A polygenic resilience score moderates the genetic risk for schizophrenia: Replication in 18,090 cases and 28,114 controls from the Psychiatric Genomics Consortium.

Identifying heritable factors that moderate the genetic risk for schizophrenia (SCZ) could help clarify why some individuals remain unaffected despite having relatively high genetic liability. Previously, we developed a framework to mine genome-wide association (GWAS) data for common genetic variants that protect high-risk unaffected individuals from SCZ, leading to derivation of the first-ever "polygenic resilience score" for SCZ (resilient controls n = 3786; polygenic risk score-matched SCZ cases n = 18,619). Here, we performed a replication study to verify the moderating effect of our polygenic resilience score on SCZ risk (OR = 1.09, p = 4.03 × 10-5 ) using newly released GWAS data from 23 independent case-control studies collated by the Psychiatric Genomics Consortium (PGC) (resilient controls n = 2821; polygenic risk score-matched SCZ cases n = 5150). Additionally, we sought to optimize our polygenic resilience-scoring formula to improve subsequent modeling of resilience to SCZ and other complex disorders. We found significant replication of the polygenic resilience score, and found that strict pruning of SNPs based on linkage disequilibrium to known risk SNPs and their linked loci optimizes the performance of the polygenic resilience score.

Genetic Influences on Cognitive Dysfunction in Schizophrenia.

Schizophrenia is a severe and debilitating psychotic disorder that is highly heritable and relatively common in the population. The clinical heterogeneity associated with schizophrenia is substantial, with patients exhibiting a broad range of deficits and symptom severity. Large-scale genomic studies employing a case-control design have begun to provide some biological insight. However, this strategy combines individuals with clinically diverse symptoms and ignores the genetic risk that is carried by many clinically unaffected individuals. Consequently, the majority of the genetic architecture underlying schizophrenia remains unexplained, and the pathways by which the implicated variants contribute to the clinically observable signs and symptoms are still largely unknown. Parsing the complex, clinical phenotype of schizophrenia into biologically relevant components may have utility in research aimed at understanding the genetic basis of liability. Cognitive dysfunction is a hallmark symptom of schizophrenia that is associated with impaired quality of life and poor functional outcome. Here, we examine the value of quantitative measures of cognitive dysfunction to objectively target the underlying neurobiological pathways and identify genetic variants and gene networks contributing to schizophrenia risk. For a complex disorder, quantitative measures are also more efficient than diagnosis, allowing for the identification of associated genetic variants with fewer subjects. Such a strategy supplements traditional analyses of schizophrenia diagnosis, providing the necessary biological insight to help translate genetic findings into actionable treatment targets. Understanding the genetic basis of cognitive dysfunction in schizophrenia may thus facilitate the development of novel pharmacological and procognitive interventions to improve real-world functioning.

Bipolar spectrum traits and the space between Madness and Genius: The Muse is in the Dose.

Creativity has long been associated with the bipolar spectrum, particularly among unaffected first-degree relatives and those with milder expressions of bipolar traits, suggesting that some aspects of the bipolar spectrum may confer advantages for creativity. Here we took a multifaceted approach to better define the shared vulnerability between creativity and bipolar disorder. We recruited 135 individuals with bipolar disorder, 102 creative controls, and 103 non-creative controls for a total of 340 participants. All participants completed a comprehensive assessment battery that included several self-report temperament and personality questionnaires, a computerized test of cognitive function across multiple domains, and an evaluation of creative performance and achievement. Significant group differences were observed for the hypothesized shared vulnerability traits of hypomanic personality, cyclothymic temperament, impulsivity, and positive schizotypy. While both the creative and bipolar groups demonstrated superior creative ability, the creative group alone revealed enhanced cognitive performance. Accounting for intercorrelations between traits, a combination of openness, hypomanic personality, divergent thinking, and reasoning ability emerged as the strongest predictors of creativity, collectively explaining 34% of the variance in creative achievement and correctly classifying 85% of individuals with high achievement irrespective of diagnosis. These results confirm and extend earlier observations of a shared vulnerability between creativity and bipolar disorder and suggest that mild to moderate expressions of bipolar spectrum traits are associated with enhanced cognitive functioning and creative expression. Further investigation of these traits is needed to clarify the nature of this shared vulnerability and suggest individualized treatment strategies to improve clinical outcomes in bipolar disorder.

Anticholinergic Medication Burden-Associated Cognitive Impairment in Schizophrenia.

OBJECTIVE: Many 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. METHODS: Cross-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). RESULTS: ACB 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. CONCLUSIONS: Anticholinergic 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.

A polygenic resilience score moderates the genetic risk for schizophrenia.

Based on the discovery by the Resilience Project (Chen R. et al. Nat Biotechnol 34:531-538, 2016) of rare variants that confer resistance to Mendelian disease, and protective alleles for some complex diseases, we posited the existence of genetic variants that promote resilience to highly heritable polygenic disorders1,0 such as schizophrenia. Resilience has been traditionally viewed as a psychological construct, although our use of the term resilience refers to a different construct that directly relates to the Resilience Project, namely: heritable variation that promotes resistance to disease by reducing the penetrance of risk loci, wherein resilience and risk loci operate orthogonal to one another. In this study, we established a procedure to identify unaffected individuals with relatively high polygenic risk for schizophrenia, and contrasted them with risk-matched schizophrenia cases to generate the first known "polygenic resilience score" that represents the additive contributions to SZ resistance by variants that are distinct from risk loci. The resilience score was derived from data compiled by the Psychiatric Genomics Consortium, and replicated in three independent samples. This work establishes a generalizable framework for finding resilience variants for any complex, heritable disorder.

Genome-Wide Association Studies of Schizophrenia and Bipolar Disorder in a Diverse Cohort of US Veterans.

BACKGROUND: Schizophrenia (SCZ) and bipolar disorder (BIP) are debilitating neuropsychiatric disorders, collectively affecting 2% of the world's population. Recognizing the major impact of these psychiatric disorders on the psychosocial function of more than 200 000 US Veterans, the Department of Veterans Affairs (VA) recently completed genotyping of more than 8000 veterans with SCZ and BIP in the Cooperative Studies Program (CSP) #572. METHODS: We performed genome-wide association studies (GWAS) in CSP #572 and benchmarked the predictive value of polygenic risk scores (PRS) constructed from published findings. We combined our results with available summary statistics from several recent GWAS, realizing the largest and most diverse studies of these disorders to date. RESULTS: Our primary GWAS uncovered new associations between CHD7 variants and SCZ, and novel BIP associations with variants in Sortilin Related VPS10 Domain Containing Receptor 3 (SORCS3) and downstream of PCDH11X. Combining our results with published summary statistics for SCZ yielded 39 novel susceptibility loci including CRHR1, and we identified 10 additional findings for BIP (28 326 cases and 90 570 controls). PRS trained on published GWAS were significantly associated with case-control status among European American (P < 10-30) and African American (P < .0005) participants in CSP #572. CONCLUSIONS: We have demonstrated that published findings for SCZ and BIP are robustly generalizable to a diverse cohort of US veterans. Leveraging available summary statistics from GWAS of global populations, we report 52 new susceptibility loci and improved fine-mapping resolution for dozens of previously reported associations.

Heritability of acoustic startle magnitude and latency from the consortium on the genetics of schizophrenia.

BACKGROUND: Latency of the acoustic startle reflex is the time from presentation of the startling stimulus until the response, and provides an index of neural processing speed. Schizophrenia subjects exhibit slowed latency compared to healthy controls. One prior publication reported significant heritability of latency. The current study was undertaken to replicate and extend this solitary finding in a larger cohort. METHODS: Schizophrenia probands, their relatives, and control subjects from the Consortium on the Genetics of Schizophrenia (COGS-1) were tested in a paradigm to ascertain magnitude, latency, and prepulse inhibition of startle. Trial types in the paradigm were: pulse-alone, and trials with 30, 60, or 120 ms between the prepulse and pulse. Comparisons of subject groups were conducted with ANCOVAs to assess startle latency and magnitude. Heritability of startle magnitude and latency was analyzed with a variance component method implemented in SOLAR v.4.3.1. RESULTS: 980 subjects had analyzable startle results: 199 schizophrenia probands, 456 of their relatives, and 325 controls. A mixed-design ANCOVA on startle latency in the four trial types was significant for subject group (F(2,973) = 4.45, p = 0.012) such that probands were slowest, relatives were intermediate and controls were fastest. Magnitude to pulse-alone trials differed significantly between groups by ANCOVA (F(2,974) = 3.92, p = 0.020) such that controls were lowest, probands highest, and relatives intermediate. Heritability was significant (p < 0.0001), with heritability of 34-41% for latency and 45-59% for magnitude. CONCLUSION: Both startle latency and magnitude are significantly heritable in the COGS-1 cohort. Startle latency is a strong candidate for being an endophenotype in schizophrenia.

The effects of age and sex on cognitive impairment in schizophrenia: Findings from the Consortium on the Genetics of Schizophrenia (COGS) study.

Recently emerging evidence indicates accelerated age-related changes in the structure and function of the brain in schizophrenia, raising a question about its potential consequences on cognitive function. Using a large sample of schizophrenia patients and controls and a battery of tasks across multiple cognitive domains, we examined whether patients show accelerated age-related decline in cognition and whether an age-related effect differ between females and males. We utilized data of 1,415 schizophrenia patients and 1,062 healthy community collected by the second phase of the Consortium on the Genetics of Schizophrenia (COGS-2). A battery of cognitive tasks included the Letter-Number Span Task, two forms of the Continuous Performance Test, the California Verbal Learning Test, Second Edition, the Penn Emotion Identification Test and the Penn Facial Memory Test. The effect of age and gender on cognitive performance was examined with a general linear model. We observed age-related changes on most cognitive measures, which was similar between males and females. Compared to controls, patients showed greater deterioration in performance on attention/vigilance and greater slowness of processing social information with increasing age. However, controls showed greater age-related changes in working memory and verbal memory compared to patients. Age-related changes (η2p of 0.001 to .008) were much smaller than between-group differences (η2p of 0.005 to .037). This study found that patients showed continued decline of cognition on some domains but stable impairment or even less decline on other domains with increasing age. These findings indicate that age-related changes in cognition in schizophrenia are subtle and not uniform across multiple cognitive domains.

Creativity and Bipolar Disorder: A Shared Genetic Vulnerability.

Bipolar disorder is a lifelong mood disorder characterized by extreme mood swings between mania and depression. Despite fitness costs associated with increased mortality and significant impairment, bipolar disorder has persisted in the population with a high heritability and a stable prevalence. Creativity and other positive traits have repeatedly been associated with the bipolar spectrum, particularly among unaffected first-degree relatives and those with milder expressions of bipolar traits. This suggests a model in which large doses of risk variants cause illness, but mild to moderate doses confer advantages, which serve to maintain bipolar disorder in the population. Bipolar disorder may thus be better conceptualized as a dimensional trait existing at the extreme of normal population variation in positive temperament, personality, and cognitive traits, aspects of which may reflect a shared vulnerability with creativity. Investigations of this shared vulnerability may provide insight into the genetic mechanisms underlying illness and suggest novel treatments.

Genome-wide association study of cognitive performance in U.S. veterans with schizophrenia or bipolar disorder.

Cognitive impairment is a frequent and serious problem in patients with various forms of severe mental illnesses (SMI), including schizophrenia (SZ) and bipolar disorder (BP). Recent research suggests genetic links to several cognitive phenotypes in both SMI and in the general population. Our goal in this study was to identify potential genomic signatures of cognitive functioning in veterans with severe mental illness and compare them to previous findings for cognition across different populations. Veterans Affairs (VA) Cooperative Studies Program (CSP) Study #572 evaluated cognitive and functional capacity measures among SZ and BP patients. In conjunction with the VA Million Veteran Program, 3,959 European American (1,095 SZ, 2,864 BP) and 2,601 African American (1,095 SZ, 2,864 BP) patients were genotyped using a custom Affymetrix Axiom Biobank array. We performed a genome-wide association study of global cognitive functioning, constructed polygenic scores for SZ and cognition in the general population, and examined genetic correlations with 2,626 UK Biobank traits. Although no single locus attained genome-wide significance, observed allelic effects were strongly consistent with previous studies. We observed robust associations between global cognitive functioning and polygenic scores for cognitive performance, intelligence, and SZ risk. We also identified significant genetic correlations with several cognition-related traits in UK Biobank. In a diverse cohort of U.S. veterans with SZ or BP, we demonstrate broad overlap of common genetic effects on cognition in the general population, and find that greater polygenic loading for SZ risk is associated with poorer cognitive performance.

Genome-wide Association of Endophenotypes for Schizophrenia From the Consortium on the Genetics of Schizophrenia (COGS) Study.

Importance: The Consortium on the Genetics of Schizophrenia (COGS) uses quantitative neurophysiological and neurocognitive endophenotypes with demonstrated deficits in schizophrenia as a platform from which to explore the underlying neural circuitry and genetic architecture. Many of these endophenotypes are associated with poor functional outcome in schizophrenia. Some are also endorsed as potential treatment targets by the US Food and Drug Administration. Objective: To build on prior assessments of heritability, association, and linkage in the COGS phase 1 (COGS-1) families by reporting a genome-wide association study (GWAS) of 11 schizophrenia-related endophenotypes in the independent phase 2 (COGS-2) cohort of patients with schizophrenia and healthy comparison participants (HCPs). Design, Setting, and Participants: A total of 1789 patients with schizophrenia and HCPs of self-reported European or Latino ancestry were recruited through a collaborative effort across the COGS sites and genotyped using the PsychChip. Standard quality control filters were applied, and more than 6.2 million variants with a genotyping call rate of greater than 0.99 were available after imputation. Association was performed for data sets stratified by diagnosis and ancestry using linear regression and adjusting for age, sex, and 5 principal components, with results combined through weighted meta-analysis. Data for COGS-1 were collected from January 6, 2003, to August 6, 2008; data for COGS-2, from June 30, 2010, to February 14, 2014. Data were analyzed from October 28, 2016, to May 4, 2018. Main Outcomes and Measures: A genome-wide association study was performed to evaluate association for 11 neurophysiological and neurocognitive endophenotypes targeting key domains of schizophrenia related to inhibition, attention, vigilance, learning, working memory, executive function, episodic memory, and social cognition. Results: The final sample of 1533 participants included 861 male participants (56.2%), and the mean (SD) age was 41.8 (13.6) years. In total, 7 genome-wide significant regions (P < 5 × 10-8) and 2 nearly significant regions (P < 9 × 10-8) containing several genes of interest, including NRG3 and HCN1, were identified for 7 endophenotypes. For each of the 11 endophenotypes, enrichment analyses performed at the level of P < 10-4 compared favorably with previous association results in the COGS-1 families and showed extensive overlap with regions identified for schizophrenia diagnosis. Conclusions and Relevance: These analyses identified several genomic regions of interest that require further exploration and validation. These data seem to demonstrate the utility of endophenotypes for resolving the genetic architecture of schizophrenia and characterizing the underlying biological dysfunctions. Understanding the molecular basis of these endophenotypes may help to identify novel treatment targets and pave the way for precision-based medicine in schizophrenia and related psychotic disorders.

Endophenotypes in Schizophrenia: Digging Deeper to Identify Genetic Mechanisms.

Schizophrenia (SZ) is a severe psychotic disorder that is highly heritable and common in the general population. The genetic heterogeneity of SZ is substantial, with contributions from common, rare, and de novo variants, in addition to environmental factors. Large genome-wide association studies have detected many variants that are associated with SZ, yet the pathways by which these variants influence risk remain largely unknown. SZ is also clinically heterogeneous, with patients exhibiting a broad range of deficits and symptom severity that vary over the course of illness and treatment, which has complicated efforts to identify risk variants. However, the underlying brain dysfunction forms a more stable trait marker that quantitative neurocognitive and neurophysiological endophenotypes may be able to objectively measure. These endophenotypes are less likely to be heterogeneous than the disorder and provide a neurobiological context to detect risk variants and underlying pathways among genes associated with SZ diagnosis. Furthermore, many endophenotypes are translational into animal model systems, allowing for direct evaluation of the neural circuit dysfunctions and neurobiological substrates. We review a selection of the most promising SZ endophenotypes, including prepulse inhibition, mismatch negativity, oculomotor antisaccade, letter-number sequencing, and continuous performance tests. We also highlight recent findings from large consortia that suggest the potential role of genes, particularly in the neuregulin and glutamate pathways, in several of these endophenotypes. Although endophenotypes require additional time and effort to assess, the insight into the underlying neurobiology that they provide may ultimately reveal the underlying genetic architecture for SZ and suggest novel treatment targets.

Implementing a college mental health program - an overview of the first twelve months.

OBJECTIVE: To evaluate the demographics and clinical utilization patterns among college students during the initial 12 months of a novel, multi-disciplinary, collaborative, college mental health program (CMHP). PARTICIPANTS: Undergraduate and graduate students receiving treatment at the CMHP from Jan-Dec 2015. METHODS: De-identified data was obtained via electronic health records for all students receiving care through the CMHP. RESULTS: 1.2 FTE clinical providers treated 278 undergraduate and graduate students during the year (65.1% < age 26, 53.6% female, 49.6% caucasian). There were 1822 CMHP outpatient visits, 318 other medical visits and 103 total emergency room (ER)/inpatient visits. Ten students were identified as high utilizers of ER/inpatient services, while charges to the CMHP totaled $470,157 and total charges to the Health System were $2,378,315. CONCLUSIONS: Students with complex psychiatric/medical co-morbidities received cost effective, convenient and integrative treatment. Over time, we hope to intervene earlier and decrease ER/inpatient visits.

Efficient region-based test strategy uncovers genetic risk factors for functional outcome in bipolar disorder.

Genome-wide association studies of case-control status have advanced the understanding of the genetic basis of psychiatric disorders. Further progress may be gained by increasing sample size but also by new analysis strategies that advance the exploitation of existing data, especially for clinically important quantitative phenotypes. The functionally-informed efficient region-based test strategy (FIERS) introduced herein uses prior knowledge on biological function and dependence of genotypes within a powerful statistical framework with improved sensitivity and specificity for detecting consistent genetic effects across studies. As proof of concept, FIERS was used for the first genome-wide single nucleotide polymorphism (SNP)-based investigation on bipolar disorder (BD) that focuses on an important aspect of disease course, the functional outcome. FIERS identified a significantly associated locus on chromosome 15 (hg38: chr15:48965004 - 49464789 bp) with consistent effect strength between two independent studies (GAIN/TGen: European Americans, BOMA: Germans; n = 1592 BD patients in total). Protective and risk haplotypes were found on the most strongly associated SNPs. They contain a CTCF binding site (rs586758); CTCF sites are known to regulate sets of genes within a chromatin domain. The rs586758 - rs2086256 - rs1904317 haplotype is located in the promoter flanking region of the COPS2 gene, close to microRNA4716, and the EID1, SHC4, DTWD1 genes as plausible biological candidates. While implication with BD is novel, COPS2, EID1, and SHC4 are known to be relevant for neuronal differentiation and function and DTWD1 for psychopharmacological side effects. The test strategy FIERS that enabled this discovery is equally applicable for tag SNPs and sequence data.

A Genetic Study of Psychosis in Huntington's Disease: Evidence for the Involvement of Glutamate Signaling Pathways.

BACKGROUND: Psychotic symptoms of delusions and hallucinations occur in about 5% of persons with Huntington's disease (HD). The mechanisms underlying these occurrences are unknown, but the same symptoms also occur in schizophrenia, and thus genetic risk factors for schizophrenia may be relevant to the development of psychosis in HD. OBJECTIVE: To investigate the possible role of genes associated with schizophrenia in the occurrence of psychotic symptoms in HD. METHODS: DNA from subjects with HD and psychosis (HD+P; n = 47), subjects with HD and no psychosis (HD-P; n = 126), and controls (CTLs; n = 207) was genotyped using the Infinium PsychArray-24 v1.1 BeadChip. The allele frequencies of single-nucleotide polymorphisms (SNPs) that were previously associated with schizophrenia and related psychiatric disorders were compared between these groups. RESULTS: Of the 30 candidate genes tested, 10 showed an association with psychosis in HD. The majority of these genes, including CTNNA2, DRD2, ERBB4, GRID2, GRIK4, GRM1, NRG1, PCNT, RELN, and SLC1A2, demonstrate network interactions related to glutamate signaling. CONCLUSIONS: This study suggests genetic associations between several previously identified candidate genes for schizophrenia and the occurrence of psychotic symptoms in HD. These data support the potential role of genes related to glutamate signaling in HD psychosis.

Deficient prepulse inhibition in schizophrenia in a multi-site cohort: Internal replication and extension.

BACKGROUND: The Consortium on the Genetics of Schizophrenia (COGS) collected case-control endophenotype and genetic information from 2457 patients and healthy subjects (HS) across 5 test sites over 3.5 years. Analysis of the first "wave" (W1) of 1400 subjects identified prepulse inhibition (PPI) deficits in patients vs. HS. Data from the second COGS "wave" (W2), and the combined W(1+2), were used to assess: 1) the replicability of PPI deficits in this design; 2) the impact of response criteria on PPI deficits; and 3) PPI in a large cohort of antipsychotic-free patients. METHODS: PPI in W2 HS (n=315) and schizophrenia patients (n=326) was compared to findings from W1; planned analyses assessed the impact of diagnosis, "wave" (1 vs. 2), and startle magnitude criteria. Combining waves allowed us to assess PPI in 120 antipsychotic-free patients, including many in the early course of illness. RESULTS: ANOVA of all W(1+2) subjects revealed robust PPI deficits in patients across "waves" (p<0.0004). Strict response criteria excluded almost 39% of all subjects, disproportionately impacting specific subgroups; ANOVA in this smaller cohort confirmed no significant effect of "wave" or "wave x diagnosis" interaction, and a significant effect of diagnosis (p<0.002). Antipsychotic-free, early-illness patients had particularly robust PPI deficits. DISCUSSION: Schizophrenia-linked PPI deficits were replicable across two multi-site "waves" of subjects collected over 3.5years. Strict response criteria disproportionately excluded older, male, non-Caucasian patients with low-normal hearing acuity. These findings set the stage for genetic analyses of PPI using the combined COGS wave 1 and 2 cohorts.

Positive Traits in the Bipolar Spectrum: The Space between Madness and Genius.

Bipolar disorder is a severe, lifelong mood disorder for which little is currently understood of the genetic mechanisms underlying risk. By examining related dimensional phenotypes, we may further our understanding of the disorder. Creativity has a historical connection with the bipolar spectrum and is particularly enhanced among unaffected first-degree relatives and those with bipolar spectrum traits. This suggests that some aspects of the bipolar spectrum may confer advantages, while more severe expressions of symptoms negatively influence creative accomplishment. Creativity is a complex, multidimensional construct with both cognitive and affective components, many of which appear to reflect a shared genetic vulnerability with bipolar disorder. It is suggested that a subset of bipolar risk variants confer advantages as positive traits according to an inverted-U-shaped curve with clinically unaffected allele carriers benefitting from the positive traits and serving to maintain the risk alleles in the population. The association of risk genes with creativity in healthy individuals (e.g., NRG1), as well as an overall sharing of common genetic variation between bipolar patients and creative individuals, provides support for this model. Current findings are summarized from a multidisciplinary perspective to demonstrate the feasibility of research in this area to reveal the mechanisms underlying illness.

Investigating Cortical Inhibition in First-Degree Relatives and Probands in Schizophrenia.

Deficits in GABAergic inhibitory neurotransmission are a reliable finding in schizophrenia (SCZ) patients. Previous studies have reported that unaffected first-degree relatives of patients with SCZ demonstrate neurophysiological abnormalities that are intermediate between probands and healthy controls. In this study, first-degree relatives of patients with SCZ and their related probands were investigated to assess frontal cortical inhibition. Long-interval cortical inhibition (LICI) was measured from the dorsolateral prefrontal cortex (DLPFC) using combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG). The study presents an extended sample of 129 subjects (66 subjects have been previously reported): 19 patients with SCZ or schizoaffective disorder, 30 unaffected first-degree relatives of these SCZ patients, 13 obsessive-compulsive disorder (OCD) patients, 18 unaffected first-degree relatives of these OCD patients and 49 healthy subjects. In the DLPFC, cortical inhibition was significantly decreased in patients with SCZ compared to healthy subjects. First-degree relatives of patients with SCZ showed significantly more cortical inhibition than their SCZ probands. No differences were demonstrated between first-degree relatives of SCZ patients and healthy subjects. Taken together, these findings show that more studies are needed to establish an objective biological marker for potential diagnostic usage in severe psychiatric disorders.

Modeling Deficits From Early Auditory Information Processing to Psychosocial Functioning in Schizophrenia.

IMPORTANCE: Neurophysiologic measures of early auditory information processing (EAP) are used as endophenotypes in genomic studies and biomarkers in clinical intervention studies. Research in schizophrenia has established correlations among measures of EAP, cognition, clinical symptoms, and functional outcome. Clarifying these associations by determining the pathways through which deficits in EAP affect functioning would suggest when and where to therapeutically intervene. OBJECTIVES: To characterize the pathways from EAP to outcome and to estimate the extent to which enhancement of basic information processing might improve cognition and psychosocial functioning in schizophrenia. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional data were analyzed using structural equation modeling to examine the associations among EAP, cognition, negative symptoms, and functional outcome. Participants were recruited from the community at 5 geographically distributed laboratories as part of the Consortium on the Genetics of Schizophrenia 2 from July 1, 2010, through January 31, 2014. This well-characterized cohort of 1415 patients with schizophrenia underwent EAP, cognitive, and thorough clinical and functional assessment. MAIN OUTCOME AND MEASURES: Mismatch negativity, P3a, and reorienting negativity were used to measure EAP. Cognition was measured by the Letter Number Span test and scales from the California Verbal Learning Test-Second Edition, the Wechsler Memory Scale-Third Edition, and the Penn Computerized Neurocognitive Battery. Negative symptoms were measured by the Scale for the Assessment of Negative Symptoms. Functional outcome was measured by the Role Functioning Scale. RESULTS: Participants included 1415 unrelated outpatients diagnosed with schizophrenia or schizoaffective disorder (mean [SD] age, 46 [11] years; 979 males [69.2%] and 619 white [43.7%]). Early auditory information processing had a direct effect on cognition (ß = 0.37, P < .001), cognition had a direct effect on negative symptoms (ß = -0.16, P < .001), and both cognition (ß = 0.26, P < .001) and experiential negative symptoms (ß = -0.75, P < .001) had direct effects on functional outcome. The indirect effect of EAP on functional outcome was significant as well (ß = 0.14, P < .001). Overall, EAP had a fully mediated effect on functional outcome, engaging general rather than modality-specific cognition, with separate pathways that involved or bypassed negative symptoms. CONCLUSIONS AND RELEVANCE: The data support a model in which EAP deficits lead to poor functional outcome via impaired cognition and increased negative symptoms. Results can be used to help guide mechanistically informed, personalized treatments and support the strategy of using EAP measures as surrogate end points in early-stage procognitive intervention studies.