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Background Accumulated evidence from non-human animal studies suggests that the prominent deficits in memory and executive function that characterise individuals with psychosis may, at least in part, be due to the effects of stress on the brain regions that support these functions. However, studies of patients with established psychosis have yielded inconsistent findings with regards to the relationship between stress and cognition, and research in high-risk populations is notably lacking. Utilising data from the North American Prodrome Longitudinal Study 2 (NAPLS 2), we aimed to further elucidate the relationship between stress (daily stressors, life events, and childhood trauma) and cognitive function in clinical high-risk (CHR) individuals and healthy controls (HC). We additionally explored the role of potential mediators [hypothalamic-pituitary-adrenal (HPA) axis function] and moderators (group status, sex, family history of illness). Methods The sample comprised 885 participants (CHR=646; HC=239) who completed measures of stress and cognitive function at the NAPLS 2 baseline assessment. Stress measures included the Daily Stress Inventory and a modified version of the Psychiatric Epidemiology Research Interview Life Events Scale, both of which provided continuous measures of stress exposure (number of events) and distress (subjective feelings of distress). Participants were also interviewed using the Childhood Trauma and Abuse Scale to determine any exposure to childhood trauma (abuse, neglect, and bullying occurring prior to age 16 years). Basal HPA axis activity was determined via salivary cortisol samples obtained at the baseline assessment and standardised scores from selected subtests from the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) were used to derive two cognitive domain scores (memory and executive function). To examine relationships between stress and cognitive domain scores, linear regression analyses were performed on standardised variables. Results Daily stressor exposure, daily stressor distress, and life event exposure exhibited negative quadratic (i.e., inverted U-shaped) associations with both memory and executive function (P < 0.01 for all). In contrast, the reverse pattern (i.e., a negative linear relationship and a positive quadratic relationship) was shown in the model for life event distress and memory domain scores (P < 0.01) whilst trauma history showed only a trend-level association with poorer memory performance (P = 0.084). These relationships, which did not differ across CHR and healthy control groups, were largely unchanged after adjusting for demographic factors and salivary cortisol. Exploratory analyses suggested that trauma exposure and a family history of psychosis may moderate the relationship between daily stressors/life events and cognitive function. Discussion In this large sample of predominately CHR individuals, we observed that the association between stress and cognition is complex and differs across stressor types. The negative quadratic associations that we observed for daily stressor exposure, daily stressor distress, and life event exposure imply that whist lower levels of stress may facilitate memory and executive function, there may be a negative impact on cognition when these stressors become more frequent and distressing. Interventions aiming to minimise stress exposure and promote effective coping strategies might feasibly improve cognition in CHR individuals.

To clarify effects of partial sleep deprivation (SD) on morning (07:00) serum cortisol concentrations in two protocols that restricted sleep to 3h/day in healthy adult men. The study was also designed to delineate the relationship between anxiety levels in the morning and slow wave sleep (SWS) periods at night.Ten young adult Han Chinese males were recruited to participate in an 'earlier-night' sleep restriction (SR) period (sleep from 00:00 to 03:00) and then a 'later-night' SR period (sleep from 03:00 to 06:00). The duration of each SR period was 4 days, followed by a recovery night. The SR periods were separated by 10 days of normal sleep. Blood samples of serum cortisol were drawn at 07:00 during each of two SR periods for six consecutive mornings (for a total of 12 measurements per subject), and anxiety levels were also assessed over the same period by the State portion of the State-Trait Anxiety Inventory (STAI). Sleeping processes were monitored by polysomnogram.Serum cortisol levels decreased after SR (P0.05) in both paradigms, with greater decreases evident after later-night sleep loss than after earlier-night sleep loss. Cortisol levels were significantly, negatively correlated to the number of days of earlier-night SR, but not to later-night SR. Anxiety scores increased gradually in both conditions. The time of SWS changed indiscriminately in both paradigms. Cortisol levels returned to baseline after one night of recovery sleep.Cortisol decreased in both SR conditions, especially in the earlier-night SR protocol, even though SWS time and anxiety levels changed roughly in the same manner in both conditions. Data suggested that sleep loss at different times of the night affects the hypothalamic-pituitary-adrenal axis (HPA-axis) differentially.

Working memory (WM) impairment is a promising candidate endophenotype for schizophrenia that could facilitate the identification of susceptibility genes for this disorder. The validity of this putative endophenotype was assessed by determining whether 149 probands with schizophrenia and 337 of their first-degree relatives demonstrated WM impairment as compared to 190 unaffected community comparison subjects. Subjects were participants in the Consortium on the Genetics of Schizophrenia (COGS) project, a seven-site research network that was established to investigate the genetic architecture of endophenotypes for schizophrenia. Participants received comprehensive clinical assessments and completed two verbal WM tasks, one requiring transient on-line storage and another requiring maintenance plus complex manipulation of information by reordering the stimuli. Schizophrenia probands performed worse than the other groups on both tasks, with larger deficits found for the more challenging reordering WM task. The probands' relatives performed more poorly than community comparison subjects on both tasks, but the difference was significant only for the more challenging maintenance plus complex manipulation WM task. This WM impairment was not attributable to diagnoses of schizophrenia spectrum disorder, mood disorders, or substance use disorders in the relatives. In conjunction with evidence that WM abilities are substantially heritable, the current results support the validity and usefulness of verbal WM impairments in manipulation of information as endophenotypes for schizophrenia in large-scale genetic linkage and association studies.

Recognition of the need to treat cognitive deficits in schizophrenia is compelling and well established, with empirical findings and conceptual arguments related to cognitive enhancement appearing regularly in the literature. Cognitive enhancement itself, however, remains at an early stage. Biological approaches have centered on the development of antipsychotic medications that also improve cognition, but the results have so far remained modest. As a way to facilitate the development of cognitive enhancers in schizophrenia, this article focuses on adjunctive pharmacological approaches to antipsychotic medications and highlights the need for systematic explorations of relevant brain mechanisms. While numerous conceptual criteria might be employed to guide the search, we will focus on 4 points that are especially likely to be useful and which have not yet been considered together. First, the discussion will focus on deficits in a particular cognitive domain, verbal declarative memory. Second, we will review the current status of preclinical and clinical efforts to improve declarative memory using antipsychotic medications, which is the main, existing mode of treatment. Third, we will examine an example of an adjunctive intervention-glucose administration-that improves memory in animals and humans, modulates function in brain regions related to verbal declarative memory, and is highly amenable to translational research. Finally, a heuristic model will be outlined to explore how the intervention maps on to the underlying neurobiology of schizophrenia. More generally, the discussion underlines the promise of cognitive improvement in schizophrenia and the need to approach the issue in a programmatic manner.

Objective: The aim of this study was to explore the microstructural integrity of whole-brain white matter by diffusion tensor imaging in first-episode, treatment-naive young adults with major depressive disorder. Method: Diffusion tensor imaging scans were obtained from 14 first-episode, treatment-naive young adult patients with major depressive disorder and 14 healthy comparison subjects. A voxel-based method was used to analyze the scans. Results: The patient group exhibited significantly lower fractional anisotropy values than healthy comparison subjects in the white matter of the right middle frontal gyrus, the left lateral occipitotemporal gyrus, and the subgyral and angular gyri of the right parietal lobe. There were no regions of significantly higher fractional anisotropy values in patients compared with healthy comparison subjects. Conclusions: These findings suggest that abnormalities of brain white matter may be present early in the course of major depressive disorder. They also support the idea...

© 2014. The impaired ability to make correct antisaccades (i.e., antisaccade performance) is well documented among schizophrenia subjects, and researchers have successfully demonstrated that antisaccade performance is a valid schizophrenia endophenotype that is useful for genetic studies. However, it is unclear how the ascertainment biases that unavoidably result from recruitment differences in schizophrenia subjects identified in family versus case-control studies may influence patient-control differences in antisaccade performance. To assess the impact of ascertainment bias, researchers from the Consortium on the Genetics of Schizophrenia (COGS) compared antisaccade performance and antisaccade metrics (latency and gain) in schizophrenia and control subjects from COGS-1, a family-based schizophrenia study, to schizophrenia and control subjects from COGS-2, a corresponding case-control study. COGS-2 schizophrenia subjects were substantially older; had lower education status, worse psychosocial function, and more severe symptoms; and were three times more likely to be a member of a multiplex family than COGS-1 schizophrenia subjects. Despite these variations, which were likely the result of ascertainment differences (as described in the introduction to this special issue), the effect sizes of the control-schizophrenia differences in antisaccade performance were similar in both studies (Cohen's d effect size of 1.06 and 1.01 in COGS-1 and COGS-2, respectively). This suggests that, in addition to the robust, state-independent schizophrenia-related deficits described in endophenotype studies, group differences in antisaccade performance do not vary based on subject ascertainment and recruitment factors.

© 2014 Elsevier B.V. Reduced auditory P300 amplitude is a robust schizophrenia deficit exhibiting the qualities of a viable genetic endophenotype. These include heritability, test-retest reliability, and trait-like stability. Recent evidence suggests that P300 may also serve as a predictive biomarker for transition to psychosis during the schizophrenia prodrome. Historically, the utility of the P300 has been limited by its clinical nonspecificity, cross-site measurement variability, and required EEG expertise. The Consortium on the Genetics of Schizophrenia (COGS-2) study provided an opportunity to examine the consistency of the measure across multiple sites with varying degrees of EEG experience, and to identify important modulating factors that contribute to measurement variability. Auditory P300 was acquired from 649 controls and 587 patients at 5 sites. An overall patient deficit was observed with effect size 0.62. Each site independently observed a significant patient deficit, but site differences also existed. In patients, site differences reflected clinical differences in positive symptomatology and functional capacity. In controls, site differences reflected differences in racial stratification, smoking and substance use history. These factors differentially suppressed the P300 response, but only in control subjects. This led to an attenuated patient-control difference among smokers and among African Americans with history of substance use. These findings indicate that the P300 can be adequately assessed quantitatively, across sites, without substantial EEG expertise. Measurements are suitable for both genetic endophenotype analyses and studies of psychosis risk and conversion. However, careful attention must be given to selection of appropriate comparison samples to avoid misleading false negative results.

Background: The Consortium on the Genetics of Schizophrenia (COGS) is an ongoing, National Institute of Mental Health–funded, 7-site collaboration investigating the occurrence and genetic architecture of quantitative endophenotypes related to schizophrenia. The purpose of this article is to provide a description of the COGS structure and methods, including participant recruitment and assessment. Methods: The hypothesis-driven recruitment strategy ascertains families that include a proband with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of schizophrenia, and at least one unaffected full sibling available for genotyping and endophenotyping, along with parents available for genotyping and (optional depending on age) endophenotyping. The family structure is selected to provide contrast in quantitative endophenotypic traits and thus to maximize the power of the planned genetic analyses. Probands are recruited from many sources including clinician referrals, local National Alliance for the Mentally Ill chapters, and advertising via the media. All participants undergo a standardized protocol that includes clinical characterization, a blood draw for genotyping, and endophenotype assessments (P50 suppression, prepulse inhibition, antisaccade performance, continuous performance tasks, letter-number span, verbal memory, and a computerized neurocognitive battery). Investigators participate in weekly teleconferences to coordinate and evaluate recruitment, clinical assessment, endophenotyping, and continuous quality control of data gathering and analyses. Data integrity is maintained through use of a highly quality-assured, centralized web-based database. Results: As of February 2006, 355 families have been enrolled and 688 participants have been endophenotyped, including schizophrenia probands (n = 154, M:F = 110:44), first-degree biological relatives (n = 343, M:F = 151:192), and community comparison subjects (n = 191, M:F = 81:110). Discussion: Successful multisite genetics collaborations must institute standardized methodological criteria for assessment and recruitment that are clearly defined, well communicated, and uniformly applied. In parallel, studies utilizing endophenotypes require strict adherence to criteria for cross-site data acquisition, equipment calibration and testing and software equivalence, and continuous quality assurance for many measures obtained across sites. This report describes methods and presents the structure of the COGS as a model of multisite endophenotype genetic studies. It also provides demographic information after the first 2 years of data collection on a sample for whom the behavioral data and genetics of endophenotype performance will be fully characterized in future articles. Some issues discussed in the reviews that follow reflect the challenges of evaluating endophenotypes in studies of the genetic architecture of endophenotypes in schizophrenia.

© 2013. Mismatch negativity (MMN) and P3a are auditory event-related potential (ERP) components that show robust deficits in schizophrenia (SZ) patients and exhibit qualities of endophenotypes, including substantial heritability, test-retest reliability, and trait-like stability. These measures also fulfill criteria for use as cognition and function-linked biomarkers in outcome studies, but have not yet been validated for use in large-scale multi-site clinical studies. This study tested the feasibility of adding MMN and P3a to the ongoing Consortium on the Genetics of Schizophrenia (COGS) study. The extent to which demographic, clinical, cognitive, and functional characteristics contribute to variability in MMN and P3a amplitudes was also examined. Participants (HCS n. =. 824, SZ n. =. 966) underwent testing at 5 geographically distributed COGS laboratories. Valid ERP recordings were obtained from 91% of HCS and 91% of SZ patients. Highly significant MMN (d. =. 0.96) and P3a (d. =. 0.93) amplitude reductions were observed in SZ patients, comparable in magnitude to those observed in single-lab studies with no appreciable differences across laboratories. Demographic characteristics accounted for 26% and 18% of the variance in MMN and P3a amplitudes, respectively. Significant relationships were observed among demographically-adjusted MMN and P3a measures and medication status as well as several clinical, cognitive, and functional characteristics of the SZ patients. This study demonstrates that MMN and P3a ERP biomarkers can be feasibly used in multi-site clinical studies. As with many clinical tests of brain function, demographic factors contribute to MMN and P3a amplitudes and should be carefully considered in future biomarker-informed clinical studies.

Siblings and offspring of persons with schizophrenia carry elevated genetic risk for the illness and manifest attentional and memory impairments. Because less is known about other neuropsychological functions and their specificity in adolescents, we conducted a genetic high-risk (HR) study of schizophrenia (HR-SCZ) and affective psychosis (HR-AFF). Participants (ages 12–25) were from the Harvard Adolescent High-Risk and Hillside Family studies, including 73 HR-SCZ, 18 HR-AFF, and 84 community controls (CCs) recruited in metropolitan Boston and New York. Groups were compared on overall neurocognitive functioning, 6 domains, and 13 test scores, controlling for age, parental education, and correlated data within families. The HR-SCZ group was significantly impaired overall, while the HR-AFF group demonstrated a trend toward overall impairment. HR-SCZ subjects showed significantly lower Verbal Ability (d = .73) and Executive Functioning/Working Memory (d = .47) than CCs. HR-AFF subjects showed reduced Verbal Ability (d = .64) compared to CCs. Excluding 12 CCs with a parental history of depression (without psychosis) led to larger differences between HR and CC groups across domains. Moreover, HR-SCZ and CC group differences in Verbal Memory (d = .39) and Visual-Spatial (d = .34) became statistically significant. There were no significant differences between HR-SCZ and HR-AFF groups. Data support a modest neuropsychological deficit in persons at genetic HR for psychosis, with a broader range of deficits in HR-SCZ. Future work should assess the relationship of neurocognition to adaptive functioning and possible onset of psychosis in HR samples. Ascertainment criteria for controls may markedly influence results and interpretation of group differences.

Conceptualizations of the liability for schizophrenia help guide the development of research protocols, which, in turn, provide empirical confirmations or disconfirmations of the conceptualization's tenets. This paper focuses on a conception of liability and its relationships to genetic adolescent high-risk studies. Specifically, the derivation and nature of a proposed multidimensional syndrome of liability to schizophrenia ("schizotaxia") are outlined, followed by a representative review of features reported in previous high-risk studies that may be related to schizotaxia, and a perspective on future high-risk investigations. Overall, genetic high-risk studies generally confirm the concept of liability in the offspring of parents with schizophrenia, as expressed by deficits or abnormalities in multiple dimensions. It is concluded that high-risk studies on the liability to schizophrenia provide an important tool with which to explore the etiology and development of schizophrenia, in part by contributing to the identification and validation of specific liability syndromes.

Observations of impaired glucose regulation in schizophrenia are long-standing, although their pathological and etiological significance is uncertain. One approach to the issue that minimizes environmental variables (e.g., medication and diet) is to determine whether genes related to glucose regulation show genetic linkage to schizophrenia. We examined the potential role of glucose metabolism in schizophrenia through a genome scan of affection status in schizophrenia and an empirical method for deriving P-values. Data were utilized from the NIMH Genetics Initiative for Schizophrenia dataset, which comprises a total sample consisting of 71 pedigrees containing 218 nuclear families and 987 individuals. A genome scan with 459 markers spaced at an average of 10 cM intervals was conducted using the linkage analysis program Genehunter separately for European- and African-American groups. Enzymes that regulate glycolysis were identified and the genes regulating these enzymes were located through the Online Mendelian Inheritance in Man (OMIM) website. The focus in this study was on genes located near previously reported schizophrenia susceptibility regions. The genome-wide significance of these genes to schizophrenia was assessed using permutation testing. When results were adjusted for multiple testing within and across ethnic groups, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2; chromosome 1q32.2) achieved genome-wide significance (P = 0.04). In addition, hexokinase 3 (HK3; chromosome 5q35.3) was also suggestive of linkage (P = 0.09). For the European-American sample, PFKFB2 (1q32.2), hexokinase 3 (HK3; 5q35.3), and pyruvate kinase 3 (PK3; chromosome 15q23) achieved significance at the 0.05 level. None of the genes showed significance in the African-American sample. Our results provide further support for the view that genes that regulate glucose metabolism may also influence susceptibility to schizophrenia. More generally, they support the view that relationships between glucose dysregulation and schizophrenia are inherent to the disorder, and are not merely epiphenomena related to medication or other treatment factors.

Clozapine has been shown to improve verbal declarative memory and other cognitive functions in chronic schizophrenia. This raises the possibility that additional adjunctive manipulations might improve memory further. In this study, we hypothesized that glucose, which improves memory in a variety of conditions, including schizophrenia, would improve memory more than saccharin in a group of patients stabilized on clozapine. Twelve outpatients with schizophrenia who received treatment with clozapine participated in a double-blind, counterbalanced, crossover study. Subjects received beverages containing either glucose or saccharin on one occasion, and then the other beverage about a week later. Fifteen minutes after ingesting the beverage, subjects received a brief battery of neuropsychological tests to assess verbal declarative memory, attention, and executive functions. Blood glucose levels were assessed at baseline, and at 15 and 50 min after beverage ingestion. The main findings were that retention of a list of words was improved in the glucose condition, while performance on a complex test of sustained vigilance declined after glucose ingestion. These findings provide evidence that glucose improves declarative memory in patients with schizophrenia who were treated with clozapine, and underscore the possibility of developing effective protocols to reduce cognitive dysfunctions in the disorder. They also highlight the need to explore the extent to which glucose modulates nonmemory cognitive functions such as attention, and to understand more generally how glucose availability and regulation influence cognition.

Objective:Early intervention to prevent schizophrenia is one of the most important goals of schizophrenia research. However, the field is not yet ready to initiate trials to prevent prodromal or psychotic symptoms in people who are at risk for developing the disorder. In this paper, we consider some of the major obstacles that must be studied before prevention strategies become feasible.Method and Results:One of the most important hurdles is the identification of a syndrome or set of traits that reflects a predisposition to schizophrenia and that might provide potential targets for intervention. In a recent reformulation of Paul Meehl's concept of schizotaxia, we integrate research findings obtained over the last 4 decades to propose a syndrome with meaningful clinical manifestations. We review the conceptualization of this syndrome and consider its multidimensional clinical expression. We then describe preliminary research diagnostic criteria for use in adult, nonpsychotic, first-degree relatives of patients diagnosed with schizophrenia, based on negative symptoms and neuropsychological deficits. We follow this with evidence supporting the validity of the proposed syndrome, which mainly includes social dysfunction and response to a low dosage of one of the newer antipsychotic medications.Conclusions:Continued progress toward the eventual initiation of prevention strategies for schizophrenia will include sustained efforts to validate the traits reflecting a predisposition to develop the disorder (for example, schizotaxia), follow-up studies to confirm initial findings, and the identification of potentially useful preventive interventions.

Michael Ruse's Darwin and Design : Science, Philosophy, Religion explains the history and philosophical arguments of the design metaphor of evolution. It recounts the historical uses of the metaphor from Plato to twentieth-century American science. Ruse explores the criticisms of the design metaphor and ultimately concludes that it is a beneficial term. The chief contribution of Darwin and Design is that it offers a clear understanding and comparison of the argument from design and the argument to design.

Background: In 2012, the “ShangHai At Risk for Psychosis (SHARP)” study was launched at the Shanghai Mental Health Center (SMHC), the largest outpatient mental health clinic in China. This study identified individuals at Clinical High Risk (CHR) for psychosis and evaluated clinical, neurocognitive, and biological features. We address the question of whether baseline clinical and neurocognitive characteristics (such as higher levels of unusual thought content [UTC], greater decline in functioning and poorer neurocognitive performance) predict subsequent conversion to psychosis similar to Western samples.

© 2014 Elsevier B.V. Objectives: Working memory impairment has been extensively studied in schizophrenia, but less is known about moderators of the impairment. Using the Consortium on the Genetics of Schizophrenia case-control study (COGS-2), we examined smoking status, types of antipsychotic medication, and history of substance as moderators for working memory impairment in schizophrenia. Methods: From 5 sites, 1377 patients with schizophrenia or schizoaffective, depressed type and 1037 healthy controls completed the letter-number span (LNS) task. The LNS uses intermixed letter and digit stimuli that increase from 2 up to 8 stimuli. In the forward condition, participants repeated the letters and numbers in the order they were presented. In the reorder condition, participants repeated the digits in ascending order followed by letters in alphabetical order. Results: Schizophrenia patients performed more poorly than controls, with a larger difference on reorder than forward conditions. Deficits were associated with symptoms, functional capacity, and functional outcome. Patients who smoked showed larger impairment than nonsmoking patients, primarily due to deficits on the reorder condition. The impairing association of smoking was more pronounced among patients taking first-generation than those taking second-generation antipsychotic medications. Correlations between working memory and community functioning were stronger for nonsmokers. History of substance use did not moderate working memory impairment. Conclusions: Results confirm the working memory impairment in schizophrenia, and indicate smoking status as an important moderator for these deficits. The greater impairment in smokers may reflect added burden of smoking on general health or that patients with greater deficits are more likely to smoke.

We evaluated the discrepancy of endophenotypic performance between probands with schizophrenia and unaffected siblings by paternal age at proband birth, a possible marker for de novo mutations. Pairs of schizophrenia probands and unaffected siblings (N=220 pairs) were evaluated on 11 neuropsychological or neurophysiological endophenotypes previously identified as heritable. For each endophenotype, the sibling-minus-proband differences were transformed to standardized scores. Then for each pair, the average discrepancy was calculated from its standardized scores. We tested the hypothesis that the discrepancy is associated with paternal age, controlling for the number of endophenotypes shared between proband and his or her sibling, and proband age, which were both associated with paternal age. The non-significant association between the discrepancy and paternal age was in the opposite direction from the hypothesis. Of the 11 endophenotypes only sensori-motor dexterity was significant, but in the opposite direction. Eight other endophenotypes were also in the opposite direction, but not significant. The results did not support the hypothesized association of increased differences between sibling/proband pairs with greater paternal age. A possible explanation is that the identification of heritable endophenotypes was based on samples for which schizophrenia was attributable to inherited rather than de novo/non-inherited causes. © 2014.

Attention/vigilance impairments are present in individuals with schizophrenia across psychotic and remitted states and in their first-degree relatives. An important question is whether deficits in attention/vigilance can be consistently and reliably measured across sites varying in many participant demographic, clinical, and functional characteristics, as needed for large-scale genetic studies of endophenotypes. We examined Continuous Performance Test (CPT) data from phase 2 of the Consortium on the Genetics of Schizophrenia (COGS-2), the largest-scale assessment of cognitive and psychophysiological endophenotypes relevant to schizophrenia. The CPT data from 2251 participants from five sites were examined. A perceptual-load vigilance task (the Degraded Stimulus CPT or DS-CPT) and a memory-load vigilance task (CPT-Identical Pairs or CPT-IP) were utilized. Schizophrenia patients performed more poorly than healthy comparison subjects (HCS) across sites, despite significant site differences in participant age, sex, education, and racial distribution. Patient-HCS differences in signal/noise discrimination (d') in the DS-CPT varied significantly across sites, but averaged a medium effect size. CPT-IP performance showed large patient-HCS differences across sites. Poor CPT performance was independent of or weakly correlated with symptom severity, but was significantly associated with lower educational achievement and functional capacity. Current smoking was associated with poorer CPT-IP d'. Patients taking both atypical and typical antipsychotic medication performed more poorly than those on no or atypical antipsychotic medications, likely reflecting their greater severity of illness. We conclude that CPT deficits in schizophrenia can be reliably detected across sites, are relatively independent of current symptom severity, and are related to functional capacity.

© 2015 Elsevier B.V. Background: Although many endophenotypes for schizophrenia have been studied individually, few studies have examined the extent to which common neurocognitive and neurophysiological measures reflect shared versus unique endophenotypic factors. It may be possible to distill individual endophenotypes into composite measures that reflect dissociable, genetically informative elements. Methods: The first phase of the Consortium on the Genetics of Schizophrenia (COGS-1) is a multisite family study that collected neurocognitive and neurophysiological data between 2003 and 2008. For these analyses, participants included schizophrenia probands (n=. 83), their nonpsychotic siblings (n=. 151), and community comparison subjects (n=. 209) with complete data on a battery of 12 neurocognitive tests (assessing domains of working memory, declarative memory, vigilance, spatial ability, abstract reasoning, facial emotion processing, and motor speed) and 3 neurophysiological tasks reflecting inhibitory processing (P50 gating, prepulse inhibition and antisaccade tasks). Factor analyses were conducted on the measures for each subject group and across the entire sample. Heritability analyses of factors were performed using SOLAR. Results: Analyses yielded 5 distinct factors: 1) Episodic Memory, 2) Working Memory, 3) Perceptual Vigilance, 4) Visual Abstraction, and 5) Inhibitory Processing. Neurophysiological measures had low associations with these factors. The factor structure of endophenotypes was largely comparable across probands, siblings and controls. Significant heritability estimates for the factors ranged from 22% (Episodic Memory) to 39% (Visual Abstraction). Conclusions: Neurocognitive measures reflect a meaningful amount of shared variance whereas the neurophysiological measures reflect largely unique contributions as endophenotypes for schizophrenia. Composite endophenotype measures may inform our neurobiological and genetic understanding of schizophrenia.

© 2014. Background: Neurocognitive deficits in schizophrenia (SZ) are established and the Consortium on the Genetics of Schizophrenia (COGS) investigated such measures as endophenotypes in family-based (COGS-1) and case-control (COGS-2) studies. By requiring family participation, family-based sampling may result in samples that vary demographically and perform better on neurocognitive measures. Methods: The Penn computerized neurocognitive battery (CNB) evaluates accuracy and speed of performance for several domains and was administered across sites in COGS-1 and COGS-2. Most tests were included in both studies. COGS-1 included 328 patients with SZ and 497 healthy comparison subjects (HCS) and COGS-2 included 1195 patients and 1009 HCS. Results: Demographically, COGS-1 participants were younger, more educated, with more educated parents and higher estimated IQ compared to COGS-2 participants. After controlling for demographics, the two samples produced very similar performance profiles compared to their respective controls. As expected, performance was better and with smaller effect sizes compared to controls in COGS-1 relative to COGS-2. Better performance was most pronounced for spatial processing while emotion identification had large effect sizes for both accuracy and speed in both samples. Performance was positively correlated with functioning and negatively with negative and positive symptoms in both samples, but correlations were attenuated in COGS-2, especially with positive symptoms. Conclusions: Patients ascertained through family-based design have more favorable demographics and better performance on some neurocognitive domains. Thus, studies that use case-control ascertainment may tap into populations with more severe forms of illness that are exposed to less favorable factors compared to those ascertained with family-based designs.

Author(s): Light, Gregory; Greenwood, Tiffany A; Swerdlow, Neal R; Calkins, Monica E; Freedman, Robert; Green, Michael F; Gur, Raquel E; Gur, Ruben C; Lazzeroni, Laura C; Nuechterlein, Keith H; Olincy, Ann; Radant, Allen D; Seidman, Larry J; Siever, Larry J; Silverman, Jeremy M; Sprock, Joyce; Stone, William S; Sugar, Catherine A; Tsuang, Debby W; Tsuang, Ming T; Turetsky, Bruce I; Braff, David L | Abstract: BackgroundTwin and multiplex family studies have established significant heritability for schizophrenia (SZ), often summarized as 81%. The Consortium on the Genetics of Schizophrenia (COGS-1) family study was designed to deconstruct the genetic architecture of SZ using neurocognitive and neurophysiological endophenotypes, for which heritability estimates ranged from 18% to 50% (mean = 30%). This study assessed the heritability of SZ in these families to determine whether there is a "heritability gap" between the diagnosis and related endophenotypes.MethodsNuclear families (N = 296) with a SZ proband, an unaffected sibling, and both parents (n = 1366 subjects; mean family size = 4.6) underwent 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 of interviewed subjects (N = 3304 subjects; mean family size = 11.2). Heritability estimates of psychotic disorders were computed for both nuclear and extended families.ResultsThe heritability of SZ was 31% and 44% for nuclear and extended families. The inclusion of bipolar disorder increased the heritability to 37% for the nuclear families. When major depression was added, heritability estimates dropped to 34% and 20% for nuclear and extended families, respectively.ConclusionsEndophenotypes and psychotic disorders exhibit comparable levels of heritability in the COGS-1 family sample. The ascertainment of families with discordant sibpairs to increase endophenotypic contrast may underestimate diagnostic heritability relative to other studies. However, population-based studies also report significantly lower heritability estimates for SZ. Collectively, these findings support the importance of endophenotype-based strategies and the dimensional view of psychosis.

The children of older fathers have increased risks of developing schizophrenia spectrum disorders, and among those who develop these disorders, those with older fathers present with more severe clinical symptoms. However, the influence of advanced paternal age on other important domains related to schizophrenia, such as quantitative endophenotype deficit levels, remains unknown. This study investigated the associations between paternal age and level of endophenotypic impairment in a well-characterized family-based sample from the Consortium on the Genetics of Schizophrenia (COGS). All families included at least one affected subject and one unaffected sibling. Subjects met criteria for schizophrenia (probands; n = 293) or were unaffected first-degree siblings of those probands (n = 382). Paternal age at the time of subjects’ birth was documented. Subjects completed a comprehensive clinical assessment and a battery of tests that measured 16 endophenotypes. After controlling for covariates, potential paternal age–endophenotype associations were analyzed using one model that included probands alone and a second model that included both probands and unaffected siblings. Endophenotype deficits in the Identical Pairs version of the 4-digit Continuous Performance Test and in the Penn Computerized Neurocognitive Battery verbal memory test showed significant associations with paternal age. However, after correcting for multiple comparisons, no endophenotype was significantly associated with paternal age. These findings suggest that factors other than advanced paternal age at birth may account for endophenotypic deficit levels in schizophrenia.

Background: Many first-degree relatives of patients with schizophrenia show deficits in clinical, neuropsychological, neurobiological and social domains, in the absence of psychosis. We recently reformulated Meehl’s concept of schizotaxia to conceptualize the liability to schizophrenia, and we proposed preliminary criteria based on the presence of negative symptoms and neuropsychological deficits. Here we investigate the concurrent validity of schizotaxia by comparing a group of subjects who met criteria for schizotaxia with a group who did not on independent measures of clinical function, and on lifetime rates of selected comorbid psychiatric disorders. Methods: Twenty-seven adults who were first-degree, biological relatives of patients with schizophrenia were evaluated for schizotaxia based on our predetermined criteria involving negative symptoms and neuropsychological deficits. Subjects also received portions of the Diagnostic Interview for Genetic Studies, the Structured Interview for Schizotypy, the Family Interview for Genetic Studies, the DSM-IV Global Assessment of Functioning, the Physical Anhedonia Scale, the Social Adjustment Scale and the Symptom Checklist-90-Revised. Subjects who met criteria for schizotaxia were compared with those who did not on each of the clinical measures, and on their rates of comorbid DSM-IV psychiatric diagnoses. Results: Eight subjects met criteria for schizotaxia, and 19 did not. Subjects with schizotaxia showed significantly lower levels of function on each of the clinical scales. Differences in comorbid psychiatric diagnoses were not significant, although the rate of lifetime substance abuse diagnoses in the schizotaxic group (50%) approached levels that are often seen in schizophrenia. Conclusions: These findings provide the first evidence of concurrent validation for a proposed syndrome of schizotaxia. They are also consistent with the view that the vulnerability to schizophrenia may be defined, at least partially, although larger studies to assess both the concurrent and predictive validity of schizotaxia will be required to confirm these results.

BackgroundData from family, twin and adoption studies show overwhelming evidence of a substantial genetic component in schizophrenia and although molecular genetic studies have been more difficult to replicate, recent improvements in technology have resulted in the implication of genes at several chromosomal loci. Nevertheless, it remains clear that environmental factors both add to and interact with genetic factors to produce the disorder.AimsTo incorporate genetic and environmental risk factors into a neurodevelopmental model in order to conceptualise the liability to schizophrenia.MethodA representative selection of the literature related to this issue is reviewed, together with a reformulation of Meehl's term ‘schizotaxia’ to describe the liability to the disorder.ResultsThe literature supports a multi-factorial view of the liability to schizophrenia, which includes both genetic and environmental components.ConclusionsSchizotaxia provides a useful way to conceptualise both the liability for schizophrenia, and also the development of treatment strategies aimed at the eventual prevention of the illness.

Objective Our study was designed to assess symptomatology and occurrences of narcolepsy in Eastern China between 2003 and 2012. Herein we report the substantial changes in the occurrence and clinical features of narcolepsy over the last decade in China. Methods We performed a retrospective analysis of 162 Han Chinese patients with narcolepsy at Changzheng Hospital, Shanghai, China. Clinical histories and precipitating factors were recorded, in addition to narcolepsy and H1N1 winter flu pandemic (pH1N1) occurrences at Changzheng Hospital. The occurrences also were compared between the Changzheng Hospital and the People’s Hospital, Beijing, China. Results In our sample, narcolepsy occurred 1.73 times more frequently in men than in women. Most of the participants were children, which peaked to 91% in 2010. Excessive daytime sleepiness (EDS), disrupted nocturnal sleep, cataplexy, and weight gain were the four major symptoms. We found that 40% of patients had identifiable precipitating factors. The occurrence of narcolepsy in 2010 showed an approximate three-fold difference from the baseline levels at the Changzheng Hospital, which showed positive relationships with occurrences of pH1N1 in Shanghai and the occurrence of narcolepsy at the People’s Hospital. Conclusions Our findings show the interactive effects of geography and H1N1 disease in relation to narcolepsy in Han Chinese populations, and strengthen the theoretic hypothesis that immune and mental factors facilitate the onset of narcolepsy.

A substantial part of the contribution of genetic studies to the treatment of schizophrenia involves its emphasis on reliable and valid diagnoses. One consequence of this focus is the recognition that schizophrenic illness is broader than the diagnostic entity of schizophrenia itself, and instead consists of a “spectrum” of related disorders. Because some of the symptoms in these disorders differ from each other, they provide an opportunity to determine which ones reflect a common etiology. To the extent that such symptoms are identifiable, they may provide a foundation for treatment and even prevention strategies. In this paper, we focus on a clinical condition - “schizotaxia” - that may reflect the liability for schizophrenia. To characterize the nature and extent of this proposed syndrome, we will review results from family studies in our laboratory, and consider conceptual foundations and criteria for assessment. A more general consideration of treatment strategies for schizophrenia spectrum disorders follows, along with suggestions for future research. Our initial attempts to treat and validate schizotaxia are encouraging, and raise the possibility that early treatment might eventually prevent or attenuate the development of other, more severe disorders in the schizophrenia spectrum, including schizophrenia itself.

One of the most important trends in the treatment of schizophrenia involves its early diagnosis and intervention. The ultimate goal of research is the prevention of the disorder, A major impediment to the development of prevention strategies, however, is that we do not yet know what the liability for schizophrenia is before the onset of psychosis. Consequently, early treatment attempts are focused on the "prodrome," which involves the early symptoms of psychosis. In a companion paper, we recently suggested that prevention work should focus not only on the prodrome, but also on "schizotaxia," which is a clinically meaningful condition that may reflect the vulnerability to schizophrenia in the absence of psychosis. Because schizotaxia can be assessed prior to the prodrome, studies of schizotaxia might lead to more effective prevention programs. We continue the characterization of schizotaxia in this paper by focusing on the etiological roots of schizotaxia, plus its likely neurodevelopmental course, clinical expression, and treatment. Finally, the importance of including neurobiological variables in the conceptualization and eventual diagnosis of schizotaxia is reviewed.

Historically, the Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnostic criteria for schizophrenia have emphasized several features, including symptoms of psychosis, a dissociation of symptoms from their etiology, a reliance on clinical symptoms, and a categorical approach to classifying the disorder. Although these emphases are quite useful, they have limitations. We review these here, and stress the importance of incorporating recent data on the genetic /biological and neurodevelopmental origins of schizophrenia into current conceptions of the disorder. We also review "schizotaxia, " which is a concept thai embodies this point of view, occurs before the onset of psychosis, and is hypothesized to represent the liability for schizophrenia. If our hypothesis on this point is correct, the identification of schizotaxic individuals will eventually facilitate the development of prevention strategies by identifying a premorbid (but clinically significant) condition for schizophrenia. Moreover, the identification of biological or neuropsychological components of schizotaxia will provide more specific bases for developing novel treatment interventions. Our initial attempts to develop protocols for the assessment and treatment of schizotaxia are encouraging, and will be reviewed.

Despite the complexities of schizophrenia, notable progress has been achieved in its diagnosis and treatment over the last 25 years. In this article we review the genetic research that provides the foundation for continued advances. One of the bases of our current understanding involves the observation that schizophrenia often runs in families. The development and utilization of stringent, reliable diagnostic criteria, together with the advent of modern family, twin, and adoption paradigms, demonstrate the importance of genetic factors in understanding the familial basis of the disorder. Refinements in diagnostic criteria have also enabled advances in understanding the likely mode--or modes--of genetic transmission of both schizophrenia and related disorders. After reviewing representative studies in these areas, we examine genetic linkage studies and our progress toward identifying the genes that cause schizophrenia. Although consistent results have been difficult to obtain and much work remains to be done, evidence for areas of vulnerability has been converging at particular chromosomal sites (e.g., 6p, 8p, and 22q), allowing for cautious optimism. Finally, we discuss challenges and prospects for the new millennium, including the clinical and ethical implications of genetic investigations.

Background: Substantial evidence now shows that the genetic vulnerability to schizophrenia can be manifested clinically in first-degree relatives of people with schizophrenia, even without the full manifestations of the disorder. One pattern of problems observed involves the combination of negative symptoms and neuropsychological deficits. We have investigated whether a low dose of a novel antipsychotic medication, risperidone, could attenuate these clinical problems in non-psychotic, first-degree relatives, and report here findings from our first 4 cases. Methods: Twelve adults who were first-degree relatives of patients with schizophrenia were evaluated for the presence of negative symptoms and neuropsychological deficits (in attention and working memory, long-term verbal memory and executive functions). Four subjects who met our predetermined criteria, and who did not demonstrate medical contraindications, were enrolled in a 6-week trial of risperidone. Clinical and medical measures were assessed before, during and after treatment. Doses of risperidone started at 0.25 mg and were increased to 1.0–2.0 mg/day. Results: Three subjects showed substantial reductions in negative symptoms, and one subject showed modest reductions. All four subjects showed substantial improvements on some tests of attention and working memory. Side effects of risperidone were temporary and mainly mild. Conclusions: These initial findings support two conclusions. First, clinical deficits in non-psychotic first-degree relatives of people with schizophrenia are identifiable, and to a significant extent, reversible. Second, risperidone may eventually serve as an effective treatment for people whose lives are impaired by similar or related problems.

The goal of this study was to further characterize episodic memory functioning in schizophrenia. This study compared verbal and visual learning and memory performance in (1) patients with schizophrenia (N = 35), (2) patients with temporal lobe epilepsy (TLE; N = 30), and (3) normal controls (N = 25). Results indicated significant memory impairments in patients with schizophrenia and TLE. “Savings” score measures of memory decay showed that the loss of information in schizophrenia and TLE was approximately equal, and quantitatively mild compared to that found in most neurologic groups with memory disorders. The severe difficulty shown by the schizophrenia group on a task of incidental recall suggested that the absence of instructional set added to a vulnerability to memory deficit. In contrast, relatively mildly impaired performance on paired associate learning suggested that patients with schizophrenia benefited from retrieval cues, multiple trials, and short (nonsupraspan) informational loads. Because patients with schizophrenia consisted of a relatively nonchronic sample with a mean IQ of 99.7, their memory disorder could not be attributed to schizophrenic dementia, nor was it accounted for by other potential confounds. Patients with schizophrenia, even those relatively early in the course of illness, have a mild episodic memory disorder. (JINS, 1998, 4, 342–352.)

Objective Studies in healthy individuals show that exerting self-control consumes cognitive resources, which reduces subsequent self-control performance. Restoring the availability of blood glucose eliminates this impairment. Patients with schizophrenia are found to have self-regulatory dysfunctions. This study aims to investigate whether patient's (a) glucose facilitation effects will be impaired, and (b) will have exaggerated depletion in a self-control task. Method 40 patients with schizophrenia-spectrum disorders and 40 normal controls were recruited. A two drinks (glucose vs. placebo) × two depleting phases (self-control depleted vs. non-depleted) between-groups design was used. We examined the blood glucose levels before and after the selfcontrol depletion phase and the subsequent performances in two self-control tasks (handgrip and Stroop tests) after the drink condition. Results The four groups (depleting × glucose, depleting × placebo, non-depleting × glucose and nondepleting × placebo) of both patients and normal controls were comparable on a number of characteristics. The change in blood glucose level in the depleting group was significantly different from those in the non-depleting group. Two × two between-subjects ANOVAs were carried out to test the performances in the handgrip and Stroop tasks. Significant interactions were found in healthy controls regarding both tasks. However, a significant interaction was only found in patients regarding the handgrip task but not the Stroop task. Conclusions This study demonstrated an abnormal glucose facilitation effect in patients during a cognitive self-control task but not during a physical self-control task. The findings also suggested for the first time that a self-control depletion effect is intact in patients with schizophrenia.

Previous studies have linked vitamin D deficiency to hypertension, dyslipidemia, diabetes mellitus, and cardiovascular disease. The aim of this study was to investigate the short-term effects of vitamin D₃ supplementation on weight and glucose and lipid metabolism in antipsychotic-treated patients. A total of 19 schizophrenic or schizoaffective patients (BMI27 kg/m²) taking atypical antipsychotics were recruited and dispensed a 2000 IU daily dose of vitamin D₃. On comparing baseline with week 8 (study end) results, we found a statistically significant increase in vitamin D₃ and total vitamin D levels but no statistically significant changes in weight, glucose, or lipids measurements. Patients whose vitamin D₃ level at week 8 was 30 ng/ml or more achieved a significantly greater decrease in total cholesterol levels compared with those whose week 8 vitamin D₃ measurement was less than 30 ng/ml. These results suggest that a randomized trial with a longer follow-up period would be helpful in further evaluating the effects of vitamin D₃ on weight, lipid metabolism, and on components of metabolic syndrome in antipsychotic-treated patients.

When administered systemically, glucose attenuates deficits in memory produced by several classes of drugs, including cholinergic antagonists and opiate agonists. Glucose also enhances memory in aged rats, mice, and humans. In addition, glucose ameliorates age-related reductions in paradoxical sleep. Because deficits in paradoxical sleep are most marked in those individual aged rats that also have deficits in memory, treatments which improve one of these functions may similarly improve the other. The present experiments show that glucose attenuates deficits in paradoxical sleep and memory after atropine administration, with similar dose-response curves for both actions. In the first experiment, rats received saline, atropine (1 mg/kg), glucose (100 mg/kg) or combinations of atropine + glucose (10, 100, 250, and 500 mg/kg) 30 min before assessment on a spontaneous alternation task. In the second experiment, 3-h EEGs were assessed for spontaneous daytime sleep in rats administered saline, atropine (1 mg/kg), glucose (100 mg/kg) or combinations of atropine + glucose (10, 100 and 250 mg/kg). In both experiments, glucose significantly attenuated deficits at an optimal dose of 100 mg/kg. A third experiment assessed blood glucose levels after injections of atropine + glucose (100 mg/kg) and determined that blood glucose levels were similar to those produced by other treatments which enhance memory. These results are consistent with the view that paradoxical sleep and at least one test of memory are similarly influenced by atropine and glucose.

OBJECTIVES The search for predictors of schizophrenia has accelerated with a growing focus on early intervention and prevention of psychotic illness. Studying nonpsychotic relatives of individuals with schizophrenia enables identification of markers of vulnerability for the illness independent of confounds associated with psychosis. The goal of these studies was to develop new auditory continuous performance tests (ACPTs) and evaluate their effects in individuals with schizophrenia and their relatives. METHODS We carried out two studies of auditory vigilance with tasks involving working memory (WM) and interference control with increasing levels of cognitive load to discern the information-processing vulnerabilities in a sample of schizophrenia patients, and two samples of nonpsychotic relatives of individuals with schizophrenia and controls. Study 1 assessed adults (mean age = 41), and Study 2 assessed teenagers and young adults age 13-25 (M = 19). RESULTS Patients with schizophrenia were impaired on all five versions of the ACPTs, whereas relatives were impaired only on WM tasks, particularly the two interference tasks that maximize cognitive load. Across all groups, the interference tasks were more difficult to perform than the other tasks. Schizophrenia patients performed worse than relatives, who performed worse than controls. For patients, the effect sizes were large (Cohen's d = 1.5), whereas for relatives they were moderate (d = ~0.40-0.50). There was no age by group interaction in the relatives-control comparison except for participants

Background: Recent studies suggest that anhedonia, an inability to experience pleasure, can be measured as an enduring trait in non-clinical samples. In order to examine trait anhedonia in a non-clinical sample, we examined the properties of a range of widely used questionnaires capturing anhedonia. Methods: 887 young adults were recruited from colleges. All of them were administered a set of checklists, including Chapman Scale for Social Anhedonia (CRSAS) and the Chapman Scale for Physical Anhedonia Scale (CPAS), The Temporal Experience of Pleasure Scale(TEPS), and The Schizotypal Personality Questionnaire (SPQ). Results: Males showed significantly higher level of physical (F = 5.09, p, China. Ministry of Science and Technology. National Key Technologies R&D Program (2012BAI36B01), National Science Fund China (Grant no. 81088001), National Science Fund China (Grant no. 91132701), Chinese Academy of Sciences. Knowledge Innovation Project (KSCX2-EW-J-8)

Many first-degree relatives of patients with schizophrenia demonstrate deficits in neurocognitive, social, clinical and other dimensions, in the absence of psychosis. Based on a reformulation of Meehl's concept of “schizotaxia” as a clinically meaningful syndrome reflecting liability to schizophrenia, we proposed research criteria in relatives focused on negative symptoms and neurocognitive deficits. Here we assess validity of the syndrome in a sample of Chinese adult relatives by assessing measures of concurrent validity, and by using cluster analysis to test the hypothesis that relatives could be grouped into distinct schizotaxic and non-schizotaxic subgroups based on our diagnostic criteria. Thirty community comparison subjects (CCS) and 189 relatives were evaluated with measures of clinical, cognitive, medical and social function at the Mental Health Institute, Second Xiangya Hospital of Central South University, Changsha (Hunan, China), as part of a larger study to identify and ameliorate symptoms of schizotaxia. Using modified research criteria based on negative symptoms and neurocognitive deficits, 103 relatives did not meet criteria for schizotaxia, and 86 did. The cluster analysis confirmed a two-group solution that corresponded to our non-schizotaxic and schizotaxic groups, but it increased the non-schizotaxic group to 135, and reduced the schizotaxic group to 53. Both schizotaxic groups, but especially the cluster-derived group, showed significant impairment in a variety of independent (i.e. non-criterion related) measures of clinical and social function. These findings provide additional validity for a liability syndrome, and for its utility as an intervention target for strategies aimed at ameliorating both its core and its associated symptoms.

This chapter focuses on two disorders in the schizophrenia ‘spectrum’: schizoaffective disorder and schizotypal personality disorder. The emphasis includes the clinical features, classification, diagnosis, epidemiology, aetiology, course, prognosis, and possibilities for prevention for each disorder. Some aspects will be underscored to reflect controversial issues, such as the heterogeneity apparent in each condition. Such issues relate to the accurate classification of the disorders, which is important for at least two reasons. First, it is essential to develop reliable and valid diagnostic criteria in order to study the aetiology of the disorders and then utilize that knowledge to develop rational and testable intervention strategies. Heterogeneity adds variance to the process that reduces both the reliability of diagnosis and also the statistical power of experimental designs to detect intervention/treatment effects. Second, the development of newer generations of psychopharmacological treatments holds the promise of matching more appropriate and efficacious medications with specific syndromes or types of symptoms. This trend underscores the importance of differential diagnosis in determining what treatment a patient will receive. Heterogeneity within a diagnostic category complicates achievement of this goal. Another area to be emphasized involves the goal of early interventions, in addition to palliative treatments for these disorders. In contrast, other areas such as the genetic aetiology of schizoaffective disorder and schizotypal personality disorder, and treatments for schizoaffective disorder, will receive less emphasis here, to avoid redundancies with other chapters in this volume. Each disorder will be considered separately, starting with a review of schizoaffective disorder, the more severe of the two spectrum conditions.

Difficulties in feeling pleasure and expressing emotions are one of the key features of schizophrenia spectrum conditions, and are significant contributors to constricted interpersonal interactions. The current study examined the experience of pleasure and emotional expression in college students who demonstrated high and low levels of schizotypal personality disorder (SPD) traits on self-report questionnaires. One hundred and seventeen subjects with SPD traits and 116 comparison controls were recruited to participate. Cluster analyses conducted in the SPD group identified negative SPD and positive SPD subgroups. The negative SPD group exhibited deficient emotional expression and anticipatory pleasure, but showed intact consummatory pleasure. The positive SPD group reported significantly greater levels of anticipatory, consummatory and total pleasure compared to the control group. Both SPD groups reported significantly more problems in everyday memory and greater levels of depressive and anxiety-related symptoms., China. Ministry of Science and Technology. National Key Technologies R&D Program (2012BAI36B01), National Science Fund China (Grant no. 81088001), National Science Fund China (Grant no. 91132701), Chinese Academy of Sciences. Knowledge Innovation Project (KSCX2-EW-J-8)

Several studies have evaluated the potential utility of blood-based whole-transcriptome signatures as a source of biomarkers for schizophrenia. This endeavor has been complicated by the fact that individuals with schizophrenia typically differ from appropriate comparison subjects on more than just the presence of the disorder; for example, individuals with schizophrenia typically receive antipsychotic medications, and have been dealing with the sequelae of this chronic illness for years. The inability to control such factors introduces a considerable degree of uncertainty in the results to date. To overcome this, we performed a blood-based gene-expression profiling study of schizophrenia patients (n = 9) as well as their unmedicated, nonpsychotic, biological siblings (n = 9) and unaffected comparison subjects (n = 12). The unaffected biological siblings, who may harbor some of the genetic predisposition to schizophrenia, exhibited a host of gene-expression differences from unaffected comparison subjects, many of which were shared by their schizophrenic siblings, perhaps indicative of underlying risk factors for the disorder. Several genes that were dysregulated in both individuals with schizophrenia and their siblings related to nucleosome and histone structure and function, suggesting a potential epigenetic mechanism underlying the risk state for the disorder. Nonpsychotic siblings also displayed some differences from comparison subjects that were not found in their affected siblings, suggesting that the dysregulation of some genes in peripheral blood may be indicative of underlying protective factors. This study, while exploratory, illustrated the potential utility and increased informativeness of including unaffected first-degree relatives in research in pursuit of peripheral biomarkers for schizophrenia. © 2011 Wiley Periodicals, Inc.

Increasing efforts to identify alternate expressions of mental disorders that are broader than the DSM or ICD diagnostic criteria needed to diagnose them reflects a growing consensus that multidimensional expressions of psychiatric disorders may advance the search for underlying etiological or modulatory factors. These alternate phenotypes or “endophenotypes” (e.g., social, psychophysiological or neuropsychological abnormalities) of disorders may be more specific and amenable to objective measurement than clinical symptoms, which presumably reflects variation among smaller numbers of genes than more distal clinical symptoms. These features support the current usefulness of endophenotypes in genetic studies, and their potential usefulness in the development of strategies for early intervention. In this chapter, we review potential neurological and neuropsychological endophenotypes for schizophrenia and for schizophrenia spectrum disorders, with an emphasis on key conceptual criteria for assessing endophenotypes, including their relationships to schizophrenia, to non-psychotic relatives, and to heritability. Future directions for establishing the validity of endophenotype research are also discussed.

Cognitive deficits are among the most important factors leading to poor functional outcomes in schizophrenia, with deficits in declarative memory among the largest and most robust of these. Thus far, attempts to enhance cognition in schizophrenia have shown only modest success, which underlies increasing efforts to develop effective treatment strategies. This review is divided into three main parts. The first section delineates the nature and extent of the deficits in both patients with schizophrenia and in their adult, non-psychotic relatives. The second part focuses on structural and functional abnormalities in the hippocampus, both in people with schizophrenia and in animal studies that model relevant features of the illness. The third section views problems in declarative memory and hippocampal function from the perspective of elevated rates of common medical disorders in schizophrenia, with a focus on insulin insensitivity/diabetes. The likelihood that poor glucose regulation/availability contribute to declarative memory deficits and hippocampal abnormalities is considered, along with the possibility that schizophrenia and poor glucose regulation share common etiologic elements, and with clinical implications of this perspective for enhancing declarative memory.

This article reviews progress made in the identification of vulnerability to schizophrenia in genetic high-risk groups. Dimensions of vulnerability include cognitive, clinical and social functions, among others. Based on studies of dysfunction in these areas, specialized programs are being developed to focus on recognizing rates and patterns of transition to schizophrenia, and intervention techniques that include psychopharmacological and psychotherapeutic techniques. After considering a current conceptualization of schizotaxia, the identification of novel endophenotypes that may include brain function, molecular biology or other medical functions will be considered, in addition to clinical, social and neuropsychological measures. Eventually, it is hoped that areas of vulnerability will coalesce into validated syndromes of liability that can be used to identify individuals who are most likely to develop schizophrenia-related disorders. This strategy will then allow the formation of more homogenous treatment groups to use in developing early intervention and prevention strategies in the not-too-distant future.

Background Early invasive electrical stimulation studies suggested that enhancement of cerebellar vermal activity might prove valuable in symptomatic treatment of refractory neuropsychiatric diseases via modulation of emotion and affect. This proof of principle study aimed to test this hypothesis using noninvasive brain stimulation, and to explore the safety of this protocol in schizophrenia. Methods Eight treatment-refractory patients with schizophrenia underwent ten sessions of intermittent theta burst stimulation (TBS) to the cerebellar vermis using MRI-guided transcranial magnetic stimulation (TMS). Assessments included side effect questionnaires, cardiovascular monitoring, psychiatric evaluations and comprehensive neuropsychological testing before and after TBS and at one-week follow-up. Results Overall, TBS was tolerated well with mild side effects primarily comprising neck pain and headache. No serious adverse events occurred. Diastolic blood pressure (BP) showed mild decreases for five minutes post-TBS; no significant changes were detected for systolic BP or pulse. PANSS negative subscale showed significant improvements following TBS and during the follow-up. Calgary Depression Scale and self-report visual analog scales for Happiness and Sadness pointed to significant mood elevation. Neuropsychological testing revealed significantly fewer omissions in working memory and interference conditions of a Continuous Performance Test, a longer spatial span and better delay organization on the Rey–Osterrieth Complex Figure during follow-up. No significant worsening in psychiatric or neuropsychological measures was detected. Conclusions Theta burst stimulation of the cerebellar vermis is safe and well-tolerated, while offering the potential to modulate affect, emotion and cognition in schizophrenia. Future randomized, sham-stimulation controlled studies are warranted to support the clinical efficacy of this technique.

Sleep is regulated by complex biological systems and environmental influences, neither of which is fully clarified. This study demonstrates differential effects of partial sleep deprivation (SD) on sleep architecture and psychomotor vigilance task (PVT) performance using two different protocols (sequentially) that each restricted daily sleep to 3 hours in healthy adult men. The protocols differed only in the period of sleep restriction; in one, sleep was restricted to a 3-hour block from 12:00 AM to 3:00 AM, and in the other, sleep was restricted to a block from 3:00 AM to 6:00 AM. Subjects in the earlier sleep restriction period showed a significantly lower percentage of rapid-eye-movement (REM) sleep after 4 days (17.0 vs. 25.7 %) and a longer latency to the onset of REM sleep (L-REM) after 1 day (78.8 vs. 45.5 min) than they did in the later sleep restriction period. Reaction times on PVT performance were also better (i.e. shorter) in the earlier SR period on day 4 (249.8 vs. 272 ms). These data support the view that earlier-night sleep may be more beneficial for daytime vigilance than later-night sleep. The study also showed that cumulative declines in daytime vigilance resulted from loss of total sleep time, rather than from specific stages, and underscored the reversibility of SR effects with greater amounts of sleep.