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TianHong Zhang,1 HuiJun Li,2,3 Kristen A Woodberry,3 Larry J Seidman,3 Annabelle Chow,4 ZePing Xiao,1 JiJun Wang1 1Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Psychology, Florida A&M University, Tallahassee, FL, USA; 3Department of Psychiatry, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA; 4Department of Psychological Medicine, Changi General Hospital, Singapore Abstract: Clinical high risk of psychosis is defined as the period in which the first signs of psychotic symptoms begin to appear. During this period, there is an increased probability of developing frank psychosis. It is crucial to investigate the interaction between psychotic symptoms and the individual’s personality and life experiences in order to effectively prevent, or delay the development of psychosis. This paper presents case reports of three Chinese female subjects with attenuated positive symptoms, attending their initial outpatient assessment in a mental health service, and their longitudinal clinical outcomes. Information regarding each subject’s symptoms and life stressors was collected at 2-month intervals over a 6-month period. The assessments indicated that these women were suffering from the recent onset of symptoms in different ways. However, all three hid their symptoms from others in their school or workplace, and experienced a decline in performance related to their social roles and in their daily functioning. They were often excluded from the social groups to which they had previously belonged. A decline in social activities may be a risk factor in the development of psychosis and a mediator of functional sequelae in psychosis. Effective treatment strategies may include those that teach individuals to gain insights related to their symptoms and a service that provides a context in which individuals can discuss their psychotic symptoms. Keywords: prodromal psychosis, ultra high risk, follow-up, functional sequelae, transition

BackgroundSeverity of negative symptoms has been associated with poor functioning, cognitive deficits, and defeatist beliefs in schizophrenia patients. However, one area that remains understudied is persistent negative symptoms (PNS). Negative symptoms, including PNS, have been observed in those at clinical high-risk (CHR) for psychosis. The aim of this study was to determine if PNS were associated with functioning, neurocognition, and defeatist beliefs in a CHR sample.MethodCHR participants (n = 764) were recruited for the North American Prodrome Longitudinal Study. Negative symptoms were rated on the Scale of Psychosis-risk Symptoms. Generalized linear mixed models for repeated measures were used to examine changes over time between and within groups (PNS vs non-PNS).ResultsThe PNS group (n = 67) had significant deficits in functioning at baseline, 6, 12, 18, and 24-months compared to the non-PNS group (n = 673). Functioning improved over time in the non-PNS group, while functioning in the PNS group remained relatively stable and poor over a two-year period. A consistent trend emerged demonstrating higher defeatist beliefs in the PNS group; however, this result was lost when controlling for persistent depressive symptoms. There were no significant differences between the groups on neurocognition, social cognition, and transition to psychosis.ConclusionsPNS exist in youth at CHR for psychosis, resulting in significant and persistent functional impairment, which remains when controlling for persistent depressive symptoms. PNS remain even in CHR youth who do not transition to psychosis. Thus, PNS may represent an unmet therapeutic need in CHR populations for which there are currently no effective treatments.

Social cognition deficits have been observed in individuals at clinical high risk (CHR) for psychosis. Longitudinal change in social cognition were analyzed in CHR individuals from the North American Prodrome Longitudinal Study (NAPLS2) based on outcome at 24 months. Individuals (n = 359) were classified into remission, symptomatic, prodromal progression and transition to psychosis (CHR-T) groups. Social cognition was assessed using theory of mind, emotion perception, and social perception tasks. There were no differences at baseline or 24 months between the groups on social cognition. Non-transition groups improved significantly over time on social cognition, but CHR-T did not show this effect.

Aim: Examining ethnically related variables in evaluating those at risk for psychosis is critical. This study investigated sociodemographic and clinical characteristics of Latino versus non-Latino clinical high-risk (CHR) subjects and healthy control (HC) subjects in the first North American Prodrome Longitudinal Study. Methods: Fifty-six Latino CHR subjects were compared to 25 Latino HC and 423 non-Latino CHR subjects across clinical and demographic variables. Thirty-nine of the 56 CHR subjects completed at least one subsequent clinical evaluation over the 2.5-year period with 39% developing a psychotic illness. Characteristics of Latino CHR subjects who later converted to psychosis ('converters') were compared to those who did not ('non-converters'). Results: Latino CHR subjects were younger than non-Latino CHR subjects and had less education than Latino HC subjects and non-Latino CHR counterparts. Latino CHR converters had higher scores than Latino non-converters on the Structured Interview for Prodromal Syndromes total negative symptoms that were accounted for by decreased expression of emotion and personal hygiene/social attentiveness subsections. Latino CHR converters scored lower on the global functioning:social scale, indicating worse social functioning than Latino non-converters. Conclusion: Based on this sample, Latino CHR subjects may seek treatment earlier and have less education than non-Latino CHR subjects. Deficits in social functioning and impaired personal hygiene/social attentiveness among Latino CHR subjects predicted later psychosis and may represent important areas for future study. Larger sample sizes are needed to more thoroughly investigate the observed ethnic differences and risk factors for psychosis in Latino youth.

BackgroundA series of research reports has indicated that the use of substances such as cannabis, alcohol and tobacco are higher in youth at clinical high risk (CHR) of developing psychosis than in controls. Little is known about the longitudinal trajectory of substance use, and findings on the relationship between substance use and later transition to psychosis in CHR individuals are mixed.MethodAt baseline and 6- and 12-month follow-ups, 735 CHR and 278 control participants completed the Alcohol and Drug Use Scale and a cannabis use questionnaire. The longitudinal trajectory of substance use was evaluated with linear mixed models.ResultsCHR participants endorsed significantly higher cannabis and tobacco use severity, and lower alcohol use severity, at baseline and over a 1-year period compared with controls. CHR youth had higher lifetime prevalence and frequency of cannabis, and were significantly younger upon first use, and were more likely to use alone and during the day. Baseline substance use did not differentiate participants who later transitioned to psychosis (n = 90) from those who did not transition (n = 272). Controls had lower tobacco use than CHR participants with a prodromal progression clinical outcome and lower cannabis use than those with a psychotic clinical outcome at the 2-year assessment.ConclusionsIn CHR individuals cannabis and tobacco use is higher than in controls and this pattern persists across 1 year. Evaluation of clinical outcome may provide additional information on the longitudinal impact of substance use that cannot be detected through evaluation of transition/non-transition to psychosis alone.

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.

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.

The first phase of the Consortium on the Genetics of Schizophrenia (COGS-1) showed performance deficits in learning and memory on the California Verbal Learning Test, Second Edition (CVLT-II) in individuals with schizophrenia (SZ), compared to healthy comparison subjects (HCS). A question is whether the COGS-1 study, which used a family study design (i.e. studying relatively intact families), yielded "milder" SZ phenotypes than those acquired subsequently in the COGS-2 case-control design that did not recruit unaffected family members. CVLT-II performance was compared for the COGS-1 and COGS-2 samples. Analyses focused on learning, recall and recognition variables, with age, gender and education as covariates. Analyses of COGS-2 data explored effects of additional covariates and moderating factors in CVLT-II performance. 324 SZ subjects and 510 HCS had complete CVLT-II and covariate data in COGS-1, while 1356 SZ and 1036 HCS had complete data in COGS-2. Except for recognition memory, analysis of covariance showed significantly worse performance in COGS-2 on all CVLT-II variables for SZ and HCS, and remained significant in the presence of the covariates. Performance in each of the 5 learning trials differed significantly. However, effect sizes comparing cases and controls were comparable across the two studies. COGS-2 analyses confirmed SZ performance deficits despite effects of multiple significant covariates and moderating factors. CVLT-II performance was worse in COGS-2 than in COGS-1 for both the SZ and the HCS in this large cohort, likely due to cohort effects. Demographically corrected data yield a consistent pattern of performance across the two studies in SZ.

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.

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.

BackgroundPrevious studies suggest that abnormalities in maternal immune activity during pregnancy alter the offspring's brain development and are associated with increased risk for schizophrenia (SCZ) dependent on sex.MethodUsing a nested case-control design and prospectively collected prenatal maternal sera from which interleukin (IL)-1β, IL-8, IL-6, tumor necrosis factor (TNF)-α and IL-10 were assayed, we investigated sex-dependent associations between these cytokines and 88 psychotic cases [SCZ = 44; affective psychoses (AP) = 44] and 100 healthy controls from a pregnancy cohort followed for > 40 years. Analyses included sex-stratified non-parametric tests adjusted for multiple comparisons to screen cytokines associated with SCZ risk, followed by deviant subgroup analyses using generalized estimating equation (GEE) models.ResultsThere were higher prenatal IL-6 levels among male SCZ than male controls, and lower TNF-α levels among female SCZ than female controls. The results were supported by deviant subgroup analyses with significantly more SCZ males with high IL-6 levels (>highest quartile) compared with controls [odd ratio (OR)75 = 3.33, 95% confidence interval (CI) 1.13-9.82], and greater prevalence of low TNF-α levels (ConclusionsThe results underscore the importance of immunologic processes affecting fetal brain development and differential risk for psychoses depending on psychosis subtype and offspring sex.

Self-esteem and well-being are important for successful aging, and some evidence suggests that self-esteem and well-being are associated with hippocampal volume, cognition and stress responsivity. Whereas most of this evidence is based on studies on older adults, we investigated self-esteem, well-being and hippocampal volume in 474 male middle-aged twins. Self-esteem was significantly positively correlated with hippocampal volume (0.09, P = 0.03 for left hippocampus, 0.10, P = 0.04 for right). Correlations for well-being were not significant (Ps > 0.05). There were strong phenotypic correlations between self-esteem and well-being (0.72, P < 0.001) and between left and right hippocampal volume (0.72, P < 0.001). In multivariate genetic analyses, a two-factor additive genetic and unique environmental (AE) model with well-being and self-esteem on one factor and left and right hippocampal volumes on the other factor fits the data better than Cholesky, independent pathway or common pathway models. The correlation between the two genetic factors was 0.12 (P = 0.03); the correlation between the environmental factors was 0.09 (P > 0.05). Our results indicate that largely different genetic and environmental factors underlie self-esteem and well-being on one hand and hippocampal volume on the other.

The presence of an ApoE ε4 allele (ε4+) increases the risk of developing Alzheimer's disease (AD). Previous studies support an adverse relationship between ε4+ status and brain structure and function in mild cognitive impairment and AD; in contrast, the presence of an ε2 allele may be protective. Whether these findings reflect disease-related effects or pre-existing endophenotypes, however, remains unclear. The present study examined the influence of ApoE allele status on brain structure solely during middle-age in a large, national sample. Participants were 482 men, ages 51-59, from the Vietnam Era Twin Study of Aging (VETSA). T1-weighted images were used in volumetric segmentation and cortical surface reconstruction methods to measure regional volume and thickness. Primary linear mixed effects models predicted structural measures with ApoE status (ε3/3, ε2/3, ε3/4) and control variables for effects of site, non-independence of twin data, age, and average cranial vault or cortical thickness. Relative to the ε3/3 group, the ε3/4 group demonstrated significantly thinner cortex in superior frontal and left rostral and right caudal midfrontal regions; there were no significant effects of ε4 status on any temporal lobe measures. The ε2/3 group demonstrated significantly thicker right parahippocampal cortex relative to the ε3/3 group. The ApoE ε4 allele may influence cortical thickness in frontal areas, which are later developing regions thought to be more susceptible to the natural aging process. Previous conflicting findings for mesial temporal regions may be driven by the inclusion of older individuals, who may evidence preclinical manifestations of disease, and by unexamined moderators of ε4-related effects. The presence of the ε2 allele was related to thicker cortex, supporting a protective role. Ongoing follow-up of the VETSA sample may shed light on the potential for age-and disease-related mediation of the influence of ApoE allele status. © 2011 The authors and IOS Press. All rights reserved.

There is a growing literature on brain activity in the nonpsychotic first-degree relatives of patients with schizophrenia as measured using functional imaging. This systematic review examined 20 studies in 4 domains of cognition, including cognitive control (7 samples), working memory (5 samples), long-term memory (4 samples), and language (4 samples). While the literature was widely divergent, these studies did consistently find activation differences between patients' relatives and controls. The most consistent increases in activation within hemisphere were found in right ventral prefrontal cortex (PFC) and right parietal cortex. Abnormal activity, defined as significant increases or decreases in activation relative to controls irrespective of hemisphere, was found in about two-thirds of contrasts in the cerebellum, dorsal prefrontal, lateral temporal, and parietal cortices, and thalamus, with basal ganglia and ventral PFC showing abnormalities in approximately half of those contrasts. Anterior cingulate was generally spared in patients' relatives. The diversity of findings in studies of patients' relatives may derive from differences between the cognitive demands across studies. We identify avenues for building a more accurate and cumulative literature, including symmetrical inclusion criteria for relatives and controls, recording in-scanner responses, using both a priori and whole-brain tests, explicitly reporting threshold values, reporting main effects of task, reporting effect sizes, and quantifying the risk of false negatives. While functional imaging in the relatives of schizophrenia patients remains a promising methodology for understanding the impact of the unexpressed genetic liability to schizophrenia, no single region or mechanism of abnormalities has yet emerged. [ABSTRACT FROM AUTHOR]

Background: A previously conducted study of prenatal lead exposure and schizophrenia using delta-aminolevulinic acid, a biologic marker of Pb exposure, in archived maternal serum samples collected from subjects enrolled in the Childhood Health and Development Study (1959-1966) based in Oakland, California, suggested a possible association between prenatal Pb exposure and the development of schizophrenia in later life.Objectives: In the present study we extend these findings using samples collected from the New England cohort of the National Collaborative Perinatal Project (1959-1966) . Using similar methods, in this study we found results that suggest a comparable association in this cohort.Methods: We pooled matched sets of cases and controls from both the California and New England sites using a multilevel random-intercept logistic regression model, accounting for matching and site structure as well as adjusting for maternal age at delivery and maternal education.Results: The estimated odds ratio for schizophrenia associated with exposure corresponding to 15 µg/dL of blood Pb was 1.92 (95% confidence interval, 1.05-3.87 ; p = 0.03) .Conclusion: Although several limitations constrain generalizability, these results are consistent with previous findings and provide further evidence for the role of early environmental exposures in the development of adult-onset psychiatric disorders. [ABSTRACT FROM AUTHOR]

BACKGROUND: Although attention deficit hyperactivity disorder (ADHD) and bipolar disorder (BPD) co-occur frequently and represent a particularly morbid clinical form of both disorders, neuroimaging research addressing this co-morbidity is scarce. Our aim was to evaluate the morphometric magnetic resonance imaging (MRI) underpinnings of the co-morbidity of ADHD with BPD, testing the hypothesis that subjects with this co-morbidity would have neuroanatomical correlates of both disorders.MethodMorphometric MRI findings were compared between 31 adults with ADHD and BPD and with those of 18 with BPD, 26 with ADHD, and 23 healthy controls. The volumes (cm3) of our regions of interest (ROIs) were estimated as a function of ADHD status, BPD status, age, sex, and omnibus brain volume using linear regression models. RESULTS: When BPD was associated with a significantly smaller orbital prefrontal cortex and larger right thalamus, this pattern was found in co-morbid subjects with ADHD plus BPD. Likewise, when ADHD was associated with significantly less neocortical gray matter, less overall frontal lobe and superior prefrontal cortex volumes, a smaller right anterior cingulate cortex and less cerebellar gray matter, so did co-morbid ADHD plus BPD subjects. CONCLUSIONS: Our results support the hypothesis that ADHD and BPD independently contribute to volumetric alterations of selective and distinct brain structures. In the co-morbid state of ADHD plus BPD, the profile of brain volumetric abnormalities consists of structures that are altered in both disorders individually. Attention to co-morbidity is necessary to help clarify the heterogeneous neuroanatomy of both BPD and ADHD. [ABSTRACT FROM AUTHOR]

Objective: Over the past three decades, there have been significant changes in the diagnostic criteria for schizophrenia as well as changes in measurement of IQ. The last quantitative review of the literature on premorbid IQ in schizophrenia was published more than two decades ago. Since that time, there have been many published studies of data sets pertaining to this issue. The purpose of the present review was to provide an updated meta-analysis of premorbid IQ in individuals who later develop schizophrenia.Method: The authors performed a systematic literature search, which yielded 18 studies that met criteria for the meta-analysis. Inclusion criteria were 1) premorbid psychometric measures of IQ in subjects who were later diagnosed with schizophrenia, schizoaffective disorder, or schizophreniform disorder, 2) similar comparison data, and 3) sufficient data for calculation of an effect size. The analogue to the analysis of variance method was used to model between-study variance due to key study-design features.Results: Overall, schizophrenia samples demonstrated a reliable, medium-sized impairment in premorbid IQ. The heterogeneity of effect sizes was minimal and almost exclusively the result of one study. Methodological differences, such as diagnostic criteria, type of IQ measure, sample ascertainment, and age at premorbid testing, contributed minimally to the effect size variance. A cross-sectional analysis of all studies by age and a descriptive review of studies that used repeated measures of IQ in a single sample did not support the presence of a relative decline in IQ during the premorbid period in individuals with schizophrenia. However, all studies with pre- and post-onset testing within the same sample suggested that a significant decline in the IQ of individuals with schizophrenia, relative to comparison subjects, was associated with the onset of frank psychosis.Conclusions: Years before the onset of psychotic symptoms, individuals with schizophrenia, as a group, demonstrate mean IQ scores approximately one-half of a standard deviation below that of healthy comparison subjects. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The association between deficits in executive functioning and functional outcomes was examined among adults with attention deficit hyperactivity disorder (ADHD). METHOD: Subjects were adults who did (N=213) and did not (N=145) meet DSM-IV criteria for ADHD. The authors defined having deficits in executive functioning as having at least two measures of executive functioning with scores 1.5 standard deviations below those of matched comparison subjects. RESULTS: Significantly more adults with ADHD had deficits of executive functioning than comparison subjects. Deficits of executive functioning were associated with lower academic achievement, irrespective of ADHD status. Subjects with ADHD with deficits of executive functioning had a significantly lower socioeconomic status and a significant functional morbidity beyond the diagnosis of ADHD alone. CONCLUSIONS: Psychometrically defined deficits of executive functioning may help identify a subgroup of adults with ADHD at high risk for occupational and academic underachievement. More efforts are needed to identify cost-effective approaches to screen individuals with ADHD for deficits of executive functioning. [ABSTRACT FROM AUTHOR]

BACKGROUND: A limited number of studies have examined neuropsychological functioning in the family members of ADHD youth, and none have focused exclusively on relatives of females. METHOD: Structured diagnostic interviews and neuropsychological batteries were administered to parents and siblings enrolled in a family study of girls with and without ADHD. Relatives were stratified into three groups: relatives of DSM-IV ADHD probands with ADHD (n = 106), relatives of ADHD probands without ADHD (n = 189) and relatives of controls without ADHD (n = 243). Analyses were also conducted on a subgroup of families in which more than one member had RESULTS: The neuropsychological battery as a whole distinguished affected and unaffected ADHD relatives from controls. The Wechsler Oral Arithmetic subtest, the Stroop Word, Color and Color-Word subscales were impaired in affected ADHD relatives, as were the WRAT-R Arithmetic and Reading subtests. Only the Stroop Color-Word and Interference subtests and the WRAT-R Arithmetic subtest showed significant impairments in unaffected relatives. In multiplex families, additional impairments were found in unaffected relatives on the Stroop Color subtest and the Wechsler Oral Arithmetic subtest. Analyses based on DSM-III-R diagnoses produced nearly identical results. Minor differences emerged across relatives of probands with different DSM-IV subtypes. CONCLUSIONS: Data were consistent with our previous study of relatives of boys with ADHD. Neuropsychological impairments in relatives of female ADHD probands were primarily associated with the diagnosis of ADHD, but subtle cognitive impairments that index familial vulnerability to the disorder may exist. [ABSTRACT FROM AUTHOR]

Background: Previous voxelwise Diffusion Tensor Imaging (DTI) investigations of white matter in first-episode schizophrenia (FESZ) have been limited to the analysis of Fractional Anisotropy (FA) and mean diffusivity (MD), with their findings inconsistent in terms of the anatomical locations and extent of abnormalities. This study examines white matter abnormalities in FESZ, compared with healthy controls, using a tract-based spatial statistics (TBSS) approach applied to multiple measures of tract integrity, and correlates these findings with symptom severity.Methods: Seventeen first-episode patients with schizophrenia and seventeen age- and gender-matched healthy controls (HC) participated in this imaging study where FA, MD, and axial and radial diffusivities were compared between the two groups using TBSS.Results: First-episode patients with schizophrenia showed lower FA values in the genu and body of corpus callosum, the internal capsule, the external capsule, the fornix, the superior, inferior fronto-occipital fasciculus, the cingulum, and the uncinate fasciculus compared with HC. Increased MD and radial diffusivity were shown in virtually all white matter regions. There was no significant difference, however, observed for axial diffusivity between the two groups. Pearson correlation analysis showed that the FA values of the right inferior fronto-occipital fasciculus were positively correlated with positive symptoms, negative symptoms, and total correct items of the Wisconsin Card Sorting Test. FA values of right external capsule also showed significant positive correlation with category completed scores of the WCST.Conclusions: These data suggest extensive, possibly myelin related white matter disruptions in FESZ. [ABSTRACT FROM AUTHOR]

Insomnia and suicidal ideation (SI) are common in schizophrenia, including in individuals at clinical high-risk for psychosis (CHR-P). Previous studies have found associations between sleep disturbance, SI, and psychopathology in schizophrenia. We explored these associations in a CHR-P cohort. We leveraged data from CHR-P individuals in the North American Prodrome Longitudinal Studies (NAPLS-3) (n = 688) cohort. We investigated relationships between sleep disturbance (Scale of Prodromal Symptoms [SOPS]; Calgary Depression Scale for Schizophrenia [CDSS], and the Pittsburgh Sleep Quality Index [PSQI]), suicidal ideation (CDSS), and psychosis-risk symptoms. The prevalence of terminal insomnia, sleep disturbance, and SI in NAPLS3 was 25 %, 69 %, and 29 %, respectively. After controlling for potential confounders, multiple indices of sleep disturbance (SOPS, PSQI: OR = 1.05-1.40) were significant indicators of concurrent SI. Terminal insomnia was not associated with conversion to psychosis. Multiple indices of sleep problems were associated with higher total and subscale psychosis-risk symptom scores (β = 0.09-0.39). Sleep problems are prevalent and associated with SI and more severe psychosis-risk symptoms in CHR-P individuals. These findings underscore the importance of designing longitudinal intervention studies to investigate whether the treatment of sleep disturbances may reduce suicidality and symptoms in this population., Competing Interests: Declaration of competing interest We report that there are no conflicts of interest in relation to the subject of this study. In the past year, Dr. Miller received research support from NIMH, SMRI, and Augusta University; and Honoraria from Atheneum, Carlat Psychiatry, ClearView Healthcare Partners, Psychopharmacology Institute, and Psychiatric Times., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Sex differences have been observed in individuals with schizophrenia and for those at clinical high risk (CHR) for psychosis. However, specific differences in CHR individuals who transition to psychosis remain inconsistent and understudied. This study aimed to investigate sex differences in 156 CHR individuals who made the transition to psychosis. A wide range of demographics, positive and negative symptoms, depression, anxiety, social and role functioning, trauma, and substance use were assessed at baseline and symptoms and diagnoses at the time of transition. Fluctuations in positive and negative symptoms and different medications were also assessed. No sex differences were observed at baseline for those who later transitioned to psychosis. At transition, males were significantly more likely to be diagnosed as having schizophrenia or schizophreniform disorder and through the course of the study, males were more likely to be taking stimulants. Limitations in this study was the lack of longitudinal follow-up post transition. The study highlights the need for further research on sex differences in individuals who transition to psychosis. Understanding these differences can have implications for treatment and monitoring of CHR individuals., Competing Interests: Declaration of competing interest Authors declare they have no conflict of interest with respect to this study., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The time following a recent onset of psychosis is a critical period during which intervention may be maximally effective. Studying individuals in this period also offers an opportunity to investigate putative brain biomarkers of illness prior to the long-term effects of chronicity and medication. The Human Connectome Project for Early Psychosis (HCP-EP) was funded by the National Institutes of Mental Health (NIMH) as an extension of the original Human Connectome Project's approach to understanding the human brain and its structural and functional connections., Design: The HCP-EP data were collected at 3 sites in Massachusetts (Beth Israel Deaconess Medical Center, McLean Hospital, and Massachusetts General Hospital), and one site in Indiana (Indiana University). Brigham and Women's Hospital served as the data coordination center and as an imaging site., Results: The HCP-EP dataset includes high-quality clinical, cognitive, functional, neuroimaging, and blood specimen data acquired from 303 individuals between the ages of 16-35 years old with affective psychosis (n = 75), non-affective psychosis (n = 148), and healthy controls (n = 80). Participants with early psychosis were within 5 years of illness onset (mean duration = 1.9 years, standard deviation = 1.4 years). All data and novel or modified analytic tools developed as part of the study are publicly available to the research community through the NIMH Data Archive (NDA) or GitHub (https://github.com/pnlbwh)., Conclusions: This paper provides an overview of the specific HCP-EP procedures, assessments, and protocols, as well as a brief characterization of the study participants to make it easier for researchers to use this rich dataset. Although we focus here on discussing and comparing affective and non-affective psychosis groups, the HCP-EP dataset also provides sufficient information for investigators to group participants differently., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background and Hypothesis: Negative symptom trajectory in clinical high risk (CHR) for psychosis is ill defined. This study aimed to better characterize longitudinal patterns of change in negative symptoms, moderators of change, and differences in trajectories according to clinical subgroups. We hypothesized that negative symptom course will be nonlinear in CHR. Clinical subgroups known to be more severe variants of psychotic illness-deficit syndrome (DS), persistent negative syndrome (PNS), and acute psychosis onset-were expected to show more severe baseline symptoms, slower rates of change, and less stable rates of symptom resolution., Study Design: Linear, curvilinear, and stepwise growth curve models, with and without moderators, were fitted to negative symptom ratings from the NAPLS-3 CHR dataset ( N = 699) and within clinical subgroups., Study Results: Negative symptoms followed a downward curvilinear trend, with marked improvement 0-6 months that subsequently stabilized (6-24 months), particularly among those with lower IQ and functioning. Clinical subgroups had higher baseline ratings, but distinct symptom courses; DS vs non-DS: more rapid initial improvement, similar stability of improvements; PNS vs non-PNS: similar rates of initial improvement and stability; transition vs no transition: slower rate of initial improvement, with greater stability of this rate., Conclusions: Continuous, frequent monitoring of negative symptoms in CHR is justified by 2 important study implications: (1) The initial 6 months of CHR program enrollment may be a key window for improving negative symptoms as less improvement is likely afterwards, (2) Early identification of clinical subgroups may inform distinct negative symptom trajectories and treatment needs., (© The Author(s) 2023. Published by Oxford University Press on behalf of the University of Maryland's school of medicine, Maryland Psychiatric Research Center.)

Background: While comorbidity of clinical high-risk for psychosis (CHR-P) status and social anxiety is well-established, it remains unclear how social anxiety and positive symptoms covary over time in this population. The present study aimed to determine whether there are more than one covariant trajectory of social anxiety and positive symptoms in the North American Prodrome Longitudinal Study cohort (NAPLS 2) and, if so, to test whether the different trajectory subgroups differ in terms of genetic and environmental risk factors for psychotic disorders and general functional outcome., Methods: In total, 764 CHR individuals were evaluated at baseline for social anxiety and psychosis risk symptom severity and followed up every 6 months for 2 years. Application of group-based multi-trajectory modeling discerned three subgroups based on the covariant trajectories of social anxiety and positive symptoms over 2 years., Results: One of the subgroups showed sustained social anxiety over time despite moderate recovery in positive symptoms, while the other two showed recovery of social anxiety below clinically significant thresholds, along with modest to moderate recovery in positive symptom severity. The trajectory group with sustained social anxiety had poorer long-term global functional outcomes than the other trajectory groups. In addition, compared with the other two trajectory groups, membership in the group with sustained social anxiety was predicted by higher levels of polygenic risk for schizophrenia and environmental stress exposures., Conclusions: Together, these analyses indicate differential relevance of sustained v. remitting social anxiety symptoms in the CHR-P population, which in turn may carry implications for differential intervention strategies.

Introduction: Persistent negative symptoms (PNS) are described as continuing moderate negative symptoms. More severe negative symptoms have been associated with poor premorbid functioning in both chronic schizophrenia and first episode psychosis patients. Furthermore, youth at clinical high risk (CHR) for developing psychosis may also present with negative symptoms and poor premorbid functioning. The aim of this current study was to: (1) define the relationship between PNS and premorbid functioning, life events, trauma and bullying, previous cannabis use, and resource utilization, and (2) to examine what explanatory variables best predicted PNS., Method: CHR participants ( N  = 709) were recruited from the North American Prodrome Longitudinal Study (NAPLS 2). Participants were divided into two groups: those with PNS ( n  = 67) versus those without PNS ( n  = 673). A K-means cluster analysis was conducted to distinguish patterns of premorbid functioning across the different developmental stages. The relationships between premorbid adjustment and other variables were examined using independent samples t-tests or chi square for categorical variables., Results: There was significantly more males in the PNS group. Participants with PNS had significantly lower levels of premorbid adjustment in childhood, early adolescence, and late adolescence, compared to CHR participants without PNS. There were no differences between the groups in terms of trauma, bullying, and resource utilization. The non-PNS group had more cannabis use and more desirable and non-desirable life events., Conclusion: In terms of better understanding relationships between early factors and PNS, a prominent factor associated with PNS was premorbid functioning, in particular poor premorbid functioning in later adolescence., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Devoe, Lui, Cannon, Cadenhead, Cornblatt, Keshavan, McGlashan, Perkins, Seidman, Stone, Tsuang, Woods, Walker, Mathalon, Bearden and Addington.)

Over the past two decades, research and clinical resources on clinical high risk (CHR) for psychosis have both expanded, with goals to better understanding risk and protective factors on the course of illness and inform early intervention efforts. However, some studies have highlighted potential sampling bias among CHR research studies, raising questions about generalizability of findings and inequitable access to early detection and intervention. The current study sought to explore these questions by comparing 94 participants in a CHR longitudinal monitoring study across North America (NAPLS-2) who converted to syndromal psychosis over the course of the study (CHR-CV) to 171 participants who presented for treatment at a localized first-episode psychosis service (FES) after converting. CHR-CV participants were significantly more likely to be White and have a college-educated parent, while FES participants were more likely to be Black and first- or second-generation immigrants. On average, CHR-CV participants were younger at onset of attenuated positive symptoms, had a longer period of attenuated symptoms prior to conversion, and were more likely to be treated with antipsychotics prior to conversion compared to those in FES programs. After controlling for time since conversion, CHR-CV participants had higher global functioning and were less likely to have experienced recent psychiatric hospitalization. Findings suggest that CHR research and FES clinics may be sampling from different populations, although conclusions are limited by inconsistent sampling frames and methods. Integrated early detection that targets defined geographic catchments may deliver more epidemiologically representative samples to both CHR research and FES., Competing Interests: Declaration of competing interest We have no conflicts of interest to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background and Hypothesis: While individuals at clinical high-risk (CHR) for psychosis experience higher levels of discrimination than healthy controls, it is unclear how these experiences contribute to the etiology of attenuated positive symptoms. The present study examined the association of perceived discrimination with positive symptoms in a cohort from the North American Prodrome Longitudinal Study (NAPLS2). It predicted that CHR individuals will report higher levels of lifetime and past year perceived discrimination related to their race and ethnicity (ethnoracial discrimination) and that this form of discrimination will be significantly associated with baseline positive symptoms., Study Design: Participants included 686 CHR and 252 healthy controls. The present study examined data from the perceived discrimination (PD) scale, the Brief Core Schema Scale, and the Scale for the Psychosis-Risk Symptoms. Structural equation modeling was employed to examine whether negative schema of self and others mediated the relation of past year ethnoracial PD to baseline suspiciousness symptoms., Results: CHR individuals report higher levels of past year and lifetime PD compared to healthy controls. Lifetime ethnoracial PD was associated with suspiciousness and total positive symptoms. Negative schema of self and others scores partially mediated the relation of past year ethnoracial PD to suspiciousness, one of five positive symptom criteria for CHR., Conclusions: For CHR individuals, past year ethnoracial discrimination was associated with negative beliefs about themselves and others, which was associated with suspiciousness. These findings contribute to an emerging literature characterizing the mechanisms by which discrimination contributes to the positive symptoms characterizing the CHR syndrome., Competing Interests: Declaration of competing interest The authors do not have any conflicts of interest to report., (Copyright © 2023 Elsevier B.V. All rights reserved.)