Subgroup Of Schizophrenia Patients Research Articles

Circulating microRNA Profiles Identify a Patient Subgroup with High Inflammation and Severe Symptoms in Schizophrenia Experiencing Acute Psychosis.

Schizophrenia is a complex and heterogenous psychiatric disorder. This study aimed to demonstrate the potential of circulating microRNAs (miRNAs) as a clinical biomarker to stratify schizophrenia patients and to enhance understandings of their heterogenous pathophysiology. We measured levels of 179 miRNA and 378 proteins in plasma samples of schizophrenia patients experiencing acute psychosis and obtained their Positive and Negative Syndrome Scale (PANSS) scores. The plasma miRNA profile revealed three subgroups of schizophrenia patients, where one subgroup tended to have higher scores of all the PANSS subscales compared to the other subgroups. The subgroup with high PANSS scores had four distinctively downregulated miRNAs, which enriched 'Immune Response' according to miRNA set enrichment analysis and were reported to negatively regulate IL-1β, IL-6, and TNFα. The same subgroup had 22 distinctively upregulated proteins, which enriched 'Cytokine-cytokine receptor interaction' according to protein set enrichment analysis, and all the mapped proteins were pro-inflammatory cytokines. Hence, the subgroup is inferred to have comparatively high inflammation within schizophrenia. In conclusion, miRNAs are a potential biomarker that reflects both disease symptoms and molecular pathophysiology, and identify a patient subgroup with high inflammation. These findings provide insights for the precision medicinal strategies for anti-inflammatory treatments in the high-inflammation subgroup of schizophrenia.

A subtype of schizophrenia patients with altered methylation level of genes related to immune cell activity.

Epigenetic changes are plausible molecular sources of clinical heterogeneity in schizophrenia. A subgroup of schizophrenia patients with elevated inflammatory or immune-dysregulation has been reported by previous studies. However, little is known about epigenetic changes in genes related to immune activation in never-treated first-episode patients with schizophrenia (FES) and its consistency with that in treated long-term ill (LTS) patients. In this study, epigenome-wide profiling with a DNA methylation array was applied using blood samples of both FES and LTS patients, as well as their corresponding healthy controls. Non-negative matrix factorization (NMF) and k -means clustering were performed to parse heterogeneity of schizophrenia, and the consistency of subtyping results from two cohorts. was tested. This study identified a subtype of patients in FES participants (47.5%) that exhibited widespread methylation level alterations of genes enriched in immune cell activity and a significantly higher proportion of neutrophils. This clustering of FES patients was validated in LTS patients, with high correspondence in epigenetic and clinical features across two cohorts. In summary, this study demonstrated a subtype of schizophrenia patients across both FES and LTS cohorts, defined by widespread alterations in methylation profile of genes related to immune function and distinguishing clinical features. This finding illustrates the promise of novel treatment strategies targeting immune dysregulation for a subpopulation of schizophrenia patients.

Elevated endogenous GDNF induces altered dopamine signalling in mice and correlates with clinical severity in schizophrenia

Presynaptic increase in striatal dopamine is the primary dopaminergic abnormality in schizophrenia, but the underlying mechanisms are not understood. Here, we hypothesized that increased expression of endogenous GDNF could induce dopaminergic abnormalities that resemble those seen in schizophrenia. To test the impact of GDNF elevation, without inducing adverse effects caused by ectopic overexpression, we developed a novel in vivo approach to conditionally increase endogenous GDNF expression. We found that a 2–3-fold increase in endogenous GDNF in the brain was sufficient to induce molecular, cellular, and functional changes in dopamine signalling in the striatum and prefrontal cortex, including increased striatal presynaptic dopamine levels and reduction of dopamine in prefrontal cortex. Mechanistically, we identified adenosine A2a receptor (A2AR), a G-protein coupled receptor that modulates dopaminergic signalling, as a possible mediator of GDNF-driven dopaminergic abnormalities. We further showed that pharmacological inhibition of A2AR with istradefylline partially normalised striatal GDNF and striatal and cortical dopamine levels in mice. Lastly, we found that GDNF levels are increased in the cerebrospinal fluid of first episode psychosis patients, and in post-mortem striatum of schizophrenia patients. Our results reveal a possible contributor for increased striatal dopamine signalling in a subgroup of schizophrenia patients and suggest that GDNF—A2AR crosstalk may regulate dopamine function in a therapeutically targetable manner.

Hair cortisol levels in schizophrenia and metabolic syndrome.

Individuals with schizophrenia demonstrate higher rates of metabolic syndrome (MetS) than the general population. Hair cortisol concentrations (HCC) reflect longer-term cortisol secretion and can provide additional insights into the role of the hypothalamic pituitary adrenal (HPA) axis in schizophrenia and co-occurring MetS. In a case-control study of 16 patients with schizophrenia (11 first episode psychosis [FEP] and 5 chronic) and 21 controls hair samples, representing a 3-month retrospective window of cortisol, were collected and analysed utilizing liquid chromatography tandem mass spectrometry. We investigated whether schizophrenia and MetS co-occurrence were associated with HCC utilizing multivariate regression models. We also explored the longitudinal trajectory of HCC in FEP patients by conducting a mixed models analysis. At baseline HCC were significantly lower (Cohen's d=0.88) in patients with schizophrenia than in controls (p= .014). HCC increased from baseline to month-12 in FEP patients compared to controls, demonstrating a trend towards significance (p= .097). MetS was not associated with HCC at baseline, but HCC increased significantly from baseline to month-12 in relation to MetS (p= .037). In a subgroup of schizophrenia patients, psychosis may be associated with a blunted HPA axis with lower long-term cortisol output. MetS was associated with an increase in HCC and elevated cortisol levels observed in schizophrenia may be related to increased rates of MetS in schizophrenia patients.

Implications for Early Diagnosis and Treatment in Schizophrenia Due to Correlation between Auditory Perceptual Deficits and Cognitive Impairment.

It is indicated that auditory perception deficits are present in schizophrenia and related to formal thought disorder. The purpose of the present study was to investigate the association of auditory deficits with cognitive impairment in schizophrenia. An experimental group of 50 schizophrenia patients completed a battery of auditory processing evaluation and a neuropsychological battery of tests. Correlations between neuropsychological battery scores and auditory processing scores were examined. Cognitive impairment was correlated with auditory processing deficits in schizophrenia patients. All neuropsychological test scores were significantly correlated with at least one auditory processing test score. Our findings support the coexistence of auditory processing disorder, severe cognitive impairment, and formal thought disorder in a subgroup of schizophrenia patients. This may have important implications in schizophrenia research, as well as in early diagnosis and nonpharmacological treatment of the disorder.

Transcriptome Analysis of Post-Mortem Brain Tissue Reveals Up-Regulation of the Complement Cascade in a Subgroup of Schizophrenia Patients.

Schizophrenia is a genetically complex neuropsychiatric disorder with largely unresolved mechanisms of pathology. Identification of genes and pathways associated with schizophrenia is important for understanding the development, progression and treatment of schizophrenia. In this study, pathways associated with schizophrenia were explored at the level of gene expression. The study included post-mortem brain tissue samples from 68 schizophrenia patients and 44 age and sex-matched control subjects. Whole transcriptome poly-A selected paired-end RNA sequencing was performed on tissue from the prefrontal cortex and orbitofrontal cortex. RNA expression differences were detected between case and control individuals, focusing both on single genes and pathways. The results were validated with RT-qPCR. Significant differential expression between patient and controls groups was found for 71 genes. Gene ontology analysis of differentially expressed genes revealed an up-regulation of multiple genes in immune response among the patients (corrected p-value = 0.004). Several genes in the category belong to the complement system, including C1R, C1S, C7, FCN3, SERPING1, C4A and CFI. The increased complement expression is primarily driven by a subgroup of patients with increased expression of immune/inflammatory response genes, pointing to important differences in disease etiology within the patient group. Weighted gene co-expression network analysis highlighted networks associated with both synaptic transmission and activation of the immune response. Our results demonstrate the importance of immune-related pathways in schizophrenia and provide evidence for elevated expression of the complement cascade as an important pathway in schizophrenia pathology.

Comprehensive Gene Expression Analysis Detects Global Reduction of Proteasome Subunits in Schizophrenia.

The main challenge in the study of schizophrenia is its high heterogeneity. While it is generally accepted that there exist several biological mechanisms that may define distinct schizophrenia subtypes, they have not been identified yet. We performed comprehensive gene expression analysis to search for molecular signals that differentiate schizophrenia patients from healthy controls and examined whether an identified signal was concentrated in a subgroup of the patients. Transcriptome sequencing of 14 superior temporal gyrus (STG) samples of subjects with schizophrenia and 15 matched controls from the Stanley Medical Research Institute (SMRI) was performed. Differential expression and pathway enrichment analysis results were compared to an independent cohort. Replicability was tested on 6 additional independent datasets. The 2 STG cohorts showed high replicability. Pathway enrichment analysis of the down-regulated genes pointed to proteasome-related pathways. Meta-analysis of differential expression identified down-regulation of 12 of 39 proteasome subunit genes in schizophrenia. The signal of proteasome subunits down-regulation was replicated in 6 additional datasets (overall 8 cohorts with 267 schizophrenia and 266 control samples, from 5 brain regions). The signal was concentrated in a subgroup of patients with schizophrenia. We detected global down-regulation of proteasome subunits in a subgroup of patients with schizophrenia. We hypothesize that the down-regulation of proteasome subunits leads to proteasome dysfunction that causes accumulation of ubiquitinated proteins, which has been recently detected in a subgroup of schizophrenia patients. Thus, down-regulation of proteasome subunits might define a biological subtype of schizophrenia.

Hair Cortisol Is Associated With Social Support and Symptoms in Schizophrenia.

IntroductionPsychosocial stressors may worsen psychotic symptoms in schizophrenia, while social support could protect against the effects of stress in schizophrenia. Hypothalamus-pituitary-adrenal axis dysfunction has been associated with schizophrenia. Hair cortisol concentrations (HCC) allow assessment of cumulative cortisol secretion over the preceding 3 months. The relationship between HCC, psychosocial stressors, social support, and the clinical characteristics of schizophrenia needs to be explored.MethodsOne hundred nine schizophrenia patients and 86 healthy controls between the ages of 18 and 60 were enrolled in the study. Three-centimeter samples of hair were collected from the scalp and HCC were measured using ELISA kits. Linear regression and factor analysis were employed to examine the relationship between HCC, childhood trauma, the number of stressful life events (SLE), the amount of social support in the 3 months prior to the hair cortisol assessment and clinical characteristics of schizophrenia.ResultsSchizophrenia patients experience more SLE in their lifetime, receive less social support, and have lower HCC in the recent 3 months compared to healthy controls. In the schizophrenia patients, HCC are positively associated with the amount of social support and negatively associated with the severity of delusions. The interaction between social support and SLE predicts decreased HCC. Factor analysis shows that a subgroup of schizophrenia patients who experience childhood trauma and SLE are characterized by decreased HCC.ConclusionsFindings indicate social support could be a moderator for the relationship between SLE and HCC which may attenuate the effects of SLE in schizophrenia.

The Influence of Continuous Exercising on Chronotropic Incompetence in Multi-Episode Schizophrenia.

People with schizophrenia die on average 15–20 years earlier than age and gender matched controls in the general population. An essential part of this excess mortality in people with schizophrenia is caused by physical illnesses. Among the physical illnesses, cardiovascular disease (CVD) has been identified as the most common natural cause of death in up to 40–45% of the cases. Chronotropic incompetence (CI) is defined as the inability of the heart to increase its beating frequency in proportion to increased physical activity or higher metabolic demand. It is an established independent cardiovascular risk factor for major cardiac events and overall mortality and might explain adaptation intolerance of the cardiovascular system to even minor exercise courses. CI needs objective exercise testing for definitive diagnosis and therefore represents a biological marker indicating the integrity of the cardiovascular system. It was recently described in patients with schizophrenia and might help explain the reduced physical fitness in these patients and the inability of a subgroup of patients to benefit from exercise interventions. In this study, we tried to replicate the occurrence of CI in an independent sample of patients with schizophrenia and evaluated whether CI can be influenced by a continuous endurance training of 12 weeks. Therefore, we re-analyzed the fitness testing data of 43 patients with schizophrenia and 22 aged and gender matched healthy controls. Parameters of aerobic fitness and chronotropic response to exercise were calculated. Patients with schizophrenia were less physically fit than the healthy controls and displayed a significantly higher heart rate at rest. 10 of 43 patients with schizophrenia and no healthy control subject were classified as chronotropically incompetent. Chronotropic response to exercise did not change significantly after 12 weeks of continuous aerobic exercise training. No differences were observed for baseline heart rate and peak heart rate in both subgroups of schizophrenia patients. Aerobic fitness did not improve significantly in the patients with schizophrenia classified as chronotropically incompetent. Our results confirm the occurrence of CI in patients with multi-episode schizophrenia. This should be taken into account when planning an exercise or lifestyle intervention studies in this population. Schizophrenia patients with CI do not seem to benefit as well as schizophrenia patients without CI from aerobic exercise training interventions. Larger, prospective randomized controlled clinical trials with different training interventions are urgently needed to address the topic of schizophrenia patients not responding to exercise and the relationship to the illness itself.

Combining CDP-choline and galantamine, an optimized α7 nicotinic strategy, to ameliorate sensory gating to speech stimuli in schizophrenia

Neural α7 nicotinic acetylcholine receptor (nAChR) expression and functioning deficits have been extensively associated with cognitive and early sensory gating (SG) impairments in schizophrenia (SCZ) patients and their relatives. SG, the suppression of irrelevant and redundant stimuli, is measured in a conditioning-testing (S1-S2) paradigm eliciting electroencephalography-derived P50 event-related potentials (ERPs), the S2 amplitudes of which are typically suppressed relative to S1. Despite extensive reports of nicotine-related improvements and several decades of research, an efficient nicotinic treatment has yet to be approved for SCZ. Following reports of SG improvements in low P50 suppressing SCZ patients and healthy participants with the α7 agonist, CDP-choline, this pilot study examined the combined modulatory effect of CDP-choline (500 mg) and galantamine (16 mg), a nAChR positive allosteric modulator and acetylcholinesterase inhibitor, on SG to speech stimuli in twenty-four SCZ patients in a randomized, double-blind and placebo-controlled design. As expected, in low P50 suppressors CDP-choline/galantamine (vs. Placebo) improved rP50 and dP50 scores by increasing inhibitory mechanisms as reflected by S2P50 amplitude reductions. Results also suggest a moderating role for auditory verbal hallucinations in treatment response. These preliminary findings provide supportive evidence for the involvement of α7 nAChR activity in speech gating in SCZ and support additional trials, examining different dose combinations and repeated doses of this optimized and personalized targeted α7 cholinergic treatment for SG dysfunction in subgroups of SCZ patients.

T95. PREVALENCE AND CONSEQUENCES OF CARDIAC AUTONOMIC DYSFUNCTION (CADF) IN 112 UNMEDICATED PATIENTS WITH SCHIZOPHRENIA

BackgroundA shortened life expectancy of about 15–20 years in patients with schizophrenia (SZ) is very well documented. Cardiovascular disease has been identified as one of the leading causes of premature death. Beyond the effects accounted for by lifestyle and antipsychotic medications, several lines of evidence indicate a shared underlying pathophysiology between both schizophrenia and cardiovascular disease. The most obvious link lies in the relation between cardiac autonomic dysfunction (CADF) and the development of cardiovascular diseases. CADF has been extensively described in patients with schizophrenia, with main features like an increased heart rate at rest, reduced baroreflex sensitivity or increased variability of the QT interval. However, the definite influence of autonomic dysfunction for reduced life expectancy is still unknown. Thus, one has to identify patients at increased risk. Therefore, we established a scoring system based on heart rate variability (HRV)-measures from unmedicated SZ patients to quantify autonomic changes associated with an assumed cardiac risk profile.MethodsAutonomic measures were obtained from electrocardiogram recordings at rest in 112 unmedicated SZ patients and 112 age and gender matched healthy controls (HC). A rating score was obtained by relating 13 different, independent heart rate variability indices from every SZ patient to the 1st, 1.5th and 2nd standard deviations (SD) of the HC sample. According to the total amount of rating points, every SZ patient was classified into a corresponding subgroup of cardiac autonomic dysfunction (< 4 points = absent, 4 – 13 points = moderate, > 13 points = severe CADF). The selected HRV parameters contain different information of autonomic system modulation and have been proven very reliable in clinical research. Besides, symptom severity (Positive and negative syndrome scale) were determined as well as cardiac risk markers like BMI, smoking habits and physical activity.ResultsSevere CADF was present in 29% of the tested unmedicated SZ patients, whereas moderate CADF was present in 44% and absent in 27% of the cases. Therefore, about one third of the patients revealed severe cardiac autonomic changes correlating with a potential risk for cardiovascular events. Only 27 % of the SZ patients showed no pathological findings. Patients with severe CADF showed significantly higher heart rates at rest when compared to patients with moderate CADF [F(2,109) = 23,089; p < 0,001]. The ratio of Low Frequency/High Frequency was also significantly higher in SZ patients with severe CADF compared to moderate CADF [F(2,109) = 38,321; p < 0,001] which points to a shift of the autonomic balance to sympathetic modulation. The three subgroups of SZ patients did not differ significantly in terms of symptoms, BMI, smoking habits or physical activity. SZ patients with severe CADF had a significantly longer duration of the illness [F(2,109) = 12,810; p < 0,001].DiscussionThis study demonstrated that almost one third of unmedicated SZ patients show severe CADF. The close relation between CADF and the development of cardiac diseases or arrhythmias is well described. Therefore, these patients might need close cardiological follow-up appointments to reduce the likelihood of sudden cardiac death. In addition, the definite relation between the degree of autonomic dysfunction and the potential risk of cardiovascular events needs to be investigated in this patient population prospectively. Future studies need to design interventional strategies for everyday clinical settings to improve physical health and quality of life.

S23. INTRODUCING COMPASS: COMPARING BRAIN ACTIVITY ACROSS PATIENTS WITH DIFFERENTIAL TREATMENT RESPONSE IN SCHIZOPHRENIA – AN OBSERVATIONAL STUDY

BackgroundPresent pharmacological treatment approaches in schizophrenia rest on “neuroleptic” drugs, all of which act as antagonists at dopamine D2/D3 receptors but additionally display major variability in their binding capacity to neurotransmitter receptors (Van Os & Kapur 2009). At present, the choice of any particular drug does not rest on any principled criteria: Once individual treatment has been started, therapeutic efficacy is monitored clinically, and a switch to a different drug is initiated when clear improvements remain absent after a few weeks. It is presently not possible to predict in advance which patients will respond well to a particular drug and who will experience little or no benefit (Case et al. 2011; Kapur et al. 2012).For instance, clozapine and olanzapine are often prescribed after other antipsychotics have shown to be ineffective in patients with schizophrenia or related disorders due to their pronounced side-effects. Both drugs, clozapine and olanzapine, share certain pharmacodynamic properties with comparatively low affinity towards dopamine D2-receptors, but very high affinity towards muscarinic receptors – a unique constellation that distinguishes them from other common antipsychotics. Importantly, previous studies have shown that a subgroup of schizophrenia patients might particularly benefit from these properties (Raedler et al. 2003, Scarr et al. 2009).Here, we present an ongoing observational study (COMPASS) which builds on these observations and addresses the question whether functional readouts of dopaminergic and muscarinic systems in individual patients could enable personalised treatment predictions. Guided by the dysconnection hypothesis of schizophrenia (Stephan et al., 2009), which postulates aberrant interactions between NMDA receptors and neuromodulators like dopamine/acetylcholine, the COMPASS study adopts a neuromodeling approach. The focus is on EEG/fMRI paradigms and computational models with empirically demonstrated sensitivity for altered function of NMDA, dopamine and muscarinic receptors, respectively.MethodsTo detect even small effect sizes, the study aims to recruit N=120 patients with schizophrenia who begin treatment with, switch to, or augment medication with olanzapine or clozapine. If possible, a replication sample (an additional N=120) will be recruited, too. Patients will be examined +/- 96h relative to treatment onset. Data acquisition encompasses the following measurements: Clinical interview, EEG (working memory, reward learning under volatility, auditory MMN under volatility, “resting”-state), MRI (optional; fMRI during auditory MMN under volatility, “resting”-state, and structural imaging), blood samples (genetic and biochemical analyses). After 2 and 8 weeks a clinical follow-up is conducted.ResultsThe study is ongoing.DiscussionThe EEG/fMRI data will be analysed by computational models that infer functional states of glutamatergic, dopaminergic, and cholinergic systems (for review, Stephan et al. 2015). Model parameter estimates will serve as features in machine learning analyses of treatment prediction (Brodersen et al. 2014).If successful, this proof-of-concept study will lead to clinically useful tests for predicting the efficacy of clozapine/olanzapine prior to or during very early treatment. This could have a significant impact on clinical management as it would enable predicting, at an early stage, the therapeutic benefit for individual patients. Our neuromodeling approach to individual predictions may thus provide a principled basis for treatment decisions, help spare side-effects and enable informed switches in treatment strategy.

43. BUILDING ON GENETICS AND PATHOPHYSIOLOGY OF SCHIZOPHRENIA TO GUIDE DISCOVERY OF NEW TREATMENTS

Overall : Current treatments for schizophrenia (SCZ) are partially effective in treating positive symptoms, but many patients are refractory to available medications and they are ineffective in the treatment of negative symptoms and cognitive impairment. There is a tremendous need to develop novel approaches to the treatment of SCZ that have broader efficacy and fewer adverse effects than existing dopamine D2 receptor and mixed D2/5-HT2A antagonists. To achieve fundamental breakthroughs that provide efficacy for refractory patients and across multiple symptom domains, it will be critical to rely on rigorous studies in SCZ patients that guide development of novel treatment approaches. Major recent advances in the genetics, imaging, and molecular pathophysiology of SCZ point to new potential treatment strategies, and may guide patient selection and outcome measures. Speakers in this symposium will summarize examples of translational studies that may offer novel therapeutic approaches that have the potential to fundamentally change the standard of care for SCZ patients. Jeff Conn (Vanderbilt Univ., USA) will summarize recent genetic studies that point to loss of function mutations in two novel G protein-coupled receptors in SCZ patients, and the discovery of novel positive allosteric modulators for these receptors that are providing a strong proof of concept for advancing selective agents to clinical evaluation in patients, including those that bear these specific mutations. Brian Dean (Univ. Melbourne, Australia) will then review clinical studies showing that a subgroup of SCZ patients show a marked loss of cortical muscarinic M1 receptors and translational studies suggesting that selective activators of M1 receptors could provide benefits in treating this disorder. In addition, he will summarize changes in molecular cytoarchitecture in the cortex of subjects with SCZ that provide important insights in considering M1 activators as a treatment strategy. Clare Beasley (Univ. British Columbia, Canada), will review mounting evidence from postmortem tissue that implicates immune dysregulation and the complement system in SCZ and the potential utility of complement inhibitors in the treatment of this disorder. Finally, Anissa Abi-Dargham (Stony Brook Univ., USA) will discuss recent advances in the use of molecular imaging for discovery of patients with alterations in specific targets that may guide clinical development. Specifically, imaging studies suggest that nigro-striatal dopaminergic projections may play a more important role relative to mesolimbic dopaminergic projections than previously appreciated, and suggest a blunting of dopamine release in extra-striatal areas. These observations can be linked to clinical treatment response or particular domains of pathology and fit nicely with new data suggesting that activation of targets outlined in the first presentation selectively inhibit dopaminergic signaling in nigrostriatal but not in other dopaminergic pathways. In summary, this panel will highlight new therapeutic leads derived from novel insights gathered through imaging, genetic and molecular studies of SCZ patients.

A Brief Assessment of Intelligence Decline in Schizophrenia As Represented by the Difference between Current and Premorbid Intellectual Quotient.

Patients with schizophrenia elicit several clinical features, such as psychotic symptoms, cognitive impairment, and subtle decline of intelligence. The latter two features become evident around the onset of the illness, although they may exist even before the disease onset in a substantial proportion of cases. Here, we review the literature concerning intelligence decline (ID) during the progression of schizophrenia. ID can be estimated by comparing premorbid and current intellectual quotient (IQ) by means of the Adult Reading Test and Wechsler Adult Intelligence Scale (WAIS), respectively. For the purpose of brief assessment, we have recently developed the WAIS-Short Form, which consists of Similarities and Symbol Search and well reflects functional outcomes. According to the degree of ID, patients were classified into three distinct subgroups; deteriorated, preserved, and compromised groups. Patients who show deteriorated IQ (deteriorated group) elicit ID from a premorbid level (≥10-point difference between current and premorbid IQ), while patients who show preserved or compromised IQ do not show such decline (<10-point difference). Furthermore, the latter patients were divided into patients with preserved and compromised IQ based on an estimated premorbid IQ score >90 or below 90, respectively. We have recently shown the distribution of ID in a large cohort of schizophrenia patients. Consistent with previous studies, approximately 30% of schizophrenia patients had a decline of less than 10 points, i.e., normal intellectual performance. In contrast, approximately 70% of patients showed deterioration of IQ. These results indicate that there is a subgroup of schizophrenia patients who have mild or minimal intellectual deficits, following the onset of the disorder. Therefore, a careful assessment of ID is important in identifying appropriate interventions, including medications, cognitive remediation, and social/community services.

Antigliadin Antibodies (AGA IgG) Are Related to Neurochemistry in Schizophrenia.

Inflammation may play a role in schizophrenia; however, subgroups with immune regulation dysfunction may serve as distinct illness phenotypes with potential different treatment and prevention strategies. Emerging data show that about 30% of people with schizophrenia have elevated antigliadin antibodies of the IgG type, representing a possible subgroup of schizophrenia patients with immune involvement. Also, recent data have shown a high correlation of IgG-mediated antibodies between the periphery and cerebral spinal fluid in schizophrenia but not healthy controls, particularly AGA IgG suggesting that these antibodies may be crossing the blood–brain barrier with resulting neuroinflammation. Proton magnetic resonance spectroscopy (MRS) is a non-invasive technique that allows the quantification of certain neurochemicals in vivo that may proxy inflammation in the brain such as myoinositol and choline-containing compounds (glycerophosphorylcholine and phosphorylcholine). The objective of this exploratory study was to examine the relationship between serum AGA IgG levels and MRS neurochemical levels. We hypothesized that higher AGA IgG levels would be associated with higher levels of myoinositol and choline-containing compounds (glycerophosphorylcholine plus phosphorylcholine; GPC + PC) in the anterior cingulate cortex. Thirty-three participants with a DSM-IV diagnosis of schizophrenia or schizoaffective disorder had blood drawn and underwent neuroimaging using MRS within 9 months. We found that 10/33 (30%) had positive AGA IgG (≥20 U) similar to previous findings. While there were no significant differences in myoinositol and GPC + PC levels between patients with and without AGA IgG positivity, there were significant relationships between both myoinositol (r = 0.475, p = 0.007) and GPC + PC (r = 0.36, p = 0.045) with AGA IgG levels. This study shows a possible connection of AGA IgG antibodies to putative brain inflammation as measured by MRS in schizophrenia.

N-Methyl-D-aspartate receptor antibody could be a cause of catatonic symptoms in psychiatric patients: case reports and methods for detection.

The symptoms of catatonia have been reported to be similar to the initial symptoms of anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Subsequently, this autoimmune limbic encephalitis has been noticed by many psychiatrists. For a differential diagnosis of catatonic state, it is important to detect anti-NMDAR encephalitis. This encephalitis is expected to be in remission by early detection and treatment. We should be more cautious about catatonic symptoms of schizophrenia. When a patient is suspected of having encephalitis, we should screen for anti-NMDAR antibodies in cerebrospinal fluid samples using a cell-based assay. We describe the methods of NMDAR antibody detection and the etiology of this encephalitis with case reports. Two representative cases with catatonia and non-catatonia (brief psychotic disorder) were reported. Schizophrenia is a general, heterogeneous, and complicated disorder, and its pathophysiology is unknown. There is an established evidence of NMDAR hypofunction, which is the functional disconnection of the central component; this is one of the most recognized models for schizophrenia. Furthermore, it is said that autoimmune mechanisms have been involved, at least in subgroups of schizophrenia patients. Further study of anti-NMDAR antibody and its related encephalitis would give essential clues for the research of schizophrenia, catatonia, and atypical psychosis.

Peripheral kynurenine-3-monooxygenase deficiency as a potential risk factor for metabolic syndrome in schizophrenia patients.

Increased predisposition of schizophrenia patients (SP) to development of obesity and insulin resistance suggested common signaling pathway between metabolic syndrome (MetS) and schizophrenia. Deficiency of kynurenine-3-monooxygenase (KMO), enzyme catalyzing formation of 3-hydroxykynurenine (3-HK) from kynurenine (Kyn), a tryptophan (Trp) metabolite, might contribute to development of MetS as suggested by non-expression of KMO genes in human fat tissue and elevated serum concentrations of Kyn and its metabolites, kynurenic (KYNA) and anthranilic (ANA) acids, in diabetic patients and Zucker fatty rats (ZFR). Markers of KMO deficiency: decreased 3-HK and elevated Kyn, KYNA and ANA, were observed in brains and spinal fluids of SP, and in brains and serum of experimental animals with genetically- or pharmacologically-induced KMO deficiency. However, elevated concentrations of ANA and decreased 3-HK were reported in serum of SP without concurrent increase of Kyn and KYNA. Present study aimed to re-assess serum Kyn metabolites (HPLC-MS) in a sub-group of SP with elevated KYNA. We found increased Kyn concentrations (by 30%) and Kyn:Trp ratio (by 20%) in serum of SP with elevated KYNA concentrations (by 40%). Obtained results and our previous data suggest that peripheral KMO deficiency might be manifested by, at least, two different patterns: elevated ANA with decreased 3-HK; and elevated KYNA and KYN. The latter pattern was previously described in type 2 diabetes patients and might underline increased predisposition of SP to development of MetS. Assessment of peripheral KMO deficiency might identify SP predisposed to MetS. Attenuation of the consequences of peripheral KMO deficiency might be a new target for prevention/treatment of obesity and diabetes in SP.

Role of GABA Deficit in Sensitivity to the Psychotomimetic Effects of Amphetamine.

Some schizophrenia patients are more sensitive to amphetamine (AMPH)-induced exacerbations in psychosis-an effect that correlates with higher striatal dopamine release. This enhanced vulnerability may be related to gamma-aminobutyric acid (GABA) deficits observed in schizophrenia. We hypothesized that a pharmacologically induced GABA deficit would create vulnerability to the psychotomimetic effects to the 'subthreshold' dose of AMPH in healthy subjects, which by itself would not induce clinically significant increase in positive symptoms. To test this hypothesis, a GABA deficit was induced by intravenous infusion of iomazenil (IOM; 3.7 μg/kg), an antagonist and partial inverse agonist of benzodiazepine receptor. A subthreshold dose of AMPH (0.1 mg/kg) was administered by intravenous infusion. Healthy subjects received placebo IOM followed by placebo AMPH, active IOM followed by placebo AMPH, placebo IOM followed by active AMPH, and active IOM followed by active AMPH in a randomized, double-blind crossover design over 4 test days. Twelve healthy subjects who had a subclinical response to active AMPH alone were included in the analysis. Psychotomimetic effects (Positive and Negative Syndrome Scale (PANSS)), perceptual alterations (Clinician Administered Dissociative Symptoms Scale (CADSS)), and subjective effects (visual analog scale) were captured before and after the administration of drugs. IOM significantly augmented AMPH-induced peak changes in PANSS positive symptom subscale and both subjective and objective CADSS scores. There were no pharmacokinetic interactions. In conclusion, GABA deficits increased vulnerability to amphetamine-induced psychosis-relevant effects in healthy subjects, suggesting that pre-existing GABA deficits may explain why a subgroup of schizophrenia patients are vulnerable to AMPH.

Brain Structural Abnormalities in Violent Offenders with Schizophrenia

Introduction Schizophrenia patients with a history of community violence constitute a sub-group of schizophrenia patients (SCZ) that receive much public attention. While brain structural abnormalities are established in SCZ, there are few studies of brain morphology in violent SCZ. Objectives To conduct a pilot study of brain morphology in a SCZ cohort with a history of severe community violence from a high security forensic psychiatric unit. Aims Investigate differences in hippocampal, ventricular, thalamic, and amygdala volumes in violent SCZ, SCZ, and healthy controls (HC). Methods Structural 3T MRI scans were acquired of 47 subjects (violent SCZ n=11, mean age 33.2 years (SD 9.0), 91% male; SCZ n= 17, 34.3 years (7.4), 94% male; HC n=19, 33.2 years (9.1), 90% male). Violent offence included murder, attempted murder, or severe assault (with or without weapon) towards other people. The FreeSurfer 5.3.0 software was used to obtain subcortical brain volumes. Effects of age, sex, and intracranial volume were controlled for, and Bonferroni correction was applied. Results Violent SCZ had smaller right hippocampal volumes (F(2,42)=4.11, p= .024) compared to HC (padj= .028) and SCZ (pnom= .046). On a trend level, violent SCZ had larger right lateral ventricles than HC (pnom =.032) and SCZ (pnom=.049), and smaller left hippocampus than HC (pnom =.027). No differences in thalamus and amygdala volumes were found. Conclusions Violent SCZ may be associated with more pronounced brain abnormalities than non-violent SCZ. Future studies are needed to verify the observed abnormalities and determine the pathophysiological mechanisms and functional consequences.

Analysis of auto-antibodies in schizophrenia

Objectives: Schizophrenia is a neuropsychiatric disorder with a complex etiology and pathogenesis. While symptomatic treatment is available, there are no treatments that target the biological disease mechanisms. Recently, autoantibodies to neuronal cell surface antigens have been identified in patients with schizophrenia. Autoimmunity is affecting nearly 10% of the general population and its clinical spectrum varies from endocrine, musculoskeletal to neuropsychiatric syndromes. Since autoimmune patients frequently suffer from more than one autoimmune disease, we analyzed common autoantibodies as disease markers (or risk factors) to test the hypothesis that schizophrenia is correlated to autoimmunity. Methods: We tested sera from 232 schizophrenia, bipolar disorder and myasthenia gravis patients and healthy controls for the presence of autoantibodies by ELISA and immunofluorescence. The assays included: anti-nuclear antibodies (ANA), double-stranded DNA (dsDNA), and ribosomal P protein (RPP). ANA IFA screening was performed on ImmunGlo HEp-2 slides and the acquisition of images and interpretation of patterns was performed on the Immco i-Sight automated imaging system. Results: Prevalence of anti-dsDNA autoantibodies was found to be overall relatively high and to significantly differ between disease and control groups. Schizoaffective patients had highest titers of anti-dsDNA autoantibodies. The autoantibody titer anti-RPP differs significantly between the groups. Paranoid and disorganized patients had highest titers of anti-RPP autoantibodies. No significant difference was detected in the presence of ANA autoantibodies in the different study groups. Conclusions: We confirmed that a subgroup of schizophrenia patients had increased levels of autoantibodies. These findings are the first step to improve diagnosis and possibly treatment of schizophrenic patients with autoimmune etiology. Currently, control sera are being tested to match the sample size and the age and sex distribution of the disease group.