This meta-analysis was performed according to the Preferred Reporting for Systematic Reviews and Meta-analysis (PRISMA) Statement.33 The literature search was conducted by two independent researchers (C.L. and M.P.) using Pubmed (Medline), Embase, Cochrane Database of Systematic Reviews, and Psychinfo. Combinations of the following search terms were used: “raloxifene”, “evista” or “SERM” and “schizophrenia”, “psychosis”, “psychotic”, “schizoaffective”, or “schizophreniform”. The search had no year and language restrictions. See Table S2 for an example search string. The search cutoff date was 10 October 2017. Reference lists of the included studies were searched for cross-references. After independent screening was performed by M.P. and C.L., consensus about the included studies was reached between all authors.
Articles were included when the following inclusion criteria were met: (1) randomized, double-blind placebo-controlled trials (used for quantitative synthesis) or case-reports (used for qualitative synthesis) that assessed the effect of raloxifene on one of our outcome measures; (2) included patients with schizophrenia spectrum disorder (schizophrenia, schizoaffective disorder, schizophreniform disorder or psychotic disorder not otherwise specified), according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III, DSM-III-R, DSM-IV, DSM-IV-TR, DSM-5)34,35, or the International Classification of Diseases (ICD-9 or ICD-10); (3) studies were published in a peer-reviewed journal. For two studies that included the same patient sample, outcome measures that were similar were included in the analysis only once.23,24 Risk of bias was assessed independently by J.B. and M.P. using the Cochrane Risk of Bias tool for RCTs (Table S3).36
The primary outcome measure was psychotic symptom severity, measured with the Positive and Negative Syndrome Scale (PANSS).37 Secondary outcome measures were cognitive functioning (for domains and included tests, see Table S4) and depressive symptoms (assessed by the Montgomery-Asberg Depression Rating Scale (MADRS)38 or Depression Anxiety and Stress Scale (DASS).39
Comprehensive meta-analysis (CMA) software version 2.0 was used to perform all analyses, using a random-effects model.40 For every individual study, Hedges’ g was calculated for each outcome measure. To obtain this effect size, per treatment arm, mean differences in change scores (end of treatment minus baseline) and standard deviations (SD)) or pre- and post-means ( + SD) were used. To avoid overestimation of the true effect sizes caused by the pre-post treatment correlation,41 change scores were preferred. When these values were not reported, we used exact F-, t-, or p-values. All effect sizes were calculated twice independently from the original articles to check for errors.
Studies were combined in meta-analyses to calculate a mean weighted effect size for each outcome measure, using a random-effects model. To investigate whether studies could be taken together to share a common population effect size, the Q-value and I2-statistic were evaluated for each analysis. The Q-statistic tests the existence of heterogeneity, and displays a chi-square distribution with k-1 degrees of freedom (k = number of studies), where Q-values higher than the degrees of freedom indicate significant between-studies variability. I2 reflects which proportion of the observed variance reflects differences in true effect sizes, rather than sampling error, ranging from 0 to 100%. Values of 25%, 50%, and 75% can be interpreted as low, moderate, and high, respectively.42
Additionally, funnel plots were inspected for asymmetry in order to check for publication bias. Potential asymmetry was tested with Egger’s test, using a significance level of α = 0.05 (2-tailed). Effect sizes with a p-value smaller than 0.05 were considered statistically significant. Effect sizes were interpreted according to the guidelines by Cohen, with an effect size of 0.20 indicating a small effect, 0.50 a medium and over 0.80 a large effect.43
As in all papers either a dosage of 60 mg or 120 mg raloxifene was administered, a subgroup analysis was performed based on this categorization. This was done for PANSS outcomes only, as the amount of papers that reported depressive symptoms or cognitive functioning as an outcome measure was insufficient to perform this analysis. Furthermore, to assess the effect of treatment duration, this variable was used as a regressor in additional analyses.
The authors declare that the main data supporting the findings of this study are available within the article and its Supplementary files. Since this is a meta-analysis no primary data were collected during this study. Additional data are available from the corresponding author upon request.
Rajiv Tandon | Wolfgang Gaebel | Deanna M. Barch | Juan Bustillo | Raquel E. Gur | Stephan Heckers | Dolores Malaspina | Michael J. Owen | Susan Schultz | Ming Tsuang | Jim Van Os | William Carpenter
Although dementia praecox or schizophrenia has been considered a unique disease for over a century, its definitions and boundaries have changed over this period and its etiology and pathophysiology remain elusive. Despite changing definitions, DSM-IV schizophrenia is reliably diagnosed, has fair validity and conveys useful clinical information. Therefore, the essence of the broad DSM-IV definition of schizophrenia is retained in DSM-5. The clinical manifestations are extremely diverse, however, with this heterogeneity being poorly explained by the DSM-IV clinical subtypes and course specifiers. Additionally, the boundaries of schizophrenia are imprecisely demarcated from schizoaffective disorder and other diagnostic categories and its special emphasis on Schneiderian "first-rank" symptoms appears misplaced. Changes in the definition of schizophrenia in DSM-5 seek to address these shortcomings and incorporate the new information about the nature of the disorder accumulated over the past two decades. Specific changes in its definition include elimination of the classic subtypes, addition of unique psychopathological dimensions, clarification of cross-sectional and longitudinal course specifiers, elimination of special treatment of Schneiderian 'first-rank symptoms', better delineation of schizophrenia from schizoaffective disorder, and clarification of the relationship of schizophrenia to catatonia. These changes should improve diagnosis and characterization of individuals with schizophrenia and facilitate measurement-based treatment and concurrently provide a more useful platform for research that will elucidate its nature and permit a more precise future delineation of the 'schizophrenias'. © 2013 Elsevier B.V.
Jonathan Schaefer | Evan Giangrande | Daniel R. Weinberger | Dwight Dickinson
Objective: Schizophrenia results in cognitive impairments as well as positive, negative, and disorganized symptomatology. The present study examines the extent to which these cognitive deficits are generalized across domains, potential moderator variables, and whether the pattern of cognitive findings reported in schizophrenia has remained consistent over time and across cultural and geographic variation. Method: Relevant publications from 2006 to 2011 were identified through keyword searches in PubMed and an examination of reference lists. Studies were included if they (1) compared the cognitive performance of adult schizophrenia patients and healthy controls, (2) based schizophrenia diagnoses on contemporary diagnostic criteria, (3) reported information sufficient to permit effect size calculation, (4) were reported in English, and (5) reported data for neuropsychological tests falling into at least 3 distinct cognitive domains. A set of 100 non-overlapping studies was identified, and effect sizes (Hedge's g) were calculated for each cognitive variable. Results: Consistent with earlier analyses, patients with schizophrenia scored significantly lower than controls across all cognitive tests and domains (grand mean effect size, g = - 1.03). Patients showed somewhat larger impairments in the domains of processing speed (g = - 1.25) and episodic memory (g = - 1.23). Our results also showed few inconsistencies when grouped by geographic region. Conclusions: The present study extends findings from 1980 to 2006 of a substantial, generalized cognitive impairment in schizophrenia, demonstrating that this finding has remained robust over time despite changes in assessment instruments and alterations in diagnostic criteria, and that it manifests similarly in different regions of the world despite linguistic and cultural differences. © 2013.
Mark Van Der Gaag | Filip Smit | Andreas Bechdolf | Paul French | Don H. Linszen | Alison R. Yung | Patrick McGorry | Pim Cuijpers
Over the last decade many studies were conducted to assess the feasibility of early detection of people at risk of developing psychosis and intervention to prevent or delay a first psychotic episode. Most of these studies were small and underpowered. A meta-analysis can demonstrate the effectiveness of the efforts to prevent or postpone a first episode of psychosis.A search conducted according the PRISMA guideline identified 10 studies reporting 12-month follow-up data on transition to psychosis, and 5 studies with follow-ups varying from 24 to 48. months. Both random and fixed effects meta-analyses were conducted.The quality of the studies varied from poor to excellent. Overall the risk reduction at 12. months was 54% (RR. = 0.463; 95% CI. = 0.33-0.64) with a Number Needed to Treat (NNT) of 9 (95% CI. = 6-15). Although the interventions differed, there was only mild heterogeneity and publication bias was small. All sub-analyses demonstrated effectiveness. Also 24 to 48-month follow-ups were associated with a risk reduction of 37% (RR. = .635; 95% CI. = 0.44-0.92) and a NNT of 12 (95% CI. = 7-59). Sensitivity analysis excluding the methodologically weakest study showed that the findings were robust.Early detection and intervention in people at ultra-high risk of developing psychosis can be successful to prevent or delay a first psychosis. Antipsychotic medication showed efficacy, but more trials are needed. Omega-3 fatty acid needs replication. Integrated psychological interventions need replication with more methodologically sound studies. The findings regarding CBT appear robust, but the 95% confidence interval is still wide. © 2013 Elsevier B.V.
Emre Bora | Christos Pantelis
Theory of mind (ToM) deficit is a well-established feature of schizophrenia and has been suggested as a vulnerability marker of this disorder. However, as most of this evidence is based on studies in chronic patients, it is less clear whether ToM is impaired prior to or following the onset of a first-episode and whether it is evident in unaffected relatives of patients. In this meta-analysis, ToM performance of 3005 individuals with first-episode psychosis (FEP), individuals at ultra-high risk for psychosis (UHR) and unaffected relatives were compared with 1351 healthy controls. ToM was substantially impaired in first-episode psychosis (Cohen d=. 1.0) and this deficit was comparable to findings in chronic patients. ToM was also impaired in unaffected relatives (d=. 0.37) and UHR subjects (d=. 0.45) and performances of these groups were intermediate between FES and healthy controls. Severity of ToM deficits in unaffected relatives and UHR subjects was similar to other cognitive deficits observed in these groups. Longitudinal studies of clinical and genetic high-risk subjects are necessary to investigate the trajectory of development of ToM deficits in schizophrenia. © 2013 Elsevier B.V.
Rachel Upthegrove | Nuria Manzanares-Teson | Nicholas M. Barnes
This systematic review sets out to give a comprehensive overview of the cytokine profile at the onset of psychosis un-confounded by medication. We aim to provide insight into the early pathophysiological process of psychosis and areas for future research of potential biomarkers able to chart the extent of illness or effectiveness of treatment.Following PRISMA guidelines, a systematic primary search identified 4638 citations, 4651 studies were retrieved and screened, and 23 studies met the inclusion criteria (published in English before June 2013, patients with neuroleptic naive first episode psychosis, and assessed circulating cytokines). These reported 570 patients, 683 healthy control subjects, and 20 cytokine/cytokine receptors. Papers that contained sufficient stratified data were included in a random-effects pooled effect size meta-analysis.Highly significant effect sizes were found for elevated IL-1β, sIL-2r, IL-6, and TNF-α. Non-significant effect size estimates were obtained for IL-2, IL-4, and IFN-γ.Thus, we found significant elevation in pro-inflammatory cytokine levels in the serum of patients with medication-naive first episode psychosis. This adds to the evidence of a pro-inflammatory immune deregulation in schizophrenia and suggests these cytokines should be the focus for further research in biomarkers of progress and extent of illness. Future studies should focus on the medication-naive group at the early stages of illness with numbers large enough to allow for the control of other potential confounding factors. © 2014.
Sang Hyuk Lee | Marek Kubicki | Takeshi Asami | Larry J. Seidman | Jill M. Goldstein | Raquelle I. Mesholam-Gately | Robert W. McCarley | Martha E. Shenton
Background: Previous voxelwise Diffusion Tensor Imaging (DTI) investigations of white matter in first-episode schizophrenia (FESZ) have been limited to the analysis of Fractional Anisotropy (FA) and mean diffusivity (MD), with their findings inconsistent in terms of the anatomical locations and extent of abnormalities. This study examines white matter abnormalities in FESZ, compared with healthy controls, using a tract-based spatial statistics (TBSS) approach applied to multiple measures of tract integrity, and correlates these findings with symptom severity. Methods: Seventeen first-episode patients with schizophrenia and seventeen age- and gender-matched healthy controls (HC) participated in this imaging study where FA, MD, and axial and radial diffusivities were compared between the two groups using TBSS. Results: First-episode patients with schizophrenia showed lower FA values in the genu and body of corpus callosum, the internal capsule, the external capsule, the fornix, the superior, inferior fronto-occipital fasciculus, the cingulum, and the uncinate fasciculus compared with HC. Increased MD and radial diffusivity were shown in virtually all white matter regions. There was no significant difference, however, observed for axial diffusivity between the two groups. Pearson correlation analysis showed that the FA values of the right inferior fronto-occipital fasciculus were positively correlated with positive symptoms, negative symptoms, and total correct items of the Wisconsin Card Sorting Test. FA values of right external capsule also showed significant positive correlation with category completed scores of the WCST. Conclusions: These data suggest extensive, possibly myelin related white matter disruptions in FESZ. © 2012 Elsevier B.V.
Deanna M. Barch | Juan Bustillo | Wolfgang Gaebel | Raquel Gur | Stephan Heckers | Dolores Malaspina | Michael J. Owen | Susan Schultz | Rajiv Tandon | Ming Tsuang | Jim Van Os | William Carpenter
Work on the causes and treatment of schizophrenia and other psychotic disorders has long recognized the heterogeneity of the symptoms that can be displayed by individuals with these illnesses. Further, researchers have increasingly emphasized the ways in which the severity of different symptoms of this illness can vary across individuals, and have provided evidence that the severity of such symptoms can predict other important aspects of the illness, such as the degree of cognitive and/or neurobiological deficits. Additionally, research has increasingly emphasized that the boundaries between nosological entities may not be categorical and that the comorbidity of disorders may reflect impairments in common dimensions of genetic variation, human behavior and neurobiological function. As such, it is critical to focus on a dimensional approach to the assessment of symptoms and clinically relevant phenomena in psychosis, so as to increase attention to and understanding of the causes and consequences of such variation. In the current article, we review the logic and justification for including dimensional assessment of clinical symptoms in the evaluation of psychosis in the Fifth Edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM-5). © 2013 Elsevier B.V.
François Orliac | Mickael Naveau | Marc Joliot | Nicolas Delcroix | Annick Razafimandimby | Perrine Brazo | Sonia Dollfus | Pascal Delamillieure
Neuroimaging data support the idea that schizophrenia is a brain disorder with altered brain structure and function. New resting-state functional connectivity techniques allow us to highlight synchronization of large-scale networks, such as the default-mode network (DMN) and salience network (SN). A large body of work suggests that disruption of these networks could give rise to specific schizophrenia symptoms. We examined the intra-network connectivity strength and gray matter content (GMC) of DMN and SN in 26 schizophrenia patients using resting-state functional magnetic resonance imaging and voxel-based morphometry. Resting-state data were analyzed with independent component analysis and dual-regression techniques. We reported reduced functional connectivity within both DMN and SN in patients with schizophrenia. Concerning the DMN, patients showed weaker connectivity in a cluster located in the right paracingulate cortex. Moreover, patients showed decreased GMC in this cluster. With regard to the SN, patients showed reduced connectivity in the left and right striatum. Decreased connectivity in the paracingulate cortex was correlated with difficulties in abstract thinking. The connectivity decrease in the left striatum was correlated with delusion and depression scores. Correlation between the connectivity of DMN frontal regions and difficulties in abstract thinking emphasizes the link between negative symptoms and the likely alteration of the frontal medial cortex in schizophrenia. Correlation between the connectivity of SN striatal regions and delusions supports the aberrant salience hypothesis. This work provides new insights into dysfunctional brain organization in schizophrenia and its contribution to specific schizophrenia symptoms. © 2013 Elsevier B.V.
Valérie Tourjman | Édouard Kouassi | Marie Ève Koué | Matteo Rocchetti | Simon Fortin-Fournier | Paolo Fusar-Poli | Stéphane Potvin
Objectives: Evidence-based medicine suggests that schizophrenia is associated with an inflammatory syndrome, but the extent to which this syndrome is normalized by antipsychotic treatment has yet to be determined. Methods: A systematic quantitative review of the effects of antipsychotics on peripheral cytokine levels in schizophrenia was performed, using follow-up studies providing in vivo cytokine assessments before and after treatment. Results: We retrieved 23 studies (total of 762 subjects) which showed that antipsychotic treatment significantly increases plasma levels of soluble interleukin-2 receptor and reduces the plasma levels of interleukin-1β and interferon-γ. Conclusions: These results show that antipsychotics produce anti-inflammatory effects in schizophrenia. © 2013 Elsevier B.V.
M. Alvarez-Jimenez | M. A. Alcazar-Corcoles | C. González-Blanch | S. Bendall | P. D. McGorry | J. F. Gleeson
Background: Internet and mobile-based interventions provide a unique opportunity to deliver cost-effective, accessible, time-unlimited support to people with psychosis. The aims of this study were to systematically compile and analyze the evidence on the acceptability, feasibility, safety and benefits of online and mobile-based interventions for psychosis. Methods: Systematic review of peer-reviewed studies examining the usability, acceptability, feasibility, safety or efficacy of user-led, Internet or mobile-based interventions, with at least 80% of participants diagnosed with schizophrenia-spectrum disorders. Results: Of 38 potentially relevant articles, 12 were eligible for inclusion. Interventions included web-based psycho-education; web-based psycho-education plus moderated forums for patients and supporters; integrated web-based therapy, social networking and peer and expert moderation; web-based CBT; personalized advice based on clinical monitoring and text messaging interventions. Results showed that 74-86% of patients used the web-based interventions efficiently, 75-92% perceived them as positive and useful, and 70-86% completed or were engaged with the interventions over the follow-up. Preliminary evidence indicated that online and mobile-based interventions show promise in improving positive psychotic symptoms, hospital admissions, socialization, social connectedness, depression and medication adherence. Conclusions: Internet and mobile-based interventions for psychosis seem to be acceptable and feasible and have the potential to improve clinical and social outcomes. The heterogeneity, poor quality and early state of current research precludes any definite conclusions. Future research should investigate the efficacy of online and mobile interventions through controlled, well-powered studies, which investigate intervention and patient factors associated with take-up and intervention effects. © 2014 Elsevier B.V.
Louis A. Sass
This paper offers an overview and clarification of the ipseity-disturbance or self-disorder hypothesis regarding schizophrenia, with focus on some recent and recommended research and theoretical refinements. There is need to expand research and theorizing in several directions-in order to: 1, specify more precisely what is truly distinctive in the schizophrenia spectrum, 2, explore internal structure and explanatory potential of this purported disturbance of minimal- or core-self experience, 3, generate testable hypotheses concerning pathogenetic pathways and psychotherapeutic interventions.Comparative studies can make a crucial scientific contribution. Some recent, exploratory studies are described: published reports were examined for alterations of self-experience in conditions outside the schizophrenia spectrum-mania, psychotic depression, and depersonalization disorder-and in one unusual attitudinal stance: intense introspection (as refined in early 20th century psychological research). Remarkable similarities (e.g., alienation/reification of thoughts and bodily experiences, fading of self and world) as well as some important differences (e.g., absence, outside schizophrenia, of severe erosion of minimal self-experience or real confusion of self and other) in types of self-anomalies were found. These support but also refine the ipseity-disturbance model. Future research should treat self-experience as an independent variable, manipulating and measuring this dimension (in both schizophrenic and non-schizophrenic populations) to study its associations with anomalies of cognition, affect, expression, and neural functioning already identified in schizophrenia.The self-disorder model offers an integrative and dynamic view of schizophrenia congruent with recent trends in cognitive neuroscience and consistent with the heterogeneous, varying, and holistic nature of this enigmatic illness. © 2013.
Bassam Khoury | Tania Lecomte | Brandon A. Gaudiano | Karine Paquin
Background: An increasing number of mindfulness interventions are being used with individuals with psychosis or schizophrenia, but no known meta-analysis has investigated their effectiveness. Objective: To evaluate the efficacy of mindfulness interventions for psychosis or schizophrenia, we conducted an effect-size analysis of initial studies. Data sources: A systematic review of studies published in journals or in dissertations in PubMED, PsycINFO or MedLine from the first available date until July 25, 2013. Review methods: A total of 13 studies (n= 468) were included. Results: Effect-size estimates suggested that mindfulness interventions are moderately effective in pre-post analyses (n= 12; Hedge's g= .52). When compared with a control group, we found a smaller effect size (n= 7; Hedge's g= .41). The obtained results were maintained at follow-up when data were available (n= 6; Hedge's g= .62 for pre-post analyses; results only approached significance for controlled analyses, n= 3; Hedge's g= .55, p= .08). Results suggested higher effects on negative symptoms compared with positive ones. When combined together, mindfulness, acceptance, and compassion strongly moderated the clinical effect size. However, heterogeneity was significant among the trials, probably due to the diversity of interventions included and outcomes assessed. Conclusion: Mindfulness interventions are moderately effective in treating negative symptoms and can be useful adjunct to pharmacotherapy; however, more research is warranted to identify the most effective elements of mindfulness interventions. © 2013 Elsevier B.V.
Souhel Najjar | Daniel M. Pearlman
© 2014. Background: Neuroinflammation and white matter pathology have each been independently associated with schizophrenia, and experimental studies have revealed mechanisms by which the two can interact in vitro, but whether these abnormalities simultaneously co-occur in people with schizophrenia remains unclear. Method: We searched MEDLINE, EMBASE, PsycINFO and Web of Science from inception through 12 January 2014 for studies reporting human data on the relationship between microglial or astroglial activation, or cytokines and white matter pathology in schizophrenia. Results: Fifteen studies totaling 792 subjects (350 with schizophrenia, 346 controls, 49 with bipolar disorder, 37 with major depressive disorder and 10 with Alzheimer's disease) met all eligibility criteria. Five neuropathological and two neuroimaging studies collectively yielded consistent evidence of an association between schizophrenia and microglial activation, particularly in white rather than gray matter regions. Ultrastructural analysis revealed activated microglia near dystrophic and apoptotic oligodendroglia, demyelinating and dysmyelinating axons and swollen and vacuolated astroglia in subjects with schizophrenia but not controls. Two neuroimaging studies found an association between carrier status for a functional single nucleotide polymorphism in the interleukin-1β gene and abnormal white as well as gray matter volumes in schizophrenia but not controls. A neuropathological study found that orbitofrontal white matter neuronal density was increased in schizophrenia cases exhibiting high transcription levels of pro-inflammatory cytokines relative to those exhibiting low transcription levels and to controls. Schizophrenia was associated with decreased astroglial density specifically in subgenual cingulate white matter and anterior corpus callosum, but not other gray or white matter areas. Astrogliosis was consistently absent. Data on astroglial gene expression, mRNA expression and protein concentration were inconsistent. Conclusion: Neuroinflammation is associated with white matter pathology in people with schizophrenia, and may contribute to structural and functional disconnectivity, even at the first episode of psychosis.
Ming T. Tsuang | Jim Van Os | Rajiv Tandon | Deanna M. Barch | Juan Bustillo | Wolfgang Gaebel | Raquel E. Gur | Stephan Heckers | Dolores Malaspina | Michael J. Owen | Susan Schultz | William Carpenter
Despite advances in the treatment of schizophrenia over the past half-century, the illness is frequently associated with a poor outcome. This is principally related to the late identification and intervention in the course of the illness by which time patients have experienced a substantial amount of socio-occupational decline that can be difficult to reverse. The emphasis has therefore shifted to defining psychosis-risk syndromes and evaluating treatments that can prevent transition to psychosis in these ultra-high risk groups. To consider the appropriateness of adding psychosis risk syndrome to our diagnostic nomenclature, the psychotic disorders work group extensively reviewed all available data, consulted a range of experts, and carefully considered the variety of expert and public comments on the topic. It was clear that reliable methods were available to define a syndrome characterized by sub-threshold psychotic symptoms (in severity or duration) and which was associated with a very significant increase in the risk of development of a full-fledged psychotic disorder (schizophrenia spectrum, psychotic mood disorder, and other psychotic disorders) within the next year. At the same time, the majority of individuals with "attenuated psychotic symptoms" had one or more other current psychiatric comorbid conditions (usually mood or anxiety disorders, substance use disorder; Fusar-Poli 2012) and exhibited a range of psychiatric outcomes other than conversion to psychosis (significant proportions either fully recover or develop some other psychiatric disorder, with a minority developing a psychotic disorder). Although the reliability of the diagnosis is well established in academic and research settings, it was found to be less so in community and other clinical settings. Furthermore, the nosological relationship of attenuated psychosis syndrome (APS) to schizotypal personality disorder and other psychiatric conditions was unclear. Further study will hopefully resolve these questions. The work group decided to recommend the inclusion of attenuated psychosis syndrome as a category in the appendix (Section3) of DSM-5 as a condition for further study. © 2013 Elsevier B.V.
Stephan Heckers | Deanna M. Barch | Juan Bustillo | Wolfgang Gaebel | Raquel Gur | Dolores Malaspina | Michael J. Owen | Susan Schultz | Rajiv Tandon | Ming Tsuang | Jim Van Os | William Carpenter
Schizophrenia spectrum disorders attract great interest among clinicians, researchers, and the lay public. While the diagnostic features of schizophrenia have remained unchanged for more than 100. years, the mechanism of illness has remained elusive. There is increasing evidence that the categorical diagnosis of schizophrenia and other psychotic disorders contributes to this lack of progress. The 5th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) continues the categorical classification of psychiatric disorders since the research needed to establish a new nosology of equal or greater validity is lacking. However, even within a categorical system, the DSM-5 aims to capture the underlying dimensional structure of psychosis. The domains of psychopathology that define psychotic disorders are presented not simply as features of schizophrenia. The level, the number, and the duration of psychotic signs and symptoms are used to demarcate psychotic disorders from each other. Finally, the categorical assessment is complemented with a dimensional assessment of psychosis that allows for more specific and individualized assessment of patients. The structure of psychosis as outlined in the DSM-5 may serve as a stepping-stone towards a more valid classification system, as we await new data to redefine psychotic disorders. © 2013 Elsevier B.V.
Jagadeesh Sridhara Rao | Hyung Wook Kim | Gaylia Jean Harry | Stanley Isaac Rapoport | Edmund Arthur Reese
Schizophrenia (SZ) is a progressive, neuropsychiatric disorder associated with cognitive impairment. A number of brain alterations have been linked to cognitive impairment, including neuroinflammation, excitotoxicity, increased arachidonic acid (AA) signaling and reduced synaptic protein. On this basis, we tested the hypothesis that SZ pathology is associated with these pathological brain changes. To do this, we examined postmortem frontal cortex from 10 SZ patients and 10 controls and measured protein and mRNA levels of cytokines, and astroglial, microglial, neuroinflammatory, excitotoxic, AA cascade, apoptotic and synaptic markers. Mean protein and mRNA levels of interleukin-1β, tumor necrosis factor-α, glial acidic fibrillary protein (GFAP), a microglial marker CD11b, and nuclear factor kappa B subunits were significantly increased in SZ compared with control brain. Protein and mRNA levels of cytosolic and secretory phospholipase A 2 and cyclooxygenase also were significantly elevated. N-methyl-d-aspartate receptor subunits 1 and 2B, inducible nitric oxide synthase and c-Fos were not significantly different. In addition, reduced protein and mRNA levels of brain-derived neurotrophic factor, synaptophysin and drebrin were found in SZ compared with control frontal cortex. Increased neuroinflammation and AA cascade enzyme markers with synaptic protein loss could promote disease progression and cognitive defects in SZ patients. Drugs that downregulate these changes might be considered for new therapies in SZ. © 2013.
Emily G. Severance | Kristin L. Gressitt | Cassie R. Stallings | Andrea E. Origoni | Sunil Khushalani | F. Markus Leweke | Faith B. Dickerson | Robert H. Yolken
The origin of inflammation in psychiatric disorders is not well understood. The translocation of commensal microbiota across the gastrointestinal barrier can result in a persistent state of low-grade immune activation and/or inflammation. We measured serological surrogate markers of bacterial translocation (soluble CD14 (sCD14) and lipopolysaccharide binding protein (LBP)) in two psychiatric cohorts and compared these levels to C-reactive protein (CRP), body mass index (BMI), and food-related and autoimmune antibodies. The two cohorts were composed of the following: (1) n=141 schizophrenia, n=75 bipolar disorder, n=78 controls; (2) n=78 antipsychotic-naïve first-episode schizophrenia, n=38 medicated first-episode schizophrenia. sCD14 seropositivity conferred a 3.1-fold increased odds of association with schizophrenia (multivariate regressions, OR=3.09, p < 0.0001) compared to controls. Case-control differences in sCD14 were not matched by LBP. Quantitative levels of LBP, but not sCD14, correlated with BMI in schizophrenia (R 2 =0.21, p < 0.0001). sCD14 and LBP also exhibited some congruency in schizophrenia with both significantly correlated with CRP (R 2 =0.26-0.27, p < 0.0001) and elevated in females compared to males (p < 0.01). Antipsychotic treatment generally did not impact sCD14 or LBP levels except for significant correlations, especially sCD14, with gluten antibodies in antipsychotic-naïve schizophrenia (R 2 =0.27, p < 0.0001). In bipolar disorder, sCD14 levels were significantly correlated with anti-tissue transglutaminase IgG (R 2 =0.37, p < 0.001). In conclusion, these bacterial translocation markers produced discordant and complex patterns of activity, a finding that may reflect an imbalanced, activated innate immune state. Whereas both markers may upregulate following systemic exposure to Gram-negative bacteria, non-lipopolysaccharide-based monocyte activation, autoimmunity and metabolic dysfunction may also contribute to the observed marker profiles. © 2013 Elsevier B.V.