research on schizophrenia spectrum

Association of Schizophrenia Spectrum Disorders and Violence Perpetration in Adults and Adolescents From 15 Countries: A Systematic Review and Meta-analysis

Affiliations.

• 1 Department of Psychiatry, University of Oxford, Oxford, England.
• 2 University of Limerick School of Medicine and Health Service Executive, Limerick, Ireland.
• 3 Oxford Health National Health Service Foundation Trust, Warneford Hospital, Oxford, England.
• PMID: 34935869
• PMCID: PMC8696689
• DOI: 10.1001/jamapsychiatry.2021.3721

Importance: Violence perpetration outcomes in individuals with schizophrenia spectrum disorders contribute to morbidity and mortality at a population level, disrupt care, and lead to stigma.

Objective: To conduct a systematic review and meta-analysis of the risk of perpetrating interpersonal violence in individuals with schizophrenia spectrum disorders compared with general population control individuals.

Data sources: Multiple databases were searched for studies in any language from January 1970 to March 2021 using the terms violen* or homicid* and psychosis or psychoses or psychotic or schizophren* or schizoaffective or delusional and terms for mental disorders. Bibliographies of included articles were hand searched.

Study selection: The study included case-control and cohort studies that allowed risks of interpersonal violence perpetration and/or violent criminality in individuals with schizophrenia spectrum disorders to be compared with a general population group without these disorders.

Data extraction and synthesis: The study followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines and the Meta-analyses of Observational Studies in Epidemiology (MOOSE) proposal. Two reviewers extracted data. Quality was assessed using the Newcastle-Ottawa Quality Assessment Scale. Data were pooled using a random-effects model.

Main outcomes and measures: The main outcome was violence to others obtained either through official records, self-report and/or collateral-report, or medical file review and included any physical assault, robbery, sexual offenses, illegal threats or intimidation, and arson.

Results: The meta-analysis included 24 studies of violence perpetration outcomes in 15 countries over 4 decades (N = 51 309 individuals with schizophrenia spectrum disorders; reported mean age of 21 to 54 years at follow-up; of those studies that reported outcomes separately by sex, there were 19 976 male individuals and 14 275 female individuals). There was an increase in risk of violence perpetration in men with schizophrenia and other psychoses (pooled odds ratio [OR], 4.5; 95% CI, 3.6-5.6) with substantial heterogeneity (I2 = 85%; 95% CI, 77-91). The risk was also elevated in women (pooled OR, 10.2; 95% CI, 7.1-14.6), with substantial heterogeneity (I2 = 66%; 95% CI, 31-83). Odds of perpetrating sexual offenses (OR, 5.1; 95% CI, 3.8-6.8) and homicide (OR, 17.7; 95% CI, 13.9-22.6) were also investigated. Three studies found increased relative risks of arson but data were not pooled for this analysis owing to heterogeneity of outcomes. Absolute risks of violence perpetration in register-based studies were less than 1 in 20 in women with schizophrenia spectrum disorders and less than 1 in 4 in men over a 35-year period.

Conclusions and relevance: This systematic review and meta-analysis found that the risk of perpetrating violent outcomes was increased in individuals with schizophrenia spectrum disorders compared with community control individuals, which has been confirmed in new population-based longitudinal studies and sibling comparison designs.

Publication types

• Meta-Analysis
• Research Support, Non-U.S. Gov't
• Systematic Review
• Databases, Factual
• Psychotic Disorders / psychology*
• Schizophrenia*
• Violence / psychology*

Grants and funding

• WT_/Wellcome Trust/United Kingdom
• DRF-2018-11-ST2-069/DH_/Department of Health/United Kingdom
• 202836/Z/16/Z/WT_/Wellcome Trust/United Kingdom

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• Published: 24 April 2024

Three patterns link brain organization to genes in health and disease

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• Development of the nervous system
• Genetics of the nervous system

Gene expression in the human cortex is shown to exhibit a generalizable three-component architecture that reflects neuronal, metabolic, and immune programmes of healthy brain development. The three components have distinct associations with autism spectrum disorder and schizophrenia, revealing connections between previously unrelated results from studies of case–control neuroimaging, differential gene expression, and genetic risk.

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Hawrylycz, M. J. et al. An anatomically comprehensive atlas of the adult human brain transcriptome. Nature 489 , 391–399 (2012). The original paper presenting the AHBA, in which principal components of cortical gene expression were suggested to reflect brain organization.

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Burt, J. B. et al. Hierarchy of transcriptomic specialization across human cortex captured by structural neuroimaging topography. Nat. Neurosci. 21 , 1251–1259 (2018). This paper characterizes the first component of cortical gene expression, C1, as reflecting a neuronal hierarchy defined by tract-tracing and indexed by structural neuroimaging.

Sydnor, V. J. et al. Neurodevelopment of the association cortices: patterns, mechanisms, and implications for psychopathology. Neuron 109 , 2820–2846 (2021). This review proposes that neurodevelopment involves a ‘sensorimotor–association axis’ defined by ten brain maps, of which one is the cortical gene expression component C1.

Merikangas, A. K. et al. What genes are differentially expressed in individuals with schizophrenia? A systematic review. Mol. Psychiatry 27 , 1373–1383 (2022). This review demonstrates the lack of consistency in genes linked to schizophrenia across differential expression studies, which are also inconsistent with GWAS.

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This is a summary of: Dear, R. et al. Cortical gene expression architecture links healthy neurodevelopment to the imaging, transcriptomics and genetics of autism and schizophrenia. Nat. Neurosci . https://doi.org/10.1038/s41593-024-01624-4 (2024).

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PERSPECTIVE article

Evolving concepts of the schizophrenia spectrum: a research domain criteria perspective.

• National Institute of Mental Health, Bethesda, MD, United States

Several trends intersecting over the past two decades have generated increasing debate as to how the concepts of schizophrenia, the schizophrenia spectrum, and the psychotic disorders spectrum should be regarded. These trends are reflected in various areas of research such as genomics, neuroimaging, and data-driven computational studies of multiple response systems. Growing evidence suggests that schizophrenia represents a broad and heterogenous syndrome, rather than a specific disease entity, that is part of a multi-faceted psychosis spectrum. Progress in explicating these various developments has been hampered by the dependence upon sets of symptoms and signs for determining a diagnosis, and by the reliance on traditional diagnostic categories in reviewing clinical research grants. To address these concerns, the U.S. National Institute of Mental Health initiated the Research Domain Criteria (RDoC) project, a translational research program that calls for studies designed in terms of empirically-based functions (such as cognitive control or reward learning) rather than diagnostic groups. RDoC is a research framework rather than an alternative diagnostic system, intended to provide data that can inform future nosological manuals. This commentary includes a brief summary of RDoC as it pertains to schizophrenia and psychotic spectra, examples of recent data that highlight the utility of the approach, and conclusions regarding the implications for evolving conceptualizations of serious mental illness.

Introduction

The concept of schizophrenia (SZ) has elicited continual debate since the first descriptions of psychosis appeared in the middle of the nineteenth century. The nature of the concept has fluctuated across the years according to the views of the scientific zeitgeist and various schools of psychopathology, but has always persevered in one form or another ( 1 ). Within the last decade, however, advances in multiple areas of science—genomics, neuroimaging, cognitive science, and epidemiology—have begun to challenge classic conceptions of schizophrenia ( 2 , 3 ).

Progress in expanding these various developments has been hampered by two major obstacles. First, disorders continue to be defined almost exclusively by sets of symptoms and signs; however, the relationships between diagnostic categories and biological or behavioral measures have proven to be modest and inconsistent, frustrating both a more comprehensive understanding of disorders and the development of more effective treatments ( 4 ). Second, research on mental disorders has been constrained by the persistence in grant review committees of a de facto requirement that hypotheses will embody DSM/ICD categories as their scientific focus, thus foiling applications proposing alternative approaches.

To address these problems, the US National Institute of Health (NIMH) initiated the Research Domain Criteria (RDoC) project in 2009 “to develop, for research purposes, new ways of [studying] mental disorders based on dimensions of observable behavior and neurobiological measures” ( 5 ). RDoC was conceived as an experimental framework to support research in psychopathology organized around basic functional domains such as cognition, motivation, and motor activity, most of which are pertinent to multiple disorders as currently defined (and may partially account for the extensive co-morbidity in current disorders).

The various elements of the RDoC framework have been described in detail elsewhere ( 5 – 7 ) and are briefly summarized here. RDoC is intended as an explicitly translational program: The focus is on fundamental operations of adaptive behavioral/cognitive and brain functioning (e.g., working memory, fear behavior), and psychopathology is viewed in terms of dysregulation in these systems rather than starting with clinical syndromes and trying to determine their source. A core desideratum of RDoC is to study entire dimensions of functioning from the normal range to increasingly abnormal extents, and no specific cutpoints for disorders are specified in order to encourage studies of transitions from normality to degrees of pathology. To foster such analyses, RDoC calls for study designs that include a broader range of “healthy controls,” patients with mild/subsyndromal psychopathology, and unaffected relatives of probands.

The basic dimensions of RDoC are organized in six superordinate domains of functioning (negative valence, positive valence, cognition, social processes, arousal/regulatory systems, and sensorimotor systems). Each domain contains multiple constructs, which—central to the entire framework—are defined jointly by data for a behavioral or cognitive/affective function, evidence for a neural circuit or system that plays a primary role in implementing the function, and relevance to psychopathology ( 8 ).

The domains and constructs were defined in a series of workshops attended by experts in both basic and clinical research. This process was essential for two reasons. First, it is important to communicate to the field well-validated constructs from the basic behavioral neuroscience literature that have demonstrated promise for understanding psychopathology. Second (and less evident), it is critical to provide clear guidelines for grant review. Just as established criteria for defining patient groups contributed significantly to the DSM's hegemony in study sections, examples of domains and constructs are essential to serve as standards for both applicants and reviewers in submitting and evaluating RDoC applications. Since RDoC is an experimental framework, applicants are not required to use one of the current constructs, and no claim is made that the current list of constructs is complete; in fact, a major goal of the program is to encourage research that establishes new constructs or domains, based on the premise that promoting diversity of ideas in research is the best way forward (Note that NIMH accepts DSM-oriented grant applications as always, although applicants are encouraged to address pertinent heterogeneity).

In keeping with the basic-to-clinical translational approach, RDoC focuses on relatively specific aspects of disordered functioning rather than syndromal categories. Study designs might include patients from one or more DSM/ICD categories, analyzing dimensions or subgroups in the full sample or examining selected subjects with particular characteristics (e.g., cognitive control or reward-related deficits). Participants in transdiagnostic studies are typically drawn from related areas of psychopathology, such as mood/anxiety disorders or psychotic disorders (plus comparison participants appropriate for exploring dimensions of functioning). An important emphasis concerns individual differences in psychopathology, given the heterogeneity that is now recognized for all syndromal disorders. Studies that include multiple domains/constructs are encouraged, such as the relationship of threat to attention or reward-related activity to social processes. RDoC-related research further advocates the use of multiple classes of measurement, ranging from genomics and circuit measures to behavioral and self-report, in order to seek an integrative understanding of brain-behavior relationships as they relate to particular functions.

RDoC and the Psychotic Spectrum

The RDoC program has consistently emphasized its agnostic position with respect to disorders as defined in the DSM/ICD system: The goal is to stimulate research that can inform revisions to future diagnostic manuals, however similar or divergent to current disorders and their definitions. Recent developments in the field demonstrate novel conceptions across the entire range of psychopathology, employing various types of dimensions, clusters, and hierarchical approaches that align with the RDoC approach ( 9 ).

Research focused on psychotic disorders amply reflects this trend ( 10 ). As one expert recently explained in a publication for psychiatric professionals, “Over the last decade or so, our field has experienced a radical shift in our understanding of schizophrenia and other serious psychotic disorders, such as schizoaffective disorder and bipolar disorder with psychosis. …. Accumulating evidence indicates that psychotic disorders constitute syndromes rather than diseases per se . … Patients with different clinical diagnostic phenotypes … can show similar underlying patterns of cognitive dysfunction and neurobiological abnormalities” ( 11 ). Space allows only a small number of papers to be cited here as examples of RDoC approaches in the psychotic spectrum [which are treated more comprehensively in a recent chapter; ( 7 )].

Transdiagnostic Findings

The current interest in a schizophrenia or psychotic disorders spectrum is consistent with the kinds of trans-diagnostic mechanisms that RDoC prioritizes. There are multiple types of relevant research designs. These include overlaps between traditional diagnostic classes, such as SZ and bipolar Type 1 disorder (BPD), that are frequently used when it is difficult to examine disorder subtypes or dimensions due to the nature of measurement (as in GWAS studies). A second type of design involves transdiagnostic dimensions or gradients; these differ from the prior design in that the analyses focus on how functional domains are arrayed along one or more dimensions across two or more disorders. Finally, cluster or similar analyses use data-driven techniques to reveal groupings that cut across traditional disorder categories.

Psychiatric genetics has provided increasing support for systematically related trans-diagnostic mechanisms as sample sizes grow. Comparisons of GWAS data across disorders have shown results that are consistent with a recently-posited gradient of neurodevelopmental syndromes ordered by the extent of neurodevelopmental impairment (from most to least: intellectual disability, ASD, ADHD, SZ, schizoaffective disorder (SZ-A), BPD, major depressive disorder [MDD]; ( 2 , 12 )). Larger coheritabilities were observed for disorder pairs that were closer on the spectrum; e.g., SZ-BPD and BPD-MDD were larger than SZ-ASD or BPD-ADHD ( 13 ).

More elaborated data emerged from a study comparing eight disorders in a larger sample, resulting in three clusters of disorders based on shared loci—mood and psychotic disorders (SZ, BPD, and MDD), early-onset neurodevelopmental disorders, and compulsive behaviors ( 14 ). As the authors concluded, “… these results indicate a substantial pairwise genetic correlation between multiple disorders along with a higher-level genetic structure that point to broader domains underlying genetic risk to psychopathology. These findings are at odds with the classical, categorical classification of mental disorder.” (14, p. 1475).

A second aspect of trans-diagnostic comparisons involves dimensions that cut across disorders. For example, a recent study from the CNTRACS group employed multiple measures of performance that tapped distinct aspects of cognition (cognitive control, episodic memory, and visual perception) in a large sample consisting of individuals diagnosed with SZ, BPD, or SZ-A ( 15 ). A latent profile analysis returned a solution with three trans-diagnostic clusters of high ability (mostly indistinct from control subjects), medium performance, and low performance. The proportions of patients from the three diagnostic groups were distributed across the three ability clusters, indicating that the latter were not simply proxies for diagnosis. Confirmatory factor analysis was consistent with the presence of an underlying one-dimensional structure across the three cognitive profiles, suggesting a shared mechanism not related to diagnostic classes per se .

Moving toward multi-measure studies that are compatible with the RDoC approach, computational analyses that identify transdiagnostic clusters of patients illustrate the potential of empirically-derived phenotypes that align with particular biological and behavioral functions. In the exemplary B-SNIP study (Bipolar & Schizophrenia Network on Intermediate Phenotypes), investigators recruited a large sample of patients (SZ, SZ-A, or BPD with psychosis) and acquired a wide range of biological, behavioral, and clinical measures ( 16 ). A cluster analysis of factor scores from cognitive and electrophysiological measures grouped patients into three “biotypes” that cut across DSM disorder categories (as in the previous example). The first two biotypes were characterized by impaired cognitive functioning (slightly more severe in Biotype 1) but divergent sensorimotor reactivity (event-related potential responses related to simple stimuli) that was markedly blunted in Biotype 1 and hyper-responsive in Biotype 2; both measures for the third biotype were only slightly different from healthy controls. The biotypes were validated by several different measures not used in the cluster analysis, including gray matter loss as assessed by voxel-based morphometry. This study demonstrated that deriving transdiagnostic clusters based on a combination of behavioral and psychophysiological functions (cognition and perception), consistent with an RDoC approach, have promise in determining data-driven clinical phenotypes with more validity than traditional disorder classes.

Dimensionality

RDoC emphasizes the gamut of normal-to-abnormal functioning. This aspect can be considered both in terms of cross-sectional and longitudinal studies. The latter, in this context, include trajectories of neurodevelopment from conception to risk states and overt psychopathology.

Cross-sectional discussions of psychosis dimensionality date back nearly as far as the concept of schizophrenia itself, with unresolved discussions as to whether the clinical phenomena represent one or more clinical categories, one or more dimensions, or some combination ( 17 , 18 ). More recently, extensive analyses have been adduced to support replacing the schizophrenia concept with a broader “psychosis spectrum” ( 19 ) that reflects a continuous dimension of psychosis proneness from normal to abnormal ( 20 ), although also allowing for a continuous psychometric spectrum that contains one or more latent categorical structures ( 21 ).

This type of normal-to-abnormal dimensional viewpoint comports with the RDoC framework. At the same time, another RDoC principle is to remain agnostic (as with the DSM) and eschew a priori conclusions regarding the number and composition of dimensions and their clinical significance. One of the hurdles that RDoC was created to address concerns the often-modest relationships among the presence/severity of clinical symptoms and various other measures, such as cognitive tests or brain circuit activity. As noted in a recent paper on RDoC and psychosis, “… one must empirically test whether dimensionality of a symptom indicates dimensionality of a mechanism” [( 7 ), p. 32]. In short, the field is just starting to make progress in unpacking the relationships within and across multiple neurocognitive functions, multiple kinds of symptoms, and multiple neurobiological and genetic measures—compounded by the complexities of intermixed clusters and dimensions ( 22 ). In spite of the daunting challenges, the evidence is already strong that the field is moving in positive directions.

Neurodevelopmental Studies

RDoC places a high priority on neurodevelopmental trajectories. While the clinical high-risk state (CHR) state for psychosis is perhaps the most thoroughly researched example of a trajectory leading toward disorder ( 23 ), more recent studies have expanded the scope of neurodevelopment and functions consistent with RDoC principles. For instance, a recent study followed an unselected sample of children from age 8 to late adolescence, collecting a large number of measures including neurocognitive tests and symptoms; children who developed psychotic symptoms later in adolescence were on average 1–2 years behind typically-developing children in cognitive growth, suggesting that early cognitive impairment could be a marker for psychosis risk and that growth charting may be an opportunity for early detection and prevention ( 24 ). Another group has independently begun to implement this concept with a developmental battery of “gamified” tasks (running on a mobile e-platform) that assesses six cognitive domains in young children in India as a first step to developing normative growth curves ( 25 ).

Such promising programs are only the tip of the iceberg for neurodevelopmental studies involving RDoC (which comprise nearly half of RDoC-themed translational grants funded by NIMH). An equally important issue concerns the need to explicate neurodevelopmental changes from birth to adulthood – addressing both substantive and psychometric issues of identifying and assessing functions that emerge at various points in development, as well as relating growth trajectories to the complex effects of multiple environmental influences ( 26 , 27 ).

It is a stimulating time for research on mental disorders. The field is burgeoning with intriguing new results and new ideas – sparked by developments in genomics, neuroimaging, behavioral science, computational approaches, and many other disciplines. The RDoC initiative has been a part of this contemporary zeitgeist, enabling conversations about innovative approaches to psychopathology ( 28 – 30 ) and supporting research projects that represent new avenues for future directions ( 31 – 33 ).

These developments have accelerated progress regarding the schizophrenia (or more broadly, the psychotic) spectrum. Genomic data provide increasing support for the concept of systematic transdiagnostic components of neurodevelopmental spectra ( 2 , 12 ). In this view, schizophrenia represents not so much a distinct disease as one segment of multiple broader spectra. However, the evidence is also clear that a neurodevelopmental gradient is not simply a matter of performance as assessed by the usual cognitive test batteries; it is important to consider multiple functional domains whose combinations comprise potentially significant clinical phenotypes, e.g., biotypes defined by both cognitive performance and sensorimotor reactivity ( 16 ).

A further aspect of the emerging literature, consistent with the RDoC approach, concerns various gradients from normal to abnormal functioning and how these relate to illness and dysfunction. It is now evident that some types of functional impairments are not necessarily tied to manifest clinical features. As two examples, both the B-SNIP and CNTRACS studies (summarized above) reported that patients in one of the three clusters, in spite of meeting criteria for SZ, BPD, or SZ-A, were characterized by functional performance in cognition and perception that was modestly to indistinguishably different from healthy controls ( 15 , 16 ). A necessary agenda for future research is to unravel the complex relationships among the extent of such factors as genetic load, functional impairments, and clinical symptoms.

The current status of evidence about the psychotic disorders spectrum raises significant questions regarding both near-term implications for research on clinical assessment and services, and long-term directions for scientific priorities and perspectives. With respect to clinical practice, the DSM/ICD nosology continues to dominate procedures for diagnosis and treatment. However, there is increasing attention to transdiagnostic approaches for diagnosis and treatment that build upon awareness of heterogeneity and clinicians' wisdom that many (if not most) treatment plans are focused on specific problems (e.g., sleep, attention, interpersonal relationships) irrespective of formal diagnosis ( 34 , 35 ), and at least one case report specifically cites the use of a transdiagnostic, RDoC approach ( 36 ). Further, some clinical programs have explicitly adopted a transdiagnostic process for assessment and treatment of first-episode psychosis in recognition of the change in diagnosis across time in many patients ( 37 ).

Regarding scientifically-driven changes in nosology, there appears to be a clear consensus that traditional disorder classes in this spectrum need to be revamped, and dozens of promising genetic, circuit-based, and behavioral findings provide clues to future classification systems. However, the nature and extent of potential changes to nosology remain far from clear, as different measurement classes and analytical techniques have yet to coalesce. There also remains the question of the granularity of concepts and measurement that are optimal for clinical use; these concerns apply across all areas—e.g., the number and combinations of specific gene abnormalities for molecularly based therapies; the count and locations of voxel-based structural abnormalities ( 38 ); or whether cognitive difficulties are best addressed at the level of broad test batteries, intermediate functional domains (e.g., executive function), or more specific operations (e.g., working memory).

A key question concerns the routes by which research advances can be implemented in diagnostic and treatment practice. Alterations to formal nosological criteria are not likely to be made soon, given conservative approaches to change in diagnostic manuals. Revisions based upon neuroscience and/or systematic behavioral data are yet more difficult to envision since they would involve an overhaul of the long-established reliance on symptoms and signs for diagnosis.

However, it is possible that rapid change may be recognized in other ways. Regulatory agencies, e.g., are well aware of the need for improved treatments and the potential for groupings and/or dimensions that manifest within or across traditional diagnostic categories. For instance, in 2016 the US Food and Drug Administration (FDA) promulgated an innovative new Drug Development Tool (DDT) Qualification program created to evaluate and approve (Qualify) such tools as “a biomarker used for clinical trial enrichment” [e.g., approval of the N170 event-related potential as a biomarker for social processing in ASD ( 39 )] “… and a clinical outcome assessment used to evaluate clinical benefit…” ( 40 ). Further, the tools are developed in a “context of use” that represents “the manner and purpose of use for a DDT,” i.e., essentially the specific impairment to be addressed ( 40 ). Such developments could lead directly to innovative practices that advance treatment while suggesting new conceptions of clinical phenotypes that are validated inherently by their use in patient care.

In sum, the notion of a psychotic spectrum is evolving rapidly, but schizophrenia—as broad concept or specific diagnostic category—remains a core aspect of contemporary psychopathology. Both general and specialty journals continue to publish large numbers of papers devoted directly to SZ, reflecting widespread support from multiple funding agencies across the world. In September, 2020 the National Institutes of Health announced the AMP-SCZ initiative (Accelerating Medicines Partnership-Schizophrenia), bringing together NIH, the US FDA, and multiple non-profit and private organizations to seek biomarkers for the diverse array of clinical trajectories and adverse outcomes observed in individuals identified as at elevated risk of psychosis. Accordingly, there seems to be little doubt that SZ will remain a central concept in mental disorders for some time to come ( 41 ). While future directions remain difficult to predict given the nascent state of the research, novel research frameworks seem likely to foster the continued expansion of research designs and integrative science—and, in turn, to stimulate more precise thinking about the nosology of SZ and the psychosis spectrum.

Data Availability Statement

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.

Author Contributions

BC and SM contributed equally to the overall outline and scope of the manuscript. BC wrote the first draft. SM contributed extensive comments and edits that resulted in the final version. All authors contributed to the article and approved the submitted version.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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25. Mukherjee D, Bhavnani S, Swaminathan A, Verma D, Parameshwaran D, Divan G, et al. Proof of concept of a gamified developmental assessment on an e-platform (deep) tool to measure cognitive development in rural indian preschool children. Front Psychol . (2020) 11:1202. doi: 10.3389/fpsyg.2020.01202

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28. Bzdok D, Meyer-Lindenberg A. Machine learning for precision psychiatry: opportunities and challenges. Biol Psychiatry Cogn Neurosci Neuroimaging . (2018) 3:223–30. doi: 10.1016/j.bpsc.2017.11.007

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30. Sanislow CA, Ferrante M, Pacheco J, Rudorfer MV, Morris SE. Advancing translational research using NIMH research domain criteria and computational methods. Neuron . (2019) 101:779–82. doi: 10.1016/j.neuron.2019.02.024

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Keywords: psychiatric diagnosis, psychiatric nosology, research domain criteria, psychopathology, schizophrenia spectrum, psychosis spectrum

Citation: Cuthbert BN and Morris SE (2021) Evolving Concepts of the Schizophrenia Spectrum: A Research Domain Criteria Perspective. Front. Psychiatry 12:641319. doi: 10.3389/fpsyt.2021.641319

Received: 14 December 2020; Accepted: 01 February 2021; Published: 25 February 2021.

Reviewed by:

Copyright © 2021 Cuthbert and Morris. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Bruce N. Cuthbert, bcuthber@mail.nih.gov

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

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Schizophrenia

What is schizophrenia.

Schizophrenia is a serious mental illness that affects how a person thinks, feels, and behaves. People with schizophrenia may seem like they have lost touch with reality, which can be distressing for them and for their family and friends. The symptoms of schizophrenia can make it difficult to participate in usual, everyday activities, but effective treatments are available. Many people who receive treatment can engage in school or work, achieve independence, and enjoy personal relationships.

What are the signs and symptoms of schizophrenia?

It’s important to recognize the symptoms of schizophrenia and seek help as early as possible. People with schizophrenia are usually diagnosed between the ages of 16 and 30, after the first episode of psychosis . Starting treatment as soon as possible following the first episode of psychosis is an important step toward recovery. However, research shows that gradual changes in thinking, mood, and social functioning often appear before the first episode of psychosis. Schizophrenia is rare in younger children.

Schizophrenia symptoms can differ from person to person, but they generally fall into three main categories: psychotic, negative, and cognitive.

Psychotic symptoms include changes in the way a person thinks, acts, and experiences the world. A person experiencing psychotic symptoms often has disrupted thoughts and perceptions, and they may have difficulty recognizing what is real and what is not. Psychotic symptoms include:

• Hallucinations : When a person sees, hears, smells, tastes, or feels things that are not actually there. Hearing voices is common for people with schizophrenia. People who hear voices may hear them for a long time before family or friends notice a problem.
• Delusions : When a person has strong beliefs that are not true and may seem irrational to others. For example, individuals experiencing delusions may believe that people on the radio and television are sending special messages that require a certain response, or they may believe that they are in danger or that others are trying to hurt them.
• Thought disorder : When a person has ways of thinking that are unusual or illogical. People with thought disorder may have trouble organizing their thoughts and speech. Sometimes a person will stop talking in the middle of a thought, jump from topic to topic, or make up words that have no meaning.

Negative symptoms include loss of motivation, loss of interest or enjoyment in daily activities, withdrawal from social life, difficulty showing emotions, and difficulty functioning normally.

Negative symptoms include:

• Having trouble planning and sticking with activities, such as grocery shopping
• Having trouble anticipating and being motivated by pleasure in everyday life
• Talking in a dull voice and showing limited facial expression
• Avoiding social interaction or interacting in socially awkward ways
• Having very low energy and spending a lot of time in passive activities. In extreme cases, a person might stop moving or talking for a while, which is a rare condition called catatonia .

These symptoms are sometimes mistaken for symptoms of depression or other mental illnesses.

Cognitive symptoms include problems in attention, concentration, and memory. These symptoms can make it hard to follow a conversation, learn new things, or remember appointments. A person’s level of cognitive functioning is one of the best predictors of their day-to-day functioning. Health care providers evaluate cognitive functioning using specific tests.

Cognitive symptoms include:

• Having trouble processing information to make decisions
• Having trouble using information immediately after learning it
• Having trouble focusing or paying attention

The Centers for Disease Control and Prevention (CDC)  has recognized that having certain mental disorders, including depression and schizophrenia, can make people more likely to get severely ill from COVID-19. Learn more about getting help and finding a health care provider .

Risk of violence

Most people with schizophrenia are not violent. Overall, people with schizophrenia are more likely than those without the illness to be harmed by others. For people with schizophrenia, the risk of self-harm and of violence to others is greatest when the illness is untreated or co-occurs with alcohol or substance misuse. It is important to help people who are showing symptoms to get treatment as quickly as possible.

Schizophrenia vs. dissociative identity disorder

Although some of the signs may seem similar on the surface, schizophrenia is not dissociative identity disorder (which used to be called multiple personality disorder or split personality). People with dissociative identity disorder have two or more distinct identities with distinct behaviors and memories.

What are the risk factors for schizophrenia?

Several factors may contribute to a person’s risk of developing schizophrenia.

Genetics: Schizophrenia sometimes runs in families. However, just because one family member has schizophrenia, it does not mean that other members of the family also will have it. Studies suggest that many different genes may increase a person’s chances of developing schizophrenia , but that no single gene causes the disorder by itself.

Environment: Research suggests that a combination of genetic factors and aspects of a person’s environment and life experiences may play a role in the development of schizophrenia. These environmental factors that may include living in poverty, stressful or dangerous surroundings, and exposure to viruses or nutritional problems before birth.

Brain structure and function: Research shows that people with schizophrenia may be more likely to have differences in the size of certain brain areas and in connections between brain areas. Some of these brain differences may develop before birth. Researchers are working to better understand how brain structure and function may relate to schizophrenia.

How is schizophrenia treated?

Current treatments for schizophrenia focus on helping people manage their symptoms, improve day-to-day functioning, and achieve personal life goals, such as completing education, pursuing a career, and having fulfilling relationships.

Antipsychotic medications

Antipsychotic medications can help make psychotic symptoms less intense and less frequent. These medications are usually taken every day in a pill or liquid forms. Some antipsychotic medications are given as injections once or twice a month.

If a person’s symptoms do not improve with usual antipsychotic medications, they may be prescribed clozapine. People who take clozapine must have regular blood tests to check for a potentially dangerous side effect that occurs in 1-2% of patients.

People respond to antipsychotic medications in different ways. It is important to report any side effects to a health care provider. Many people taking antipsychotic medications experience side effects such as weight gain, dry mouth, restlessness, and drowsiness when they start taking these medications. Some of these side effects may go away over time, while others may last.

Shared decision making  between health care providers and patients is the recommended strategy for determining the best type of medication or medication combination and the right dose. To find the latest information about antipsychotic medications, talk to a health care provider and visit the U.S. Food and Drug Administration (FDA) website  .

Psychosocial treatments

Psychosocial treatments help people find solutions to everyday challenges and manage symptoms while attending school, working, and forming relationships. These treatments are often used together with antipsychotic medication. People who participate in regular psychosocial treatment are less likely to have symptoms reoccur or to be hospitalized.

Examples of this kind of treatment include types of psychotherapy such as cognitive behavioral therapy, behavioral skills training, supported employment, and cognitive remediation interventions.

Education and support

Educational programs can help family and friends learn about symptoms of schizophrenia, treatment options, and strategies for helping loved ones with the illness. These programs can help friends and family manage their distress, boost their own coping skills, and strengthen their ability to provide support. The National Alliance on Mental Illness website has more information about support groups and education   .

Coordinated specialty care

Coordinated specialty care (CSC) programs are recovery-focused programs for people with first episode psychosis, an early stage of schizophrenia. Health care providers and specialists work together as a team to provide CSC, which includes psychotherapy, medication, case management, employment and education support, and family education and support. The treatment team works collaboratively with the individual to make treatment decisions, involving family members as much as possible.

Compared with typical care, CSC is more effective at reducing symptoms, improving quality of life, and increasing involvement in work or school.

Assertive community treatment

Assertive community treatment (ACT)  is designed especially for people with schizophrenia who are likely to experience multiple hospitalizations or homelessness. ACT is usually delivered by a team of health care providers who work together to provide care to patients in the community.

Treatment for drug and alcohol misuse

People with schizophrenia may also have problems with drugs and alcohol. A treatment program that includes treatment for both schizophrenia and substance use is important for recovery because substance use can interfere with treatment for schizophrenia.

How can I find help for schizophrenia?

If you have concerns about your mental health, talk to a primary care provider. They can refer you to a qualified mental health professional, such as a psychologist, psychiatrist, or clinical social worker, who can help you figure out the next steps. Find  tips for talking with a health care provider  about your mental health.

You can  learn more about getting help  on the NIMH website. You can also learn about  finding support    and  locating mental health services   in your area on the Substance Abuse and Mental Health Services Administration (SAMHSA) website.

It can be difficult to know how to help someone who is experiencing psychosis.

Here are some things you can do:

• Help them get treatment and encourage them to stay in treatment.
• Remember that their beliefs or hallucinations seem very real to them.
• Be respectful, supportive, and kind without tolerating dangerous or inappropriate behavior.
• Look for support groups and family education programs, such as those offered by the National Alliance on Mental Illness   .

If you or someone you know is struggling or having thoughts of suicide, call or text the 988 Suicide & Crisis Lifeline   at 988 or chat at 988lifeline.org   . In life-threatening situations, call 911 .

How can I find a clinical trial for schizophrenia?

Clinical trials are research studies that look at new ways to prevent, detect, or treat diseases and conditions. The goal of clinical trials is to determine if a new test or treatment works and is safe. Although individuals may benefit from being part of a clinical trial, participants should be aware that the primary purpose of a clinical trial is to gain new scientific knowledge so that others may be better helped in the future.

Researchers at NIMH and around the country conduct many studies with patients and healthy volunteers. We have new and better treatment options today because of what clinical trials uncovered years ago. Talk to your health care provider about clinical trials, their benefits and risks, and whether one is right for you.

To learn more or find a study, visit:

• NIMH’s Clinical Trials webpage : Information about participating in clinical trials
• Clinicaltrials.gov: Current Studies on Schizophrenia  : List of clinical trials funded by the National Institutes of Health (NIH) being conducted across the country
• Join a Study: Schizophrenia : List of studies being conducted on the NIH Campus in Bethesda, MD

Where can I learn more about schizophrenia?

Free brochures and shareable resources.

• Schizophrenia : This brochure on schizophrenia offers basic information on signs and symptoms, treatment, and finding help. Also available en español .
• Understanding Psychosis : This fact sheet presents information on psychosis, including causes, signs and symptoms, treatment, and resources for help. Also available en español .
• Digital Shareables on Schizophrenia : These digital resources, including graphics and messages, can be used to spread the word about schizophrenia and help promote schizophrenia awareness and education in your community.

Research and statistics

• Accelerating Medicines Partnership® Program - Schizophrenia (AMP® SCZ) : This AMP   public-private collaborative effort aims to promote the development of effective, targeted treatments for those at risk of developing schizophrenia. More information about the program is also available on the AMP SCZ website   .
• Early Psychosis Intervention Network (EPINET) : This broad research initiative aims to develop models for the effective delivery of coordinated specialty care services for early psychosis.
• Journal Articles:   This webpage provides information on references and abstracts from MEDLINE/PubMed (National Library of Medicine).
• Psychotic Disorders Research Program : This program supports research into the origins, onset, course, and outcome of schizophrenia spectrum disorders and other psychotic illnesses.
• Risk and Early Onset of Psychosis Spectrum Disorders Program : This program supports research on childhood and adolescent psychosis and thought disorders.
• Recovery After an Initial Schizophrenia Episode (RAISE) : The NIMH RAISE research initiative included two studies examining different aspects of coordinated specialty care treatments for people who were experiencing early psychosis.
• Statistics: Schizophrenia : This webpage provides the statistics currently available on the prevalence and treatment of schizophrenia among people in the United States.
• NIMH Experts Discuss Schizophrenia : Learn the signs and symptoms, risk factors, treatments of schizophrenia, and the latest NIMH-supported research in this area.

Last Reviewed: April 2024

Unless otherwise specified, the information on our website and in our publications is in the public domain and may be reused or copied without permission. However, you may not reuse or copy images. Please cite the National Institute of Mental Health as the source. Read our copyright policy to learn more about our guidelines for reusing NIMH content.

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Scientists restore brain cells impaired by a rare genetic disorder.

Jon Hamilton

This image shows a brain "assembloid" consisting of two connected brain "organoids." Scientists studying these structures have restored impaired brain cells in Timothy syndrome patients. Pasca lab, Stanford University hide caption

This image shows a brain "assembloid" consisting of two connected brain "organoids." Scientists studying these structures have restored impaired brain cells in Timothy syndrome patients.

Scientists have found a way to restore brain cells impaired by a rare and life-threatening genetic disorder called Timothy syndrome .

A type of drug known as an antisense oligonucleotide allowed clusters of human neurons to develop normally even though they carried the mutation responsible for Timothy syndrome, a team reports in the journal Nature.

The approach may help researchers develop treatments for other genetic conditions, including some that cause schizophrenia, epilepsy, ADHD, and autism spectrum disorder.

Brain cells, interrupted: How some genes may cause autism, epilepsy and schizophrenia

"It's immensely exciting because we now have the tools," says Dr. Sergiu Pasca , a professor of psychiatry and behavioral sciences at Stanford University and the study's senior author.

"It's the beginning of a new era for many of these diseases that we first thought were untreatable," says Dr. Huda Zoghbi , a professor at Baylor College of Medicine who was not involved in the research.

But most of these conditions involve multiple genes, not just one — and scientists don't yet know enough about these multiple gene disorders to effectively treat them with antisense oligonucleotides, Zoghbi says.

Insights from a rare disorder

Timothy Syndrome has been diagnosed in fewer than 100 people worldwide. Children born with it often have heart problems, autism, epilepsy, developmental delay, and intellectual disability.

But because Timothy syndrome is caused by a mutation in a single gene, it offers scientists a way to study changes that affect brain development.

"Rare syndromes that are very clearly defined genetically are sort of like windows, or Rosetta Stones, into understanding other, more common conditions," Pasca says.

So Pasca has spent the past 15 years learning how the mutation responsible for Timothy syndrome alters brain cells.

Goats and Soda

Risk factor for parkinson's discovered in genes from people of african descent.

First, he and his team used skin cells from Timothy syndrome patients to grow neurons in a dish that carried the mutation. Then the team moved on to studying the mutation in brain organoids — living clusters of human neurons that assemble themselves into structures that resemble specific types of brain tissue.

Next, Pasca's team created brain "assembloids," which involve several organoids that form connections and interact, much the way areas of a developing brain do.

And in 2022, the team transplanted human organoids with the Timothy syndrome mutation into the brains of newborn rats. This allowed the human cells to keep developing much longer than they would have in a dish.

Repairing each cell

All of these experiments allowed Pasca's team to acquire a detailed understanding of how Timothy syndrome affects brain cells.

The mutation occurs on a gene called CACNA1C, which is involved in controlling the flow of calcium ions in and out of cells. This "calcium signaling," in turn, controls many of the processes a cell needs to function.

Pasca's lab showed that neurons with the Timothy syndrome mutation stayed abnormally small, and were less able to form connections. Certain mutated neurons also had an impaired ability to migrate from one area of the brain to another during development.

"We've essentially cataloged all these abnormalities," Pasca says. "And at one point, we just gathered enough information about the disease that a therapeutic approach just became self evident."

These identical twins both grew up with autism, but took very different paths

The approach meant developing an antisense nucleotide, a small piece of synthetic genetic material that alters the proteins made by a cell. The antisense nucleotide for Timothy syndrome was designed to replace a defective protein with a healthy version — in effect counteracting the mutation responsible for the disorder.

To see if the antisense drug worked, Pasca's team did an experiment with newborn rats. First, they transplanted brain organoids containing the Timothy syndrome mutation into the cerebral cortex of rats.

As the organoids grew, they began to develop the same defects seen in the brains of people with Timothy.

Then, the team injected the antisense drug into the rats' nervous systems.

"Within a couple of days, you start rescuing or restoring all those defects that we've observed over the years," Pasca says.

Neurons in the organoids became larger and formed more connections. The cells also migrated normally and had electrical activity indicating that the calcium signaling system was working properly.

From rats to people?

Pasca's lab hopes to try the antisense drug in people with Timothy syndrome in the next couple of years.

It is also studying how calcium signaling — the cellular process affected in Timothy syndrome — may play a role in much more common conditions, including schizophrenia, bipolar disorder, and autism spectrum disorder.

Meanwhile, scientists are working on antisense drugs for other rare genetic conditions that affect brain development. These include Angelman syndrome and Dravet syndrome .

An antisense drug for spinal muscular atrophy, a genetic disease that affects muscle strength, was approved by the Food and Drug Administration in 2016.

All of those conditions are caused by mutations to a single gene. Antisense treatments for conditions that involve multiple genes – like most forms of autism, schizophrenia, and epilepsy — are likely to be much harder to develop, Zoghbi says.

Even so, she says, there is now reason to believe that scientists are closing in on strategies to treat these diseases.

In 1985, Zoghbi left her practice as a child neurologist to do research because "we could offer nothing" to patients with devastating genetic disorders like Rett syndrome and spinocerebellar ataxia . "We didn't know what caused the diseases," she says.

Now, scientists know the genetic changes responsible for hundreds of childhood conditions, and they are beginning to develop treatments for some, including Timothy syndrome.

"That's a dream come true for me," Zoghbi says.

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StatPearls [Internet].

Schizophrenia.

Manassa Hany ; Baryiah Rehman ; Yusra Azhar ; Jennifer Chapman .

Affiliations

Last Update: March 20, 2023 .

• Continuing Education Activity

Schizophrenia is a psychotic disorder characterized by hallucinations, delusions, and disturbances in thought, perception, and behavior. Traditionally, schizophrenia may involve positive symptoms, such as hallucinations, delusions, formal thought disorders, and negative symptoms, such as paucity of speech, anhedonia, and lack of motivation. This activity outlines the evaluation of schizophrenia and explains the role of the interprofessional team in improving care for patients with this condition.

• Review the epidemiology of schizophrenia.
• Explain the characteristic features of schizophrenia.
• Review the management of schizophrenia.
• Summarize the importance of improving care coordination among the interprofessional team members to detect the positive and negative symptoms of the condition, which will enhance the delivery of care for those with schizophrenia.
• Introduction

Derived from the Greek 'schizo' (splitting) and 'phren' (mind) with the term first coined by Eugen Bleuler in 1908, schizophrenia is a functional psychotic disorder characterized by the presence of delusional beliefs, hallucinations, and disturbances in thought, perception, and behavior. Traditionally, symptoms have been divided into two main categories: positive symptoms, which include hallucinations, delusions, and formal thought disorders, and negative symptoms such as anhedonia, poverty of speech, and lack of motivation. The diagnosis of schizophrenia is clinical, made exclusively after obtaining a full psychiatric history and excluding other causes of psychosis. Risk factors include birthing complications, the season of birth, severe maternal malnutrition, maternal influenza in pregnancy, family history, childhood trauma, social isolation, cannabis use, minority ethnicity, and urbanization. [1] [2]  Due to its relative complexity and heterogeneity, the etiology and pathophysiological mechanisms are not fully understood. Despite a low prevalence, schizophrenia's global burden of disease is immense. Over half of the patients have significant co-morbidities, both psychiatric and medical, making it one of the leading causes of disability worldwide. [3]  The diagnosis correlates with a 20% reduction in life expectancy, with up to 40% of deaths attributed to suicide. [4]

Several studies postulate that the development of schizophrenia results from abnormalities in multiple neurotransmitters, such as dopaminergic, serotonergic, and alpha-adrenergic hyperactivity or glutaminergic and GABA hypoactivity. Genetics also plays a fundamental role - there is a 46% concordance rate in monozygotic twins and a 40% risk of developing schizophrenia if both parents are affected. The gene neuregulin (NGR1), which is involved in glutamate signaling and brain development, has been implicated, alongside dysbindin (DTNBP1), which helps glutamate release, and catecholamine O-methyl transferase (COMT) polymorphism, which regulates dopamine function.

As aforementioned, there are also several environmental factors associated with an enhanced risk of developing the disease:

• Abnormal fetal development and low birth weight
• Gestational diabetes
• Preeclampsia
• Emergency cesarean section and other birthing complications
• Maternal malnutrition and vitamin D deficiency
• Winter births - associated with a 10% higher relative risk
• Urban residence - increases the risk of developing schizophrenia by 2 to 4%

The incidence is also up to ten times greater in children of African and Caribbean migrants compared to whites, according to a study conducted in Britain. [1]  The association between cannabis use and psychosis has been widely studied, with recent longitudinal studies suggesting a 40% increased risk, while also suggesting a dose-effect relationship between the use of the drug and the risk of developing schizophrenia. [2]

• Epidemiology

Though the prevalence of the disease varies globally, estimates are that schizophrenia affects approximately 1% of adults, whereas prevalence in the United States is 0.6 to 1.9% [5] . Men are slightly more likely to be diagnosed and have an earlier onset than women, while African-Caribbean migrants and their descendants also have a higher incidence. [6]

• Pathophysiology

There are three main hypotheses regarding the development of schizophrenia. The neurochemical abnormality hypothesis argues that an imbalance of dopamine, serotonin, glutamate, and GABA results in the psychiatric manifestations of the disease. It postulates that four main dopaminergic pathways are involved in the development of schizophrenia. This dopamine hypothesis attributes the positive symptoms of the illness to excessive activation of D2 receptors via the mesolimbic pathway, while low levels of dopamine in the nigrostriatal pathway are theorized to cause motor symptoms through their effect on the extrapyramidal system. Low mesocortical dopamine levels resulting from the mesocortical pathway are thought to elicit the negative symptoms of the disease. Other symptoms such as amenorrhea and decreased libido may be caused by elevated prolactin levels due to decreased availability of tuberoinfundibular dopamine as a result of blockage of the tuberoinfundibular pathway. Evidence showing exacerbation of positive and negative symptoms in schizophrenia by NMDA receptor antagonists insinuates the potential role of glutaminergic hypoactivity while serotonergic hyperactivity has also been shown to play a role in schizophrenia development. [5]  

There are also arguments that schizophrenia is a neurodevelopmental disorder based on abnormalities present in the cerebral structure, an absence of gliosis suggesting in utero changes, and the observation that motor and cognitive impairments in patients precede the illness onset.

Conversely, the disconnect hypothesis focuses on the neuroanatomical changes seen in PET and fMRI scans. There is a reduction in grey matter volume in schizophrenia, present not only in the temporal lobe but in the parietal lobes as well. Differences in the frontal lobes and hippocampus are also seen, potentially contributing to a range of cognitive and memory impairments associated with the disease. 

• History and Physical

There are slight variations in the diagnostic criteria of schizophrenia depending on the classification system used.

Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5)  

Two or more of the following symptoms must be present for a significant portion of time during a one-month period:

• Hallucinations
• Disorganized speech
• Grossly disorganized or catatonic behavior
• Negative symptoms. 

There must also be social/occupational dysfunction, while signs of disturbance must persist for at least six months, including at least one month of symptoms.

International Classification of Diseases (ICD-10)

The patient must exhibit at least one of the following, for a period greater than or equal to a month:

• Thought insertion, echo, broadcast, or withdrawal
• Delusions of control, influence, or passivity
• Hallucinatory voices providing a running commentary of the patient
• Persistent delusions that are culturally inappropriate or implausible

Or, at least two of the following symptoms must be observed, for a period greater than or equal to a month [7] :

• Persistent hallucinations in any modality when accompanied by fleeting delusions
• Breaks of interpolations in thought resulting in incoherence or neologisms
• Catatonic behavior
• Negative symptoms
• Significant and consistent transformation in the overall quality of behavior manifesting as anhedonia and social withdrawal

Unlike DSM-5, ICD-10 further subcategories schizophrenia based on the key presenting symptoms as either paranoid schizophrenia, hebephrenic schizophrenia, catatonic schizophrenia, undifferentiated schizophrenia, post-schizophrenic depression, residual schizophrenia, and simple schizophrenia.  

 In addition to asking about these symptoms, it is also important to elicit:

• Past medical history, drug history, and family history
• Social history, including the use of recreational drugs and alcohol
• Any recent neurological impairments such as altered consciousness or memory problems, head injury, stroke, seizures, faints, dizzy spells, visual impairment, marked tremor, or muscle stiffness
• Potential organic causes of psychosis such as Parkinson's disease, multiple sclerosis, syphilis, AIDS, brain lesions, heavy metal toxicity, delirium, metabolic/endocrine disorders, and dementias including Alzheimer's disease, frontotemporal dementia, and Lewy body dementias

A thorough risk assessment must also be undertaken to determine the risk of harm to self and others. The first schizophrenic episode usually occurs during early adulthood or late adolescence. Individuals often lack insight at this stage; therefore, few will present directly to seek help for their psychotic symptoms. Common presentations include a relative noticing social withdrawal, personality changes, or uncharacteristic behavior; deliberate self-harm or suicide attempts; calling the police to report their delusional symptoms, or referral via the criminal justice system. The use of screening tools such as COPS (Criteria of Prodromal Syndromes), SIPS (Structured Interview for Prodromal Syndromes), and PACE (Personal Assessment and Crisis Evaluation Clinic) has been shown to increase the detection rate of schizophrenia in premorbid states although there is controversy surrounding indicating treatment at this stage.

After conducting a full psychiatric history, it is imperative to conduct a thorough systems review and a mental state examination where appearance, behavior, mood, speech, cognition, and insight need to be assessed, alongside determining evidence of perceptual delusions or formal thought disorders. Though schizophrenia is primarily a clinical diagnosis, specific laboratory and radiographic investigations are useful to exclude other potential causes:

• Urea and electrolytes - an electrolyte imbalance can cause delirium
• Serum calcium - hypoparathyroidism or hyperparathyroidism can, on occasion, have psychiatric manifestations
• Blood glucose - hypoglycemia can produce confusion which can be mistaken for psychosis
• Thyroid function tests - depression is associated with hypothyroidism and may present with psychotic features - severe hyperthyroidism also correlates with changes in mental state
• 24-hour cortisol collection - both hypercortisolism (Cushing syndrome) and adrenocortical insufficiency (Addison disease) can present with psychiatric symptoms
• 24 hour catecholamine/5-HIAA collection - in cases of suspected phaeochromocytoma/carcinoid syndrome
• Urinary toxicology screen - detection of recreational drugs such as cannabis
• CT head/MRI - in cases of significant neurological impairment or suspected neurological abnormality
• HIV/syphilis serology - both infections can cause psychiatric symptoms
• Treatment / Management

For the initial treatment of acute psychosis, it is recommended to start an oral second-generation antipsychotic (SGA) such as aripiprazole, olanzapine, risperidone, quetiapine, asenapine, lurasidone, sertindole, ziprasidone, brexpiprazole, molindone, iloperidone, etc. Sometimes, if clinically needed, alongside a benzodiazepine such as diazepam, clonazepam, or lorazepam to control behavioral disturbances and non-acute anxiety. First-generation antipsychotics (FGA) like trifluoperazine, fluphenazine, haloperidol, pimozide, sulpiride, flupentixol, chlorpromazine, etc., are not commonly used as the first line but can be used.

Once the acute phase is controlled, switching to a depot preparation like aripiprazole, paliperidone, zuclopenthixol, fluphenazine, haloperidol, pipotiazine, or risperidone is recommended as it increases medication adherence and compliance, improving outcomes and decreasing relapses.

Cognitive behavioral therapy (CBT) and the use of art and drama therapies help counteract the negative symptoms of the disease, improve insight, and assist relapse prevention.

Clozapine is used in case of treatment resistance - if there has been a poor response to at least two different antipsychotics, and require initial weekly blood tests for six months, biweekly for six months, and then every four weeks to monitor white blood cell count due to the risk of agranulocytosis.

Other options in treatment resistance include combining antipsychotics, adding lamotrigine, mirtazapine, donepezil, D-alanine, D-serine, estradiol, memantine, or allopurinol to an antipsychotic. The role of electroconvulsive therapy (ECT) is limited but has been used.

During the maintenance phase, prophylaxis and rehabilitation back into the community are vital priorities - and establishing the minimum necessary effective dose of antipsychotics should also take place during this period. Post-schizophrenic depression occurs in up to 30% of patients: if a dysphoric mood is evident, consider reducing the antipsychotic dose, treating with antidepressants or anxiolytics, or switching to a second-generation antipsychotic. There is significant substance abuse amongst patients with schizophrenia which can exacerbate both positive and negative symptoms; therefore, psychosocial and pharma therapeutic approaches should be used to treat the misuse. Clozapine may be given in patients with extensive, persisting substance misuse. 

The treatment of those identified as at risk of developing a psychotic disorder is controversial. Treatment of co-existing disorders and with individual CBT and family intervention is advocated, although no long-term evidence exists regarding its efficacy in preventing a psychotic episode or reducing its severity.

• Differential Diagnosis

As psychotic features can manifest in various other mental disorders, there are wide-ranging differentials for schizophrenia, including but not limited to:

• Substance-induced psychotic disorder
• Mood disorders with psychotic features
• Sleep-related disorders
• Delusional disorder
• Paranoid personality disorder
• Schizotypal personality disorder
• Pervasive developmental disorder
• Psychosis secondary to organic causes
• Toxicity and Adverse Effect Management

Antipsychotic side effects subdivide into five categories.

Extrapyramidal

• Tardive dyskinesia: though symptoms are irreversible, vitamin E has been shown to prevent further deterioration
• Parkinsonism: bradykinesia, tremors, and rigidity can occur a week after administration - can be managed via a reduction in dose or the use of an antimuscarinic such as oral benztropine 
• Akathisia: can occur after a month of antipsychotic use and treated using propranolol and benzodiazepines
• Acute dystonia: managed via a parenteral muscarinic such as benztropine administered intravenously or intramuscularly 

Anticholinergic

• Dry mouth; urinary retention; blurred vision; glaucoma; constipation

Anti-adrenergic

• Sexual dysfunction; tachycardia; postural hypotension

Antihistaminic

• Weight gain, sedation; All patients should be advised to increase their physical activity and monitor their dietary intake.

Idiosyncratic

• Altered glucose tolerance, skin photosensitivity, cholestatic jaundice, hypersensitivity reactions, yellow pigmentation of the skin, neuroleptic malignant syndrome; The neuroleptic malignant syndrome may be fatal and is characterized by increasing rigidity, pyrexia, and fluctuating consciousness - the patient should receive immediate medical care.

Recent efficacy studies such as Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and European First-Episode Schizophrenia Trials (EUFEST) found no significant difference between the first-generation antipsychotics such as haloperidol and newer second-generation antipsychotics such as olanzapine and risperidone. [8]  However, SGAs have far fewer extrapyramidal side effects than their FGA counterparts; therefore, they may be preferentially used.

In schizophrenia, the prognosis is dependent on several factors. Insidious onset, childhood or adolescent onset, poor premorbid adjustment, and cognitive impairment are indicative of a poor prognostic outcome, whereas acute onset, female sex, and living in a developed country signal comparatively better prognostic factors. However, suicide is the most common cause of premature death in schizophrenia, with two-thirds of patients reporting at least one episode of suicidal ideation. [9]

• Complications

Treatment-resistant schizophrenia is when the condition fails to respond to at least two antipsychotic medications for at least six weeks; up to 30% of patients with schizophrenia respond poorly to antipsychotics, and around 7% show no response. Clozapine is the therapeutic option in such instances.

• Deterrence and Patient Education

A significant percentage of patients with schizophrenia die from cardiovascular disease. [10] Educating patients on the importance of modifying risk factors such as increasing exercise, healthier diets, and smoking cessation will decrease their risk of cardiovascular problems and reduce the mortality rate. Moreover, cognitive behavioral therapy has been shown to improve patient compliance and decrease future hospital admissions.

• Enhancing Healthcare Team Outcomes

Alongside educating patients about the importance of making healthy lifestyle choices, it is also imperative that the physicians, nurses, and other allied health professionals work together as an interprofessional team in diligently monitoring patients while admitted. Patients on clozapine need to have their WBC measured regularly as they are at risk of agranulocytosis, while a risk assessment should be carried out on all new patients to evaluate their risk of harm to self or others. Outside of the hospital setting, community psychiatric nurses and family physicians can also educate the patient and provide further information while also monitoring for early signs of relapse. 

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Disclosure: Manassa Hany declares no relevant financial relationships with ineligible companies.

Disclosure: Baryiah Rehman declares no relevant financial relationships with ineligible companies.

Disclosure: Yusra Azhar declares no relevant financial relationships with ineligible companies.

Disclosure: Jennifer Chapman declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

• Cite this Page Hany M, Rehman B, Azhar Y, et al. Schizophrenia. [Updated 2023 Mar 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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