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One Mind, in partnership with Meadows Mental Health Policy Institute, convened several virtual meetings of mental health researchers, clinicians, and other stakeholders in 2020 to identify first steps toward creating an initiative for early screening and linkage to care for youths (individuals in early adolescence through early adulthood, ages 10–24 years) with mental health difficulties, including serious mental illness, in the United States. This article synthesizes and builds on discussions from those meetings by outlining and recommending potential steps and considerations for the development and integration of a novel measurement-based screening process in youth-facing school and medical settings to increase early identification of mental health needs and linkage to evidence-based care. Meeting attendees agreed on an initiative incorporating a staged assessment process that includes a first-stage brief screener for several domains of psychopathology. Individuals who meet threshold criteria on the first-stage screener would then complete an interview, a second-stage in-depth screening, or both. Screening must be followed by recommendations and linkage to an appropriate level of evidence-based care based on acuity of symptoms endorsed during the staged assessment. Meeting attendees proposed steps and discussed additional considerations for creating the first nationwide initiative for screening and linkage to care, an initiative that could transform access of youths to mental health screening and care. [ABSTRACT FROM AUTHOR]

Objective: High comorbidity among psychiatric disorders suggests that they may share underlying neurobiological deficits. Abnormalities in cortical thickness and volume have been demonstrated in clinical samples of adults, but less is known when these structural differences emerge in youths. The purpose of this study was to examine the association between dimensions of psychopathology and brain structure.Methods: The authors studied 1,394 youths who underwent brain imaging as part of the Philadelphia Neurodevelopmental Cohort. Dimensions of psychopathology were constructed using a bifactor model of symptoms. Cortical thickness and volume were quantified using high-resolution 3-T MRI. Structural covariance networks were derived using nonnegative matrix factorization and analyzed using generalized additive models with penalized splines to capture both linear and nonlinear age-related effects.Results: Fear symptoms were associated with reduced cortical thickness in most networks, and overall psychopathology was associated with globally reduced gray matter volume across all networks. Structural covariance networks predicted psychopathology symptoms above and beyond demographic characteristics and cognitive performance.Conclusions: The results suggest a dissociable relationship whereby fear is most strongly linked to reduced cortical thickness and overall psychopathology is most strongly linked to global reductions in gray matter volume. Such results have implications for understanding how abnormalities of brain development may be associated with divergent dimensions of psychopathology. [ABSTRACT FROM AUTHOR]

Objective: Anhedonia is central to multiple psychiatric disorders and causes substantial disability. A dimensional conceptualization posits that anhedonia severity is related to a transdiagnostic continuum of reward deficits in specific neural networks. Previous functional connectivity studies related to anhedonia have focused on case-control comparisons in specific disorders, using region-specific seed-based analyses. Here, the authors explore the entire functional connectome in relation to reward responsivity across a population of adults with heterogeneous psychopathology.Method: In a sample of 225 adults from five diagnostic groups (major depressive disorder, N=32; bipolar disorder, N=50; schizophrenia, N=51; psychosis risk, N=39; and healthy control subjects, N=53), the authors conducted a connectome-wide analysis examining the relationship between a dimensional measure of reward responsivity (the reward sensitivity subscale of the Behavioral Activation Scale) and resting-state functional connectivity using multivariate distance-based matrix regression.Results: The authors identified foci of dysconnectivity associated with reward responsivity in the nucleus accumbens, the default mode network, and the cingulo-opercular network. Follow-up analyses revealed dysconnectivity among specific large-scale functional networks and their connectivity with the nucleus accumbens. Reward deficits were associated with decreased connectivity between the nucleus accumbens and the default mode network and increased connectivity between the nucleus accumbens and the cingulo-opercular network. In addition, impaired reward responsivity was associated with default mode network hyperconnectivity and diminished connectivity between the default mode network and the cingulo-opercular network.Conclusions: These results emphasize the centrality of the nucleus accumbens in the pathophysiology of reward deficits and suggest that dissociable patterns of connectivity among large-scale networks are critical to the neurobiology of reward dysfunction across clinical diagnostic categories. [ABSTRACT FROM AUTHOR]

Objective: Disruption of executive function is present in many neuropsychiatric disorders. However, determining the specificity of executive dysfunction across these disorders is challenging given high comorbidity of conditions. Here the authors investigate executive system deficits in association with dimensions of psychiatric symptoms in youth using a working memory paradigm. The authors hypothesize that common and dissociable patterns of dysfunction would be present.Method: The authors studied 1,129 youths who completed a fractal n-back task during functional magnetic resonance imaging at 3-T as part of the Philadelphia Neurodevelopmental Cohort. Factor scores of clinical psychopathology were calculated using an item-wise confirmatory bifactor model, describing overall psychopathology as well as four orthogonal dimensions of symptoms: anxious-misery (mood and anxiety), behavioral disturbance (attention deficit hyperactivity disorder and conduct disorder), psychosis-spectrum symptoms, and fear (phobias). The effect of psychopathology dimensions on behavioral performance and executive system recruitment (2-back > 0-back) was examined using both multivariate (matrix regression) and mass-univariate (linear regression) analyses.Results: Overall psychopathology was associated with both abnormal multivariate patterns of activation and a failure to activate executive regions within the cingulo-opercular control network, including the frontal pole, cingulate cortex, and anterior insula. In addition, psychosis-spectrum symptoms were associated with hypoactivation of the left dorsolateral prefrontal cortex, whereas behavioral symptoms were associated with hypoactivation of the frontoparietal cortex and cerebellum. In contrast, anxious-misery symptoms were associated with widespread hyperactivation of the executive network.Conclusions: These findings provide novel evidence that common and dissociable deficits within the brain's executive system are present in association with dimensions of psychopathology in youth. [ABSTRACT FROM AUTHOR]

Objective: The Consortium on the Genetics of Schizophrenia Family Study evaluated 12 primary and other supplementary neurocognitive and neurophysiological endophenotypes in schizophrenia probands and their families. Previous analyses of prepulse inhibition (PPI) and P50 gating measures in this sample revealed heritability estimates that were lower than expected based on earlier family studies. Here the authors investigated whether gating measures were more heritable in multiply affected families with a positive family history compared with families with only a single affected proband (singleton).Method: A total of 296 nuclear families consisting of a schizophrenia proband, at least one unaffected sibling, and both parents underwent a comprehensive endophenotype and clinical characterization. The Family Interview for Genetic Studies was administered to all participants and used to obtain convergent psychiatric symptom information for additional first-degree relatives. Among the families, 97 were multiply affected, and 96 were singletons.Results: Both PPI and P50 gating displayed substantially increased heritability in the 97 multiply affected families (47% and 36%, respectively) compared with estimates derived from the entire sample of 296 families (29% and 20%, respectively). However, no evidence for heritability was observed for either measure in the 96 singleton families. Schizophrenia probands derived from the multiply affected families also displayed a significantly increased severity of clinical symptoms compared with those from singleton families.Conclusions: PPI and P50 gating measures demonstrate substantially increased heritability in schizophrenia families with a higher genetic vulnerability for illness, providing further support for the commonality of genes underlying both schizophrenia and gating measures. [ABSTRACT FROM AUTHOR]

Objective: The Consortium on the Genetics of Schizophrenia has undertaken a large multisite study to characterize 12 neurophysiological and neurocognitive endophenotypic measures as a step toward understanding the complex genetic basis of schizophrenia. The authors previously demonstrated the heritability of these endophenotypes; in the present study, genetic linkage was evaluated. Method: Each family consisted of a proband with schizophrenia, at least one unaffected sibling, and both parents. A total of 1,286 participants from 296 families were genotyped in two phases, and 1,004 individuals were also assessed for the endophenotypes. Linkage analyses of the 6,055 singlenucleotide polymorphisms that were successfully assayed, 5,760 of which were common to both phases, were conducted using both variance components and pedigreewide regression methods. Results: Linkage analyses of the 12 endophenotypes collectively identified one region meeting genome-wide significance criteria, with a LOD (log of odds) score of 4.0 on chromosome 3p14 for the antisaccade task, and another region on 1p36 nearly meeting genome-wide significance, with a LOD score of 3.5 for emotion recognition. Chromosomal regions meeting genome-wide suggestive criteria with LOD scores >2.2 were identified for spatial processing (2p25 and 16q23), sensorimotor dexterity (2q24 and 2q32), prepulse inhibition (5p15), the California Verbal Learning Test (8q24), the degradedstimulus Continuous Performance Test (10q26), face memory (10q26 and 12p12), and the Letter-Number Span (14q23). Conclusions: Twelve regions meeting genome-wide significant and suggestive criteria for previously identified heritable, schizophrenia-related endophenotypes were observed, and several genes of potential neurobiological interest were identified. Replication and further genomic studies are needed to assess the biological significance of these results. [ABSTRACT FROM AUTHOR]

Objective: The authors used a custom array of 1,536 single-nucleotide polymorphisms (SNPs) to interrogate 94 functionally relevant candidate genes for schizophrenia and identify associations with 12 heritable neurophysiological and neurocognitive endophenotypes in data collected by the Consortium on the Genetics of Schizophrenia. Method: Variance-component association analyses of 534 genotyped subjects from 130 families were conducted by using Merlin software. A novel bootstrap total significance test was also developed to overcome the limitations of existing genomic multiple testing methods and robustly demonstrate significant associations in the context of complex family data and possible population stratification effects. Results: Associations with endopheno- types were observed for 46 genes of potential functional significance, with three SNP5 at p<10-4, 27 SNPs at p<10-3, and 147 SNPs at p<0.01. The bootstrap analyses confirmed that the 47 SNP-endophenotype combinations with the strongest evidence of association significantly exceeded that expected by chance alone, with 93% of these findings expected to be true. Many of the genes interact on a molecular level, and eight genes (e.g., NRG1 and ERBB4) displayed evidence for pleiotropy, revealing associations with four or more endophenotypes. The results collectively support a strong role for genes related to glutamate signaling in mediating schizophrenia susceptibility. conclusions: This study supports use of relevant endophenotypes and the boot-strap total significance test for identifying genetic variation underlying the etiology of schizophrenia. In addition, the observation of extensive pleiotropy for some genes and singular associations for others suggests alternative, independent pathways mediating pathogenesis in the "group of schizophrenias." [ABSTRACT FROM AUTHOR]

Objective: Neurocognitive impairments in schizophrenia are well replicated and widely regarded as candidate endophenotypes that may facilitate understanding of schizophrenia genetics and pathophysiology. The Project Among African-Americans to Explore Risks for Schizophrenia (PAARTNERS) aims to identify genes underlying liability to schizophrenia. The unprecedented size of its study group (N=1,872), made possible through use of a computerized neurocognitive battery, can help further investigation of the genetics of neurocognition. The current analysis evaluated two characteristics not fully addressed in prior research: 1) heritability of neurocognition in African American families and 2) relationship between neurocognition and psychopathology in families of African American probands with schizophrenia or schizoaffective disorder. Method: Across eight data collection sites, patients with schizophrenia or schizoaffective disorder (N=610), their biological relatives (N=928), and community comparison subjects (N=334) completed a standardized diagnostic evaluation and the computerized neurocognitive battery. Performance accuracy and response time (speed) were measured separately for 10 neurocognitive domains. Results: The patients with schizophrenia or schizoaffective disorder exhibited less accuracy and speed in most neurocognitive domains than their relatives both with and without other psychiatric disorders, who in turn were more impaired than comparison subjects in most domains. Estimated trait heritability after inclusion of the mean effect of diagnostic status, age, and sex revealed significant heritabilities for most neurocognitive domains, with the highest for accuracy of abstraction/ flexibility, verbal memory, face memory, spatial processing, and emotion processing and for speed of attention. Conclusions: Neurocognitive functions in African American families are heritable and associated with schizophrenia. They show potential for gene-mapping studies. [ABSTRACT FROM AUTHOR]

Objective: Deficits in neurocognitive function have been demonstrated in individuals with schizophrenia and in the unaffected family members of these individuals. Genetic studies of such complementary traits, along with traditional analyses of diagnosis, may help to elucidate the biological pathways underlying familial liability to schizophrenia and related disorders. The authors conducted a multiplex, multigenerational family study using a genome-wide screen for schizophrenia and related neurocognitive phenotypes. Method: Participants were I) 676 European American individuals from 43 families, ascertained through an individual with schizophrenia, and 2) 236 healthy comparison subjects. Participants were evaluated clinically and examined through the use of a computerized neurocognitive test battery that provided measures of accuracy and speed on the cognitive domains of abstraction and mental flexibility; attention; verbal, face, and spatial memory; language and reasoning; spatial and emotion processing; and sensorimotor dexterity. A genome-wide linkage screen was also performed. Healthy comparison subjects were included in order to obtain normative phenotypic data but were not genotyped. Results: Significant evidence for linkage of schizophrenia to chromosome 19q was observed. Analysis of cognitive traits revealed significant linkage to chromosome 5q for the domains of abstraction and mental flexibility. A variety of other neurocognitive traits also showed nominal evidence of linkage to the 5q region. Joint analyses with diagnosis suggested that this quantitative trait locus may also influence schizophrenia. Conclusions: Although chromosome 5 has been implicated in previous linkage studies of schizophrenia, the identification of the chromosome 19 quantitative trait locus is a novel finding. The identification of the chromosome 5 quantitative trait locus through linkage to neurocognitive phenotypes in the present study may inform functional hypotheses pertaining to how genotypes are connected to disease. [ABSTRACT FROM AUTHOR]

Objective: Studies of emotion recognition abilities in schizophrenia show greater impairment for non-Caucasians with schizophrenia compared with Caucasians. These studies, however, included only Caucasian faces as stimuli. There is evidence from healthy individuals for a performance disadvantage on face memory and emotion recognition when processing faces from a different ethnicity. The authors sought to measure the "other-race effect" in schizophrenia, which could account for previous findings and provide information about sensitivity to such social cues in patients. Method: The study included 540 participants from four groups: African Americans with schizophrenia (N=1.35), Caucasians with schizophrenia (N=135), African American community comparison subjects (N=135), and Caucasian community comparison subjects (N=135). All participants completed face recognition and facial emotion identification tasks that included both Caucasian and African American faces as stimuli. Results: Although comparison participants performed better than individuals with schizophrenia across all tasks, both comparison participants and participants with schizophrenia exhibited a strong and significant other-race effect for face memory and emotion recognition. The magnitude of the other-race effect did not differ between these two groups. Conclusions: These findings reveal an intact other-race effect in patients with schizophrenia and highlight a methodological concern in the measurement of face processing abilities in schizophrenia, namely, that findings of greater impairment in African American patients are spurious when Caucasian faces are used as stimuli. Despite overall impairments in face memory and emotion recognition, the presence of a normative other-race effect in schizophrenia may reflect typical experiences with faces during development. [ABSTRACT FROM AUTHOR]

Objective: Genetic factors contribute to the development of schizophrenia where cognitive dysfunction is a hallmark. The purpose of this article was to examine computerized neurocognitive measures as candidate endophenotypic markers of liability for schizophrenia in a genetically informative cohort. Method: European Americans from 35 multiplex multigenerational families (N= 349) and healthy participants (N:154) underwent clinical assessments and neurocognitive measurements and provided blood samples. The neurocognitive measures included performance (accuracy and speed) from a computerized battery that assessed abstraction/mental flexibility; attention; verbal, face, and spatial memory; spatial processing; sensorimotor processing; and emotion intensity discrimination. Results: Probands, relatives, and comparison subjects differed from each other in performance. Probands demonstrated greatest impairment relative to comparison subjects, followed by family members. Liability for schizophrenia affected the speed-accuracy tradeoff differently for specific neurocognitive domains. Significant heritability estimates were obtained for accuracy of verbal, facial, and spatial memory and spatial and emotion processing. For speed, estimates of heritability were significant for abstraction/mental flexibility, attention, face memory, and spatial and sensorimotor processing. Conclusions: In a multigenerational multiplex design, the authors demonstrated that neurocognitive measures are associated with schizophrenia, differentiate unaffected relatives from comparison subjects, and may have significant presumed heritability. Therefore, they are endophenotypes suitable for genetic studies. Accuracy and speed can be differentially sensitive to presumed genetic liability. [ABSTRACT FROM AUTHOR]

Objective: Face recognition memory deficits in schizophrenia are attributed to frontotemporal dysfunction. Biological relatives of patients have similar deficits, suggesting genetic susceptibility. Because the impairment may reflect generalized object memory deficits, the authors evaluated both face and visual object recognition. Method: The Penn Face Memory Test and Visual Object Learning Test were given to 102 patients with schizophrenia, 60 of their biological relatives, and 135 healthy comparison subjects. Results: Significant immediate and delayed face recognition deficits were observed in patients and their relatives. Although patients were more impaired in visual object memory than comparison subjects, relatives were not. Conclusions: Face recognition deficits in patients with schizophrenia and their families are not secondary to generalized object memory deficits and may be an endophenotype reflecting frontotemporal impairment. [ABSTRACT FROM AUTHOR]

Examines the association of saccadic disinhibition with genetic liability in patients with acute and remitted schizophrenia. Use of antisaccade task performance as indicator of prefrontal integrity; Difficulty of schizophrenics in inhibiting unwanted saccades; Impact of medications on antisaccade deficits regardless of clinical state.