SYMPTOM SEVERITY IN SCHIZOPHRENIA PATIENTS WITH NPAS3, DYSBINDIN-1 AND/OR TRIOBP PROTEIN PATHOLOGY IN THEIR BLOOD SERUM: A PANSS-BASED FOLLOW UP STUDY.

BACKGROUND: It has been proposed that aggregation of specific proteins in the brain may be a pathological element in schizophrenia and other chronic disorders. Multiple such aggregating proteins have now been implicated through post mortem investigation, including NPAS3 (Neuronal PAS domain protein 3), dysbindin-1 (encoded by the DTNBP1, Dystrobrevin Binding Protein 1, gene) and TRIOBP (Trio-Binding Protein, multiple isoforms). While the presence of protein aggregates in the brain is interesting in terms of understanding pathology, it is impractical as a biomarker. These proteins were therefore investigated recently in blood serum of schizophrenia patients and controls, showing patients to have higher levels of NPAS3 in their serum generally. TRIOBP-1 and dysbindin-1 were also found in an insoluble state, implying aggregation, but did not clearly corresponding to disease state. SUBJECT AND METHODS: We revisit 47 of the originally recruited 50 patients with schizophrenia, all of whom are Croatian and aged between 18 and 72. We assessed their symptom specificity and severity using PANSS (the Positive and Negative Symptoms Scale), comparing those with NPAS3, insoluble dysbindin-1 and/or insoluble TRIOBP-1 in their blood serum to those lacking any such protein dysregulation. RESULTS: The frequency of each individual potential protein pathology among these patients was too low for meaningful statistical analysis, however the 11 patients that displayed one or more of these pathologies (NPAS3, dysbindin-1, TRIOBP-1 and/or TRIOBP-5/6) showed a subtle but significant increase in total PANSS scores compared to the 36 patients displaying none of the pathologies (p = 0.031), seemingly driven principally by increased scores on the general psychopathology scale. CONCLUSION: While the numbers of patients involved do not allow firm conclusions to be drawn at this time, this provides the first indication that disturbed proteostasis in blood serum, of proteins that aggregate in the brains of schizophrenia patients, may correlate with the severity of schizophrenia symptoms.

Onset of Schizophrenia Prior to the End of Brain Maturation Alters Grey Matter Volume Loss.

BACKGROUND: Brain maturation is considered completed around the age of 25, when prefrontal cortex maturation has been achieved. The aim of our study was to investigate the alterations of grey matter (GM) in patients with the onset of schizophrenia before and after the completion of brain maturation. SUBJECTS AND METHODS: The study group included 100 schizophrenia patients, while the control group comprised 50 healthy individuals. Brain magnetic resonance imaging was acquired on a 1.5 T scanner. Voxel-based morphometry (VBM) analyses were performed between groups. RESULTS: GM of the schizophrenic patients is reduced in many regions (p<0.005 FDR corrected). Most widespread reduction is detected in frontal cortex and cerebellum, the other regions being limbic cortex, insula, cuneus, precuneus, superior temporal gyrus and motor cortex. The decrease of grey matter volume (GMV) increases with the increase in number of psychotic episodes and is more pronounced in the patients with earlier onset of the disease. CONCLUSIONS: The age of the onset of the disease is important for both total and relative loss of GMV. Earlier onset of schizophrenia, prior to full brain maturation results in significant reduction of GM in comparison with healthy subjects and patients with later, post full brain maturation onset of the disease.

Influence of Psychotic Episodes on Grey Matter Volume Changes in Patients with Schizophrenia.

BACKGROUND: Schizophrenia is a severe illness whose clinical course is characterized by various numbers of psychotic episodes (PE). The neurotoxic hypothesis (NH) of schizophrenia assumes that psychosis is biologically toxic. The aim of the study was to investigate whether schizophrenia patients (SP) with multiple PE have greater grey matter volume (GMV) reduction compared to SP with fewer PE. SUBJECTS AND METHODS: We enrolled 106 adult SP and 63 healthy controls. Demographic and clinical data were collected and statistically analysed for all included subjects. Magnetic resonance imaging (MRI) of the brain was acquired on a 1.5 T scanner. SP were grouped according to the number of PE into a group with up to 3 PE (SCHG-1) and with 4 or more PE (SCHG-2). SCHG-1 was further subdivided into two groups regarding to disease duration (DD). Voxel-based morphometry (VBM) analyses were performed between SP groups as well as between SP groups and the healthy controls group (HCG). RESULTS: No relevant GMV differences were detected between SP groups. Comparison between HCG and SCHG-1 showed only 3 regions with reduced GMV, while multiple regions with reduced GMV were detected when comparing HCG and SCHG-2. CONCLUSIONS: GMV reduction in schizophrenia varies depending on the number of PE when compared to HCG, regardless of disease duration (DD), but PE is not the only contributing factor that leads to neurotoxicity.

Immunological Characteristics of Schizophrenia.

There are many theories about the etiology of schizophrenia. This paper presents the assumptions and latest findings about many immunological characteristics of schizophrenia. According to the neuroimunological theory, this disorder is due to neuroimunological disbalance, increased microglial activity and increased levels of proinflammatory cytokines. Studies have found that intrauterine infections in pregnant women have an effect on the fetal brain development, and that infections with rubella, measles, herpes virus, and toxoplasma are associeted with schizophrenia onset in adult life. In the first episode of schizophrenia and during exacerbation in the serum of the patient, an increased level of proinflammatory cytokines was found. Increased levels of IL-6, TNF-α and IL-1ß, and decreased levels of anti-inflammatory cytokines, Il-10. Interleukin 6 levels increase in the psychotic phase of the disease and normalize after the antipsychotic drug treatment. Increased level of IL-6 is associated with severe cognitive impairment and it is more common with patients who had been without adequate treatment for a long time and patients with therapeutic-resistant schizophrenia. Treatment of schizophrenia could be improved by the introduction of anti-inflammatory drug in the therapy.

Satisfaction with life and coping skills in the acute and chronic urticaria.

BACKGROUND: The purpose of this study was to examine the differences in satisfaction with life and coping strategies between patients with acute and chronic urticaria. SUBJECTS AND METHODS: Sixty patients with urticaria were divided into 2 groups after 6 weeks of standardized dermatology treatment (33 patients with acute and 27 patients with chronic urticaria). At baseline, all patients answered the following questionnaires: Satisfaction with Life Scale (SWLS), Personal Wellbeing Index (PWI-A), The Multidimensional Coping Inventory (COPE) and General questionnaire (age, gender, education, employment, marital status). After six weeks all the participants were re-tested with 2 questionnaires: SWLS and PWI-A. RESULTS: Six weeks after the initial testing there was a statistically significant difference in satisfaction with life between patients with acute and chronic urticaria. Patients with acute urticaria were more satisfied with their lives than patients with chronic urticaria. Also, there was a statistically significant difference in the use of emotion-focused coping, seeking social support for emotional reasons and seeking social support for instrumental reasons. Patients with acute urticaria used emotion-focused coping and sought social support for emotional and instrumental reasons to a greater degree than patients with chronic urticaria. CONCLUSION: Patients with acute urticaria were more satisfied with their lives than patients with chronic urticaria. Patients with acute urticaria used emotion-focused coping and sought social support for emotional and instrumental reasons to a greater degree than patients with chronic urticaria.

HFE mutations and transferrin C1/C2 polymorphism among Croatian patients with schizophrenia and schizoaffective disorder.

The aim of this study was to investigate the possible influence of hemochromatosis gene mutations (HFE-C282Y and H63D) and transferrin gene C2 variant (TF-C2) on susceptibility to schizophrenia and schizoaffective disorder and/or age at first hospital admission. Genotyping was performed in 176 Croatian patients and 171 non-psychiatric Croatian controls using PCR-RFLP analyses. Regarding the H63D mutation, allele and genotype frequencies reached boundary statistical significance. Other allele and genotype distributions were not significantly different between two groups. We also analyzed age at first hospital admission as a continuous variable using the non-parametric Mann-Whitney U-test and Kruskal-Wallis test, and multiple regression analysis. The results of these tests were negative. We concluded that investigated HFE mutations and TF-C2 variant are not high-risk genetic variants for schizophrenia/schizoaffective disorder in our population. Also our data do not support their impact on age at onset of the first psychotic symptoms.

The influence of aesthetic surgery on the profile of emotion.

In the clinical practise it has been observed that the person changes physically, too, after aesthetic surgery. The aim of this work was to examine, by objective psychological measurements, what changes occur, and what personality features change. Forty six subjects that had an aesthetic surgery were examined; they were tested before, and eighteen month after the surgery by the Profile Index of Emotion (PIE). Before the re-testing the subjects were analyzed by "The Life Events Scale" to exclude the possibility of the influence of new life events on the results of the re-test. The control group of 29 volunteers was tested by the same psychological instruments. The control group never verbalized the wish for an aesthetic surgery; they were never in psychiatric treatment, and the corresponded to the experimental group in the age, sex and education level. Analysis of the data obtained from PIE test before and after the operation shows a statistical significant increase of the adaptability segments and an improvement of capacity for taking and giving. Emotional conflict does not disappear, but a new balance is established, satisfaction is higher, and the identity is more integrated.

Protein Aggregation of NPAS3, Implicated in Mental Illness, Is Not Limited to the V304I Mutation.

An emerging phenomenon in our understanding of the pathophysiology of mental illness is the idea that specific proteins may form insoluble aggregates in the brains of patients, in partial analogy to similar proteinopathies in neurodegenerative diseases. Several proteins have now been detected as forming such aggregates in the brains of patients, including DISC1, dysbindin-1 and TRIOBP-1. Recently, neuronal PAS domain protein 3 (NPAS3), a known genetic risk factor for schizophrenia, was implicated through a V304I point mutation in a family with major mental illness. Investigation of the mutation revealed that it may lead to aggregation of NPAS3. Here we investigated NPAS3 aggregation in insular cortex samples from 40 individuals, by purifying the insoluble fraction of these samples and testing them by Western blotting. Strikingly, full-length NPAS3 was found in the insoluble fraction of 70% of these samples, implying that aggregation is far more widely spread than can be accounted for by this rare mutation. We investigated the possible mechanism of aggregation further in neuroblastoma cells, finding that oxidative stress plays a larger role than the V304I mutation. Finally, we tested to see if NPAS3 aggregation could also be seen in blood serum, as a more accessible tissue than the human brain for future diagnosis. While no indication of NPAS3 aggregation was seen in the serum, soluble NPAS3 was detected, and was more prevalent in patients with schizophrenia than in those with major depressive disorder or controls. Aggregation of NPAS3 therefore appears to be a widespread and multifactorial phenomenon. Further research is now needed to determine whether it is specifically enhanced in schizophrenia or other mental illnesses.

Niacin skin flush test: a research tool for studying schizophrenia.

BACKGROUND: A body of biochemical evidence suggests that abnormal phospholipid metabolism may play a role in the etiology of schizophrenia, and possibly, other psychiatric and neurological diseases. Niacin, a B-complex vitamin, induces prostaglandin synthesis, vasodilatation, and skin flushing when applied as a solution on the skin or taken orally. In schizophrenia, diminished or absent skin response to niacin represents a robust finding. RESULTS: Attenuated niacin skin-flush response has been analysed as a potential biochemical marker of impaired prostaglandin signaling in schizophrenia. Diminished skin redness after topical application of niacin might be caused by a reduced level of the precursor arachidonic acid in the peripheral membranes, increased activity of the enzyme phospholipase A2, abnormal expression of niacin or prostaglandin receptors, or poor vasomotor activity of cutaneous capillary walls. Heritability estimates established in several studies support niacin skin flush response as a vulnerability trait for the development of psychosis. However, the exact mechanism of a reduced skin flush, the possible influence of the long-term use of antipsychotics, and the usefulness of the test for diagnostic purpose are not clear yet. CONCLUSIONS: Niacin skin flush test is a simple, non-invasive and easily replicable method in the research of schizophrenia. The studies investigating niacin flushing in schizophrenia are numerous but incoherent regarding methods of niacin application and evaluation of the results. New studies, controlling adequately for age, sex, drug abuse, diet, as well as genetic factors that may influence the intensity and reaction time, are necessary to clarify the usefulness of niacin testing in psychiatry.

Phospholipid membrane abnormalities and reduced niacin skin flush response in schizophrenia.

OBJECTIVES: Reduced n-3 and n-6 polyunsaturated fatty acids (PUFAs) content in red blood cell (RBC) membranes and abnormal membrane phospholipid metabolism were repeatedly implicated in the etiology of schizophrenia. FINDINGS: Prenatal and perinatal depletion of PUFAs interferes with normal brain development and function. The lack of docosahexaenoic acid - DHA in the brain is reflected in lower membrane DHA/AA (AA - arachidonic acid) ratio, increased activity of AA-metabolizing enzymes, and disturbance of downstream metabolic pathways involved in signaling, growth modulation, brain glucose uptake, immune functions, neurotransmission, synaptogenesis and neurogenesis. Preliminary high-throughput metabolomic studies revealed abnormal biochemical profile in patients with schizophrenia or brief psychotic disorder when compared to healthy controls. The results of both metabolomic and proteomic studies pointed to energy metabolism and lipid biosynthesis being impaired in schizophrenia. The usefulness of antipsychotic medication and supplementation with PUFAs in reverting to the normal metabolic state has been suggested in early treatment of the first psychotic episode. Abnormalities of phospholipid metabolism can be also detected as attenuated niacin skin flush response in the variety of neuropsychiatric disorders. CONCLUSIONS: Disturbances of lipid homeostasis could represent biochemical markers in the preclinical phase of neuropsychiatric illnesses and could serve as triggers in genetically vulnerable individuals. The assessment of patients' lipid status may also help in monitoring the course of the disease and treatment response. In this regard, simple, cheap and fast niacin skin flush test might be valuable. It might help in diagnosis of adolescents and young adults with psychotic behaviour, or in defining the necessity for long-term antipsychotic therapy. Along with antipsychotic medication schizophrenic patients need specific medical nutrition therapies.

Craniofacial morphologic and anthropometric features of Croatian schizophrenia patients and non-psychiatric controls--a pilot study.

AIM: to evaluate differences in craniofacial morphologic features and several anthropometric measures between schizophrenia patients and non-psychiatric controls, and to find the best-fit model to differentiate between two groups. METHODS: 40 morphologic features of the head and face, and 5 craniofacial anthropometric measures were evaluated using the Lane Dysmorphology Scale in 58 patients and 46 controls. Total MPA score and subscores for different craniofacial regions were calculated. Individual items were examined using logistic regression analyses to define a model that can discriminate between patient vs. control status. RESULTS: total MPA score, and several subscores (general asymmetry, nasal, lip, ear and tongue) were significantly higher in the patient group. Patients were distinguished by significantly higher measures of maxillary and mandibular facial arcs, general and subtle facial asymmetries presented as deviation of facial landmarks from the vertical facial midline and horizontals, more variable vermilion of the upper lip, tongue surface, frenulum and anterior hair margin, and more adherent and underdeveloped earlobes. A final regression model including maxillary are, facial asymmetry, and adherent earlobes as independent predictors proved useful to efficiently recognize schizophrenia patients (specificity and positive prediction value of 100% when all the three items were present in an individual) or to exclude risk for schizophrenia (sensitivity and negative prediction value of 96.6% and 84.6%, respectively, in cases no one of the three items was present). CONCLUSIONS: schizophrenia patients evidenced significantly more craniofacial dysmorphology than controls. The model revealed in the study needs to be verified in larger samples and other populations.

Aspects of sexual self-perception in schizophrenic patients

Objective: Self-perception is a complex, dynamic system and sexual self-perception’s only one of the items in that complex system. Our goal was to establish whether the differences in sexual self-perception between schizophrenic patients and healthy individuals exist, and to establish possible differences in sexual self-perception between acute and chronic schizophrenic patients. Method: Bezinovic’s test for sexual self-perception was used because it assesses multiple aspects of sexual self-perception and provides thorough insight of that part of self. Results: Results revealed that schizophrenic patients, compared to healthy individuals, scored significantly higher on the aspects of negative emotionality and sexual incompetence and significantly lower on the aspect of sexual satisfaction. No statistically significant differences were established between acute and chronic schizophrenic patients. Conclusions: It can be concluded that the conscious part of libido organization in schizophrenic patients exhibits proper consciousness of own sexuality, normal readiness for sexual activity, normal sexual adventurism, significantly higher negative emotionality and sexual incompetence and significantly lower sexual satisfaction (AU)

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