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What are the effects of risperidone, olanzapine, quetiapine, and ziprasidone on time to discontinuation in people who have discontinued another atypical antipsychotic?METHODSDesign: Randomised controlled trial.Allocation: Concealed.Blinding: Double blind.Follow up period: Eighteen months.Setting: Fifty seven clinical sites, USA; from January 2001 to December 2004.Patients: 333 people aged between 16 and 65 years with schizophrenia (DSM-IV; mean age 40.8 years; 69% male) who discontinued treatment with the assigned atypical antipsychotic in the first phase of the study (for any reason). Exclusions: prior resistance to study drugs or treatment with clozapine for resistance; history of serious adverse reaction to study drugs; first episode schizophrenia; schizoaffective disorder; mental retardation; cognitive disorder; pregnant; breast feeding; or serious medical comorbidity.Intervention: Olanzapine (7.5-30 mg/day); quetiapine (200-800 mg/day); risperidone (1.5-6 mg/day); or ziprasidone (40-160 mg/day). Participants were randomised to a different antipsychotic to the one they had previously discontinued.Outcomes: Time until discontinuation of treatment for any reason.Patient follow up: 98.5% of participants provided time to discontinuation data.MAIN RESULTSTime to discontinuation for any reason differed significantly between treatments (p = 0.004; see http://www.ebmentalhealth.com/supplemental for table 1). Discontinuation was significantly earlier with quetiapine and ziprasidone than with olanzapine or risperidone, but there was no significant difference in time to discontinuation between risperidone and olanzapine or ziprasidone and quetiapine (see http://www.ebmentalhealth.com/supplemental for table 2). Although there was a significant difference between treatments in time to discontinuation because of lack of efficacy overall (p<0.05), pairwise comparisons between treatments found no significant differences after corrections for multiple comparisons. There was no significant difference overall in time to discontinuation owing to adverse events.CONCLUSIONSRisperidone and olanzapine increase time to treatment discontinuation compared with quetiapine and ziprasidone in people with schizophrenia who have previously discontinued taking another atypical antipsychotic. [ABSTRACT FROM AUTHOR]

Alternatives to traditional categorical diagnoses have been proposed to improve the validity and utility of psychiatric nosology. This paper continues the companion review of an alternative model, the psychosis superspectrum of the Hierarchical Taxonomy of Psychopathology (HiTOP). The superspectrum model aims to describe psychosis-related psychopathology according to data on distributions and associations among signs and symptoms. The superspectrum includes psychoticism and detachment spectra as well as narrow subdimensions within them. Auxiliary domains of cognitive deficit and functional impairment complete the psychopathology profile. The current paper reviews evidence on this model from neurobiology, treatment response, clinical utility, and measure development. Neurobiology research suggests that psychopathology included in the superspectrum shows similar patterns of neural alterations. Treatment response often mirrors the hierarchy of the superspectrum with some treatments being efficacious for psychoticism, others for detachment, and others for a specific subdimension. Compared to traditional diagnostic systems, the quantitative nosology shows an approximately 2-fold increase in reliability, explanatory power, and prognostic accuracy. Clinicians consistently report that the quantitative nosology has more utility than traditional diagnoses, but studies of patients with frank psychosis are currently lacking. Validated measures are available to implement the superspectrum model in practice. The dimensional conceptualization of psychosis-related psychopathology has implications for research, clinical practice, and public health programs. For example, it encourages use of the cohort study design (rather than case-control), transdiagnostic treatment strategies, and selective prevention based on subclinical symptoms. These approaches are already used in the field, and the superspectrum provides further impetus and guidance for their implementation. Existing knowledge on this model is substantial, but significant gaps remain. We identify outstanding questions and propose testable hypotheses to guide further research. Overall, we predict that the more informative, reliable, and valid characterization of psychopathology offered by the superspectrum model will facilitate progress in research and clinical care., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

With new data about different aspects of schizophrenia being continually generated, it becomes necessary to periodically revisit exactly what we know. Along with a need to review what we currently know about schizophrenia, there is an equal imperative to evaluate the construct itself. With these objectives, we undertook an iterative, multi-phase process involving fifty international experts in the field, with each step building on learnings from the prior one. This review assembles currently established findings about schizophrenia (construct, etiology, pathophysiology, clinical expression, treatment) and posits what they reveal about its nature. Schizophrenia is a heritable, complex, multi-dimensional syndrome with varying degrees of psychotic, negative, cognitive, mood, and motor manifestations. The illness exhibits a remitting and relapsing course, with varying degrees of recovery among affected individuals with most experiencing significant social and functional impairment. Genetic risk factors likely include thousands of common genetic variants that each have a small impact on an individual's risk and a plethora of rare gene variants that have a larger individual impact on risk. Their biological effects are concentrated in the brain and many of the same variants also increase the risk of other psychiatric disorders such as bipolar disorder, autism, and other neurodevelopmental conditions. Environmental risk factors include but are not limited to urban residence in childhood, migration, older paternal age at birth, cannabis use, childhood trauma, antenatal maternal infection, and perinatal hypoxia. Structural, functional, and neurochemical brain alterations implicate multiple regions and functional circuits. Dopamine D-2 receptor antagonists and partial agonists improve psychotic symptoms and reduce risk of relapse. Certain psychological and psychosocial interventions are beneficial. Early intervention can reduce treatment delay and improve outcomes. Schizophrenia is increasingly considered to be a heterogeneous syndrome and not a singular disease entity. There is no necessary or sufficient etiology, pathology, set of clinical features, or treatment that fully circumscribes this syndrome. A single, common pathophysiological pathway appears unlikely. The boundaries of schizophrenia remain fuzzy, suggesting the absence of a categorical fit and need to reconceptualize it as a broader, multi-dimensional and/or spectrum construct., Competing Interests: Declaration of competing interest There are no financial or other conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Psychiatric disorders are associated with significant social and economic burdens, many of which are related to issues with current diagnosis and treatments. The coronavirus (COVID-19) pandemic is estimated to have increased the prevalence and burden of major depressive and anxiety disorders, indicating an urgent need to strengthen mental health systems globally. To date, current approaches adopted in drug discovery and development for psychiatric disorders have been relatively unsuccessful. Precision psychiatry aims to tailor healthcare more closely to the needs of individual patients and, when informed by neuroscience, can offer the opportunity to improve the accuracy of disease classification, treatment decisions, and prevention efforts. In this review, we highlight the growing global interest in precision psychiatry and the potential for the National Institute of Health-devised Research Domain Criteria (RDoC) to facilitate the implementation of transdiagnostic and improved treatment approaches. The need for current psychiatric nosology to evolve with recent scientific advancements and increase awareness in emerging investigators/clinicians of the value of this approach is essential. Finally, we examine current challenges and future opportunities of adopting the RDoC-associated translational and transdiagnostic approaches in clinical studies, acknowledging that the strength of RDoC is that they form a dynamic framework of guiding principles that is intended to evolve continuously with scientific developments into the future. A collaborative approach that recruits expertise from multiple disciplines, while also considering the patient perspective, is needed to pave the way for precision psychiatry that can improve the prognosis and quality of life of psychiatric patients.

Categorical diagnosis, a pillar of the medical model, has not worked well in psychiatry where most diagnoses are still exclusively symptom based. Uncertainty continues about whether categories or dimensions work better for the assessment and treatment of idiopathic psychoses. The Bipolar Schizophrenia Network for Intermediate Phenotypes (B-SNIP) examined multiple cognitive and electrophysiological biomarkers across a large transdiagnostic psychosis data set. None of the variables supported neurobiological distinctiveness for conventional clinical psychosis diagnoses but showed a continuum of severity. Using numerical taxonomy of these data, B-SNIP identified three biological subtypes (Biotypes) agnostic to DSM diagnoses. Biotype-1 is characterized by reduced physiological response to salient stimuli, while Biotype-2 showed accentuated intrinsic (background or ongoing) neural activity and the worst inhibition. Biotype-3 cases are like healthy persons on many laboratory measures. These Biotypes differed in imaging and other electrophysiological measures not included in subgroup creation, illustrating external validation. The Biotypes solution also replicated in an independent sample of psychosis cases. Biotypes are differentiable by clinical characteristics, leading to a feasible algorithm for Biotype estimates. Identifying Biotypes may aid treatment selection and outcome prediction. As an example, preliminary cross-sectional B-SNIP data suggest that Biotype-1 cases may have physiological features that predict a more favorable response to clozapine. While psychosis Biotypes reveal physiological heterogeneity across cases with similar clinical characteristics, data also suggest a dimensional vulnerability for serious psychopathology that cuts across diagnostic boundaries. Both categorical and dimensional diagnostic approaches should be considered within idiopathic psychosis for optimum diagnosis, care, and research., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Current pharmacological treatment of schizophrenia employs drugs that interfere with dopamine neurotransmission, aiming to suppress acute exacerbation of psychosis and maintenance treatment to reduce the risk of psychosis recurrence. According to this treatment scheme, available psychotropic drugs intended to treat negative symptoms, cognitive impairment, or anxiety are administered as add-ons to treatment with antipsychotics. However, an alternative treatment scheme proposes a targeted or intermittent treatment approach, by which antipsychotic drugs are administered upon psychosis exacerbation and discontinued upon remission or stabilization, while negative symptoms, cognitive impairment, or anxiety are treated with specific psychotropics as monotherapy. Along these lines, antipsychotics are renewed only in the event of recurrence of psychotic symptoms. This 50-year-old debate between targeted and continuous treatment schemes arises from disagreements about interpreting scientific evidence and discordant views regarding benefit/risk assessment. Among the debate's questions are: (1) what is the percentage of individuals who can maintain stability without antipsychotic maintenance treatment, and what is the percentage of those who exacerbate despite antipsychotic treatment? (2) how to interpret results of placebo-controlled 9- to 18-month-long maintenance trials in a life-long chronic disorder, and how to interpret results of the targeted trials, some of which are open label or not randomized; (3) how to weigh the decreased risk for psychotic recurrence vs the almost certainty of adverse effects on patient's quality of life. Patients' profiles, preferences, and circumstances of the care provision should be considered as the targeted vs continuous treatment options are considered., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Background: There is no consensus on defining relapse in schizophrenia, and scale-derived criteria with unclear clinical relevance are widely used. We aimed to develop an evidence-based scale-derived set of criteria to define relapse in patients with schizophrenia or schizoaffective disorder., Methods: We searched the Yale University Open Data Access (YODA) for randomised controlled trials (RCTs) in clinically stable adults with schizophrenia or schizoaffective disorder, and obtained individual participant data on Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression Severity (CGI-S), Personal and Social Performance (PSP), and Social and Occupational Functioning Assessment Scale (SOFAS). Our main outcomes were PANSS-derived criteria based on worsening in PANSS total score. We examined their relevance using equipercentile linking with CGI-S and functioning scales, and their test-performance in defining relapse with diagnostic test accuracy meta-analysis against CGI-S worsening (≥1-point increase together with a score ≥4 points) and psychiatric hospitalisation., Findings: Based on data from seven RCTs (2354 participants; 1348 men [57·3%] and 1006 women [42·7%], mean age of 39·5 years [SD 12·0, range 17-89]; 303 Asian [12.9%], 255 Black [10.8%], 1665 White [70.7%], and other or unspecified 131 [5.6%]), an increase of 12 points or more in PANSS total (range 30-210 points) corresponded to clinically important deterioration in global severity of illness (≥1 point increase in CGI-S, range 1-7) and functioning (≥10 points decline in PSP or SOFAS, range 1-100). The interpretation of percentage changes varied importantly across different baseline scores. An increase of 12 points or more in PANSS total had good sensitivity and specificity using CGI-S as reference standard (sensitivity 82·1% [95% CI 77·1-86·4], specificity 86·9% [82·9-90·3]), as well as good sensitivity but lower specificity compared to hospitalisation (sensitivity 81·7% [74·1-87·7], specificity 69·2% [60·5-76·9]). Requiring either an increase in PANSS total or in specific items for positive and disorganization symptoms further improved test-performance. Cutoffs for situations where high sensitivity or specificity is needed are presented., Interpretation: An increase of either 12 points or more in the PANSS total score, or worsening of specific positive and disorganisation symptom items could be a reasonable evidence-based definition of relapse in schizophrenia, potentially linking symptoms used to define remission and relapse. Percentage changes should not be used to define relapse because their interpretation depends on baseline scores., Funding: German Research Foundation (grant number: 428509362)., Competing Interests: Declaration of interests RAM has received speaker or consultancy fees from Karuna, Janssen, Boehringer Ingelheim, and Otsuka, and co-directs a company that designs digital resources to support treatment of mental illness. JMK has been a consultant or advisor for, or has received honoraria from, Alkermes, Allergan, LB Pharmaceuticals, H Lundbeck, Intracellular Therapies, Janssen Pharmaceuticals, Johnson & Johnson, Merck, Minerva, Neurocrine, Newron, Otsuka, Pierre Fabre, Reviva, Roche, Sumitomo Dainippon, Sunovion, Takeda, Teva, and UpToDate, and is a shareholder in LB Pharmaceuticals and Vanguard Research Group. CA has been a consultant to, or has received honoraria or grants from, Acadia, Abbot, Ambrosetti, AMGEN, AstraZeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Forum, Gedeon Richter, Janssen Cilag, Lundbeck, Merck, Otsuka, Pfizer, Roche, Servier, Shire, Schering Plough, Sunovion, and Takeda. WWF has received consulting fees from Boehringer Ingelheim, Angelini, Richter, and Recordati, and grant support from Lundbeck and Otsuka. PF received paid speakership from Otsuka, Recordati, Richter, Rovi, and Janssen, and is a member of advisory boards of Richter, Rovi, and Janssen. AH has received paid speakerships from AbbVie, Janssen, Otsuka, Rercordati, and Lundbeck. He was member of Rovi, Recordati, Otsuka, Lundbeck, and Janssen advisory boards. SRM has received consulting fees from Boehringer-Ingelheim, H. Lundbeck, Otsuka, Takeda, Teva, Roche, Genentech, Targacept, Forum, AbbVie, Allergan, and Neurocrine. He has received research support from Boehringer-Ingelheim, Takeda, and Neurocrine. NS has been a consultant or advisor to, or has received honoraria, from Alkermes, Lundbeck, Otsuka, Otsuka Canada, and Teva. WGH has received consulting fees or sat on paid advisory boards for In Silico Biosciences, Translational Life Sciences, Newron, Otsuka, and AbbVie. RWB is a data and safety monitoring board member for Merck, Newron, and Roche; on the advisory board for Acadia, Boehringer Ingelheim, Karuna, Neurocrine, and Roche; and consultant for Boehringer Ingelheim. MD is an employee of Minerva Neurosciences. MW He has received advisory board, speaker's, or consultant fees from, and owns stock, with Acadia, Dexcel, Janssen, Lundbeck, Minerva, Pfizer, Roche, and Teva. OH was a part-time employee of H. Lundbeck, and has received investigator-initiated research funding from, or participated in, advisory or speaker meetings organised by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Jansenn, Lundbeck, Neurocrine, Otsuka, Sunovion, Rand, Recordati, Roche, and Viatris/Mylan. Neither he nor his family have holdings/a financial stake in any pharmaceutical company. He has a patent for the use of dopaminergic imaging. CUC has been a consultant or advisor to, or has received honoraria from, AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Axsome, Cardio Diagnostics, Compass, Damitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Medscape, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Noven, Otsuka, Pfizer, Recordati, Relmada, Reviva, Rovi, Seqirus, Servier, SK Life Science, Sumitomo Dainippon, Sunovion, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a data safety monitoring board for Lundbeck, Relmada, Reviva, Rovi, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma and Quantics. In the past 3 years, SL has received honoraria as a consultant, adviser, or lecturer from Alkermes, Angelini, Eisai, Gedeon Richter, Janssen, Lundbeck, Lundbeck Institute, Merck Sharpp and Dome, Otsuka, Recordati, Rovi, Sanofi Aventis, TEVA, Medichem, and Mitsubishi. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Kurt Schneider has played a leading role in shaping our current view of schizophrenia, placing certain manifestations of delusions and hallucinations at the center of the disorder, especially ideas of persecution and voice-hearing. The first part of this review summarizes Schneider's original ideas and then traces how the different editions of the DSM merged aspects of Kraepelin's, Bleuler's, and Schneider's historical concepts. Special attention is given to the transition from the DSM-IV to the DSM-5, which eliminated much of Schneider's original concept. In the second part of the article, we contrast the current definition of hallucination in the DSM-5 with that of Schneider. We present empirically derived arguments that favor a redefinition of hallucinations, much in accordance with Schneider's original ideas. We plea for a two-dimensional model of hallucinations that represents the degree of insight and perceptuality, ranging from thoughts with full "mineness" via perception-laden thoughts and intrusions (including "as if" experiences") to hallucinations. While we concur with the DSM-5 that cognitions that are indistinguishable from perceptions should be labeled as hallucinations, we suggest expanding the definition to internally generated sensory phenomena, including those with only partial resemblance to external perceptions, that the individual considers real and that may lie at the heart of a subsequent delusional superstructure., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

There has been a major drive in research trying to understand the onset of psychosis. Clinical-high risk (CHR) studies focus on opportunistic help-seeking samples with non-psychotic disorders and a degree of psychosis admixture of variable outcome, but it is unlikely that these represent the population incidence of psychotic disorders. Longitudinal cohort studies of representative samples in the general population have focused on development and outcome of attenuated psychotic symptoms, but typically have low power to detect transition to clinical psychotic disorder. In this issue of Schizophrenia Bulletin, Cupo and colleagues resurrect a time-honored method to examine psychosis onset: the epidemiological follow-back study, modernizing it to fit the research framework of the early intervention era. The authors set out to investigate the hypothesis that psychotic disorder represents the poorest outcome fraction of initially non-psychotic, common mental disorders and present compelling findings, unifying previous opportunistic CHR and representative cohort-based work., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

Shortcomings of approaches to classifying psychopathology based on expert consensus have given rise to contemporary efforts to classify psychopathology quantitatively. In this paper, we review progress in achieving a quantitative and empirical classification of psychopathology. A substantial empirical literature indicates that psychopathology is generally more dimensional than categorical. When the discreteness versus continuity of psychopathology is treated as a research question, as opposed to being decided as a matter of tradition, the evidence clearly supports the hypothesis of continuity. In addition, a related body of literature shows how psychopathology dimensions can be arranged in a hierarchy, ranging from very broad "spectrum level" dimensions, to specific and narrow clusters of symptoms. In this way, a quantitative approach solves the "problem of comorbidity" by explicitly modeling patterns of co-occurrence among signs and symptoms within a detailed and variegated hierarchy of dimensional concepts with direct clinical utility. Indeed, extensive evidence pertaining to the dimensional and hierarchical structure of psychopathology has led to the formation of the Hierarchical Taxonomy of Psychopathology (HiTOP) Consortium. This is a group of 70 investigators working together to study empirical classification of psychopathology. In this paper, we describe the aims and current foci of the HiTOP Consortium. These aims pertain to continued research on the empirical organization of psychopathology; the connection between personality and psychopathology; the utility of empirically based psychopathology constructs in both research and the clinic; and the development of novel and comprehensive models and corresponding assessment instruments for psychopathology constructs derived from an empirical approach.

Background: Despite adequate antipsychotic treatment, most people with schizophrenia continue to exhibit persistent positive and negative symptoms and cognitive impairments. The current study was designed to examine the efficacy and safety of adjunctive anti-inflammatory combination therapy for these illness manifestations., Methods: Thirty-nine people with either Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, schizophrenia or schizoaffective disorder were entered into a 12-week double-blind, 2-arm, triple-dummy, placebo-controlled, randomized clinical trial: 19 were randomized to anti-inflammatory combination therapy and 20 were randomized to placebo. The Brief Psychiatric Rating Scale positive symptom item total score was used to assess positive symptom change, the Scale for the Assessment of Negative Symptoms total score was used to assess negative symptom change, the Calgary Depression Scale total score was used to assess depressive symptom change, and the MATRICS Consensus Cognitive Battery was used to assess neuropsychological test performance., Results: There was a significant time effect for Brief Psychiatric Rating Scale positive symptom item score (t226 = -2.66, P = 0.008), but the treatment (t54=1.52, P = 0.13) and treatment × time (t223 = 0.47, P = 0.64) effects were not significant. There were no significant time (t144 = 0.53, P = 0.72), treatment (t58=0.48, P = 0.63), or treatment × time (t143 = -0.20, P = 0.84) effects for the Scale for the Assessment of Negative Symptoms total score; or for any of the other symptom measures. There were no significant group differences in the change in the MATRICS Consensus Cognitive Battery composite score over the course of the study (F1,26=2.20, P = 0.15)., Conclusions: The study results suggest that there is no significant benefit of combined anti-inflammatory treatment for persistent positive symptoms or negative symptoms or cognitive impairments (clinicaltrials.gov trial number: NCT01514682).

The Hierarchical Taxonomy of Psychopathology (HiTOP) is a scientific effort to address shortcomings of traditional mental disorder diagnoses, which suffer from arbitrary boundaries between psychopathology and normality, frequent disorder co-occurrence, heterogeneity within disorders, and diagnostic instability. This paper synthesizes evidence on the validity and utility of the thought disorder and detachment spectra of HiTOP. These spectra are composed of symptoms and maladaptive traits currently subsumed within schizophrenia, other psychotic disorders, and schizotypal, paranoid and schizoid personality disorders. Thought disorder ranges from normal reality testing, to maladaptive trait psychoticism, to hallucinations and delusions. Detachment ranges from introversion, to maladaptive detachment, to blunted affect and avolition. Extensive evidence supports the validity of thought disorder and detachment spectra, as each spectrum reflects common genetics, environmental risk factors, childhood antecedents, cognitive abnormalities, neural alterations, biomarkers, and treatment response. Some of these characteristics are specific to one spectrum and others are shared, suggesting the existence of an overarching psychosis superspectrum. Further research is needed to extend this model, such as clarifying whether mania and dissociation belong to thought disorder, and explicating processes that drive development of the spectra and their subdimensions. Compared to traditional diagnoses, the thought disorder and detachment spectra demonstrated substantially improved utility: greater reliability, larger explanatory and predictive power, and higher acceptability to clinicians. Validated measures are available to implement the system in practice. The more informative, reliable and valid characterization of psychosis-related psychopathology offered by HiTOP can make diagnosis more useful for research and clinical care., (© 2020 World Psychiatric Association.)

Prior studies examining the impact of oxytocin on negative symptoms in schizophrenia have yielded mixed results. The current study explored whether oxytocin can improve more proximal indicators of social affiliation as indicated by changes in behavior, language and subjective indices of social affiliation among individuals with schizophrenia spectrum disorders during a role-play designed to elicit affiliative responses. We tested the hypothesis that daily intranasal oxytocin administered for 6 weeks would improve social affiliation as manifested by increased social skill ratings, use of positive, affiliative, and social words, and subjective responses from a previously published randomized controlled trial. Forty outpatients with schizophrenia or schizoaffective disorder were randomized to the oxytocin, galantamine, or placebo group and completed affiliative role-plays and self-report questionnaires of affect, reactions to the affiliative confederate, and willingness to interact at baseline and post-treatment. Results demonstrated that oxytocin was not effective at improving behavioral or subjective indicators of social affiliation. This study adds to a growing literature that the prosocial effects of oxytocin in schizophrenia are limited or null., (© The Author(s) 2020. Published by Oxford University Press on behalf of the University of Maryland's school of medicine, Maryland Psychiatric Research Center.)

Background: Approximately one-third of people with schizophrenia have elevated levels of anti-gliadin antibodies of the immunoglobulin G type (AGA IgG) — a higher rate than seen in healthy controls. We performed the first double-blind clinical trial of gluten-free versus gluten-containing diets in a subset of patients with schizophrenia who were positive for AGA IgG., Methods: In this pilot feasibility study, 16 participants with schizophrenia or schizoaffective disorder who had elevated AGA IgG (≥ 20 U) but were negative for celiac disease were admitted to an inpatient unit for a 5-week trial. All participants received standardized gluten-free meals and were randomized in a double-blind fashion to receive a shake containing 10 g of gluten flour or 10 g of rice flour each day. Participants were rated for psychiatric, cognitive and gastrointestinal symptoms at baseline and endpoint., Results: Of the 16 participants, 14 completed the 5-week trial (2 discontinued early for administrative reasons). Compared with participants on the gluten-containing diet, participants on the gluten-free diet showed improvement on the Clinical Global Impressions scale (Cohen d = –0.75) and in negative symptoms (Cohen d = –0.53). We noted no improvement in positive or global cognitive symptoms, but did observe an improvement in attention favouring the gluten-free diet (Cohen d = 0.60). Robust improvements in gastrointestinal adverse effects occurred in the gluten-free group relative to the glutencontaining group. Adverse effects were similar between groups., Limitations: This study was limited by its small sample size; larger studies are needed., Conclusion: This feasibility study suggests that removal of gluten from the diet is associated with improvement in psychiatric and gastrointestinal symptoms in people with schizophrenia or schizoaffective disorder., Competing Interests: D. Kelly served as an advisor to Lundbeck and HLS Therapeutics. A. Fasano is the founder and a stock holder of Alba Therapeutics. R. Buchanan served on the advisory boards for Astellas Pharma, Avanir, Boehringer Ingelheim-RCV, ITI, Inc., Lundbeck and Roche. He was a consultant for Takeda and Upsher-Smith Laboratories and on the DSMB for Pfizer. W. Carpenter has served as an advisor to Boehringer Ingelheim, Allergan, Health Analytics and Teva. All other authors have nothing to disclose., (© 2019 Joule Inc. or its licensors)

Intranasal administration of the neuropeptide oxytocin (OT) has yielded inconsistent effects on social cognition and general cognition in individuals with schizophrenia (SZ). Few studies have examined whether endogenous peripheral OT levels are also associated with social and general cognition in SZ. The current study examined whether plasma OT levels are associated with performance on a higher-order social cognition measure (i.e., a task that requires inferential processes and knowledge not directly presented in social stimuli), as well as domains of general cognition. Participants included 30 individuals with SZ and 21 demographically matched healthy controls (CN). The MATRICS Consensus Cognitive Battery was administered to assess neuropsychological impairment in relation to 7 domains (processing speed, attention/vigilance, working memory, verbal learning, visual learning, reasoning/problem solving, and social cognition). Plasma OT levels were measured via radioimmunoassay. SZ had significantly lower endogenous OT levels and poorer MCCB performance on all 7 domains than CN. In CN and SZ, lower endogenous OT was associated with poorer social cognition. In SZ, lower endogenous OT was also associated with poorer processing speed and working memory. The significant association between OT and social cognition in both CN and SZ highlights the importance of endogenous OT levels as a biological predictor of social cognition, irrespective of clinical status. Significant associations between plasma OT and general neurocognition may reflect either an anxiolytic effect of plasma OT that results in better neurocognitive performance, or OT's action on dopamine and enhancement of dopamine tone that results in improved cognition., (Copyright © 2019. Published by Elsevier Ltd.)

The latent structure of schizotypy and psychosis-spectrum symptoms remains poorly understood. Furthermore, molecular genetic substrates are poorly defined, largely due to the substantial resources required to collect rich phenotypic data across diverse populations. Sample sizes of phenotypic studies are often insufficient for advanced structural equation modeling approaches. In the last 50 years, efforts in both psychiatry and psychological science have moved toward (1) a dimensional model of psychopathology (eg, the current Hierarchical Taxonomy of Psychopathology [HiTOP] initiative), (2) an integration of methods and measures across traits and units of analysis (eg, the RDoC initiative), and (3) powerful, impactful study designs maximizing sample size to detect subtle genomic variation relating to complex traits (the Psychiatric Genomics Consortium [PGC]). These movements are important to the future study of the psychosis spectrum, and to resolving heterogeneity with respect to instrument and population. The International Consortium of Schizotypy Research is composed of over 40 laboratories in 12 countries, and to date, members have compiled a body of schizotypy- and psychosis-related phenotype data from more than 30000 individuals. It has become apparent that compiling data into a protected, relational database and crowdsourcing analytic and data science expertise will result in significant enhancement of current research on the structure and biological substrates of the psychosis spectrum. The authors present a data-sharing infrastructure similar to that of the PGC, and a resource-sharing infrastructure similar to that of HiTOP. This report details the rationale and benefits of the phenotypic data collective and presents an open invitation for participation.

Shortcomings of approaches to classifying psychopathology based on expert consensus have given rise to contemporary efforts to classify psychopathology quantitatively. In this paper, we review progress in achieving a quantitative and empirical classification of psychopathology. A substantial empirical literature indicates that psychopathology is generally more dimensional than categorical. When the discreteness versus continuity of psychopathology is treated as a research question, as opposed to being decided as a matter of tradition, the evidence clearly supports the hypothesis of continuity. In addition, a related body of literature shows how psychopathology dimensions can be arranged in a hierarchy, ranging from very broad "spectrum level" dimensions, to specific and narrow clusters of symptoms. In this way, a quantitative approach solves the "problem of comorbidity" by explicitly modeling patterns of co-occurrence among signs and symptoms within a detailed and variegated hierarchy of dimensional concepts with direct clinical utility. Indeed, extensive evidence pertaining to the dimensional and hierarchical structure of psychopathology has led to the formation of the Hierarchical Taxonomy of Psychopathology (HiTOP) Consortium. This is a group of 70 investigators working together to study empirical classification of psychopathology. In this paper, we describe the aims and current foci of the HiTOP Consortium. These aims pertain to continued research on the empirical organization of psychopathology; the connection between personality and psychopathology; the utility of empirically based psychopathology constructs in both research and the clinic; and the development of novel and comprehensive models and corresponding assessment instruments for psychopathology constructs derived from an empirical approach., (© 2018 World Psychiatric Association.)

Altered immune function and inflammation are seen in schizophrenia, however, peripheral inflammatory markers are not consistently elevated in all people, suggesting inflammation may be present only in a subgroup. We measured TNF-α and IL-Iβ in 100 people with schizophrenia or schizoaffective disorder and correlated these with antibodies to gliadin, a protein found in wheat, barley and rye that has been found to be elevated in some people with schizophrenia. We hypothesized that higher peripheral antigliadin antibodies (AGA IgG) would be associated with higher peripheral inflammation as measured by TNF-α and IL-1β. Mean log transformed values of TNF-α, (p=.029) and IL-1β (p=.016) were over twofold higher in people with schizophrenia who had high levels of AGA IgG (≥7 U) compared to those who did not have positivity to AGA IgG. We found a significant positive correlation between AGA IgG and the log transformed TNF-α (r=0.42, p<.0001) as well as IL-Iβ (r=0.51, p<.0001). The relationship was independent of cigarette smoking, body mass index and antipsychotic medications. People with schizophrenia having higher levels of AGA IgG show higher levels of peripheral inflammation and may define a subgroup with distinct pathophysiology and potentially novel treatment targets., (Copyright © 2017. Published by Elsevier Inc.)