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Cognitive remediation is now widely recognized as an effective treatment for cognitive deficits in schizophrenia. Its effects are meaningful, durable, and related to improvements in everyday functional outcomes. As with many therapies, the evolution of cognitive remediation has resulted in treatment programs that use a variety of specific techniques, yet share common core principles. This paper is the product of a cognitive remediation expert working group consensus meeting to identify core features of the treatment and produce recommendations for its design, conduct, reporting, and implementation. Four techniques were identified as core features of cognitive remediation: facilitation by a therapist, cognitive exercise, procedures to develop problem-solving strategies, and procedures to facilitate transfer to real world functioning. Treatment techniques within each of these core features are presented to facilitate decisions for clinical trials and implementation in clinical settings.

article i nfo Background: The Social Security Administration is considering whether schizophrenia may warrant inclusion in their new "Compassionate Allowance" process, which aims to identify diseases and other medical conditions that almost always qualify for Social Security disability benefits simply on the basis of their confirmed presence. This paper examines the reliability and validity of schizophrenia diagnosis, how a valid diagnosis is established, and the stability of the diagnosis over time. A companion paper summarizes evidence on the empirical association between schizophrenia and disability, thus leading to this paper that evaluates how valid clinical diagnoses of schizophrenia are. Methods: Literature review and synthesis, based on a workplan developed in an expert meeting convened by the National Institute of Mental Health and the Social Security Administration. Findings: At least since the introduction of the 3rd edition of the American Psychiatric Association's Diagnostic and Statistical Manual (DSM-III) in 1980, diagnoses of schizophrenia made by mental health specialists are valid, reliable, and stable over time, across community as well as academic practice settings, and across different assessment methods. These analyses are particularly valid during the time-frame relevant to social security awards: at least 2 years after the initial stages of illness. We could not find studies that have evaluated the validity or reliability of schizophrenia diagnoses made exclusively by primary care providers (vs. mental health professionals). Discussion: In the post-DSM-III era, schizophrenia diagnosis—using modern diagnostic criteria—is valid and reliable when performed by doctoral-level mental health specialists (i.e., psychiatrists and psychologists), in community as As we note in the accompanying white paper, it is our position that the presence of schizophrenia is consistently associated with the occurrence of impairments in the ability to function adequately in everyday life. In this paper, we present information regarding the accuracy with which schizophrenia in established cases with an extended duration of illness can be identified by mental health clinicians in regular community settings. We also consider the reliability of the identification of schizophrenia as a diagnosis across different sources of diagnostic information, using different methods, and across individuals who may be generating these diagnoses (typically, doctoral-level mental health professionals). We also consider whether there are any specific procedures that may be required to generate a valid and reliable diagnosis of schizophrenia. Of particular interest is the duration of illness after which the diagnosis of schizophrenia and its associated disability can be con- sidered stable. The SSA requires a continuous duration of illness and disability of 2 years before considering a person with the illness for disabilitycompensation.Thus,thecritical focus is not prior to the illness (the prodome), or at the first episode, or after accrual of a minimal treatment history, but rather after there is an established illness. Much of the data that we review is older, but still supportive of the conclusion that after a certain initialperiod of evaluation and treatment, a clinically derived diagnosis is likely to betemporally stable andobtainable from a variety of medical records generated by mental health professionals.

article i nfo Background: The Social Security Administration (SSA) is considering whether schizophrenia may warrant in- clusion in their new "Compassionate Allowances" process, which aims to identify diseases and other medical conditions that invariably quality for Social Security disability benefits and require no more than minimal ob- jective medical information. This paper summarizes evidence on the empirical association between schizo- phrenia and vocational disability. A companion paper examines the reliability and validity of schizophrenia diagnosis which is critically relevant for granting a long-term disability on the basis of current diagnosis. Methods: Thisisaselectiveliteraturereviewandsynthesis,basedonaworkplandevelopedinameetingofexperts convened by the National Institute of Mental Health and the SSA. This review of the prevalence of disability is fo- cused on the criteria for receipt of disability compensation for psychotic disorders currently employed by the SSA. Results: Disability in multiple functional domains is detected in nearly every person with schizophrenia. Clinical remission is much more common than functional recovery, but most patients experience occasional relapses even with treatment adherence, and remissions do not predict functional recovery. Under SSA's current disability determination process, approximately80% of SSDI/SSI applications in SSA'sdiagnosticcategory of "Schizophrenia/ Paranoid Functional Disorders" are allowed, compared to around half of SSDI/SSI applications overall. Moreover, the allowance rate is even higher among applicants with schizophrenia. Many unsuccessful applicants are not de- nied, but rather simply are unable to manage the process of appeal after initial denials. Discussion: Research evidence suggests that disability applicants with a valid diagnosis of schizophrenia have sig- nificant impairment across multiple dimensions of functioning, and will typically remain impaired for the dura- tion of normal working ages or until new interventions are developed.

The term schizophrenia is increasingly contested by researchers, clinicians, patients and families. Mental health users and professionals around the world have started calling for a change of the name, seeing it as stigmatizing and harmful. This paper reviews the literature published so far on the issue of renaming schizophrenia, carefully weighing the pros and cons of the proposed changes. Forty seven papers have been published so far, encompassing editorials, research papers, commentaries to editorials, letters, forum papers and narrative reviews. The advantages of renaming schizophrenia far outweigh the disadvantages. It would reduce stigma and benefit communication between clinicians, patients and families. The most conservative option for renaming schizophrenia would be the use of eponyms since they are neutral and avoid adverse connotations. Renaming schizophrenia is not only a matter of semantics, but also an attempt to change the stigma carried by the present name. Nevertheless, a change will not be useful unless accompanied by parallel changes in legislation, services and the education of professionals and the public.

Incoherent speech in schizophrenia has long been described as the mind making “leaps” of large distances between thoughts and ideas. Such a view seems intuitive, and for almost two decades, attempts to operationalize these conceptual “leaps” in spoken word meanings have used language-based embedding spaces. An embedding space represents meaning of words as numerical vectors where a greater proximity between word vectors represents more shared meaning. However, there are limitations with word vector-based operationalizations of coherence which can limit their appeal and utility in clinical practice. First, the use of esoteric word embeddings can be conceptually hard to grasp, and this is complicated by several different operationalizations of incoherent speech. This problem can be overcome by a better visualization of methods. Second, temporal information from the act of speaking has been largely neglected since models have been built using written text, yet speech is spoken in real time. This issue can be resolved by leveraging time stamped transcripts of speech. Third, contextual information - namely the situation of where something is spoken - has often only been inferred and never explicitly modeled. Addressing this situational issue opens up new possibilities for models with increased temporal resolution and contextual relevance. In this paper, direct visualizations of semantic distances are used to enable the inspection of examples of incoherent speech. Some common operationalizations of incoherence are illustrated, and suggestions are made for how temporal and spatial contextual information can be integrated in future implementations of measures of incoherence.

Studies attempting to deconstruct the heterogeneity of schizophrenia and the attenuated psychosis syndrome consistently find that negative symptoms are a core dimension that is distinct from other aspects of the illness (e.g., positive and disorganized symptoms). Negative symptoms are also highly predictive of poor community-based functional outcomes, suggesting they are a critical treatment target. Unfortunately, pharmacological and psychosocial treatments for negative symptoms have demonstrated limited effectiveness. To address this critical unmet therapeutic need, the NIMH sponsored a consensus development conference to delineate research priorities for the field and stimulate treatment development. A primary conclusion of this meeting was that next-generation negative symptom rating scales should be developed to address methodological and conceptual limitations of existing instruments. Although second-generation rating scales were developed for adults with schizophrenia, progress in this area has lagged behind for youth at clinical-high risk (CHR) for developing psychosis (i.e. those meeting criteria for a prodromal syndrome). Given that negative symptoms are highly predictive of the transition to diagnosable psychotic illness, enhancing our ability to detect negative symptoms in CHR youth is paramount. The current paper discusses conceptual and methodological limitations inherent to existing scales that assess negative symptoms in CHR youth. The theoretical and clinical implications of these limitations are evaluated. It is concluded that new scales specifically designed to assess negative symptoms in CHR youth are needed to accurately chart mental illness trajectories and determine when, where, and how to intervene. Recent efforts to develop next-generation measures designed specifically for CHR youth to meet this urgent need in the field are discussed. These new approaches offer significant progress for addressing issues inherent to earlier scales.

Background Differences between people with schizophrenia and psychiatrically healthy controls have been consistently demonstrated on measures of retinal function such as electroretinography (ERG), and measures of retinal structure such as optical coherence tomography (OCT). Since our 2015 review of this literature, multiple new studies have been published using these techniques. At the same time, the accumulation of data has highlighted the “fault lines” in these fields, suggesting methodological considerations that need greater attention in future studies. Methods We reviewed studies of ERG and OCT in schizophrenia, as well as data from studies whose findings are relevant to interpreting these papers, such as those on effects of the following on ERG and OCT data: comorbid medical conditions that are over-represented in schizophrenia, smoking, antipsychotic medication, substance abuse, sex and gender, obesity, attention, motivation, and influences of brain activity on retinal function. Results Recent ERG and OCT studies continue to support the hypothesis of retinal structural and functional abnormalities in schizophrenia, and suggest that these are relevant to understanding broader aspects of pathophysiology, neurodevelopment, and neurodegeneration in this disorder. However, there are differences in findings which suggest that the effects of multiple variables on ERG and OCT data need further clarification. Conclusions The retina, as the only component of the CNS that can be imaged directly in live humans, has potential to clarify important aspects of schizophrenia. With greater attention to specific methodological issues, the true potential of ERG and OCT as biomarkers for important clinical phenomena in schizophrenia should become apparent.

Social functioning is an important part of recovery and a key treatment target in clinical research in schizophrenia. Evaluating and comparing interventions is challenged by the choice of many measures which focus on different aspects of functioning, with little to guide selection. This results in difficulties comparing outcomes of treatment where studies have used different measures. To improve the measurement of social functioning in intervention research, we aimed to provide practical information on suitability of measures. We conducted a systematic review of measures developed or psychometrically evaluated since 2007, and assessed and discussed the structure, content, quality, and the use of the measures in intervention research. Thirty-two measures of social functioning and 22 validation papers were identified. Measures included structured questionnaires, semi-structured interviews, and assessment of performance on specific tasks. The content of measures was organised into eight categories, which are in order of frequency with which they were covered by measures: activities of daily living, productive activity, relationships, leisure activities, cognition, anti-social behaviour, psychosis symptoms and self-esteem and empowerment. In terms of quality, most measures were rated as moderate, with the Personal and Social Performance Scale gaining the highest rating. However, there was little data on responsiveness of measures, or how they compare to objective or 'real-world' indicators of functioning. The Social Functioning Scale and Personal and Social Performance Scale have been most frequently used in intervention studies to date. Future research should aim to provide further data on psychometric properties relevant to intervention research.

The COVID-19 outbreak may profoundly impact population mental health because of exposure to substantial psychosocial stress. An increase in incident cases of psychosis may be predicted. Clinical advice on the management of psychosis during the outbreak needs to be based on the best available evidence. We undertook a rapid review of the impact of epidemic and pandemics on psychosis. Fourteen papers met inclusion criteria. Included studies reported incident cases of psychosis in people infected with a virus of a range of 0.9% to 4%. Psychosis diagnosis was associated with viral exposure, treatments used to manage the infection, and psychosocial stress. Clinical management of these patients, where adherence with infection control procedures is paramount, was challenging. Increased vigilance for psychosis symptoms in patients with COVID-19 is warranted. How to support adherence to physical distancing requirements and engagement with services in patients with existing psychosis requires careful consideration. Registration details: https://osf.io/29pm4.

Studies attempting to deconstruct the heterogeneity of schizophrenia and the attenuated psychosis syndrome consistently find that negative symptoms are a core dimension that is distinct from other aspects of the illness (e.g., positive and disorganized symptoms). Negative symptoms are also highly predictive of poor community-based functional outcomes, suggesting they are a critical treatment target. Unfortunately, pharmacological and psychosocial treatments for negative symptoms have demonstrated limited effectiveness. To address this critical unmet therapeutic need, the NIMH sponsored a consensus development conference to delineate research priorities for the field and stimulate treatment development. A primary conclusion of this meeting was that next-generation negative symptom rating scales should be developed to address methodological and conceptual limitations of existing instruments. Although second-generation rating scales were developed for adults with schizophrenia, progress in this area has lagged behind for youth at clinical-high risk (CHR) for developing psychosis (i.e. those meeting criteria for a prodromal syndrome). Given that negative symptoms are highly predictive of the transition to diagnosable psychotic illness, enhancing our ability to detect negative symptoms in CHR youth is paramount. The current paper discusses conceptual and methodological limitations inherent to existing scales that assess negative symptoms in CHR youth. The theoretical and clinical implications of these limitations are evaluated. It is concluded that new scales specifically designed to assess negative symptoms in CHR youth are needed to accurately chart mental illness trajectories and determine when, where, and how to intervene. Recent efforts to develop next-generation measures designed specifically for CHR youth to meet this urgent need in the field are discussed. These new approaches offer significant progress for addressing issues inherent to earlier scales.

Background: Patients with psychotic disorders are at risk of developing mental health and social problems, and physical disorders. To monitor and treat these problems when indicated, an annual routine outcome monitoring program, Pharmacotherapy Monitoring and Outcome Survey (PHAMOUS), was developed. This paper presents the background and content of PHAMOUS, implementation of PHAMOUS, characteristics of the patients screened in 2015, and the outcome of patients with three annual screenings between 2011 and 2015.Methods: PHAMOUS was implemented in four mental health institutions in the Northern Netherlands in 2006. During the PHAMOUS screening, patients are assessed on socio- demographics, psychiatric symptoms, medication, physical parameters, lifestyle, (psycho) social functioning and quality of life, using internationally validated instruments.Results: In 2015, 1955 patients with psychotic disorders were enrolled in the PHAMOUS screening. The majority (72%) was receiving mental healthcare for ten years or longer. A small group was hospitalized (10%) in the past year. Half of the patients were in symptomatic remission. Less than 10% had a paid job. More than half of the patients fulfilled the criteria for metabolic syndrome (54%). The subsamplewith three annual screenings from2011 to 2015 (N= 1230) was stable, except the increasing prevalence of high glucose levels and satisfaction with social relationships (Cochran's Q= 16.33, p=. 001 resp. Q= 14.79, p =.001).Conclusion: The annual PHAMOUS screening enables to follow themental, physical and social health problems of patients, which offers a good basis for shared- decision making with regard to updating the annual treatment plan, next to a wealth of data for scientific research. (C) 2018 Elsevier B. V. All rights reserved.

Depressed mood appears to be highly prevalent in clinical high risk (CHR) samples. However, many prior CHR studies utilize modest size samples and do not report on the specific impact of depression on CHR symptoms. The aim of the current paper is to investigate the prevalence of depressive disorders and the impact of lifetime depression on baseline clinical presentation and longitudinal outcomes in a large cohort of individuals meeting CHR criteria in the second phase of the North American Prodrome Longitudinal Study (NAPLS-2). Depression was assessed both categorically (via DSM-IV-TR diagnoses) and symptomatically (using a clinician-rated scale of depressive symptoms) within a sample of 764 individuals at CHR and 279 controls. Current and lifetime depressive disorders were highly prevalent (60%) in this sample. Depression diagnoses were associated with more pronounced negative and general symptoms; individuals with remitted depression had significantly less severe negative, disorganized, and general symptoms and better social and role functioning relative to those with current depression. Current mood disturbance, as measured by scores on a clinician-rated symptom scale, contributed beyond the impact of positive and negative symptoms to impairments in social functioning. Both symptomatic and diagnostic baseline depression was significantly associated with decreased likelihood of remission from CHR status; however depression did not differentially distinguish persistent CHR status from transition to psychosis at follow-up. These findings suggest that depressed mood may function as a marker of poor prognosis in CHR, yet effective treatment of depression within this population can yield improvements in symptoms and functioning.

The aim of this paper is to provide a brief review of mitochondrial structure as it relates to function and then present abnormalities in mitochondria in postmortem schizophrenia with a focus on ultrastructure. Function, morphology, fusion, fission, motility, ΔΨmem, ATP production, mitochondrial derived vesicles, and mitochondria-associated ER membranes will be briefly covered. Pathology in mitochondria has long been implicated in schizophrenia, as shown by genetic, proteomic, enzymatic and anatomical abnormalities. The cortex and basal ganglia will be reviewed. In the anterior cingulate cortex, the number of mitochondria per neuronal somata in layers 5/6 in schizophrenia is decreased by 43%. There are also fewer mitochondria in terminals forming axospinous synapses. In the caudate and putamen the number of mitochondria is abnormal in both glial cells and neurons in schizophrenia subjects, the extent of which depends on treatment, response and predominant lifetime symptoms. Treatment-responsive schizophrenia subjects had about a 40% decrease in the number of mitochondria per synapse in the caudate nucleus and putamen, while treatment resistant cases had normal values. A decrease in mitochondrial density in the neuropil distinguishes paranoid from undifferentiated schizophrenia. The appearance, size and density of mitochondria were normal in the nucleus accumbens. In the substantia nigra, COX subunits were affected in rostral regions. Mitochondrial hyperplasia occurs within axon terminals that synapse onto dopamine neurons, but mitochondria in dopamine neuronal somata are similar in size and number. In schizophrenia, mitochondria are differentially affected depending on the brain region, cell type, subcellular location, treatment status, treatment response and symptoms.

Primary and persistent negative symptoms (PPNS) represent an unmet need in the care of people with schizophrenia. They have an unfavourable impact on real-life functioning and do not respond to available treatments. Underlying etiopathogenetic mechanisms of PPNS are still unknown. The presence of primary and enduring negative symptoms characterizes deficit schizophrenia (DS), proposed as a separate disease entity with respect to non-deficit schizophrenia (NDS). More recently, to reduce the heterogeneity of negative symptoms by using criteria easily applicable in the context of clinical trials, the concept of persistent negative symptoms (PNS) was developed.Both PNS and DS constructs include enduring negative symptoms (at least 6months for PNS and 12months for DS) that do not respond to available treatments. PNS exclude secondary negative symptoms based on a cross-sectional evaluation of severity thresholds on commonly used rating scales for positive symptoms, depression and extrapyramidal side effects; the DS diagnosis, instead, excludes all potential sources of secondary negative symptoms based on a clinical longitudinal assessment.In this paper we review the evolution of concepts and assessment modalities relevant to PPNS, data on prevalence of DS and PNS, as well as studies on clinical, neuropsychological, brain imaging electrophysiological and psychosocial functioning aspects of DS and PNS.

Maternal influenza during pregnancy has been suggested to increase the psychosis risk for the offspring. This hypothesis has been tested using "ecological" studies, which examined the risk for individuals born after epidemics, and "serological" studies, based on serological evidence. A study of the latter type obtained an increased schizophrenia risk for individuals exposed during the first trimester. A second study found a relationship between influenza at any time during gestation and risk for bipolar disorder with psychotic features. The aims of this paper are to assess the validity of the serological studies and to evaluate the combined results of ecological and serological investigations using meta-analysis. The serological studies turned out to be of limited validity, because they utilized a single serum specimen. Since influenza antibodies can remain positive for years after infection, manymothers of casesmay have been infected before pregnancy. For an adequate timing of exposure one needs an acute and a convalescent specimen, obtained 10-20 days later. Meta-analysis with respect to schizophrenia: we pooled the results of the single serological investigation and 8 ecological studies related to the 1957 pandemic (with negative results) and found that the first investigation carried hardly any weight. Bipolar disorder: we pooled the results of the serological investigation and three other studies and obtained a mean, weighted odds ratio of 1.34 (95% CI 0.78-2.29) for individuals possibly exposed during prenatal life. The evidence for gestational influenza as psychosis risk factor is insufficient. (C) 2016 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Current functional capacity (FC) measures for patients with schizophrenia typically involve informant assessments or are in paper and pencil format, requiring in-person administration by a skilled assessor. This approach presents logistic problems and limits the possibilities for remote assessment, an important issue for these patients. This study evaluated the feasibility of using a computer-based assessment battery, including simulations of everyday activities. The battery was compared to in-person standard assessments of cognition and FC with respect to baseline convergence and sensitivity to group differences. The battery, administered on a touch screen computer, included measures of critical everyday activities, including: ATM Banking/Financial Management, Prescriptions Refill via Telephone/Voice Menu System, and Forms Completion (simulating a clinic and patient history form). The sample included 77 older adult patients with schizophrenia and 24 older adult healthy controls that were administered the battery at two time points. The results indicated that the battery was sensitive to group differences in FC. Performance on the battery was also moderately correlated with standard measures of cognitive abilities and showed convergence with standard measures of FC, while demonstrating good test-retest reliability. Our results show that it is feasible to use technology-based assessment protocols with older adults and patients with schizophrenia. The battery overcomes logistic constraints associated with current FC assessment protocols as the battery is computer-based, can be delivered remotely and does not require a healthcare professional for administration.

Cognitive deficits are a fundamental feature of schizophrenia for which currently no effective treatments exist. This paper examines the possibility to use transcranial direct current stimulation (tDCS) to target cognitive deficits in schizophrenia as evidence from studies in healthy participants suggests that tDCS may improve cognitive functions and associated neural processes. We carried out a systematic review with the following search terms: ‘tDCS’, ‘electric brain stimulation’, ‘schizophrenia’, ‘cognitive’, ‘cognition’ until March 2019. 659 records were identified initially, 612 of which were excluded after abstract screening. The remaining 47 articles were assessed for eligibility based on our criteria and 26 studies were excluded. In addition, we compared several variables, such as online vs. offline-stimulation protocols, stimulation type and intensity on mediating positive vs. negative study outcomes. The majority of studies (n = 21) identified significant behavioural and neural effects on a range of cognitive functions (versus n = 11 with null results), including working memory, attention and social cognition. However, we could not identify tDCS parameters (electrode montage, stimulation protocol, type and intensity) that clearly mediated effects on cognitive deficits. There is preliminary evidence for the possibility that tDCS may improve cognitive deficits in schizophrenia. We discuss the rationale and strength of evidence for using tDCS for targeting cognitive deficits in schizophrenia as well as methodological issues and potential mechanisms of action.

The North American Prodrome Longitudinal Study (NAPLS) is a consortium of nine programs focusing on youth at clinical high risk (CHR) for psychosis. Funded by the National Institute of Mental Health (NIMH), the sites are located at Emory University, Harvard University, University of Calgary, University of California at Los Angeles, at San Diego, and at San Francisco, University of North Carolina Chapel Hill, Yale University, and Zucker Hillside Hospital. There have been two previous endeavors completed by this consortium, known as NAPLS-1 and NAPLS-2. This paper first offers an overview of the methodology of the third phase of the NAPLS consortium, the second five-year prospective study NAPLS-3, which aims to determine mechanisms of the development of psychosis. In addition, we report on the ascertainment and demographics of the 710 CHR participants in NAPLS-3.

Autoimmunity, gastrointestinal (GI) disorders and schizophrenia have been associated with one another for a long time. This paper reviews these connections and provides a context by which multiple risk factors for schizophrenia may be related. Epidemiological studies strongly link schizophrenia with autoimmune disorders including enteropathic celiac disease. Exposure to wheat gluten and bovine milk casein also contribute to non-celiac food sensitivities in susceptible individuals. Co-morbid GI inflammation accompanies humoral immunity to food antigens, occurs early during the course of schizophrenia and appears to be independent from antipsychotic-generated motility effects. This inflammation impacts endothelial barrier permeability and can precipitate translocation of gut bacteria into systemic circulation. Infection by the neurotropic gut pathogen, Toxoplasma gondii, will elicit an inflammatory GI environment. Such processes trigger innate immunity, including activation of complement C1q, which also functions at synapses in the brain. The emerging field of microbiome research lies at the center of these interactions with evidence that the abundance and diversity of resident gut microbiota contribute to digestion, inflammation, gut permeability and behavior. Dietary modifications of core bacterial compositions may explain inefficient gluten digestion and how immigrant status in certain situations is a risk factor for schizophrenia. Gut microbiome research in schizophrenia is in its infancy, but data in related fields suggest disease-associated altered phylogenetic compositions. In summary, this review surveys associative and experimental data linking autoimmunity, GI activity and schizophrenia, and proposes that understanding of disrupted biological pathways outside of the brain can lend valuable information regarding pathogeneses of complex, polygenic brain disorders.

Second-generation antipsychotics have demonstrated efficacy for patients with schizophrenia but are associated with wide-ranging side effects. Brexpiprazole, a serotonin-dopamine activity modulator, has demonstrated efficacy in adult patients with schizophrenia. This paper provides an overview of the safety and tolerability of brexpiprazole in patients with schizophrenia through examination of pooled safety data from one Phase 2 and two Phase 3 6-week, short-term studies, and two open-label, 52-week, long-term studies.In the short-term studies, there were no reports of treatment-emergent adverse events (TEAEs) with an incidence≥5% and twice that of placebo in patients treated with brexpiprazole 2–4mg. In the long-term studies, TEAEs reported by ≥5% of patients were schizophrenia (10.7%), insomnia (8.0%), weight increase (7.7%), headache (6.0%), and agitation (5.2%). Akathisia rates were low in the short- (5.8%, pooled brexpiprazole group) and long-term studies (4.6%). Sedation rates were low in the short- (2.3%, pooled brexpiprazole group) and long-term studies (0.9%). Mean body weight increase was 1.1kg in both short- and long-term studies.For all studies, changes from baseline to last visit in laboratory parameters, electrocardiogram values, and vital signs were small and not clinically relevant. Changes in lipid profiles or other metabolic parameters were also small. Collectively, these studies suggest that brexpiprazole was well tolerated, with a favorable safety profile that does not exhibit significant rates of important adverse events that can be seen with existing antipsychotics (akathisia, sedation, weight gain, or QTc prolongation), and therefore may provide a useful treatment option for patients with schizophrenia.ClinicalTrials.gov: NCT00905307; NCT01396421; NCT01393613; NCT01649557; NCT01397786.

Background The rate of transition to psychotic disorder in ultra high risk (UHR) patients has declined in recent cohorts. The reasons for this are unclear, but may include a lead-time bias, earlier intervention, a change in clinical characteristics of cohorts, and treatment changes. Aims In this paper we examined the two possibilities related to reduction in duration of symptoms prior to clinic entry, i.e., lead-time bias and earlier intervention. Method The sample consisted of all UHR research participants seen at the PACE clinic, Melbourne between 1993 and 2006 ( N = 416), followed for a mean of 7.5 years (the ‘PACE 400’ cohort). Duration of symptoms was analysed by four baseline year time periods. Analysis of transition rate by duration of symptoms was restricted to more homogenous sub-samples (pre-1998 and pre-2001) in order to minimize confounding effects of change in patient characteristics or treatments. These cohorts were divided into those with a short and long duration of symptoms using a cut-point approach. Results Duration of symptoms prior to entry did not reduce significantly between 1993 and 2006 ( p = 0.10). The group with a short duration of symptoms showed lower transition rates and did not catch up in transition rate compared to the long duration of symptoms group. Discussion These data suggest that, while earlier intervention or lead-time bias do not fully account for the declining transition rate in UHR cohorts, it appears that earlier intervention may have exerted a stronger influence on this decline than length of follow-up period (lead-time bias).

Perineuronal nets (PNNs) were shown to be markedly altered in subjects with schizophrenia. In particular, decreases of PNNs have been detected in the amygdala, entorhinal cortex and prefrontal cortex. The formation of these specialized extracellular matrix (ECM) aggregates during postnatal development, their functions, and association with distinct populations of GABAergic interneurons, bear great relevance to the pathophysiology of schizophrenia. PNNs gradually mature in an experience-dependent manner during late stages of postnatal development, overlapping with the prodromal period/age of onset of schizophrenia. Throughout adulthood, PNNs regulate neuronal properties, including synaptic remodeling, cell membrane compartmentalization and subsequent regulation of glutamate receptors and calcium channels, and susceptibility to oxidative stress. With the present paper, we discuss evidence for PNN abnormalities in schizophrenia, the potential functional impact of such abnormalities on inhibitory circuits and, in turn, cognitive and emotion processing. We integrate these considerations with results from recent genetic studies showing genetic susceptibility for schizophrenia associated with genes encoding for PNN components, matrix-regulating molecules and immune system factors. Notably, the composition of PNNs is regulated dynamically in response to factors such as fear, reward, stress, and immune response. This regulation occurs through families of matrix metalloproteinases that cleave ECM components, altering their functions and affecting plasticity. Several metalloproteinases have been proposed as vulnerability factors for schizophrenia. We speculate that the physiological process of PNN remodeling may be disrupted in schizophrenia as a result of interactions between matrix remodeling processes and immune system dysregulation. In turn, these mechanisms may contribute to the dysfunction of GABAergic neurons.

Patients with schizophrenia show impairments in processing of biological motion. This is especially important since deficits in domains of social cognition has been associated with functional outcome and everyday functioning in this population.We conducted a systematic review and meta-analysis of studies which have used point-light displays to present whole-body motion to patients with schizophrenia and healthy controls, to evaluate the magnitude of differences between these groups in biological motion processing.Firstly, relevant publications were identified by a systematic search of Google Scholar and PubMed databases. Secondly, we excluded non-relevant studies for the meta-analysis according to our exclusion criteria. Effect sizes were expressed as standardized mean difference (SMD).15 papers reporting results of 14 different experiments with 571 patients and 482 controls were included in the meta-analysis. The results for the general biological motion perception analysis revealed that patients with schizophrenia (compared with healthy controls) present reduced biological motion processing capacity with the effect size (SMD) of 0.66 (95% CI, -0.79 to -0.54; p0.001). The results for the specific biological motion-based tasks were also statistically significant with SMD of 0.72 for Basic Biological Motion task (95% CI: -0.94 to -0.51; p0.001) and SMD of 0.61 for Emotion in Biological Motion task, (95% CI: -0.79 to -0.43; p0.001) respectively.The findings from our meta-analysis highlight abnormalities in general and specific domains of biological motion perception in schizophrenia patients as compared with healthy controls.

The neurocognitive theory of insight posits that poor insight in psychotic illnesses is related to cognitive deficits in cognitive self-appraisal mechanisms. In this paper we perform a comprehensive meta-analysis examining relationships between clinical insight and neurocognition in psychotic disorders. We have also completed a meta-analysis of studies examining 'cognitive insight', as measured by the Beck Cognitive Insight Scale (BCIS), and its relationship with neurocognitive function in patients with psychosis. The clinical insight analysis included data from 72 studies and a total population of 5429 patients. We found that insight in psychosis was significantly associated with total cognition (r = 0.16, p

Cannabis use is highly prevalent worldwide and it is associated with psychosis, but its effects on brain structure and cognition are still controversial. The aim of this paper is to investigate cognitive functioning and brain structure in patients with their first episode of psychosis who used Cannabis. We examined gray matter and lateral ventricle volumes in 28 patients with first-episode psychosis and a history of Cannabis use, 78 patients without a history of Cannabis use and 80 healthy controls who had not used Cannabis. Cognition was assessed using forward and backwards digit span tests, from the Wechsler Memory Scale-Third Edition (WMS-III) and the Controlled Oral Word Association Test (COWAT). Patients with a history of Cannabis use had less brain abnormalities, characterized by gray matter and lateral ventricle volume preservation, as well as less attentional and executive impairments compared to patients without a history of Cannabis use. Cannabis-using patients who develop psychosis have less neurodevelopmental impairment and better cognitive reserve than other psychotic patients; perhaps reflecting different etiological processes.

In this review, we seek to answer the following question: Do findings in the current literature support the idea that thalamo-cortical dysfunction in schizophrenia is due to structural abnormalities in the thalamus? We base our review on the existing literature of design-unbiased stereological studies of the postmortem thalamus from subjects with schizophrenia. Thus, all reported results are based upon the use of unbiased principles of sampling to determine volume and/or total cell numbers of thalamus or its constituent nuclei. We found 28 such papers covering 26 studies. In a series of tables we list all positive and negative findings from the total thalamus, the mediodorsal, pulvinar and anterior nuclei, as well as less frequently studied thalamic regions. Only four studies examined the entire thalamus and the results were inconsistent. We found largely consistent evidence for structural changes (reduced volume and cell numbers) in the pulvinar located in the posterior thalamus. In contrast, findings in the mediodorsal thalamic nucleus are inconsistent, with the largest and most recent studies generally failing to support earlier reports of a lower number of neurons in schizophrenia. Thus, the current findings of stereological studies of the thalamus in schizophrenia support the idea that thalamo-cortical dysfunction in schizophrenia might be attributable, at least in part, to structural alterations in the pulvinar that could impair thalamic inputs to higher order cortical association areas in the frontal and parietal lobes. However, more studies are needed before robust conclusions can be drawn.

New findings are rapidly revealing an increasingly detailed image of neural - and molecular-level dysfunction in schizophrenia, distributed throughout interconnected cortico-striato-pallido-thalamic circuitry. Some disturbances appear to reflect failures of early brain maturation, that become codified into dysfunctional circuit properties, resulting in a substantial loss of, or failure to develop, both cells and/or appropriate connectivity across widely dispersed brain regions. These circuit disturbances are variable across individuals with schizophrenia, perhaps reflecting the interaction of multiple different risk genes and epigenetic events. Given these complex and variable hard-wired circuit disturbances, it is worth considering how new and emerging findings can be integrated into actionable treatment models. This paper suggests that future efforts towards developing more effective therapeutic approaches for the schizophrenias should diverge from prevailing models in genetics and molecular neuroscience, and focus instead on a more practical three-part treatment strategy: 1) systematic rehabilitative psychotherapies designed to engage healthy neural systems to compensate for and replace dysfunctional higher circuit elements, used in concert with 2) medications that specifically target cognitive mechanisms engaged by these rehabilitative psychotherapies, and 3) antipsychotic medications that target nodal or convergent circuit points within the limbic-motor interface, to constrain the scope and severity of psychotic exacerbations and thereby facilitate engagement in cognitive rehabilitation. The use of targeted cognitive rehabilitative psychotherapy plus synergistic medication has both common sense and time-tested efficacy with numerous other neuropsychiatric disorders.

Many studies have confirmed that the risk of suicide in patients with first-episode psychosis (FEP) is high, and high rates of premature mortality, particularly from suicide, may occur in the early phases of schizophrenia. However, suicide rates are difficult to measure in FEP patients, even in carefully defined samples, and there is relatively little specific information about the risk of suicide at illness onset or retrospectively concerning the untreated psychotic period. This selected review of the literature investigates suicidal behaviour with particular regard to severe suicidality (plans and attempts) and risk factors associated with suicide in FEP patients. A search was performed to identify all papers and book chapters during the period 1965-2010, and approximately 100 studies met the inclusion criteria. Most of evidence suggests that risk of suicidal behaviour is relatively high in FEP patients. The research reports highlight the need for universal, comprehensive, public mental health interventions aimed, not only toward early detection, but also toward the rapid engagement in treatment of people with psychoses. These interventions should include an adequate assessment of suicidal behaviour in patients with FEP, and an examination of the efficacy of specific components of the interventions.

artículo -- Universidad de Costa Rica. Centro Investigación en Biología Molecular y Celular, 2010. Este documento es privado debido a limitaciones de derechos de autor. Objectives:The aims of this study were to estimate the frequency and course of substances use disorders in Latino patients with schizophrenia and to ascertain risk factors associated with substance use disorders in this population. Method: We studied 518 subjects with schizophrenia recruited for a genetic study from the Southwest United States, Mexico, and Central America (Costa Rica and Guatemala). Subjects were assessed using structured interviews and a best estimate consensus process. Logistic regression, χ 2 , ttest, Fisher's exact test, and Yates' correction, as appropriate, were performed to assess the sociodemographic variables associated with dual diagnosis. We defined substance use disorder as either alcohol or substance abuse or dependence. Results: Out of 518 patients with schizophrenia, 121 (23.4%) had substance use disorders. Comorbid substance use disorders were associated with male gender, residence in the United States, immigration of Mexican men to the United States, history of depressive syndrome or episode, and being unemployed. The most frequent substance use disorder was alcohol abuse/ dependence, followed by marijuana abuse/dependence, and solvent abuse/dependence. Conclusion: This study provides data suggesting that depressive episode or syndrome, unemployment, male gender, and immigration of Mexican men to the United States were factors associated with substance use disorder comorbidity in schizophrenia. Binary logistic regression showed that country of residence was associated with substance use disorder in schizophrenic patients. The percentage of subjects with comorbid substance use disorders was higher in the Latinos living in the United States compared with subjects living in Central America and Mexico. Universidad de Costa Rica. This research was supported by the following grants from the National Institute of Mental Health: MH60881 and MH60875. Dr. Jimenez-Castro was supported by a fellowship of grant D43 TW06152-01 from the National Institute of Mental Health, the National Institute of Drug Abuse and the Fogarty Institute. These institutions had no further role in the study design, in the collection, analysis and interpretation of data, in writing of the report, and in the decision to submit the paper for publication UCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias Básicas::Centro de Investigación en Biología Celular y Molecular (CIBCM)

Deficits in visual processing are now recognized as a core feature of schizophrenia. In the 1940s, Louis Thurstone developed a series of tests designed to evaluate specific aspects of visual perceptual processing including the Closure Flexibility Test (CFT), which was designed to measure "the ability to hold a configuration in mind despite distraction." The present study evaluated patients' performance on this task and its relationship to other tests of neuropsychological function, particularly to a measure of sustained visual attention. Thirty-nine patients with schizophrenia or schizoaffective disorder and 40 controls participated. The CFT was administered both in its original form (10 min) and also in a briefer form (3 min) in which only a portion of stimuli were given. Patients showed highly significant large effect-size deficits on both the original (d=1.6) and brief (d=1.2) CFT. Between-group deficits in performance survived co-variation for IQ. In addition, the CFT score was significantly related to performance on the MATRICS measure of attention/vigilance, the Continuous Performance Test-Identical Pairs version (CPT-IP). This correlation remained significant even after controlling for non-specific intercorrelations among neurocognitive measures. Results confirm the severity of early visual processing deficits in schizophrenia. In addition, the CFT is a brief, easy to administer alphabet-independent, paper-and-pencil test with established psychometric properties that may be useful as an index of the sustained visual attention construct in schizophrenia.

Schizophrenia is a debilitating syndrome with high heritability. Genomic studies reveal more than a hundred genetic variants, largely nonspecific and of small effect size, and not accounting for its high heritability. De novo mutations are one mechanism whereby disease related alleles may be introduced into the population, although these have not been leveraged to explore the disease in general samples. This paper describes a framework to find high impact genes for schizophrenia. This study consists of two different datasets. First, whole exome sequencing was conducted to identify disruptive de novo mutations in 14 complete parent–offspring trios with sporadic schizophrenia from Jerusalem, which identified 5 sporadic cases with de novo gene mutations in 5 different genes (PTPRG, TGM5, SLC39A13, BTK, CDKN3). Next, targeted exome capture of these genes was conducted in 48 well-characterized, unrelated, ethnically diverse schizophrenia cases, recruited and characterized by the same research team in New York (NY sample), which demonstrated extremely rare and potentially damaging variants in three of the five genes (MAF < 0.01) in 12/48 cases (25%); including PTPRG (5 cases), SCL39A13 (4 cases) and TGM5 (4 cases), a higher number than usually identified by whole exome sequencing. Cases differed in cognition and illness features based on which mutation-enriched gene they carried. Functional de novo mutations in protein-interaction domains in sporadic schizophrenia can illuminate risk genes that increase the propensity to develop schizophrenia across ethnicities.

In the past 25 years, research on the human brain has been providing a clear path toward understanding the pathophysiology of psychiatric illnesses. The successes that have been accrued are matched by significant difficulties identifying and controlling a large number of potential confounding variables. By systematically and effectively accounting for unwanted variance in data from imaging and postmortem human brain studies, meaningful and reliable information regarding the pathophysiology of human brain disorders can be obtained. This perspective paper focuses on postmortem investigations to discuss some of the most challenging sources of variance, including diagnosis, comorbidity, substance abuse and pharmacological treatment, which confound investigations of the human brain.

Dysfunctional mirror neuron activity (MNA) has been posited to underlie diverse symptoms of schizophrenia (e.g., ego-boundary disturbances, negative symptoms, social cognition impairments and catatonic symptoms). In this paper, we systematically review studies that have empirically compared putative MNA in schizophrenia patients and healthy subjects using different neurophysiological probes. Majority of the studies (n=9) reported reduced MNA in patients. Two each reported either increased MNA or mixed (both increased and decreased) results, while only one study reported normal findings. Reduced MNA was associated with greater negative symptoms and theory of mind deficits. The neurophysiological technique, task paradigms used, specific brain regions studied and laterality did not influence these findings. Further, we propose an overarching model to understand the heterogeneous symptom dimensions of schizophrenia, in which an inherent mirror system deficit underlying persistent negative symptoms, social cognition impairments and self-monitoring deficits triggers a pathological metaplastic reorganization of this system resulting in aberrant excessive MNA and the phasic catatonic symptoms, affective instability and hallucinations. Despite being preliminary in nature, evidence of abnormal MNA in schizophrenia reported necessitates more detailed investigation. Future research directions of using this model within the Research Domain Criteria framework of the National Institute of Mental Health are discussed.

This paper tests the hypothesis that patients with schizophrenia have a deficit in selectively attending to predictable events. We used dynamic causal modeling (DCM) of electrophysiological responses – to predictable and unpredictable visual targets – to quantify the effective connectivity within and between cortical sources in the visual hierarchy in 25 schizophrenia patients and 25 age-matched controls. We found evidence for marked differences between normal subjects and schizophrenia patients in the strength of extrinsic backward connections from higher hierarchical levels to lower levels within the visual system. In addition, we show that not only do schizophrenia subjects have abnormal connectivity but also that they fail to adjust or optimize this connectivity when events can be predicted. Thus, the differential intrinsic recurrent connectivity observed during processing of predictable versus unpredictable targets was markedly attenuated in schizophrenia patients compared with controls, suggesting a failure to modulate the sensitivity of neurons responsible for passing sensory information of prediction errors up the visual cortical hierarchy. The findings support the proposed role of abnormal connectivity in the neuropathology and pathophysiology of schizophrenia.

The purpose of this paper is to provide a concise, selective review of the major issues and findings germane to structural and functional neuroimaging studies of bipolar affective disorder (BPD). In attempting to identify the brain changes associated with BPD, investigators have used neuroimaging techniques to focus on several interrelated questions. These are: What are the changes and where do they occur? Do their nature and location suggest a particular etiopathologic basis or have notable clinical correlates? With regard to specificity, are the changes unique to BPD, or do they overlap with those reported in other neuropsychiatric illnesses, especially schizophrenia? Do they occur in brain systems that normally play a role in modulating mood? Finally, how do the brain changes integrate with neurocognitive, neurogenetic, and neuropathologic data in the same patients? To date, these questions have been addressed only preliminarily. We outline some of the strategies used to pursue answers to these questions and review conclusions to date.

The reliability of psychiatric diagnosis has a direct effect on the validity of post-mortem analyses of neuropathological data, yet little is known about the reliability of retrospective diagnostic procedures which rely on review of medical records. In this paper, we report on the reliability of DSM-III-R psychiatric diagnoses assigned by a pool of 8 raters to a set of 106 state hospital charts of elderly, chronic patients who had died while institutionalized and were autopsied. Diagnoses were grouped by general diagnostic class, and Kappa coefficients computed for agreement among raters, as well as for agreement between ultimate consensus diagnoses and those made while subjects were living. Interrater agreement for those diagnoses that occurred most frequently in this sample (e.g. Schizophrenia and Dementia) was excellent, and comparable to the the agreement observed for ratings of live patients. Interrater agreement for less frequently occurring diagnoses (e.g. Mental Retardation, Mood Disorders, other non-Schizophrenic Psychoses) ranged from excellent to poor. We found high agreement between our raters diagnoses and those assigned by state hospital personnel while patients were living, although post-mortem review produced lower rates of diagnosis of both schizophrenia and Alzheimer-type dementias. Overall, results suggest that the reliability of chart review diagnosis is comparable to that obtained from interviews of live patients when experienced raters are used and diagnostic base rates are high enough to produce stable estimates of reliability.

Background: Longer duration of untreated psychosis (DUP) is associated with poorer outcome in terms of positive symptoms, relapse rate, and time to remission. In contrast, the association with negative symptoms is less consistent. Aims: The study had three aims. First, to arrive at a more precise estimate of the correlation between DUP and negative symptoms than previous reviews, by substantially increasing the amount of available data. Second, to see whether the strength of this correlation attenuated over longer follow-up intervals. Third, to determine whether there is a relationship between DUP and changes in negative symptoms. Method: Relevant databases were searched for studies published between December 1992 and March 2009 that reported data on DUP and negative symptoms. We obtained individual patient data where possible and calculated summary correlations between DUP and negative symptoms for each study at baseline, short and long-term follow-up. We used multilevel regression analysis to examine whether the effect of DUP on negative symptoms was the greatest in the early stages of illness. Results: We included 28 non-overlapping studies from the 402 papers detected by the search strategy. After contacting the authors we obtained individual patient data from 16 of these studies involving 3339 participants. The mean DUP was 61.4 weeks (SD = 132.7, median DUP = 12.0). Shorter DUP was significantly associated with less severe negative symptoms at baseline and also at short (1-2 years) and longer term follow-up (5-8 years) (r = 0.117, 0.180 and 0.202 respectively, p

Dear Editor, The recent paper by Chintoh and colleagues (2008) reporting olanzapine-induced dysfunction in glucose metabolism, enhanced visceral fat and reduced locomotor activity in female rats was highly interesting as it illustrated olanzapine’s ability to replicate aspects of metabolic dysfunction in the rodent model in a similar manner to the human scenario. However, contrary to previous reports in the rat and the clinic, the authors reported no change in body weight or food intake following olanzapine treatment, questioning the validity of the rat model

This is the last of a series of four papers, here focussing on schizophrenia, which report followup data up to 18 months from a randomized clinical trial of a psychoeducational family intervention (IFI), which was added to medication and limited to the inpatient phase of treatment, after which post-hospital care was not controlled. Our data suggested that patients with poor prehospital functioning (i.e., the chronic patients) may benefit from inpatient family intervention, but this therapeutic effect appears to be limited to females and does not appear until 18 months postadmission. Families of patients with schizophrenia also show benefit from having received IFI, the effect is seen earlier than with the patients, and is associated with achieving the goals of IFI. The results in the IFI group could not be accounted for by improved post-hospital medication compliance, but they may be related to this group's greater tendency to obtain further family treatment after discharge.

Objective: A literature review was conducted to ascertain whether or not EEG spectral abnormalities are consistent enough to warrant additional effort towards developing them into a clinical diagnostic test for schizophrenia. Methods: Fifty three papers met criteria for inclusion into the review and 15 were included in a meta-analysis of the degree of significance of EEG deviations as compared to healthy controls. Studies were classified based on a 4-step approach based on guidelines for evaluating the clinical usefulness of a diagnostic test. Results: Our review and meta-analysis revealed that most of the abnormalities are replicated in the expected directions with the most consistent results related to the increased preponderance of slow rhythms in schizophrenia patients. This effect remained consistent in un-medicated patients. Only a small number of studies provided data on the sensitivity and specificity of the findings in differentiating among the psychiatric disorders that frequently appear on the same differential diagnostic list as schizophrenia (Step 3 studies). No multicenter studies using standardized assessment criteria were found (Step 4 studies). Conclusions: Additional Step 3 and Step 4 studies are needed to draw conclusions on the usefulness of EEG spectral abnormalities as a diagnostic test for schizophrenia.

Many adverse effects of atypical antipsychotic treatment are associated with antagonism of monoamine receptors; however, data indicate that important metabolic effects, such as hypertriglyceridemia and impairment in glucose/insulin homeostasis, may not be related to these mechanisms, leading investigators to explore alternative hypotheses. Promising candidates include a possible impact of antipsychotics on peptide hormonal regulators of metabolic control such as leptin, ghrelin, and adiponectin. The purpose of this review is to summarize recent data on changes in these hormones during atypical antipsychotic treatment.A Medline search was performed for papers published from January 1999 to January 2007 using key words antipsychotic, atypical antipsychotic, and individual atypical antipsychotic drug names cross-referenced with leptin, ghrelin, and adiponectin.The bulk of the published work focused on changes in body weight and serum leptin, with far less data on ghrelin, and adiponectin, and nonweight metabolic changes. Leptin changes were directly related to a medication's weight gain liability, with no added antipsychotic effects on leptin signaling. Conflicting results emerged for the other markers, but all three long-term studies on ghrelin showed increased levels in patients on atypical antipsychotics with weight gain liabilities.Leptin increases during antipsychotic treatment are a result of weight gain rather than a direct impact of atypical antipsychotics on leptin physiology. Preliminary long-term data show increased ghrelin levels, but this finding must be replicated. The association with antipsychotic effects on glucose and lipid metabolism and these hormones remains virtually unstudied. Future research should indicate whether ghrelin and other peptide hormones may be useful predictors of weight gain or metabolic changes in patients on antipsychotics.

It was a field-changing clinical insight when German-speaking psychiatrists, most notably Kraepelin, described the clinical syndrome of schizophrenia. Kraeplin, Bleuler and their contemporaries worked in an era before the era of molecular biology and brain imaging. They did the best with the tools of their time, and made many crucial contributions. The series of papers by Keshavan and colleagues provide a valuable introduction to important biological findings about schizophrenia for students and those working in other disciplines, and a trajectory for planning future research and conceptual developments for clinicians and researchers working within the field. The lays out the argument that it is time to move on from the ideas of our “fathers”, and boldly deconstruct and reconfigure our understanding of the causes and boundaries of the schizophrenia syndrome.

This paper presents a neurologic formulation for the clinical features of the schizophrenic syndrome, and tests it against a systematic, region by region review of available postmortem neuroanatomical and neuropharmacological data. Based on this review a model is proposed that postulates a developmental lesion affecting the midline neurotransmitter-specific ascending projection systems. Due to the facilitatory role these systems play in the development of the brain regions to which they project, such a lesion is one parsimonious, and testable, explanation for virtually all the clinical, laboratory, and pathological findings reported to date in schizophrenia research. A case is made for establishing a global antemortem-postmortem collaboration using a Latin square design; the alternative may be that, as has happened in the past, the best efforts of dilligent researchers around the world may lead to little improvement in our understanding of schizophrenia.

The disorganized symptoms of schizophrenia, including severely disordered thought patterns, may be indicative of a problem with the construction and maintenance of cell assemblies during sensory processing and attention. The gamma and beta frequency bands (15–70 Hz) are believed relevant to such processing. This paper addresses the results of an experimental examination of the cortical response of 12 schizophrenia patients and 12 control subjects when presented with auditory click-train stimuli in the gamma/beta frequency band during measurement using magnetoencephalography (MEG), as well as earlier work by Kwon et al. These data indicate that control subjects show an increased 40-Hz response to both 20- and 40-Hz stimulation as compared with patients, whereas schizophrenic subjects show a preference for 20-Hz response to the same driving frequencies. In this work, two computational models of the auditory cortex are constructed based on postmortem studies that indicate cortical interneurons in schizophrenic subjects have decreased GAT-1 (a GABA transporter) and GAD67(1 of 2 enzymes responsible for GABA synthesis). The models transition from control to schizophrenic frequency response when an extended inhibitory decay time is introduced; this change captures a possible effect of these GABA alterations. Modeling gamma/beta range auditory entrainment in schizophrenia provides insight into how biophysical mechanisms can impact cognitive function. In addition, the study of dynamics that underlie auditory entrainment in schizophrenia may contribute to the understanding of how gamma and beta rhythms impact cognition in general.

This paper tests the hypothesis that patients with schizophrenia have a deficit in selectively attending to predictable events. We used dynamic causal modeling (DCM) of electrophysiological responses – to predictable and unpredictable visual targets – to quantify the effective connectivity within and between cortical sources in the visual hierarchy in 25 schizophrenia patients and 25 age-matched controls. We found evidence for marked differences between normal subjects and schizophrenia patients in the strength of extrinsic backward connections from higher hierarchical levels to lower levels within the visual system. In addition, we show that not only do schizophrenia subjects have abnormal connectivity but also that they fail to adjust or optimize this connectivity when events can be predicted. Thus, the differential intrinsic recurrent connectivity observed during processing of predictable versus unpredictable targets was markedly attenuated in schizophrenia patients compared with controls, suggesting a failure to modulate the sensitivity of neurons responsible for passing sensory information of prediction errors up the visual cortical hierarchy. The findings support the proposed role of abnormal connectivity in the neuropathology and pathophysiology of schizophrenia.

This article reviews key methodological considerations for clinical trials that utilize explanatory and pragmatic trial designs and relates these contrasting approaches to the interpretation of results from comparisons of oral versus long-acting injectable (LAI) antipsychotics in schizophrenia. Explanatory randomized controlled trials (RCTs) generally measure the efficacy of a treatment in a homogeneous population with intensive, frequent, and often clinical trial-specific assessments. In contrast, pragmatic trials measure effectiveness in routine clinical practice and frequently aim to inform choices between treatments. Comparative effectiveness outcomes with pragmatic designs in naturalistic settings for schizophrenia treatments are of increasing interest to healthcare providers because outcomes of treatment (both efficacy and safety) may vary significantly when identified in an explanatory setting compared with a naturalistic pragmatic setting. Indeed, it has been suggested that the inconsistent outcomes observed in trials comparing oral and LAI antipsychotic medications may be a function of the use of explanatory or pragmatic trial designs.In practice, clinical trial designs are seldom purely explanatory or pragmatic. To identify the predominant orientation of a trial, one must consider multiple features. This paper reviews the relative impact of these features when comparing LAI and oral antipsychotic treatments and makes recommendations for improving these comparative designs.

Cognitive impairment is a primary feature of schizophrenia, with alterations in several cognitive domains appearing in the pre-morbid phase of the disorder. White matter microstructure is also affected in schizophrenia and considered to be related to cognition, but the relationship of the two is unclear. As interaction between cognition and white matter structure involves the interplay of several brain structures and cognitive abilities, investigative methods which can examine the interaction of multiple variables are preferred. A multiple-groups structural equation model (SEM) was used to assess the relationship between diffusion tension imaging data (fractional anisotropy of selected white matter tracts) and cognitive abilities of 196 subjects - 135 healthy subjects and 61 patients with schizophrenia. It was found that multiple-indicators, multiple-causes model best fitted the data analysed. Schizophrenia moderated the relation of white matter function on cognition with a large effect size. This paper extends previous work on modelling intelligence within a SEM framework by incorporating neurological elements into the model, and shows that white matter microstructure in patients with schizophrenia interacts with cognitive abilities.

This paper tests the hypothesis that patients with schizophrenia have a deficit in selectively attending to predictable events. We used dynamic causal modeling (DCM) of electrophysiological responses - to predictable and unpredictable visual targets - to quantify the effective connectivity within and between cortical sources in the visual hierarchy in 25 schizophrenia patients and 25 age-matched controls. We found evidence for marked differences between normal subjects and schizophrenia patients in the strength of extrinsic backward connections from higher hierarchical levels to lower levels within the visual system. In addition, we show that not only do schizophrenia subjects have abnormal connectivity but also that they fail to adjust or optimize this connectivity when events can be predicted. Thus, the differential intrinsic recurrent connectivity observed during processing of predictable versus unpredictable targets was markedly attenuated in schizophrenia patients compared with controls, suggesting a failure to modulate the sensitivity of neurons responsible for passing sensory information of prediction errors up the visual cortical hierarchy. The findings support the proposed role of abnormal connectivity in the neuropathology and pathophysiology of schizophrenia.