pilot study. / Zwiazek poprawy objawów klinicznych u pacjentów z pierwszym epizodem psychozy i jej zwiazek ze spadkiem ogólnoustrojowej dostepnosci tlenku azotu. Badanie pilotazowe.

OBJECTIVES: The aim of the study was to assess the relationship between the improvement of the clinical condition of patients with the first episode of psychosis (FEP) and changes in - nitric oxide (NO) plasma concentration based on the level of its metabolites NO2- and NO3, as well as changes in lipid profile and biomarkers of systemic inflammation. METHODS: The study was carried out in agroup of 25 young patients with FEP (aged 14-35). Blood samples were collected in the 1st and 12th week after admission to the hospital to assess NO metabolites, lipid profile and inflammatory biomarkers. Demographic and clinical data were also analysed. RESULTS: In the study group, three months after admission to the hospital, an improvement in the clinical symptoms was observed, as evidenced by a decrease in the Positive and Negative Syndrome Scale (PANSS) scores. This improvement was associated with a decrease in the plasma nitrite concentration, a deterioration of the lipid profile and the activation of systemic inflammation. Interestingly, in the 1st week after the hospital admission, a longer duration of untreated psychosis (DUP) was associated with a lower NO2- plasma concentration, and a higher intensity of positive symptoms (PANSS Positive Symptoms Scale) was associated with higher CRP plasma level. CONCLUSIONS: Our results suggest that adverse metabolic response, systemic inflammation and a fall in systemic NO bioavailability represent early systemic manifestations of FEP that are not controlled by short-term anti-psychotic treatment and may pose cardiovascular risk.

Determinants of Schizophrenia Endophenotypes Based on Neuroimaging and Biochemical Parameters.

Despite extensive research, there is no convincing evidence of a reliable diagnostic biomarker for schizophrenia beyond clinical observation. Disorders of glutamatergic neurotransmission associated with N-methyl-D-aspartate (NMDA) receptor insufficiency, neuroinflammation, and redox dysregulation are the principal common mechanism linking changes in the periphery with the brain, ultimately contributing to the emergence of negative symptoms of schizophrenia that underlie differential diagnosis. The aim of the study was to evaluate the influence of these systems via peripheral and cerebral biochemical indices in relation to the patient's clinical condition. Using neuroimaging diagnostics, we were able to define endophenotypes of schizophrenia based on objective laboratory data that form the basis of a personalized approach to diagnosis and treatment. The two distinguished endophenotypes differed in terms of the quality of life, specific schizophrenia symptoms, and glutamatergic neurotransmission metabolites in the anterior cingulate gyrus. Our results, as well as further studies of the excitatory or inhibitory balance of microcircuits, relating the redox systems on the periphery with the distant regions of the brain might allow for predicting potential biomarkers of neuropsychiatric diseases, including schizophrenia. To the best of our knowledge, our study is the first to identify an objective molecular biomarker of schizophrenia outcome.

The Relationship between the Level of Anterior Cingulate Cortex Metabolites, Brain-Periphery Redox Imbalance, and the Clinical State of Patients with Schizophrenia and Personality Disorders.

Schizophrenia is a complex mental disorder whose course varies with periods of deterioration and symptomatic improvement without diagnosis and treatment specific for the disease. So far, it has not been possible to clearly define what kinds of functional and structural changes are responsible for the onset or recurrence of acute psychotic decompensation in the course of schizophrenia, and to what extent personality disorders may precede the appearance of the appropriate symptoms. The work combines magnetic resonance spectroscopy imaging with clinical evaluation and laboratory tests to determine the likely pathway of schizophrenia development by identifying peripheral cerebral biomarkers compared to personality disorders. The relationship between the level of metabolites in the brain, the clinical status of patients according to International Statistical Classification of Diseases and Related Health Problems, 10th Revision ICD-10, duration of untreated psychosis (DUP), and biochemical indices related to redox balance (malondialdehyde), the efficiency of antioxidant systems (FRAP), and bioenergetic metabolism of mitochondria, were investigated. There was a reduction in the level of brain N-acetyl-aspartate and glutamate in the anterior cingulate gyrus of patients with schisophrenia compared to the other groups that seems more to reflect a biological etiopathological factor of psychosis. Decreased activity of brain metabolites correlated with increased peripheral oxidative stress (increased malondialdehyde MDA) associated with decreased efficiency of antioxidant systems (FRAP) and the breakdown of clinical symptoms in patients with schizophrenia in the course of psychotic decompensation compared to other groups. The period of untreated psychosis correlated negatively with glucose value in the brain of people with schizophrenia, and positively with choline level. The demonstrated differences between two psychiatric units, such as schizophrenia and personality disorders in relation to healthy people, may be used to improve the diagnosis and prognosis of schizophrenia compared to other heterogenous psychopathology in the future. The collapse of clinical symptoms of patients with schizophrenia in the course of psychotic decompensation may be associated with the occurrence of specific schizotypes, the determination of which is possible by determining common relationships between changes in metabolic activity of particular brain structures and peripheral parameters, which may be an important biological etiopathological factor of psychosis. Markers of peripheral redox imbalance associated with disturbed bioenergy metabolism in the brain may provide specific biological factors of psychosis however, they need to be confirmed in further studies.