Search

Background: Neurocognitive impairment is a core feature of schizophrenia spectrum disorders (SSDs), and the relationship between cognition and symptoms in SSDs has been widely researched. Negative symptoms are related to a wide range of cognitive impairments; however, the aspects of negative symptoms that underpin this relationship have yet to be specified., Study Design: We used iterative Constrained Principal Component Analysis (iCPCA) to explore the relationship between 18 cognitive measures (including processing speed, attention, working, spatial and verbal memory and executive functions) and 46 symptoms in schizophrenia at the individual item level while minimizing the risk of Type I errors. ICPCA was conducted on a sample of SSD patients in the early stages of psychiatric treatment (n = 121) to determine the components of cognition overlapping with symptoms measured by the Scale for the Assessment of Negative Symptoms (SANS) and the Scale for the Assessment of Positive Symptoms (SAPS)., Results: We found that a verbal memory component was associated with items from SANS and SAPS related to impoverished and disorganized emotional communication, language, and thought. In contrast, a working memory component was associated with SANS items related to motor system impoverishment., Conclusions: The iCPCA allowed us to explore the associations between individual items, optimized to understand the overlap between symptoms and cognition. The specific symptoms linked to verbal and working memory impairments imply distinct brain networks, which further investigation may lead to our deeper understanding of the illness and the development of treatment methods., Competing Interests: Declaration of competing interest There are no financial or other conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Preventing relapse in schizophrenia improves long-term health outcomes. Repeated episodes of psychotic symptoms shape the trajectory of this illness and can be a detriment to functional recovery. Despite early intervention programs, high relapse rates persist, calling for alternative approaches in relapse prevention. Predicting imminent relapse at an individual level is critical for effective intervention. While clinical profiles are often used to foresee relapse, they lack the specificity and sensitivity needed for timely prediction. Here, we review the use of speech through Natural Language Processing (NLP) to predict a recurrent psychotic episode. Recent advancements in NLP of speech have shown the ability to detect linguistic markers related to thought disorder and other language disruptions within 2-4 weeks preceding a relapse. This approach has shown to be able to capture individual speech patterns, showing promise in its use as a prediction tool. We outline current developments in remote monitoring for psychotic relapses, discuss the challenges and limitations and present the speech-NLP based approach as an alternative to detect relapses with sufficient accuracy, construct validity and lead time to generate clinical actions towards prevention., Competing Interests: Declaration of competing interest LP reports personal fees from Janssen Canada, Otsuka Canada, SPMM Course Limited, UK, Canadian Psychiatric Association; book royalties from Oxford University Press; investigator-initiated educational grants from Sunovion, Janssen Canada, Otsuka Canada outside the submitted work. M. L. reports grants from Otsuka Lundbeck Alliance and Roche, personal fees from Otsuka Canada, personal fees from Lundbeck Canada, personal fees from Boehringer Ingelheim, and grants and personal fees from Janssen. KL reports grants from Otsuka Lundbeck Alliance and personal fees from Otsuka Canada and Lundbeck Canada. SL and RJ reports none in the last 3 yrs. MAR reports personal honoraria from Janssen, Otsuka-Lundbeck Alliance, Viatris; research grants from Janssen; Research contracts from Lundbeck, Boehringer-Ingelheim, Otsuka-Lundbeck Alliance. FZ, MD, AA, MFD, P Subramanian, DG, IZ, KD, MM, P Sabesan, and AV report no conflicts., (Copyright © 2024 Elsevier B.V. All rights reserved.)

There is widespread overlap across major psychiatric disorders, and this is the case at different levels of observations, from genetic variants to brain structures and function and to symptoms. However, it remains unknown to what extent these commonalities at different levels of observation map onto each other. Here, we systematically review and compare the degree of similarity between psychiatric disorders at all available levels of observation. We searched PubMed and EMBASE between January 1, 2009 and September 8, 2022. We included original studies comparing at least four of the following five diagnostic groups: Schizophrenia, Bipolar Disorder, Major Depressive Disorder, Autism Spectrum Disorder, and Attention Deficit Hyperactivity Disorder, with measures of similarities between all disorder pairs. Data extraction and synthesis were performed by two independent researchers, following the PRISMA guidelines. As main outcome measure, we assessed the Pearson correlation measuring the degree of similarity across disorders pairs between studies and biological levels of observation. We identified 2975 studies, of which 28 were eligible for analysis, featuring similarity measures based on single-nucleotide polymorphisms, gene-based analyses, gene expression, structural and functional connectivity neuroimaging measures. The majority of correlations (88.6%) across disorders between studies, within and between levels of observation, were positive. To identify a consensus ranking of similarities between disorders, we performed a principal component analysis. Its first dimension explained 51.4% (95% CI: 43.2, 65.4) of the variance in disorder similarities across studies and levels of observation. Based on levels of genetic correlation, we estimated the probability of another psychiatric diagnosis in first-degree relatives and showed that they were systematically lower than those observed in population studies. Our findings highlight that genetic and brain factors may underlie a large proportion, but not all of the diagnostic overlaps observed in the clinic., (© 2024. The Author(s).)

Background: Cognitive impairment are among the core features of schizophrenia, experienced by up to 75% of patients. Available treatment options for schizophrenia including dopamine antagonists and traditional antipsychotic medications have not been shown to confer significant benefits on cognitive deficits. Contrary to the focus on management of positive symptoms in schizophrenia, cognitive abilities are main predictor of independent living skills, functional abilities, employment, engagement in relapse prevention, and patients' subjective sense of well-being and quality of life. This review aims to provide a summary of recent literature on pharmacological options for the treatment of cognitive deficits in schizophrenia., Methods: We conducted a literature search of studies from 2011 to 2021 across four electronic databases including PubMed, PsycInfo, MEDLINE, and Embase. Human studies using a pharmacological treatment for cognitive impairment in schizophrenia were included., Results: Fifty-eight eligible publications, representing 11 pharmacological classes, were included in this review. Major limitations involved small sample size, methodological limitations as well as heterogeneity of participants and outcome measures., Conclusions: Overall evidence remains inconclusive for any pharmacological classes studied for the treatment of cognitive deficits in schizophrenia. Methodological limitations in a majority of the studies rendered their findings preliminary. We further discuss possible explanations for these findings that could guide future research., (© 2023 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Psychotic disorders are highly heterogeneous. Understanding relationships between symptoms will be relevant to their underlying pathophysiology. We apply dimensionality-reduction methods across two unique samples to characterize the patterns of symptom organization. We analyzed publicly-available data from 153 participants diagnosed with schizophrenia or schizoaffective disorder (fBIRN Data Repository and the Consortium for Neuropsychiatric Phenomics), as well as 636 first-episode psychosis (FEP) participants from the Prevention and Early Intervention Program for Psychosis (PEPP-Montreal). In all participants, the Scale for the Assessment of Positive Symptoms (SAPS) and Scale for the Assessment of Negative Symptoms (SANS) were collected. Multidimensional scaling (MDS) combined with cluster analysis was applied to SAPS and SANS scores across these two groups of participants. MDS revealed relationships between items of SAPS and SANS. Our application of cluster analysis to these results identified: 1 cluster of disorganization symptoms, 2 clusters of hallucinations/delusions, and 2 SANS clusters (asocial and apathy, speech and affect). Those reality distortion items which were furthest from auditory hallucinations had very weak to no relationship with hallucination severity. Despite being at an earlier stage of illness, symptoms in FEP presentations were similarly organized. While hallucinations and delusions commonly co-occur, we found that their specific themes and content sometimes travel together and sometimes do not. This has important implications, not only for treatment, but also for research-particularly efforts to understand the neurocomputational and pathophysiological mechanism underlying delusions and hallucinations., (© 2023. The Author(s).)

Background: In people with schizophrenia, major areas of everyday life are impaired, including independent living, productive activities, social relationships and overall quality of life. Enhanced understanding of factors that hinder real-life functioning is vital for treatments to translate into more positive outcomes., Aim: The goal of the present study was to identify factors associated with motivation deficits in real-life schizophrenia, and to assess its contribution to impaired functioning and quality of life., Methods: Based on previous literature and clinical experience, several factors were selected and grouped into factors potentially explaining motivation deficits. Some of these variables were never investigated before in relationship with motivation deficits., Results: In 561 patients with schizophrenia of the national FACE-SZ cohort living in the community, 235 (41.9%) reported severe motivation deficits. These deficits were found to be significantly associated with impaired socially useful activities, psychological and physical quality of life (in almost all domains), alcohol use disorder (aOR = 2.141, p  = 0.021), severe nicotine dependence (aOR = 2.906, p  < 0.001) independently of age and sex. No significant association was found for body mass index, metabolic syndrome or physical activity level. In the second model, we identified the following modifiable factors associated with motivation deficits: history of suicide attempt (aOR = 2.297, p  = 0.001), positive symptoms (aOR = 1.052, p  = 0.006), current major depressive episode (aOR = 2.627, p  < 0.001), sleep disorders (aOR = 1.474, p  = 0.024) and lower medication adherence (aOR = 0.836, p  = 0.001) independently of gender, current alcohol use disorder, second-generation antipsychotics and akathisia. No significant association was found for negative symptoms, childhood trauma and inflammation. These results were maintained after removing patients with schizoaffective disorders or those with major depressive disorder., Interpretation: Motivation deficits are frequent and remain persistent unmet need in real-world schizophrenia that should be addressed in future guidelines. Based on our results, literature and clinical experience, we recommend to address in priority major depression, sleep, suicide, positive symptoms (when present and as early as possible) and medication adherence to improve motivation deficits of schizophrenia.

Introduction: Measurement-based care (MBC) is an evidence-based practice wherein clinical decisions are informed by patient data collected throughout treatment. MBC has yielded superior patient outcomes compared to standard care. However, the implementation of MBC in the day-to-day practice, particularly in psychotic disorders, poses several challenges. This study evaluates the clinician-rated Clinical Global Impressions Scale of Severity (CGI-S), for MBC implementation at a first-episode psychosis program., Methods: The CGI-S was evaluated in the context of routine care on fidelity to practice, inter-rater reliability among psychiatrists and concurrent validity with scales measuring different domains of psychopathology (SAPS, SANS, GAF, BPRS, PANSS-6)., Results: A high fidelity to practice (67%) and inter-rater reliability was found (r wg  = 0.92). CGI-S correlations were significant and strongest with BPRS (r = 0.55; p < 0.01), GAF (r = 0.53; p < 0.01), SAPS (r = 0.52, p < 0.01), and PANSS-6 (r = 0.41; p < 0.05) scores. However, correlations with SANS and PANSS-6 Negative sub-scale were weak., Conclusion: Findings suggest the CGI may be used to overcome important barriers towards MBC implementation within the context of first episode psychosis. However, as suggested by data, further improvements in capturing negative symptoms by rating clinicians are needed., Twitter: A novel strategy for measurement-based care to optimize treatment for individuals with first episode psychosis and related psychotic disorders., (Copyright © 2022. Published by Elsevier B.V.)

Apart from increasing risk for psychotic disorders, childhood adversity has been associated with worse outcomes. One way in which childhood adversity may worsen outcomes is by lengthening treatment delays, which are associated with negative impacts. We tested the influence of childhood trauma on treatment delays, measured as the duration of untreated psychosis (DUP), and its help-seeking and referral components, in a first-episode psychosis cohort (N = 203). We accounted for pertinent social (e.g., migrant status) and other determinants (i.e., age at onset, diagnosis, symptoms) of treatment delays. Multiple linear regression analyses revealed that for a one-unit increase in Childhood Trauma Questionnaire (CTQ) scores, average overall DUP increased by 25%. Higher CTQ scores also significantly predicted help-seeking and referral DUPs. Patients with schizophrenia-spectrum psychosis had longer help-seeking and total DUPs than those with affective psychosis. More severe positive symptoms predicted longer help-seeking DUPs, while more severe negative symptoms predicted longer referral DUPs. Indicators of social disadvantage did not affect DUP. Our results show that childhood trauma increases DUP by prolonging the help-seeking process and delaying access to mental healthcare even after help is sought. Early identification of psychosis among populations with trauma histories seems warranted and can likely positively impact outcomes., (Copyright © 2021. Published by Elsevier B.V.)

Verbal memory (VM) is one of the most affected cognitive domains in first-episode psychosis (FEP) and is a robust predictor of functioning. Given that healthy females demonstrate superior VM relative to males and that female patients show less-severe illness courses than male patients, this study examined whether normative sex differences in VM extend to FEP and influence functioning. Four hundred and thirty-five patients (299 males, 136 females) with affective or nonaffective psychosis were recruited from a catchment-based specialized FEP intervention service and 138 nonclinical controls (96 males, 42 females) were recruited from the same community. One of the two neurocognitive batteries comprising six cognitive domains (VM, visual memory, working memory, attention, executive function, processing speed) were administered at baseline. In patients, positive and negative symptoms were evaluated at baseline and functioning was assessed at 1-year follow-up. Patients were more impaired than controls on all cognitive domains, but only VM showed sex differences (both patient and control males performed worse than females), and these results were consistent across batteries. In patients, better baseline VM in females was related to better functioning after 1 year, mediated through fewer baseline negative symptoms. Supplemental analyses revealed these results were not driven by affective psychosis nor by age and parental education. Thus, normative sex differences in VM are preserved in FEP and mediate functioning at 1-year follow-up via negative symptoms. This study highlights the importance of investigating sex effects for understanding VM deficits in early psychosis and suggests that sex may be a disease-modifying variable with important treatment implications., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Cognitive difficulties are a core deficit for people with schizophrenia and are generally assessed with neuropsychological tests. Self-report assessments are also useful in understanding difficulties from the service user's perspective. This study aims to introduce and test the shorter version of the Subjective Scale to Investigate Cognition in Schizophrenia (SSTICS) to improve its acceptability and comprehensibility. Methods: In consultation with service users and clinicians, we identified items from the original 21-item SSTICS that were found difficult and these were excluded. The reduced scale was explored with Confirmatory Factor Analysis (CFA) in two independent samples in the UK and Canada. Convergent validity with symptoms and IQ was assessed and compared between the original and the reduced scale. Results: Six-hundred and seven people with schizophrenia and first-episode psychosis took part in this study. Seven items were removed to produce the SSTICS-Brief. This had good reliability and the CFA confirmed a unidimensional structure. Convergent validity with symptoms and IQ were optimal between the long and short versions. Conclusions: The SSTICS-B has better acceptability than its longer form and could be administered in less time. The resulting measure is likely to be a valuable short self-assessment of cognitive complaints for people with schizophrenia.

Objective: To test whether duration of untreated psychosis (DUP) < 3 months, recommended by the World Health Organization/International Early Psychosis Association, enhances the effects of an extended early intervention service (EEIS) on symptom remission., Method: We examined data from a randomized controlled trial in which patients who received 2 years of treatment in EIS for psychosis were subsequently randomized to either 3 years of EEIS or 3 years of regular care (RC). Using a DUP cut-off ≤ 12 weeks (approximately < 3 months), patients were split into two groups. Length of positive, negative and total symptom remission were the outcomes., Results: Patients (N = 217) were mostly male (68%) with schizophrenia spectrum disorder (65%); 108 (50%) received EEIS (58 had DUP ≤12 weeks; 50 had DUP >12 weeks). Interaction between treatment condition (EEIS vs. RC) and DUP cut-off ≤ 12 weeks was only significant in multiple linear regression model examining length of negative symptom remission as the outcome (adjusted β = 36.88 [SE = 15.88], t = 2.32, P = 0.02). EEIS patients with DUP ≤12 weeks achieved 25 more weeks of negative symptom remission than EEIS patients with DUP >12 weeks., Conclusion: Having a short DUP may be critical in deriving long-term benefits from EIS for psychosis, including EEIS settings. This work empirically supports policy recommendations of reducing DUP <3 months., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Recent Genome-Wide Association Studies (GWAS) have provided evidence for the involvement of a number of genetic variants in schizophrenia (SCZ). The objective of the current study was to examine the association between these variants and symptom dimensions, evaluated prospectively over a period of 24months, in a clinically well-characterized sample of individuals (n=241) with first-episode psychosis (FEP). The genetic variants were analyzed collectively as captured through a Polygenic Risk Score (PRS), calculated for each individual. At each evaluation time point (baseline, 1, 2, 6 and 24months), correlation analysis was conducted with PRS and symptom dimension scores assessed by the Positive and Negative Syndrome Scale (PANSS). We also examined the association of PRS with global symptom rating, depression, anxiety, social and occupational functioning as measured by widely used and well validated scales. At baseline, significant positive correlation was observed between PRS and the general psychopathology dimension of the PANSS but no associations were observed with the positive or negative symptom dimensions. Anxiety, assessed using the Hamilton Anxiety Rating Scale, was also significantly correlated with the PRS. No significant correlation was observed with other symptom dimensions or with the PANSS score at the later evaluations. These results provide novel evidence of an association between general psychopathology and PRS in young people with first episode psychosis. They also demonstrate that it is important to note the dynamic changes of symptoms over time when trying to refine the relationship between genetic factors and phenotypes., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Insomnia is an important problem in patients with schizophrenia and is an emerging area of interest for researchers. We propose a treatment algorithm that synthesizes the various psychological and pharmacological interventions for insomnia in this population., Methods: Our selective literature review incorporates English language articles from 4 medicine databases through May 2016. Selected articles discuss risk factors and treatments for insomnia, as well as comorbid sleep disorders that coexist in this population., Results: Various lifestyle factors and comorbid sleep disorders may predispose patients with schizophrenia to insomnia. Cognitive-behavioral therapy for insomnia shows promising results in treating insomnia in patients with schizophrenia spectrum disorders. Additionally, studies of eszopiclone and melatonin have yielded significant results in short-term trials that evaluated both subjective and objective insomnia symptoms., Conclusions: We have summarized the relevant literature regarding the treatment of insomnia in this patient population and propose an algorithm comprising 6 sequential steps, beginning with the assessment of sleep complaints and medication adherence. This is followed by a targeted treatment of any co-occurring sleep disorders, and ends with psychoeducation, cognitive-behavioral therapy, and pharmacotherapy. This algorithm provides a detailed guideline to improve the assessment and therapeutic intervention for managing insomnia among patients with schizophrenia.

Background: Despite being diagnostically associated uniquely with schizophrenia, negative symptoms are also observed in bipolar disorder (BD). Genome-wide association studies (GWAS) have uncovered a number of shared risk genes between schizophrenia and BD. The objectives of this study were to examine whether previously identified risk genes for BD are associated with negative symptom severity within a first-episode schizophrenia (FES) cohort and to examine whether such genes influence brain morphology., Methods: Patients experiencing FES were genotyped for 21 previously identified BD risk genes; a series of univariate analyses of covariance examined the association between negative symptom severity, as measured using the Scale for the Assessment of Negative Symptoms (SANS), and genotype. A subset of participants underwent a structural 1.5 T MRI T 1 scan, analyzed for surface area and cortical thickness changes via the CIVET pipeline and LPBA40 atlas., Results: We included 133 patients with FES in our analysis; 61 of them underwent structural MRI. We observed a significant association between negative symptom severity and the BD risk gene FOXO6 (rs4660531). Individuals with the CC genotype presented significantly higher negative symptoms (Cohen d = 0.46, F = 5.854, p = 0.017) and significantly smaller surface area within the right middle orbitofrontal gyrus (Cohen d = 0.69, F = 7.289, p = 0.009) than carriers of allele A., Limitations: Limitations of this study include its modest sample size and lack of a control sample., Conclusion: Lacking the FOXO6 risk allele was associated with an increase in negative symptoms and surface area reduction in the right orbitofrontal gyrus - an area previously associated with negative symptoms - suggesting that presence of the FOXO6 risk allele confers resistance against negative symptoms and associated neuroanatomical changes in individuals with FES.

Aim: Duration of untreated psychosis (DUP) has been associated with negative symptoms in several studies; however, longitudinal findings have been inconsistent. No previous study has accounted for active psychosis after presentation, although this could impact on outcomes in a manner similar to DUP., Methods: We measured Scale for the Assessment of Positive Symptoms at frequent intervals during the 12 months after initial presentation to determine the active psychosis duration for 230 individuals with first-episode psychosis. This duration was added to DUP prior to presentation to create a new variable, duration of active psychosis (DAP). Negative symptoms were divided into expressivity and motivation/pleasure domains as measured by Scale for the Assessment of Negative Symptoms (SANS). The relationship of DUP and DAP with negative symptoms at 24-month follow up was determined and confounders controlled for using regression analysis., Results: When DUP and DAP were compared as binary variables with long and short groups, 25.2% of individuals had differing category membership. DAP had a significant uncorrected association with both expressivity domain and motivation/pleasure domains at 24 months; however, relationship with DUP was not significant. DAP remained a significant predictor of 24-month expressivity domain after controlling for potential confounders., Conclusions: Active psychosis after presentation is substantial, which is a limitation of DUP studies if active psychosis is considered as the key factor within DUP. DAP is a better predictor of negative symptoms than DUP at 2-year follow up, which suggests this concept requires further research., (© 2015 Wiley Publishing Asia Pty Ltd.)

In people with psychoses, Self-Reflectiveness may rely on the right ventrolateral prefrontal cortex (VLPFC). We used functional magnetic resonance imaging (fMRI) and a novel virtual reality paradigm to evaluate the role of the VLPFC for Self-Reflectiveness in 25 first-episode of schizophrenia (FES) participants and 24 controls. Participants first viewed 20 characters each paired with a unique object/location, and later completed source memory judgements during fMRI scanning. Self-Reflectiveness, measured with the Beck Cognitive Insight Scale, was significantly and positively correlated to activation in bilateral VLPFC in FES, but not in controls, providing further evidence that the VLPFC supports Self-Reflectiveness in FES., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Schizophrenia (SCZ) is a very heterogeneous disease that affects approximately 1% of the general population. Recently, the genetic complexity thought to underlie this condition was further supported by three independent studies that identified an increased number of damaging de novo mutations DNM in different SCZ probands. While these three reports support the implication of DNM in the pathogenesis of SCZ, the absence of overlap in the genes identified suggests that the number of genes involved in SCZ is likely to be very large; a notion that has been supported by the moderate success of Genome-Wide Association Studies (GWAS)., Methods: To further examine the genetic heterogeneity of this disease, we resequenced 62 genes that were found to have a DNM in SCZ patients, and 40 genes that encode for proteins known to interact with the products of the genes with DNM, in a cohort of 235 SCZ cases and 233 controls., Results: We found an enrichment of private nonsense mutations amongst schizophrenia patients. Using a kernel association method, we were able to assess for association for different sets. Although our power of detection was limited, we observed an increased mutation burden in the genes that have DNM.

Background: Histone deacetylases (HDACs) are key enzymes of histone acetylation, and abnormalities in histone modifications and in the level of HDAC proteins have been reported in schizophrenia. The objective of the present study was to systematically test the HDAC genes for its association with schizophrenia., Methods: A family-based genetic association study (951 Caucasian subjects in 313 nuclear families) using 601 tag-single nucleotide polymorphisms in HDAC genes was conducted followed by a replication study of top-ranked markers in a sample of 1427 Caucasian subjects from 241 multiplex families and 176 trios. Epistasis interaction was tested by using the pedigree-based generalized multifactor dimensionality reduction (GMDR). Furthermore, we analyzed exome sequencing data of 1134 subjects for detection of rare mutations in HDAC genomic regions., Results: In the exploratory study, ten markers were in significant association with schizophrenia (P<0.01). One maker rs14251 (HDAC3) was replicated (P=0.04) and remained significant in the whole sample (P=0.004). GMDR identified that a significant three-locus interaction model was detected involving rs17265596 (HDAC9), rs7290710 (HDAC10) and rs7634112 (HDAC11) with a good testing accuracy (0.58). No rare mutations were found associated with schizophrenia., Conclusion: This first exploratory systematic study of the HDAC genes provides consistent support for the involvement of the HDAC3 gene in the etiology of schizophrenia. A statistical epistatic interaction between HDAC9, HDAC10, and HDAC11 was detected and seems biologically plausible., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Source memory, the ability to identify the context in which a memory occurred, is impaired in schizophrenia and has been related to clinical symptoms such as hallucinations. The neurobiological underpinnings of this deficit are not well understood. Twenty-five patients with recent onset schizophrenia (within the first 4.5 years of treatment) and twenty-four healthy controls completed a source memory task. Participants navigated through a 3D virtual city, and had 20 encounters of an object with a person at a place. Functional magnetic resonance imaging was performed during a subsequent forced-choice recognition test. Two objects were presented and participants were asked to either identify which object was seen (new vs. old object recognition), or identify which of the two old objects was associated with either the person or the place being presented (source memory recognition). Source memory was examined by contrasting person or place with object. Both patients and controls demonstrated significant neural activity to source memory relative to object memory, though activity in controls was much more widespread. Group differences were observed in several regions, including the medial parietal and cingulate cortex, lateral frontal lobes and right superior temporal gyrus. Patients with schizophrenia did not differentiate between source and object memory in these regions. Positive correlations with hallucination proneness were observed in the left frontal and right middle temporal cortices and cerebellum. Patients with schizophrenia have a deficit in the neural circuits which facilitate source memory, which may underlie both the deficits in this domain and be related to auditory hallucinations.

Objective: Functional recovery remains the primary goal following treatment of a psychotic disorder, especially after a first episode. Evidence regarding relative contributions of predictors of functional outcome, including symptoms and cognition, remains equivocal. The objective of the study was to determine the relative contribution of cognition, in particular verbal memory, and symptomatic remission to social and occupational functioning while controlling for established predictors of functioning in a large sample of patients presenting with a first episode of a schizophrenia spectrum or affective psychosis., Method: Patients (aged 14-35 years) met DSM-IV criteria for a first episode of a schizophrenia spectrum or affective psychosis and had been admitted to the Prevention and Early Intervention Program for Psychoses, Montreal, Quebec, Canada, between 2003 and 2009 for treatment and follow-up for 2 years. Established predictors (duration of untreated psychosis, medication adherence, age at onset, substance use, premorbid adjustment), verbal memory, and length of positive and negative symptom remission were regressed on functioning (using the Strauss Carpenter Scale) at 1 (n = 208) and 2 (n = 159) years. Regressions were conducted with established predictors in the first step, followed by verbal memory and consecutive months of combined positive and negative symptom remission in the third step. Regressions were then repeated with length of positive and negative symptom remission, respectively., Results: Length of combined positive and negative symptom remission explained the most variance in functioning at 1 (R² adjusted = 0.35, F₉,₁₂₉ = 9.33, P < .001) and 2 (R² adjusted = 0.38, F₉,₉₇ = 8.21, P < .001) years, and verbal memory contributed only slightly to such outcome. While length of remission of negative symptoms was a stronger predictor of functioning than remission of positive symptoms at 1 year, length of positive symptom remission also made a large contribution at 2 years., Conclusions: These results highlight the importance of achieving and maintaining remission of both negative and positive symptoms for longer periods in patients with a first episode of a psychotic disorder and the need for effective interventions to do so., (© Copyright 2014 Physicians Postgraduate Press, Inc.)

With the introduction of a clear definition of symptomatic remission from the Remission in Schizophrenia Working Group (RSWG), studies have sought to characterize cognitive functioning in remitted and non-remitted schizophrenia patients. However, most investigations of cognition and remission are cross-sectional or have studied samples of chronically ill patients. Therefore, the aim of this study was to compare cognitive performance between remitted and non-remitted first-episode psychosis (FEP) patients longitudinally. Seventy patients were categorized as remitted (n=17) or non-remitted (n=53) using the full RSWG criteria after being treated for approximately 15months, during which cognition was evaluated twice. Since our previous investigations in FEP have isolated verbal memory as a potential cognitive marker of symptomatic remission, analyses were limited to verbal, visual and working memory. We have found that non-remitted patients had a significantly worse verbal memory performance than remitted patients after 3months (F(1,68)=6.47, p=0.006) and 15months of treatment (F(1,68)=19.49, p<0.001). Visual memory was also significantly lower in non-remitted patients compared to those in remission but only at initial assessment (F(1,68)=8.21, p=0.003) while working memory performance was similar at both time points. Our findings suggest that verbal memory may be a specific and stable marker of clinical remission in FEP patients. This cognitive domain can easily be evaluated at treatment intake in the hope of identifying early on patients who are less likely to remit., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Increasing evidence supports the role of childhood trauma in the etiology of psychosis but underlying mechanisms are poorly understood. Early maltreatment has been linked to dissociative symptoms in psychosis patients. We explored associations between childhood trauma (Childhood Trauma Questionnaire) and dissociation (Dissociative Experiences Scale) in first-episode psychotic patients (n=62), chronic psychotic patients (n=43), and non-psychotic community controls (n=66). Multivariate analyses of covariance were used to test associations between childhood trauma and dissociation by group while controlling for sex. Chronic patients reported the highest level of dissociation. More severe childhood trauma was associated with greater dissociative symptoms in all groups although most strongly in chronic patients. Emotional abuse showed the strongest associations with dissociation, with these being strongest for chronic patients, followed by first-episode patients--and least for controls. Men showed a stronger association between physical neglect and dissociation than women, irrespective of group. There were no significant group by sex interactions. Our findings replicate the strong association between childhood trauma and dissociative symptoms in chronic and first-episode psychotic patients relative to non-psychotic control subjects. We also demonstrate the salience of emotional abuse in explaining variance in dissociation, especially in chronic patients., (© 2013 Elsevier Ireland Ltd. All rights reserved.)

Objective: Diagnostic stability is an important indicator of the reliability and validity of psychiatric diagnoses and has implications in clinical practice and research. While several studies have investigated the diagnostic stability of first-episode psychosis (FEP) disorders, less is known about psychiatric comorbidity in FEP and the persistence of such comorbid conditions over time. Our study aimed to confirm the diagnostic stability of FEP disorders and determine the variation in persistence of comorbid substance use disorders (SUDs), mood disorders, and anxiety disorders over 1 year., Method: The Structured Clinical Interview for DSM-IV-TR Axis I Disorders-Patient Edition was conducted at first presentation and repeated after 1 year (or reconstructed) for 214 FEP patients at the Prevention and Early Intervention Program for Psychoses-Montreal., Results: Psychotic disorder diagnoses were retained by 76.2% of patients at 1 year, schizophrenia being the most stable diagnosis (92.1%). Most diagnostic shifts were to schizophrenia and schizophrenia spectrum disorders. Comorbid SUDs, anxiety disorders, and mood disorders persisted for 50.7%, 64.0%, and 16.7% of patients, respectively. Many new cases of each of these disorders also emerged at 1-year follow-up., Conclusions: These findings demonstrate the stability of primary psychotic disorder diagnoses and greater fluidity of comorbid psychiatric diagnoses, with anxiety disorders persisting as comorbid conditions more than mood disorders and SUDs. These results highlight the importance of repeating a structured diagnostic assessment longitudinally, especially for consideration of comorbid conditions.

Background: Schizophrenia is a severe psychiatric disease characterized by a high heritability and a complex genetic architecture. Recent reports based on exome sequencing analyses have highlighted a significant increase of potentially deleterious de novo mutations in different genes in individuals with schizophrenia., Findings: This report presents the mutation screening results of four candidate genes for which such de novo mutations were previously reported (LRP1, KPNA1, ALS2CL and ZNF480). We have not identified any excess of rare variants in the additional SCZ cases we have screened., Conclusions: This supports the notion that de novo mutations in these four genes are extremely rare in schizophrenia and further highlights the high degree of genetic heterogeneity of this disease.

Language and oculomotor disturbances are 2 of the best replicated findings in schizophrenia. However, few studies have examined skilled reading in schizophrenia (e.g., Arnott, Sali, Copland, 2011; Hayes & O'Grady, 2003; Revheim et al., 2006; E. O. Roberts et al., 2012), and none have examined the contribution of cognitive and motor processes that underlie reading performance. Thus, to evaluate the relationship of linguistic processes and oculomotor control to skilled reading in schizophrenia, 20 individuals with schizophrenia and 16 demographically matched controls were tested using a moving window paradigm (McConkie & Rayner, 1975). Linguistic skills supporting reading (phonological awareness) were assessed with the Comprehensive Test of Phonological Processing (R. K. Wagner, Torgesen, & Rashotte, 1999). Eye movements were assessed during reading tasks and during nonlinguistic tasks tapping basic oculomotor control (prosaccades, smooth pursuit) and executive functions (predictive saccades, antisaccades). Compared with controls, schizophrenia patients exhibited robust oculomotor markers of reading difficulty (e.g., reduced forward saccade amplitude) and were less affected by reductions in window size, indicative of reduced perceptual span. Reduced perceptual span in schizophrenia was associated with deficits in phonological processing and reduced saccade amplitudes. Executive functioning (antisaccade errors) was not related to perceptual span but was related to reading comprehension. These findings suggest that deficits in language, oculomotor control, and cognitive control contribute to skilled reading deficits in schizophrenia. Given that both language and oculomotor dysfunction precede illness onset, reading may provide a sensitive window onto cognitive dysfunction in schizophrenia vulnerability and be an important target for cognitive remediation., (2013 APA, all rights reserved)

Objective: Our study examines the unique influence of social and family support on adherence to medication in a sample of patients treated for first-episode psychosis (FEP)., Method: Social and family support using the Multidimensional Scale of Perceived Social Support and medication adherence (consensus of subjective and objective data) were evaluated on a monthly basis during a 6-month period in a sample of 82 FEP patients. The relation between social support and adherence was evaluated using correlational and linear regression analyses, controlling for other relevant variables. A longitudinal analysis using hierarchical linear models was conducted to model change in adherence over time., Results: Monthly correlations between social support and adherence were significant at 4 of 7 time points during a 6-month period. There was a modest correlation between the percentage of months of good adherence and the average level of family support across the study period. The linear regression failed to demonstrate a significant relation between baseline social support and overall adherence during the entire study period. Change in social support over time was inversely associated with change in adherence., Conclusions: Our study emphasizes the concurrent influence of social (mostly family) support on adherence but this effect does not persist over time. Changes in the degree of social support may have a complex effect on changes in adherence.

Background: Although persistent negative symptoms (PNS) are known to contribute significantly to poor functional outcome, they remain poorly understood. We examined the heuristic value of various PNS definitions and their respective prevalence in patients with first episode psychosis (FEP). We also contrasted those definitions to the Proxy for the Deficit Syndrome (PDS) to identify deficit syndrome (DS) in the same FEP cohort., Methods: One hundred and fifty-eight FEP patients were separated into PNS and non-PNS groups based on ratings from the Scale for Assessment of Negative Symptoms (SANS). PNS was defined in the following ways: 1) having a score of 3 or greater on at least 1 global subscale of the SANS (PNS&#95;1); 2) having a score of 3 or more on at least 2 global subscales of the SANS (PNS&#95;2); and 3) having a score of 3 or more on a combination of specific SANS subscales and items (PNS&#95;H). For all three definitions, symptoms had to be present for a minimum of six consecutive months. Negative symptoms were measured upon entry to the program and subsequently at 1,2,3,6,9 and 12 months. Functional outcome was quantified at first assessment and month 12., Results: PNS prevalence: PNS&#95;1 (27%); PNS&#95;2 (13.2%); PNS&#95;H (13.2%). The prevalence of DS was found to be 3% when applying the PDS. Regardless of the definition being applied, when compared to non-PNS, patients in the PNS group were shown to have significantly worse functioning at month 12. All three PNS definitions showed similar associations with functional outcome at month 12., Conclusion: Persistent negative symptoms are present in about 27% of FEP patients with both affective and non-affective psychosis. Although there has previously been doubt as to whether PNS represents a separate subdomain of negative symptoms, the current study suggests that PNS may be more applicable to FEP when compared to DS. Although all three PNS definitions were comparable in predicting functional outcome, we suggest that the PNS definition employed is dependent on the clinical or research objective at hand.

One dimension of insight in psychosis is the ability to attribute correctly one's symptoms to a mental disorder. Recent work suggests that gray matter volumes of the orbitofrontal cortex (OFC) are correlated with aggregate symptom attribution scores in first-episode schizophrenia. Whether regions beyond the OFC are important for symptom attribution remains to be established. Further, whether common or separable neural systems underlie attribution of specific symptoms (e.g., delusions, asociality) has not been studied. In the current magnetic resonance imaging study, 52 people with a first-episode psychosis (FEP) were rated with the Scale for Assessment of Unawareness of Mental Disorder on attribution of hallucinations, delusions, flat affect and asociality. Attribution ratings were regressed on cortical thickness at 81,924 vertices. Mapping statistics revealed that delusion misattribution was associated with thickness in the OFC [Brodmann's area (BA) 11/47]. Delusion, flat affect and asociality misattribution were associated with cortical thinness in the dorsolateral prefrontal cortex (BA 9/46). Differential associations emerged between each attribution item and cortical thickness/thinness in a variety of frontal, temporal, parietal and occipital areas. The results imply a selective role for the OFC in delusion misattribution in FEP. Evidence for cortical thickness covariation in a variety of regions suggests partial independence in the neural architecture underlying attribution for different symptoms in FEP., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Schizophrenia is a highly heritable neurodevelopmental disorder associated with alterations in synaptic connectivity. Deleted in colorectal cancer (DCC), a receptor for the guidance cue netrin-1, plays a pivotal role in organizing neuronal circuitry by guiding growing axons and dendrites to their correct targets and by influencing synaptic connectivity. Results from experiments we previously conducted in dcc-heterozygous mice show that DCC plays a critical role in the developmental organization of the mesocorticolimbic dopamine (DA) circuitry. Furthermore we have shown that reduced expression of DCC during development and/or throughout life confers resilience to the development of schizophrenia-like DA and behavioural abnormalities. Importantly, this "protective" phenotype only emerges after puberty. Here we assess whether DCC may contribute to the risk of schizophrenia. We examined single nucleotide polymorphisms (SNPs) located in the DCC gene for association with schizophrenia using a case-control sample consisting of 556 unrelated schizophrenic patients and 208 healthy controls. We found one SNP, rs2270954, to be nominally associated with schizophrenia; patients were less likely to be heterozygous at this locus and more likely to be homozygous for the minor allele (χ(2)=9.84, df=2, nominal p=0.0071). Intriguingly, this SNP is located within the 3' untranslated region, an area known to contain a number of regulatory sequences that determine the stability and translation efficacy of mRNA. These results, together with our previous findings from studies in rodents, point at DCC as a promising novel candidate gene that may contribute to the genetic basis behind individual differences in susceptibility to schizophrenia., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Previous studies in schizophrenia have shown a strong relationship between memory deficits and a poor clinical outcome. However, no previous study has identified the functional neural correlates of memory encoding in relation to remission., Aims: To determine whether functional magnetic resonance imaging (fMRI) activation patterns differed between individuals that later achieved remission v. those who did not., Method: Forty-two participants with first-episode schizophrenia were divided into two groups after 1 year of treatment as per the 2005 remission in schizophrenia consensus definition. We then examined fMRI activation using three contrasts (associative v. item-oriented strategy, semantically unrelated v. related image pairs, and successful v. unsuccessful memory encoding) among 15 participants who had achieved remission (remitted group), 27 who had not (non-remitted group) and 31 healthy controls (control group)., Results: Participants in the non-remitted group displayed a positive activation in the posterior cingulate compared with those in the remitted group when encoding related images; no significant differences between the two groups were identified for the other contrasts. From the behavioural data, compared with the remitted and control groups, the non-remitted group demonstrated an inability to encode related images and displayed worse recognition memory overall., Conclusions: This is the first study to identify differential neural activation between individuals with first-episode schizophrenia that later achieved remission v. those who did not. The behavioural and functional results together add to the growing evidence relating a poor clinical outcome in schizophrenia to memory-related deficits.

Using voxel-based morphometry (VBM), our laboratory recently identified significantly lower grey matter concentration in the parahippocampal gyrus bilaterally in non-remitted patients with a first episode of psychosis (FEP) compared with remitted FEP patients. These results identified a localized difference but did not reveal which cortex (entorhinal, perirhinal, or parahippocampal), if any, was predominantly affected. So, the parahippocampal gyrus was manually segmented and grey matter volumes from the three cortices were compared between 42 non-remitted and 17 remitted patients with a first episode of schizophrenia (FES). Remission was defined as mild or less on eight key symptoms and maintained for 6 consecutive months following the 2005 consensus definition. The non-remitted patients displayed smaller volumes in the parahippocampal cortex - trend-level difference on the left [mm(3), mean (S.D.): non-remitted=2486 (413); remitted=2775 (593)] and significant difference on the right [mm(3), mean (S.D.): non-remitted=2546 (463); remitted=2926 (525)]. No notable differences were found in the entorhinal or perirhinal cortices. This result supported our VBM finding of reduced parahippocampal grey matter bilaterally in non-remitted patients and further suggested differences may be selectively limited to the parahippocampal cortex. A smaller parahippocampal cortex may represent a neural marker in FES patients who do not achieve remission after 1 year of treatment., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Pharmacological, genetic and expression studies implicate N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia (SCZ). Similarly, several lines of evidence suggest that autism spectrum disorders (ASD) could be due to an imbalance between excitatory and inhibitory neurotransmission. As part of a project aimed at exploring rare and/or de novo mutations in neurodevelopmental disorders, we have sequenced the seven genes encoding for NMDA receptor subunits (NMDARs) in a large cohort of individuals affected with SCZ or ASD (n=429 and 428, respectively), parents of these subjects and controls (n=568). Here, we identified two de novo mutations in patients with sporadic SCZ in GRIN2A and one de novo mutation in GRIN2B in a patient with ASD. Truncating mutations in GRIN2C, GRIN3A and GRIN3B were identified in both subjects and controls, but no truncating mutations were found in the GRIN1, GRIN2A, GRIN2B and GRIN2D genes, both in patients and controls, suggesting that these subunits are critical for neurodevelopment. The present results support the hypothesis that rare de novo mutations in GRIN2A or GRIN2B can be associated with cases of sporadic SCZ or ASD, just as it has recently been described for the related neurodevelopmental disease intellectual disability. The influence of genetic variants appears different, depending on NMDAR subunits. Functional compensation could occur to counteract the loss of one allele in GRIN2C and GRIN3 family genes, whereas GRIN1, GRIN2A, GRIN2B and GRIN2D appear instrumental to normal brain development and function.

Growing genetic evidence is converging in favor of common pathogenic mechanisms for autism spectrum disorders (ASD), intellectual disability (ID or mental retardation) and schizophrenia (SCZ), three neurodevelopmental disorders affecting cognition and behavior. Copy number variations and deleterious mutations in synaptic organizing proteins including NRXN1 have been associated with these neurodevelopmental disorders, but no such associations have been reported for NRXN2 or NRXN3. From resequencing the three neurexin genes in individuals affected by ASD (n = 142), SCZ (n = 143) or non-syndromic ID (n = 94), we identified a truncating mutation in NRXN2 in a patient with ASD inherited from a father with severe language delay and family history of SCZ. We also identified a de novo truncating mutation in NRXN1 in a patient with SCZ, and other potential pathogenic ASD mutations. These truncating mutations result in proteins that fail to promote synaptic differentiation in neuron coculture and fail to bind either of the established postsynaptic binding partners LRRTM2 or NLGN2 in cell binding assays. Our findings link NRXN2 disruption to the pathogenesis of ASD for the first time and further strengthen the involvement of NRXN1 in SCZ, supporting the notion of a common genetic mechanism in these disorders.

Autism spectrum disorder (ASD) and schizophrenia (SCZ) are two common neurodevelopmental syndromes that result from the combined effects of environmental and genetic factors. We set out to test the hypothesis that rare variants in many different genes, including de novo variants, could predispose to these conditions in a fraction of cases. In addition, for both disorders, males are either more significantly or more severely affected than females, which may be explained in part by X-linked genetic factors. Therefore, we directly sequenced 111 X-linked synaptic genes in individuals with ASD (n = 142; 122 males and 20 females) or SCZ (n = 143; 95 males and 48 females). We identified >200 non-synonymous variants, with an excess of rare damaging variants, which suggest the presence of disease-causing mutations. Truncating mutations in genes encoding the calcium-related protein IL1RAPL1 (already described in Piton et al. Hum Mol Genet 2008) and the monoamine degradation enzyme monoamine oxidase B were found in ASD and SCZ, respectively. Moreover, several promising non-synonymous rare variants were identified in genes encoding proteins involved in regulation of neurite outgrowth and other various synaptic functions (MECP2, TM4SF2/TSPAN7, PPP1R3F, PSMD10, MCF2, SLITRK2, GPRASP2, and OPHN1).

Schizophrenia is a severe psychiatric disorder that profoundly affects cognitive, behavioral and emotional processes. The wide spectrum of symptoms and clinical variability in schizophrenia suggest a complex genetic etiology, which is consistent with the numerous loci thus far identified by linkage, copy number variation and association studies. Although schizophrenia heritability may be as high as ∼80%, the genes responsible for much of this heritability remain to be identified. Here we sequenced the exomes of 14 schizophrenia probands and their parents. We identified 15 de novo mutations (DNMs) in eight probands, which is significantly more than expected considering the previously reported DNM rate. In addition, 4 of the 15 identified DNMs are nonsense mutations, which is more than what is expected by chance. Our study supports the notion that DNMs may account for some of the heritability reported for schizophrenia while providing a list of genes possibly involved in disease pathogenesis.

Background: Delay in treatment of psychosis is associated with poor clinical and social outcome and is measured as the duration of untreated psychosis (DUP) prior to treatment of the first episode. It has been suggested that this may be mediated through toxic effects of psychosis on the structure and function of the brain. Equivocal evidence exists regarding association between longer DUP and neuro-anatomical changes such as, reduced grey matter volume in specific regions in the brain and deficits in neurocognitive functions., Objective: To examine if duration of untreated psychosis (DUP) preceding treatment of a first episode of psychosis is associated with structural brain abnormalities and deficits in neurocognitive functions., Method: We investigated the relationship between DUP and grey matter volume using voxel-based morphometry techniques and with multiple domains of cognition. Eighty patients with a first episode of psychosis were separated into two equal sized groups based on a median split (18 weeks) of their DUP., Results: Compared to the short-DUP group (mean DUP 7.9 weeks ± 5.6), the long-DUP group (mean 113.7 weeks ± 170 .4) showed significant grey matter volume reductions in orbital-frontal regions (bilateral medial frontal gyrus and bilateral rectal gyrus, BA 11) and parietal regions (postcentral gyrus and superior parietal lobule) as well as a significant reduction in whole brain grey matter volume (p<0.04). For schizophrenia spectrum cases only these findings were confined to left rectal gyrus. There were no differences in white matter or cerebral spinal fluid volumes or on cognitive functions. Results are controlled for antipsychotic medication exposure., Limitations: The inherent difficulty in separating slow and insidious onset from long-DUP may limit the interpretation of our results and there may be an overlap between DUP and duration of illness (including the prodrome)., Conclusion: Patients with a longer delay in treatment of psychosis show a significant reduction in overall grey matter volume with specific reductions in the inferior-orbital region. These results provide some support to a possible neurotoxic effect of prolonged untreated psychosis., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: Schizophrenia (SCZ) is one of the most disabling psychiatric disorders. It is thought to be due to a complex interplay between polygenic and various environmental risk factors, although recent reports on genomic copy number variations suggest that a fraction of the cases could result from variably penetrant de novo variants. The gene encoding the synaptic motor protein kinesin 17 (KIF17) involved in glutamatergic synapse is a candidate gene for SCZ., Methods: As part of our Synapse to Disease project, we resequenced KIF17 in a cohort of individuals with sporadic SCZ (188 subjects). Additional populations included autism spectrum disorder (142 subjects), nonsyndromic mental retardation (95 subjects), and control subjects (568 subjects). Functional validation of the human mutation was done in developing zebrafish., Results: Here we report the identification of a de novo nonsense truncating mutation in one patient with SCZ, in kinesin 17, a synaptic motor protein. No de novo or truncating KIF17 mutations were found in the additional samples. We further validated the pathogenic nature of this mutation by knocking down its expression in zebrafish embryos, which resulted in a developmental defect., Conclusions: Together our findings suggest that disruption of KIF17, although rare, could result in a schizophrenia phenotype and emphasize the possible involvement of rare de novo mutations in this disorder., (Copyright © 2010 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

The role of de novo mutations (DNMs) in common diseases remains largely unknown. Nonetheless, the rate of de novo deleterious mutations and the strength of selection against de novo mutations are critical to understanding the genetic architecture of a disease. Discovery of high-impact DNMs requires substantial high-resolution interrogation of partial or complete genomes of families via resequencing. We hypothesized that deleterious DNMs may play a role in cases of autism spectrum disorders (ASD) and schizophrenia (SCZ), two etiologically heterogeneous disorders with significantly reduced reproductive fitness. We present a direct measure of the de novo mutation rate (μ) and selective constraints from DNMs estimated from a deep resequencing data set generated from a large cohort of ASD and SCZ cases (n = 285) and population control individuals (n = 285) with available parental DNA. A survey of ∼430 Mb of DNA from 401 synapse-expressed genes across all cases and 25 Mb of DNA in controls found 28 candidate DNMs, 13 of which were cell line artifacts. Our calculated direct neutral mutation rate (1.36 × 10(-8)) is similar to previous indirect estimates, but we observed a significant excess of potentially deleterious DNMs in ASD and SCZ individuals. Our results emphasize the importance of DNMs as genetic mechanisms in ASD and SCZ and the limitations of using DNA from archived cell lines to identify functional variants., (2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Our previous work has linked verbal learning and memory with cognitive insight, but not clinical insight, in individuals with a first-episode psychosis (FEP). The current study reassessed the neurocognitive basis of cognitive and clinical insight and explored their neural basis in 61 FEP patients. Cognitive insight was measured with the Beck Cognitive Insight Scale (BCIS) and clinical insight with the Scale to assess Unawareness of Mental Disorder (SUMD). Global measures for 7 domains of cognition were examined. Hippocampi were manually segmented in to 3 parts: the body, head, and tail. Verbal learning and memory significantly correlated with the BCIS composite index. Composite index scores were significantly associated with total left hippocampal (HC) volume; partial correlations, however, revealed that this relationship was attributable largely to verbal memory performance. The BCIS self-certainty subscale significantly and inversely correlated with bilateral HC volumes, and these associations were independent of verbal learning and memory performance. The BCIS self-reflectiveness subscale significantly correlated with verbal learning and memory but not with HC volume. No significant correlations emerged between the SUMD and verbal memory or HC volume. These results strengthen our previous assertion that in individuals with an FEP cognitive insight may rely on memory whereby current experiences are appraised based on previous ones. The HC may be a viable location among others for the brain system that underlies aspects of cognitive insight in individuals with an FEP.

Objective: The temporolimbic region has been implicated in the pathophysiology in schizophrenia. More specifically, significantly smaller hippocampal volumes but not amygdala volumes have been identified at onset in first-episode schizophrenia (FES) patients. However, volumetric differences (namely, in the hippocampus) exhibit an ambiguous relationship with long-term outcome. So, we examined the relationship between hippocampus and amygdala volumes and early remission status., Methods: We compared hippocampus and amygdala volumes between 40 non-remitted and 17 remitted FES patients and 57 healthy controls. Amygdala and hippocampus were manually traced with the hippocampus additionally segmented into three parts: body, head, and tail. Remission was defined as mild or less on both positive and negative symptoms over a period of 6 consecutive months as per the 2005 Remission in Schizophrenia Working Group criteria., Results: A significant [group x structure x side] interaction revealed outcome groups differed in hippocampus tail volumes; significantly on the left (non-remitted=694+/-175 mm(3); remitted=855+/-133 mm(3); p=0.001) with a trend difference on the right (non-remitted=723+/-162 mm(3); remitted=833+/-126 mm(3); p=0.023). Groups did not differ in body, head, or amygdala volumes bi-laterally., Conclusions: A smaller hippocampal tail volume may represent a neural marker in FES patients who do not achieve early remission after the first 6 months of treatment. The early identification of patients with poor outcome with respect to the hippocampus tail may encourage the search for new, more target-specific, medications in hope of improving outcome and moving us towards a better understanding of the pathophysiology of schizophrenia., ((c) 2010 Elsevier B.V. All rights reserved.)

Objective: In psychotic disorders, impairments in cognition have been associated with both clinical and functional outcome, while deficits in social cognition have been associated with functional outcome. As an extension to a recent report on neurocognition and short-term clinical outcome in first-episode psychosis (FEP), the current study explored whether social cognitive deficits could also identify poor short-term clinical outcome among FEP patients., Methods: We defined the social-cognition domain based on the scores from the Hinting Task and the Four Factor Tests of Social Intelligence. Data were collected in 45 FEP patients and 26 healthy controls. The patients were divided into good- and poor-outcome groups based on clinical data at six months following initiation of treatment. Social cognition was compared among 27 poor-outcome, 18 good-outcome, and 26 healthy-control participants., Results: Outcome groups significantly differed in the social cognition domain (z-scores: poor outcome=-2.0 [SD=1.4]; good outcome=-1.0 [SD=1.0]; p=0.005), with both groups scoring significantly lower than the control group (p<0.003). Moreover, outcome groups differed significantly only on the Cartoon Predictions subtest (z-scores: poor outcome=-2.7 [SD=2.7]; good outcome=-0.7 [SD=1.8]; p=0.001) among the five subtests used., Conclusions: Overall, social cognition appears to be compromised in all FEP patients compared to healthy controls. More interestingly, significant differences in social cognitive impairments exist between good and poor short-term clinical outcome groups, with the largest effect found in the Cartoon Predictions subtest.

Alterations of the fornix in chronic patients with psychosis are well established, but its integrity in the early stage of schizophrenia remains unknown. Thirty-two patients experiencing first-episode schizophrenia (FES) and 25 matched controls completed a DTI scan. DTI-tractography was used to estimate fractional anisotropy (FA) in bilateral fornices. The analysis showed significant overall FA reductions in the fornix in FES patients relative to controls. No significant correlations were found between FA values and clinical and sociodemographic data in FES patients. These findings revealed slight alterations along the fornix in early stage of schizophrenia., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Background: Cognitive deficits in schizophrenia are well established and are known to be present during the first episode of a psychotic disorder. In addition, consistent heterogeneity within these impairments remains unexplained. One potential source of variability may be the level of pre-morbid adjustment prior to the onset of first-episode psychosis (FEP)., Method: Ninety-four FEP patients and 32 healthy controls were assessed at baseline on several neuropsychological tests comprising six cognitive domains (verbal memory, visual memory, working memory, processing speed, reasoning/problem-solving and attention) and an abbreviated version of the full IQ. A global neurocognitive domain was also computed. Pre-morbid adjustment patterns were divided into three distinct groups: stable-poor, stable-good and deteriorating course., Results: Based on a cut-off of 0.8 for effect size, the stable-poor pre-morbid adjustment group was significantly more impaired on most cognitive domains and full IQ compared to the deteriorating group, who were more severely impaired on all measures compared to the stable-good group. The type of cognitive deficit within each subgroup did not differ and the results indicate that a global neurocognition measure may reliably reflect the severity of cognitive impairment within each subgroup., Conclusions: Pre-morbid adjustment patterns prior to onset of psychosis are associated with severity but not type of cognitive impairment. Patients in the stable-poor group are generally more impaired compared to the deteriorating group, who are, in turn, more impaired than the stable-good group.

Schizophrenia likely results from poorly understood genetic and environmental factors. We studied the gene encoding the synaptic protein SHANK3 in 285 controls and 185 schizophrenia patients with unaffected parents. Two de novo mutations (R1117X and R536W) were identified in two families, one being found in three affected brothers, suggesting germline mosaicism. Zebrafish and rat hippocampal neuron assays revealed behavior and differentiation defects resulting from the R1117X mutant. As mutations in SHANK3 were previously reported in autism, the occurrence of SHANK3 mutations in subjects with a schizophrenia phenotype suggests a molecular genetic link between these two neurodevelopmental disorders.

Background: Patients with schizophrenia may differ from healthy controls by having dysregulated physiological responses to stress. Our objective was to determine the extent to which cortisol reaction can discriminate between controls and schizophrenia patients while controlling for symptom severity, personality, body mass index (BMI) and smoking., Method: 30 chronic schizophrenia patients and 30 matched controls underwent a modified version of the Trier Social Stress Test (TSST), consisting of public speaking and mental arithmetic. Heart rate, blood pressure, and salivary cortisol were measured repeatedly throughout the TSST. In addition, participants completed the NEO Personality Inventory (NEO-FFI), and were interviewed with the Brief Psychiatric Rating Scale (BPRS)., Results: Both groups had a significant increase in heart rate and mean arterial pressure following the TSST. Results of a logistic regression suggests that patients can be discriminated from controls with a smaller change in cortisol between baseline and 15 min post-TSST, controlling for BMI and severity of positive symptoms. There was a trend for lower overall cortisol secretion in patients., Conclusions: Despite demonstrable effects of the stressor on cardiac measures, schizophrenia patients tend to have smaller acute cortisol reaction to psychosocial stress. The significance of this conclusion for vulnerability-stress models of schizophrenia is discussed.

Objective: To examine the hypothesis that poorer social and family support, identifiable at the onset of treatment, is associated with nonadherence in the first 6 months of treatment of patients with first-episode psychosis (FEP), independent of other patient-related factors., Method: Consecutive patients (n = 100) admitted to a specialized early intervention service for FEP who met the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, criteria for either a schizophrenia spectrum disorder or an affective psychosis were evaluated monthly for 6 months regarding their adherence to medications. Using sociodemographic and illness-related factors, including social and family support, as independent variables and adherence as the dependent variable, univariate analyses were followed by logistic regression., Results: Fifty-six patients (54.9%) were adherent (76% to 100% of doses taken) and 46 (45.1%) nonadherent (less than 76% of doses taken). Nonadherent patients were less likely to have received a good level of social support (chi (2) = 5.89, df = 1, P = 0.02), as rated by their respective case manager, and more likely to be single (Fisher exact test, P = 0.019) and to have refused medication at the first offer of treatment (chi (2) = 19.70, df = 1, P = 0.001). Using logistic regression, both the level of social support (OR = 3.552, P = 0.03) and early medication acceptance (OR = 11.092, P < 0.001) were significant as predictors of adherence., Conclusion: These results suggest the significance of social and family support in achieving adherence to medications very early in the course of treatment of FEP, in addition to the influence of early acceptance or rejection of medication.