Schizophrenia Research - Articles in Press

Cortical thickness, neuron density and size in the inferior parietal lobe in schizophrenia - Corrected Proof

John F. Smiley, Kira Konnova, Cynthia Bleiwas — 2012-02-03

Abstract: The inferior parietal lobe (IPL) is a center of multisensory integration, and both functional and structural MRI studies have found evidence that pathology in this region may contribute to disrupted sensory perception in schizophrenia. To further define this pathology, we used postmortem samples from the left and right IPL, to compare the thickness and volume of the upper (I–III) and lower (IV–VI) cortical layers. The samples were divided into supramarginal and angular gyri, and neuron density and size were measured in the supramarginal gyrus. The laminar thickness and volume measurements did not demonstrate significant changes in schizophrenia, but did show that the angular gyrus was thinner than the supramarginal gyrus, due to a difference mainly in the lower layers. Measurements of cortical thickness, neuron size and neuron density all showed some evidence of previously reported normal hemispheric differences. These asymmetries were reduced in schizophrenia, but the small changes were at the threshold of detection, and are discussed in the context of the sensitivity of the methods applied.

mGluR3 and not mGluR2 receptors mediate the efficacy of NAAG peptidase inhibitor in validated model of schizophrenia - Corrected Proof

Rafal T. Olszewski, Tomasz Bzdega, Joseph H. Neale — 2012-02-02

The limited efficacy of antipsychotic drugs and their extrapyramidal side effects militate in favor of developing drug therapies aimed at different receptors. The metabotropic glutamate receptors (mGluRs) have emerged as such targets (). Heterotropic agonists of group II mGluRs (mGluR2 and mGluR3) are effective in animal models, including phencyclidine (PCP) and d-amphetamine-induced motor activation, working memory and prepulse inhibition of acoustic startle () and are currently undergoing clinical trials (). Studies in mice null mutant for mGluR2 and mGluR3 mice demonstrated that the activities of the group II mGluR agonists in the PCP motor activation model of schizophrenia are mediated by mGluR2 and not mGluR3 ().

Apathy in first episode psychosis patients: A ten year longitudinal follow-up study - Corrected Proof

2012-01-30

Abstract: Background: Apathy is a common symptom in first episode psychosis (FEP), and is associated with poor functioning. Prevalence and correlates of apathy 10years after the first psychotic episode remain unexplored.Objective: The aims of the study were twofold: 1) to examine prevalence and predictors of apathy at 10years, and 2) to examine the relationship between apathy at 10years and concurrent symptoms, functioning and outcome, including subjective quality of life.Methods: Three-hundred-and-one patients with FEP were included at baseline, 186 participated in the 10year follow-up. Of these, 178 patients completed the Apathy Evaluation Scale (AES-S-Apathy).Patients were classified as having apathy (AES-S-Apathy≥27) or not. The relationship between apathy and baseline variables (Demographics, Diagnosis, Duration of Untreated Psychosis), measures of symptomatology (Positive and Negative Syndrome Scale, Calgary Depression Scale for Schizophrenia), functioning (Global Assessment of Functioning Scale, Strauss Carpenter Level of Functioning Scale) and subjective quality of life (Lehman's Quality of Life Interview) were estimated through correlation analyses and blockwise multiple hierarchical regression analysis.Results: Nearly 30% of patients met the threshold for being apathetic at follow-up. No baseline variables predicted apathy significantly at 10years. Apathy was found to contribute independently to functioning and subjective quality of life, even when controlling for other significant correlates.Conclusions: Apathy is a common symptom in a FEP cohort 10years after illness debut, and its presence relates to impaired functioning and poorer subjective quality of life.

Schizophrenia and risk-taking: Impaired reward but preserved punishment processing - Corrected Proof

2012-01-30

Abstract: Risky decision-making is subserved by the frontostriatal system, which includes a network of interconnected brain regions known to be dysfunctional in patients with schizophrenia. This study aimed to investigate whether and to what extent patients with schizophrenia display a different pattern of risk-taking behavior relative to matched healthy controls. The Balloon Analogue Risk Task (BART) and the Risky-Gains Task were used as naturalistic measures of risk-taking behavior in 25 patients with schizophrenia and 25 controls. Results of the BART revealed that patients behaved more conservatively, and this in turn led to suboptimal risky decision-making. Consistently, patients behaved more conservatively in the Risky-Gains Task. Interestingly, however, they adjusted the pattern of risk-taking following a punished trial similar to controls. These findings indicate that patients have impaired reward but preserved punishment processing. This study complements previous studies on decision-making in schizophrenia and suggests specific rather than widespread abnormalities along the frontostriatal system in schizophrenia.

Auditory steady state response in the schizophrenia, first-degree relatives, and schizotypal personality disorder - Corrected Proof

2012-01-30

Abstract: The power and phase synchronization of the auditory steady state response (ASSR) at 40Hz stimulation is usually reduced in schizophrenia (SZ). The sensitivity of the 40Hz ASSR to schizophrenia spectrum phenotypes, such as schizotypal personality disorder (SPD), or to familial risk has been less well characterized. We compared the ASSR of patients with SZ, persons with schizotypal personality disorder, first degree relatives of patients with SZ, and healthy control participants. ASSRs were obtained to 20, 30, 40 and 50Hz click trains, and assessed using measures of power (mean trial power or MTP) and phase consistency (phase locking factor or PLF). The MTP to 40Hz stimulation was reduced in relatives, and there was a trend for MTP reduction in SZ. The 40Hz ASSR was not reduced in SPD participants. PLF did not differ among groups. These data suggest the 40Hz ASSR is sensitive to familial risk factors associated with schizophrenia.

α7 neuronal nicotinic receptor agonist (TC-7020) reverses increased striatal dopamine release during acoustic PPI testing in a transgenic mouse model of schizophrenia - Corrected Proof

2012-01-30

Abstract: Genetic and post mortem evidence has implicated the α7 neuronal nicotinic receptor (NNR) in the etiology of schizophrenia and related disorders. In schizophrenia, enhanced subcortical dopamine (DA) correlates with positive and cognitive of the disease, including impairments in sensorimotor gating. We measured the levels of extracellular DA and DA metabolites during an acoustic test session of prepulse inhibition (PPI) of the startle response, a measure of sensorimotor gating, by microdialysis and HPLC-EC in a transgenic mouse model of schizophrenia. In th-fgfr1(tk−) mice, blockade of fibroblast growth factor receptor 1 (FGFR1) signaling during development in catecholaminergic neurons results in reduced size and density of midbrain DA neurons of the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). These mice displayed reduced PPI and enhanced startle response relative to control mice as well as a potentiation of DA release in the dorsal striatum during a 30minute PPI test session. Acute administration of a partial α7 NNR agonist TC-7020 (1.0mg/kg) normalized PPI and startle deficits and attenuated increases of DA release during acoustic PPI testing. These results provide direct evidence of elevated striatal dopaminergic transmission with impaired sensorimotor gating that may underlie cognitive and positive symptoms and motor deficits in schizophrenia and related disorders. Also, systemic targeting of alpha7 NNRs may ameliorate these deficits by functionally suppressing striatal DA activity.

The effect of rTMS on auditory hallucinations: Clues from an EEG-rTMS study - Corrected Proof

2012-01-30

Abstract: Objective: Repetitive transcranial magnetic stimulation (rTMS) to the temporoparietal region has been proposed as a therapeutic option for auditory verbal hallucinations (AVH). However, most large randomized controlled trials failed to demonstrate a superior effect of rTMS treatment as compared to sham. Previous studies applied daily rTMS sessions for one or more weeks to summate its effects. However, the effect of a single rTMS treatment on AVH-severity has never been studied, making it unclear if there is an initial effect that could be increased by repeated treatment.Methods: In three separate sessions, twenty-four patients with a psychotic disorder received 1-Hz rTMS to the left temporoparietal cortex, its right-sided homologue or a centro-occipital control site. Severity of AVH was assessed before and after each rTMS session and resting-state EEGs were recorded to investigate the neuronal effects of rTMS.Results: Stimulation of the temporoparietal cortices was not more effective in reducing AVH-severity than control-site stimulation. In addition, EEG-related power and connectivity measures were not affected differently across stimulation sites and changes in neuronal activity did not correlate with changes in AVH-severity.Conclusions: These results may suggest a placebo effect of a single session of 1-Hz rTMS treatment on AVH-severity.

Prevalence of item level negative symptoms in first episode psychosis diagnoses - Corrected Proof

2012-01-27

Abstract: The relevance of negative symptoms across the diagnostic spectrum of the psychoses remains uncertain. The purpose of this study was to report on prevalence of item and subscale level negative symptoms across the first episode psychosis (FEP) diagnostic spectrum in an epidemiological sample, and to ascertain whether items and subscales were more prevalent in a schizophrenia spectrum diagnoses group compared to an ‘all other psychotic diagnoses’ group. We measured negative symptoms in 330 patients presenting with FEP using the Scale for Assessment of Negative Symptoms (SANS), and ascertained diagnosis using the Structured Clinical Interview for DSM IV. Prevalence of SANS items and subscales were tabulated across all psychotic diagnoses, and logistic regression analysis determined which items and subscales were predictive of schizophrenia spectrum diagnoses. SANS items were most prevalent in schizophrenia spectrum conditions but frequently presented in other FEP diagnoses, particularly substance induced psychotic disorder and Major Depressive Disorder. Brief psychotic disorder and bipolar disorders had low levels of negative symptoms. SANS items and subscales which significantly predicted schizophrenia spectrum diagnoses, were also frequently present in some of the other psychotic diagnoses. Conclusions: SANS items have high prevalence in FEP, and while commonest in schizophrenia spectrum conditions are not restricted to this diagnostic subgroup.

Genetic overlap between schizophrenia and bipolar disorder: A study with AKT1 gene variants and clinical phenotypes - Corrected Proof

2012-01-25

Abstract: Introduction: A number of epidemiological and genetic studies suggests an overlap of Schizophrenia and Bipolar disorder across the traditional binary classification. AKT1 gene variants were previously shown to be associated with schizophrenia. In this study, our aim was to determine whether AKT1 gene variants are associated with particular phenotypes for schizophrenia (SCZ) and bipolar disorder (BPD).Methods: This study included 529 subjects of European ancestry: 364 patients suffering from SCZ, BPD or schizoaffective disorder and 165 healthy controls. BPD patients were additionally subdivided into two groups: BPD with or without psychosis. Six AKT1 variants were assessed in a case–control study and allelic associations were analyzed. Moreover, meta-analyses were performed for those variants found in case–control studies of schizophrenia and schizoaffective disorder.Results: Nominal associations were found for three AKT1 gene variants, namely rs3803300, rs2494732 and rs2498804, in the four phenotypes. Two SNP survived Bonferroni corrections for multiple testing: rs3803300 (p<0.001) and rs2498804 (p<0.03) in group 1 (BPD without psychosis). In group 2 (BPD with psychosis) and in group 4 (SCZ), rs3803300 was significant but did not survive multiple testing. While rs2494732 was associated with the presence of psychosis (group-2, 3 and 4), rs2498804 was associated with affective symptoms (groups-1, 2 and 3). One meta-analysis found a significant level of association between rs3803300 and schizophrenia in Asian subjects.Conclusion: AKT1 gene variations appeared to impact the risk for a class of psychiatric symptoms, comprising SCZ and BPD. Our findings support the view that AKT1 genetic variants are shared by both BPD and SCZ.

Automated classification of fMRI during cognitive control identifies more severely disorganized subjects with schizophrenia - Corrected Proof

2012-01-25

Abstract: The establishment of a neurobiologically based nosological system is one of the ultimate goals of modern biological psychiatry research. Developments in neuroimaging and statistical/machine learning have provided useful basic tools for these efforts. Recent studies have demonstrated the utility of fMRI as input data for the classification of schizophrenia, but none, to date, has used fMRI of cognitive control for this purpose. In this study, we evaluated the accuracy of an unbiased classification method on fMRI data from a large cohort of subjects with first episode schizophrenia and a cohort of age matched healthy control subjects while they completed the AX version of the Continuous Performance Task (AX-CPT). We compared these results to classifications based on AX-CPT behavioral data. Classification accuracy for DSM-IV defined schizophrenia using fMRI data was modest and comparable to classifications conducted with behavioral data. Interestingly fMRI classifications did however identify a distinct subgroup of patients with greater behavioral disorganization, whereas behavioral data classifications did not. These results suggest that fMRI-based classification could be a useful tool in defining a neurobiologically distinct subgroup within the clinically defined syndrome of schizophrenia, reflecting alterations in discrete neural circuits. Independent validation of classification-based phenotypes using other biological data such as genetics would provide a strong test of this hypothesis.

Screening for negative symptoms: Preliminary results from the self-report version of the Clinical Assessment Interview for Negative Symptoms - Corrected Proof

2012-01-24

Abstract: Though negative symptoms in schizophrenia are associated with a host of deleterious outcomes (e.g., White et al., 2009), not all individuals with schizophrenia suffer from negative symptoms (e.g., Blanchard et al., 2005). Thus, methods to quickly screen and identify patients for more intensive clinical interview assessments may have significant clinical and research utility. The present study is a preliminary examination of the reliability and validity of a self-report version of the newly developed Clinical Assessment Interview for Negative Symptoms (CAINS; Blanchard et al., 2011; Forbes et al., 2010; Horan et al., 2011). The CAINS-SR is a 30-item self-report measure that assesses Experiential (avolition, anhedonia, asociality) and Expressive (blunted affect, alogia) domains of negative symptoms. Participants (N=69) completed the CAINS-SR questionnaire and were evaluated with symptom interviews using the CAINS and other non-negative symptom interviews that assessed psychotic, affective, and other symptoms. The Experience subscale of the CAINS-SR demonstrated good internal consistency, convergent validity, and discriminant validity, while the poorer psychometric properties of the Expression subscale suggest that self-report of negative symptoms should focus on the experiential domain. Overall, preliminary findings indicate that the CAINS-SR (addressing experiential deficits) may be a useful complement to the clinician-rated interview measure. Future research on the sensitivity and specificity of the CAINS-SR will determine its suitability as a screening measure.

Regional differences in expression of β-tubulin isoforms in schizophrenia - Corrected Proof

2012-01-24

Abstract: A growing body of evidence suggests that abnormal elements of the cytoskeleton may be associated with the pathophysiology of schizophrenia. Isoforms of a major cytoskeleton protein, β-tubulin, were recently demonstrated to have distinct roles in neuronal differentiation and cell viability. For these reasons, we tested the hypothesis that there are differences in the expression of β-tubulin isoforms (βI-βIV) in the brain in schizophrenia, using western blot analysis in an elderly group of subjects with this illness and a control group. We found that βI-tubulin protein expression was decreased in the anterior cingulate cortex and increased in the dorsolateral prefrontal cortex, but not changed in superior temporal gyrus or hippocampus in schizophrenia. Our data supports the growing body of evidence suggesting abnormalities of the cytoskeleton in schizophrenia.

Cognitive adaptation training combined with assertive community treatment: A randomised longitudinal trial - Corrected Proof

Jens Peter Hansen, Birte Østergaard, Merete Nordentoft, Lise Hounsgaard — 2012-01-24

Abstract: Background: Cognitive adaptation training (CAT) targets the adaptive behaviour of patients with schizophrenia and has shown promising results regarding the social aspects of psychosocial treatment. As yet, no reports have appeared on the use of CAT in combination with assertive community treatment (ACT). Our purpose was to evaluate the effect of CAT in comparison with ACT, focusing on social functions (primary outcome), symptoms, relapse, re-hospitalisation, and quality of life of outpatients with schizophrenia.Methods: The trial was a parallel, randomised, multicentre trial conducted in three centres treating patients with a first episode of schizophrenia disorder. A total of 62 outpatients diagnosed as having schizophrenia were randomly assigned to CAT+ACT or ACT alone. The CAT was conducted in the patient's home and included instruction in prompting for specific actions. The treatment lasted for 6months, and the patients were assessed at baseline and at 6- and 9-month follow-ups.Results: The results of mixed-effects regression models indicated no significant differences between intervention group and control group at 6 and 9months in any outcome [Global Assessment of Functioning at 6months (p=0.32) and the Health of the Nation Outcome Scales social subscale at 6months (p=0.30)].Conclusion: The results from this trial differ from previous CAT trials because use of CAT showed no significant effects. However, the low number of participants may have been responsible for these results. Thus, additional studies are needed to determine whether the use of some elements of CAT can help to make ACT more economically effective.

Motivational intervention increases exercise in schizophrenia and co-occurring substance use disorders - Corrected Proof

2012-01-20

Persons with schizophrenia spectrum disorders (SSDs) and co-occurring substance abuse seldom exercise consistently; lack of motivation is proposed as the primary reason (). We completed a randomized controlled trial (RCT) testing effects of a motivational intervention on exercise behavior, published elsewhere (). We report results from a sub-sample of 17 outpatients with SSDs and co occurring substance abuse.

Executive function in first-episode schizophrenia: A three-year prospective study of the Hayling Sentence Completion Test - Corrected Proof

2012-01-20

Abstract: In recent decade, deficits in the mechanism of Supervisory Attentional System (SAS) have become increasingly influential in explaining the nature of dysexecutive syndrome experienced by schizophrenic patients. The SAS model is characterized by having a detailed sub-classification of specific executive function components, among which semantic inhibition has been investigated using the Hayling Sentence Completion Test (HSCT). Several studies thus far have indicated that schizophrenic patients show impairment in HSCT performance. However, HSCT data concerning first-episode patients is still scarce. Besides, as previous HSCT studies were all cross-sectional in nature, they were not able to assess changes in HSCT performance over time. In order to address the paucity of knowledge about the longitudinal trajectories and correlates of semantic inhibition deficits in early schizophrenia, this paper reports a three-year prospective study of HSCT performance in medication-naïve, first-episode patients with schizophrenia-spectrum disorders. HSCT performance was assessed in 34 patients at four times over a period of three years, while the 34 healthy controls were assessed once. We found that medication-naïve patients demonstrated impairment in the inhibition condition in HSCT as compared to controls, but not in the initiation condition. Such HSCT impairment gradually improved in the three years following the first psychotic episode; however, HSCT performance did not predict improvement in negative or positive symptoms over the three-year period. The present findings suggest that semantic inhibition impairment is a specific deficit in schizophrenia that may require early intervention efforts, with the goal of facilitating more successful verbal communication and thereby better interpersonal functioning.

Abnormal intrinsic and extrinsic connectivity within the magnetic mismatch negativity brain network in schizophrenia: A preliminary study - Corrected Proof

D. Dima, S. Frangou, L. Burge, S. Braeutigam, A.C. James — 2012-01-20

Abstract: Altered neuroplasticity is increasingly invoked as a mechanism underpinning dysconnectivity in schizophrenia. We used Dynamic Causal Modelling to compare connectivity during the magnetic auditory Mismatch Negativity (MMN), an index of error prediction, between schizophrenia patients and controls. Patients showed reduced intrinsic connectivity within the primary auditory cortex suggestive of impaired local neuronal adaptation and disrupted forward and backward extrinsic connectivity throughout the MMN network indicative of reduced higher order input in disambiguating activity in lower network nodes. Our study provides the first empirical description of the dysplastic changes underpinning dysconnectivity between primary sensory and higher order cortical areas in schizophrenia.

Clozapine administration ameliorates disrupted long-range synchrony in a neurodevelopmental animal model of schizophrenia - Corrected Proof

Desiree D. Dickerson, Aleisha M. Restieaux, David K. Bilkey — 2012-01-19

Abstract: The abnormal synchronisation of neural networks may underlie some of the deficits observed in schizophrenia. Abnormal synchronisation can be induced in animal models. We investigated whether acute clozapine treatment might function therapeutically by ameliorating the deficit in theta frequency coherence between the prefrontal cortex and the hippocampus that is induced in rats exposed to maternal immune activation (MIA)—a risk-factor for schizophrenia. Clozapine treatment increased synchrony levels to that of control animals in a dose-dependent manner. Clozapine's effect on synchrony may in part be mediated through increases in local synchrony that occurred in prefrontal cortex but not hippocampus.

A ticking clock for the production of sequential actions: Where does the problem lie in schizophrenia? - Corrected Proof

Yvonne Delevoye-Turrell, Hélène Wilquin, Anne Giersch — 2012-01-19

Abstract: Schizophrenia has been associated to a distorted time clock. By subtracting contact duration from Inter Response Interval, we report evidence for preserved internal clock in schizophrenia, with normal spontaneous tapping tempo. Contact durations were however increased in patients suggesting a specific problem in the fast integration of incoming haptic feedback with outgoing motor efferences. This integration deficit would emerge at an early phase, since Ultra High Risk patients also revealed abnormal tapping stability. Tactile screens revealed to be a simple and low cost apparatus that may constitute a suitable measuring kit for the characterisation of sensory motor deficits in clinical settings.

Do psychiatric registries include all persons with schizophrenia in the general population? A population-based longitudinal study - Corrected Proof

2012-01-19

Abstract: Background: Psychiatric hospitalization registries are utilized to investigate the incidence and prevalence of schizophrenia for both research and administrative purposes. The assumption behind this is that most individuals with schizophrenia will be hospitalized at least once in their life-time.Method: In an epidemiological survey conducted in the 1980s, a population-based sample (n=4914) of Israel-born individuals then aged 25–34 were screened in the community, and 29 (0.6%) were subsequently diagnosed by psychiatrists using SADS/RDC criteria. Twenty four years later we linked data from the epidemiological survey with the Israeli National Psychiatric Hospitalization Registry.Results: Twenty seven of the 29 individuals (93%) diagnosed with schizophrenia in the survey were identified in the hospitalization registry with the same diagnosis. Fifty-two (1.0%) participants not diagnosed during the survey with schizophrenia were identified in the psychiatric hospitalization registry 24years later with schizophrenia. The majority of them were diagnosed with other psychiatric disorders in the survey. If all diagnoses of schizophrenia are accepted at face value, the lifetime prevalence rate would be 1.8% for this cohort.Conclusion: The overwhelming majority of individuals diagnosed with schizophrenia at ages 25–34 in an epidemiological survey were present in the Psychiatric Hospitalization Registry. However, the assessment of life-time rates of schizophrenia at these ages is problematic because some future cases are asymptomatic, others have premorbid non-psychotic disorders, while in others it is difficult to differentiate between affective disorders and schizophrenia. Availability of psychiatric services and hospitalization policy must be considered when generalizing these findings to other countries.

Sleep propensity at daytime as assessed by Multiple Sleep Latency Tests (MSLT) in patients with schizophrenia increases with clozapine and olanzapine - Corrected Proof

2012-01-18

Abstract: Sleep propensity at daytime has not been investigated in untreated patients with schizophrenia. Furthermore, while the antipsychotics clozapine and olanzapine are considered to frequently cause ‘sleepiness’ or ‘sedation’, this has not been objectified yet. Therefore, 30 patients with schizophrenia were included in this randomized, double-blind study. Sleep propensity was assessed before and after 2, 4 and 6weeks of treatment with either clozapine or olanzapine using a Multiple Sleep Latency Test (MSLT); in the MSLT, sleep latencies of 5 nap opportunities of 20min during daytime are averaged. In addition, the number of sleep onsets was recorded. Mean sleep latency in untreated schizophrenic patients was 16.2±0.8min at baseline. Both antipsychotics induced an increase of sleep propensity as indicated by a shortened sleep latency and more sleep onsets during the treatment period as compared to baseline. These effects were strongest in the morning. Four patients receiving clozapine and 3 patients receiving olanzapine reported subjective sleepiness, in all but one commencing in the first treatment week and persisting until study end. While the mean sleep latency during treatment was significantly shorter in these patients (12.3±0.8min) than in those without subjective sleepiness (14.9±0.7min), a short sleep latency was not necessarily associated with subjective sleepiness.In conclusion, mean sleep latency was >36% longer (i.e. sleep propensity was lower) in untreated patients with schizophrenia than in healthy subjects previously consistently reported. Furthermore, clozapine and olanzapine increased sleep propensity in schizophrenic patients. A minority of patients reported subjective sleepiness.

The association between early autistic traits and psychotic experiences in adolescence - Corrected Proof

Rhys Bevan Jones, Anita Thapar, Glyn Lewis, Stanley Zammit — 2012-01-16

Abstract: Background: There has been growing interest in the clinical and biological links between autistic spectrum disorder and psychotic disorders, and between symptoms of these disorders that exist below diagnostic thresholds. Whilst autism and schizophrenia are regarded as distinct disorders, recent studies support an overlap in the genetic architecture across these conditions. Although early neurodevelopmental impairment is associated with psychotic disorders in later life, evidence from longitudinal studies of the relationship between autistic traits and psychotic experiences is limited.AimsThe aim of the study is to explore whether children with early autistic traits (social interaction and communication problems, and restricted, repetitive interests and behaviours) are more likely to present with psychotic experiences in early adolescence.Method: Longitudinal study using the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. The mothers of 8232 children were asked about autistic traits in their children as part of the Development and Well-Being Assessment (DAWBA) at the age of 7. Of those, 6439 children completed a semi-structured clinical assessment for psychotic experiences at the age of 12.Results: Children whose mothers had concerns about autistic traits in early life, in particular with regard to speech development or ‘rituals’/‘habits’, were more likely to develop psychotic experiences in early adolescence. The greater the number of early autistic traits a child had, the greater their risk of developing psychotic experiences. These associations were not confounded by IQ, family history of depression or schizophrenia, gender or socio-demographic characteristics.Conclusions: Childhood autistic traits, and particularly speech problems and odd rituals or unusual habits, are associated with psychotic experiences in adolescence. This may be a result of a shared aetiology or because autistic traits may also be an early precursor of psychotic experiences.

Is it possible to have impaired neurocognition but good social cognition in schizophrenia? - Corrected Proof

Jennifer R. Fanning, Morris D. Bell, Joanna M. Fiszdon — 2012-01-16

Abstract: Social cognitive impairment in schizophrenia is common and associated with poor functional outcome. While correlations in the moderate range suggest that social cognition and neurocognition are separate but overlapping domains, less is known about whether intact neurocognition represents a “necessary but not sufficient” condition for intact social cognition, as has been suggested. In the present study we examined the following in a sample of 119 psychiatrically stable outpatients with schizophrenia: 1) correlations between multiple social cognitive measures and neurocognition, 2) the predictive value of neurocognitive domains in explaining social cognitive performance, and 3) the co-occurrence of social cognitive and neurocognitive impairment within participants. While ¼ of participants showed intact overall neurocognition and impaired overall social cognition, only one participant had normal-range social cognition and impaired neurocognition. Results support the notion that normal range neurocognition is a necessary though not necessarily sufficient building block for good social cognitive performance.

A second look: No effect of the COMT Val158Met polymorphism on conflict adaptation in youth with chromosome 22q11.2 deletion syndrome - Corrected Proof

Joel Stoddard, Yukari Takarae, Tony J. Simon — 2012-01-16

The catechol o-methyltransferase gene (COMT) gene is located at chromosome 22q11.2, where the most common human genetic microdeletion occurs. The resultant syndrome (22q11.2DS) confers both a high risk of psychotic disorder (~25 fold) and schizophrenia-related executive dysfunction (e.g. ). Therefore, 22q11.2DS has been a model population in which to study COMT behavioral phenotypes, specifically executive function and clinical psychosis (e.g. ). However, in 22q11.2DS, neither allele of the codominant, functional COMT Val108/158Met polymorphism (rs4680) has been reliably associated with clinical psychosis () or executive function (). We have previously reported an association between the rs4680 Met allele and conflict adaptation () but not to flanker interference () within the same task. To resolve this discrepancy, we re-examined the association between rs4860 and impairment in conflict adaptation in the larger sample () using the same method as before ().

Clinical and cognitive correlates of insight in first-episode schizophrenia - Corrected Proof

2012-01-16

Abstract: This study aims to explore the relationship between clinical symptoms and cognitive functions with different insight dimensions in patients with first-episode schizophrenia. Seventy-nine patients were assessed following six months of treatment. Insight was assessed using the abridged version of Scale of Unawareness of Mental Disorder (SUMD). Symptoms were assessed using Positive and Negative Syndrome Scale (PANSS). Cognitive functions were assessed using the Modified Wisconsin Card Sorting Test (MWCST), semantic verbal fluency and the letter-number sequencing (LNS) test from the Wechsler Adult Intelligence Scale (WAIS). Positive, negative and disorganized symptoms were found to be correlated with overall insight and all three general insight dimensions. Only perseverative errors and categories completed of MWCST were correlated with overall insight. Perseverative errors and non-perseverative errors of MWCST were correlated with the awareness of medication effects; perseverative errors of MWCST were also correlated with the awareness of social consequence of the illness. These support the link between poor insight and impaired executive function particularly measured by MWCST. The specific correlation of cognitive functions and different dimensions of insight suggests different underlying mechanism within each dimension of insight. The combined model of symptomatology and cognitive function explained 20.6% to 36.4% of the variance in the lack of insight within the different dimensions. The modest combined relationship of clinical and cognitive function with insight suggests that the exploration of other models in relationship to different insight dimensions is important.

Structural abnormalities in the cuneus associated with Herpes Simplex Virus (type 1) infection in people at ultra high risk of developing psychosis - Corrected Proof

2012-01-13

Abstract: It has been suggested that some cases of schizophrenia may be caused by an interaction between physiological risk factors and exposure to certain neurotropic infectious agents such as Herpes Simplex Virus type 1 (HSV1). This study investigated whether HSV1 exposure was associated with structural brain abnormalities in individuals who, because of genetic or other factors, were deemed at ultra high risk (UHR) of developing psychosis. Twenty-five UHR individuals with a history of HSV1 exposure (HSV1+), 33 UHR participants without a history of HSV1 exposure (HSV1−) and 19 healthy controls participated in the study. All participants underwent a T1-weighted structural MRI scan, and HSV1 exposure was determined based on the presence of IgG class antibodies in the blood serum. Voxel based morphometry revealed that the HSV1+ participants exhibited volumetric gray matter reductions in the cuneus, relative to both the HSV1− and healthy control participants (p<0.05, small volume corrected for familywise error). The results of the study suggest that a history of HSV1 infection is associated with volumetric gray matter reductions in individuals at ultra-high risk for developing psychosis, and are consistent with previous studies that have identified structural gray matter abnormalities in HSV1-infected patients with established schizophrenia.

Olfaction, “olfiction,” and the schizophrenia-spectrum: An updated meta-analysis on identification and acuity - Corrected Proof

Alex S. Cohen, Laura A. Brown, Tracey L. Auster — 2012-01-13

Abstract: Olfaction deficits in individuals with schizophrenia are well documented. A meta-analysis conducted nearly a dozen years ago on the topic revealed a deficit of a full standard deviation in magnitude compared to nonpatient controls. Recent efforts have been attempted to determine whether deficits in olfactory identification and acuity reflect a vulnerability marker of schizophrenia-spectrum pathology. To address this issue, the present study conducted a meta-analysis of 16 studies of individuals with schizotypy, defined in terms of a) “ultra-high risk” status, b) having an affected biological family member, or c) having extreme scores on a schizotypy questionnaire. We also conducted an updated meta-analysis of 40 studies of olfactory functioning in schizophrenia. Consistent with the prior meta-analysis, patients with schizophrenia showed impairments in olfaction identification on a full standard deviation in magnitude (d=−.99). Individuals with schizotypy showed much more subtle (d=−.24) differences in olfaction, though the effect sizes were higher for studies examining individuals at “ultra-high risk” (d=−.67) versus studies examining individuals with psychometrically-defined (d=−.14) schizotypy. Differences in olfactory acuity, relative to their respective control groups, were small for both the schizophrenia (d=−.45) and schizotypy (d=−.38) studies but were similar in magnitude. The present findings argue against the notion that deficits in olfaction identification are a vulnerability marker of schizophrenia. Suggestions for future research are recommended.

Screening and assessing ideas and delusions of reference using a semi-structured interview scale: A validation study of the Ideas of Reference Interview Scale (IRIS) in early psychosis patients - Corrected Proof

2012-01-13

Abstract: Background: Ideas and delusions of reference (IOR/DOR) are an important but underrecognized research target. Difficulty in their reliable assessment has been a barrier. A screening and assessment tool incorporating a self-information processing framework, the Ideas of Reference Interview Scale (IRIS), was developed and validated in patients with early psychosis.Methods: Comprehensive review of IOR/DOR phenomena in the literature and pilot interviews were conducted for scale item development. Self-referential themes were summarized into 15 items. A consecutive sample of 137 outpatients with early psychosis was interviewed using IRIS. Their IOR/DOR experiences were also rated independently by clinicians on the Scale for the Assessment of Positive Symptoms (SAPS) and self-rated using the IOR subscale on the Schizotypal Personality Questionnaire (SPQ). Inter-rater reliability of IRIS was examined in a subsample of 15 participants.Results: IRIS demonstrated good internal consistency (Cronbach's alpha 0.80), inter-rater reliability (intraclass correlation coefficient 0.95), and divergent validity with other symptoms. IRIS correlated satisfactorily with the IOR/DOR item or subscale on SAPS and SPQ (Spearman's rho=0.71 and 0.47, respectively).Discussion: IRIS provided a reliable high-resolution tool for progressing single-symptom research into IOR/DOR, a potential target feature of schizophrenia. The scale allows future investigation into self-referential processing and detailed phenomenological comparison in different clinical, subclinical, and healthy populations.

Inhibition of return and schizophrenia: A meta-analysis - Corrected Proof

Aislin R. Mushquash, Jonathan M. Fawcett, Raymond M. Klein — 2012-01-09

Abstract: Inhibition of return (IOR) is a phenomenon that involves inhibited or delayed orienting to previously cued locations in favor of attending to novel locations. To date, research on IOR in patients with schizophrenia has generated mixed, and seemingly conflicting, results. Some researchers report patients with schizophrenia exhibit blunted or delayed IOR, while other researchers report normal IOR, in terms of time course and magnitude. This meta-analysis summarizes the literature that has employed an IOR task in patients with schizophrenia and with controls while focusing upon a procedural feature, the use of a cue back to fixation, between the cue and target that is known to be important when executive control has been hampered in non-clinical populations. Fifteen experiments were located yielding a total sample of 362 patients with schizophrenia or schizoaffective disorder and 285 controls. Using a meta-analytic approach, results of the present analyses show that patients with schizophrenia demonstrate delayed IOR in the single cue procedure. In the cue back to fixation procedure, the time course of IOR among patients is more consistent with that of controls. Differences in measured IOR between patients with schizophrenia and controls are largely related to a deficit in endogenous disengagement of attention.

HPA axis function and symptoms in adolescents at clinical high risk for schizophrenia - Corrected Proof

C.M. Corcoran, C. Smith, D. McLaughlin, A. Auther, D. Malaspina, B. Cornblatt — 2012-01-09

Abstract: Background: Stress sensitivity and HPA axis activity may be relevant to the development and expression of psychotic disorders. Cortisol secretion has been associated with positive symptoms both in patients with psychotic disorders and in young people at clinical risk for psychosis. Herein, we aimed to replicate these findings, to determine which positive symptoms may be associated with cortisol levels, and to explore any associations with affective symptoms and impaired stress tolerance.Methods: Thirty-one clinical high risk patients were evaluated in cross-section for associations between salivary cortisol levels upon clinic entry at 11am, demographic variables, and clinical symptoms.Results: Salivary cortisol levels were unrelated to medication exposure or demographics, except for higher levels in the ten females studied. Salivary cortisol bore no relationship to overall positive symptom severity but was associated with anxiety, as well as with suspiciousness and impaired stress tolerance, which were themselves highly intercorrelated.Conclusions: Cortisol secretion in the context of a putative novel social situation (i.e. clinic entry) may be a biological correlate of suspiciousness, impaired stress tolerance and affective symptoms in individuals vulnerable to developing psychosis. These associations are consistent with findings from experience sampling studies in individuals at risk for psychosis as well as basic studies of animal models of schizophrenia.

Abnormal connectivity between attentional, language and auditory networks in schizophrenia - Corrected Proof

2012-01-09

Abstract: Brain circuits involved in language processing have been suggested to be compromised in patients with schizophrenia. This does not only include regions subserving language production and perception, but also auditory processing and attention. We investigated resting state network connectivity of auditory, language and attention networks of patients with schizophrenia and hypothesized that patients would show reduced connectivity.Patients with schizophrenia (n=45) and healthy controls (n=30) underwent a resting state fMRI scan. Independent components analysis was used to identify networks of the auditory cortex, left inferior frontal language regions and the anterior cingulate region, associated with attention. The time courses of the components where correlated with each other, the correlations were transformed by a Fisher's Z transformation, and compared between groups.In patients with schizophrenia, we observed decreased connectivity between the auditory and language networks. Conversely, patients showed increased connectivity between the attention and language network compared to controls. There was no relationship with severity of symptoms such as auditory hallucinations.The decreased connectivity between auditory and language processing areas observed in schizophrenia patients is consistent with earlier research and may underlie language processing difficulties. Altered anterior cingulate connectivity in patients may be a correlate of habitual suppression of unintended speech, or of excessive attention to internally generated speech. This altered connectivity pattern appears to be present independent of symptom severity, and may be suggestive of a trait, rather than a state characteristic.

Hierarchical structure of the cognitive processes in schizophrenia: the fundamental role of processing speed - Corrected Proof

2012-01-09

Abstract: Objective: Decreased processing speed (PS) is a key feature of schizophrenia with respect to cognition, functional outcome and clinical symptoms. Our objective was to test whether PS slowing mediates other neuropsychological deficits among patients with chronic schizophrenia.Method: One hundred patients with schizophrenia and 53 healthy adults completed a series of neuropsychological measures that assess six cognitive domains. In addition to PS these included attention, verbal memory, visual memory, working memory, and executive functioning. Confirmatory factor analysis (CFA) was used to evaluate the fit of the 6-factor model. The cognitive performances of both groups were compared before and after controlling for the effect of PS, but also after controlling for the effect of each cognitive factor at a time. Finally, the PS-related variance was removed and the effect of the other cognitive factors was tested again.Results: CFA supported the hypothesized 6-factor cognitive structure. As expected, the patients and controls differed on all cognitive measures. However, after controlling for the effects of PS, group differences on the other five cognitive factors decreased substantially. Controlling for other factors produced smaller attenuation of group differences, and these effects were also partially accounted for by decreased PS.Conclusions: PS deficits account for most of the differences in cognition between patients with schizophrenia and healthy controls. PS slowing appears to be a core feature of schizophrenia, one that underlies impairments of working memory, executive functioning, and other abilities.

Decreased peripheral expression of neuregulin 1 in high-risk individuals who later converted to psychosis - Corrected Proof

Imre Kiss, Oguz Kelemen, Szabolcs Kéri — 2012-01-09

Efforts to identify individuals with high psychosis risk have focused on biological markers that show a marked association with later conversion to full-blown psychosis. found that a variant in the human neuregulin 1 (NRG1) promoter region is associated with increased development of psychotic symptoms in high-risk individuals. These results were replicated in a Hungarian sample (). NRG1 plays an important role in neurodevelopment and synaptic plasticity by the regulation of glutamatergic and gamma-amynobutiric acidergic (GABAergic) neurons, and its risk variants are related to altered gene expression in postmortem brain tissue (). Previous studies demonstrated decreased peripheral NRG1expression in schizophrenia (), but it is not clear whether these changes can reliably predict psychosis conversion in high-risk individuals.

Characteristics and clinical correlates of prospective memory performance in first-episode schizophrenia - Corrected Proof

2012-01-06

Abstract: Objective: The aim of this study was to examine prospective memory (PM) and its socio-demographic, clinical, and neurocognitive correlates in first episode schizophrenia (FES).Methods: Fifty-one FES patients and 42 healthy controls formed the study sample. Time- and event-based PM (TBPM and EBPM) performance were measured with the Chinese version of the Cambridge Prospective Memory Test (C-CAMPROMPT). A battery of neuropsychological tests was also administered. Patients' clinical symptoms were evaluated with the Positive and Negative Symptom Scale (PANSS).Results: Patients performed significantly worse in both TBPM (8.7±5.3 vs. 14.8±3.5) and EBPM (11.3±4.7 vs. 15.7±2.7) than the controls. After controlling for age, gender, education level and neurocognitive test score, the difference in performance on the two types of PM tasks between patients and controls was no longer present. In multiple linear regression analyses, longer duration of untreated psychosis (DUP), lower scores of the Hopkins Verbal Learning Test-Revised (HVLT-R) and the categories completed of the Wisconsin Card Sorting Test (WCST-CC) and higher score of the Color Trails Test-2 (CTT-2) contributed to poorer TBPM performance, while lower score of HVLT-R, higher score of the perseverative errors of the Wisconsin Card Sorting Test (WCST-PE) and longer DUP contributed to worse performance on EBPM.Conclusions: Both subtypes of PM are impaired in first-episode schizophrenia suggesting that PM deficits are an integral part of the cognitive dysfunction in the disease process.

The efficacy of supported employment for middle-aged and older people with schizophrenia - Corrected Proof

2011-12-26

Abstract: Objective: Supported employment is the evidence-based treatment of choice for assisting individuals with severe mental illness to achieve competitive employment, but few supported employment programs specifically target older clients with psychiatric illness. The purpose of this study was to evaluate the efficacy of supported employment for middle-aged or older people with schizophrenia.Method: Participants included 58 outpatients with schizophrenia or schizoaffective disorder aged 45 or older who were recruited from a community mental health clinic. Participants were randomly assigned to receive Individual Placement and Support (IPS; the manualized version of supported employment) or conventional vocational rehabilitation (CVR) for one year, and completed assessments at baseline, six months, and twelve months.Results: IPS was superior to CVR on nearly all work outcome measures, including attainment of competitive employment, weeks worked, and wages earned. Fifty-seven percent of IPS participants worked competitively, compared with 29% of CVR participants; 70% of IPS participants obtained any paid work, compared with 36% of CVR participants. Within the IPS group, better baseline functional capacity (as measured by the UCSD Performance Based Skills Assessment) and more recent employment were modestly associated with better work outcomes.Conclusions: Middle-aged and older adults with schizophrenia are good candidates for supported employment services.

Phonological versus semantic fluency: Key to pathophysiology? - Corrected Proof

Timothy J. Crow, Simon L. Collinson, Anthony C. James — 2011-12-22

Individuals at high risk of psychosis are reported by as having difficulty in retrieving words in response to categories but not to letters. This finding is documented in adolescent onset schizophrenia () and may be regarded as an established characteristic (). We wish to suggest the category-letter discrepancy, while not specific to psychosis, is also a lead to pathophysiology.

Adjunctive armodafinil for negative symptoms in adults with schizophrenia: A double-blind, placebo-controlled study - Corrected Proof

John M. Kane, Ronghua Yang, James M. Youakim — 2011-12-19

Abstract: Objective: A prior 4-week, proof-of-concept study suggested that adjunctive therapy with armodafinil 200mg/day decreases negative symptoms in patients with clinically stable schizophrenia. This study investigated the efficacy and tolerability of adjunctive armodafinil for treatment of negative symptoms in adults with schizophrenia receiving antipsychotic medications.Methods: This parallel-group, 24-week study enrolled adults with schizophrenia who were receiving oral olanzapine, risperidone, or paliperidone for ≥6weeks, and had a Positive and Negative Syndrome Scale (PANSS) negative symptom subscale score of ≥15. Patients received one of 3 doses of once-daily armodafinil (150mg, 200mg, or 250mg) or placebo. The primary efficacy measure was the change from baseline to final visit in the PANSS negative symptom subscale score. Secondary measures included the PANSS total score, Clinical Global Impression of Severity, Personal and Social Performance Scale, and CNSVitalSigns cognitive battery.Results: Of 285 randomized patients, 213 received armodafinil and 72 received placebo. The mean (SD) changes in PANSS negative symptom subscale score were −1.9 (3.8) for armodafinil 150mg (n=70), –2.3 (3.6) for armodafinil 200mg (n=69), –2.0 (3.3) for armodafinil 250mg (n=71), and −2.2 (4.1) for placebo (n=70) (p≥0.70 for each armodafinil group versus placebo). Secondary measures were generally not different between groups. Armodafinil was generally well tolerated, without worsening positive symptoms.Conclusions: This study found no benefit of adjunctive armodafinil versus placebo for negative symptoms in patients with schizophrenia receiving treatment with olanzapine, risperidone, or paliperidone. Armodafinil was generally well tolerated in these patients.

Context influences social cognitive judgments in paranoid individuals with schizophrenia - Corrected Proof

Amy E. Pinkham, Joseph Hopfinger, David L. Penn — 2011-12-16

We previously presented a study investigating neural activation during judgments of trustworthiness in non-paranoid individuals with schizophrenia (NP-SCZ), paranoid individuals with schizophrenia (P-SCZ), and healthy individuals (CON) (). During functional neuroimaging, participants viewed photos of faces and made dichotomous decisions of trustworthiness (i.e. trustworthy or untrustworthy) for each image. Analysis of these behavioral responses, provided in the original publication, demonstrated that P-SCZ, as compared to the other groups, rated significantly more faces as untrustworthy. However, individuals were also asked to make trustworthiness judgments about the same stimuli immediately following the MRI session. These additional ratings utilized the Likert-scale from −3 (not at all trustworthy) to +3 (very trustworthy) implemented in the original Trustworthiness/Approachability Task developed by . Our goal was to obtain ratings that would allow for a parametric examination of neural responses that increased or decreased according to varying levels of trustworthiness. While not our primary motivation, these ratings also permit examination of the potential role of testing context on behavioral responding by comparing ratings provided in the scanner to those provided out of the scanner. Effects of context on reaction time have previously been observed in imaging studies utilizing cognitive paradigms (), but to our knowledge, no studies have examined this issue in regard to social cognitive tasks or distinctions between paranoid and non-paranoid individuals with schizophrenia.

Olfactory processing, sex effects and heterogeneity in schizophrenia - Corrected Proof

2011-12-16

Abstract: Introduction: Smell identification deficits are associated with negative symptoms in schizophrenia, particularly in males. Far less information is known about the relationship of odor detection sensitivity (acuity) and negative symptoms in schizophrenia, and currently there is a dearth in sex-stratified research specifically examining odor sensitivity and smell identification.Methods: Fifty-eight individuals with schizophrenia and 42 healthy comparison subjects were assessed on tests of odor sensitivity, smell identification and cognition. Negative symptoms were assessed with the Positive and Negative Syndrome Scale and the Schedule for the Deficit Syndrome.Results: In healthy males, increased odor detection sensitivity predicted better smell identification scores. In contrast, male schizophrenia patients showed a significant inverse relationship, in which increased odor sensitivity predicted lower smell identification scores. Odor sensitivity and smell identification were unrelated in both schizophrenia and healthy females. Olfactory processing was strongly linked to negative symptoms, but the relationships differed by sex. Emotional expression deficits were related to odor detection hypersensitivity in female patients, whereas smell identification deficits predicted these emotional deficits in male cases.Conclusion: Sex differences in olfactory functioning were identified in healthy subjects and in schizophrenia patients. Smell identification was related to negative symptoms in males with schizophrenia, whereas odor detection sensitivity predicted these features in females. Sex differences should be considered in future analyses that employ odor stimuli for neuropsychiatric research.

Effect of the neuroprotective peptide davunetide (AL-108) on cognition and functional capacity in schizophrenia - Corrected Proof

2011-12-14

Abstract: Background: Cognitive dysfunction is a key predictor of functional disability in schizophrenia. Davunetide (AL-108, NAP) is an intranasally administered peptide currently being developed for treatment of Alzheimer's disease and related disorders. This study investigates effects of davunetide on cognition in schizophrenia.Method: Sixty-three subjects with schizophrenia received davunetide at one of two different doses (5, 30mg) or placebo for 12weeks in a multicenter, double-blind, parallel-group randomized clinical trial. The MATRICS Consensus Cognitive Battery (MCCB) assessed cognitive effects. The UCSD Performance-based Skills Assessment (UPSA) and the Schizophrenia Cognition Rating Scale (SCoRS) assessed functional capacity. Subjects continued their current antipsychotic treatment during the trial.Results: There were no significant differences in MCCB change between davunetide and placebo over the three treatment arms (p=.45). Estimated effect-size (d) values were .34 and .21 favoring the 5 and 30mg doses vs. placebo, respectively. For UPSA, there was a significant main effect of treatment across study arms (p=.048). Between-group effect size (d) values were.74 and .48, favoring the 5 and 30mg doses, respectively. No significant effects were observed on the SCoRS or on symptom ratings. No significant side effects or adverse events were observed.Conclusion: Davunetide was well tolerated. Effects of davunetide on MCCB-rated cognition were not significant relative to placebo. In contrast, a significant beneficial effect was detected for the UPSA. Based upon effect-size considerations, sample sizes of at least 45–50 subjects/group would be required to obtain significant effects on both MCCB and UPSA, providing guidance for continued clinical development in schizophrenia.

Predictive power of attenuated psychosis syndrome: Is it really low? The case of mild cognitive impairment - Corrected Proof

Paolo Fusar-Poli, Stefan Borgwardt — 2011-12-14

Over the past years, interest in the prodromal psychosis area has grown to the extent that there is an on-going debate about including a new psychosis diagnostic category in DSM5 () (Attenuated Psychosis Syndrome, APS). A key finding to emerge from work in this area is that while people presenting with APS features have a greatly increased risk of developing a psychotic disorder within a relatively short period, only a minority will do so. In a recent meta-analysis, the risk of developing a psychotic episode was 18% at six months, 22% at one year, 29% at two years, and 36% after three years (). As the majority of APS subject will not develop a psychotic episode over the follow-up time, there are great concerns about the high number of false positives who are not actually at risk of psychotic disorder (). However, the only other risk syndrome that seems ready for consideration for DSM5 is the dementia risk syndrome (known as mild cognitive impairment, MCI), conversion rate to dementia is 12% per year (), comparable to the risk of developing a psychotic episode within two years since first presentation of APS symptoms ().

Spatial memory deficits in a virtual reality eight-arm radial maze in schizophrenia - Corrected Proof

2011-12-12

Abstract: Learning and memory impairments are present in schizophrenia (SZ) throughout the illness course and predict psychosocial function. Abnormalities in prefrontal and hippocampal function are thought to contribute to SZ deficits. The radial arm maze (RAM) is a test of spatial learning and memory in rodents that relies on intact prefrontal and hippocampal function. The goal of the present study was to investigate spatial learning in SZ using a virtual RAM. Thirty-three subjects with SZ and thirty-nine healthy controls (HC) performed ten trials of a virtual RAM task. Subjects attempted to learn to retrieve four rewards each located in separate arms. As expected, subjects with SZ used more time and traveled more distance to retrieve rewards, made more reference (RM) and working memory (WM) errors, and retrieved fewer rewards than HC. It is important to note that the SZ group did learn but did not reach the level of HC. Whereas RM errors decreased across trials in the SZ group, WM errors did not. There were no significant relationships between psychiatric symptom severity and maze performance. To our knowledge, use of a virtual 8-arm radial maze task in SZ to assess spatial learning is novel. Impaired virtual RAM performance in SZ is consistent with studies that examined RAM performance in animal models of SZ. Results provide further support for compromised prefrontal and hippocampal function underlying WM and RM deficits in SZ. The virtual RAM task could help bridge preclinical and clinical research for testing novel drug treatments of SZ.

Interactive effects of background facial emotion stimulus and target salience on sustained attention performance in schizophrenia - Corrected Proof

2011-12-06

Abstract: Schizophrenia impairs both facial emotion processing and sustained attention. Through separate studies, it is known that the presence of a task-irrelevant facial stimulus disproportionately interferes with performance, whereas increasing the salience of task stimulus improves performance during a sustained attention task in patients with schizophrenia. We wished to investigate a potential interaction effect of background facial emotion expression (black and white happy faces vs. grey oval) and target stimulus salience (bright white vs. grey) using the Continuous Performance Test-Identical Pairs version (CPT-IP) in patients with schizophrenia. Thirty-six patients with schizophrenia and 28 healthy control subjects completed 4 different versions of the CPT-IP. We found that healthy controls exhibited higher signal detection sensitivity (d′) when salient target stimuli were presented on the facial background than when the same stimuli were presented on the grey-oval background. By contrast, patients were not affected by background stimuli when target number stimuli were salient. When target number stimuli were not salient, both patients and controls showed higher d′ in the grey-oval background condition compared with the facial background condition. This study highlight the significance of stimulus salience during CPT-IP in schizophrenia as background stimuli did not produce a differential effect on performance. Our results suggest that, in the situations where facial emotion stimuli are present, patients' sustained attention can be deteriorated and that the use of salient materials is important in improving performance in schizophrenia.

The association between self-disorders and neurocognitive dysfunction in schizophrenia - Corrected Proof

2011-12-05

Abstract: Background: Neurocognitive deficits and self-disorders (i.e. altered basic self-awareness or — sense of self) have both been suggested as fundamental trait features of schizophrenia. However, no study until now has investigated the relationship between these two core features.Aim: To investigate the relationship between self-disorders and neurocognitive performance in patients with schizophrenia.Method: Self-disorders were assessed in 57 patients in the early phase of schizophrenia by means of the Examination of Anomalous Self-Experience (EASE) instrument. The neurocognitive assessments included measures of psychomotor speed, working memory, executive- and memory functions.Results: There were few associations between self-disorders and neurocognitive impairments. However, high levels of SDs were significantly associated with impaired verbal memory.Conclusion: The reason for the general lack of associations between self-disorders and neurocognition could be that they represent different basic features of the illness. Verbal memory may however be linked to deficits in the patients' ability to comprehend, direct, remember and reason about their thoughts, functions that are intimately related to the basic sense of self.

Are there specific neuropsychological deficits underlying poor insight in first episode psychosis? - Corrected Proof

2011-12-05

Abstract: Insight in psychosis is a multi-dimensional phenomenon, and has been hypothesised to have some sort of neuropsychological basis. It is unclear to what extent specific neuropsychological abilities are able to predict insight beyond the effect of generalised cognitive ability. We aimed to test this association, alongside the relationship of insight with illness duration and diagnosis, in a sample of first episode psychosis patients. 110 first episode psychosis patients were recruited and a comprehensive assessment was administered, including insight, symptoms, diagnosis and neuropsychological function. Low insight was related to worse performance in a variety of neuropsychological tasks. Regression analysis tested whether any specific tasks were related to insight (or dimensions of insight) beyond the effect of IQ. Verbal memory had an effect on total insight and all dimensions of insight (except compliance) beyond the effect of IQ. Insight appeared to vary with diagnosis, with those diagnosed with depressive affective psychoses having better insight than those with manic affective psychoses. There was no relationship between insight and DUP, but there was a relationship between time spent in treatment before assessment and insight, even after controlling for severity of symptoms. These results suggest a model of insight in early psychosis with a significant neuropsychological component, particularly with verbal memory but also with generalised cognitive ability. There is likely to be a social component to insight affected by initial time spent in contact with treatment, helping patients to understand and come to terms with their illness.

Randomized controlled trial of peer-led recovery education using Building Recovery of Individual Dreams and Goals through Education and Support (BRIDGES) - Corrected Proof

2011-11-30

Abstract: Objective: The purpose of this study was to test the efficacy of a peer-led, mental illness education intervention called Building Recovery of Individual Dreams and Goals through Education and Support (BRIDGES).Method: Subjects were recruited from outpatient community mental health settings in eight Tennessee communities. Using a single-blind, randomized controlled trial design, 428 individuals with serious mental illness (SMI) were interviewed at baseline and assigned to BRIDGES or to a services as usual wait list control condition. Two-and-one-half hour classes were taught once a week for 8weeks by peers who were certified BRIDGES instructors. Subjects were followed-up at immediate post-intervention and 6-months later. The primary outcome was self-perceived recovery, measured by the Recovery Assessment Scale (RAS). A secondary outcome was hopefulness as assessed by the State Hope Scale (SHS). An exploratory hypothesis examined the impact of depressive symptoms on both recovery outcomes.Results: Eighty six percent of participants were followed up. On average, participants attended five sessions. Intent-to-treat analysis using mixed-effects random regression found that, compared to controls, intervention participants reported: 1) significantly greater improvement in total RAS scores as well as subscales measuring personal confidence and tolerable symptoms; and 2) significantly greater improvement in hopefulness as assessed by the agency subscale of the SHS. While study subjects with high levels of depressive symptoms had significantly poorer outcomes, outcomes were superior for BRIDGES participants regardless of depressive symptoms.Conclusions: Peer-led mental illness education improves participants' self-perceived recovery and hopefulness over time, even controlling for severity of depressive symptoms.

Independent estimation of the frequency of rare CNVs in the UK population confirms their role in schizophrenia - Corrected Proof

2011-11-30

Abstract: Background: Several large, rare chromosomal copy number variants (CNVs) have recently been shown to increase risk for schizophrenia and other neuropsychiatric disorders including autism, ADHD, learning difficulties and epilepsy.Aims: We wanted to examine the frequencies of these schizophrenia-associated variants in a large sample of individuals with non-psychiatric illnesses to better understand the robustness and specificity of the association with schizophrenia.Methods: We used Affymetrix 500K microarray data from 10,259 individuals from the UK Wellcome Trust Case Control Consortium (WTCCC) who are affected with six non-psychiatric disorders (coronary artery disease, Crohn's disease, hypertension, rheumatoid arthritis, types 1 and 2 diabetes) to establish the frequencies of nine CNV loci strongly implicated in schizophrenia, and compared them with the previous findings.Results: Deletions at 1q21.1, 3q29, 15q11.2, 15q13.1 and 22q11.2 (VCFS region), and duplications at 16p11.2 were found significantly more often in schizophrenia cases, compared with the WTCCC reference set. Deletions at 17p12 and 17q12, were also more common in schizophrenia cases but not significantly so, while duplications at 16p13.1 were found at nearly the same rate as in previous schizophrenia samples. The frequencies of CNVs in the WTCCC non-psychiatric controls at three of the loci (15q11.2, 16p13.1 and 17p12) were significantly higher than those reported in previous control populations.Conclusions: The evidence for association with schizophrenia is compelling for six rare CNV loci, while the remaining three require further replication in large studies. Risk at these loci extends to other neurodevelopmental disorders but their involvement in common non-psychiatric disorders should also be investigated.

Intact motivated attention in schizophrenia: Evidence from event-related potentials - Corrected Proof

William P. Horan, Dan Foti, Greg Hajcak, Jonathan K. Wynn, Michael F. Green — 2011-11-30

Abstract: Emotionally significant stimuli typically capture attention (called motivated attention) even when they are irrelevant to tasks where attention is directed. Previous studies indicate that several components of emotional processing are intact in schizophrenia when subjects are instructed to attend to emotionally-evocative stimuli. However, few studies have examined whether emotional stimuli capture attention to a normal degree in people with schizophrenia when attention is directed elsewhere. The current event-related potential study examined motivated attention to task-irrelevant emotional stimuli in 35 stabilized outpatients and 26 healthy controls with a modified visual P300 oddball detection task. Participants viewed images of rare target and commonly occurring standard letter stimuli, as well as intermixed emotional (unpleasant, pleasant, neutral) pictures. Subjects were instructed to count the number of rare targets; the emotional valence of the picture stimuli was, therefore, task-irrelevant. We separately evaluated the Early Posterior Negativity (EPN) and Late Positive Potential (LPP) to emotional pictures and the P300 to target stimuli. Patients and controls showed similar patterns of EPN and LPP amplitude to the emotional stimuli, such that the EPN and LPP were larger for both pleasant and unpleasant versus neutral pictures. Although patients performed worse than controls on the target counting task, both groups showed comparable P300 differentiation between target versus non-target stimuli. Emotional stimuli captured attentional resources in people with schizophrenia even when the emotional stimuli were task-irrelevant, suggesting intact motivated attention at the level of early electrophysiological responding.

Differential patterns of premorbid social and academic deterioration in deficit and nondeficit schizophrenia - Corrected Proof

2011-11-30

Abstract: Numerous studies indicate that social dysfunction is associated with negative symptoms of schizophrenia during the chronic phase of illness. However, it is unclear whether social abnormalities exist during the premorbid phase in people who later develop schizophrenia with prominent negative symptoms, or whether social functioning becomes progressively worse in these individuals from childhood to late adolescence. The current study examined differences in academic and social premorbid functioning in people with schizophrenia meeting criteria for deficit (i.e., primary and enduring negative symptoms) (DS: n=74) and non-deficit forms of schizophrenia (ND: n=271). Premorbid social and academic functioning was assessed for childhood, early adolescence, and late adolescence developmental periods on the Premorbid Adjustment Scale (PAS). Results indicated that both DS and ND participants showed deterioration in social and academic functioning from childhood to late adolescence. However, while ND schizophrenia demonstrated greater deterioration of academic compared to social premorbid functioning from childhood to late adolescence, the DS group exhibited comparable deterioration across both premorbid domains, with more severe social deterioration than the ND group. Findings suggest that people with DS show poorer social premorbid adjustment than those with ND as early as childhood, and are particularly susceptible to accelerated deterioration as the onset of schizophrenia becomes imminent. Thus, poor premorbid social adjustment and significant social deterioration from childhood to adolescence may be a hallmark feature of people who later go on to develop prominent negative symptoms and a unique marker for the DS subtype of schizophrenia.

Reduced source activity of event-related potentials for affective facial pictures in schizophrenia patients - Corrected Proof

Hyung-Tae Jung, Do-Won Kim, Sangrae Kim, Chang-Hwan Im, Seung-Hwan Lee — 2011-11-28

Abstract: The ability to recognize facial affect is impaired in schizophrenia patients. This study compared source activities of the event-related potentials (ERPs) for affective facial pictures between schizophrenia patients and healthy controls. Twenty-three schizophrenia patients (11 females) and 24 healthy controls (12 females) were recruited. The standardized low-resolution brain electromagnetic tomography (sLORETA) source activities of four ERP components (P100, N170, N250, and P300) were compared between schizophrenia patients and healthy controls in response to fearful, happy, and neutral facial expressions. Group differences of sLORETA source activities were found only for the N170 component in response to the fearful face. Source activities in the middle frontal gyrus and inferior frontal gyrus were lower in schizophrenia patients compared to healthy controls. Source activity in the insula was lower in male schizophrenia patients compared to male healthy controls. Source activities in the superior temporal gyrus, middle temporal gyrus, insula and inferior frontal gyrus were lower in male compared to female schizophrenia patients. However, there was no gender difference on ERP source activities in the healthy controls. These results support the hypothesis that schizophrenia patients have reduced N170 current source density in response to fearful faces. The area exhibiting reduced current source density includes the frontal and temporal cortex. The present results suggest that there may be gender differences in facial affect processing in schizophrenia patients.

The role of endogenous neurotensin in psychostimulant-induced disruption of prepulse inhibition and locomotion - Corrected Proof

Ricardo Cáceda, Elisabeth B. Binder, Becky Kinkead, Charles B. Nemeroff — 2011-11-21

Abstract: The neuropeptide neurotensin (NT) is closely associated with dopaminergic and glutamatergic systems in the rat brain. Central injection of NT into the nucleus accumbens (NAcc) or peripheral administration of NT receptor agonists, reduces many of the behavioral effects of psychostimulants. However, the role of endogenous NT in the behavioral effects of psychostimulants (e.g. DA agonists and NMDA receptor antagonists) remains unclear. Using a NTR antagonist, SR142948A, the current studies were designed to examine the role of endogenous NT in DA receptor agonist- and NMDA receptor antagonist-induced disruption of prepulse inhibition of the acoustic startle response (PPI), locomotor hyperactivity and brain-region specific c-fos mRNA expression. Adult male rats received a single i.p. injection of SR142948A or vehicle followed by d-amphetamine, apomorphine or dizocilpine challenge. SR142948A had no effect on baseline PPI, but dose-dependently attenuated d-amphetamine- and dizocilpine-induced PPI disruption and enhanced apomorphine-induced PPI disruption. SR142948A did not significantly affect either baseline locomotor activity or stimulant-induced hyperlocomotion. Systemic SR142948A administration prevented c-fos mRNA induction in mesolimbic terminal fields (prefrontal cortex, lateral septum, NAcc, ventral subiculum) induced by all three psychostimulants implicating the VTA as the site for NT modulation of stimulant-induced PPI disruption. Further characterization of the NT system may be valuable to find clinical useful compounds for schizophrenia and drug addiction.