Antipsychotic-naive Schizophrenia Research Articles

Decreased Plasma Levels of Kynurenine and Kynurenic Acid in Previously Treated and First-Episode Antipsychotic-Naive Schizophrenia Patients.

Tryptophan (TRP) catabolites exert neuroactive effects, with the plethora of evidence suggesting that kynurenic acid (KYNA), a catabolite of the kynurenine pathway (KP), acts as the regulator of glutamate and acetylcholine in the brain, contributing to the schizophrenia pathophysiology. Newer evidence regarding measures of KP metabolites in the blood of schizophrenia patients and from the central nervous system suggest that blood levels of these metabolites by no means could reflect pathological changes of TRP degradation in the brain. The aim of this study was to investigate plasma concentrations of TRP, kynurenine (KYN) and KYNA at the acute phase and remission of schizophrenia in a prospective, case-control study of highly selected and matched schizophrenia patients and healthy individuals. Our study revealed significantly decreased KYN and KYNA in schizophrenia patients (p < 0.001), irrespective of illness state, type of antipsychotic treatment, number of episodes or illness duration and no differences in the KYN/TRP ratio between schizophrenia patients and healthy individuals. These findings could be interpreted as indices that kynurenine pathway might not be dysregulated in the periphery and that other factors contribute to observed disturbances in concentrations, but as our study had certain limitations, we cannot draw definite conclusions. Further studies, especially those exploring other body compartments that participate in kynurenine pathway, are needed.

The cortical hypogyrification pattern in antipsychotic-naive first-episode schizophrenia.

Schizophrenia is thought to be a neurodevelopmental disease with high genetic heritability, and evidence from neuroimaging studies has consistently shown widespread cortical local gyrification index (LGI) alterations; however, genes accounting for LGI alterations in schizophrenia remain unknown. The present study examined the LGI alterations in first-episode antipsychotic-naive schizophrenia compared with controls (235 patients and 214 controls); transcription-neuroimaging association analysis was used to evaluate the relationship between LGI deficits and specific risk genes. The expression profiles of 232 schizophrenia risk genes were extracted from six donated normal brains from the Allen Human Brain Atlas database. The correlation between LGI alterations and clinical symptoms was also tested. We found lower LGI values involved in frontotemporal regions and limbic systems. Nonparametric correlation analysis showed that 83 risk genes correlated with the hypogyrification pattern in schizophrenia. These identified risk genes were functionally enriched for the development of the central nervous system. The LGI in the left superior temporal gyrus was negatively associated with Positive and Negative Syndrome Scale negative symptoms. In summary, the present study provides a set of risk genes possibly related to the hypogyrification pattern in antipsychotic-naive first-episode schizophrenia, which could help to unveil the neurobiological underpinnings of cortical impairments in early-stage schizophrenia.

Comprehensive and integrative analyses identify TYW5 as a schizophrenia risk gene

BackgroundIdentifying the causal genes at the risk loci and elucidating their roles in schizophrenia (SCZ) pathogenesis remain significant challenges. To explore risk variants associated with gene expression in the human brain and to identify genes whose expression change may contribute to the susceptibility of SCZ, here we report a comprehensive integrative study on SCZ.MethodsWe systematically integrated the genetic associations from a large-scale SCZ GWAS (N = 56,418) and brain expression quantitative trait loci (eQTL) data (N = 175) using a Bayesian statistical framework (Sherlock) and Summary data-based Mendelian Randomization (SMR). We also measured brain structure of 86 first-episode antipsychotic-naive schizophrenia patients and 152 healthy controls with the structural MRI.ResultsBoth Sherlock (P = 3. 38 × 10−6) and SMR (P = 1. 90 × 10−8) analyses showed that TYW5 mRNA expression was significantly associated with risk of SCZ. Brain-based studies also identified a significant association between TYW5 protein abundance and SCZ. The single-nucleotide polymorphism rs203772 showed significant association with SCZ and the risk allele is associated with higher transcriptional level of TYW5 in the prefrontal cortex. We further found that TYW5 was significantly upregulated in the brain tissues of SCZ cases compared with controls. In addition, TYW5 expression was also significantly higher in neurons induced from pluripotent stem cells of schizophrenia cases compared with controls. Finally, combining analysis of genotyping and MRI data showed that rs203772 was significantly associated with gray matter volume of the right middle frontal gyrus and left precuneus.ConclusionsWe confirmed that TYW5 is a risk gene for SCZ. Our results provide useful information toward a better understanding of the genetic mechanism of TYW5 in risk of SCZ.

Grey matter connectome abnormalities and age-related effects in antipsychotic-naive schizophrenia.

BackgroundConvergent evidence is increasing to indicate progressive brain abnormalities in schizophrenia. Knowing the brain network features over the illness course in schizophrenia, independent of effects of antipsychotic medications, would extend our sight on this question.MethodsWe recruited 237 antipsychotic-naive patients with schizophrenia range from 16 to 73 years old, and 254 healthy controls. High-resolution T1 weighted images were obtained with a 3.0T MR scanner. Grey matter networks were constructed individually based on the similarities of regional grey matter measurements. Network metrics were compared between patient groups and healthy controls, and regression analyses with age were conducted to determine potential differential rate of age-related changes between them.FindingsNodal centrality abnormalities were observed in patients with untreated schizophrenia, particularly in the central executive, default mode and salience networks. Accelerated age-related declines and illness duration-related declines were observed in global assortativity, and in nodal metrics of left superior temporal pole in schizophrenia patients. Although no significant intergroup differences in age-related regression were observed, the pattern of network metric alternation of left thalamus indicated higher nodal properties in early course patients, which decreased in long-term ill patients.InterpretationsGlobal and nodal alterations in the grey matter connectome related to age and duration of illness in antipsychotic-naive patients, indicating potentially progressive network organizations mainly involving temporal regions and thalamus in schizophrenia independent from medication effects.FundingThe National Natural Science Foundation of China, Sichuan Science and Technology Program, the Fundamental Research Funds for the Central Universities, Post-Doctor Research Project, West China Hospital, Sichuan University , the Science and Technology Project of the Health Planning Committee of Sichuan, Postdoctoral Interdisciplinary Research Project of Sichuan University and 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University.

Psychosis in Parkinson's disease and parkinsonism in antipsychotic-naive schizophrenia spectrum psychosis: clinical, nosological and pathobiological challenges.

Following the formulation of operational criteria for the diagnosis of psychosis in Parkinson’s disease, a neurodegenerative disorder, the past decade has seen increasing interest in such nonmotor psychopathology that appears to be independent of dopaminergic therapy. Similarly, there has been a resurgence of interest in motor aspects of the neurodevelopmental disorder of schizophrenia, including spontaneous parkinsonism that appears to be independent of antipsychotic treatment. This review first addresses the clinical and nosological challenges of these superficially paradoxical insights and then considers pathobiological challenges. It proposes that diverse modes of disturbance to one or more element(s) in a cortical-striatal-thalamocortical neuronal network, whether neurodegenerative or neurodevelopmental, can result in movement disorder, psychosis or both. It then proposes that time- and site-dependent dysfunction in such a neuronal network may be a generic substrate for the emergence of psychosis not only in Parkinson’s disease and schizophrenia-spectrum disorders but also in other neuropsychiatric disorders in which psychosis, and sometimes movement disorders, can be encountered; these include substance abuse, cerebrovascular disease, cerebral trauma, cerebral neoplasia, epilepsy, Huntington’s disease, frontotemporal dementia, Alzheimer’s disease and multiple sclerosis.

Reduced cortical thickness related to single nucleotide polymorphisms in the major histocompatibility complex region in antipsychotic-naive schizophrenia.

Instructions The aim of this study was to explore the relationships between changes in cortical thickness and single nucleotide polymorphisms (SNPs) in the major histocompatibility complex (MHC) region in a group of antipsychotic‐naive schizophrenia (AN‐SCZ) patients.MethodsTwenty‐five AN‐SCZ patients and 51 healthy controls (HCs) participated in this study. General linear models were used to identify associations between the average cortical thicknesses of each brain region (N = 68) and each of the 11 SNPs in the MHC region in the AN‐SCZ patients and HCs. Next, we performed independent‐sample t tests to investigate whether cortical thickness was significantly lower in the AN‐SCZ patients than in HCs in the brain regions that were significantly associated with the SNPs. Finally, we examined the correlations between clinical symptoms and cortical thickness in the above brain areas in the whole AN‐SCZ group using Pearson correlation tests.ResultsSeven of the 11 SNPs within the MHC region were significantly associated with cortical thickness only in the AN‐SCZ patients; these included rs1635, rs1736913, rs2021722, rs204999, rs2523722, rs3131296, and rs9272105. The AN‐SCZ patients had significantly thinner cortical thicknesses in the above brain regions, especially the prefrontal cortex. Furthermore, the left entorhinal region was negatively correlated with Positive and Negative Symptom Scale (PANSS) activation scores in the AN‐SCZ group (r = −0.601, p = 0.03).ConclusionsThis study provides evidence demonstrating the potential effects of MHC risk variants in cortical thickness deficits in AN‐SCZ. These data also support the notion that the immune system plays critical roles in the pathology of schizophrenia, which is mediated via the modulation of the development of cerebral cortical structures.

Attenuated mismatch negativity in patients with first-episode antipsychotic-naive schizophrenia using a source-resolved method.

BackgroundMismatch negativity (MMN) is a measure of pre-attentive auditory information processing related to change detection. Traditional scalp-level EEG methods consistently find attenuated MMN in patients with chronic but not first-episode schizophrenia. In the current paper, we use a source-resolved method to assess MMN and hypothesize that more subtle changes can be identified with this analysis method.MethodFifty-six first-episode antipsychotic-naïve schizophrenia (FEANS) patients (31 males, 25 females, mean age 24.6) and 64 matched controls (37 males, 27 females, mean age 24.8) were assessed for duration-, frequency- and combined-type MMN and P3a as well as 4 clinical, 3 cognitive and 3 psychopathological measures. To evaluate and correlate MMN at source-level, independent component analysis (ICA) was applied to the continuous EEG data to derive equivalent current dipoles which were clustered into 19 clusters based on cortical location.ResultsNo scalp channel group MMN or P3a amplitude differences were found. Of the localized clusters, several were in or near brain areas previously suggested to be involved in the MMN response, including frontal and anterior cingulate cortices and superior temporal and inferior frontal gyri. For duration deviants, MMN was attenuated at the right superior temporal gyrus in patients compared to healthy controls (p = 0.01), as was P3a at the superior frontal cortex (p = 0.01). No individual patient correlations with clinical, cognitive, or psychopathological measures survived correction for multiple comparisons.ConclusionAttenuated source-localized MMN and P3a peak contributions can be identified in FEANS patients using a method based on independent component analysis (ICA). This indicates that deficits in pre-attentive auditory information processing are present at this early stage of schizophrenia and are not the result of disease chronicity or medication. This is to our knowledge the first study on FEANS patients using this more detailed method.

Altered cortical thickness related to single nucleotide polymorphisms in the human leukocyte antigen in antipsychotic-naive schizophrenia

Objective To explore the relationship between changes in cortical thickness and single nucleotide polymorphisms(SNPs) in the human leukocyte antigen(HLA) in a group of antipsychotic-naive schizophrenia (AN-SCZ) patients. Methods Twenty-five chronically ill AN-SCZ patients and 51 healthy controls (HCs) were recruited and studied from May 2014 to July 2016. All participants received 3.0 T MR head scans and blood collection to obtain high resolution T1WI images and detailed genetic data. Next, we extracted and averaged the values of cortical thickness from each brain region(n=68) for each participant by FreeSurfer and then used general linear models to explore the relationship of each SNP with cortical thickness in the AN-SCZ and HCs while including age, gender and duration of disease in the models as covariates. In the next step, we applied an independent-samples t-test with a threshold of 0.05 to explore whether the cortical thicknesses differed significantly between the AN-SCZ and HCs in the brain regions that were significantly associated with the SNPs in the MHC. Finally, we examined the correlation of clinical symptoms with cortical thickness in the above brain areas in the whole AN-SCZ group using Pearson correlation tests. Results Seven of the 11 SNPs within the HLA regions exhibited significant associations with the cortical thickness only in the AN-SCZ patients, including rs1635, rs1736913, rs2021722, rs204999, rs2523722, rs3131296 and rs9272105. Furthermore, the AN-SCZ patients also exhibited significant reductions in cortical thickness in the above brain regions, which included the left entorhinal cortex, the left pars triangularis cortex, the left rostral middle frontal cortex, the right lateral occipital cortex, the right medial orbitofrontal cortex, the gray matter surrounding the right calcarine gyrus, the right rostral middle frontal cortex, the right frontal pole and the caudal part of the right anterior cingulate. The left entorhinal region also exhibited a negative correlation with PANSS activation scores in the AN-SCZ(r=-0.601, P=0.03). Conclusion The present study provided evidence for the significant association of HLA risk variants with cortical thickness in AN-SCZ. Key words: Schizophrenia; Magnetic resonance imaging; Polymorphism, single nucleotide; HLA antigens

F176. CLINICAL CORRELATES OF CORTICAL STRUCTURE IN ANTIPSYCHOTIC-NAïVE SCHIZOPHRENIA PATIENTS BEFORE AND AFTER SIX-WEEK TREATMENT WITH A DOPAMINE D2/3 RECEPTOR ANTAGONIST

BackgroundSchizophrenia has been associated with changes in both cortical thickness and surface area, but antipsychotic exposure, illness progression, and substance use may confound the observations. We investigated cortical thickness and surface area, as well as mean curvature, before and after antipsychotic monotherapy with a relatively selective dopamine D2/3 antagonist (amisulpride), in antipsychotic-naïve schizophrenia patients.MethodsFifty-six patients and 59 matched healthy controls (HC) underwent T1-weighted 3T magnetic resonance imaging. Forty-one patients and 51 HCs were re-scanned. FreeSurfer-processed baseline values and symmetrized percentage changes (SPC) in cortical structures were analysed using univariate ANOVA. Clinical measures comprised psychopathology ratings, assessment of functioning, and tests of premorbid and current intelligence.ResultsAt baseline, groups did not differ in cortical thickness or surface area, while left curvature was higher in patients (p=0.015). In the complete sample, a higher curvature was associated with lower premorbid- (p=0.009) and current intelligence (p<0.001). Also, a lower surface area was associated with lower premorbid intelligence (p=0.014) and, in patients, a higher PANSS total (p=0.037). Lifetime substance use was associated with reduced cortical thickness (p=0.043). After six weeks, groups did not differ in overall change in cortical structures. Amisulpride dose (275.0 mg/day) did not correlate with cortical structures (p>0.43). A decrease in cortical thickness SPC was associated with less symptom improvement (p=0.002) and increase in surface area SPC was associated with improvement in GAF (p=0.047).DiscussionOur results indicate that schizophrenia may be associated with subtle aberrations in cortical structures and these changes appear clinically relevant. Mean curvature holds promise as a sensitive supplement to cortical thickness and surface area, to detect complex structural brain abnormalities.

87. Glutamate and GABA in Antipsychotic-Naive Schizophrenia and Association With Treatment Outcome

87. Glutamate and GABA in Antipsychotic-Naive Schizophrenia and Association With Treatment Outcome

203. Nigral Stress-Induced Dopamine Release in Clinical High Risk and Antipsychotic-Naive Schizophrenia

203. Nigral Stress-Induced Dopamine Release in Clinical High Risk and Antipsychotic-Naive Schizophrenia

Endogenous and Antipsychotic-Related Risks for Diabetes Mellitus in Young People With Schizophrenia: A Danish Population-Based Cohort Study.

Diabetes mellitus contributes to excessive cardiovascular deaths and reduced life expectancy in schizophrenia. This population-based cohort study investigated the endogenous risk for diabetes in antipsychotic-naive schizophrenia and evaluated the risks added by starting antipsychotic treatment in people with schizophrenia. The study followed all people born in Denmark on or after Jan. 1, 1977, until Jan. 1, 2013 (N=2,736,510). The Danish Psychiatric Central Research Register ascertained schizophrenia diagnoses. The Danish National Prescription Registry provided data on prescriptions of antipsychotics. Diabetes was ascertained from the Danish National Patient Register and Danish National Prescription Registry. The authors estimated the endogenous and antipsychotic-related risks for diabetes by using Cox proportional hazards regression models, while accounting for potential confounders. Of the cohort members, 14,118 (0.52%) developed diabetes, and 8,945 (0.33%) developed schizophrenia during follow-up (49,582,279 person-years). The adjusted hazard ratio for diabetes was 3.07 (95% confidence interval [CI], 1.71-5.41) in antipsychotic-naive schizophrenia compared with the general population. The risk for diabetes after starting antipsychotic treatment was significantly higher (adjusted hazard ratio, 3.64; 95% CI, 1.95-6.82) than the risk in antipsychotic-naive schizophrenia, after adjustment for family history of diabetes and other potential confounders. First-line treatment with either first-generation antipsychotics (adjusted hazard ratio, 3.06; 95% CI, 1.32-7.05) or second-generation antipsychotics (adjusted hazard ratio, 3.44; 95% CI, 1.73-6.83) increased the risk for diabetes without a statistically significant difference. Appropriate sensitivity analyses limited to type 2 diabetes corroborated these results. Schizophrenia confers a high endogenous risk for diabetes, and the risk is further increased by both first-generation and second-generation antipsychotics. Early detection and effective treatment of diabetes should be an integral part of multidisciplinary management of schizophrenia regardless of antipsychotic drug exposure.

Prevalence of metabolic syndrome in drug-naive patients with schizophrenia

Background: Asians are physiologically and genetically at a higher risk of metabolic syndrome. India is at the top with highest prevalence of metabolic syndrome. In recent times, it is established that antipsychotics, especially second generations, increases the risk of metabolic syndrome – which could be an already existing co-morbidity of schizophrenia in drug-naive patients. Objectives: This was a hospital-based cross-sectional study with the aim to know the prevalence of metabolic syndrome in the antipsychotic naive schizophrenia patients. Material and Methods: Following pre-decided inclusion and exclusion criteria, 65 patients were selected and assessed using socio-demographic and clinical data sheet, physical examinations like blood pressure, waist circumferences, and biochemical with normal values prescribed by API. Results: The prevalence of metabolic syndrome in patients with schizophrenia was 15.6% but major concern was the higher percentage of subsyndromal metabolic syndrome 1 and 2 (SMS1 and SMS2, 46.2% and 32.3%, respectively). Hypertension topped the list (65%) followed by low ‘high-density lipoproteins’ (HDL) (50%). Gender did not appear to be affecting the metabolic syndrome in schizophrenia but metabolic syndrome (MS) was commoner in those with age > 35 years while SMS was commoner in those with age < 35 years. Conclusion: Even in drug-naive schizophrenic, metabolic syndrome is more often full blown than none at all – sub-syndromal status is the commonest. Triacylglyceride (TAG) and fasting blood sugar (FBS) impairments are rare (< 5% occurrence) unless full blown MS. HDL anomaly is commoner in SMS1 while waist circumference (WC) and blood pressure (BP) anomaly is commoner in SMS2. Age appears to be the only independent factor in the prevalence (but not the duration of the disease). Diagnosis and awareness about these co-morbidities can help primary, secondary or tertiary prevention.

In vivo measurement of GABA transmission in healthy subjects and schizophrenia patients.

Postmortem studies in schizophrenia reveal alterations in gene products that regulate the release and extracellular persistence of GABA. However, results of in vivo studies of schizophrenia measuring total tissue GABA with magnetic resonance spectroscopy (MRS) have been inconsistent. Neither the postmortem nor the MRS studies directly address the physiological properties of GABA neurotransmission. The present study addresses this question through an innovative positron emission tomography (PET) paradigm. The binding of [(11)C]flumazenil, a benzodiazepine-specific PET radiotracer, was measured before and after administration of tiagabine (0.2 mg/kg of body weight), a GABA membrane transporter (GAT1) blocker, in 17 off-medication patients with schizophrenia and 22 healthy comparison subjects. Increased extracellular GABA, through GAT1 blockade, enhances the affinity of GABAA receptors for benzodiazepine ligands, detected as an increase in [(11)C]flumazenil tissue distribution volume (VT). [(11)C]Flumazenil VT was significantly increased across all cortical brain regions in the healthy comparison group but not in the schizophrenia group. This lack of effect was most prominent in the antipsychotic-naive schizophrenia group. In this subgroup, [(11)C]flumazenil ΔVT in the medial temporal lobe was correlated with positive symptoms, and baseline [(11)C]flumazenil VT in the medial temporal lobe was negatively correlated with visual learning. In the healthy comparison group but not the schizophrenia group, [(11)C]flumazenil ΔVT was positively associated with gamma-band oscillation power. This study demonstrates, for the first time, an in vivo impairment in GABA transmission in schizophrenia, most prominent in antipsychotic-naive individuals. The impairment in GABA transmission appears to be linked to clinical symptoms, disturbances in cortical oscillations, and cognition.

P.8.b.024 MAOA-VNTR polymorphism modulates context-dependent dopamine release and aggressive behaviour

onset antipsychotic naive (4 cohorts; N = 133), individuals with Asperger syndrome were drug free (1 cohort; N = 30), and bipolar disorder (7 cohorts; N = 90) and major depression patients (4 cohorts; N = 119) were receiving medication and were at various stages of illness. We found a number of distinct and overlapping sex-specific markers associated with each illness by evaluating the sex-diagnosis interaction for each analyte in a linear model. In particular, we found male-specific increases in the levels of several inflammatory markers in schizophrenia, major depression and Asperger syndrome. These markers included a number of interleukins, intercellular adhesion molecule 1, alpha-1-antitrypsin, and others, raising the possibility that some aspects of the widely reported immunological abnormalities in psychiatric illness [3] are male-specific. In line with the numerous sex differences reported in schizophrenia, our findings in first episode antipsychotic naive schizophrenia included alterations in the levels of several hormones, including elevated free and total testosterone in female patients and concomitant sex differences in sex hormone binding globulin (SHBG) and prolactin concentrations. Previous studies of chronic schizophrenia have similarly found long-term antipsychotic use to be associated with hyperprolactinaemia in females and a hypogonadal state [2]. In addition, we found that SHBG levels were also reduced in females with Asperger syndrome, pointing again to higher levels of free testosterone and overall to sex-specific hormonal disturbances in Asperger syndrome and in chronic and first episode schizophrenia. Other findings included female specific alterations of markers related to lipid metabolism in Asperger syndrome, increased levels of markers related to oxidative stress in males with bipolar disorder, and disruptions in serum levels of cardiovascular factors in schizophrenia. We conclude that different molecular mechanisms may be involved in the pathophysiology of these conditions, with implications for how we study and treat psychiatric illnesses and developmental disorders.

EPA-1234 – Distinct molecular phenotypes in male and female schizophrenia patients

In schizophrenia, sex differences related to age of onset, course of illness and response to antipsychotic treatment may be mirrored by differences in the underlying molecular pathways. We attempted to increase our understanding of these phenomena by carrying out multiplex immunoassay profiling of 95 serum molecules using samples from 4 independent cohorts of male and female first episode antipsychotic naive schizophrenia patients (n=133) and matched controls (n=133). The concentrations of 16 molecules associated with hormonal, inflammation and growth factor pathways showed significant sex differences in schizophrenia patients compared with controls. In line with the numerous sex differences reported in schizophrenia, our findings included alterations in the levels of several hormones, including elevated free and total testosterone in female patients and concomitant sex differences in sex hormone binding globulin and prolactin concentrations. We also found higher levels of thyroxine binding globulin and seven inflammatory markers in male schizophrenia patients only, raising the possibility that some aspects of the widely-reported immunological abnormalities in schizophrenia may be specific for males. Several of these markers showed sexspecific associations with positive and negative syndrome scale (PANSS) scores and changes in concentration after 6 weeks of treatment with antipsychotics. Finally, we also evaluated overlapping and distinct sex-specific biomarkers for schizophrenia, Asperger syndrome, major depressive disorder and bipolar disorder. We propose that future studies should investigate the common and sex-specific aetiologies of schizophrenia, as the current findings suggest that different therapeutic strategies may be required for male and female patients.

Identification of a Molecular Profile Associated with Immune Status in First-Onset Schizophrenia Patients

Alterations in immunological parameters have been reported for schizophrenia although little is known about the effects of inflammatory status on immune-related functional changes at disease onset. Here, we have investigated such T cell-dependent molecular changes in first-onset, antipsychotic-naive schizophrenia patients using a novel ex vivo blood culture system. Blood samples from patients (n=17) and controls (n=17) were collected into stimulant-containing or null control TruCulture™ tubes, incubated 24 hours and the concentrations of 107 immune and metabolic molecules measured in the conditioned media using the HumanMAP™ immunoassay system. Nine molecules showed altered release from schizophrenia blood cells compared to those from controls and this was replicated in an independent cohort. In silico pathway analysis showed that these molecules had roles in endothelial cell function, inflammation, acute phase response and fibrinolysis pathways. Importantly, five of these molecules showed altered release only after stimulation. This study has identified a reproducible peripheral molecular signature associated with altered immune function in first-onset schizophrenia subjects. This suggests that immune status can affect the biomarker profile which could be important for personalized medicine strategies. Furthermore, whole blood culture analysis may be useful in the identification of diagnostic tools or novel treatment strategies due to ease-of-use and clinical accessibility.

Distinct Molecular Phenotypes in Male and Female Schizophrenia Patients

BackgroundIn schizophrenia, sex specific dimorphisms related to age of onset, course of illness and response to antipsychotic treatment may be mirrored by sex-related differences in the underlying molecular pathways.Methodology/Principal FindingsHere, we have carried out multiplex immunoassay profiling of sera from 4 independent cohorts of first episode antipsychotic naive schizophrenia patients (n = 133) and controls (n = 133) to identify such sex-specific illness processes in the periphery. The concentrations of 16 molecules associated with hormonal, inflammation and growth factor pathways showed significant sex differences in schizophrenia patients compared with controls. In female patients, the inflammation-related analytes alpha-1-antitrypsin, B lymphocyte chemoattractant BLC and interleukin-15 showed negative associations with positive and negative syndrome scale (PANSS) scores. In male patients, the hormones prolactin and testosterone were negatively associated with PANSS ratings. In addition, we investigated molecular changes in a subset of 33 patients before and after 6 weeks of treatment with antipsychotics and found that treatment induced sex-specific changes in the levels of testosterone, serum glutamic oxaloacetic transaminase, follicle stimulating hormone, interleukin-13 and macrophage-derived chemokine. Finally, we evaluated overlapping and distinct biomarkers in the sex-specific molecular signatures in schizophrenia, major depressive disorder and bipolar disorder.Conclusions/SignificanceWe propose that future studies should investigate the common and sex-specific aetiologies of schizophrenia, as the current findings suggest that different therapeutic strategies may be required for male and female patients.

Reduced Mirror Neuron Activity in Schizophrenia and Its Association With Theory of Mind Deficits: Evidence From a Transcranial Magnetic Stimulation Study

The "mirror-neuron system" has been proposed to be a neurophysiological substrate for social cognition (SC) ability. We used transcranial magnetic stimulation (TMS) paradigms to compare putative mirror neuron activity (MNA) in 3 groups: antipsychotic-naive, medicated schizophrenia patients, and healthy comparison subjects. We also explored the association between MNA and SC ability in patients. Fifty-four consenting right-handed schizophrenia patients (33 antipsychotic naive) and 45 matched healthy comparison subjects completed a TMS experiment to assess putative premotor MNA. We used 4 TMS paradigms of eliciting motor-evoked potentials (MEP) in the right first dorsal interosseous (FDI) muscle. These were applied while the subjects observed a goal-directed action involving the FDI (actual action and its video) and a static image. The difference in the amplitude of the MEP while they observed the static image and the action provided a measure of MNA. Subjects also underwent SC assessments (theory of mind [ToM], emotion processing, and social perception). Two-way repeated measures ANOVA revealed significant group × occasion interaction effect in 3 TMS paradigms, indicating deficient motor facilitation during action observation relative to rest state in antipsychotic-naive schizophrenia patients as compared with the other two groups. Among patients, there were significant direct correlations between measures of MNA and ToM performance. Antipsychotic-naive schizophrenia patients have poorer MNA than medicated patients and healthy controls. Measures of putative MNA had significant and consistent associations with ToM abilities. These findings suggest a possibility of deficient mirror neuron system underlying SC deficits in schizophrenia.

Neural markers of negative symptom outcomes in distributed working memory brain activity of antipsychotic-naive schizophrenia patients

Since working memory deficits in schizophrenia have been linked to negative symptoms, we tested whether features of the one could predict the treatment outcome in the other. Specifically, we hypothesized that working memory-related functional connectivity at pre-treatment can predict improvement of negative symptoms in antipsychotic-treated patients. Fourteen antipsychotic-naive patients with first-episode schizophrenia were clinically assessed before and after 7 months of quetiapine monotherapy. At baseline, patients underwent functional magnetic resonance imaging while performing a verbal n-back task. Spatial independent component analysis identified task-modulated brain networks. A linear support vector machine was trained with these components to discriminate six patients who showed improvement in negative symptoms from eight non-improvers. Classification accuracy and significance was estimated by leave-one-out cross-validation and permutation tests, respectively. Two frontoparietal and one default mode network components predicted negative symptom improvement with a classification accuracy of 79% (p=0.003). Discriminating features were found in the frontoparietal networks but not the default mode network. These preliminary data suggest that functional patterns at baseline can predict negative symptom treatment-response in schizophrenia. This information may be used to stratify patients into subgroups thereby facilitating personalized treatment.