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Large-scale genome-wide association studies of schizophrenia have uncovered hundreds of associated loci but with extremely limited representation of African diaspora populations. We surveyed electronic health records of 200,000 individuals of African ancestry in the Million Veteran and All of Us Research Programs, and, coupled with genotype-level data from four case-control studies, realized a combined sample size of 13,012 affected and 54,266 unaffected persons. Three genome-wide significant signals - near PLXNA4 , PMAIP1 , and TRPA1 - are the first to be independently identified in populations of predominantly African ancestry. Joint analyses of African, European, and East Asian ancestries across 86,981 cases and 303,771 controls, yielded 376 distinct autosomal loci, which were refined to 708 putatively causal variants via multi-ancestry fine-mapping. Utilizing single-cell functional genomic data from human brain tissue and two complementary approaches, transcriptome-wide association studies and enhancer-promoter contact mapping, we identified a consensus set of 94 genes across ancestries and pinpointed the specific cell types in which they act. We identified reproducible associations of schizophrenia polygenic risk scores with schizophrenia diagnoses and a range of other mental and physical health problems. Our study addresses a longstanding gap in the generalizability of research findings for schizophrenia across ancestral populations, underlining shared biological underpinnings of schizophrenia across global populations in the presence of broadly divergent risk allele frequencies.

Persons diagnosed with schizophrenia (SCZ) or bipolar I disorder (BPI) are at high risk for self-injurious behavior, suicidal ideation, and suicidal behaviors (SB). Characterizing associations between diagnosed health problems, prior pharmacological treatments, and polygenic scores (PGS) has potential to inform risk stratification. We examined self-reported SB and ideation using the Columbia Suicide Severity Rating Scale (C-SSRS) among 3,942 SCZ and 5,414 BPI patients receiving care within the Veterans Health Administration (VHA). These cross-sectional data were integrated with electronic health records (EHRs), and compared across lifetime diagnoses, treatment histories, follow-up screenings, and mortality data. PGS were constructed using available genomic data for related traits. Genome-wide association studies were performed to identify and prioritize specific loci. Only 20% of the veterans who reported SB had a corroborating ICD-9/10 EHR code. Among those without prior SB, more than 20% reported new-onset SB at follow-up. SB were associated with a range of additional clinical diagnoses, and with treatment with specific classes of psychotropic medications (e.g., antidepressants, antipsychotics, etc.). PGS for externalizing behaviors, smoking initiation, suicide attempt, and major depressive disorder were associated with SB. The GWAS for SB yielded no significant loci. Among individuals with a diagnosed mental illness, self-reported SB were strongly associated with clinical variables across several EHR domains. Analyses point to sequelae of substance-related and psychiatric comorbidities as strong correlates of prior and subsequent SB. Nonetheless, past SB was frequently not documented in health records, underscoring the value of regular screening with direct, in-person assessments, especially among high-risk individuals., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Purpose of Review: To provide a summary of the most up-to-date thoughts about treatment for schizophrenia at different stages of illness., Recent Findings: The use of Coordinated Specialty Care clinics has arisen as the standard for early on in the treatment of psychosis, providing the notion that recovery is possible. New medications that do not depend on postsynaptic dopamine receptor blockade are soon becoming available., Summary: A focus should be made by clinicians to personalize treatment plans for each patient who has the possibility of being diagnosed with a primary psychosis and the plan should be to predict outcomes based on biological markers that include genetic vulnerability, early psychosocial combined with pharmacological treatments as needed and then a plan to determine or maintain treatments going forward into the future. It is important to individualize treatment by stage of illness, as well as characteristics of the individual patient. Research is ongoing to advance knowledge for interventions at each stage from the premorbid period through to chronicity., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Tobacco use has been established as a possible risk factor for psychosis, but the effect of electronic nicotine delivery systems (ex. nicotine vapes) has not been independently established. Using the Population Assessment of Tobacco and Health study, we found that use of electronic nicotine products was significantly associated with later first episode psychosis after controlling for substance use and other confounders, and that this relationship was only significant among the heaviest users (>20 puffs/day). Given the rapid rise in electronic nicotine products use, clinicians and public health professionals should consider potential impacts and closely monitor trends in the coming years., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background/Objective. Enlarged lateral ventricle (LV) volume and decreased volume in the corpus callosum (CC) are hallmarks of schizophrenia (SZ). We previously showed an inverse correlation between LV and CC volumes in SZ, with global functioning decreasing with increased LV volume. This study investigates the relationship between LV volume, CC abnormalities, and the microRNA MIR137 and its regulated genes in SZ, because of MIR137's essential role in neurodevelopment. Methods . Participants were 1224 SZ probands and 1466 unaffected controls from the GENUS Consortium. Brain MRI scans, genotype, and clinical data were harmonized across cohorts and employed in the analyses. Results. Increased LV volumes and decreased CC central, mid-anterior, and mid-posterior volumes were observed in SZ probands. The MIR137-regulated ephrin pathway was significantly associated with CC:LV ratio, explaining a significant proportion (3.42 %) of CC:LV variance, and more than for LV and CC separately. Other pathways explained variance in either CC or LV, but not both. CC:LV ratio was also positively correlated with Global Assessment of Functioning, supporting previous subsample findings. SNP-based heritability estimates were higher for CC central:LV ratio (0.79) compared to CC or LV separately. Discussion. Our results indicate that the CC:LV ratio is highly heritable, influenced in part by variation in the MIR137-regulated ephrin pathway. Findings suggest that the CC:LV ratio may be a risk indicator in SZ that correlates with global functioning., Competing Interests: 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 paper. The author is an Editorial Board Member/Editor-in-Chief/Associate Editor/Guest Editor for International Journal of Clinical and Health Psychology and was not involved in the editorial review or the decision to publish this article., (© 2024 The Author(s).)

Objective: This study aimed to identify risk factors for relapse (psychiatric emergency department visits or hospitalization) and lack of follow-up with outpatient psychiatric care in the 12 months after ending services in an urban safety net coordinated specialty care (CSC) program for first episode psychosis (FEP)., Methods: The study population (n = 143) were individuals with FEP who had any CSC care between 2014 and 2021. To identify risk factors for relapse and follow up after exit, multivariable logistic regression was performed using data from electronic health records and linked insurance claims data., Results: Individuals with any emergency department visit or hospitalization 12 months prior to ending CSC (aOR = 4.69, 95 % CI 1.78-12.34) and those who were using cannabis at last CSC contact (aOR = 4.06, 95 % CI 1.56-10.56) had a higher risk of relapse after ending CSC services. Cannabis use at last contact was also associated with lower rates of outpatient psychiatric follow-up (aOR = 0.32, 95 % CI 0.12-0.94), while CSC duration in months had a small positive association with post-CSC psychiatric follow-up. There were no differences in relapse or follow-up by race or ethnicity, primary diagnosis, or medication usage., Conclusions: Prior relapse during CSC predicted relapse in the 12 months after ending CSC services, but not outpatient follow up. Cannabis use predicted both a higher rate of relapse and a lower rate of follow up after ending services. There were no differences by race or ethnicity in our sample, suggesting that once individuals engaged in FEP care there were no evident disparities in the observed outcomes., Competing Interests: Declaration of competing interest The authors have no relevant conflicts of interest to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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

Treatment-resistant symptoms occur in about a third of patients with schizophrenia and are associated with a substantial reduction in their quality of life. The development of new treatment options for clozapine-resistant schizophrenia constitutes a crucial, unmet need in psychiatry. Additionally, an overview of past and possible future research avenues to optimise the early detection, diagnosis, and management of clozapine-resistant schizophrenia is unavailable. In this Health Policy, we discuss the ongoing challenges associated with clozapine-resistant schizophrenia faced by patients and health-care providers worldwide to improve the understanding of this condition. We then revisit several clozapine guidelines, the diagnostic tests and treatment options for clozapine-resistant schizophrenia, and currently applied research approaches in clozapine-resistant schizophrenia. We also suggest methodologies and targets for future research, divided into innovative nosology-oriented field trials (eg, examining dimensional symptom staging), translational approaches (eg, genetics), epidemiological research (eg, real-world studies), and interventional studies (eg, non-traditional trial designs incorporating lived experiences and caregivers' perspectives). Finally, we note that low-income and middle-income countries are under-represented in studies on clozapine-resistant schizophrenia and propose an agenda to guide multinational research on the cause and treatment of clozapine-resistant schizophrenia. We hope that this research agenda will empower better global representation of patients living with clozapine-resistant schizophrenia and ultimately improve their functional outcomes and quality of life., Competing Interests: Declaration of interests JL has received honoraria from Otsuka, Janssen, Lundbeck, and Sumitomo Pharmaceuticals. CUC has been a consultant or advisor to, or has received honoraria from AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Boehringer Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Darnitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen (Johnson & Johnson), Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Newron, Noven, Otsuka, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris. He has provided expert testimony for Janssen and Otsuka. He has served on a data safety monitoring board for Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva. He has received grant support from Janssen and Takeda. He has received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma, and Quantic. ROC has received research funding (awarded to his institution) from Roche and Alkermes, is a consultant to Saladax Biomedical, and is a speaker for Clinical Care Options. ST has received speaker honoraria from Otsuka, Mochida, Takeda, Meiji, Eisai, Sumitomo, Viatris, and Teijin. JT has participated in research projects funded by grants from Janssen-Cilag and Eli Lilly awarded to his institution. He also reports personal fees from Eli Lilly, Evidera, Janssen-Cilag, Lundbeck, Mediuutiset, Otsuka, Sidera, and Suvovion; and he is a consultant to HLS Therapeutics, Orion, and WebMed Global. AH is co-editor of the German Association for Psychiatry, Psychotherapy and Psychosomatics schizophrenia treatment guidelines and first author of the World Federation of Societies of Biological Psychiatry schizophrenia treatment guidelines. He has been on the advisory boards and has received speaker fees from Janssen, Lundbeck, and Otsuka. EW has been on the advisory boards of Recordati. JMG-D is funded by a grant from Ministerio de Ciencia y Tecnología (Colombia), and has been a consultant for, received honoraria from, or been on the speakers or advisory boards of Janssen, Eurofarma, Servier, Sanofi, Lilly, and Pfizer. DSh is an expert advisor to the National Institute for Health and Care Excellence (NICE) centre for guidelines; the views expressed in this Health Policy are the authors' and not those of NICE. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The Long COVID syndrome has now been documented clearly in the literature, but whether or not psychiatric symptoms are prominent is unclear. We performed a retrospective chart review of all patients receiving medical care during the pandemic in an outpatient Long-COVID specialty clinic that serves a large racial and ethnic minority population. As many as 44% of patients had symptoms that necessitated referrals to psychiatrists, predominantly depression or anxiety. Spanish speaking patients had greater COVID severity (48%) than did predominantly English speakers (15%). We conclude that the long COVID syndrome is predominantly a cluster of physical symptoms that are sequelae of the viral infection., (Copyright © 2023. Published by Elsevier B.V.)

Research on schizophrenia has been pursued for over a century. While the ability to view the brain and also the entire human genome advanced dramatically during this time and particularly in recent years, it is still unclear whether these advances helped to understand the nature of schizophrenia. What appears, however, to be the case is that early detection and treatment of people who are at high risk for developing schizophrenia due to various clinical signs, lead to better outcomes and recovery in many cases. Medications have also dramatically improved and have not been associated with the side-effects of earlier treatments, although they still are not without new sets of adverse effects. Over the years it was shown that structural brain abnormalities were present in the brains of people with chronic schizophrenia and that these observations were present early in the onset of illness. It was then shown these were not static and changed over the years of illness. At the same time it was shown that the brain centers for perceiving and speaking language appeared particularly abnormal in patients with schizophrenia and that these abnormalities could underlie the misperceptions and experiences of auditory hallucinations so characteristic of this illness. In a separate set of investigations that began with family, then twin and adoption studies, it was shown that schizophrenia is inherited, but in a complex manner. At present many genetic studies now find that genes, whose variants can lead to a high risk for schizophrenia, are ones specifically involving brain development and functioning. At present, although still speculative, it can be concluded that the progressive changes in brain structure, particularly related to language processing, take place in genetically vulnerable people and put them ultimately at high risk for developing schizophrenia in a trajectory for a lifelong illness. It is hoped that in the future these brain changes can be prevented by intervening early on the processes of brain growth and plasticity, thus arresting the illness before it begins., (Copyright © 2022. Published by Elsevier B.V.)

The news from Ukraine is currently full of heart-wrenching stories accompanied by graphic images of civilian casualties and massacres that are telecast world-wide on a daily basis. It is hard to fathom the magnitude of the devastation and disruption to regular lives and everyday routines that war brings with it, the witnessing of countless deaths, the associated trauma of living in perpetual fear, and the daily experience of many families and orphans who are crowded into basement bomb shelters now for months on end. These issues make us contemplate the mental health consequences, among other lasting effects, of this costly war in Ukraine, and wars in other countries not so widely featured in Western news. Despite people of all ages being affected by war, children are especially vulnerable. This commentary outlines some of the epidemiology of the consequences of war, the mental health sequelae specifically, and the complexity of providing culturally and contextually relevant interventions that meet the needs of children., Competing Interests: Declaration of Competing Interest The authors do not have any conflicts of interests to disclose., (Copyright © 2022. Published by Elsevier B.V.)

Schizophrenia has a heritability of 60-80% 1 , much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Importance: Suicide and suicide attempts are persistent and increasing public health problems. Observational studies and meta-analyses of randomized clinical trials have suggested that lithium may prevent suicide in patients with bipolar disorder or depression., Objective: To assess whether lithium augmentation of usual care reduces the rate of repeated episodes of suicide-related events (repeated suicide attempts, interrupted attempts, hospitalizations to prevent suicide, and deaths from suicide) in participants with bipolar disorder or depression who have survived a recent event., Design, Setting, and Participants: This double-blind, placebo-controlled randomized clinical trial assessed lithium vs placebo augmentation of usual care in veterans with bipolar disorder or depression who had survived a recent suicide-related event. Veterans at 29 VA medical centers who had an episode of suicidal behavior or an inpatient admission to prevent suicide within 6 months were screened between July 1, 2015, and March 31, 2019., Interventions: Participants were randomized to receive extended-release lithium carbonate beginning at 600 mg/d or placebo., Main Outcomes and Measures: Time to the first repeated suicide-related event, including suicide attempts, interrupted attempts, hospitalizations specifically to prevent suicide, and deaths from suicide., Results: The trial was stopped for futility after 519 veterans (mean [SD] age, 42.8 [12.4] years; 437 [84.2%] male) were randomized: 255 to lithium and 264 to placebo. Mean lithium concentrations at 3 months were 0.54 mEq/L for patients with bipolar disorder and 0.46 mEq/L for patients with major depressive disorder. No overall difference in repeated suicide-related events between treatments was found (hazard ratio, 1.10; 95% CI, 0.77-1.55). No unanticipated safety concerns were observed. A total of 127 participants (24.5%) had suicide-related outcomes: 65 in the lithium group and 62 in the placebo group. One death occurred in the lithium group and 3 in the placebo group., Conclusions and Relevance: In this randomized clinical trial, the addition of lithium to usual Veterans Affairs mental health care did not reduce the incidence of suicide-related events in veterans with major depression or bipolar disorders who experienced a recent suicide event. Therefore, simply adding lithium to existing medication regimens is unlikely to be effective for preventing a broad range of suicide-related events in patients who are actively being treated for mood disorders and substantial comorbidities., Trial Registration: ClinicalTrials.gov Identifier: NCT01928446.

Women have historically faced many barriers to professional achievement that have not been suffered by most men; and those women who chose psychiatry as a profession are not exceptions, despite psychiatry having a reputation for attracting more women members than many of the other fields of medicine. While a couple of generations ago, blatant discrimination against women was accepted, whether it was because men were thought to traditionally be the family bread winners and women in charge of household stability, or because their appearances and personalities generated a stereotype of what a leader is meant not to "look like". However, more recently, women have been raising awareness that these views can no longer be tolerated and are calling for change that requires equal opportunities for leadership roles and academic success. The ways in which change can occur include: developing mentorship programs, requiring all faculty, particularly anyone in a leadership role, to be trained in ways in which implicit bias occurs and how to remedy it, providing networking opportunities, and practicing transparent non-biased hiring practices. These will reduce not only the male/ female gap in academic success, but similarly that which exists between racial, ethnic and gender minorities and those who are not thought of as such., (Copyright © 2021 Elsevier B.V. All rights reserved.)