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The current construct of schizophrenia as a unitary disease is far from satisfactory, and is in need of reconceptualization. The first five papers in our "facts" series reviewed what is known about schizophrenia to date, and a limited number of key facts appear to stand out. Schizophrenia is characterized by persistent cognitive deficits, positive and negative symptoms typically beginning in youth, substantive heritability, and brain structural, functional and neurochemical alterations including dopaminergic dysregulation. Several pathophysiological models have been proposed with differing interpretations of the illness, like the fabled six blind Indian men groping different parts of an elephant coming up with different conclusions. However, accumulating knowledge is integrating the several extant models of schizophrenia etiopathogenesis into unifying constructs; we discuss an example, involving a neurodevelopmental imbalance in excitatory/inhibitory neural systems leading to impaired neural plasticity. This imbalance, which may be proximal to clinical manifestations, could result from a variety of genetic, epigenetic and environmental causes, as well as pathophysiological processes such as inflammation and oxidative stress. Such efforts to "connect the dots" (and visualizing the elephant) are still limited by the substantial clinical, pathological, and etiological heterogeneity of schizophrenia and its blurred boundaries with several other psychiatric disorders leading to a "fuzzy cluster" of overlapping syndromes, thereby reducing the content, discriminant and predictive validity of a unitary construct of this illness. The way ahead involves several key directions: a) choosing valid phenotype definitions increasingly derived from translational neuroscience; b) addressing clinical heterogeneity by a cross-diagnostic dimensional and a staging approach to psychopathology; c) addressing pathophysiological heterogeneity by elucidating independent families of "extended" intermediate phenotypes and pathophysiological processes (e.g. altered excitatory/inhibitory, salience or executive circuitries, oxidative stress systems) that traverse structural, functional, neurochemical and molecular domains; d) resolving etiologic heterogeneity by mapping genomic and environmental factors and their interactions to syndromal and specific pathophysiological signatures; e) separating causal factors from consequences and compensatory phenomena; and f) formulating or reformulating hypotheses that can be refuted/tested, perhaps in the mouse or other experimental models. These steps will likely lead to the current entity of schizophrenia being usefully deconstructed and reconfigured into phenotypically overlapping, but etiopathologically unique and empirically testable component entities (similar to mental retardation, epilepsy or cancer syndromes). The mouse may be the way to rescue the trapped elephant! [ABSTRACT FROM AUTHOR]

In vivo proton ((1)H) Magnetic Resonance spectroscopy ((1)H MRS) has shown abnormalities in young first-episode patients with schizophrenia. It is unclear whether these abnormalities reflect trait related vs. state related alterations in schizophrenia. We compared young first-degree relatives of schizophrenia patients and healthy controls using (1)H MRS. We hypothesized alterations in the (1)H MRS metabolites N-acetyl aspartate (NAA) and glutamate in corticostriatal and thalamic brain regions. We obtained multi-voxel, short-TE (1)H MRS measurements at 1.5 Tesla in 40 consenting adolescent offspring at risk for schizophrenia (HR), and 48 age matched healthy controls (HC). Absolute levels of NAA, phosphocreatine plus creatine (PCr+Cr), choline-containing compounds (GPC+PC), myo-inositol and glutamate plus glutamine (Glu+Gln) were obtained from the seven different anatomical brain areas (nominal voxel size of 4.5cm(3) each) and corrected for tissue voxel composition. HR subjects showed NAA (p=.0049), PCr+Cr (p=0.028) and GPC+PC (p=0.0086) reductions in the caudate compared with HC subjects. Male HR subjects had significant Glu+Gln reductions compared to male HC subjects (p=.0022). HR subjects had increased NAA in prefrontal white matter. NAA levels in the prefrontal white matter and Glu+Gln levels in the inferior parietal/occipital region were both increased in HR without psychopathology compared with HC subjects. Lower NAA, PCr+Cr and GPC+PC levels may reflect an overall reduction in cellular processes in the caudate of HC subjects, perhaps related to decreases in cell density, or synaptic overpruning. Further studies are needed to examine the pathophysiologic significance of these observations, and their potential predictive value for schizophrenia related psychopathology that may emerge in these at risk relatives during adolescence and early adulthood. [ABSTRACT FROM AUTHOR]

Investigating the neurobiological basis of schizophrenia is a critical step toward establishing its diagnostic validity, predicting outcome, delineating causative mechanisms and identifying objective targets for treatment research. Over the past two decades, there have been several advances in this field, principally related to developments in neuroimaging, electrophysiological and neuropathological approaches. Several neurobiological alterations in domains of brain structure, physiology and neurochemistry have been documented that may reflect diverse pathophysiological pathways from the "genome to the phenome". While none of the observed abnormalities are likely to qualify as diagnostic markers at this time, many can serve as potential intermediate phenotypes for elucidating etiological factors including susceptibility genes, and as therapeutic targets for novel drug discovery. Despite several challenges including the substantial phenotypic, pathophysiologic and etiological heterogeneity of schizophrenia, technological limitations, and the less than ideal animal models, considerable progress has been made in characterizing the neurobiological substrate of schizophrenia. The accumulating fact-base on the neurobiology of schizophrenia calls for novel integrative model(s) that may generate new, testable predictions. [ABSTRACT FROM AUTHOR]

Converging data from multiple lines of research provide growing understanding of the pharmacological basis of the efficacy and tolerability of antipsychotic agents. This review highlights some of the drawbacks of the current practice of classifying antipsychotic agents into first- and second-generation agents, and argues that much of what is known about an antipsychotic agent in terms of its efficacy and tolerability can be predicted from its binding affinity at different receptors. This makes a case for a new system of classification that reflects the receptor binding affinity profiles of individual antipsychotic agents. In its quest to make a compelling case, the review provides detailed explanations for the pharmacological basis of antipsychotic efficacy, antipsychotic-induced weight gain and diabetes mellitus, cognitive effects and other adverse effects. [ABSTRACT FROM AUTHOR]

Although we have studied schizophrenia as a major disease entity over the past century, its causes and pathogenesis remain obscure. In this article, we critically review genetic and other epidemiological findings and discuss the insights they provide into the causes of schizophrenia. The annual incidence of schizophrenia averages 15 per 100,000, the point prevalence averages approximately 4.5 per population of 1000, and the risk of developing the illness over one's lifetime averages 0.7%. Schizophrenia runs in families and there are significant variations in the incidence of schizophrenia, with urbanicity, male gender, and a history of migration being associated with a higher risk for developing the illness. Genetic factors and gene-environment interactions together contribute over 80% of the liability for developing schizophrenia and a number of chromosomal regions and genes have been "linked" to the risk for developing the disease. Despite intensive research and spectacular advances in molecular biology, however, no single gene variation has been consistently associated with a greater likelihood of developing the illness and the precise nature of the genetic contribution remains obscure at this time. Environmental factors linked to a higher likelihood of developing schizophrenia include cannabis use, prenatal infection or malnutrition, perinatal complications, and a history of winter birth; the exact relevance or nature of these contributions is, however, unclear. How various genetic and environmental factors interact to cause schizophrenia and via which precise neurobiological mechanisms they mediate this effect is not understood. Etiological heterogeneity, complex patterns of gene-gene and gene-environment interaction, and inadequately elucidated schizophrenia pathophysiology are among the explanations invoked to explain our inadequate understanding of the etio-pathogenesis of schizophrenia. The ability to question some of our basic assumptions about the etiology and nature of schizophrenia and greater rigor in its study appear critical to improving our understanding about its causation. [ABSTRACT FROM AUTHOR]

For every disorder, there is a set of established findings and accepted constructs upon which further understanding is built. The concept of schizophrenia as a disease entity has been with us for a little more than a century, although descriptions resembling this condition predate this conceptualization. In 1988, for the inaugural issue of Schizophrenia Research, at the invitation of the founding editors, a senior researcher, since deceased (RJ Wyatt) published a summary of generally accepted ideas about the disorder, which he termed "the facts" of schizophrenia. Ten years later, in conjunction with two of the authors (MSK, RT), he compiled a more extensive set of "facts" for the purpose of evaluating conceptual models or theoretical constructs developed to understand the nature of schizophrenia. On the 20th anniversary of this journal, we update and substantially expand our effort to periodically summarize the current body of information about schizophrenia. We compile a body of seventy-seven representative major findings and group them in terms of their specific relevance to schizophrenia -- etiologies, pathophysiology, clinical manifestations, and treatments. We rate each such "fact" on a 0-3 scale for measures of reproducibility, whether primary to schizophrenia, and durability over time. We also pose one or more critical questions with reference to each "fact", answers to which might help better elucidate the meaning of that finding for our understanding of schizophrenia. We intend to follow this paper with the submission to the journal of a series of topic-specific articles, critically reviewing the evidence. [ABSTRACT FROM AUTHOR]

Objectives: The factors that contribute to functional disability in schizophrenia are only partially known and likely consist of an array of biopsychosocial constructs. This research sought to further elucidate the factors that conspire against functional recovery from schizophrenia by introducing the concept of foresight and exploring its unique contribution to functional outcome.Methods: Patients in the early course of schizophrenia or schizoaffective disorder were studied over the course of one year as part of a clinical trial of cognitive enhancement therapy. Fifty-eight patients were assessed by using measures of foresight, functional disability, neurocognitive function, and psychopathology at baseline, and 49 were reassessed on the aforementioned domains at the one-year follow-up.Results: Patients displayed significant deficits in foresightfulness throughout the study period. Cross-sectionally, measures of foresight exhibited significant and moderate to large relationships with measures of functional disability at both baseline and the one-year follow-up. Longitudinal analyses revealed that baseline levels of foresight were significantly predictive of future functional disability, after adjusting for neurocognitive function, psychopathology, and treatment assignment.Conclusions: This exploratory investigation suggests that foresight may be an important determinant of functional disability in schizophrenia. Future research will need to investigate whether impairments within this domain can be remediated to help promote a more functional recovery from the disorder. [ABSTRACT FROM AUTHOR]

The objective of this study was to examine the relationship between thalamic volume and brain size in individuals with Asperger's disorder (ASP). Volumetric measurements of the thalamus were performed on MRI scans obtained from 12 individuals with ASP (age range: 10-35 years) and 12 healthy controls (age range: 9-33 years). A positive correlation was found between total brain volume and thalamic size in controls, but not in ASP subjects. This occurred in the absence of differences in mean thalamic volumes between the study groups. Findings from this investigation point to an abnormal relationship between the thalamus and its projection areas in ASP and are consistent with similar studies in autism, supporting that these disorders are qualitatively similar and possibly quantitatively different. [ABSTRACT FROM AUTHOR]

BACKGROUND: Prefrontal cortical dysfunctions, including disturbances in adaptive context-specific behavior, have been reported in neuropsychological and brain imaging studies of schizophrenia. Some data suggest that treatment with antipsychotic medications may ameliorate these deficits. METHOD: We investigated antisaccade performance in 39 antipsychotic-naive, first-episode schizophrenia patients who were re-evaluated 6 weeks after treatment initiation. A group of matched healthy subjects were examined at similar time-points. Patients and healthy individuals available for longer-term testing were re-assessed 26 and 52 weeks after initial testing. RESULTS: Before treatment, patients showed elevated rates of response suppression errors and prolonged latencies of correct antisaccades. Increased rates of antisaccade errors were associated with faster response latencies during a separate, visually guided saccade task, but only prior to treatment. Throughout the 1-year follow-up, patients progressively improved in their ability to voluntarily suppress context-inappropriate behavior. Although treatment assignment was by clinician choice, results of exploratory analyses revealed that patients treated with risperidone progressively planned and initiated correct antisaccades more quickly than patients receiving haloperidol. CONCLUSIONS: Deficits in the voluntary control of spatial attention are exaggerated during acute episodes of illness, but remain an enduring aspect of prefrontal dysfunction in schizophrenia even after treatment. During acute illness, speeded sensorimotor transformations may compound these deficits and contribute to the heightened distractibility associated with acute psychosis. Continued improvement in task performance throughout the 1-year follow-up suggests that partial normalization of prefrontal cognitive functions resulting from antipsychotic treatment may have a longer and more gradual time course than the reduction of acute psychotic symptoms. [ABSTRACT FROM AUTHOR]

The introduction of second-generation antipsychotics and cognitive therapies for schizophrenia over the past two decades generated considerable optimism about possibilities for recovery. To what extent have these developments resulted in better outcomes for affected individuals? What is the current state of our science and how might we address the many unmet needs in the prevention and treatment of schizophrenia? We trace the evolution of various treatments for schizophrenia and summarize current knowledge about available pharmacological and psychosocial treatments. We consider the widely prevalent efficacy-effectiveness gap in the application of available treatments and note the significant variability in individual treatment response and outcome. We outline an individualized treatment approach which emphasizes careful monitoring and collaborative decision-making in the context of ongoing benefit-risk assessment. We note that the evolution of both pharmacological and psychosocial treatments thus far has been based principally on serendipity and intuition. In view of our improved understanding of the etiology and pathophysiology of schizophrenia, there is an opportunity to develop prevention strategies and treatments based on this enhanced knowledge. In this context, we discuss potential psychopathological treatment targets and enumerate current pharmacological and psychosocial development efforts directed at them. Considering the stages of schizophrenic illness, we review approaches to prevent progression from the pre-symptomatic high-risk to the prodrome to the initial psychotic phase to chronicity. In view of the heterogeneity of risk factors, we summarize approaches towards targeted prevention. We evaluate the potential contribution of pharmacogenomics and other biological markers in optimizing individual treatment and outcome in the future. [ABSTRACT FROM AUTHOR]

Although dementia praecox or schizophrenia has been considered a unique disease entity for the past century, its definitions and boundaries have continued to vary over this period. At any given time, the changing concept of schizophrenia has been influenced by available diagnostic tools and treatments, related conditions from which it most needs to be distinguished, extant knowledge and scientific paradigms. There is significant heterogeneity in the etiopathology, symptomatology, and course of schizophrenia. It is characterized by an admixture of positive, negative, cognitive, mood, and motor symptoms whose severity varies across patients and through the course of the illness. Positive symptoms usually first begin in adolescence or early adulthood, but are often preceded by varying degrees of negative and cognitive symptomatology. Schizophrenia tends to be a chronic and relapsing disorder with generally incomplete remissions, variable degrees of functional impairment and social disability, frequent comorbid substance abuse, and decreased longevity. Although schizophrenia may not represent a single disease with a unitary etiology or pathogenetic process, alternative approaches have thus far been unsuccessful in better defining this syndrome or its component entities. The symptomatologic, course, and etio-pathological heterogeneity can usefully be addressed by a dimensional approach to psychopathology, a clinical staging approach to illness course, and by elucidating endophenotypes and markers of illness progression, respectively. This will allow an approach to the deconstruction of schizophrenia into its multiple component parts and strategies to reconfigure these components in a more meaningful manner. Possible implications for DSM-V and ICD-11 definitions of schizophrenia are discussed. [ABSTRACT FROM AUTHOR]

Objective: Brain-derived neurotrophic factor (BDNF) is a key factor known to mediate neuronal proliferation, differentiation, survival and response to stress. Decreases in BDNF levels have been reported in schizophrenia, but studies in treatment naïve patients are few. Herein we report on serum BDNF levels in a series of patients with first-episode treatment naïve psychoses in comparison to age matched healthy controls.Method: Fasting serum BDNF levels were measured in 41 patients with treatment naive first episode psychosis (24 with schizophrenia, schizoaffective disorder or schizophreniform disorder, and 17 with non-schizophrenia psychotic disorders) and 41 age-matched healthy controls.Results: A three group analyses of covariance (ANCOVA) showed a diagnosis effect (p=.038) in which patients with schizophrenia had lesser serum BDNF levels than patient with non-schizophrenia psychosis, who in turn had lesser BDNF levels than matched healthy controls. Planned two-group ANCOVAs suggested that patients with schizophrenia had lower serum BDNF level than matched controls (p=.016), whereas patients with non-schizophrenia psychosis did not differ from controls. There were no age effects on BDNF, but there was a trend (p=.08) for a gender by group interaction with greater reductions in female patients with schizophrenia. The BDNF levels did not correlate with magnitude of smoking, body mass index, severity of positive and negative symptoms or overall functioning.Conclusions: Serum BDNF may be reduced at the onset of psychosis but its role in the pathogenesis of schizophrenia remains unclear. Elucidating the role of BDNF in schizophrenia and related psychotic disorders may provide an important therapeutic target. Further studies are also needed to examine if patients with schizophrenia have more pronounced reductions in BDNF than those with affective psychosis. [ABSTRACT FROM AUTHOR]

The Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT) is a key measure of social cognition recommended by the MATRICS committee. While the psychometric properties of the MSCEIT appear strong, previous evidence suggested its factor structure may have shifted when applied to schizophrenia patients, posing important implications for cross-group comparisons. Using multi-group confirmatory factor analysis, we explicitly tested the factorial invariance of the MSCEIT across schizophrenia (n=64) and two normative samples (n=2099 and 451). Results indicated that the factor structure of the MSCEIT was significantly different between the schizophrenia and normative samples. Implications for future research are discussed. [ABSTRACT FROM AUTHOR]

Background: Past studies associating personality with psychosis have been limited by small nonclinical samples and a focus on general symptom burden. This study uses a large clinical sample to examine personality's relationship with psychosis-specific features and compare personality dimensions across clinically and neurobiologically defined categories of psychoses., Methods: A total of 1352 participants with schizophrenia, schizoaffective disorder, and bipolar with psychosis, as well as 623 healthy controls (HC), drawn from the Bipolar-Schizophrenia Network for Intermediate Phenotypes (BSNIP-2) study, were included. Three biomarker-derived biotypes were used to separately categorize the probands. Mean personality factors (openness, conscientiousness, extraversion, agreeableness, and neuroticism) were compared between HC and proband subgroups using a generalized linear model. A robust linear regression was utilized to determine personality differences across biotypes and diagnostic subgroups. Associations between personality factors and cognition were determined through Pearson's correlation. A canonical correlation was run between the personality factors and general functioning, positive symptoms, and negative symptoms to delineate the relationship between personality and clinical outcomes of psychosis., Results: There were significant personality differences between the proband and HC groups across all five personality factors. Overall, the probands had higher neuroticism and lower extraversion, agreeableness, conscientiousness, and openness. Openness showed the greatest difference across the diagnostic subgroups and biotypes, and greatest correlation with cognition. Openness, agreeableness, and extraversion had the strongest associations with symptom severity., Conclusions: Individuals with psychotic disorders have different personality traits compared to HC. In particular, openness may be relevant in distinguishing psychosis-specific phenotypes and experiences, and associated with biological underpinnings of psychosis, including cognition. Further studies should identify potential causal factors and mediators of this relationship., Competing Interests: Declaration of competing interest There are no conflicts of interest to declare., (Copyright © 2025. Published by Elsevier B.V.)

The Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) created psychosis Biotypes based on neurobiological measurements in a multi-ancestry sample. These Biotypes cut across DSM diagnoses of schizophrenia, schizoaffective disorder, and bipolar disorder with psychosis. Two recently developed post hoc ancestry adjustment methods of Polygenic Risk Scores (PRSs) generate Ancestry-Adjusted PRSs (AAPRSs), which allow for PRS analysis of multi-ancestry samples. Applied to schizophrenia PRS, we found the Khera AAPRS method to show superior portability and comparable prediction accuracy as compared with the Ge method. The three Biotypes of psychosis disorders had similar AAPRSs across ancestries. In genomic analysis of Biotypes, 12 genes, and isoforms showed significant genomic associations with specific Biotypes in a Transcriptome-Wide Association Study (TWAS) of genetically regulated expression (GReX) in the adult brain and fetal brain. TWAS inflation was addressed by the inclusion of genotype principal components in the association analyses. Seven of these 12 genes/isoforms satisfied Mendelian Randomization (MR) criteria for putative causality, including four genes TMEM140, ARTN, C1orf115, CYREN, and three transcripts ENSG00000272941, ENSG00000257176, ENSG00000287733. These genes are enriched in the biological pathways of Rearranged during Transfection (RET) signaling, Neural Cell Adhesion Molecule 1 (NCAM1) interactions, and NCAM signaling for neurite out-growth. The specific associations with Biotypes suggest that pharmacological clinical trials and biological investigations might benefit from analyzing Biotypes separately., Competing Interests: Competing interests: CX: None. NA-R: None. CAT: B-SNIP Diagnostics, Board of Managers; Kynexis, Scientific Advisory Board and retainer; Merck DSMB; Neuventis, Board, own stock. MSK: B-SNIP Diagnostics, Board of Managers; Advisor to Alkermes. GDP: B-SNIP Diagnostics, Board of Managers. SKK: B-SNIP Diagnostics, Board of Managers. BC: B-SNIP Diagnostics, Board of Managers; Kynexis Corporation, Scientific Advisory Board. JEM: B-SNIP Diagnostics, Board of Managers. DP: None. RL: None. SKH: None. JRB: None. EII: B-SNIP Diagnostics, Board of Managers. CW: None. RD: None. CC: None. CL: None. ESG: B-SNIP Diagnostics, Board of Managers; Consultant: Kynexis Corporation. Ethics approval and consent to participate: All methods were performed in accordance with the relevant guidelines and regulations. B-SNIP recruitment sites were in Athens GA (the University of Georgia and Augusta University Medical College of Georgia), Baltimore MD (Maryland Psychiatric Research Center), Boston MA (Beth Israel Deaconess Medical Center), Chicago IL (the University of Illinois-Chicago and University of Chicago), Dallas TX (UT Southwestern Medical Center), Detroit MI (Wayne State University), and Hartford CT (Institute of Living). All recruitments, interviews, and laboratory data collections were completed at those locations. The Institutional Review Board at participating institutions approved the projects; all participants provided informed consent prior to involvement., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

We investigated the impact of COVID-19 restrictions on the duration of untreated psychosis (DUP). First-episode psychosis admissions ( n = 101) to the STEP Clinic in Connecticut showed DUP reduction ( P = 0.0015) during the pandemic, with the median reducing from 208 days pre-pandemic to 56 days in the early pandemic period, and subsequently increasing to 154 days ( P = 0.0281). Time from psychosis onset to antipsychotic prescription decreased significantly in the pandemic ( P = 0.0183), with the median falling from 117 to 35 days. This cohort study demonstrates an association between greater pandemic restrictions and marked DUP reduction, and provides insights for future early detection efforts.

Schizophrenia is a complex, heritable brain disorder characterized by psychotic, negative, cognitive, mood, and motor symptoms. This pictorial review explores the multifaceted nature of schizophrenia, from its etiology to prevention strategies. We discuss the interplay of genetic and environmental risk factors, neurobiological underpinnings, and stepwise progression. Recent advances in understanding circuit-level pathophysiology and neurotransmitter systems beyond dopamine are highlighted along with neuropathological findings, particularly the exaggerated synaptic pruning hypothesis. Based on these developments, we present an updated perspective on pharmacological interventions. Finally, we outline preventative strategies across different stages, emphasizing early intervention. This overview, designed as a teaching resource, aims to provide trainees, clinicians and researchers with a current understanding of schizophrenia's neurobiological underpinnings and the implications of such understanding to the evolving landscape of its diagnosis and management., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024. Published by Elsevier B.V.)

Competing Interests: Declaration of competing interest The authors declare no competing financial interests, disclosures, or grant support related to the work presented in this paper.

The tripartite classification of mental faculties into cognition, affect, and conation (motivation and action) continues to be the edifice on which the mind and the methods to address mental afflictions are studied. Eastern spiritual traditions offer insights into mental health as it pertains to each of these domains. Following up on our previous paper on the cognition path to psychotherapy (Knowing oneself, or Jnana Yoga), we herein focus on the path of selfless action (Karma Yoga). We review eastern concepts on the nature of karma and the approaches to optimal action (the will to do things, doing the right things, and doing them well). We then place these eastern insights in the context of emerging concepts in psychology on motivation and action. Current psychological concepts such as autonomy and intrinsic motivation, mastery, flow and growth mindset, higher purpose and value driven self-less action, equanimity and balance are convergent with ancient eastern concepts. We also review current neuroscientific underpinnings (such as neural circuitries, neurotransmitter systems and epigenetics and how these facilitate neural plasticity) relevant to karma, including free will, focused action, prosocial behaviors, extrinsic and intrinsic and motivation. These concepts have significant implications for psychotherapeutic models, especially in the areas of positive psychology and preventive psychiatry., Competing Interests: Declaration of Competing Interest Authors declare that there is no conflict of interest in submitting this manuscript to Asian Journal of Psyhciatry, (Copyright © 2024 Elsevier B.V. All rights reserved.)

The Clinical High Risk (CHR) stage of psychosis is characterized by subthreshold symptoms of schizophrenia including negative symptoms, dysphoric mood, and functional deterioration. Hyperconnectivity of the default-mode network (DMN) has been observed in early schizophrenia, but the extent to which hyperconnectivity is present in CHR, and the extent to which such hyperconnectivity may underlie transdiagnostic symptoms, is not clear. As part of the Shanghai At-Risk for Psychosis (SHARP) program, resting-state fMRI data were collected from 251 young adults (158 CHR and 93 controls, M = 18.72, SD = 4.68, 129 male). We examined functional connectivity of the DMN by performing a whole-brain seed-to-voxel analysis with the MPFC as the seed. Symptom severity across a number of dimensions, including negative symptoms, positive symptoms, and affective symptoms were assessed. Compared to controls, CHRs exhibited significantly greater functional connectivity (p < 0.001 uncorrected) between the MPFC and 1) other DMN nodes including the posterior cingulate cortex (PCC), and 2) auditory cortices (superior and middle temporal gyri, STG/MTG). Furthermore, these two patterns of hyperconnectivity were differentially associated with distinct symptom clusters. Within CHR, MPFC-PCC connectivity was significantly correlated with anxiety (r= 0.23, p=0.006), while MPFC-STG/MTG connectivity was significantly correlated with negative symptom severity (r=0.26, p=0.001). Secondary analyses using item-level symptom scores confirmed a similar dissociation. These results demonstrate that two dissociable patterns of DMN hyperconnectivity found in the CHR stage may underlie distinct dimensions of symptomatology., Competing Interests: Conflict of Interest Disclosures: The authors declare that they have no conflicts of interest.

Aims: For over 30 years, combined research and treatment settings in the US have been critical to conceptualizing care for first-episode psychosis (FEP). Here we describe an early example of such a context, the Services for the Treatment of Early Psychosis (STEP) clinic, which is affiliated with the University of Pittsburgh., Methods: We describe STEP's historical roots and establishment in the early 1990s; STEP's research and treatment contributions, alongside its growth and ongoing leadership., Results: Research-based clinics, like STEP, preceded and helped pave the way for the Recovery After an Initial Schizophrenia Episode project in the US and the ensuing Coordinated Specialty Care (CSC) approach, now widely adopted in the US. Early clinic-based research at STEP helped establish protocols for psychopharmacology, the relevance of effective early treatment, including psychosocial approaches, and highlighted disparities in treatment outcomes across race/ethnicity. Multidisciplinary collaboration and dialogue with consumers contributed to early treatment, combining psychosocial and pharmacological approaches. STEP adopted CSC and is situated within a bi-state Learning Health System. STEP has retained a relatively unique 5-year treatment model and exists within continuum of care ideally suited to studying psychotic illness and treatment outcomes., Conclusions: STEP remains the largest academic FEP clinic in Pennsylvania. Academic FEP clinics like STEP will have a critical role within Learning Health Systems nationally to model participatory approaches, sustain early intervention treatment quality and ongoing treatment developments., (© 2024 The Authors. Early Intervention in Psychiatry published by John Wiley & Sons Australia, Ltd.)

Background: Identifying stable and consistent resting-state functional connectivity patterns across illness trajectories has the potential to be considered fundamental to the pathophysiology of schizophrenia. We aimed to identify consistent resting-state functional connectivity patterns across heterogeneous schizophrenia groups defined based on treatment response., Methods: In phase 1, we used a cross-sectional case-control design to characterize and compare stable independent component networks from resting-state functional magnetic resonance imaging scans of antipsychotic-naïve participants with first-episode schizophrenia (n = 54) and healthy participants (n = 43); we also examined associations with symptoms, cognition, and disability. In phase 2, we examined the stability (and replicability) of our phase 1 results in 4 groups (N = 105) representing a cross-sequential gradation of schizophrenia based on treatment response: risperidone responders, clozapine responders, clozapine nonresponders, and clozapine nonresponders following electroconvulsive therapy. Hypothesis-free whole-brain within- and between-network connectivity were examined., Results: Phase 1 identified posterior and anterior cerebellar hypoconnectivity and limbic hyperconnectivity in schizophrenia at a familywise error rate-corrected cluster significance threshold of p < .01. These network aberrations had unique associations with positive symptoms, cognition, and disability. During phase 2, we replicated the phase 1 results while comparing each of the 4 schizophrenia groups to the healthy participants. The participants in 2 longitudinal subdatasets did not demonstrate a significant change in these network aberrations following risperidone or electroconvulsive therapy. Posterior cerebellar hypoconnectivity (with thalamus and cingulate) emerged as the most consistent finding; it was replicated across different stages of treatment response (Cohen's d range -0.95 to -1.44), reproduced using different preprocessing techniques, and not confounded by educational attainment., Conclusions: Posterior cerebellar-thalamo-cingulate hypoconnectivity is a consistent and stable state-independent neural marker of schizophrenia., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The profiles of cortical gyrification across schizophrenia, bipolar I disorder, and schizoaffective disorder have been studied to a limited extent, report discordant findings, and are rarely compared in the same study. Here we assess gyrification in a large dataset of psychotic disorder probands, categorized according to the DSM-IV. Furthermore, we explore gyrification changes with age across healthy controls and probands., Methods: Participants were recruited within the Bipolar-Schizophrenia Network of Intermediate Phenotypes study and received T1-MPRAGE and clinical assessment. Gyrification was measured using FreeSurfer 7.1.0. Pairwise t-tests were conducted in R, and age-related gyrification changes were analyzed in MATLAB. P values <0.05 after false discovery rate correction were considered significant., Results: Significant hypogyria in schizophrenia, bipolar disorder, and schizoaffective disorder probands compared to controls was found, with a significant difference bilaterally in the frontal lobe between schizophrenia and bipolar disorder probands. Verbal memory was associated with gyrification in the right frontal and right cingulate cortex in schizophrenia. Age-fitted gyrification curves differed significantly among psychotic disorders and controls., Conclusions: Findings indicate hypogyria in DSM-IV psychotic disorders compared to controls and suggest differential patterns of gyrification across the different diagnoses. The study extends age related models of gyrification to psychotic disorder probands and supports that age-related differences in gyrification may differ across diagnoses. Fitted gyrification curves among probands categorized by DSM-IV significantly deviate from controls, with the model capturing early hypergyria and later hypogyria in schizophrenia compared to controls; this suggests unique disease and age-related changes in gyrification across psychotic disorders., Competing Interests: Declaration of competing interest The authors Rychagov, Zeng, Oykhman, Dr. del Re, Dr. Yassin, Dr. Lizano, Dr. Sweeny, Dr. Gershon, Dr. Pearlson, Dr. McDowell, and Dr. Clementz reported no potential conflicts of interest. Dr. Keshavan reports serving as an advisor to Alkermes, Takeda, and Vanna Inc. Dr. Tamminga reports the following financial disclosures: American Psychiatric Association – Deputy Editor; Astellas – Ad Hoc Consultant; Autifony – Ad Hoc Consultant; The Brain and Behavior Foundation – Council Member; Eli Lilly Pharmaceuticals – Ad Hoc Consultant; Intra-cellular Therapies (ITI, Inc.) – Advisory Board, drug development; Institute of Medicine – Council Member; National Academy of Medicine – Council Member; Pfizer – Ad Hoc Consultant; Sunovion – Investigator Initiated grant funding., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Schizophrenia spectrum disorders (SSDs) are characterized by substantial clinical and genetic heterogeneity. Multiple recurrent copy number variants (CNVs) increase risk for SSDs; however, how known risk CNVs and broader genome-wide CNVs influence clinical variability is unclear. The current study examined associations between borderline intellectual functioning or childhood-onset psychosis, known risk CNVs, and burden of deletions affecting genes in 18 previously validated neurodevelopmental gene-sets in 618 SSD individuals. CNV associations were assessed for replication in 235 SSD relatives and 583 controls, and 9,930 youth from the Adolescent Brain Cognitive Development (ABCD) Study. Known SSD- and neurodevelopmental disorder (NDD)-risk CNVs were associated with borderline intellectual functioning in SSD cases (odds ratios (OR) = 7.09 and 4.57, respectively); NDD-risk deletions were nominally associated with childhood-onset psychosis (OR = 4.34). Furthermore, deletion of genes involved in regulating gene expression during fetal brain development was associated with borderline intellectual functioning across SSD cases and non-cases (OR = 2.58), with partial replication in the ABCD cohort. Exploratory analyses of cortical morphology showed associations between fetal gene regulatory gene deletions and altered gray matter volume and cortical thickness across cohorts. Results highlight contributions of known risk CNVs to phenotypic variability in SSD and the utility of a neurodevelopmental framework for identifying mechanisms that influence phenotypic variability in SSDs, as well as the broader population, with implications for personalized medicine approaches to care.

Sleep is a vital restorative process that has occupied our curiosity for millennia. Despite our longstanding research efforts, the biology of sleep and its connection to mental states remains enigmatic. Unsurprisingly, sleep and wakefulness, the fundamental processes between which our mental states oscillate, are inseparable from our physical and mental health. Thus, clinical consideration of sleep impairments warrants a transdiagnostic approach whilst appropriately acknowledging that certain individual disorders (e.g. depression, schizophrenia) may have somewhat distinct sleep disturbances. Moreover, our knowledge of the anatomy and physiology of sleep regulation-albeit limited-forms the foundation for current treatments for sleep difficulties. This pictorial article overviews the core concepts and future of sleep neuroscience and mental state biology for trainees and practitioners in psychiatry and related professions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The time following a recent onset of psychosis is a critical period during which intervention may be maximally effective. Studying individuals in this period also offers an opportunity to investigate putative brain biomarkers of illness prior to the long-term effects of chronicity and medication. The Human Connectome Project for Early Psychosis (HCP-EP) was funded by the National Institutes of Mental Health (NIMH) as an extension of the original Human Connectome Project's approach to understanding the human brain and its structural and functional connections., Design: The HCP-EP data were collected at 3 sites in Massachusetts (Beth Israel Deaconess Medical Center, McLean Hospital, and Massachusetts General Hospital), and one site in Indiana (Indiana University). Brigham and Women's Hospital served as the data coordination center and as an imaging site., Results: The HCP-EP dataset includes high-quality clinical, cognitive, functional, neuroimaging, and blood specimen data acquired from 303 individuals between the ages of 16-35 years old with affective psychosis (n = 75), non-affective psychosis (n = 148), and healthy controls (n = 80). Participants with early psychosis were within 5 years of illness onset (mean duration = 1.9 years, standard deviation = 1.4 years). All data and novel or modified analytic tools developed as part of the study are publicly available to the research community through the NIMH Data Archive (NDA) or GitHub (https://github.com/pnlbwh)., Conclusions: This paper provides an overview of the specific HCP-EP procedures, assessments, and protocols, as well as a brief characterization of the study participants to make it easier for researchers to use this rich dataset. Although we focus here on discussing and comparing affective and non-affective psychosis groups, the HCP-EP dataset also provides sufficient information for investigators to group participants differently., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Past research has found that family involvement in psychosis treatment leads to better patient outcomes. Thus, caregiver communication skills training can be a viable approach to reducing caregiver stress and increasing self-efficacy and communication., Aim: The purpose of this qualitative study was to describe family caregivers' perceptions of changes in themselves and their family member with psychosis following their participation in Motivational Interviewing in Loved Ones (MILO), a brief four to five-hour psychoeducational intervention for caregivers., Methods: Sixty-three participants in the MILO trials provided written qualitative responses to the prompt, "Since learning the ideas and techniques in this course, what is the most significant change you noticed in yourself, your family, or your relationships?" Responses were collected immediately following MILO participation and 12 weeks later. Qualitative themes were identified through an iterative consensus process., Results: Most participants reported positive changes in multiple domains of their lives. Major themes included: (1) Changes in Self, (2) Changes in Relationships, (3) Changes in Mindset, (4) Use of MILO Skills, and (5) Challenges., Conclusion: Qualitative results support and add context to the previously reported quantitative results from this study. MILO is a promising family intervention that positively influenced family environment and communication in pilot trials. Adaptations of MILO for families outside of a highly educated North American context should be considered., (© 2024 John Wiley & Sons Australia, Ltd.)

Smooth pursuit eye movements are considered a well-established and quantifiable biomarker of sensorimotor function in psychosis research. Identifying psychotic syndromes on an individual level based on neurobiological markers is limited by heterogeneity and requires comprehensive external validation to avoid overestimation of prediction models. Here, we studied quantifiable sensorimotor measures derived from smooth pursuit eye movements in a large sample of psychosis probands (N = 674) and healthy controls (N = 305) using multivariate pattern analysis. Balanced accuracies of 64% for the prediction of psychosis status are in line with recent results from other large heterogenous psychiatric samples. They are confirmed by external validation in independent large samples including probands with (1) psychosis (N = 727) versus healthy controls (N = 292), (2) psychotic (N = 49) and non-psychotic bipolar disorder (N = 36), and (3) non-psychotic affective disorders (N = 119) and psychosis (N = 51) yielding accuracies of 65%, 66% and 58%, respectively, albeit slightly different psychosis syndromes. Our findings make a significant contribution to the identification of biologically defined profiles of heterogeneous psychosis syndromes on an individual level underlining the impact of sensorimotor dysfunction in psychosis., (© 2024. The Author(s).)

Background: Past studies associating personality with psychosis have been limited by small nonclinical samples and a focus on general symptom burden. This study uses a large clinical sample to examine personality's relationship with psychosis-specific features and compare personality dimensions across clinically and neurobiologically defined categories of psychoses., Methods: A total of 1352 participants with schizophrenia, schizoaffective disorder, and bipolar with psychosis, as well as 623 healthy controls (HC), drawn from the Bipolar-Schizophrenia Network for Intermediate Phenotypes (BSNIP-2) study, were included. Three biomarker-derived biotypes were used to separately categorize the probands. Mean personality factors (openness, conscientiousness, extraversion, agreeableness, and neuroticism) were compared between HC and proband subgroups using independent sample t-tests. A robust linear regression was utilized to determine personality differences across biotypes and diagnostic subgroups. Associations between personality factors and cognition were determined through Pearson's correlation. A canonical correlation was run between the personality factors and general functioning, positive symptoms, and negative symptoms to delineate the relationship between personality and clinical outcomes of psychosis., Results: There were significant personality differences between the proband and HC groups across all five personality factors. Overall, the probands had higher neuroticism and lower extraversion, agreeableness, conscientiousness, and openness. Openness showed the greatest difference across the diagnostic subgroups and biotypes, and greatest correlation with cognition. Openness, agreeableness, and extraversion had the strongest associations with symptom severity., Conclusions: Individuals with psychosis have different personality profiles compared to HC. In particular, openness may be relevant in distinguishing psychosis-specific phenotypes and experiences, and associated with biological underpinnings of psychosis, including cognition. Further studies should identify potential causal factors and mediators of this relationship.