| 1 | Psychol Med 2004 Oct 34: 1165-76 |
|---|---|
| PMID | 15697043 |
| Title | The impact of beliefs about mental health problems and coping on outcome in schizophrenia. |
| Abstract | Using the theoretical framework of the Self Regulation Model (SRM), many studies have demonstrated that beliefs individuals hold about their physical health problems are important in predicting health outcomes. This study tested the SRM in the context of a mental health problem, schizophrenia. One hundred and twenty-four people with a diagnosis of schizophrenia were assessed on measures of symptom severity, beliefs about their mental health problems, coping and appraisal of outcome at two time points, 6 months apart. Using multivariate analyses and controlling for severity of symptoms, beliefs about mental health were found to be significant predictors of outcome. Beliefs about greater negative consequences were the strongest and most consistent predictors of a poorer outcome in both cross-sectional and longitudinal analyses. These results suggest that the SRM is a promising model for mental health problems and may highlight important areas for development in clinical, and especially psychosocial interventions. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 2 | Prog. Neuropsychopharmacol. Biol. Psychiatry 2005 May 29: 621-5 |
| PMID | 15866367 |
| Title | Cognitive functions in prepsychotic patients. |
| Abstract | Cognitive dysfunctions are now widely understood as an essential feature of schizophrenia. A great number of cognitive disturbances have been described in drug-naive first-episode patients as well. The full-blown psychotic symptoms are usually preceded by a longer prodromal period, in which non-specific psychological disturbances are already present. The late prodromal phase is also coined as the prepsychotic state, with attenuated, isolated psychotic symptoms. The aim of the present study was to detect cognitive dysfunctions among young adults at the prepsychotic stage with the use of a standardized computer based cognitive test battery. Eleven (9 men, 2 women) young Hungarian adults referred to the Outpatient Clinic of the Department of Psychiatry at the University of Debrecen were studied. The patients were re-evaluated for psychotic symptoms after 12 months. The patients had no history of psychiatric disorders or psychotic episodes and were referred by general practitioners on account of non-specific emotional or behavioural abnormalities. The subjects were asked to perform a series of 13 computerized neuropsychological tests of the Cambridge Neuropsychological Test. The performance of the patients were compared to that of the standardized database of the Cambridge Neuropsychological Test. The performance of the prepsychotic patients was significantly lower compared to the healthy individuals in the paired associate learning (PAL, p<0.001), Spatial recognition memory (SRM, p<0.05), Rapid visual processing (RVP, p<0.05), and Spatial working memory (SWM, p<0.05) tests. Cognitive deficits were found mainly in attentional, frontal and prefrontal cognitive functions. These impairments may be present at the early stages of the development of psychosis and the standardized cognitive test battery (CANTAB) might be a useful tool for the detection of early cognitive impairments and provide a rationale for early intervention in individuals at risk of developing psychosis. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 3 | BMC Res Notes 2012 -1 5: 146 |
| PMID | 22420779 |
| Title | The application of selective reaction monitoring confirms dysregulation of glycolysis in a preclinical model of schizophrenia. |
| Abstract | Establishing preclinical models is essential for novel drug discovery in schizophrenia. Most existing models are characterized by abnormalities in behavioral readouts, which are informative, but do not necessarily translate to the symptoms of the human disease. Therefore, there is a necessity of characterizing the preclinical models from a molecular point of view. Selective reaction monitoring (SRM) has already shown promise in preclinical and clinical studies for multiplex measurement of diagnostic, prognostic and treatment-related biomarkers. We have established an SRM assay for multiplex analysis of 7 enzymes of the glycolysis pathway which is already known to be affected in human schizophrenia and in the widely-used acute PCP rat model of schizophrenia. The selected enzymes were hexokinase 1 (Hk1), aldolase C (Aldoc), triosephosphate isomerase (Tpi1), glyceraldehyde-3-phosphate dehydrogenase (Gapdh), phosphoglycerate mutase 1 (Pgam1), phosphoglycerate kinase 1 (Pgk1) and enolase 2 (Eno2). The levels of these enzymes were analyzed using SRM in frontal cortex from brain tissue of PCP treated rats. Univariate analyses showed statistically significant altered levels of Tpi1 and alteration of Hk1, Aldoc, Pgam1 and Gapdh with borderline significance in PCP rats compared to controls. Most interestingly, multivariate analysis which considered the levels of all 7 enzymes simultaneously resulted in generation of a bi-dimensional chart that can distinguish the PCP rats from the controls. This study not only supports PCP treated rats as a useful preclinical model of schizophrenia, but it also establishes that SRM mass spectrometry could be used in the development of multiplex classification tools for complex psychiatric disorders such as schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 4 | J. Proteome Res. 2012 Apr 11: 2533-43 |
| PMID | 22360420 |
| Title | Proteomic analysis identifies dysfunction in cellular transport, energy, and protein metabolism in different brain regions of atypical frontotemporal lobar degeneration. |
| Abstract | Frontotemporal lobar degeneration (FTLD) is an umbrella term for a heterogeneous group of young-onset dementias of uncertain prevalence and incidence worldwide. Atypical cases of FTLD with fused in sarcoma inclusions (aFTLD-U) have been described recently, but their molecular characterization is still due. Using shotgun mass spectrometry, we identified a total of 107 differentially expressed proteins in the prefrontal cortex, cerebellum and occipital lobe from aFTLD-U patients compared to controls. These proteins are involved in a range of biological pathways such as cellular transport in the prefrontal cortex, energy metabolism in the cerebellum, and protein metabolism in the occipital lobe. In addition, they were validated by selective reaction monitoring (SRM). Comparison of the aFTLD-U proteomic findings with similar studies of Alzheimer's disease and schizophrenia led to identification of proteins that may be related to dementias and psychoses, respectively. Further studies of aFTLD-U and other FTLD subtypes are warranted, although this will require intensive biobanking efforts. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 5 | Neurosci. Lett. 2013 Mar 537: 17-22 |
| PMID | 23353103 |
| Title | COMT and MTHFR polymorphisms interaction on cognition in schizophrenia: an exploratory study. |
| Abstract | The investigation of the catechol-O-methyltransferase (COMT-[rs4680]) and methylenetetrahydrofolate reductase (MTHFR-[rs1801133]) polymorphisms' interaction might shed light into the pathogenetic mechanisms of the cognitive dysfunction in schizophrenia. In an exploratory study, we hypothesized that the MTHFR 677T allele which has been related to a hypoactive MTHFR enzyme would augment the unfavorable effects of COMT Val158 homozygosity which has been associated with COMT enzyme hyperfunction. 90 schizophrenia patients and 55 healthy volunteers were assessed on psychomotor speed, pattern and spatial recognition memory (SRM), spatial working memory (SWM), attentional flexibility and planning (Stockings of Cambridge-SOC). IQ scores in a random subgroup of patients were also measured. A significant COMT×MTHFR interaction on SWM (p=0.048) and planning (p=0.026) was revealed in both groups. Among COMT-Val/Val participants, MTHFR-C/C made more SWM errors (p=0.033) and solved fewer SOC problems (p=0.025) than MTHFR-T carriers. In patients, there was a significant COMT×MTHFR interaction on full scale IQ (p=0.035): among COMT-Met carriers, MTHFR-T carriers performed significantly worse than MTHFR-C/C (p=0.021), which was driven by a COMT×MTHFR interaction involving performance IQ (p=0.047). In conclusion, COMT and MTHFR polymorphisms interacted on cognition, suggesting that the MTHFR enzyme activity might moderate the effects of the COMT enzyme. In contrast to our initial hypothesis, the MTHFR T-allele attenuated the cognitive effects of COMT Val homozygosity. In this preliminary study, we propose that dopaminergic and intracellular methylation mechanisms could interact on cognitive deficits in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 6 | Clin. Chim. Acta 2013 Aug 423: 69-74 |
| PMID | 23623924 |
| Title | Development and validation of a sensitive and robust LC-MS/MS with electrospray ionization method for simultaneous quantitation of quetiapine and its active metabolite norquetiapine in human plasma. |
| Abstract | Quetiapine is an atypical antipsychotic agent for the treatment of schizophrenia, acute mania, and acute bipolar depression. The antidepressive response is considered to be mediated by the metabolite norquetiapine (N-desalkylquetiapine), and the aim of this study was to develop an LC-MS/MS method to measure concentrations of these compounds in human plasma. Following one step liquid-liquid extraction, the analytes were separated using an isocratic mobile phase on a Sunfire C18 column (50mm×2.1mm, 5?m). The retention times were 2.12, 2.24, 2.12 and 2.19min for quetiapine, norquetiapine and their respective stable labeled internal standards, respectively. Cycle time was 4min. Selected reaction monitoring (SRM) in positive ion mode was used for quantitation. The present method exhibited a linear dynamic range of 0.5-500ng/ml for quetiapine and 0.6-600ng/ml for norquetiapine. The applicable range was extended by dilution up to 5-fold with blank matrix. The accuracy and precision for quetiapine were <103.0% and 8.8%, for norquetiapine were <108.8% and 11.1%, respectively. A rapid, sensitive, and robust LC-MS/MS method for quantifying quetiapine and its metabolite norquetiapine levels in human plasma was validated and successfully applied to samples from schizophrenic patients in clinical pharmacokinetics studies. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 7 | Clin. Chim. Acta 2013 Aug 423: 69-74 |
| PMID | 23623924 |
| Title | Development and validation of a sensitive and robust LC-MS/MS with electrospray ionization method for simultaneous quantitation of quetiapine and its active metabolite norquetiapine in human plasma. |
| Abstract | Quetiapine is an atypical antipsychotic agent for the treatment of schizophrenia, acute mania, and acute bipolar depression. The antidepressive response is considered to be mediated by the metabolite norquetiapine (N-desalkylquetiapine), and the aim of this study was to develop an LC-MS/MS method to measure concentrations of these compounds in human plasma. Following one step liquid-liquid extraction, the analytes were separated using an isocratic mobile phase on a Sunfire C18 column (50mm×2.1mm, 5?m). The retention times were 2.12, 2.24, 2.12 and 2.19min for quetiapine, norquetiapine and their respective stable labeled internal standards, respectively. Cycle time was 4min. Selected reaction monitoring (SRM) in positive ion mode was used for quantitation. The present method exhibited a linear dynamic range of 0.5-500ng/ml for quetiapine and 0.6-600ng/ml for norquetiapine. The applicable range was extended by dilution up to 5-fold with blank matrix. The accuracy and precision for quetiapine were <103.0% and 8.8%, for norquetiapine were <108.8% and 11.1%, respectively. A rapid, sensitive, and robust LC-MS/MS method for quantifying quetiapine and its metabolite norquetiapine levels in human plasma was validated and successfully applied to samples from schizophrenic patients in clinical pharmacokinetics studies. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 8 | Mol Autism 2014 -1 5: 38 |
| PMID | 25061506 |
| Title | Integrative proteomic analysis of the NMDA NR1 knockdown mouse model reveals effects on central and peripheral pathways associated with schizophrenia and autism spectrum disorders. |
| Abstract | Over the last decade, the transgenic N-methyl-D-aspartate receptor (NMDAR) NR1-knockdown mouse (NR1(neo-/-)) has been investigated as a glutamate hypofunction model for schizophrenia. Recent research has now revealed that the model also recapitulates cognitive and negative symptoms in the continuum of other psychiatric diseases, particularly autism spectrum disorders (ASD). As previous studies have mostly focussed on behavioural readouts, a molecular characterisation of this model will help to identify novel biomarkers or potential drug targets. Here, we have used multiplex immunoassay analyses to investigate peripheral analyte alterations in serum of NR1(neo-/-) mice, as well as a combination of shotgun label-free liquid chromatography mass spectrometry, bioinformatic pathway analyses, and a shotgun-based 40-plex selected reaction monitoring (SRM) assay to investigate altered molecular pathways in the frontal cortex and hippocampus. All findings were cross compared to identify translatable findings between the brain and periphery. Multiplex immunoassay profiling led to identification of 29 analytes that were significantly altered in sera of NR1(neo-/-) mice. The highest magnitude changes were found for neurotrophic factors (VEGFA, EGF, IGF-1), apolipoprotein A1, and fibrinogen. We also found decreased levels of several chemokines. Following this, LC-MS(E) profiling led to identification of 48 significantly changed proteins in the frontal cortex and 41 in the hippocampus. In particular, MARCS, the mitochondrial pyruvate kinase, and CamKII-alpha were affected. Based on the combination of protein set enrichment and bioinformatic pathway analysis, we designed orthogonal SRM-assays which validated the abnormalities of proteins involved in synaptic long-term potentiation, myelination, and the ERK-signalling pathway in both brain regions. In contrast, increased levels of proteins involved in neurotransmitter metabolism and release were found only in the frontal cortex and abnormalities of proteins involved in the purinergic system were found exclusively in the hippocampus. Taken together, this multi-platform profiling study has identified peripheral changes which are potentially linked to central alterations in synaptic plasticity and neuronal function associated with NMDAR-NR1 hypofunction. Therefore, the reported proteomic changes may be useful as translational biomarkers in human and rodent model drug discovery efforts. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 9 | Psychol Med 2014 Feb 44: 477-87 |
| PMID | 23721746 |
| Title | Neural correlates of the abolished self-referential memory effect in schizophrenia. |
| Abstract | The self-referential memory (SRM) effect refers to the phenomenon that stimuli processed with reference to the self are better remembered than those referenced to others. Studies have shown that schizophrenia patients do not have this memorial advantage for self-referenced information. The current study investigated the electrophysiological mechanism of the abolished SRM effect in schizophrenia. Twenty schizophrenia patients and 22 controls were recruited to complete an SRM task. We used a high-time resolution event-related potential (ERP) technique to analyze the electrophysiological differences between patients and controls during self- and other-reflection processing. Behavior data indicated that healthy controls had a typical SRM bias that was absent in the schizophrenia patients. ERP comparison between groups showed that the schizophrenia patients presented smaller voltages in both self- and other-reflection conditions in the 160-260 ms (P2 component) and 800-1200 ms (positive slow wave) time windows over the pre/frontal cortex. Furthermore, the N2 amplitudes (270-380 ms) differed between self- and other-reflection conditions in patients but not in normal controls. More importantly, we found that the P3 amplitudes in the parietal cortex correlated significantly with the SRM bias score in the patients (r = -0.688). These results provide comprehensive and direct electrophysiological evidence for self- and other-reflective dysfunction in schizophrenia patients and contribute to our understanding of the underlying neural substrates of the abolished SRM effect in schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 10 | J. Proteome Res. 2015 Jan 14: 411-21 |
| PMID | 25363195 |
| Title | A targeted multiplexed proteomic investigation identifies ketamine-induced changes in immune markers in rat serum and expression changes in protein kinases/phosphatases in rat brain. |
| Abstract | There is substantial interest in the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine in psychiatric research because it exerts acute psychotomimetic and rapid antidepressant effects in rodents and humans. Here, we investigated proteomic changes in brain and serum after acute treatment of rats with ketamine using two targeted proteomic profiling methods. Multiplex immunoassay profiling of serum identified altered levels of interleukin 4, tumor necrosis factor alpha, and fibroblast growth factor 9, suggesting a link between ketamine exposure and peripheral inflammation and growth factor dysregulation. Selected reaction monitoring mass spectrometry profiling of rat brain tissue found that proteomic changes occurred in the frontal cortex and to a greater extent in the hippocampus. This involved changes in signaling kinases and proteases such as protein kinase C beta, neurochondrin (NCDN), calcineurin, extracellular signal-regulated kinsase 1 (ERK1), and mammalian target of rapamycin (MTOR). Furthermore, altered levels were found for proteins associated with neurotransmitter metabolism (mitochondrial aspartate aminotransferase, catechol O-methyl transferase, synaptic vesicle endo-/exocytosis (vesicle fusing ATPase (NSF), synapsin 1 (SYN1), syndapin-1 (PACN1)). Consistent with previous global proteomic studies, we confirmed known changes in mitochondrial complex I, prohibitin (PHB) and neurofilament proteins (neurofilament light chain and ?-internexin (AINX)). Taken together, the proteomic changes parallel those described in human psychiatric pathology. The results will help to elucidate ketamine's mechanism of action, which will facilitate development of novel drugs for the treatment of schizophrenia and major depressive disorder. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 11 | J. Proteome Res. 2015 Aug 14: 3174-87 |
| PMID | 26043028 |
| Title | Hippocampal Proteomic and Metabonomic Abnormalities in Neurotransmission, Oxidative Stress, and Apoptotic Pathways in a Chronic Phencyclidine Rat Model. |
| Abstract | schizophrenia is a neuropsychiatric disorder affecting 1% of the world's population. Due to both a broad range of symptoms and disease heterogeneity, current therapeutic approaches to treat schizophrenia fail to address all symptomatic manifestations of the disease. Therefore, disease models that reproduce core pathological features of schizophrenia are needed for the elucidation of pathological disease mechanisms. Here, we employ a comprehensive global label-free liquid chromatography-mass spectrometry proteomic (LC-MS(E)) and metabonomic (LC-MS) profiling analysis combined with the targeted proteomics (selected reaction monitoring and multiplex immunoassay) of serum and brain tissues to investigate a chronic phencyclidine (PCP) rat model in which glutamatergic hypofunction is induced through noncompetitive NMDAR-receptor antagonism. Using a multiplex immunoassay, we identified alterations in the levels of several cytokines (IL-5, IL-2, and IL-1?) and fibroblast growth factor-2. Extensive proteomic and metabonomic brain tissue profiling revealed a more prominent effect of chronic PCP treatment on both the hippocampal proteome and metabonome compared to the effect on the frontal cortex. Bioinformatic pathway analysis confirmed prominent abnormalities in NMDA-receptor-associated pathways in both brain regions, as well as alterations in other neurotransmitter systems such as kainate, AMPA, and GABAergic signaling in the hippocampus and in proteins associated with neurodegeneration. We further identified abundance changes in the level of the superoxide dismutase enzyme (SODC) in both the frontal cortex and hippocampus, which indicates alterations in oxidative stress and substantiates the apoptotic pathway alterations. The present study could lead to an increased understanding of how perturbed glutamate receptor signaling affects other relevant biological pathways in schizophrenia and, therefore, support drug discovery efforts for the improved treatment of patients suffering from this debilitating psychiatric disorder. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 12 | Health Qual Life Outcomes 2015 -1 13: 114 |
| PMID | 26530986 |
| Title | The responsiveness of the EQ-5D and time trade-off scores in schizophrenia, affective disorders, and alcohol addiction. |
| Abstract | To compare the responsiveness of the EQ-5D index (German and British tariff), the EQ-5D visual analogue scale (EQ VAS), and time trade-off (TTO) scores in schizophrenia, affective disorders, and alcohol addiction. We used a sample of 502 patients and examined the measures at baseline and after 14 months. We used the generic "WHO Quality of Life BREF" (WHOQOL) and the disorder-specific "Global Severity Index" (GSI) as anchors for a relevant improvement in a patient's health status. In a complete case analysis, we assessed the responsiveness, which is the ability to detect a change given a relevant change on the anchor. We computed the effect sizes (ESs) and standardised response means (SRMs). In patients with schizophrenia, the ESs and SRMs were large (ES/SRM?>?0.8) for the British EQ-5D index (ESGSI: 0.93; SRMGSI: 0.89; SRMWHOQOL: 0.82). In patients with affective disorders, we found large ESs and SRMs for the EQ VAS (ESGSI: 1.79; ESWHOQOL: 0.90; SRMGSI: 1.52; SRMWHOQOL: 0.93) and a large ES for the British EQ-5D index (ESGSI: 0.88). In patients with alcohol addiction, the ESs and SRMs were large for the EQ VAS (ESGSI: 1.40; ESWHOQOL: 0.94; SRMGSI: 1.04; SRMWHOQOL: 0.83). The ESs and SRMs of the German EQ-5D index were consistently lower than those of the British EQ-5D index. Regarding TTO score, ESs and SRMs were generally less than 0.5. No preference-based instrument was consistently more responsive than others across all mental disorders. While the EQ VAS was the most responsive instrument in patients with affective disorders or alcohol addiction, the British EQ-5D index was reasonably responsive in patients with schizophrenia. |
| SCZ Keywords | schizophrenia, schizophrenic |
| 13 | Int. J. Neuropsychopharmacol. 2015 -1 18: -1 |
| PMID | 25609598 |
| Title | Proteomic enrichment analysis of psychotic and affective disorders reveals common signatures in presynaptic glutamatergic signaling and energy metabolism. |
| Abstract | Although genetic studies suggest an overlap in risk alleles across the major psychiatric disorders, disease signatures reflecting overlapping symptoms have not been found. Profiling studies have identified candidate protein markers associated with specific disorders of the psychoaffective spectrum, but this has always been done in a selective fashion without accounting for the entire proteome composition of the system under investigation. Employing an orthogonal system-based proteomic enrichment approach based on label-free liquid chromatography mass spectrometry, we analyzed anterior prefrontal human post-mortem brain tissue of patients affected by schizophrenia (n = 23), bipolar disorder (n = 23), major depressive disorder with (n = 12) and without psychotic features (n = 11), and healthy controls (n = 23). Labeled selected reaction monitoring (SRM) was used to validate these findings on a pathway level. Independent in silico analyses of biological annotations revealed common pathways across the diseases, associated with presynaptic glutamatergic neurotransmission and energy metabolism. We validated the proteomic findings using SRM and confirmed that there were no effects of post-mortem confounders. schizophrenia and affective psychosis were linked to a hypoglutamatergic state and hypofunction of energy metabolism, while bipolar disorder and major depressive disorder were linked to a hyperglutamatergic state and hyperfunction of energy metabolism. These findings support recent investigations, which have focused on the therapeutic potential of glutamatergic modulation in psychotic and affective disorders. We suggest a disease model in which disturbances of the glutamatergic system and ensuing adaptations of neuronal energy metabolism are linked to distinct psychiatric symptom dimensions, delivering novel evidence for targeted treatment approaches. |
| SCZ Keywords | schizophrenia, schizophrenic |