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Maternal immune activation (MIA) during pregnancy is an established environmental risk factor for schizophrenia. Timing of immune activation exposure as well as sex of the exposed offspring are critical factors in defining the effects of MIA. However, the specificity of MIA on the component structure of schizophrenia, especially cognition, has been difficult to assess due to a lack of translational validity of maze-like testing paradigms. We aimed to assess cognitive domains relevant to schizophrenia using highly translational touchscreen-based tasks in male and female mice exposed to the viral mimetic, poly(I:C) (5mg/k, i.p.), during early (gestational day (GD) 9-11) and late (GD13-15) gestational time points. Gene expression of schizophrenia candidate pathways were assessed in fetal brain immediately following poly(I:C) exposure and in adulthood to identify its influence on neurodevelopmental processes. Sex and window specific alterations in cognitive performance were found with the early window of MIA exposure causing female-specific disruptions to working memory and reduced perseverative behaviour, while late MIA exposure caused male-specific changes to working memory and deficits in reversal learning. GABAergic specification marker, Nkx2.1 gene expression was reduced in fetal brains and reelin expression was reduced in adult hippocampus of both early and late poly(I:C) exposed mice. Neuregulin and EGF signalling were initially upregulated in the fetal brain, but were reduced in the adult hippocampus, with male mice exposed in the late window showing reduced Nrg3 expression. Serine racemase was reduced in both fetal and adult brain, but again, adult reductions were specific to male mice exposed at the late time point. Overall, we show that cognitive constructs relevant to schizophrenia are altered by in utero exposure to maternal immune activation, but are highly dependent on the timing of infection and the sex of the offspring. Glutamatergic and epidermal growth factor pathways were similarly altered by MIA in a timing and sex dependent manner, while MIA-induced GABAergic deficits were independent of timing or sex.

Despite loss of grey matter volume and emergence of distinct cognitive deficits in young adults diagnosed with schizophrenia, current treatments for schizophrenia do not target disruptions in late maturational reshaping of the prefrontal cortex. Iron, the most abundant transition metal in the brain, is essential to brain development and function, but in excess, it can impair major neurotransmission systems and lead to lipid peroxidation, neuroinflammation and accelerated aging. However, analysis of cortical iron biology in schizophrenia has not been reported in modern literature. Using a combination of inductively coupled plasma-mass spectrometry and western blots, we quantified iron and its major-storage protein, ferritin, in post-mortem prefrontal cortex specimens obtained from three independent, well-characterised brain tissue resources. Compared to matched controls (n = 85), among schizophrenia cases (n = 86) we found elevated tissue iron, unlikely to be confounded by demographic and lifestyle variables, by duration, dose and type of antipsychotic medications used or by copper and zinc levels. We further observed a loss of physiologic age-dependent iron accumulation among people with schizophrenia, in that the iron level among cases was already high in young adulthood. Ferritin, which stores iron in a redox-inactive form, was paradoxically decreased in individuals with the disorder. Such iron-ferritin uncoupling could alter free, chemically reactive, tissue iron in key reasoning and planning areas of the young-adult schizophrenia cortex. Using a prediction model based on iron and ferritin, our data provide a pathophysiologic link between perturbed cortical iron biology and schizophrenia and indicate that achievement of optimal cortical iron homeostasis could offer a new therapeutic target.

The trial-unique non-matching to location (TUNL) touchscreen task shows promise as a translational assay of working memory deficits in disorders including autism, ADHD, and schizophrenia. Although it is commonly assumed that the TUNL task predominantly measures spatial working memory in rodents, this proposition has not previously been tested. In this project, we used computational modelling of behaviour from mice performing the TUNL task (totalN= 163 mice across three datasets; 158,843 total trials). Contrary to common assumptions, behaviour on the TUNL task did not exclusively reflect spatial working memory. Instead, choice behaviour was explained as a mixture of both retrospective (spatial) working memory and prospective working memory for an intended behavioural response, as well as animal-specific response biases. We suggest that these findings can be understood within a resource-rational cognitive framework, and propose several task-design principles that we predict will maximise spatial working memory and minimise alternative behavioural strategies.

Background: The COVID 19 pandemic has created unprecedented acute global health challenges. However, it also presents a set of unquantified and poorly understood risks in the medium to long term, specifically, risks to children whose mothers were infected with the SARS-CoV-2 virus during pregnancy. Methods: We have designed a prospective, case-controlled study to investigate the long-term impacts of SARS-CoV2 exposure on children exposed in utero. Women infected with SARS-CoV-2 during pregnancy will be recruited from Monash Health, the Royal Women’s Hospital and Western Health (Melbourne, Australia) and Londrina Municipal Maternity Hospital Lucilla Ballalai and PUCPR Medical Clinical (Londrina, Brazil). A control group in a 2:1 ratio (2 non-exposed: 1 exposed mother infant dyad) comprising women who gave birth in the same month of delivery, are of similar age but did not contract SARS-CoV-2 during their pregnancy will also be recruited. We aim to recruit 150 exposed and 300 non-exposed mother-infant dyads. Clinical and socio-demographic data will be collected directly from the mother and medical records. Biospecimens and clinical and epidemiological data will be collected from the mothers and offspring at multiple time points from birth through to 15 years of age using standardised sample collection, and neurological and behavioural measures. Discussion: The mapped neurodevelopmental trajectories and comparisons between SARS-CoV2 exposed and control children will indicate the potential for an increase in atypical neurodevelopment. This has significant implications for strategic planning in the mental health and paediatrics sectors and long-term monitoring of children globally.

While the biological substrates of brain and behavioural changes in persons with schizophrenia remain unclear, increasing evidence implicates that inflammation is involved. In schizophrenia, including first-episode psychosis and anti-psychotic naive patients, there are numerous reports of increased peripheral inflammation, cognitive deficits and neuropathologies such as cortical thinning. Research defining the relationship between inflammation and schizophrenia symptomatology and neuropathology is needed. Therefore, we analysed the level of C-reactive protein (CRP), a peripheral inflammation marker, and its relationship with cognitive functioning in a cohort of 644 controls and 499 schizophrenia patients. In a subset of individuals who underwent MRI scanning (99 controls and 194 schizophrenia cases), we tested if serum CRP was associated with cortical thickness. CRP was significantly increased in schizophrenia patients compared to controls, co-varying for age, sex, overweight/obesity and diabetes (p

BackgroundCigarette smoking is associated with worse cognition and decreased cortical volume and thickness in healthy cohorts. Chronic cigarette smoking is prevalent in schizophrenia spectrum disorders (SSD), but the effects of smoking status on the brain and cognition in SSD are not clear. This study aimed to understand whether cognitive performance and brain morphology differed between smoking and non-smoking individuals with SSD compared to healthy controls.MethodsData were obtained from the Australian Schizophrenia Research Bank. Cognitive functioning was measured in 299 controls and 455 SSD patients. Cortical volume, thickness and surface area data were analysed from T1-weighted structural scans obtained in a subset of the sample (n = 82 controls, n = 201 SSD). Associations between smoking status (cigarette smoker/non-smoker), cognition and brain morphology were tested using analyses of covariance, including diagnosis as a moderator.ResultsNo smoking by diagnosis interactions were evident, and no significant differences were revealed between smokers and non-smokers across any of the variables measured, with the exception of a significantly thinner left posterior cingulate in smokers compared to non-smokers. Several main effects of smoking in the cognitive, volume and thickness analyses were initially significant but did not survive false discovery rate (FDR) correction.ConclusionsDespite the general absence of significant FDR-corrected findings, trend-level effects suggest the possibility that subtle smoking-related effects exist but were not uncovered due to low statistical power. An investigation of this topic is encouraged to confirm and expand on our findings.

Residents of Residential Age Care Facilities (RACFs) have particularly high rates of Emergency Department (ED) visits, with up to 55% being potentially avoidable (e.g. not resulting in a hospital admission). This is concerning as ED visits by RACF residents are associated with negative outcomes including longer hospital stays, iatrogenic illness, complications and mortality. Limited English proficiency (LEP) has significant negative impacts on the healthcare quality and outcomes for older people but has not been studied as a factor in ED visits from RACFs. This study aimed to examine if RACF residents with LEP have a lower rate of hospital admission via the ED compared to non-LEP controls and identify any associated factors. We hypothesised that LEP-related communication difficulties would reduce the ability to manage minor health issues in the RACF, leading to a lower proportion of LEP ED transfers being admitted. We used a parallel mixed-methods design, comprising a quantitative matched cohort study of ED visit data from two Local Hospital Networks (LHNs) in South-East Melbourne, Australia and secondary thematic analysis of 25 interviews with LEP residents, family carers and staff from two RACFs in the same region. We found no differences in the proportion of hospital ED transfers that led to admission (LHN1, 87.1% LEP, 85.6% non-LEP controls, p = 0.57; LHN2, 76.0% LEP, 76.9% non-LEP controls, p = 0.41) and no direct qualitative evidence suggesting that resident LEP affected decisions to transfer residents to ED, despite communication difficulties being reported during the transfer process. These results may be due to the high level of family carer involvement in residents' care identified in the qualitative study. However, additional research using different measures of LEP is recommended to further explore a broader range of cultural and linguistic factors in both rates of ED presentations and the decision-making processes underpinning resident transfers to ED.

BackgroundThe ability to generate a precise internal model of statistical regularities is impaired in schizophrenia. Predictive coding accounts of schizophrenia suggest that psychotic symptoms may be explained by a failure to build precise beliefs or a model of the world. The precision of this model may vary with context. For example, in a noisy environment the model will be more imprecise compared to a model built in an environment with lower noise. However compelling, this idea has not yet been empirically studied in schizophrenia. Methods: In this study, 62 participants engaged in a stochastic mismatch negativity paradigm with high and low precision. We included inpatients with a schizophrenia spectrum disorder (N=20), inpatients with a psychiatric disorder but without psychosis (N=20), and healthy controls (N=22), with comparable sex ratio and age distribution. Bayesian mapping and dynamic causal modelling were employed to investigate the underlying microcircuitry of precision encoding of auditory stimuli. Results: We found strong evidence (exceedance p > 0.99) for differences in the underlying connectivity associated with precision encoding between the three groups as well as on the continuum of psychotic-like experiences assessed across all participants. Critically, we show changes in interhemispheric connectivity between the two inpatient groups, with some connections further aligning on the continuum of psychotic-like experiences. Conclusions: While our results suggest continuity in backward connectivity alterations with psychotic-like experiences regardless of diagnosis, they also point to specificity for the schizophrenia spectrum disorder group in interhemispheric connectivity alterations.

Background: \ud Early warning signs monitoring by service users with schizophrenia has shown promise in preventing relapse but the quality of evidence is low. We aimed to establish the feasibility of undertaking a definitive randomised controlled trial to determine the effectiveness of a blended digital intervention for relapse prevention in schizophrenia.\ud \ud Methods: \ud This multicentre, feasibility, cluster randomised controlled trial aimed to compare Early signs Monitoring to Prevent relapse in psychosis and prOmote Well-being, Engagement, and Recovery (EMPOWER) with treatment as usual in community mental health services (CMHS) in Glasgow and Melbourne. CMHS were the unit of randomisation, selected on the basis of those that probably had five or more care coordinators willing to participate. Participants were eligible if they were older than 16 years, had a schizophrenia or related diagnosis confirmed via case records, were able to provide informed consent, had contact with CMHS, and had had a relapse within the previous 2 years. Participants were randomised within stratified clusters to EMPOWER or to continue their usual approach to care. EMPOWER blended a smartphone for active monitoring of early warning signs with peer support to promote self-management and clinical triage to promote access to relapse prevention. Main outcomes were feasibility, acceptability, usability, and safety, which was assessed through face-to-face interviews. App usage was assessed via the smartphone and self-report. Primary end point was 12 months. Participants, research assistants and other team members involved in delivering the intervention were not masked to treatment conditions. Assessment of relapse was done by an independent adjudication panel masked to randomisation group. The study is registered at ISRCTN (99559262).\ud \ud Findings: \ud We identified and randomised eight CMHS (six in Glasgow and two in Melbourne) comprising 47 care coordinators. We recruited 86 service users between Jan 19 and Aug 8, 2018; 73 were randomised (42 [58%] to EMPOWER and 31 [42%] to treatment as usual). There were 37 (51%) men and 36 (49%) women. At 12 months, main outcomes were collected for 32 (76%) of service users in the EMPOWER group and 30 (97%) of service users in the treatment as usual group. Of those randomised to EMPOWER, 30 (71%) met our a priori criterion of more than 33% adherence to daily monitoring that assumed feasibility. Median time to discontinuation of these participants was 31·5 weeks (SD 14·5). There were 29 adverse events in the EMPOWER group and 25 adverse events in the treatment as usual group. There were 13 app-related adverse events, affecting 11 people, one of which was serious. Fear of relapse was lower in the EMPOWER group than in the treatment as usual group at 12 months (mean difference –7·53 (95% CI –14·45 to 0·60; Cohen's d –0·53).\ud \ud Interpretation: \ud A trial of digital technology to monitor early warning signs blended with peer support and clinical triage to detect and prevent relapse appears to be feasible, safe, and acceptable. A further main trial is merited.\ud \ud Funding: \ud UK National Institute for Health Research Health Technology Assessment programme and the Australian National Health and Medical Research Council.

BACKGROUND People with serious mental illness (SMI) are underserved from a hepatitis C Virus (HCV) screening and treatment perspective. AIMS To examine the HCV care cascade in people with SMI and to pilot a supported HCV treatment integration program. METHODS HCV prevalence was retrospectively analysed from 4,492 consecutive individuals admitted to a tertiary hospital mental health service between January 2017 and December 2018. Sub-cohort analysis of screening patterns and predictors of seropositive infection was performed. Referral pathways and community care integration were analysed for HCV positive individuals, and a prospective community-based 'identify and treat' HCV program was assessed. RESULTS Screening for HCV had been performed in 18.6% (835/4,492) of the cohort. Seroprevalence was 4.6% (207/4,492). HCV seropositivity was associated with age > 40-years (OR = 9.30, CI 3.69-23.45, p

A hallmark feature of schizophrenia is altered high frequency neural oscillations, including reduced auditory-evoked gamma oscillatory power, which is underpinned by parvalbumin (PV) interneuron dysfunction. Maternal immune activation (MIA) in rodents models an environmental risk factor for schizophrenia and recapitulates these PV interneuron changes. This study sought to link reduced PV expression in the MIA model with alterations to auditory-evoked gamma oscillations and transcript expression. We further aligned transcriptional findings from the animal model with human genome sequencing data. We show that MIA, induced by the viral mimetic, poly-I:C in C57Bl/6 mice, caused in adult offspring reduced auditory-evoked gamma and theta oscillatory power paralleled by reduced PV protein levels. We then showed the Arx gene, critical to healthy neurodevelopment of PV interneurons, is reduced in the forebrain of MIA exposed mice. Finally, in a whole-genome sequenced patient cohort, we identified a novel missense mutation of ARX in a patient with schizophrenia and in the Psychiatric Genomics Consortium 2 cohort, a nominal association of proximal ARX SNPs with the disorder. This suggests MIA, as a risk factor for schizophrenia, may be influencing Arx expression to induce the GABAergic dysfunction seen in schizophrenia and that the ARX gene may play a role in the prenatal origins of schizophrenia pathophysiology.

Recent theories in computational psychiatry propose that unusual perceptual experiences and delusional beliefs may emerge as a consequence of aberrant inference and disruptions in sensory learning. The current study investigates these theories and examines the alterations that are specific to schizophrenia spectrum disorders vs those that occur as psychotic phenomena intensify, regardless of diagnosis. We recruited 66 participants: 22 schizophrenia spectrum inpatients, 22 nonpsychotic inpatients, and 22 nonclinical controls. Participants completed the reversal oddball task with volatility manipulated. We recorded neural responses with electroencephalography and measured behavioral errors to inferences on sound probabilities. Furthermore, we explored neural dynamics using dynamic causal modeling (DCM). Attenuated prediction errors (PEs) were specifically observed in the schizophrenia spectrum, with reductions in mismatch negativity in stable, and P300 in volatile, contexts. Conversely, aberrations in connectivity were observed across all participants as psychotic phenomena increased. DCM revealed that impaired sensory learning behavior was associated with decreased intrinsic connectivity in the left primary auditory cortex and right inferior frontal gyrus (IFG); connectivity in the latter was also reduced with greater severity of psychotic experiences. Moreover, people who experienced more hallucinations and psychotic-like symptoms had decreased bottom-up and increased top-down frontotemporal connectivity, respectively. The findings provide evidence that reduced PEs are specific to the schizophrenia spectrum, but deficits in brain connectivity are aligned on the psychosis continuum. Along the continuum, psychotic experiences were related to an aberrant interplay between top-down, bottom-up, and intrinsic connectivity in the IFG during sensory uncertainty. These findings provide novel insights into psychosis neurocomputational pathophysiology.

Impairments in social cognition—including recognition of facial expressions—are increasingly recognised as a core deficit in schizophrenia. It remains unclear whether other aspects of face processing (such as identity recognition) are also impaired, and whether such deficits can be attributed to more general cognitive difficulties. Moreover, while the majority of past studies have used picture-based tasks to assess face recognition, literature suggests that video-based tasks elicit different neural activations and have greater ecological validity. This study aimed to characterise face processing using video-based stimuli in psychiatric inpatients with and without psychosis. Symptom correlates of face processing impairments were also examined. Eighty-six psychiatric inpatients and twenty healthy controls completed a series of tasks using video-based stimuli. These included two emotion recognition tasks, two non-emotional facial identity recognition tasks, and a non-face control task. Symptoms were assessed using the Positive and Negative Syndrome Scale. Schizophrenia and bipolar disorder groups were significantly impaired on the emotion-processing tasks and the non-face task compared to healthy controls and patients without psychosis. Patients with other forms of psychosis performed intermediately. Groups did not differ in non-emotional face processing. Positive symptoms of psychosis correlated directly with both emotion-processing performance and non-face discrimination across patients. We found that identity processing performance was inversely associated with cognition-related symptoms only. Findings suggest that deficits in emotion-processing reflect symptom pathology independent of diagnosis. Emotion-processing deficits in schizophrenia may be better accounted for by task-relevant factors—such as attention—that are not specific to emotion processing.

While the biological substrates of brain and behavioural changes in persons with schizophrenia remain unclear, increasing evidence implicates that inflammation is involved. In schizophrenia, including first-episode psychosis and anti-psychotic naïve patients, there are numerous reports of increased peripheral inflammation, cognitive deficits and neuropathologies such as cortical thinning. Research defining the relationship between inflammation and schizophrenia symptomatology and neuropathology is needed. Therefore, we analysed the level of C-reactive protein (CRP), a peripheral inflammation marker, and its relationship with cognitive functioning in a cohort of 644 controls and 499 schizophrenia patients. In a subset of individuals who underwent MRI scanning (99 controls and 194 schizophrenia cases), we tested if serum CRP was associated with cortical thickness. CRP was significantly increased in schizophrenia patients compared to controls, co-varying for age, sex, overweight/obesity and diabetes (p 0.006E-10). In schizophrenia, increased CRP was mildly associated with worse performance in attention, controlling for age, sex and education (R =- 0.15, p = 0.001). Further, increased CRP was associated with reduced cortical thickness in three regions related to attention: the caudal middle frontal, the pars opercularis and the posterior cingulate cortices, which remained significant after controlling for multiple comparisons (all p 0.05). Together, these findings indicate that increased peripheral inflammation is associated with deficits in cognitive function and brain structure in schizophrenia, especially reduced attention and reduced cortical thickness in associated brain regions. Using CRP as a biomarker of peripheral inflammation in persons with schizophrenia may help to identify vulnerable patients and those that may benefit from adjunctive anti-inflammatory treatments.

The similarities between the depressive symptoms of Major Depressive Disorders (MDD) and Bipolar Disorders (BD) suggest these disorders have some commonality in their molecular pathophysiologies, which is not apparent from the risk genes shared between MDD and BD. This is significant, given the growing literature suggesting that changes in non-coding RNA may be important in both MDD and BD, because they are causing dysfunctions in the control of biochemical pathways that are affected in both disorders. Therefore, understanding the changes in non-coding RNA in MDD and BD will lead to a better understanding of how and why these disorders develop. Furthermore, as a significant number of individuals suffering with MDD and BD do not respond to medication, identifying non-coding RNA that are altered by the drugs used to treat these disorders offer the potential to identify biomarkers that could predict medication response. Such biomarkers offer the potential to quickly identify patients who are unlikely to respond to traditional medications so clinicians can refocus treatment strategies to ensure more effective outcomes for the patient. This review will focus on the evidence supporting the involvement of non-coding RNA in MDD and BD and their potential use as biomarkers for treatment response.

Maternal immune activation (MIA) increases risk for neuropsychiatric disorders such as autism spectrum disorder (ASD) in offspring later in life through unknown causal mechanisms. Growing evidence implicates parvalbumin-containing GABAergic interneurons as a key target in rodent MIA models. We targeted a specific neurodevelopmental window of parvalbumin interneurons in a mouse MIA model to examine effects on spatial working memory, a key domain in ASD that can manifest as either impairments or improvements both clinically and in animal models. Pregnant dams received three consecutive intraperitoneal injections of Polyinosinic:polycytidylic acid (poly(I:C), 5 mg/kg) at gestational days 13, 14 and 15. Spatial working memory was assessed in young adult offspring using touchscreen operant chambers and the Trial-Unique Non-matching to Location (TUNL) task. Anxiety, novelty seeking and short-term memory were assessed using Elevated Plus Maze (EPM) and Y-maze novelty preference tasks. Fluorescent immunohistochemistry was used to assess hippocampal parvalbumin cell density, intensity and co-expression with perineuronal nets. qPCR was used to assess the expression of putatively implicated gene pathways. MIA targeting a window of parvalbumin interneuron development increased spatial working memory performance on the TUNL touchscreen task which was not influenced by anxiety or novelty seeking behaviour. The model reduced fetal mRNA levels of Gad1 and adult hippocampal mRNA levels of Pvalb and the distribution of low intensity parvalbumin interneurons was altered. We speculate a specific timing window for parvalbumin interneuron development underpins the apparently paradoxical improved spatial working memory phenotype found both across several rodent models of autism and clinically in ASD.

BackgroundRelapse in schizophrenia is a major cause of distress and disability and is predicted by changes in symptoms such as anxiety, depression, and suspiciousness (early warning signs [EWSs]). These can be used as the basis for timely interventions to prevent relapse. However, there is considerable uncertainty regarding the implementation of EWS interventions.ObjectiveThis study was designed to establish the feasibility of conducting a definitive cluster randomized controlled trial comparing Early signs Monitoring to Prevent relapse in psychosis and prOmote Well-being, Engagement, and Recovery (EMPOWER) against treatment as usual (TAU). Our primary outcomes are establishing parameters of feasibility, acceptability, usability, safety, and outcome signals of a digital health intervention as an adjunct to usual care that is deliverable in the UK National Health Service and Australian community mental health service (CMHS) settings. We will assess the feasibility of candidate primary outcomes, candidate secondary outcomes, and candidate mechanisms for a definitive trial.MethodsWe will randomize CMHSs to EMPOWER or TAU. We aim to recruit up to 120 service user participants from 8 CMHSs and follow them for 12 months. Eligible service users will (1) be aged 16 years and above, (2) be in contact with local CMHSs, (3) have either been admitted to a psychiatric inpatient service or received crisis intervention at least once in the previous 2 years for a relapse, and (4) have an International Classification of Diseases-10 diagnosis of a schizophrenia-related disorder. Service users will also be invited to nominate a carer to participate. We will identify the feasibility of the main trial in terms of recruitment and retention to the study and the acceptability, usability, safety, and outcome signals of the EMPOWER intervention. EMPOWER is a mobile phone app that enables the monitoring of well-being and possible EWSs of relapse on a daily basis. An algorithm calculates changes in well-being based on participants’ own baseline to enable tailoring of well-being messaging and clinical triage of possible EWSs. Use of the app is blended with ongoing peer support.ResultsRecruitment to the trial began September 2018, and follow-up of participants was completed in July 2019. Data collection is continuing. The database was locked in July 2019, followed by analysis and disclosing of group allocation.ConclusionsThe knowledge gained from the study will inform the design of a definitive trial including finalizing the delivery of our digital health intervention, sample size estimation, methods to ensure successful identification, consent, randomization, and follow-up of participants, and the primary and secondary outcomes. The trial will also inform the final health economic model to be applied in the main trial.Trial RegistrationInternational Standard Randomized Controlled Trial Number (ISRCTN): 99559262; http://isrctn.com/ISRCTN99559262International Registered Report Identifier (IRRID)DERR1-10.2196/15058

Genetic and environmental etiologies may contribute to schizophrenia and its associated neurobiological profile. We examined the interaction between dopaminergic polymorphisms, childhood adversity and diagnosis (schizophrenia/schizoaffective disorder) on dopamine-related brain structures. Childhood adversity histories and structural MRI data were obtained from 249 (153 schizophrenia/schizoaffective, 96 controls) participants registered in the Australian Schizophrenia Research Bank. Polymorphisms in DRD2 and COMT were genotyped and a dopaminergic risk allelic load (RAL) was calculated. Regression analysis was used to test the main and interaction effects of RAL, childhood adversity and diagnosis on volumes of dopamine-related brain structures (caudate, putamen, nucleus accumbens, dorsolateral prefrontal cortex and hippocampus). A schizophrenia/schizoaffective diagnosis showed significant main effects on bilateral hippocampus, left dorsolateral prefrontal cortex and bilateral putamen volumes. RAL showed a significant main effect on left putamen volumes. Furthermore, across the whole sample, a significant two-way interaction between dopaminergic RAL and childhood adversity was found for left putamen volumes. No brain structure volumes were predicted by a three-way interaction that included diagnosis. Our finding suggests the left putamen may be particularly sensitive to dopaminergic gene-environment interactions regardless of diagnosis. However, larger studies are needed to assess whether these interactions are more or less pronounced in those with schizophrenia/schizoaffective disorders.

International audience; The transparency of two-dimensional (2D) materials to intermolecular interactions of crystalline materials has been an unresolved topic. Here we report that remote atomic interaction through 2D materials is governed by the binding nature, that is, the polarity of atomic bonds, both in the underlying substrates and in 2D material interlayers. Although the potential field from covalent-bonded materials is screened by a monolayer of graphene, that from ionic-bonded materials is strong enough to penetrate through a few layers of graphene. Such field penetration is substantially attenuated by 2D hexagonal boron nitride, which itself has polarization in its atomic bonds. Based on the control of transparency, modulated by the nature of materials as well as interlayer thickness, various types of single-crystalline materials across the periodic table can be epitaxially grown on 2D material-coated substrates. The epitaxial films can subsequently be released as free-standing membranes, which provides unique opportunities for the heterointegration of arbitrary single-crystalline thin films in functional applications.

Background There is no screening tool for major depressive disorder (MDD) or post-traumatic stress disorder (PTSD) in asylum-seekers or refugees (ASR) that can be readily administered by non-mental health workers. Hence, we aimed to develop a brief, sensitive and rapidly administrable tool for non-mental health workers to screen for MDD and PTSD in ASR. Methods The screening tool was developed from an extant dataset (n = 121) of multiply screened ASR and tested prospectively (N = 192) against the M.I.N.I. (Mini International Neuropsychiatric Interview) structured psychiatric interview. Rasch, Differential Item Functioning and ROC analyses evaluated the psychometric properties and tool utility. Results A 9-item tool with a median administration time of six minutes was generated, comprising two ‘immediate screen-in’ items, and a 7-item scale. The prevalence of PTSD &/or MDD using the M.I.N.I. was 32%, whilst 99% of other diagnosed mental disorders were comorbid with one or both of these. Using a cut-score of ≥2, the tool provided a sensitivity of 0.93, specificity of 0.75 and predictive accuracy of 80.7%. Conclusions A brief sensitive screening tool with robust psychometric properties that was easy to administer at the agency of first presentation was developed to facilitate mental health referrals for asylum-seekers and new refugees. Electronic supplementary material The online version of this article (10.1186/s12888-018-1660-8) contains supplementary material, which is available to authorized users.

Objective Progress toward understanding brain mechanisms in psychosis is hampered by failures to account for within-group heterogeneity that exists across neuropsychological domains. We recently identified distinct cognitive subgroups that might assist in identifying more biologically meaningful subtypes of psychosis. In the present study, we examined whether underlying structural brain abnormalities differentiate these cognitively derived subgroups. Method 1.5T T1 weighted structural scans were acquired for 168 healthy controls and 220 patients with schizophrenia/schizoaffective disorder. Based on previous work, 47 patients were categorized as being cognitively compromised (impaired premorbid and current IQ), 100 as cognitively deteriorated (normal premorbid IQ, impaired current IQ), and 73 as putatively cognitively preserved (premorbid and current IQ within 1 SD of controls). Global, subcortical and cortical volume, thickness, and surface area measures were compared among groups. Results Whole cortex, subcortical, and regional volume and thickness reductions were evident in all subgroups compared to controls, with the largest effect sizes in the compromised group. This subgroup also showed abnormalities in regions not seen in the other patient groups, including smaller left superior and middle frontal areas, left anterior and inferior temporal areas and right lateral medial and inferior frontal, occipital lobe and superior temporal areas. Conclusions This pattern of more prominent brain structural abnormalities in the group with the most marked cognitive impairments-both currently and putatively prior to illness onset, is consistent with the concept of schizophrenia as a progressive neurodevelopmental disorder. In this group, neurodevelopmental and neurodegenerative factors may be important for cognitive function.

Although brain changes in schizophrenia have been proposed to mirror those found with advancing age, the trajectory of gray matter and white matter changes during the disease course remains unclear. The authors sought to measure whether these changes in individuals with schizophrenia remain stable, are accelerated, or are diminished with age.Gray matter volume and fractional anisotropy were mapped in 326 individuals diagnosed with schizophrenia or schizoaffective disorder and in 197 healthy comparison subjects aged 20-65 years. Polynomial regression was used to model the influence of age on gray matter volume and fractional anisotropy at a whole-brain and voxel level. Between-group differences in gray matter volume and fractional anisotropy were regionally localized across the lifespan using permutation testing and cluster-based inference.Significant loss of gray matter volume was evident in schizophrenia, progressively worsening with age to a maximal loss of 8% in the seventh decade of life. The inferred rate of gray matter volume loss was significantly accelerated in schizophrenia up to middle age and plateaued thereafter. In contrast, significant reductions in fractional anisotropy emerged in schizophrenia only after age 35, and the rate of fractional anisotropy deterioration with age was constant and best modeled with a straight line. The slope of this line was 60% steeper in schizophrenia relative to comparison subjects, indicating a significantly faster rate of white matter deterioration with age. The rates of reduction of gray matter volume and fractional anisotropy were significantly faster in males than in females, but an interaction between sex and diagnosis was not evident.The findings suggest that schizophrenia is characterized by an initial, rapid rate of gray matter loss that slows in middle life, followed by the emergence of a deficit in white matter that progressively worsens with age at a constant rate.

There is currently no treatment available for the cognitive symptoms of schizophrenia, but evidence suggests that selective estrogen receptor modulators (SERMs) may provide relief. Our recent animal model data showed that a lack of female sex hormones in mice impairs the ability of hippocampal neurons to synchronise and generate oscillations within the frequency range of 30-80 Hz (gamma power) leading to cognitive impairment, while both estradiol and the SERM, raloxifene, recovered this. Given that cognitive impairment is accompanied by abnormal gamma power in schizophrenia, this study aimed to determine the effects of raloxifene on gamma power during spatial memory tasks in the prenatal immune challenged (poly-I:C) mouse model with relevance to schizophrenia. Pregnant dams received the viral mimetic poly-I:C (20 mg/kg, i.p.) at gestational day 17. Male and female offspring were treated with placebo or raloxifene implants at adulthood. Local field potentials from the CA1 hippocampus were simultaneously recorded during the Y-maze test of short term spatial memory and the cheeseboard maze test of long-term spatial learning and memory and cognitive flexibility. In female but not male mice, poly I:C exposure reduced gamma power during decision making and prolonged the time spent in the centre (decision making phase) during the Y-maze task. Female poly-I:C exposed mice also showed increased gamma power during acquisition of the cheeseboard long term memory task and perseverative behaviour. Treatment with raloxifene recovered gamma power and decision making deficits in the Y-maze and restored gamma power changes during the cheeseboard maze task as well as perseverative behaviour. Male mice showed no electrophysiological or behavioural effects of poly-I:C or raloxifene treatment. In summary, poly-I:C exposure induced female specific cognitive impairments accompanied by altered neural oscillations in the gamma frequency and raloxifene recovered these abnormalities.

BACKGROUND Relapse in schizophrenia is a major cause of distress and disability and is predicted by changes in symptoms such as anxiety, depression, and suspiciousness (early warning signs [EWSs]). These can be used as the basis for timely interventions to prevent relapse. However, there is considerable uncertainty regarding the implementation of EWS interventions. OBJECTIVE This study was designed to establish the feasibility of conducting a definitive cluster randomized controlled trial comparing Early signs Monitoring to Prevent relapse in psychosis and prOmote Well-being, Engagement, and Recovery (EMPOWER) against treatment as usual (TAU). Our primary outcomes are establishing parameters of feasibility, acceptability, usability, safety, and outcome signals of a digital health intervention as an adjunct to usual care that is deliverable in the UK National Health Service and Australian community mental health service (CMHS) settings. We will assess the feasibility of candidate primary outcomes, candidate secondary outcomes, and candidate mechanisms for a definitive trial. METHODS We will randomize CMHSs to EMPOWER or TAU. We aim to recruit up to 120 service user participants from 8 CMHSs and follow them for 12 months. Eligible service users will (1) be aged 16 years and above, (2) be in contact with local CMHSs, (3) have either been admitted to a psychiatric inpatient service or received crisis intervention at least once in the previous 2 years for a relapse, and (4) have an International Classification of Diseases-10 diagnosis of a schizophrenia-related disorder. Service users will also be invited to nominate a carer to participate. We will identify the feasibility of the main trial in terms of recruitment and retention to the study and the acceptability, usability, safety, and outcome signals of the EMPOWER intervention. EMPOWER is a mobile phone app that enables the monitoring of well-being and possible EWSs of relapse on a daily basis. An algorithm calculates changes in well-being based on participants’ own baseline to enable tailoring of well-being messaging and clinical triage of possible EWSs. Use of the app is blended with ongoing peer support. RESULTS Recruitment to the trial began September 2018, and follow-up of participants was completed in July 2019. Data collection is continuing. The database was locked in July 2019, followed by analysis and disclosing of group allocation. CONCLUSIONS The knowledge gained from the study will inform the design of a definitive trial including finalizing the delivery of our digital health intervention, sample size estimation, methods to ensure successful identification, consent, randomization, and follow-up of participants, and the primary and secondary outcomes. The trial will also inform the final health economic model to be applied in the main trial. CLINICALTRIAL International Standard Randomized Controlled Trial Number (ISRCTN): 99559262; http://isrctn.com/ISRCTN99559262

Despite their widespread use, typical visual observation practices are not evidence-based and adverse events - such as self-harm and absconding - still occur even under the most intense forms of observation. This study aimed to (i) develop and implement an engagement-focused systematized model of clinical risk management in an adult acute psychiatric inpatient unit; and (ii) prospectively evaluate its effect on rates of violence, self-harm, absconding, sexually inappropriate behaviour, and seclusion. A new model of engagement-focused clinical risk management was developed using a participatory action research framework and implemented in an adult acute psychiatric inpatient unit. Using a mirror-image design, rates of violence/aggression, self-harm, absconding, sexually inappropriate behaviour, and seclusion were compared before and after implementation, and staff satisfaction levels were measured. The clinical engagement-based model was introduced, and 1087 admissions before implementation (24 months) were compared with 965 admissions post-implementation (18 months). The new model was associated with significantly reduced rates of absconding (pre: 10.5/1000 occupied bed days, 95% CI [9.0, 12.1] compared with post: 6.5/1000 occupied bed days [5.2, 8.1], P