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Behavioural, cognitive, and pharmacological interventions can all be effective for insomnia. However, because of inadequate resources, medications are more frequently used worldwide. We aimed to estimate the comparative effectiveness of pharmacological treatments for the acute and long-term treatment of adults with insomnia disorder. In this systematic review and network meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, PsycINFO, WHO International Clinical Trials Registry Platform, ClinicalTrials.gov, and websites of regulatory agencies from database inception to Nov 25, 2021, to identify published and unpublished randomised controlled trials. We included studies comparing pharmacological treatments or placebo as monotherapy for the treatment of adults (≥18 year) with insomnia disorder. We assessed the certainty of evidence using the confidence in network meta-analysis (CINeMA) framework. Primary outcomes were efficacy (ie, quality of sleep measured by any self-rated scale), treatment discontinuation for any reason and due to side-effects specifically, and safety (ie, number of patients with at least one adverse event) both for acute and long-term treatment. We estimated summary standardised mean differences (SMDs) and odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with Open Science Framework, https://doi.org/10.17605/OSF.IO/PU4QJ. We included 170 trials (36 interventions and 47 950 participants) in the systematic review and 154 double-blind, randomised controlled trials (30 interventions and 44 089 participants) were eligible for the network meta-analysis. In terms of acute treatment, benzodiazepines, doxylamine, eszopiclone, lemborexant, seltorexant, zolpidem, and zopiclone were more efficacious than placebo (SMD range: 0·36–0·83 [CINeMA estimates of certainty: high to moderate]). Benzodiazepines, eszopiclone, zolpidem, and zopiclone were more efficacious than melatonin, ramelteon, and zaleplon (SMD 0·27–0·71 [moderate to very low]). Intermediate-acting benzodiazepines, long-acting benzodiazepines, and eszopiclone had fewer discontinuations due to any cause than ramelteon (OR 0·72 [95% CI 0·52–0·99; moderate], 0·70 [0·51–0·95; moderate] and 0·71 [0·52–0·98; moderate], respectively). Zopiclone and zolpidem caused more dropouts due to adverse events than did placebo (zopiclone: OR 2·00 [95% CI 1·28–3·13; very low]; zolpidem: 1·79 [1·25–2·50; moderate]); and zopiclone caused more dropouts than did eszopiclone (OR 1·82 [95% CI 1·01–3·33; low]), daridorexant (3·45 [1·41–8·33; low), and suvorexant (3·13 [1·47–6·67; low]). For the number of individuals with side-effects at study endpoint, benzodiazepines, eszopiclone, zolpidem, and zopiclone were worse than placebo, doxepin, seltorexant, and zaleplon (OR range 1·27–2·78 [high to very low]). For long-term treatment, eszopiclone and lemborexant were more effective than placebo (eszopiclone: SMD 0·63 [95% CI 0·36–0·90; very low]; lemborexant: 0·41 [0·04–0·78; very low]) and eszopiclone was more effective than ramelteon (0.63 [0·16–1·10; very low]) and zolpidem (0·60 [0·00–1·20; very low]). Compared with ramelteon, eszopiclone and zolpidem had a lower rate of all-cause discontinuations (eszopiclone: OR 0·43 [95% CI 0·20–0·93; very low]; zolpidem: 0·43 [0·19–0·95; very low]); however, zolpidem was associated with a higher number of dropouts due to side-effects than placebo (OR 2·00 [95% CI 1·11–3·70; very low]). Overall, eszopiclone and lemborexant had a favorable profile, but eszopiclone might cause substantial adverse events and safety data on lemborexant were inconclusive. Doxepin, seltorexant, and zaleplon were well tolerated, but data on efficacy and other important outcomes were scarce and do not allow firm conclusions. Many licensed drugs (including benzodiazepines, daridorexant, suvorexant, and trazodone) can be effective in the acute treatment of insomnia but are associated with poor tolerability, or information about long-term effects is not available. Melatonin, ramelteon, and non-licensed drugs did not show overall material benefits. These results should serve evidence-based clinical practice. UK National Institute for Health Research Oxford Health Biomedical Research Centre.

Subtle formal thought disorders are difficult to quantify. Their relationship to florid thought disorder is unknown. To assess the interrater reliability, sensitivity and factor structure of a new assessment instrument, the Thought and Language Index (TLI), and to determine if minor aberrations detectable in the speech of healthy individuals are related to the more severe formal thought disorders characteristic of schizophrenia. Interrater reliability was evaluated by determining the intraclass correlation for the ratings by five assessors. Factor analysis of the TLI scores of 87 patients was performed, and TLI scores in matched patients and controls were compared. The intraclass correlation was good for individual TLI items, and excellent for sub-scale scores. Factor analysis identified three groups of approximately orthogonal disorders. Mild speech aberrations were observed in healthy participants and in patients with schizophrenia. The prevalence of mild aberrations was correlated with the prevalence of definite formal thought disorders. The TLI is reliable and capable of detecting subtle disorders. Some mild aberrations occurring in the speech of healthy individuals appear to be attenuated forms of the florid disorders characteristic of schizophrenia.

AimsThe Oxford City and NE Oxon Adult Mental Health Team (AMHT) is an adult mental health team receiving referrals from GPs for most cases suspected to have a mental health illness requiring secondary mental health services’ input in Oxford city. In January 2020, the team was remodelled with care coordinators working in separate functions based on the duration AMHT support was required for, i.e. an assessment team and a treatment team, but with medics covering both functions of the team. This quality improvement project examines AMHT referrals over 2020/21, hypothesising a reduction in the proportion of inappropriate referrals following the remodelling compared to a 2018/19 pre-remodelling audit.MethodsThe project covers a total of 2803 referrals the team has received from 13/01/2020 to 12/01/2021. The outcomes measured included the number of inappropriate referrals returned to the GP, referrals only requiring a single assessment, the proportion of these referrals as university students in Oxford, and the diagnostic groupings of the referrals in students vs non-students. These outcomes were measured pre- and during the COVID-19 pandemic over 2020/21.ResultsA reduction in the total number of referrals to the team was noted over 2020/21 but this was compared to an 11 month audit in 2018/2019. During the study period, 19.5% (546/2803) of referrals were deemed inappropriate compared to 21% of referrals received in 2018/2019. Of 2803 referrals, 14.7% (97/658) were inappropriate pre-COVID-19 vs 20.9% (449/2145) during the pandemic. Of the total number of referrals, 32.9% were returned to the GP following a single assessment.The top 3 diagnostic categories in ‘non-students’ were mood/affective disorders (33.7%), anxiety/stress related disorders (17.2%), and neurodevelopmental disorders (7.8% total - ADHD was 3%). A significant increase in ADHD referrals and mood disorders amongst students compared to non-students is notable with the top 3 diagnostic categories for students being mood/affective (24.7%), neurodevelopmental disorders (19.5% - ADHD 17.7%), and anxiety/stress related disorders (13.4%). Students constituted 26% of the total number of referrals.It was notable that during the pandemic there was a higher proportion of inappropriate referrals.ConclusionOur project demonstrates a reduction in the proportion of inappropriate referrals sent to the AMHT following remodelling as compared to 2018/19. Further work is necessary to elucidate the contributing factors and reduce inappropriate referrals even further. An innovation is planned to automate the logging of referral outcomes to expedite a re-audit.

Accumulating evidence suggests that early-onset schizophrenia arises from a disturbance in the normal trajectory of cerebral development. To investigate brain structure, asymmetry and IQ in early-onset schizophrenia. Volumes of left and right cerebral hemispheres and IQ were assessed in 33 participants with early-onset DSM-IV schizophrenia and 30 members of a matched, normal control group. Total brain volume was significantly smaller in the group with early-onset disease ('cases') relative to the control group (4.5%), especially for the left hemisphere in males (6.0%). A significant sex x diagnosis interaction in hemisphere asymmetry revealed that the female cases group had significantly reduced rightward asymmetry relative to the female control group and that the male cases tended to have reduced leftward asymmetry relative to the male control group. Decreased left hemisphere volume in males and decreased rightward hemispheric asymmetry in females correlated with reduced IQ. Sexually dimorphic alterations in asymmetry correlate with degree of intellectual impairment in early-onset schizophrenia.

Transcriptomic imputation approaches combine eQTL reference panels with large-scale genotype data in order to test associations between disease and gene expression. These genic associations could elucidate signals in complex genome-wide association study (GWAS) loci and may disentangle the role of different tissues in disease development. We used the largest eQTL reference panel for the dorso-lateral prefrontal cortex (DLPFC) to create a set of gene expression predictors and demonstrate their utility. We applied DLPFC and 12 GTEx-brain predictors to 40,299 schizophrenia cases and 65,264 matched controls for a large transcriptomic imputation study of schizophrenia. We identified 413 genic associations across 13 brain regions. Stepwise conditioning identified 67 non-MHC genes, of which 14 did not fall within previous GWAS loci. We identified 36 significantly enriched pathways, including hexosaminidase-A deficiency, and multiple porphyric disorder pathways. We investigated developmental expression patterns among the 67 non-MHC genes and identified specific groups of pre- and postnatal expression. This study uses gene expression predictors for the dorsolateral prefrontal cortex and other brain regions to perform a transcriptomic imputation analysis of schizophrenia, identifying 413 genic associations across 13 brain regions and 36 significantly enriched pathways.

Background Previous linkage and association studies have implicated the D-amino acid oxidase activator gene (DAOA)/G30 locus or neighbouring region of chromosome 13q33.2 in the genetic susceptibility to both schizophrenia and bipolar disorder. Four single nucleotide polymorphisms (SNPs) within the D-amino acid oxidase (DAO) gene located at 12q24.11 have also been found to show allelic association with schizophrenia. Methods We used the case control method to test for genetic association with variants at these loci in a sample of 431 patients with schizophrenia, 303 patients with bipolar disorder and 442 ancestrally matched supernormal controls all selected from the UK population. Results Ten SNPs spanning the DAOA locus were genotyped in these samples. In addition three SNPs were genotyped at the DAO locus in the schizophrenia sample. Allelic association was detected between the marker rs3918342 (M23), 3' to the DAOA gene and both schizophrenia (χ 2 = 5.824 p = 0.016) and bipolar disorder (χ 2 = 4.293 p = 0.038). A trend towards association with schizophrenia was observed for two other DAOA markers rs3916967 (M14, χ 2 = 3.675 p = 0.055) and rs1421292 (M24; χ 2 = 3.499 p = 0.062). A test of association between a three marker haplotype comprising of the SNPs rs778293 (M22), rs3918342 (M23) and rs1421292 (M24) and schizophrenia gave a global empirical significance of p = 0.015. No evidence was found to confirm the association of genetic markers at the DAO gene with schizophrenia. Conclusion Our results provide some support for a role for DAOA in susceptibility to schizophrenia and bipolar disorder.

BackgroundFormal thought disorder is a characteristic feature of psychosis, but little is known of its pathophysiology. We have investigated this in schizophrenia using positron emission tomography (PET).MethodRegional cerebral blood flow was measured using H215O and PET while six people with schizophrenia were describing a series of 12 ambiguous pictures which elicited different degrees of thought-disordered speech. In a within-subject design, the severity of positive thought disorder was correlated with cerebral blood flow across the 12 scans in each subject.ResultsVerbal disorganisation (‘positive’ thought disorder) was inversely correlated with activity in the inferior frontal, cingulate and left superior temporal cortex, and positively correlated with activity in the parahippocampal/anterior fusiform region bilaterally, and in the body of the right caudate (P<0.001). The total amount of speech produced (independent of thought disorder) was positively correlated with activity in the left inferior frontal and left superior temporal cortex.ConclusionsThe severity of positive thought disorder was inversely correlated with activity in areas implicated in the regulation and monitoring of speech production. Reduced activity in these regions may contribute to the articulation of the linguistic anomalies that characterise positive thought disorder. The positive correlations between positive thought disorder and parahippocampal/anterior fusiform activity may reflect this regions role in the processing of linguistic anomalies.

Translating a set of disease regions into insight about pathogenic mechanisms requires not only the ability to identify the key disease genes within them, but also the biological relationships among those key genes. Here we describe a statistical method, Gene Relationships Among Implicated Loci (GRAIL), that takes a list of disease regions and automatically assesses the degree of relatedness of implicated genes using 250,000 PubMed abstracts. We first evaluated GRAIL by assessing its ability to identify subsets of highly related genes in common pathways from validated lipid and height SNP associations from recent genome-wide studies. We then tested GRAIL, by assessing its ability to separate true disease regions from many false positive disease regions in two separate practical applications in human genetics. First, we took 74 nominally associated Crohn's disease SNPs and applied GRAIL to identify a subset of 13 SNPs with highly related genes. Of these, ten convincingly validated in follow-up genotyping; genotyping results for the remaining three were inconclusive. Next, we applied GRAIL to 165 rare deletion events seen in schizophrenia cases (less than one-third of which are contributing to disease risk). We demonstrate that GRAIL is able to identify a subset of 16 deletions containing highly related genes; many of these genes are expressed in the central nervous system and play a role in neuronal synapses. GRAIL offers a statistically robust approach to identifying functionally related genes from across multiple disease regions--that likely represent key disease pathways. An online version of this method is available for public use (http://www.broad.mit.edu/mpg/grail/).

Susceptibility to schizophrenia and bipolar disorder may involve a substantial, shared contribution from thousands of common genetic variants, each of small effect. Identifying whether risk variants map to specific molecular pathways is potentially biologically informative. We report a molecular pathway analysis using the single-nucleotide polymorphism (SNP) ratio test, which compares the ratio of nominally significant ( P <0.05) to nonsignificant SNPs in a given pathway to identify the ‘enrichment’ for association signals. We applied this approach to the discovery (the International Schizophrenia Consortium ( n =6909)) and validation (Genetic Association Information Network ( n =2729)) of schizophrenia genome-wide association study (GWAS) data sets. We investigated each of the 212 experimentally validated pathways described in the Kyoto Encyclopaedia of Genes and Genomes in the discovery sample. Nominally significant pathways were tested in the validation sample, and five pathways were found to be significant ( P =0.03–0.001); only the cell adhesion molecule (CAM) pathway withstood conservative correction for multiple testing. Interestingly, this pathway was also significantly associated with bipolar disorder (Wellcome Trust Case Control Consortium ( n =4847)) ( P =0.01). At a gene level, CAM genes associated in all three samples ( NRXN1 and CNTNAP2 ), which were previously implicated in specific language disorder, autism and schizophrenia. The CAM pathway functions in neuronal cell adhesion, which is critical for synaptic formation and normal cell signaling. Similar pathways have also emerged from a pathway analysis of autism, suggesting that mechanisms involved in neuronal cell adhesion may contribute broadly to neurodevelopmental psychiatric phenotypes.

Rare coding variation has historically provided the most direct connections between gene function and disease pathogenesis. By meta-analyzing the whole-exomes of 24,248 cases and 97,322 controls, we implicate ultra-rare coding variants (URVs) in ten genes as conferring substantial risk for schizophrenia (odds ratios 3 – 50, P < 2.14 × 10−6), and 32 genes at a FDR < 5%. These genes have the greatest expression in central nervous system neurons and have diverse molecular functions that include the formation, structure, and function of the synapse. The associations of NMDA receptor subunit GRIN2A and AMPA receptor subunit GRIA3 provide support for the dysfunction of the glutamatergic system as a mechanistic hypothesis in the pathogenesis of schizophrenia. We observe an overlap of rare variant risk between schizophrenia, autism spectrum disorders (ASD)1, epilepsy and severe neurodevelopmental disorders (DD/ID)2, though in some shared genes different mutation types are implicated. Most genes described here however are not implicated in neurodevelopment and we demonstrate that genes prioritized from common variant analyses of schizophrenia are enriched in rare variant risk3, suggesting that common and rare genetic risk factors at least partially converge on the same underlying pathogenic biological processes. Even after excluding significantly associated genes, schizophrenia cases still carry a substantial excess of URVs, implying that more risk genes await discovery using this approach.