Development and environment in the National Institute of Mental Health (NIMH) Research Domain Criteria.

The integration of developmental processes is essential for a full understanding of psychopathology. The National Institute of Mental Health (NIMH) Research Domain Criteria (RDoC) provide a scaffold on which to organize the components and processes of psychopathology and to detail behavioral and biological disruptions in developmental processes gone awry. This special section on Integrating Developmental Psychopathology With the RDoC Framework provides the opportunity to comment on five extraordinary developmental psychopathology articles that report results and theory integral to RDoC. An introductory overview provides context for RDoC's approach to developmental issues. This is followed by brief summaries of each article and points regarding its particularly salient aspects, and concludes with broader comments about the import of the articles as a set. Collectively, the work by these eminent translational scholars illustrates how to conduct significant research on developmental psychopathology using RDoC, and simultaneously raises important questions and future directions to integrate development and environment in RDoC-framed research. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Research Domain Criteria (RDoC): Progress and Potential.

The National Institute of Mental Health (NIMH) addressed in its 2008 Strategic Plan an emerging concern that the current diagnostic system was hampering translational research, as accumulating data suggested that disorder categories constituted heterogeneous syndromes rather than specific diseases. However, established practices in peer review placed high priority on extant disorders in evaluating grant applications for mental illness. To provide guidelines for alternative study designs, NIMH included a goal to develop new ways of studying psychopathology based on dimensions of measurable behavior and related neurobiological measures. The Research Domain Criteria (RDoC) project is the result, intended to build a literature that informs new conceptions of mental illness and future revisions to diagnostic manuals. The framework calls for the study of empirically-derived fundamental dimensions as characterized by related behavioral/psychological and neurobiological data (e.g., reward valuation, working memory). RDoC also emphasizes full-range dimensional approaches (from typical to increasingly abnormal), neurodevelopment and environmental effects, and research designs that integrate data across behavioral, biological, and self-report measures. This commentary provides an overview of the project's first decade and its potential future directions. RDoC remains grounded in experimental psychopathology perspectives, and its progress is strongly linked to psychological measurement and integrative approaches to brain-behavior relationships.

Revisiting the seven pillars of RDoC.

BACKGROUND: In 2013, a few years after the launch of the National Institute of Mental Health's Research Domain Criteria (RDoC) initiative, Cuthbert and Insel published a paper titled "Toward the future of psychiatric diagnosis: the seven pillars of RDoC." The RDoC project is a translational research effort to encourage new ways of studying psychopathology through a focus on disruptions in normal functions (such as reward learning or attention) that are defined jointly by observable behavior and neurobiological measures. The paper outlined the principles of the RDoC research framework, including emphases on research that acquires data from multiple measurement classes to foster integrative analyses, adopts dimensional approaches, and employs novel methods for ascertaining participants and identifying valid subgroups. DISCUSSION: To mark the first decade of the RDoC initiative, we revisit the seven pillars and highlight new research findings and updates to the framework that are related to each. This reappraisal emphasizes the flexible nature of the RDoC framework and its application in diverse areas of research, new findings related to the importance of developmental trajectories within and across neurobehavioral domains, and the value of computational approaches for clarifying complex multivariate relations among behavioral and neurobiological systems. CONCLUSION: The seven pillars of RDoC have provided a foundation that has helped to guide a surge of new studies that have examined neurobehavioral domains related to mental disorders, in the service of informing future psychiatric nosology. Building on this footing, future areas of emphasis for the RDoC project will include studying central-peripheral interactions, developing novel approaches to phenotyping for genomic studies, and identifying new targets for clinical trial research to facilitate progress in precision psychiatry.

Posttraumatic stress symptom dimensions and brain responses to startling auditory stimuli in combat veterans.

Posttraumatic stress disorder (PTSD) is marked by alterations in emotional functioning, physiological reactivity, and attention. Neural reactivity to acoustic startle stimuli can be used to understand brain functions related to these alterations. Investigations of startle reactivity in PTSD have yielded inconsistent findings, which may reflect the heterogeneity of the disorder. Furthermore, little is known of how the common co-occurrence of mild traumatic brain injury (mTBI; i.e., concussion) may influence neural reactivity. We examined the event-related potentials (ERPs) of combat veterans (n = 102) to acoustic startle probes delivered during viewing of pleasant, neutral, unpleasant, and combat-related pictures. Interview-based assessments yielded dimensional characterizations of PTSD and mTBI. The P3 ERP response to startle probes was reduced during all affective relative to neutral pictures but failed to be associated with a PTSD diagnosis. However, two separable domains of PTSD symptomatology were associated with startle ERPs regardless of the picture conditions. Maladaptive avoidance was associated with smaller N1, P2, and P3 amplitudes, while intrusive reexperiencing was associated with larger P2 amplitudes. There were no main effects of mTBI. Findings suggest that level of symptomatology rather than a formal diagnosis of PTSD better explains alterations in neural reactivity after traumatic events, while mild brain injuries have little impact. Avoidance symptoms of PTSD may dampen neural functions that facilitate reorientation to threat while intrusive reexperiencing of traumatic events appears to heighten sensory reactivity. Considering specific aspects of symptomatology provides insight into the neural basis of trauma-related psychopathology and may help guide individualization of clinical interventions. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Evolving Concepts of the Schizophrenia Spectrum: A Research Domain Criteria Perspective.

Several trends intersecting over the past two decades have generated increasing debate as to how the concepts of schizophrenia, the schizophrenia spectrum, and the psychotic disorders spectrum should be regarded. These trends are reflected in various areas of research such as genomics, neuroimaging, and data-driven computational studies of multiple response systems. Growing evidence suggests that schizophrenia represents a broad and heterogenous syndrome, rather than a specific disease entity, that is part of a multi-faceted psychosis spectrum. Progress in explicating these various developments has been hampered by the dependence upon sets of symptoms and signs for determining a diagnosis, and by the reliance on traditional diagnostic categories in reviewing clinical research grants. To address these concerns, the U.S. National Institute of Mental Health initiated the Research Domain Criteria (RDoC) project, a translational research program that calls for studies designed in terms of empirically-based functions (such as cognitive control or reward learning) rather than diagnostic groups. RDoC is a research framework rather than an alternative diagnostic system, intended to provide data that can inform future nosological manuals. This commentary includes a brief summary of RDoC as it pertains to schizophrenia and psychotic spectra, examples of recent data that highlight the utility of the approach, and conclusions regarding the implications for evolving conceptualizations of serious mental illness.

Effects of Oxytocin on Emotion Recognition in Schizophrenia: A Randomized Double-Blind Pilot Study.

BACKGROUND: Schizophrenia (SCZ) is a neurodevelopmental disorder that leads to poor social function. Oxytocin (OXT), a neuropeptide involved in social cognition, is a potential therapeutic agent for alleviating social dysfunction. Therefore, we investigated the effects of intranasal oxytocin (IN-OXT) on emotional processes in experimental interactive social contexts in individuals with SCZ. METHODS: In a male-only parallel randomized placebo-controlled double-blind trial, we investigated the effects of IN-OXT (24 IU) on visual fixation on pictures of faces and emotion recognition in an interactive ball-tossing game that probed processing of social and nonsocial stimuli. RESULTS: Intranasal oxytocin enhanced the recognition of emotions during an emotion-based ball-tossing game. This improvement was specific to the game that included social cue processing. Intranasal oxytocin did not affect eye gaze duration or gaze dwell time on faces in these patients. CONCLUSIONS: An acute low dose of IN-OXT had a modest effect on social cue processing and was limited to emotion recognition. Higher doses and long-term trials targeting emotional processing in SCZ may lead to improved social function.

The Effect of Aerobic Exercise on Physical and Cognitive Outcomes in a Small Cohort of Outpatients with Schizophrenia.

BACKGROUND: Schizophrenia (SCZ) is a severe, chronic illness characterized by psychotic symptoms and impairments in many cognitive domains. Dysregulation of brain derived neurotrophic factor (BDNF) is associated with the cognitive impairments seen in patients with SCZ. Given the growing literature supporting a positive effect of aerobic exercise on cognition in other populations, we hypothesized that a structured aerobic exercise program would improve cognitive and functional outcomes in subjects with SCZ, potentially mediated by increases in BDNF. METHODS: The study was a small randomized parallel group clinical trial of subjects with SCZ comparing 12 weeks of aerobic exercise (AE) against control (CON) stretching and balance training. At Baseline, Week 12, and Week 20 we collected serum samples for analysis of brain derived neurotrophic factor (BDNF), and assessed functional, physical, and cognitive outcomes. Linear regression models were used to compare change scores between timepoints. RESULTS: We randomized 21 subjects to AE and 17 to CON; however, only 9 AE and 6 CON completed their programs. Subjects in both groups were slower at the 400 m walk in Week 12 compared to Baseline, but the AE group had significantly less slowing than the CON group (B = -28.32, p = 0.011). Between Week 12 and Week 20, the AE group had a significantly greater change score on the Composite and Visual Learning Domain of the MATRICS Consensus Cognitive Battery (B = 5.11, p = 0.03; B = 13.96, p = 0.006). CONCLUSION: These results indicate that participation in a structured aerobic exercise paradigm may modestly blunt physical function decline and enhance cognitive function in individuals with SCZ.

Toxoplasma gondii Effects on the Relationship of Kynurenine Pathway Metabolites to Acoustic Startle Latency in Schizophrenia vs. Control Subjects.

Background: Chronic infection with Toxoplasma gondii (TOXO) results in microcysts in the brain that are controlled by inflammatory activation and subsequent changes in the kynurenine pathway. TOXO seropositivity is associated with a heightened risk of schizophrenia (SCZ) and with cognitive impairments. Latency of the acoustic startle response, a putative index of neural processing speed, is slower in SCZ. SCZ subjects who are TOXO seropositive have slower latency than SCZ subjects who are TOXO seronegative. We assessed the relationship between kynurenine pathway metabolites and startle latency as a potential route by which chronic TOXO infection can lead to cognitive slowing in SCZ. Methods: Fourty-seven SCZ subjects and 30 controls (CON) were tested on a standard acoustic startle paradigm. Kynurenine pathway metabolites were measured using liquid chromatography-tandem mass spectrometry were kynurenine (KYN), tryptophan (TRYP), 3-hydroxyanthranilic acid (3-OHAA), anthranilic acid (AA), and kynurenic acid (KYNA). TOXO status was determined by IgG ELISA. Results: In univariate ANCOVAs on onset and peak latency with age and log transformed startle magnitude as covariates, both onset latency [F(1,61) = 5.76; p = 0.019] and peak latency [F(1,61) = 4.34; p = 0.041] were slower in SCZ than CON subjects. In stepwise backward linear regressions after stratification by Diagnosis, slower onset latency in SCZ subjects was predicted by higher TRYP (B = 0.42; p = 0.008) and 3-OHAA:AA (B = 3.68; p = 0.007), and lower KYN:TRYP (B = -185.42; p = 0.034). In regressions with peak latency as the dependent variable, slower peak latency was predicted by higher TRYP (B = 0.47; p = 0.013) and 3-OHAA:AA ratio (B = 4.35; p = 0.010), and by lower KYNA (B = -6.67; p = 0.036). In CON subjects neither onset nor peak latency was predicted by any KYN metabolites. In regressions stratified by TOXO status, in TOXO positive subjects, slower peak latency was predicted by lower concentrations of KYN (B = -8.08; p = 0.008), KYNA (B = -10.64; p = 0.003), and lower KYN:TRYP ratios (B = -347.01; p = 0.03). In TOXO negative subjects neither onset nor peak latency was predicted by any KYN metabolites. Conclusions: KYN pathway markers predict slowing of startle latency in SCZ subjects and in those with chronic TOXO infection, but this is not seen in CON subjects nor TOXO seronegative subjects. These findings coupled with prior work indicating a relationship of slower latency with SCZ and TOXO infection suggest that alterations in KYN pathway markers may be a mechanism by which neural processing speed, as indexed by startle latency, is affected in these subjects.

The role of RDoC in future classification of mental disorders
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The Research Domain Criteria (RDoC) project constitutes a translational framework for psychopathology research, initiated by the National Institute of Mental Health in an attempt to provide new avenues for research to circumvent problems emerging from the use of symptom-based diagnostic categories in diagnosing disorders. The RDoC alternative is a focus on psychopathology based on dimensions simultaneously defined by observable behavior (including quantitative measures of cognitive or affective behavior) and neurobiological measures. Key features of the RDoC framework include an emphasis on functional dimensions that range from normal to abnormal, integration of multiple measures in study designs (which can foster computational approaches), and high priority on studies of neurodevelopment and environmental influences (and their interaction) that can contribute to advances in understanding the etiology of disorders throughout the lifespan. The paper highlights key implications for ways in which RDoC can contribute to future ideas about classification, as well as some of the considerations involved in translating basic behavioral and neuroscience data to psychopathology.
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El proyecto Research Domain Criteria (Criterios de Dominio de Investigación, CDI) constituye un marco traslacional para la investigación en psicopatología y fue iniciado por el Instituto Nacional de Salud Mental en un intento por proporcionar nuevas alternativas de investigación para sortear los problemas que surgen del uso de categorías diagnósticas basadas en síntomas para el diagnóstico de los trastornos mentales. La propuesta CDI se centra en la psicopatología basada en dimensiones, las cuales se definen simultáneamente por el comportamiento observable (incluyendo las mediciones cuantitativas del comportamiento cognitivo o afectivo) y las mediciones neurobiológicas. Las características clave de los CDI incluyen un énfasis en las dimensiones funcionales que van de lo normal a lo anormal, la integración de múltiples mediciones en los diseños de estudio (que pueden fomentar enfoques computacionales) y una alta prioridad en los estudios del neurodesarrollo y de las influencias ambientales (y de su interacción), todo lo cual puede contribuir a los avances en la comprensión de la etiología de los trastornos a lo largo de la vida. Este artículo destaca las consecuencias clave de las formas en que los CDI pueden contribuir a futuras ideas acerca de la clasificación, así como a algunas de las consideraciones involucradas en la traducción de datos básicos del comportamiento y de la neurociencia para la psicopatología.

Le National Institute of Mental Health a créé le projet des Critères de domaines de recherche (RDoC, Research Domain Criteria) comme cadre de recherche en psychopathologie, dans le but d'ouvrir les champs de recherche en contournant les problèmes issus des catégories diagnostiques basées sur les symptômes des maladies. Le RDoC est centré sur la psychopathologie et s'appuie sur un comportement observable (y compris des données quantitatives de comportement cognitif ou affectif) comme sur des données neurobiologiques. Structuré autour de caractéristiques essentielles, le RDoC valorise les dimensions fonctionnelles (de normales à anormales), les études de conceptions différentes (pouvant favoriser les méthodes numériques), et prioritairement les études de neurodéveloppement, les influences environnementales et leurs interactions qui peuvent améliorer la compréhension de l'étiologie des maladies au cours de la vie. Cet article souligne les principaux messages concernant les apports du RDoC aux nouvelles méthodes de classification, ainsi que certaines observations en lien avec la traduction des données fondamentales neuroscientifiques et comportementales en psychopathologie.

Inflammatory markers are associated with psychomotor slowing in patients with schizophrenia compared to healthy controls.

Patients with schizophrenia exhibit psychomotor deficits that are associated with poor functional outcomes. One pathway that may be associated with psychomotor slowing is inflammation. Inflammatory markers have been shown to be elevated in patients with schizophrenia and are associated with psychomotor deficits in both animal and human studies. Forty-three patients with schizophrenia and 29 healthy controls were recruited and underwent a battery of psychomotor tasks. The following immune measures in peripheral blood were assayed: IL-6, IL-1 beta, IL-10, TNF, MCP-1, IL-6sr, IL-1RA, and TNFR2. Generalized linear models were used to determine which immune markers, in addition to their interaction with diagnosis, were associated with performance on the psychomotor tasks. As expected, patients with schizophrenia demonstrated slower performance compared with healthy controls on the finger tapping test (FTT, tested on dominant and non-dominant hands), trail making test (TMT), and symbol coding test (SC). Interactive effects with diagnosis were found for TNF, IL-10, IL-6sr, and TNFR2 for the FTT (dominant), IL-10 and IL-6sr for FTT (non-dominant), TNF and IL-10 for TMT and TNF, IL-10, IL-6sr, TNFR2, and IL-1RA for SC. The results of this study provide evidence that peripheral inflammatory markers contribute to psychomotor slowing in patients with schizophrenia. These data are consistent with a growing literature, demonstrating that inflammation may target the basal ganglia to contribute to psychomotor deficits as is seen in other psychiatric disorders such as depression. These data also indicate that psychomotor speed may be a relevant construct to target in studies of the immune system in schizophrenia.

The Research Domain Criteria (RDoC) and the historical roots of psychopathology: A viewpoint.

In this article we aim at conceptual reconstruction of the historical background behind RDoC project. It incorporates some elements that have not heretofore been included in frameworks for psychopathology research. At the same time, however, RDoC - like any approach to mental illness - must grapple with longstanding challenges in addressing issues about the roles and relationships of mind, brain, and patients' reports in considering the nature of disorder. In this respect, the historical roots of psychopathology remain as relevant as ever.

The PRISM project: Social withdrawal from an RDoC perspective.

The PRISM (Psychiatric Ratings using Intermediate Stratified Markers) project was funded under the auspices of the European Union Innovative Medicine Initiative (EU-IMI) to explore quantitative approaches to the biological and behavioral aspects of neuropsychiatric disorders. PRISM focuses specifically on social withdrawal, although its principles are applicable to a wide range of disorders. This commentary explores some of the major aspects of the PRISM design from the perspective of the Research Domain Criteria (RDoC) project initiated by the National Institute of Mental Health. PRISM represents an apt exemplar of the principles developed in the RDoC framework, with the potential to contribute palpable advances in precision diagnosis and innovative approaches to treatment development.

Impaired reward responsiveness in schizophrenia.

BACKGROUND: Anhedonia is a core negative symptom of schizophrenia. Schizophrenia patients report largely intact pleasure in consuming rewards, but have impairments in generating motivated behavior to pursue rewards, and show reduced fMRI activation of the reward pathway during presentation of rewarded stimuli. A computer based task measuring the development of a response bias in favor of rewarded stimuli permits assessment of reward-induced motivation. We hypothesized that subjects with schizophrenia would be impaired on this task. METHODS: 58 schizophrenia subjects (SCZ) and 52 healthy controls (CON) were studied with a signal detection task to assess reward responsiveness. In multiple trials over three blocks subjects were asked to correctly identify two stimuli that were paired with unequal chance of monetary reward. The critical outcome variable was response bias, the development of a greater percent correct identification of the stimulus that was rewarded more often. RESULTS: An ANOVA on response bias with Block as a repeated-measures factor and Diagnosis as a between-group factor indicated that SCZ subjects achieved a lower bias to rewarded stimuli than CON subjects (F(1,105)=8.82, p=0.004, η2=0.078). Post hoc tests indicated that SCZ subjects had significantly impaired bias in Block 1 (p=0.002) and Block 2 (p=0.05), indicating that SCZ were slower to achieve normal levels of bias during the session. CONCLUSIONS: SCZ subjects were slower to develop response bias to rewarded stimuli than CON subjects. This finding is consonant with the hypothesis that people with schizophrenia have a blunted capacity to modify behavior in response to reward.

Symptoms of Posttraumatic Stress Rather Than Mild Traumatic Brain Injury Best Account for Altered Emotional Responses in Military Veterans.

Emotional dysfunction is evident in posttraumatic stress disorder (PTSD), yet it is unclear what aspects of the disorder most directly relate to aberrant emotional responding. Also, the frequent co-occurrence of blast-related mild traumatic brain injuries (mTBIs) among recently deployed U.S. military personnel complicates efforts to understand the basis for emotional disruption. We studied a cross-sectional sample (enriched for PTSD and mTBI) of 123 U.S. veterans of wars in Iraq and Afghanistan. We measured subjective affective evaluations and peripheral psychophysiological responses to images with pleasant, neutral, unpleasant, and combat-related aversive content. When compared with other postdeployment participants, those who had combat-related PTSD rated pleasant image content as less positive (ηp2 = .04) and less arousing (ηp2 = .06), and exhibited heightened physiological responsivity to combat image content (ηp2 = .07). Symptoms of PTSD were associated with elevated skin conductance responses (ß = .28), reduced heart rate deceleration (ß = .44 to .47), and increased corrugator facial muscle electromyography (ß = .47). No effects for blast-related mTBI were observed across any affective modulation measures. These findings point to a greater impact of PTSD symptomatology than blast-related mTBI on emotional functioning and highlight the utility of dimensional assessments of psychopathology for understanding the effects of combat-stress conditions on adjustment to civilian life.

The effect of antipsychotic medications on acoustic startle latency in schizophrenia.

Prepulse inhibition of the acoustic startle reflex (PPI) is extensively studied as a biomarker of schizophrenia (SCZ); however, antipsychotic medication can confound the measure. Latency, the time between the startling stimulus and the reflexive eye blink, provides an index of neural processing speed and is 90% heritable. SCZ subjects have slower latency than controls (CON). This study examined the effects of antipsychotic medication on startle latency. 108 CON and 132 SCZ subjects in three medication subgroups (94 on second-generation antipsychotics (SGA), 25 on first-generation antipsychotics (FGA), 13 unmedicated (NoMed)) were tested on a standard acoustic startle paradigm designed to measure startle magnitude, PPI, and latency. Latency was slower in SCZ compared to CON subjects (p=0.005). Latency did not differ between the three SCZ medication groups. When CON were added to that model, both the NoMed subjects (p=0.04) and the SGA subjects (p=0.003) were slower than CON subjects. For PPI, CON did not differ from SCZ analyzed as a single group. When SCZ subjects were divided into medication groups, PPI was lower in NoMed subjects than the CON group (p=0.03), the SGA group (p=0.02) and the FGA group (p=0.05). SCZ subjects on any medication did not differ from CON. Thus, latency was partially normalized by antipsychotic medication, but this did not obscure the slower latency in SCZ compared to CON. Therefore latency is both trait and state related, whereas medication normalized PPI and obscured any difference between SCZ and CON.

Three Approaches to Understanding and Classifying Mental Disorder: ICD-11, DSM-5, and the National Institute of Mental Health's Research Domain Criteria (RDoC).

The diagnosis of mental disorder initially appears relatively straightforward: Patients present with symptoms or visible signs of illness; health professionals make diagnoses based primarily on these symptoms and signs; and they prescribe medication, psychotherapy, or both, accordingly. However, despite a dramatic expansion of knowledge about mental disorders during the past half century, understanding of their components and processes remains rudimentary. We provide histories and descriptions of three systems with different purposes relevant to understanding and classifying mental disorder. Two major diagnostic manuals-the International Classification of Diseases and the Diagnostic and Statistical Manual of Mental Disorders-provide classification systems relevant to public health, clinical diagnosis, service provision, and specific research applications, the former internationally and the latter primarily for the United States. In contrast, the National Institute of Mental Health's Research Domain Criteria provides a framework that emphasizes integration of basic behavioral and neuroscience research to deepen the understanding of mental disorder. We identify four key issues that present challenges to understanding and classifying mental disorder: etiology, including the multiple causality of mental disorder; whether the relevant phenomena are discrete categories or dimensions; thresholds, which set the boundaries between disorder and nondisorder; and comorbidity, the fact that individuals with mental illness often meet diagnostic requirements for multiple conditions. We discuss how the three systems' approaches to these key issues correspond or diverge as a result of their different histories, purposes, and constituencies. Although the systems have varying degrees of overlap and distinguishing features, they share the goal of reducing the burden of suffering due to mental disorder.

A Gene-Based Analysis of Acoustic Startle Latency.

Latency of the acoustic startle response is the time required from the presentation of startling auditory stimulus until the startle response is elicited and provides an index of neural processing speed. Latency is prolonged in subjects with schizophrenia compared to controls in some but not all studies and is 68-90% heritable in baseline startle trials. In order to determine the genetic association with latency as a potential inroad into genetically based vulnerability to psychosis, we conducted a gene-based study of latency followed by an independent replication study of significant gene findings with a single-nucleotide polymorphism (SNP)-based analysis of schizophrenia and control subjects. 313 subjects from an urban population of low socioeconomic status with mixed psychiatric diagnoses were included in the gene-based study. Startle testing was conducted using a Biopac M150 system according to our published methods. Genotyping was performed with the Omni-Quad 1M or the Omni Express BeadChip. The replication study was conducted on 154 schizophrenia subjects and 123 psychiatric controls. Genetic analyses were conducted with Illumina Human Omni1-Quad and OmniExpress BeadChips. Twenty-nine SNPs were selected from four genes that were significant in the gene-based analysis and also associated with startle and/or schizophrenia in the literature. Linear regressions on latency were conducted, controlling for age, race, and diagnosis as a dichotomous variable. In the gene-based study, 2,870 genes demonstrated the evidence of association after correction for multiple comparisons (false discovery rate < 0.05). Pathway analysis of these genes revealed enrichment for relevant biological processes including neural transmission (p = 0.0029), synaptic transmission (p = 0.0032), and neuronal development (p = 0.024). The subsequent SNP-based replication analysis revealed a strong association of onset latency with the SNP rs901561 on the neuregulin gene (NRG1) in an additive model (beta = 0.21, p = 0.001), indicating that subjects with the AA and AG genotypes had slower mean latency than subjects with GG genotype. In conclusion, startle latency, a highly heritable measure that is slowed in schizophrenia, may be a useful biological probe for genetic contributions to psychotic disorders. Our analyses in two independent populations point to a significant prediction of startle latency by genetic variation in NRG1.

Predictors of Calf Arterial Compliance in Male Veterans With Psychiatric Diagnoses.

BACKGROUND: Peripheral arterial compliance (PAC) is a measure of the ability of the vascular tree to dilate in response to a pressure wave. Reduced PAC is seen in patients with psychiatric diagnoses and has been associated with increased risk for stroke, myocardial infarction, and mortality. The objective of this pilot study was to identify predictors of reduced PAC in subjects with psychiatric diagnoses. METHODS: Male psychiatric subjects (N = 77) were studied in a cross-sectional study of medication effects on PAC conducted from August 2005 to February 2010. Calf and thigh compliance were modeled in separate linear regressions. The models were adjusted for age, race, smoking status, presence or absence of the metabolic syndrome, current treatment with a statin, diagnosis of schizophrenia or schizoaffective disorder, current antipsychotic treatment, and body mass index (BMI). RESULTS: Of the 77 subjects (mean ± SD age of 53.7 ± 8.8 years), 41 were white, 36 were black, and 27 were diagnosed with schizophrenia or schizoaffective disorder (DSM-IV criteria). Fifty participants were being treated with an antipsychotic medication, while the remaining 27 were off of antipsychotics for at least 2 months. Our model explained 27% of the variance in calf compliance. Black subjects had reduced calf compliance compared to white subjects (P = .02). Having metabolic syndrome was associated with reduced PAC at a trend level (P < .08), and BMI (P = .004) and BMI2 (P = .011) were significant predictors of calf compliance. Schizophrenia versus other psychiatric diagnoses and antipsychotic treatment were not significantly associated with calf compliance. CONCLUSIONS: In this pilot study, significant predictors of calf compliance were race (black vs white) and BMI. PAC is a noninvasive measure that may be a predictor of cardiovascular risk in psychiatric patients. The reduced PAC seen in patients with psychiatric diagnoses does not appear to be directly related to their diagnosis or antipsychotic treatment but rather to other characteristics inherent to the subject. Future studies are warranted to better understand the pathophysiology of PAC including but not limited to inflammation in psychiatric patients.