Behavioural and molecular endophenotypes in psychotic disorders reveal heritable abnormalities in glutamatergic neurotransmission.

Psychotic disorders such as schizophrenia are biologically complex and carry huge population morbidity due to their prevalence, persistence and associated disability. Defined by features such as delusions and hallucinations, they involve cognitive dysfunction and neurotransmitter dysregulations that appear mostly to involve the dopaminergic and glutamatergic systems. A number of genetic and environmental factors are associated with these disorders but it has been difficult to identify the biological pathways underlying the principal symptoms. The endophenotype concept of stable, heritable traits that form a mechanistic link between genes and an overt expression of the disorder has potential to reduce the complexity of psychiatric phenotypes. In this study, we used a genetically sensitive design with individuals with a first episode of psychosis, their non-affected first-degree relatives and non-related healthy controls. Metabolomic analysis was combined with neurocognitive assessment to identify multilevel endophenotypic patterns: one concerned reaction times during the performance of cognitive and emotional tests that have previously been associated with the glutamate neurotransmission system, the other involved metabolites involved directly and indirectly in the co-activation of the N-methyl-D-aspartate receptor, a major receptor of the glutamate system. These cognitive and metabolic endophenotypes may comprise a single construct, such that genetically mediated dysfunction in the glutamate system may be responsible for delays in response to cognitive and emotional functions in psychotic disorders. This focus on glutamatergic neurotransmission should guide drug discovery and experimental medicine programmes in schizophrenia and related disorders.This study was funded by the Mason Medical Research Trust, the Stanley Medical Research Institute, the GlaxoSmithKlein and the Pinsent Darwin funding.This is the final published version. It first appeared at http://www.nature.com/tp/journal/v5/n3/full/tp201526a.html

Prevalence and clinical characteristics of serum neuronal cell surface antibodies in first-episode psychosis: a case-control study

$\textbf{Background}$ Psychosis is a common presenting feature in antibody-mediated encephalitis, for which prompt recognition and treatment usually leads to remission. We aimed to investigate whether people with circumscribed schizophrenia-like illnesses have such antibodies—especially antibodies against the N-methyl-D-aspartate receptor (NMDAR)—more commonly than do healthy controls. $\textbf{Methods}$ We recruited patients aged 14–35 years presenting to any of 35 mental health services sites across England with first-episode psychosis, less than 6 weeks of treatment with antipsychotic medication, and a score of 4 or more on at least one selected Positive and Negative Syndrome Scale (PANSS) item. Patients and controls provided venous blood samples. We completed standardised symptom rating scales (PANSS, ACE-III, GAF) at baseline, and tested serum samples for antibodies against NMDAR, LGI1, CASPR2, the GABAA receptor, and the AMPA receptor using live cell-based assays. Treating clinicians assessed outcomes of ICD diagnosis and functioning (GAF) at 6 months. We included healthy controls from the general population, recruited as part of another study in Cambridge, UK. $\textbf{Findings}$ Between Feb 1, 2013, and Aug 31, 2014, we enrolled 228 patients with first-episode psychosis and 105 healthy controls. 20 (9%) of 228 patients had serum antibodies against one or more of the neuronal cell surface antibodies compared with four (4%) of 105 controls (unadjusted odds ratio 2·4, 95% CI 0·8–7·3). These associations remained non-significant when adjusted for current cigarette smoking, alcohol consumption, and illicit drug use. Seven (3%) patients had NMDAR antibodies compared with no controls (p=0·0204). The other antibodies did not differ between groups. Antibody-positive patients had lower PANSS positive, PANSS total, and catatonia scores than did antibody-negative patients. Patients had comparable scores on other PANSS items, ACE-III, and GAF at baseline, with no difference in outcomes at 6 months. $\textbf{Interpretation}$ Some patients with first-episode psychosis had antibodies against NMDAR that might be relevant to their illness, but did not differ from patients without NMDAR antibodies in clinical characteristics. Our study suggests that the only way to detect patients with these potentially pathogenic antibodies is to screen all patients with first-episode psychosis at first presentation.Medical Research Counci

Using directed acyclic graphs in epidemiological research in psychosis:an analysis of the role of bullying in psychosis

Modern psychiatric epidemiology researches complex interactions between multiple variables in large datasets. This creates difficulties for causal inference. We argue for the use of probabilistic models represented by directed acyclic graphs (DAGs). These capture the dependence structure of multiple variables and, used appropriately, allow more robust conclusions about the direction of causation. We analyzed British national survey data to assess putative mediators of the association between bullying victimization and persecutory ideation. We compared results using DAGs and the Karlson-Holm-Breen (KHB) logistic regression commands in STATA. We analyzed data from the 2007 English National Survey of Psychiatric Morbidity, using the equivalent 2000 survey in an instant replication. Additional details of methods and results are provided in the supplementary material. DAG analysis revealed a richer structure of relationships than could be inferred using the KHB logistic regression commands. Thus, bullying had direct effects on worry, persecutory ideation, mood instability, and drug use. Depression, sleep and anxiety lay downstream, and therefore did not mediate the link between bullying and persecutory ideation. Mediation by worry and mood instability could not be definitively ascertained. Bullying led to hallucinations indirectly, via persecutory ideation and depression. DAG analysis of the 2000 dataset suggested the technique generates stable results. While causality cannot be fully determined from cross-sectional data, DAGs indicate the relationships providing the best fit. They thereby advance investigation of the complex interactions seen in psychiatry, including the mechanisms underpinning psychiatric symptoms. It may consequently be used to optimize the choice of intervention targets.</p

Adolescent Major Depressive Disorder: Neuroimaging Evidence of Sex Difference during an Affective Go/No-Go Task

Compared to female major depressive disorder (MDD), male MDD often receives less attention. However, research is warranted since there are significant sex differences in the clinical presentation of MDD and a higher rate of suicide in depressed men. To the best of our knowledge, this is the first functional magnetic resonance imaging (fMRI) study with a large sample addressing putative sex differences in MDD during adolescence, a period when one of the most robust findings in psychiatric epidemiology emerges; that females are twice as likely to suffer from MDD than males. Twenty-four depressed and 10 healthy male adolescents, together with 82 depressed and 24 healthy female adolescents, aged 11–18  years, undertook an affective go/no-go task during fMRI acquisition. In response to sad relative to neutral distractors, significant sex differences (in the supramarginal gyrus) and group-by-sex interactions (in the supramarginal gyrus and the posterior cingulate cortex) were found. Furthermore, in contrast to the healthy male adolescents, depressed male adolescents showed decreased activation in the cerebellum with a significant group-by-age interaction in connectivity. Future research may consider altered developmental trajectories and the possible implications of sex-specific treatment and prevention strategies for MDD.The study was funded by the Medical Research Council (grant: G0802226). The IMPACT clinical trial was funded by the NHS Health Technology Assessment (HTA) Programme, Central Manchester and Manchester Children’s University Hospitals NHS Trust, and the Cambridge and Peterborough Mental Health Trust. Additional support was provided by the jointly funded Medical Research Council/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre

MIDA boronates are hydrolysed fast and slow by two different mechanisms

MIDA boronates (N-methylimidodiacetic boronic acid esters) serve as an increasingly general platform for small-molecule construction based on building blocks, largely because of the dramatic and general rate differences with which they are hydrolysed under various basic conditions. Yet the mechanistic underpinnings of these rate differences have remained unclear, which has hindered efforts to address the current limitations of this chemistry. Here we show that there are two distinct mechanisms for this hydrolysis: one is base mediated and the other neutral. The former can proceed more than three orders of magnitude faster than the latter, and involves a rate-limiting attack by a hydroxide at a MIDA carbonyl carbon. The alternative 'neutral' hydrolysis does not require an exogenous acid or base and involves rate-limiting B-N bond cleavage by a small water cluster, (H2O)n. The two mechanisms can operate in parallel, and their relative rates are readily quantified by (18)O incorporation. Whether hydrolysis is 'fast' or 'slow' is dictated by the pH, the water activity and the mass-transfer rates between phases. These findings stand to enable, in a rational way, an even more effective and widespread utilization of MIDA boronates in synthesis

Oscillatory Cortical Network Involved in Auditory Verbal Hallucinations in Schizophrenia

Auditory verbal hallucinations (AVH), a prominent symptom of schizophrenia, are often highly distressing for patients. Better understanding of the pathogenesis of hallucinations could increase therapeutic options. Magnetoencephalography (MEG) provides direct measures of neuronal activity and has an excellent temporal resolution, offering a unique opportunity to study AVH pathophysiology.Twelve patients (10 paranoid schizophrenia, 2 psychosis not otherwise specified) indicated the presence of AVH by button-press while lying in a MEG scanner. As a control condition, patients performed a self-paced button-press task. AVH-state and non-AVH state were contrasted in a region-of-interest (ROI) approach. In addition, the two seconds before AVH onset were contrasted with the two seconds after AVH onset to elucidate a possible triggering mechanism.AVH correlated with a decrease in beta-band power in the left temporal cortex. A decrease in alpha-band power was observed in the right inferior frontal gyrus. AVH onset was related to a decrease in theta-band power in the right hippocampus.These results suggest that AVH are triggered by a short aberration in the theta band in a memory-related structure, followed by activity in language areas accompanying the experience of AVH itself

Evidence-based Kernels: Fundamental Units of Behavioral Influence

This paper describes evidence-based kernels, fundamental units of behavioral influence that appear to underlie effective prevention and treatment for children, adults, and families. A kernel is a behavior–influence procedure shown through experimental analysis to affect a specific behavior and that is indivisible in the sense that removing any of its components would render it inert. Existing evidence shows that a variety of kernels can influence behavior in context, and some evidence suggests that frequent use or sufficient use of some kernels may produce longer lasting behavioral shifts. The analysis of kernels could contribute to an empirically based theory of behavioral influence, augment existing prevention or treatment efforts, facilitate the dissemination of effective prevention and treatment practices, clarify the active ingredients in existing interventions, and contribute to efficiently developing interventions that are more effective. Kernels involve one or more of the following mechanisms of behavior influence: reinforcement, altering antecedents, changing verbal relational responding, or changing physiological states directly. The paper describes 52 of these kernels, and details practical, theoretical, and research implications, including calling for a national database of kernels that influence human behavior

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified