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Schizotypy represents an index of psychosis-proneness in the general population often associated with childhood trauma exposure. Both schizotypy and childhood trauma are linked to structural brain alterations, and it is possible that trauma exposure moderates the extent of brain morphological differences associated with schizotypy. We addressed this question using data from a total of 1,182 healthy adults (age range: 18-65 years old, 647 females/535 males), pooled from nine sites worldwide, contributing to the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Schizotypy working group. All participants completed both the Schizotypal Personality Questionnaire Brief version (SPQ-B), and the Childhood Trauma Questionnaire (CTQ), and underwent a 3D T1-weighted brain MRI scan from which regional indices of subcortical grey matter volume and cortical thickness were determined. A series of multiple linear regressions revealed that differences in cortical thickness in four regions-of-interest were significantly associated with interactions between schizotypy and trauma; subsequent moderation analyses indicated that increasing levels of schizotypy were associated with thicker left caudal anterior cingulate gyrus, right middle temporal gyrus and insula, and thinner left caudal middle frontal gyrus, in people exposed to higher (but not low or average) levels of childhood trauma. This was found in the context of thicker bilateral medial orbitofrontal gyri, right rostral anterior cingulate gyrus, left temporal pole, left insula, and thinner left paracentral lobule directly associated with increasing levels of schizotypy. In addition, thinner left postcentral, superior parietal and lingual gyri, as well as thicker left caudal middle frontal gyrus and smaller left thalamus and right caudate were associated with increasing levels of childhood trauma exposure. These results suggest that alterations in brain regions critical for higher cognitive and integrative processes that are associated with schizotypy may be enhanced in individuals exposed to high levels of trauma.

BACKGROUND: Cognitive deficits, particularly in processing speed, are widely recognized as a critical feature of schizophrenia, and are also present across schizophrenia spectrum disorders. A number of important confounders, however, such as hospitalization effects and antipsychotic medication, have been shown to affect processing speed, causing debate as to the core cognitive deficits of schizophrenia. The study of individuals who are not clinically psychotic but have schizotypal traits allows investigation of cognitive deficits associated with both positive and negative schizotypy dimensions while excluding potential confounds. METHODS: A population-based community sample of 242 healthy adult volunteers assessed using the Structured Interview of Schizotypy – Revised (SIS-R) scale, and a neuropsychological testing battery that included measures of verbal ability, visual and verbal memory, verbal fluency, working memory, executive functions and processing speed. Participants were classified in High or Low Positive Schizotypy (H-PST or L-PST), High or Low Paranoia-like traits (H-PAR or L-PAR) and High or Low Negative Schizotypy (H-NST or L-NST) groups, respectively. RESULTS: Individuals with H-PST performed significantly (p

Neuroanatomical abnormalities have been reported along a continuum from at-risk stages, including high schizotypy, to early and chronic psychosis. However, a comprehensive neuroanatomical mapping of schizotypy remains to be established. The authors conducted the first large-scale meta-analyses of cortical and subcortical morphometric patterns of schizotypy in healthy individuals, and compared these patterns with neuroanatomical abnormalities observed in major psychiatric disorders. The sample comprised 3004 unmedicated healthy individuals (12–68 years, 46.5% male) from 29 cohorts of the worldwide ENIGMA Schizotypy working group. Cortical and subcortical effect size maps with schizotypy scores were generated using standardized methods. Pattern similarities were assessed between the schizotypy-related cortical and subcortical maps and effect size maps from comparisons of schizophrenia (SZ), bipolar disorder (BD) and major depression (MDD) patients with controls. Thicker right medial orbitofrontal/ventromedial prefrontal cortex (mOFC/vmPFC) was associated with higher schizotypy scores (r = 0.067, pFDR = 0.02). The cortical thickness profile in schizotypy was positively correlated with cortical abnormalities in SZ (r = 0.285, pspin = 0.024), but not BD (r = 0.166, pspin = 0.205) or MDD (r = −0.274, pspin = 0.073). The schizotypy-related subcortical volume pattern was negatively correlated with subcortical abnormalities in SZ (rho = −0.690, pspin = 0.006), BD (rho = −0.672, pspin = 0.009), and MDD (rho = −0.692, pspin = 0.004). Comprehensive mapping of schizotypy-related brain morphometry in the general population revealed a significant relationship between higher schizotypy and thicker mOFC/vmPFC, in the absence of confounding effects due to antipsychotic medication or disease chronicity. The cortical pattern similarity between schizotypy and schizophrenia yields new insights into a dimensional neurobiological continuity across the extended psychosis phenotype.

Background: Cognitive flexibility deficits are present in patients with schizophrenia and are strong predictors of functional outcome but, as yet, have no pharmacological treatments. Aims: The purpose of this study was to investigate whether the phosphodiesterase type-4 inhibitor, roflumilast, can improve cognitive flexibility performance and functional brain activity in patients with schizophrenia. Methods: This was a within-subject, randomised, double-blind, placebo-controlled, three-period crossover study using a version of the Intradimensional/Extradimensional (ID/ED) task, optimised for functional magnetic resonance imaging (fMRI), in 10 patients with schizophrenia who were scanned after receiving placebo, 100 µg or 250 µg roflumilast for 8 consecutive days. Data from an additional fMRI ID/ED study of 18 healthy participants on placebo was included to contextualise the schizophrenia-related performance and activations. The fMRI analyses included a priori driven region of interest (ROI) analysis of the dorsal frontoparietal attention network. Results: Patients on placebo demonstrated broad deficits in task performance compared to the healthy comparison group, accompanied by preserved network activity for solution search, but reduced activity in left ventrolateral prefrontal cortex (VLPFC) and posterior parietal cortex for attentional set-shifting and reduced activity in left dorsolateral prefrontal cortex (DLPFC) for reversal learning. These ROI deficits were ameliorated by 250 µg roflumilast, whereas during solution search 100 µg roflumilast reduced activity in the left orbitofrontal cortex, right DLPFC and bilateral PPC, which was associated with an improvement in formation of attentional sets. Conclusions: The results suggest roflumilast has dose-dependent cognitive enhancing effects on the ID/ED task in patients with schizophrenia, and provides sufficient support for larger studies to test roflumilast’s role in improving cognitive flexibility deficits in this clinical population.

Rationale Schizophrenia is associated with impairments in cognitive functioning yet there are no approved drugs to treat these deficits. Objectives Based on animal models, we investigated the potential for roflumilast, a selective inhibitor of phosphodiesterase type 4 (PDE4), to improve cognition, which may act by increasing intracellular cyclic adenosine monophosphate in brain regions underlying cognitive deficits in schizophrenia. Methods This study consisted of a randomised, double-blind, placebo-controlled, crossover design involving 15 schizophrenia patients. In 3 treatment periods, patients were given 8 days of placebo or one of the two doses of roflumilast (100 and 250 μg daily) with 14 days of washout between treatments. The primary endpoints were dorsolateral prefrontal cortex (DLPFC) activation during a visuospatial working memory task measured with fMRI on dosing day 8 and verbal memory and working memory performance change from baseline to day 8. Least square mean change scores were calculated for behavioural outcomes; fMRI data were analysed in SPM12 with bilateral DLPFC as regions of interest. Results Verbal memory was significantly improved under 250 μg roflumilast (effect size (ES) = 0.77) compared to placebo. fMRI analyses revealed that increasing dose of roflumilast was associated with reduction of bilateral DLPFC activation during working memory compared to placebo, although this was not statistically significant (ES = 0.31 for the higher dose). Working memory was not improved (ES = 0.03). Conclusions Results support the mechanistic validation of potential novel strategies for improving cognitive dysfunction in schizophrenia and suggest that PDE4 inhibition may be beneficial for cognitive dysfunction in schizophrenia. Trial registration NCT02079844.

Neuroanatomical abnormalities have been reported along a continuum from at-risk stages, including high schizotypy, to early and chronic psychosis. However, a comprehensive neuroanatomical mapping of schizotypy remains to be established. The authors conducted the first large-scale meta-analyses of cortical and subcortical morphometric patterns of schizotypy in healthy individuals, and compared these patterns with neuroanatomical abnormalities observed in major psychiatric disorders. The sample comprised 3,004 unmedicated healthy individuals (12-68 years, 46.5% male) from 29 cohorts of the worldwide ENIGMA Schizotypy working group. Cortical and subcortical effect size maps with schizotypy scores were generated using standardized methods. Pattern similarities were assessed between the schizotypy-related cortical and subcortical maps and effect size maps from comparisons of schizophrenia (SZ), bipolar disorder (BD) and major depression (MDD) patients with controls. Thicker right medial orbitofrontal/ventromedial prefrontal cortex (mOFC/vmPFC) was associated with higher schizotypy scores (r=.07, pFDR=.02). The cortical thickness profile in schizotypy was positively correlated with cortical abnormalities in SZ (r=.33, pspin=.01), but not BD (r=.19, pspin=.16) or MDD (r=-.22, pspin=.10). The schizotypy-related subcortical volume pattern was negatively correlated with subcortical abnormalities in SZ (rho=-.65, pspin=.01), BD (rho=-.63, pspin=.01), and MDD (rho=-.69, pspin=.004). Comprehensive mapping of schizotypy-related brain morphometry in the general population revealed a significant relationship between higher schizotypy and thicker mOFC/vmPFC, in the absence of confounding effects due to antipsychotic medication or disease chronicity. The cortical pattern similarity between schizotypy and schizophrenia yields new insights into a dimensional neurobiological continuity across the extended psychosis phenotype.

Background The coronavirus disease 2019 (COVID-19) pandemic has had a significant psychological impact on healthcare workers (HCWs). Aims There is an urgent need to understand the risk and protective factors associated with poor mental well-being of UK HCWs working during the COVID-19 pandemic. Method Shortly after the April 2020 UK COVID-19 peak 2773 HCWs completed a survey containing measures of anxiety, depression, post-traumatic stress disorder and stress, as well as questions around potential predictors such as roles, COVID-19 risk perception and workplace-related factors. Respondents were classified as high or low symptomatic on each scale and logistic regression revealed factors associated with severe psychiatric symptoms. Change in well-being from pre- to during COVID-19 was also quantified. Results Nearlya third of HCWs reported moderate to severe levels of anxiety and depression, and the number reporting very high symptoms was more than quadruple that pre-COVID-19. Several controllable factors were associated with the most severe level of psychiatric symptoms: insufficient personal protective equipment availability, workplace preparation, training and communication, and higher workload. Being female, ‘front line’, previous psychiatric diagnoses, traumatic events, and being an allied HCW or manager were also significantly associated with severe psychiatric symptoms. Sharing stress, resilience and ethical support for treatment decisions were significantly associated with low psychiatric symptoms. Front-line workers showed greater worsening of mental health compared with non-front-line HCWs. Conclusions Poor mental well-being was prevalent during the COVID-19 response, however, controllable factors associated with severe psychiatric symptoms are available to be targeted to reduce the detrimental impact of COVID-19 and other pandemics on HCW mental health.

BackgroundThere is an urgent need to understand the psychological impact the COVID-19 pandemic has had on UK healthcare workers (HCW).AimsTo reveal risk and protective factors associated with poor mental wellbeing of HCW working during the COVID-19 pandemic in the UK.Method2773 UK HCWs completed a survey between 22ndApril and 10th May 2020 containing scales measuring anxiety, depression, PTSD, and stress, and questions about roles and COVID-19-related factors including workplace preparation and risk management. Respondents were classified as high or low symptomatic on each mental health scale and logistic regression revealed risk and protective factors associated with each outcome. Change in wellbeing from pre to during COVID-19 was also quantified.ResultsA large proportion of UK HCW had high mental health symptoms. ‘Fixed’ risk factors of poor mental health included being female, being ‘frontline’, pre-existing mental health diagnoses, and experience of stressful/traumatic events. An additional set of ‘controllable’ factors also significantly increased risk: PPE availability, workload, lack of COVID-19 preparation and training, and insufficient communication of clinical procedures. Resilience and sharing stress reduced risk, as did ethical support for those making treatment decisions. Allied HCW and managers were at elevated risk of high symptoms particularly PTSD. Wellbeing, especially of frontline workers, had significantly worsened compared to before COVID-19.ConclusionsPoor mental wellbeing was prevalent in HCW during the UK COVID-19 response. A number of controllable factors should be targeted, and protective factors promoted, to reduce the detrimental effect of COVID-19 and other pandemics on HCW mental health.

Background: Patients with schizophrenia have significant cognitive deficits, which may profoundly impair quality of life. These deficits are also evident at the neurophysiological level with patients demonstrating altered event-related potential in several stages of cognitive processing compared to healthy controls; within the auditory domain, for example, there are replicated alterations in Mismatch Negativity, P300 and Auditory Steady State Response. However, there are no approved pharmacological treatments for cognitive deficits in schizophrenia. Aims: Here we examine whether the phosphodiesterase-4 inhibitor, roflumilast, can improve neurophysiological deficits in schizophrenia. Methods: Using a randomised, double-blind, placebo-controlled, crossover design study in 18 patients with schizophrenia, the effect of the phosphodiesterase-4 inhibitor, roflumilast (100 µg and 250 µg) on auditory steady state response (early stage), mismatch negativity and theta (intermediate stage) and P300 (late stage) was examined using electroencephalogram. A total of 18 subjects were randomised and included in the analysis. Results: Roflumilast 250 µg significantly enhanced the amplitude of both the mismatch negativity ( p=0.04) and working memory-related theta oscillations ( p=0.02) compared to placebo but not in the other (early- or late-stage) cognitive markers. Conclusions: The results suggest that phosphodiesterase-4 inhibition, with roflumilast, can improve electroencephalogram cognitive markers, which are impaired in schizophrenia, and that phosphodiesterase-4 inhibition acts at an intermediate rather than early or late cognitive processing stage. This study also underlines the use of neurophysiological measures as cognitive biomarkers in experimental medicine.

Background Negative symptoms can be seen to represent a continuum from subclinical manifestations in the general population to severe symptoms in schizophrenia. Neuroanatomical studies show evidence of fronto-striatal structural abnormalities linked to negative symptoms in patients with schizophrenia (Walton et al. 2018). However, it remains an open question whether these structural associations are also observed in ostensibly healthy individuals reporting subclinical negative symptoms. The present study used structural T1-weighted brain imaging data from the ENIGMA Schizotypy Working Group to investigate the relationship between subclinical negative symptoms and fronto-striatal structural measures. Methods We included 2,235 healthy unmedicated individuals with varying levels of schizotypy from 17 centers around the world. The complete sample had a weighted mean (range) age of 29.2 (15.9–39.6) and 59.4% (51–100) were male. Subclinical negative symptoms were assessed at each site separately using factor scores from self-report schizotypy questionnaires (i.e., the Community Assessment of Psychic Experiences, the Oxford-Liverpool Inventory of Feelings and Experiences, or the Schizotypal Personality Questionnaire). Based on prior studies in schizophrenia, we obtained cortical thickness from 22 frontal regions-of-interest (ROIs) and subcortical volumes from 6 striatal ROIs using FreeSurfer. We performed meta-analyses of effect sizes (standardized regression coefficients) from a model predicting mean cortical thickness by subclinical negative symptom scores, adjusting for age, sex, and site. The same analysis was repeated for subcortical volumes including intracranial volume as additional covariate. Results Meta-analyses revealed significant positive associations between subclinical negative symptoms and cortical thickness of the left frontal pole (βstd=0.091; pFDR=0.009), right medial orbitofrontal cortex (βstd=0.083; pFDR=0.009) and right anterior cingulate cortex (βstd=0.07; pFDR=0.011). Discussion Using a large sample of healthy unmedicated individuals with varying levels of schizotypal personality traits, this ENIGMA meta-analysis showed that subclinical negative symptoms are associated with thicker prefrontal cortex. The present data are contrary to previous findings in schizophrenia, which demonstrates a relationship between negative symptoms and lower prefrontal cortical thickness (Walton et al. 2018). These divergent neural correlates suggest that thicker cortex could be a potential compensatory mechanism preventing individuals with schizotypy from the clinical manifestation of severe negative symptoms. Alternatively, greater prefrontal cortical thickness could also be associated with pathological processes along the negative symptom continuum prior to clinical manifestation.

Highlights • Controlled experiment on functional connectivity-based real-time fMRI neurofeedback. • Reduced anxiety levels in the experimental group after neurofeedback training. • Altered activity and connectivity in neurofeedback ROIs in the experimental group. • Increased resting state functional connectivity in the PCC in the experimental group., High levels of trait anxiety are associated with impaired attentional control, changes in brain activity during attentional control tasks and altered network resting state functional connectivity (RSFC). Specifically, dorsolateral prefrontal cortex to anterior cingulate cortex (DLPFC – ACC) functional connectivity, thought to be crucial for effective and efficient attentional control, is reduced in high trait anxious individuals. The current study examined the potential of connectivity-based real-time functional magnetic imaging neurofeedback (rt-fMRI-nf) for enhancing DLPFC – ACC functional connectivity in trait anxious individuals. We specifically tested if changes in DLPFC - ACC connectivity were associated with reduced anxiety levels and improved attentional control. Thirty-two high trait anxious participants were assigned to either an experimental group (EG), undergoing veridical rt-fMRI-nf, or a control group (CG) that received sham (yoked) feedback. RSFC (using resting state fMRI), anxiety levels and Stroop task performance were assessed pre- and post-rt-fMRI-nf training. Post-rt-fMRI-nf training, relative to the CG, the EG showed reduced anxiety levels and increased DLPFC-ACC functional connectivity as well as increased RSFC in the posterior default mode network. Moreover, in the EG, changes in DLPFC – ACC functional connectivity during rt-fMRI-nf training were associated with reduced anxiety levels. However, there were no group differences in Stroop task performance. We conclude that rt-fMRI-nf targeting DLPFC – ACC functional connectivity can alter network connectivity and interactions and is a feasible method for reducing trait anxiety.

Social decision-making is fundamental for successful functioning and can be affected in psychiatric illness and by serotoninergic modulation. The Prisoner's Dilemma is the archetypal paradigm to model cooperation and trust. However, the effect of serotonergic enhancement is poorly characterized, and its influence on the effect of variations in opponent behavior unknown. To address this, we conducted a study investigating how the serotonergic enhancer 3,4-methylenedioxy-methamphetamine (MDMA) modulates behavior and its neural correlates during an iterated Prisoner's Dilemma with both trustworthy and untrustworthy opponents. We administered 100 mg MDMA or placebo to 20 male participants in a double-blind, placebo-controlled, crossover study. While being scanned, participants played repeated rounds with opponents who differed in levels of cooperation. On each round, participants chose to compete or cooperate and were asked to rate their trust in the other player. Cooperation with trustworthy, but not untrustworthy, opponents was enhanced following MDMA but not placebo (respectively: odds ratio = 2.01; 95% CI, 1.42–2.84,p< 0.001; odds ratio = 1.37; 95% CI, 0.78–2.30, not significant). Specifically, MDMA enhanced recovery from, but not the impact of, breaches in cooperation. During trial outcome, MDMA increased activation of four clusters incorporating precentral and supramarginal gyri, superior temporal cortex, central operculum/posterior insula, and supplementary motor area. There was a treatment × opponent interaction in right anterior insula and dorsal caudate. Trust ratings did not change across treatment sessions. MDMA increased cooperative behavior when playing trustworthy opponents. Underlying this was a change in brain activity of regions linked to social cognition. Our findings highlight the context-specific nature of MDMA's effect on social decision-making.SIGNIFICANCE STATEMENTWe provide a detailed analysis of the effect of 3,4-methylenedioxy-methamphetamine (MDMA) on cooperative behavior during interpersonal interactions, as well as the neural correlates underlying these effects. We find that, following administration of MDMA, participants behave more cooperatively, but only when interacting with trustworthy partners. While breaches of trustworthy behavior have a similar impact following administration of MDMA compared with placebo, MDMA facilitates a greater recovery from these breaches of trust. Underlying this altered behavior are changes in brain activity during the viewing of opponents' behavior in regions whose involvement in social processing is well established. This work provides new insights into the impact of MDMA on social interactions, emphasizing the important role of the behavior of others toward us.

Background: Neuroanatomical abnormalities have been reported along a continuum from at-risk stages, including high schizotypy, to early and chronic psychosis. However, a comprehensive neuroanatomical mapping of schizotypy remains to be established. The authors conducted the first large-scale meta-analyses of cortical and subcortical morphometric patterns of schizotypy in healthy individuals and compared these patterns with neuroanatomical abnormalities observed in major psychiatric disorders. Methods: The sample comprised 2,952 unmedicated healthy individuals (12-68 years, 46.5% male) from 26 cohorts of the worldwide ENIGMA Schizotypy working group. Cortical and subcortical effect size maps with schizotypy scores were generated using standardized methods. Pattern similarities were assessed between the schizotypy-related cortical and subcortical maps and effect size maps from comparisons of schizophrenia (SZ), bipolar disorder (BD) and major depression (MDD) patients with controls. Results: Cortical thickness in the right medial orbitofrontal/ventromedial prefrontal cortex (mOFC/vmPFC) showed a significant positive correlation with schizotypy scores (r=.07, pFDR=.02). The cortical thickness profile in schizotypy was positively correlated with cortical abnormalities in SZ (r=.33, pspin=.01), but not BD (r=.19, pspin=.16) or MDD (r=-.22, pspin=.10). The schizotypy-related subcortical volume pattern was negatively correlated with subcortical abnormalities in SZ (rho=-.65, pspin=.01), BD (rho=-.63, pspin=.01), and MDD (rho=-.69, pspin=.004). Conclusions: Comprehensive mapping of schizotypy-related brain morphometry in the general population revealed a significant relationship between higher schizotypy and thicker mOFC/vmPFC, in the absence of confounding effects due to antipsychotic medication or disease chronicity. The cortical pattern similarity between schizotypy and schizophrenia yields new insights into a dimensional neurobiological continuity across the extended psychosis phenotype. Matthias Kirschner acknowledges support from the Swiss National Foundation (P2SKP3_178175).

Poor insight in schizophrenia has been linked to poor cognitive functioning, psychological processes such as denial, or more recently with impaired metacognitive capacity. Few studies, however, have investigated the potential co-dependency of multiple factors in determining level of insight, but such a model is necessary in order to account for patients with good cognitive functioning who have very poor awareness. As evidence suggests that set-shifting and cognitive insight (self-reflection (SR) and self-certainty) are strong predictors of awareness we proposed that these factors are key mediators in the relationship between cognition and awareness. We hypothesised that deficits specifically in SR and set-shifting determine level of awareness in the context of good cognition.Thirty schizophrenia patients were stratified by high and low awareness of illness and executive functioning scores. Cognitive insight, cognition, mood and symptom measures were compared between sub-groups.A low insight/high executive functioning (LI-HE) group, a high insight/high executive functioning (HI-HE) group and a low insight/low executive functioning (LI-LE) group were revealed. As anticipated, the LI-HE patients showed significantly lower capacity for SR and set-shifting than the HI-HE patients.This study indicates that good cognitive functioning is necessary but not sufficient for good awareness; good awareness specifically demands preserved capacity to self-reflect and shift-set. Results support Nelson and Narens' [1990. Metamemory: A theoretical framework and new findings. The Psychology of Learning and Motivation, 26, 125-173] model of metacognition by which awareness is founded on control (set-shifting) and monitoring (SR) processes. These specific factors could be targeted to improve insight in patients with otherwise unimpaired cognitive function.

Background Cortical neuroanatomical abnormalities have been reported along a continuum between individuals with chronic schizophrenia, first-episode psychosis, clinical high risk for psychosis, and healthy individuals self-reporting subclinical psychotic-like experiences (or schizotypy). Recently, the Schizophrenia Working Group within the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) consortium provided meta-analytic evidence for robust cortical thickness abnormalities in schizophrenia, while also indicating that these abnormalities are influenced by illness severity and treatment with antipsychotic medications. In this context, schizotypy research allows the investigation of cortical neuroanatomy associated with the expression of subclinical psychotic-like symptoms without the potential influence of a psychotic illness, its severity, or the use of antipsychotics. This study presents the first large-scale imaging meta-analysis of cortical thickness in schizotypy using standardized methods from 23 datasets worldwide. Methods Cortical thickness and surface area were assessed in MRI scans of 2,695 healthy individuals (mean [range] age of 29.1 [17–55.8], 46.3% male) who had also completed validated self-report schizotypy questionnaires. Each site processed their local T1-weighted MRI scans using FreeSurfer and, following the protocol outlined in the ENIGMA Schizophrenia Working Group study, extracted cortical thickness for 70 Desikan-Killiany (DK) atlas regions (34 regions per hemisphere + left and right hemisphere mean thickness). At each site, partial correlation analyses were performed between regional cortical thickness by ROI and total schizotypy scores in R, predicting the left, right and mean cortical thickness, adjusting for sex, age and site. Random-effects meta-analyses of partial correlation effect sizes for each of the DK atlas regions were performed using R’s metafor package. False discovery rate (pFDR < .05) was used to control for multiple comparisons. Results We found significant positive associations between subclinical psychotic-like experiences and mean cortical thickness of the medial orbitofrontal cortex (r = .077; pFDR = .006) and the frontal pole (r = .073; pFDR = .006). When assessed separately by hemisphere, meta-analysis revealed a significant positive association between subclinical psychotic-like experiences and cortical thickness of the left medial orbitofrontal cortex (r = .066; pFDR = .044), and at trend-level with the right medial orbitofrontal cortex (r = .062; pFDR = .053) and the left frontal pole (r = .062; pFDR = .053). No significant associations were observed for surface area. Discussion Worldwide cooperative analyses of large-scale brain imaging data support a profile of cortical thickness abnormalities involving prefrontal cortical regions positively related to schizotypy in healthy individuals. These findings are not secondary to potential influences of disease chronicity or antipsychotic medication on the neuroanatomical correlates of psychotic-like experiences. The directionality of the observed meta-analytical effects in schizotypy is opposite to those previously reported in patients with schizophrenia (i.e., thinner cortex). The present findings of increased thickness may indicate early microstructural deficits (e.g. in myelination) that contribute to vulnerability for psychosis. Alternatively, these may reflect mechanisms of resilience associated with the expression of subclinical manifestations of psychotic symptoms in otherwise healthy individuals.

Subjects with a diagnosis of schizophrenia (Scz) overweight unexpected evidence in probabilistic inference: such evidence becomes “aberrantly salient.” A neurobiological explanation for this effect is that diminished synaptic gain (e.g., hypofunction of cortical NMDARs) in Scz destabilizes quasi-stable neuronal network states (or “attractors”). This attractor instability account predicts that (1) Scz would overweight unexpected evidence but underweight consistent evidence, (2) belief updating would be more vulnerable to stochastic fluctuations in neural activity, and (3) these effects would correlate. Hierarchical Bayesian belief updating models were tested in two independent datasets (n= 80 male andn= 167 female) comprising human subjects with Scz, and both clinical and nonclinical controls (some tested when unwell and on recovery) performing the “probability estimates” version of the beads task (a probabilistic inference task). Models with a standard learning rate, or including a parameter increasing updating to “disconfirmatory evidence,” or a parameter encoding belief instability were formally compared. The “belief instability” model (based on the principles of attractor dynamics) had most evidence in all groups in both datasets. Two of four parameters differed between Scz and nonclinical controls in each dataset: belief instability and response stochasticity. These parameters correlated in both datasets. Furthermore, the clinical controls showed similar parameter distributions to Scz when unwell, but were no different from controls once recovered. These findings are consistent with the hypothesis that attractor network instability contributes to belief updating abnormalities in Scz, and suggest that similar changes may exist during acute illness in other psychiatric conditions.SIGNIFICANCE STATEMENTSubjects with a diagnosis of schizophrenia (Scz) make large adjustments to their beliefs following unexpected evidence, but also smaller adjustments than controls following consistent evidence. This has previously been construed as a bias toward “disconfirmatory” information, but a more mechanistic explanation may be that in Scz, neural firing patterns (“attractor states”) are less stable and hence easily altered in response to both new evidence and stochastic neural firing. We model belief updating in Scz and controls in two independent datasets using a hierarchical Bayesian model, and show that all subjects are best fit by a model containing a belief instability parameter. Both this and a response stochasticity parameter are consistently altered in Scz, as the unstable attractor hypothesis predicts.

BACKGROUND: Neuroanatomical studies have provided some evidence for a neurobiological continuity between psychotic symptoms in patients with schizophrenia and subclinical psychotic-like experiences as identified via self-report questionnaires (or schizotypy) in otherwise healthy individuals. Despite a number of structural brain imaging studies published in subjects with schizotypy, these have often been limited by relatively small sample sizes. This study represents the first meta-analysis of structural MRI scans in schizotypy assessed with standardized methods at 17 centres worldwide. METHODS: The total sample included in the case-control meta-analysis involved 496 subjects with high schizotypy and 588 comparison subjects with low schizotypy as identified with validated self-report schizotypy questionnaires (i.e., the Community Assessment of Psychic Experiences, the Oxford-Liverpool Inventory of Feelings and Experiences, or the Schizotypal Personality Questionnaire). Left and right lateral ventricle, thalamus, caudate, putamen, pallidum, accumbens, hippocampus and amygdala volumes, as well as intracranial volumes (ICV), were obtained with FreeSurfer from high-resolution T1-weighted structural brain scans locally by each site. Analyses of individual subject data were also performed by the site that contributed the sample, using code created within the ENIGMA collaboration. Group differences for each ROI within each sample were examined using univariate linear regression analysis in R predicting the left, right and mean subcortical volumes with group (low or high schizotypy) controlling for age, sex, site and ICV. For each sample, Cohen’s d effect sizes for each ROI were computed based on the group contrast t-statistics. Random-effects meta-analyses of Cohen’s d effect sizes for each ROI were performed using R’s metafor package. RESULTS: For the case-control meta-analysis, mean (range) age across samples was 29.2 (19.2–44.9) years for subjects with high schizotypy and 28.5 (19.4–42.5) years for subjects with low schizotypy. High and low schizotypy samples were on average 48.6% (25–100) and 49.0% (8–100) male. Compared to low schizotypy, people with high schizotypy had smaller left nucleus accumbens volumes (Cohen’s d = -0.13, p = 0.04). No other significant meta-analytical effects were identified. DISCUSSION: Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities involving the ventral striatum in healthy individuals with subclinical psychotic-like experiences. Though the effect size is small, the result is consistent with findings in schizophrenia patients and suggesting that these effects are not secondary to potential influences of disease chronicity or antipsychotic medication. The lack of significant effects in other reported regions in schizophrenia research may indicate that further subcortical abnormalities may not be present or detectable in schizotypy samples and could reflect mechanisms of resilience in this population.

Schizophrenia is characterized by a constellation of heterogeneous symptoms including hallucinations and delusions, motivational and social deficits, and cognitive impairments. Although positive symptoms have historically been the target for drug development, in recent years, attention has turned to cognitive and negative symptoms. Cognitive deficits in schizophrenia are associated with significant impairments in functional, social, and employment outcomes, and although they are widely researched and relatively well understood, there are no currently approved compounds to treat them. This chapter provides a selective review of the current status of approaches developed to improve cognition in schizophrenia. It covers pharmacological approaches as well as cognitive training and cognitive remediation techniques. It also explores the various study design issues and challenges that contribute to the difficulties in discovering reliable ways to improve the cognitive deficits present in schizophrenia.

BackgroundPatients with schizophrenia have substantially reduced subjective well-being (SW) compared to healthy individuals. It has been suggested that diminished SW may be related to deficits in the neural processing of reward but this has not been shown directly. We hypothesized that, in schizophrenia, lower SW would be associated with attenuated reward-related activation in the reward network.MethodTwenty patients with schizophrenia with a range of SW underwent a functional magnetic resonance imaging (fMRI) reward task. The brain activity underlying reward anticipation and outcome in schizophrenia was examined and compared to that of 12 healthy participants using a full factorial analysis. Region of interest (ROI) analyses of areas within the reward network and whole-brain analyses were conducted to reveal neural correlates of SW.ResultsReward-related neural activity in schizophrenia was not significantly different from that of healthy participants; however, the patients with schizophrenia showed significantly diminished SW. Both ROI and whole-brain analyses confirmed that SW scores in the patients correlated significantly with activity, specifically in the dorsal anterior cingulate cortex (dACC), during both reward anticipation and reward outcome. This association was not seen in the healthy participants.ConclusionsIn patients with schizophrenia, reduced activation of the dACC during multiple aspects of reward processing is associated with lower SW. As the dACC has been widely linked to coupling of reward and action, and the link to SW is apparent over anticipation and outcome, these findings suggest that SW deficits in schizophrenia may be attributable to reduced integration of environmental rewarding cues, motivated behaviour and reward outcome.

Background Paranoid thinking, a common symptom of psychosis and schizophrenia, manifests as a sense of threat and may also be indexed by a lack of trust. Stress, in turn, exacerbates psychosis and paranoia, and is a well-established risk factor for schizophrenia as well as a component in several models of psychosis. The present study aimed to determine the impact that acute stress has on paranoid thinking during social interaction in vivo in high (HSZ) vs low (LSZ) schizotypy using an iterated social reciprocity game. The main hypothesis was that HSZ would anticipate grerater social threat and paranoia at baseline compared to LSZ, and moreover that experimentally-induced stress would exacerbate those differences, and thus show that stress differentially modulates how HSZ model the intentions of others. Methods Matched healthy participants were stratified into HSZ (N=17) and LSZ (N=17) groups and were administered a non-financial, social-reciprocity game against benevolent and malevolent opponents under both stress and no-stress conditions. Stress was manipulated using the MIST (Dedovic et al., 2005) stress paradigm. Cortisol was measured from saliva samples acquired before and after the MIST stress task. Anticipation of threat and trust scores were derived from the social interaction task. Results At baseline, cortisol levels were not significantly different between HSZ and LSZ but were significantly raised by the stressor task in HSZ (p

Patients with neuropsychiatric disorders such as Alzheimer's disease (AD), schizophrenia (Sz), and brain injury (BI) often show memory deficits and lack of awareness of those deficits. This study aimed to investigate the role of memory in awareness of memory deficits and illness in multiple patient groups. Comparison of awareness profiles between groups can reveal common or distinct patterns of awareness and predictors, which may inform theories about the structure of awareness. Using the same standardized measures, AD (N = 27) Sz (N = 31), and BI (N = 26) patients were compared on memory functioning, awareness of illness, and awareness of memory deficits-measured by discrepancy of pretest estimate and actual test scores. All groups were poor at pretest estimation of memory functioning, particularly the AD and BI groups. In AD, patients with the lowest memory functioning rated their performance highest. The BI group and to a lesser extent the AD group showed improved estimations of performance following the memory test. Those with the poorest memory showed the greatest improvement in ratings accuracy post test. The relationship between memory and awareness of memory was stronger than the association between memory and awareness of illness. There was a double dissociation between awareness of memory and awareness of illness across patient groups. The study shows that awareness of memory is linked to memory functioning, while memory is only modestly related to awareness of illness. Dissociations in the role of memory in different domains of awareness and "online" awareness of performance provide information to refine cognitive models of awareness. However, the results should be interpreted with caution given the heterogeneous nature of the sample.

Patients with schizophrenia are often characterized as lacking insight or awareness into their illness and symptoms, yet despite considerable research, we still lack a full understanding of the factors involved in causing poor awareness. Within schizophrenia, there has been shown to be a fractionation across dimensions of awareness into mental illness: of being ill, of symptoms, and of treatment compliance. Recently, attention has turned to evidence of a fractionation between awareness of illness and of cognitive impairments and functioning. The current study investigated the degree of fractionation across a broad range of domains of function in schizophrenia and how each domain may be associated with neuropsychological functioning, clinical, mood, and demographic variables. Thirty-one mostly chronic stable patients with schizophrenia completed a battery of neuropsychological tests and measures of psychopathology, including mood. Cognitive insight and awareness of illness, symptoms, memory, and behavioral functioning were also measured. Insight and awareness were assessed using a combination of semistructured interview, observer-rated, self-rated, and objective measures, and included measures of the discrepancy between carer and self-ratings of impairment. Results revealed that awareness of functioning in each domain was largely independent and that awareness in each domain was predicted by different factors. Insight into symptoms was relatively poor while insight into cognitive deficits was preserved. Relative to neuropsychological variables, cognitive insight, comprising self-certainty and self-reflexivity, was a greater predictor of awareness. In conclusion, awareness is multiply fractionated and multiply determined. Therapeutic interventions could, therefore, produce beneficial changes within specific domains of awareness.

Background. The nature of delusions remains unclear despite their interest to researchers and importance in psychopathology. Here we present a review of the contributions from various disciplines, principally cognitive neuroscience, towards a new understanding.Method. Narrative review of published research.Results. The main areas of activity revolve around reasoning biases, attributional and attentional biases, theory of mind, and the role of emotion, with each area beginning to be explored using functional neuroimaging techniques. Of heuristic interest are neurological models, which include confabulation and delusional misidentification and the one- versus two-stage (perceptual versus reasoning plus perceptual) accounts of the latter.Conclusions. These different approaches are shown to each highlight mechanisms which are suggested to cause, contribute to, or modulate the genesis and form of delusions. Such contributions coupled with traditional phenomenological methods should provide the foundations for a cognitive neuropsychiatry of delusions.

Background: Theory of mind (ToM) is an aspect of social cognition which refers in part to the capacity to perceive and understand other people’s mental state. Deficits in these mentalizing processes are commonly observed in both schizophrenia and Autism Spectrum Disorder (ASD), and are thus evident in disorders with very different symptoms and clinical presentations. The aim of this study was to conduct a meta-analysis of all published data examining ToM deficits in schizophrenia and autism in order to determine whether these two disorders have distinct deficit profiles across multiple domains of ToM. We additionally aimed to explore the relationship between clinical symptoms and phase of illness on ToM deficits in schizophrenia.

Lack of insight is common in patients with schizophrenia and a large number of studies have endeavored to clarify the relationship between level of insight and degree of clinical symptomatology. This study aimed to advance our understanding of this relationship by conducting an up-to-date meta-analysis of all relevant studies published to date. A literature search identified 151 eligible studies published up to August 2016 which together included 20 515 patients with schizophrenia. The statistical associations between insight, its sub-components, and clinical symptoms were analyzed to calculate pooled effects from all studies included. Additional planned analyses included examination of whether clinical, procedural, or demographic variables moderated the strength of these relationships. Results revealed significant negative associations between global insight and positive (ES = −.27), negative (ES = −.22) and global (ES = −.28), symptoms; and a significant though weaker association with depressive symptoms (ES = .20; all < .001). In terms of individual symptoms, insight held the strongest and most negative association with Unusual Thought Content ( = −.46, < .001) and disorganization ( = −.38, < .001). There was substantial variation in the strength of association between individual components of insight and symptoms. Meta-regression analyses revealed that illness duration, number of psychotic episodes, age, and age of onset significantly influences the strength of the relationship between insight and symptoms. Stage of illness, assessment scale, and rater (patient vs. clinician) also moderate these relationships. This study supports the general notion that insight and psychopathology are significantly associated in patients with schizophrenia, however, as the magnitude of associations are generally low to medium, overall findings suggest insight is largely independent from symptomatology. Results are of relevance to both clinical practice and future research studies.

Several efforts to develop pharmacological treatments with a beneficial effect on cognition in schizophrenia are underway, while cognitive remediation has shown modest effects on cognitive performance. Our goal was to test if pharmacological augmentation of cognitive training would result in enhancement of training-induced learning. We chose modafinil as the pharmacological augmenting agent, as it is known to have beneficial effects on learning and cognition. 49 participants with chronic schizophrenia were enroled in a double-blind, placebo-controlled study across two sites and were randomised to either modafinil (200mg/day) or placebo. All participants engaged in a cognitive training program for 10 consecutive weekdays. The primary outcome measure was the performance on the trained tasks and secondary outcome measures included MATRICS cognitive battery, proxy measures of everyday functioning and symptom measures. 84% of the participants completed all study visits. Both groups showed significant improvement in the performance of the trained tasks suggesting potential for further learning. Modafinil did not induce differential enhancement on the performance of the trained tasks or any differential enhancement of the neuropsychological and functional measures compared to placebo. Modafinil showed no significant effects on symptom severity. Our study demonstrated that combining pharmacological compounds with cognitive training is acceptable to patients and can be implemented in large double-blind randomised controlled trials. The lack of differential enhancement of training-induced learning raises questions, such as choice and optimal dose of drug, cognitive domains to be trained, type of cognitive training, intervention duration and chronicity of illness that require systematic investigation in future studies.

Lack of insight is a commonly observed problem in patients with psychosis and schizophrenia. Clinical insight in patients has been associated with low mood. Cognitive insight is a recently defined concept, relating to the ability to self-reflect and the degree to which patients are over-confident regarding their interpretations of illness-related experiences, and is related to clinical insight. We therefore sought to investigate whether there is a positive relationship between cognitive insight and mood. A literature search identified 17 relevant papers published between 2004 and 2014. Our analysis indicated that there was a small but significant positive correlation between the composite index (CI) of the Beck Cognitive Insight Scale (BCIS) and depression scores, but this was driven by a significant positive relationship between depression and the BCIS self-reflection (SR) sub-scale, where low mood was related to higher SR scores. There was no significant relationship between the self-certainty sub-scale and depression. Post-hoc analysis indicated that different depression scales did not significantly affect the relationship with SR. Our results support the idea that cognitive insight is significantly related to mood in schizophrenia, and the effect size is similar to that between clinical insight and mood. Potential applications of this knowledge into treatment and rehabilitation are discussed and a model of cognitive insight is proposed.

Lack of insight or unawareness of illness are the hallmarks of many psychiatric disorders, especially schizophrenia (SCZ) and other psychoses and could be conceived of as a failure in metacognition. Research in this area in the mental health field h as burgeoned with the development and widespread use of standard assessment instruments and the mapping out of the clinical and neuropsychological correlates of insight and its loss. There has been a growing appreciation of the multi-faceted nature of the concept and of the different ‘objects’ of insight, such as the general awareness that one is ill, to more specific metacognitive awareness of individual symptoms, impairments and performance. This in turn has led to the notion that insight may show modularity and may fractionate across different domains and disorders, supported by work that directly compares metacognition of memory deficits and illness awareness in patients with SCZ, Alzheimer's disease and brain injury. The focus of this paper will be on the varieties of metacognitive failure in psychiatry, particularly the psychoses. We explore cognitive models based on self-reflectiveness and their possible social and neurological bases, including data from structural and functional MRI. The medial frontal cortex appears to play an important role in self-appraisal in health and disease.

Metacognitive neuroscience: an introduction.- Quantifying human metacognition for the neurosciences.- Signal detection theory analysis of type 1 and type 2 data: meta-d', response-specific meta-d' and the unequal variance SDT model.- The highs and lows of theoretical interpretation in animal-metacognition research.- A computational framework for the study of confidence across species.- Shared mechanisms for confidence judgments and error detection in human decision making.- Metacognition and confidence in value-based choice.- What failure in collective decision-making tells us about metacognition.- Studying metacognitive processes at the single-neuron level.- The neural basis of metacognitive accuracy.- The cognitive neuroscience of metamemory monitoring: understanding metamemory processes, subjective levels expressed and metacognitive accuracy.- Metacognitive facilitation of spontaneous thought processes: When metacognition helps the wandering mind find its way.- What is the human sense of agency and is it metacognitive? Failures of metacognition and lack of insight in neuropsychiatric disorders.- Judgments of agency in schizophrenia: An impairment in autonoetic metacognition.- Metacognition in Alzheimer's disease.

Background: Community treatment orders (CTOs) are increasingly being used, despite a weak evidence base, and problems continue regarding Second Opinion Appointed Doctor (SOAD) certification of medication. Aims: The aim of the current study was to describe current CTO usage regarding patient characteristics, prescribed medication and CTO conditions. Method: A 1-year prospective cohort study with consecutive sampling was conducted for all patients whose CTO was registered in a large mental health trust. Only the first CTO for each patient was included. Measures included sociodemographic variables, psychiatric diagnosis, CTO date of initiation and conditions, psychotropic medication and date of SOAD certification for medication. This study was conducted in the first year of CTO legislation in England and Wales. Results: A total of195 patients were sampled (mean age 40.6 years, 65% male, 52% black ethnic origin). There was significant geographical variability in rates of CTO use ( χ2 = 11.3, p = 0.012). A total of 53% had their place of residence specified as a condition and 29% were required to allow access into their homes. Of those with schizophrenia, 64% were prescribed an antipsychotic long-acting injection (LAI). Of the total group, 7% received high-dose antipsychotics, 10% were prescribed two antipsychotics and only 15% received SOAD certification in time. Conclusions: There was geographical and ethnic variation in CTO use but higher rates of hospital detention in minority ethnic groups may be contributory. Most patients were prescribed antipsychotic LAIs and CTO conditions may not follow the least restrictive principle.

Improving cognition in people with neuropsychiatric disorders remains a major clinical target. By themselves pharmacological and non-pharmacological approaches have shown only modest effects in improving cognition. In the present study we tested a recently-proposed methodology to combine CT with a 'cognitive-enhancing' drug to improve cognitive test scores and expanded on previous approaches by delivering combination drug and CT, over a long intervention of repeated sessions, and used multiple tasks to reveal the cognitive processes being enhanced. We also aimed to determine whether gains from this combination approach generalised to untrained tests. In this proof of principle randomised-controlled trial thirty-three healthy volunteers were randomised to receive either modafinil or placebo combined with daily cognitive training over two weeks. Volunteers were trained on tasks of new-language learning, working memory and verbal learning following 200 mg modafinil or placebo for ten days. Improvements in trained and untrained tasks were measured. Rate of new-language learning was significantly enhanced with modafinil, and effects were greatest over the first five sessions. Modafinil improved within-day learning rather than between-day retention. No enhancement of gains with modafinil was observed in working memory nor rate of verbal learning. Gains in all tasks were retained post drug-administration, but transfer effects to broad cognitive abilities were not seen. This study shows that combining CT with modafinil specifically elevates learning over early training sessions compared to CT with placebo and provides a proof of principle experimental paradigm for pharmacological enhancement of cognitive remediation.

Effective estimation of the salience of environmental stimuli underlies adaptive behaviour, while related aberrance is believed to undermine rational thought processes in schizophrenia. A network including bilateral frontoinsular cortex (FIC) and dorsal anterior cingulate cortex (dACC) has been observed to respond to salient stimuli using functional magnetic resonance imaging (fMRI). To test the hypothesis that activity in this salience network (SN) is less discriminately modulated by contextually-relevant stimuli in schizophrenia than in healthy individuals, fMRI data were collected in 20 individuals with schizophrenia and 13 matched controls during performance of a modified monetary incentive delay task. After quantitatively identifying spatial components representative of the FIC and dACC features of the SN, two principal analyses were conducted. In the first, modulation of SN activity by salience was assessed by measuring response to trial outcome. First-level general linear models were applied to individual-specific time-courses of SN activity identified using spatial independent component analysis. This analysis revealed a significant salience-by-performance-by-group interaction on the best-fit FIC component’s activity at reward outcome, whereby healthy individuals but not individuals with schizophrenia exhibited significantly greater distinction between the response to hits and misses in high salience trials than in low salience trials. The second analysis aimed to ascertain whether SN component amplitude differed between the study groups over the duration of the experiment. Independent-samples T-tests on back-projected, percent-signal-change scaled SN component images importantly showed that the groups did not differ in the overall amplitude of SN expression over the entire dataset. These findings of dysregulated but not decreased SN activity in schizophrenia provide physiological support for mechanistic conceptual frameworks of delusional thought formation.

Background Delusions and hallucinations are classic positive symptoms of schizophrenia. A contemporary cognitive theory called the ‘forward output model’ suggests that the misattribution of self-generated actions may underlie some of these types of symptoms, such as delusions of control – the experience of self-generated action being controlled by an external agency. In order to examine the validity of this suggestion, we performed a longitudinal functional magnetic resonance imaging (fMRI) study examining neuronal activation associated with motor movement during acute psychosis. Methods We studied brain activation using fMRI during a motor task in 11 patients with schizophrenia and 9 healthy controls. The patient group was tested at two time points separated by 6–8 weeks. Results At initial testing, the patient group had a mean Positive and Negative Syndrome Scale score of 56.3, and showed significantly increased activation within the left inferior parietal lobe (IPL) compared to controls. Patients reported significantly decreased positive symptoms at 6–8 week followup and IPL activation had returned to normal. Our results demonstrate that first-rank positive symptoms are associated with hyperactivation in the secondary somatosensory cortex (IPL). Conclusions These findings lend further credence to the theory that a dysfunction in the sensory feedback system located in the IPL, and which is thought to underlie our sense of agency, may contribute to the aetiology of delusions of control.

Research has suggested an association between personality factors and awareness in patients with dementia, yet valid measurement of premorbid personality is problematic. The present study aimed to better reveal the relationship between premorbid personality and awareness by using improved methodology. Moreover, the study aims to contrast the strength of the relationship of premorbid personality and awareness with that of cognitive factors.Awareness of illness, symptoms, mnemonic and behavioural impairments, and treatment compliance were measured in 27 patients with mild-to-moderate Alzheimer's disease (AD) diagnosed by standard criteria for probable AD. Participant premorbid personality was measured using average retrospective Neuroticism-Extroversion-Openness Inventory (NEO-FFI) scores from two informants. Correlations were performed to investigate the relationship between awareness and personality dimensions, as well as measures of cognitive style, neuropsychological function, mood, carer burden, and sociodemographic factors.There was little relationship between awareness and personality scores, but modest associations between awareness and mood, age, and age of onset of first symptoms. Awareness of memory was related to memory functioning. Increased carer burden was associated with lack of awareness of cognitive-behavioural deficits but there were only few and weak associations between awareness and measures of cognitive functioning.There was little support for an association between previous personality and awareness in dementia. However, increased carer burden was associated specifically with lack of awareness of cognitive-behavioural deficits not deficits in ADL, whereas lower awareness of ADL and not cognitive-behavioural deficits was associated with age. Awareness of memory appeared to be a metamemory capacity. Mood and age rather than personality and cognition are stronger predictors of awareness in early Alzheimer's disease.

Background: Insight in psychosis and schizophrenia is considered a complex biopsychosocial phenomenon. Premorbid personality is regarded by some authors as part of the substrate to many psychiatric phenomena, but it is not clear if this applies to insight. Aim: To examine longitudinal relationships between personality traits and insight dimensions in first-episode psychosis. Methods: One hundred consecutive antipsychotic-naive first-episode nonaffective psychotic patients admitted to hospital were included in the study. Eighty-one patients completed at 1 month a premorbid personality evaluation, plus baseline, and 6-month insight assessments. We used the Assessment and Documentation of Psychopathology inventory for assessing insight dimensions (not feeling ill, lack of insight, and refusal of treatment) and the Personality Assessment Schedule for ascertaining 5 dimensions of premorbid personality (schizoid, passive-dependent, anancastic, sociopathic, and schizotypy). Results: At baseline, personality dimensions did not show any association with insight dimensions, with the exception of schizotypy traits. At 6 months, schizoid and sociopathic personality showed a significant association with not feeling ill (r = .30, P ≤ .007; r = .27, P = .01) and lack of insight (r = .36, P = .001; r = .41, P < .001), respectively. When we calculated insight change, schizoid and sociopathic personality had moderate correlation with the lack of insight dimension (r = −.34, P = .002; r = .38, P < .001, respectively). After applying partial correlations for potential confounders and Bonferroni correction, the associations remained significant. Moreover, using a regression model, sociopathic and schizoid personality significantly predicted lack of insight at 6 months and change from baseline to the 6 months assessment. Conclusions: Sociopathic and schizoid personality dimensions were not only significantly associated with lack of insight at 6 months but also predicted change on lack of insight over 6 months. Therefore, exploring premorbid personality traits at the beginning of a psychotic episode may be helpful in identifying patients at high risk for lack of insight during the initial course of the illness.

Background: Auditory verbal hallucinations in schizophrenia have been linked to defective monitoring of one's own verbal thoughts. Previous studies have shown that patients with auditory verbal hallucinations show attenuated activation of brain regions involved with auditory processing during the monitoring of inner speech. However, there are no functional magnetic resonance imaging studies explicitly comparing the perception of external speech with internal speech in the same patients with schizophrenia. The present study investigated the functional neuroanatomy of inner and external speech in both patients with schizophrenia and healthy control subjects. Methods: Fifteen patients with schizophrenia and 12 healthy control subjects were studied using functional magnetic resonance imaging while listening to sentences or imagining sentences. Results: Significant interactions between group (control subjects vs. patients) and task (listening vs. inner speech) were seen for the left superior temporal gyrus, as well as regions within the cingulate gyrus. Conclusions: Attenuated deactivation of the left superior temporal gyrus in schizophrenia patients during the processing of inner speech may reflect deficits in the forward models subserving self-monitoring. © 2010 Society of Biological Psychiatry.

Lack of insight or awareness of illness is a major problem in the ­management of patients with a range of neuropsychiatric disorders. Insight in schizophrenia has been extensively studied over the past 20 years, and much is known about its clinical associations. In this chapter, we review the literature on insight in schizophrenia and go on to describe the results of a study in which awareness of illness and impairment was compared in three clinical groups matched for premorbid IQ: patients with schizophrenia, Alzheimer’s disease, and brain injury. We considered performance and awareness across a number of domains: social behavior, psychopathology, and executive function. Awareness was ­measured by different methods including clinician ratings and discrepancy scores between patients’ own ratings and their relatives’ ratings using the Dysexecutive Questionnaire. All groups showed varying levels of deficit in each domain as well as varying levels of awareness. The Alzheimer group showed the most severe lack of awareness of cognitive and behavioral problems, followed by the brain-injured and schizophrenia patients. Low mood was associated with better insight in all groups. We conclude that insight is multidimensional and domain specific but that it also has associations which are common across domains and disorders.

Background Cognitive impairment in schizophrenia is a strong predictor of the functional outcome and no effective treatments are available. MATRICS Consensus Cognitive Battery (MCCB) is approved by the FDA as outcome measure for trials of cognitive-enhancing drugs in schizophrenia. CogState Schizophrenia Battery (CSB) provides a briefer cognition assessment with minimal practice effects and a strong correlation between the CSB and MCCB composite scores. We tested the sensitivity of CSB as a cognitive outcome measure in a clinical trial in schizophrenia, where a cognitive-enhancing drug and cognitive training were combined. Methods 49 participants with schizophrenia were enrolled in a double-blind, placebo-controlled study. Participants were randomised to modafinil (200mg/day) or placebo and underwent a cognitive training program for 10 weekdays. CSB was administered twice at baseline to minimise practice effects, at the last day of the intervention and two weeks after the completion of the intervention. Results There was a significant time effect at the end of the intervention on the CSB composite score (p=0.042). There was no significant treatment effect on CSB composite score at the end of the intervention (p=0.686) or at follow up (p=0.120). Conclusions Multiple administrations of CSB were well tolerated by participants. The significant time effects on the composite score may suggest the operation of practice effects. Several factors could have contributed to the lack of treatment effects on CSB, such as the burden of multiple neuropsychological testing in a relatively brief study, the duration of modafinil treatment and also the intensive nature of cognitive training.

Background: Community treatment order (CTO) legislation was initiated in November 2008 in England and Wales. Due to high rates of uptake, a shortage of second opinion appointed doctors (SOADs) to complete authorization of medication within the given timeframe for CTOs was soon identified. A strong link in the use of CTOs in combination with antipsychotic long acting injections (LAIs) has been previously identified. LAI use for patients with schizophrenia is 35% on UK acute inpatient wards. The aims of this cross-sectional observational study in the first year of CTO legislation were to (i) identify patient characteristics for those commenced on a CTO; (ii) identify the nature of psychotropic medication prescribing at CTO initiation. Hypothesis: patients with schizophrenia have higher than average rates of LAI use as compared with national prescribing data. Methods: The setting was the South London and Maudsley NHS Foundation Trust in London, United Kingdom, which provides secondary care level psychiatric services for a local population of 1.1million people, plus specialist tertiary referral inpatient facilities and forensic wards. Consecutive sampling was conducted for all patients whose CTO was registered in the Trust. Only the first CTO for each patient was included. Data for 126 patients from the first six months of data collection is presented (03/11/08-30/04/09). Measures included: sociodemographic variables, psychiatric diagnosis, CTO date of initiation, statutory reasons and stated conditions, psychotropic medication and date of Second Opinion Appointed Doctor (SOAD) authorization for medication. Results: There was geographical variability in rates of CTO use between the 4 geographical sub-regions. 52% of the 126 patients were of black ethnic origin. 52% had stated conditions regarding their place of residence and 37% were required to allow access into their homes. 99% were prescribed an antipsychotic, 27% a mood stabilizer, 8% an antidepressant, 5% a benzodiazepine. First generation antipsychotic LAIs were the most commonly prescribed group of antipsychotics (40%). 69% of those with schizophrenia on a CTO were prescribed an antipsychotic LAI. Regarding antipsychotic doses, the mean BNF% dose was 60.6% (sd 39.1 range 2.5%-183.3%). 8% of the total sample had antipsychotic (combined) doses exceeding 100%BNF dose limits. 10% were prescribed two antipsychotics. Prior to CTO initiation, 21% were LAI-naive and 78% were clozapine naive. SOAD certification of medication occurred approximately 2 months after CTO initiation (mean 59.9 days, sd 39.1, range 1-175 days). For 24% of the sample, SOAD certification was not completed within the first 6 months. Discussion: Variation in CTO use exists for geographical areas but not for ethnic diversity once other factors such as rates of hospital detention are considered. Conditions of CTOs may not follow the least restrictive principle, particularly for requirements regarding a patient's place of residence; clearer guidance for setting of conditions is required. The finding of 69% of those with schizophrenia on a CTO being prescribed an LAI is double that reported in national prescribing data. SOAD authorization of medication commonly occurs after the legal deadline and a small proportion did not achieve SOAD certification before the CTO expired.