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The introduction of the first antipsychotic drug, chlorpromazine, was a milestone for psychiatry. The authors review the history, classification, indications, mechanism, efficacy, side effects, dosing, drug initiation, switching, and other practical issues and questions related to antipsychotics. Classifications such as first-generation/typical versus second-generation/atypical antipsychotics are neither valid nor useful; these agents should be described according to the Neuroscience-based Nomenclature (NbN). Antipsychotic drugs are not specific for treating schizophrenia. They reduce psychosis regardless of the underlying diagnosis, and they go beyond nonspecific sedation. All currently available antipsychotic drugs are dopamine blockers or dopamine partial agonists. In schizophrenia, effect sizes for relapse prevention are larger than for acute treatment. A major unresolved problem is the implausible increase in placebo response in antipsychotic drug trials over the decades. Differences in side effects, which can be objectively measured, such as weight gain, are less equivocal than differences in rating-scale-measured (subjective) efficacy. The criteria for choosing among antipsychotics are mainly pragmatic and include factors such as available formulations, metabolism, half-life, efficacy, and side effects in previous illness episodes. Plasma levels help to detect nonadherence, and once-daily dosing at night (which is possible with many antipsychotics) and long-acting injectable formulations are useful when adherence is a problem. Dose-response curves for both acute treatment and relapse prevention follow a hyperbolic pattern, with maximally efficacious average dosages for schizophrenia of around 5 mg/day risperidone equivalents. Computer apps facilitating the choice between drugs are available. Future drug development should include pharmacogenetics and focus on drugs for specific aspects of psychosis. [ABSTRACT FROM AUTHOR]

This article from the American Journal of Psychiatry provides a comprehensive overview of various topics related to schizophrenia spectrum disorders and psychosis. It includes studies on the use of antipsychotic medications, the potential adverse events of long-term clozapine treatment, the benefits of hormonal replacement therapy for menopausal women with schizophrenia, the risk of inducing psychosis or mania with prescribed stimulants, neural signatures associated with depressive versus negative symptoms in schizophrenia patients, and gene expression patterns in the prefrontal cortex. The article emphasizes the importance of monitoring and preventing adverse events related to clozapine treatment and highlights the potential benefits of hormonal replacement therapy for menopausal women with schizophrenia. It also discusses the increased risk of developing psychosis or mania with prescribed amphetamines and provides insights into the neural circuitry underlying depressive and negative symptoms in schizophrenia patients. Overall, this article offers valuable information for researchers and individuals interested in understanding and addressing schizophrenia spectrum disorders. [Extracted from the article]

Objective: Conceptual similarities between depressive and negative symptoms complicate biomarker and intervention development. This study employed a data-driven approach to delineate the neural circuitry underlying depressive and negative symptoms in schizophrenia spectrum disorders (SSDs). Methods: Data from three studies were analyzed (157 participants with SSDs) to assess brain-behavior relationships: two neuroimaging studies and a randomized trial of repetitive transcranial magnetic stimulation (rTMS). Partial least squares correlation (PLSC) was used to investigate associations between resting-state functional connectivity and depressive and negative symptoms. Secondary analyses of rTMS trial data (active, N=37; sham, N=33) were used to assess relationships between PLSC-derived symptom profiles and treatment outcomes. Results: PLSC identified three latent variables (LVs) relating functional brain circuitry with symptom profiles. LV1 related a general depressive symptom factor with positive associations between and within the default mode network (DMN), the frontoparietal network (FPN), and the cingulo-opercular network (CON). LV2 related negative symptoms (no depressive symptoms) via negative associations, especially between the FPN and the CON, but also between the DMN and the FPN and the CON. LV3 related a guilt and early wakening depression factor via negative rather than positive associations with the DMN, FPN, and CON. The secondary visual network had a positive association with general depressive symptoms and negative associations with guilt and negative symptoms. Active (but not sham) rTMS applied bilaterally to the dorsolateral prefrontal cortex (DLPFC) reduced general depressive but not guilt-related or negative symptoms. Conclusions: The results clearly differentiate the neural circuitry underlying depressive and negative symptoms, and segregated across the two-factor structure of depression in SSDs. These findings support divergent neurobiological pathways of depressive symptoms and negative symptoms in people with SSDs. As treatment options are currently limited, bilateral rTMS to the DLPFC is worth exploring further for general depressive symptoms in people with SSDs. [ABSTRACT FROM AUTHOR]

Objective: In schizophrenia, impaired working memory is associated with transcriptome alterations in layer 3 pyramidal neurons (L3PNs) in the dorsolateral prefrontal cortex (DLPFC). Distinct subtypes of L3PNs that send axonal projections to the DLPFC in the opposite hemisphere (callosal projection [CP] neurons) or the parietal cortex in the same hemisphere (ipsilateral projection [IP] neurons) play critical roles in working memory. However, how the transcriptomes of these L3PN subtypes might shift during late postnatal development when working memory impairments emerge in individuals later diagnosed with schizophrenia is not known. The aim of this study was to characterize and compare the transcriptome profiles of CP and IP L3PNs across developmental transitions from prepuberty to adulthood in macaque monkeys. Methods: The authors used retrograde labeling to identify CP and IP L3PNs in the DLPFC of prepubertal, postpubertal, and adult macaque monkeys, and used laser microdissection to capture these neurons for RNA sequencing. Results: At all three ages, CP and IP L3PNs had distinct transcriptomes, with the number of genes differentially expressed between neuronal subtypes increasing with age. For IP L3PNs, age-related shifts in gene expression were most prominent between prepubertal and postpubertal animals, whereas for CP L3PNs such shifts were most prominent between postpubertal and adult animals. Conclusions: These findings demonstrate the presence of cell type–specific profiles and developmental trajectories of the transcriptomes of PPC-projecting IP and DLPFC-projecting CP L3PNs in monkey DLPFC. The evidence that IP L3PNs reach a mature transcriptome earlier than CP L3PNs suggests that these two subtypes differentially contribute to the maturation of working memory performance across late postnatal development and that they may be differentially vulnerable to the disease process of schizophrenia at specific stages of postnatal development. [ABSTRACT FROM AUTHOR]

Objective: Many but not all persons with bipolar disorder require hospital care because of severe mood episodes. Likewise, some but not all patients experience long-term occupational dysfunction that extends beyond acute mood episodes. It is not known whether these dissimilar outcomes of bipolar disorder are driven by different polygenic profiles. Here, polygenic scores (PGSs) for major psychiatric disorders and educational attainment were assessed for associations with occupational functioning and psychiatric hospital admissions in bipolar disorder. Methods: A total of 4,782 patients with bipolar disorder and 2,963 control subjects were genotyped and linked to Swedish national registers. Longitudinal measures from at least 10 years of registry data were used to derive percentage of years without employment, percentage of years with long-term sick leave, and mean number of psychiatric hospital admissions per year. Ordinal regression was used to test associations between outcomes and PGSs for bipolar disorder, schizophrenia, major depressive disorder, attention deficit hyperactivity disorder (ADHD), and educational attainment. Replication analyses of hospital admissions were conducted with data from the Bipolar Disorder Research Network cohort (N=4,219). Results: Long-term sick leave and unemployment in bipolar disorder were significantly associated with PGSs for schizophrenia, ADHD, major depressive disorder, and educational attainment, but not with the PGS for bipolar disorder. By contrast, the number of hospital admissions per year was associated with higher PGSs for bipolar disorder and schizophrenia, but not with the other PGSs. Conclusions: Bipolar disorder severity (indexed by hospital admissions) was associated with a different polygenic profile than long-term occupational dysfunction. These findings have clinical implications, suggesting that mitigating occupational dysfunction requires interventions other than those deployed to prevent mood episodes. [ABSTRACT FROM AUTHOR]

Schizophrenia is routinely referred to as a neurodevelopmental disorder, but the role of brain development in a disorder typically diagnosed during early adult life is enigmatic. The authors revisit the neurodevelopmental model of schizophrenia with genomic insights from the most recent schizophrenia clinical genetic association studies, transcriptomic and epigenomic analyses from human postmortem brain studies, and analyses from cellular models that recapitulate neurodevelopment. Emerging insights into schizophrenia genetic risk continue to converge on brain development, particularly stages of early brain development, that may be perturbed to deviate from a typical, normative course, resulting in schizophrenia clinical symptomatology. As the authors explicate, schizophrenia genetic risk is likely dynamic and context dependent, with effects of genetic risk varying spatiotemporally, across the neurodevelopmental continuum. Optimizing therapeutic strategies for the heterogeneous collective of individuals with schizophrenia may likely be guided by leveraging markers of genetic risk and derivative functional insights, well before the emergence of psychosis. Ultimately, rather than a focus on therapeutic intervention during adolescence or adulthood, principles of prediction and prophylaxis in the pre- and perinatal and neonatal stages may best comport with the biology of schizophrenia to address the early-stage perturbations that alter the normative neurodevelopmental trajectory. [ABSTRACT FROM AUTHOR]

This document provides a summary of several research papers published in the American Journal of Psychiatry. The papers cover topics related to schizophrenia, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD). The research findings indicate low levels of recovery and remission in individuals with schizophrenia spectrum disorders compared to other psychoses. A meta-analysis of neuroimaging data reveals shared and distinct patterns of brain activation in individuals with ASD and ADHD. Another study uses a mega-analytic approach to identify functional connectivity alterations in youth with ADHD. These findings contribute to our understanding of the etiology and pathophysiology of these disorders and may guide the development of new treatments. [Extracted from the article]

Objective: Cognitive remediation provides substantial improvements in cognitive performance and real-world functioning for people living with schizophrenia, but the durability of these benefits needs to be reassessed and better defined. The aims of this study were to provide a comprehensive assessment of the durability of the benefits of cognitive remediation for cognition and functioning in people living with schizophrenia and evaluating potential moderators of effects. Methods: A systematic search was conducted in PubMed, Scopus, and PsycINFO, and reference lists of included articles and Google Scholar were inspected. Eligible studies were randomized clinical trials of cognitive remediation in patients diagnosed with schizophrenia spectrum disorders in which follow-up assessments were included. Screening and data extraction were performed by at least two independent reviewers. Cohen's d was used to measure outcomes. Primary outcomes were changes in cognition and functioning from baseline to conclusion of follow-up. Moderators of the durability of effects were assessed. Results: Of 2,840 identified reports, 281 full texts were assessed and 130 reports on 67 studies with 5,334 participants were included. Cognitive remediation produced statistically significant positive effects that persisted at the end of follow-up in global cognition (d=0.23) and in global functioning (d=0.26). Smaller study samples and single-center studies were associated with better cognitive outcomes; longer treatment and follow-up duration, techniques for transferring cognitive gains to the real world, integration with psychiatric rehabilitation, group format of delivery, and more female participants in the sample were associated with better functional outcomes. Conclusions: Cognitive remediation provides durable improvements in cognition and functioning in schizophrenia. This finding corroborates the notion that cognitive remediation should be implemented more widely in clinical and rehabilitation practice. [ABSTRACT FROM AUTHOR]

Objective: Understanding prognosis is critical to anticipating public health needs and providing care to individuals with psychotic disorders. However, the long-term course of remission and recovery remains unclear. In this study, the most common trajectories of illness course are described for a cohort of individuals followed for 25 years since first admission for psychosis. Methods: Participants are from the Suffolk County Mental Health Project, an epidemiological study of first-admission psychosis. Data for the present study was collected from six follow-ups, with 311 individuals assessed at the 25-year follow-up. Common patterns of remission and recovery were assessed in the baseline cohort of 591 individuals and the subsample from the 25-year follow up. Results: In the baseline cohort and the 25-year subsample, the most common trajectory for individuals with schizophrenia spectrum disorders was no remission and no recovery. Among individuals with other psychotic disorders, in both the baseline and 25-year cohorts, the modal pattern was one of intermittent remission and recovery. Individuals with other psychotic disorders were more likely to experience stable remission (15.1%) and stable recovery (21.1%), outcomes that were rare among individuals with schizophrenia spectrum disorders (0% and 0.6%, respectively). Conclusions: The modal longitudinal pattern for individuals with other psychoses is one of multiple transitions into and out of symptomatic and functional recovery. Engagement in a long-term health care plan may help individuals detect and respond to these changes. Sustained remission and recovery are rare among people with schizophrenia spectrum disorders. Efforts should be directed toward developing more effective treatments for this population. [ABSTRACT FROM AUTHOR]

Objective: Markers for treatment resistance in schizophrenia are needed to reduce delays in effective treatment. Nigrostriatal hyperdopaminergic function plays a critical role in the pathology of schizophrenia, yet antipsychotic nonresponders do not show increased dopamine function. Neuromelanin-sensitive MRI (NM-MRI), which indirectly measures dopamine function in the substantia nigra, has potential as a noninvasive marker for nonresponders. Increased NM-MRI signal has been shown in psychosis, but has not yet been assessed in nonresponders. In this study, the authors investigated whether nonresponders show lower NM-MRI signal than responders. Methods: NM-MRI scans were acquired in 79 patients with first-episode psychosis and 20 matched healthy control subjects. Treatment response was assessed at a 6-month follow-up. An a priori voxel-wise analysis within the substantia nigra tested the relation between NM-MRI signal and treatment response in patients. Results: Fifteen patients were classified as nonresponders and 47 patients as responders. Seventeen patients were excluded, primarily because of medication nonadherence or change in diagnosis. Voxel-wise analysis revealed 297 significant voxels in the ventral tier of the substantia nigra that were negatively associated with treatment response. Nonresponders and healthy control subjects had significantly lower NM-MRI signal than responders. Receiver operating characteristic curve analysis showed that NM-MRI signal separated nonresponders with areas under the curve between 0.62 and 0.85. In addition, NM-MRI signal in patients did not change over 6 months. Conclusions: These findings provide further evidence for dopaminergic differences between medication responders and nonresponders and support the potential of NM-MRI as a clinically applicable marker for treatment resistance in schizophrenia. [ABSTRACT FROM AUTHOR]

This article discusses the risks associated with the use of the medication clozapine, particularly the high incidence of ileus and pneumonia. The authors present data from a Finnish registry, which shows that clozapine users have an increased risk of gastrointestinal hypomotility, seizures, pneumonia, respiratory infections, and tachycardia. The study highlights the higher risks for women, the association between higher clozapine dosage and adverse events, and the timing of these events following clozapine initiation. The authors emphasize the need for better clinical strategies to address these complications and raise awareness about the impact of clozapine on gastrointestinal hypomotility. They recommend implementing an aggressive bowel regimen, monitoring for signs of infection, addressing modifiable risk factors such as smoking and obesity, and promoting vaccinations. The article emphasizes the importance of monitoring and managing gastrointestinal hypomotility and pneumonia in patients treated with clozapine, as these complications can be life-threatening and require long-term monitoring and management. It also highlights the need for resources and education on managing these adverse drug events and emphasizes the importance of remaining vigilant in the use of clozapine. [Extracted from the article]

The article discusses the challenge of translating neuroimaging research on psychiatric symptoms into clinical care. The authors highlight the overlap between depressive symptoms and negative symptoms in schizophrenia and the need to identify and distinguish their underlying pathophysiology. The study by Gallucci et al. uses resting-state functional imaging to explore the connectivity correlates of these symptoms in individuals with schizophrenia spectrum disorders. The authors identify distinct brain network organization patterns associated with depressive and negative symptoms and suggest that repetitive transcranial magnetic stimulation (rTMS) targeting specific brain regions could have differential effects on these symptoms. The study supports the potential of rTMS as a therapeutic intervention for depression in schizophrenia and emphasizes the need for larger trials to further investigate its efficacy. [Extracted from the article]

The article discusses the increased risk of mental health problems in children born to parents with a mental illness. A comprehensive meta-analysis of data from around the world confirms this increased risk. However, not all children with a genetic predisposition for mental illness develop problems. The study also explores the impact of parental diagnoses on various outcomes, including criminality, suicide, and psychosocial functioning. The findings highlight the importance of understanding and addressing the transgenerational transmission of risk in families affected by mental illness. The article emphasizes the need for preventive strategies and early interventions to support these children. It also acknowledges the impact of mental illness on family life and the importance of providing support and resources for parents. The article concludes by discussing the positive developments in research and awareness of the challenges faced by these families and the potential for interventions to reduce risk and promote resilience. [Extracted from the article]

The article discusses the use of polygenic scores (PGSs) in understanding psychiatric outcomes. PGSs measure genetic risk based on common genetic variants identified through genome-wide association studies (GWASs). The study analyzed the relationship between PGSs for various psychiatric disorders and occupational disability and severity of illness in individuals with bipolar disorder. The findings showed that higher PGSs for major depressive disorder and ADHD were associated with negative occupational outcomes, and higher PGSs for schizophrenia and major depressive disorder were associated with longer periods of unemployment. The study highlights the importance of integrating genetic and phenotypic data to improve diagnosis and risk prediction in psychiatric disorders. [Extracted from the article]

This document consists of two editorials from the journals Schizophrenia Research and The American Journal of Psychiatry. The first editorial emphasizes the importance of early intervention and personalized treatment for individuals with schizophrenia. The second editorial discusses the challenges and opportunities in the field of schizophrenia research, including the need for more diverse representation in clinical trials. Both editorials provide valuable insights into the current state of schizophrenia research and highlight the importance of continued efforts in understanding and treating this complex mental illness. [Extracted from the article]

The article explores the potential use of neuromelanin-sensitive MRI (NM-MRI) as a biomarker for treatment-resistant schizophrenia. Treatment-resistant schizophrenia refers to patients who do not respond to initial antipsychotic medications. NM-MRI, which measures dopamine function, has shown promise in identifying nonresponders in previous studies. A recent study compared NM-MRI in responders and nonresponders to antipsychotic treatment and found significant differences in certain brain regions. However, the study has limitations, and more research is needed to confirm NM-MRI as a biomarker for treatment-resistant schizophrenia. [Extracted from the article]

ObjectiveMany psychotropic medications used to treat schizophrenia have significant anticholinergic properties, which are linked to cognitive impairment and dementia risk in healthy subjects. Clarifying the impact of cognitive impairment attributable to anticholinergic medication burden may help optimize cognitive outcomes in schizophrenia. The aim of this study was to comprehensively characterize how this burden affects functioning across multiple cognitive domains in schizophrenia outpatients.MethodsCross-sectional data were analyzed using inferential statistics and exploratory structural equation modeling to determine the relationship between anticholinergic medication burden and cognition. Patients with a diagnosis of schizophrenia or schizoaffective disorder (N=1,120) were recruited from the community at five U.S. universities as part of the Consortium on the Genetics of Schizophrenia-2. For each participant, prescribed medications were rated and summed according to a modified Anticholinergic Cognitive Burden (ACB) scale. Cognitive functioning was assessed by performance on domains of the Penn Computerized Neurocognitive Battery (PCNB).ResultsACB score was significantly associated with cognitive performance, with higher ACB groups scoring worse than lower ACB groups on all domains tested on the PCNB. Similar effects were seen on other cognitive tests. Effects remained significant after controlling for demographic characteristics and potential proxies of illness severity, including clinical symptoms and chlorpromazine-equivalent antipsychotic dosage.ConclusionsAnticholinergic medication burden in schizophrenia is substantial, common, conferred by multiple medication classes, and associated with cognitive impairments across all cognitive domains. Anticholinergic medication burden from all medication classes-including psychotropics used in usual care-should be considered in treatment decisions and accounted for in studies of cognitive functioning in schizophrenia.

The authors examine U.S.-based evidence that connects characteristics of the social environment with outcomes across the psychosis continuum, from psychotic experiences to schizophrenia. The notion that inequitable social and economic systems of society significantly influence psychosis risk through proxies, such as racial minority and immigrant statuses, has been studied more extensively in European countries. While there are existing international reviews of social determinants of psychosis, none to the authors' knowledge focus on factors in the U.S. context specifically-an omission that leaves domestic treatment development and prevention efforts incomplete and underinformed. In this review, the authors first describe how a legacy of structural racism in the United States has shaped the social gradient, highlighting consequential racial inequities in environmental conditions. The authors offer a hypothesized model linking structural racism with psychosis risk through interwoven intermediary factors based on existing theoretical models and a review of the literature. Neighborhood factors, cumulative trauma and stress, and prenatal and perinatal complications were three key areas selected for review because they reflect social and environmental conditions that may affect psychosis risk through a common pathway shaped by structural racism. The authors describe evidence showing that Black and Latino people in the United States suffer disproportionately from risk factors within these three key areas, in large part as a result of racial discrimination and social disadvantage. This broad focus on individual and community factors is intended to provide a consolidated space to review this growing body of research and to guide continued inquiries into social determinants of psychosis in U.S. contexts.

The article discusses the potential benefits of menopausal hormone therapy for women with schizophrenia. It highlights the increased risk of relapse in women with schizophrenia during the menopause transition and suggests that hormone therapy may help reduce this risk. The article presents findings from a nationwide cohort study that showed a 16% decreased risk of psychosis relapse in women who used menopausal hormone therapy. However, the article also acknowledges that further research is needed to fully establish the effectiveness and safety of hormone therapy as an adjunctive treatment for schizophrenia. [Extracted from the article]

The transition from childhood to adulthood represents the developmental time frame in which the majority of psychiatric disorders emerge. Recent efforts to identify risk factors mediating the susceptibility to psychopathology have led to a heightened focus on both typical and atypical trajectories of neural circuit maturation. Mounting evidence has highlighted the immense neural plasticity apparent in the developing brain. Although in many cases adaptive, the capacity for neural circuit alteration also induces a state of vulnerability to environmental perturbations, such that early-life experiences have long-lasting implications for cognitive and emotional functioning in adulthood. The authors outline preclinical and neuroimaging studies of normative human brain circuit development, as well as parallel efforts covered in this issue of the Journal, to identify brain circuit alterations in psychiatric disorders that frequently emerge in developing populations. Continued translational research into the interactive effects of neurobiological development and external factors will be crucial for identifying early-life risk factors that may contribute to the emergence of psychiatric illness and provide the key to optimizing treatments. [ABSTRACT FROM AUTHOR]

The article focuses on the sensitivity of schizophrenia endophenotype biomarkers to anticholinergic medication burden (ACMB). Topics include the impact of ACMB on cognitive performance in individuals with schizophrenia, the role of neurophysiological biomarkers (MMN and P3a) in early auditory information processing, and the association between ACMB and diminished MMN and P3a responses in schizophrenia patients.

Tweet: Young men with cannabis-induced psychosis and repeated emergency admissions have a risk for schizophrenia. The authors investigated transitions to schizophrenia spectrum or bipolar disorder following different types of substance-induced psychosis and the impact of gender, age, number of emergency admissions related to substance-induced psychosis, and type of substance-induced psychosis on such transitions. All patients in the Norwegian Patient Registry with a diagnosis of substance-induced psychosis from 2010 to 2015 were included (N=3,187). The Kaplan-Meier method was used to estimate cumulative transition rates from substance-induced psychosis to either schizophrenia spectrum disorder or bipolar disorder. Cox proportional hazard regression was used to estimate hazard ratios for transitions to schizophrenia spectrum or bipolar disorders associated with gender, age, number of emergency admissions, and type of substance-induced psychosis. The 6-year cumulative transition rate from substance-induced psychosis to schizophrenia spectrum disorder was 27.6% (95% CI=25.6–29.7). For men, the risk of transition was higher among younger individuals and those with either cannabis-induced psychosis or psychosis induced by multiple substances; for both genders, the risk of transition was higher among those with repeated emergency admissions related to substance-induced psychosis. The cumulative transition rate from substance-induced psychosis to bipolar disorder was 4.5% (95% CI=3.6–5.5), and the risk of this transition was higher for women than for men. Transition rates from substance-induced psychosis to schizophrenia spectrum disorder were six times higher than transition rates to bipolar disorder. Gender, age, number of emergency admissions, and type of substance-induced psychosis affected the risk of transition. [ABSTRACT FROM AUTHOR]

Objective22q11.2 deletion syndrome (22q11DS) is among the strongest known genetic risk factors for schizophrenia. Previous studies have reported variable alterations in subcortical brain structures in 22q11DS. To better characterize subcortical alterations in 22q11DS, including modulating effects of clinical and genetic heterogeneity, the authors studied a large multicenter neuroimaging cohort from the ENIGMA 22q11.2 Deletion Syndrome Working Group.MethodsSubcortical structures were measured using harmonized protocols for gross volume and subcortical shape morphometry in 533 individuals with 22q11DS and 330 matched healthy control subjects (age range, 6-56 years; 49% female).ResultsCompared with the control group, the 22q11DS group showed lower intracranial volume (ICV) and thalamus, putamen, hippocampus, and amygdala volumes and greater lateral ventricle, caudate, and accumbens volumes (Cohen's d values, -0.90 to 0.93). Shape analysis revealed complex differences in the 22q11DS group across all structures. The larger A-D deletion was associated with more extensive shape alterations compared with the smaller A-B deletion. Participants with 22q11DS with psychosis showed lower ICV and hippocampus, amygdala, and thalamus volumes (Cohen's d values, -0.91 to 0.53) compared with participants with 22q11DS without psychosis. Shape analysis revealed lower thickness and surface area across subregions of these structures. Compared with subcortical findings from other neuropsychiatric disorders studied by the ENIGMA consortium, significant convergence was observed between participants with 22q11DS with psychosis and participants with schizophrenia, bipolar disorder, major depressive disorder, and obsessive-compulsive disorder.ConclusionsIn the largest neuroimaging study of 22q11DS to date, the authors found widespread alterations to subcortical brain structures, which were affected by deletion size and psychotic illness. Findings indicate significant overlap between 22q11DS-associated psychosis, idiopathic schizophrenia, and other severe neuropsychiatric illnesses.

ObjectiveSchizophrenia has recently been associated with widespread white matter microstructural abnormalities, but the functional effects of these abnormalities remain unclear. Widespread heterogeneity of results from studies published to date preclude any definitive characterization of the relationship between white matter and cognitive performance in schizophrenia. Given the relevance of deficits in cognitive function to predicting social and functional outcomes in schizophrenia, the authors carried out a meta-analysis of available data through the ENIGMA Consortium, using a common analysis pipeline, to elucidate the relationship between white matter microstructure and a measure of general cognitive performance, IQ, in patients with schizophrenia and healthy participants.MethodsThe meta-analysis included 760 patients with schizophrenia and 957 healthy participants from 11 participating ENIGMA Consortium sites. For each site, principal component analysis was used to calculate both a global fractional anisotropy component (gFA) and a fractional anisotropy component for six long association tracts (LA-gFA) previously associated with cognition.ResultsMeta-analyses of regression results indicated that gFA accounted for a significant amount of variation in cognition in the full sample (effect size [Hedges' g]=0.27, CI=0.17-0.36), with similar effects sizes observed for both the patient (effect size=0.20, CI=0.05-0.35) and healthy participant groups (effect size=0.32, CI=0.18-0.45). Comparable patterns of association were also observed between LA-gFA and cognition for the full sample (effect size=0.28, CI=0.18-0.37), the patient group (effect size=0.23, CI=0.09-0.38), and the healthy participant group (effect size=0.31, CI=0.18-0.44).ConclusionsThis study provides robust evidence that cognitive ability is associated with global structural connectivity, with higher fractional anisotropy associated with higher IQ. This association was independent of diagnosis; while schizophrenia patients tended to have lower fractional anisotropy and lower IQ than healthy participants, the comparable size of effect in each group suggested a more general, rather than disease-specific, pattern of association.

ObjectiveThe 2-year risk of psychosis in persons who meet research criteria for a high-risk syndrome is about 15%-25%; improvements in risk prediction accuracy would benefit the development and implementation of preventive interventions. The authors sought to assess polygenic risk score (PRS) prediction of subsequent psychosis in persons at high risk and to determine the impact of adding the PRS to a previously validated psychosis risk calculator.MethodsPersons meeting research criteria for psychosis high risk (N=764) and unaffected individuals (N=279) were followed for up to 2 years. The PRS was based on the latest schizophrenia and bipolar genome-wide association studies. Variables in the psychosis risk calculator included stressful life events, trauma, disordered thought content, verbal learning, information processing speed, and family history of psychosis.ResultsFor Europeans, the PRS varied significantly by group and was higher in the psychosis converter group compared with both the nonconverter and unaffected groups, but was similar for the nonconverter group compared with the unaffected group. For non-Europeans, the PRS varied significantly by group; the difference between the converters and nonconverters was not significant, but the PRS was significantly higher in converters than in unaffected individuals, and it did not differ between nonconverters and unaffected individuals. The R2liability (R2 adjusted for the rate of disease risk in the population being studied, here assuming a 2-year psychosis risk between 10% and 30%) for Europeans varied between 9.2% and 12.3% and for non-Europeans between 3.5% and 4.8%. The amount of risk prediction information contributed by the addition of the PRS to the risk calculator was less than severity of disordered thoughts and similar to or greater than for other variables. For Europeans, the PRS was correlated with risk calculator variables of information processing speed and verbal memory.ConclusionsThe PRS discriminates psychosis converters from nonconverters and modestly improves individualized psychosis risk prediction when added to a psychosis risk calculator. The schizophrenia PRS shows promise in enhancing risk prediction in persons at high risk for psychosis, although its potential utility is limited by poor performance in persons of non-European ancestry.

ObjectivePrevious studies suggest that prenatal immune challenges may elevate the risk of schizophrenia and related psychoses in offspring, yet there has been limited research focused on maternal bacterial infection. The authors hypothesized that maternal bacterial infection during pregnancy increases offspring risk of psychotic disorders in adulthood, and that the magnitude of this association varies as a function of severity of infectious exposure and offspring sex.MethodsThe authors analyzed prospectively collected data from 15,421 pregnancies among women enrolled between 1959 and 1966 at two study sites through the Collaborative Perinatal Project. The sample included 116 offspring with confirmed psychotic disorders. The authors estimated associations between maternal bacterial infection during pregnancy and psychosis risk over the subsequent 40 years, stratified by offspring sex and presence of reported parental mental illness, with adjustment for covariates.ResultsMaternal bacterial infection during pregnancy was strongly associated with psychosis in offspring (adjusted odds ratio=1.8, 95% CI=1.2-2.7) and varied by severity of infection and offspring sex. The effect of multisystemic bacterial infection (adjusted odds ratio=2.9, 95% CI=1.3-5.9) was nearly twice that of less severe localized bacterial infection (adjusted odds ratio=1.6, 95% CI=1.1-2.3). Males were significantly more likely than females to develop psychosis after maternal exposure to any bacterial infection during pregnancy.ConclusionsThe study findings suggest that maternal bacterial infection during pregnancy is associated with an elevated risk for psychotic disorders in offspring and that the association varies by infection severity and offspring sex. These findings call for additional investigation and, if the findings are replicated, public health and clinical efforts that focus on preventing and managing bacterial infection in pregnant women.

An introduction to articles in the issue is presented on topics including efficacy of memantine for treating trichotillomania and skin picking disorder, efficacy of a novel treatment for motivation-related negative symptoms in schizophrenia, and antipsychotic monotherapy versus polypharmacy in relation to nonpsychiatric hospitalizations.

Negative symptoms are a primary cause of disability in schizophrenia for which there are no established pharmacotherapies. This study evaluated a novel psychosocial intervention that combined two evidence-based practices—motivational interviewing and cognitive-behavioral therapy (MI-CBT)—for the treatment of motivational negative symptoms. Seventy-nine participants with schizophrenia and moderate to severe negative symptoms were included in a randomized controlled trial comparing the 12-session MI-CBT treatment with a mindfulness control condition. Participants were assessed at three time points through the study period, which included 12 weeks of active treatment and 12 weeks of follow-up. The primary outcome measures were motivational negative symptoms and community functioning; the secondary outcomes included a posited biomarker of negative symptoms: pupillometric response to cognitive effort. Compared with the control group, participants in the MI-CBT group showed significantly greater improvements in motivational negative symptoms over the acute treatment period. Their gains relative to baseline were maintained at follow-up, although the differential benefit relative to control subjects was attenuated. There were nonsignificant effects toward improvements in community functioning and differential change in the pupillometric markers of cognitive effort. The results show that combining motivational interviewing with CBT yields improvements in negative symptoms, a feature of schizophrenia generally thought of as resistant to intervention. Motivational negative symptoms not only responded to the novel treatment, but the gains were maintained over the follow-up period. Implications for future studies and for improving the generalization of the negative symptom gains to daily functioning domains are discussed. [ABSTRACT FROM AUTHOR]

ObjectiveThe early course of illness in psychotic disorders is highly variable, and predictive biomarkers of treatment response have been lacking. Trial and error remains the basis for care in early psychosis, and poor outcomes are common. Early prediction of nonimprovement in response to treatment could help identify those who would benefit from alternative and/or supplemental interventions. The goal of this study was to evaluate the ability of functional MRI (fMRI) measures of cognitive control-related brain circuitry collected at baseline to predict symptomatic response in patients after 1 year.MethodsPatients with recent-onset (20% improvement in total score on the Brief Psychiatric Rating Scale [BPRS] at 1-year follow-up compared with baseline) or as nonimprovers. Behavioral (d' context) and fMRI (proactive control-associated activation in a priori frontoparietal regions of interest) measures of cognitive control were then evaluated on their ability to predict BPRS improvement using linear and logistic regression.ResultsCognitive control-associated measures significantly predicted BPRS improvement and improver status, with 70% positive predictive value, 60% negative predictive value, and 66% accuracy. Only the fMRI-based measure (and not the behavioral measure) significantly predicted status.ConclusionsThese results suggest that frontoparietal activation during cognitive control performance at baseline significantly predicts subsequent symptomatic improvement during early psychosis specialty care. Potential implications for fMRI-based personalized patient treatment are discussed.

ObjectiveMore than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium.MethodsThe samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders.ResultsThree genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%).ConclusionsThis study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.

ObjectiveAlcohol use disorders are common conditions that have enormous social and economic consequences. Genome-wide association analyses were performed to identify genetic variants associated with a proxy measure of alcohol consumption and alcohol misuse and to explore the shared genetic basis between these measures and other substance use, psychiatric, and behavioral traits.MethodThis study used quantitative measures from the Alcohol Use Disorders Identification Test (AUDIT) from two population-based cohorts of European ancestry (UK Biobank [N=121,604] and 23andMe [N=20,328]) and performed a genome-wide association study (GWAS) meta-analysis. Two additional GWAS analyses were performed, a GWAS for AUDIT scores on items 1-3, which focus on consumption (AUDIT-C), and for scores on items 4-10, which focus on the problematic consequences of drinking (AUDIT-P).ResultsThe GWAS meta-analysis of AUDIT total score identified 10 associated risk loci. Novel associations localized to genes including JCAD and SLC39A13; this study also replicated previously identified signals in the genes ADH1B, ADH1C, KLB, and GCKR. The dimensions of AUDIT showed positive genetic correlations with alcohol consumption (rg=0.76-0.92) and DSM-IV alcohol dependence (rg=0.33-0.63). AUDIT-P and AUDIT-C scores showed significantly different patterns of association across a number of traits, including psychiatric disorders. AUDIT-P score was significantly positively genetically correlated with schizophrenia (rg=0.22), major depressive disorder (rg=0.26), and attention deficit hyperactivity disorder (rg=0.23), whereas AUDIT-C score was significantly negatively genetically correlated with major depressive disorder (rg=-0.24) and ADHD (rg=-0.10). This study also used the AUDIT data in the UK Biobank to identify thresholds for dichotomizing AUDIT total score that optimize genetic correlations with DSM-IV alcohol dependence. Coding individuals with AUDIT total scores ≤4 as control subjects and those with scores ≥12 as case subjects produced a significant high genetic correlation with DSM-IV alcohol dependence (rg=0.82) while retaining most subjects.ConclusionsAUDIT scores ascertained in population-based cohorts can be used to explore the genetic basis of both alcohol consumption and alcohol use disorders.

The article titled "The More Things Change..." by René S. Kahn discusses the poor clinical outcomes among patients with schizophrenia. The study conducted by Tramazzo et al. found that long-term outcomes in schizophrenia are still poor, with no stable remission or recovery observed in patients after 25 years. The study also highlighted the high mortality rate among these patients. The article emphasizes the need to improve our understanding of the causes of schizophrenia in order to improve outcomes for patients. [Extracted from the article]

OBJECTIVE:Antipsychotic drugs were incidentally discovered in the 1950s, but their mechanisms of action are still not understood. Better understanding of schizophrenia pathogenesis could shed light on actions of current drugs and reveal novel "druggable" pathways for unmet therapeutic needs. Recent genome-wide association studies offer unprecedented opportunities to characterize disease gene networks and uncover drug-disease relationships. Polygenic overlap between schizophrenia risk genes and antipsychotic drug targets has been demonstrated, but specific genes and pathways constituting this overlap are undetermined. Risk genes of polygenic disorders do not operate in isolation but in combination with other genes through protein-protein interactions among gene product. METHOD:The protein interactome was used to map antipsychotic drug targets (N=88) to networks of schizophrenia risk genes (N=328). RESULTS:Schizophrenia risk genes were significantly localized in the interactome, forming a distinct disease module. Core genes of the module were enriched for genes involved in developmental biology and cognition, which may have a central role in schizophrenia etiology. Antipsychotic drug targets overlapped with the core disease module and comprised multiple pathways beyond dopamine. Some important risk genes like CHRN, PCDH, and HCN families were not connected to existing antipsychotics but may be suitable targets for novel drugs or drug repurposing opportunities to treat other aspects of schizophrenia, such as cognitive or negative symptoms. CONCLUSIONS:The network medicine approach provides a platform to collate information of disease genetics and drug-gene interactions to shift focus from development of antipsychotics to multitarget antischizophrenia drugs. This approach is transferable to other diseases.

The Psychiatric Genomics Consortium (PGC) is the largest consortium in the history of psychiatry. This global effort is dedicated to rapid progress and open science, and in the past decade it has delivered an increasing flow of new knowledge about the fundamental basis of common psychiatric disorders. The PGC has recently commenced a program of research designed to deliver "actionable" findings-genomic results that 1) reveal fundamental biology, 2) inform clinical practice, and 3) deliver new therapeutic targets. The central idea of the PGC is to convert the family history risk factor into biologically, clinically, and therapeutically meaningful insights. The emerging findings suggest that we are entering a phase of accelerated genetic discovery for multiple psychiatric disorders. These findings are likely to elucidate the genetic portions of these truly complex traits, and this knowledge can then be mined for its relevance for improved therapeutics and its impact on psychiatric practice within a precision medicine framework. [AJP at 175: Remembering Our Past As We Envision Our Future November 1946: The Genetic Theory of Schizophrenia Franz Kallmann's influential twin study of schizophrenia in 691 twin pairs was the largest in the field for nearly four decades. (Am J Psychiatry 1946; 103:309-322 )].

The article focuses on addressing racial and ethnic disparities in mental health and psychiatric care. It discusses how social determinants of health contribute to these disparities, with topics including the impact of social determinants on psychiatric care and mental health, recommendations for addressing these determinants, disparities in depression symptoms, cognitive measures, and self-reported health in older Black and Hispanic/Latinx individuals.

The author comments on a study which investigated the link between substance-induced psychosis and primary psychotic disorders including schizophrenia spectrum disorder and bipolar disorder. He suggests familial risk for drug and alcohol use disorder and psychosis as a predictor for the transition from substance-induced psychotic disorder to schizophrenia and raises question about the link between cannabis use and chronic psychosis. He calls for interventions aimed at reducing substance abuse.

The article shares insights on substance use disorders and psychiatric illnesses, opioid use disorder, and neural correlates of food and drug craving. Topics discussed are relation between prescribed opiates and suicide deaths, performance-based assessments of opioid use disorder treatment outcomes, racial and ethnic biases in diagnosing alcohol use disorder, substance-induced psychosis to schizophrenia spectrum disorder or bipolar disorder, and neural network associated with craving.

Objective: Identifying biomarkers associated with response to electroconvulsive therapy (ECT) may aid clinical decisions. The authors examined whether greater polygenic liabilities for major depressive disorder, bipolar disorder, and schizophrenia are associated with improvement following ECT for a major depressive episode.Methods: Between 2013 and 2017, patients who had at least one treatment series recorded in the Swedish National Quality Register for ECT were invited to provide a blood sample for genotyping. The present study included 2,320 participants (median age, 51 years; 62.8% women) who had received an ECT series for a major depressive episode (77.1% unipolar depression), who had a registered treatment outcome, and whose polygenic risk scores (PRSs) could be calculated. Ordinal logistic regression was used to estimate the effect of PRS on Clinical Global Impressions improvement scale (CGI-I) score after each ECT series.Results: Greater PRS for major depressive disorder was significantly associated with less improvement on the CGI-I (odds ratio per standard deviation, 0.89, 95% CI=0.82, 0.96; R2=0.004), and greater PRS for bipolar disorder was associated with greater improvement on the CGI-I (odds ratio per standard deviation, 1.14, 95% CI=1.05, 1.23; R2=0.005) after ECT. PRS for schizophrenia was not associated with improvement. In an overlapping sample (N=1,207) with data on response and remission derived from the self-rated version of the Montgomery-Åsberg Depression Rating Scale, results were similar except that schizophrenia PRS was also associated with remission.Conclusions: Improvement after ECT is associated with polygenic liability for major depressive disorder and bipolar disorder, providing evidence of a genetic component for ECT clinical response. These liabilities may be considered along with clinical predictors in future prediction models of ECT outcomes. [ABSTRACT FROM AUTHOR]

The author offers observation on genetic underpinnings of psychiatric illnesses and use of polygenic risk scores in psychiatry. Topics discussed include shared genetic risk for post traumatic stress disorder (PTSD), depression and cardiovascular disease, factors underlying the comorbidity between endocrine and metabolic disorders with depression, and polygenic risk scores associated with effective electroconvulsive therapy (ECT) treatment for major depression.

Objective: The prevalence and significance of schizophrenia-related phenotypes at the population level is debated in the literature. Here, the authors assessed whether two recently reported neuroanatomical signatures of schizophrenia-signature 1, with widespread reduction of gray matter volume, and signature 2, with increased striatal volume-could be replicated in an independent schizophrenia sample, and investigated whether expression of these signatures can be detected at the population level and how they relate to cognition, psychosis spectrum symptoms, and schizophrenia genetic risk.Methods: This cross-sectional study used an independent schizophrenia-control sample (N=347; ages 16-57 years) for replication of imaging signatures, and then examined two independent population-level data sets: typically developing youths and youths with psychosis spectrum symptoms in the Philadelphia Neurodevelopmental Cohort (N=359; ages 16-23 years) and adults in the UK Biobank study (N=836; ages 44-50 years). The authors quantified signature expression using support-vector machine learning and compared cognition, psychopathology, and polygenic risk between signatures.Results: Two neuroanatomical signatures of schizophrenia were replicated. Signature 1 but not signature 2 was significantly more common in youths with psychosis spectrum symptoms than in typically developing youths, whereas signature 2 frequency was similar in the two groups. In both youths and adults, signature 1 was associated with worse cognitive performance than signature 2. Compared with adults with neither signature, adults expressing signature 1 had elevated schizophrenia polygenic risk scores, but this was not seen for signature 2.Conclusions: The authors successfully replicated two neuroanatomical signatures of schizophrenia and describe their prevalence in population-based samples of youths and adults. They further demonstrated distinct relationships of these signatures with psychosis symptoms, cognition, and genetic risk, potentially reflecting underlying neurobiological vulnerability. [ABSTRACT FROM AUTHOR]

Schizophrenia remains a challenging disease to treat effectively with current antipsychotic medications due to their limited efficacy across the entire spectrum of core symptoms as well as their often burdensome side-effect profiles and poor tolerability. An unmet need remains for novel, mechanistically unique, and better tolerated therapeutic agents for treating schizophrenia, especially those that treat not only positive symptoms but also the negative and cognitive symptoms of the disease. Almost 25 years ago, the muscarinic acetylcholine receptor (mAChR) agonist xanomeline was reported to reduce psychotic symptoms and improve cognition in patients with Alzheimer's disease. The antipsychotic and procognitive properties of xanomeline were subsequently confirmed in a small study of acutely psychotic patients with chronic schizophrenia. These unexpected clinical findings have prompted considerable efforts across academia and industry to target mAChRs as a new approach to potentially treat schizophrenia and other psychotic disorders. The authors discuss recent advances in mAChR biology and pharmacology and the current understanding of the relative roles of the various mAChR subtypes, their downstream cellular effectors, and key neural circuits mediating the reduction in the core symptoms of schizophrenia in patients treated with xanomeline. They also provide an update on the status of novel mAChR agonists currently in development for potential treatment of schizophrenia and other neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Objective: Psychotic experiences are common in children and adolescents and are associated with concurrent and subsequent psychopathology. Most findings originate from general population studies, whereas little is known of the clinical outcomes of psychotic experiences in children and adolescents at familial high risk of psychosis. We examined the prevalence of psychotic experiences in middle childhood and whether early childhood psychotic experiences and developmental pathways of psychotic experiences predicted mental disorders in middle childhood in children at familial high risk of schizophrenia (FHR-SZ), bipolar disorder (FHR-BP), and a population-based control group.Methods: In a longitudinal population-based cohort study children at FHR-SZ (N=170), FHR-BP (N=103), and the control group (N=174) were assessed for psychotic experiences and axis I disorders with face-to-face interviews in early and middle childhood (at 7 and 11 years of age).Results: Psychotic experiences were more prevalent in children at FHR-SZ (31.8%, odds ratio 2.1, 95% CI 1.3-3.4) than in the control group (18.4%) in middle childhood. Early childhood psychotic experiences predicted mental disorders in middle childhood after adjusting for early childhood disorders and familial risk (odds ratio 2.0, 95% CI 1.2-3.1). Having three or more psychotic experiences increased odds the most (odds ratio 2.5, 95% CI 1.1-5.7). Persistent psychotic experiences were associated with increased odds of middle childhood disorders (odds ratio 4.1, 95% CI 2.1-8.4). Psychotic experiences were nondifferentially associated with mental disorders across the three familial risk groups.Conclusions: Early childhood psychotic experiences predict mental disorders in middle childhood. Psychotic experiences index vulnerability for psychopathology nondifferentially in children at familial high risk and the control group. Psychotic experiences should be included in mental health screenings including children at familial high risk. [ABSTRACT FROM AUTHOR]

ObjectiveChromosome 22q11.2 deletion syndrome (22q11.2DS) is associated with a more than 20-fold increased risk for developing schizophrenia. The aim of this study was to identify additional genetic factors (i.e., "second hits") that may contribute to schizophrenia expression.MethodThrough an international consortium, the authors obtained DNA samples from 329 psychiatrically phenotyped subjects with 22q11.2DS. Using a high-resolution microarray platform and established methods to assess copy number variation (CNV), the authors compared the genome-wide burden of rare autosomal CNV, outside of the 22q11.2 deletion region, between two groups: a schizophrenia group and those with no psychotic disorder at age ≥25 years. The authors assessed whether genes overlapped by rare CNVs were overrepresented in functional pathways relevant to schizophrenia.ResultsRare CNVs overlapping one or more protein-coding genes revealed significant between-group differences. For rare exonic duplications, six of 19 gene sets tested were enriched in the schizophrenia group; genes associated with abnormal nervous system phenotypes remained significant in a stepwise logistic regression model and showed significant interactions with 22q11.2 deletion region genes in a connectivity analysis. For rare exonic deletions, the schizophrenia group had, on average, more genes overlapped. The additional rare CNVs implicated known (e.g., GRM7, 15q13.3, 16p12.2) and novel schizophrenia risk genes and loci.ConclusionsThe results suggest that additional rare CNVs overlapping genes outside of the 22q11.2 deletion region contribute to schizophrenia risk in 22q11.2DS, supporting a multigenic hypothesis for schizophrenia. The findings have implications for understanding expression of psychotic illness and herald the importance of whole-genome sequencing to appreciate the overall genomic architecture of schizophrenia.

There is an urgent and unmet need to advance our ability to translate genetic studies of psychiatric disorders into clinically actionable information, which could transform diagnostics and even one day lead to novel (and potentially presymptomatic) therapeutic interventions. Today, although there are hundreds of significant loci associated with psychiatric disorders, resolving the target gene(s) and pathway(s) impacted by each is a major challenge. Integrating human induced pluripotent stem cell-based approaches with CRISPR-mediated genomic engineering strategies makes it possible to study the impact of patient-specific variants within the cell types of the brain. As the scale and scope of functional genomic studies expands, so does our ability to resolve the complex interplay of the many risk variants linked to psychiatric disorders. In this review, the author discusses some of the technological advances that make it possible to ask exciting questions that are fundamental to our understanding of psychiatric disorders. How do distinct risk variants converge and interact with each other (and the environment) across the diverse cell types that comprise the human brain? Can clinical trajectories and/or therapeutic response be predicted from genetic profiles? Just as critically, by spreading the message that genetic risk for psychiatric disorders is biological and fundamentally no different than for other human conditions, we can dispel the stigma associated with mental illness. [ABSTRACT FROM AUTHOR]

The major cause of disability in schizophrenia is cognitive impairment, which remains largely refractory to existing treatments. This reflects the fact that antipsychotics and other therapies have not been designed to address specific brain abnormalities that cause cognitive impairment. This overview proposes that understanding how specific cellular and synaptic loci within cortical microcircuits contribute to cortical gamma oscillations may reveal treatments for cognitive impairment. Gamma oscillations are rhythmic patterns of high frequency (∼30-100 Hz) neuronal activity that are synchronized within and across brain regions, generated by a class of inhibitory interneurons that express parvalbumin, and recruited during a variety of cognitive tasks. In schizophrenia, both parvalbumin interneuron function and task-evoked gamma oscillations are deficient. While it has long been controversial whether gamma oscillations are merely a biomarker of circuit function or actually contribute to information processing by neuronal networks, recent neurobiological studies in mice have shown that disrupting or enhancing synchronized gamma oscillations can reproduce or ameliorate cognitive deficits resembling those seen in schizophrenia. In fact, transiently enhancing the synchrony of parvalbumin interneuron-generated gamma oscillations can lead to long-lasting improvements in cognition in mice that model aspects of schizophrenia. Gamma oscillations emerge from specific patterns of connections between a variety of cell types within cortical microcircuits. Thus, a critical next step is to understand how specific cell types and synapses generate gamma oscillations, mediate the effects of gamma oscillations on information processing, and/or undergo plasticity following the induction of gamma oscillations. Modulating these circuit loci, potentially in combination with other approaches such as cognitive training and brain stimulation, may yield potent and selective interventions for enhancing cognition in schizophrenia. [ABSTRACT FROM AUTHOR]

Objective: Cognitive impairments in schizophrenia are associated with lower gamma oscillation power in the prefrontal cortex (PFC). Gamma power depends in part on excitatory drive to fast-spiking parvalbumin interneurons (PVIs). Excitatory drive to cortical neurons varies in strength, which could affect how these neurons regulate network oscillations. The authors investigated whether variability in excitatory synaptic strength across PVIs could contribute to lower prefrontal gamma power in schizophrenia.Methods: In postmortem PFC from 20 matched pairs of comparison and schizophrenia subjects, levels of vesicular glutamate transporter 1 (VGlut1) and postsynaptic density 95 (PSD95) proteins were quantified to assess variability in excitatory synaptic strength across PVIs. A computational model network was then used to simulate how variability in excitatory synaptic strength across fast-spiking (a defining feature of PVIs) interneurons (FSIs) regulates gamma power.Results: The variability of VGlut1 and PSD95 levels at excitatory inputs across PVIs was larger in schizophrenia relative to comparison subjects. This alteration was not influenced by schizophrenia-associated comorbid factors, was not present in monkeys chronically exposed to antipsychotic medications, and was not present in calretinin interneurons. In the model network, variability in excitatory synaptic strength across FSIs regulated gamma power by affecting network synchrony. Finally, greater synaptic variability interacted synergistically with other synaptic alterations in schizophrenia (i.e., fewer excitatory inputs to FSIs and lower inhibitory strength from FSIs) to robustly reduce gamma power.Conclusions: The study findings suggest that greater variability in excitatory synaptic strength across PVIs, in combination with other modest synaptic alterations in these neurons, can markedly lower PFC gamma power in schizophrenia. [ABSTRACT FROM AUTHOR]

The article reviews several articles on topics like the effectiveness of varenicline and naltrexone for smoking cessation and drinking reduction, the clinical relevance of brain imaging, and medication-associated cognitive impairments in schizophrenia.

The article expresses gratitude for the American Psychiatric Association's Resource Document on treating opioid use disorder (OUD) in general hospitals, emphasizing the importance of initiating medication-assisted treatment (MOUD) during hospital admissions. It highlights two crucial misrepresentations regarding the treatment options, emphasizing that practitioners with Schedule III authority can prescribe buprenorphine without a waiver.

The article responds to the interest in the study on methamphetamine-induced psychosis (MIP) and its relation to schizophrenia. Topics include the higher transition rates from cannabis-induced psychosis to schizophrenia spectrum disorder compared to amphetamine-induced psychosis, and the argument that substance-induced psychosis should be considered within the psychosis continuum rather than solely as a specification of substance use disorder in diagnostic classifications.