Comparative effects of pharmacological interventions for the acute and long-term management of insomnia disorder in adults: a systematic review and network meta-analysis.

BACKGROUND: 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. METHODS: 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and websites of regulatory agencies from database inception to Nov 25, 2021, to identify published and unpublished randomised controlled trials.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. FINDINGS: 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]). INTERPRETATION: 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. FUNDING: UK National Institute for Health Research Oxford Health Biomedical Research Centre.

Cervical lymph nodes and ovarian teratomas as germinal centres in NMDA receptor-antibody encephalitis.

Autoantibodies against the extracellular domain of the N-methyl-d-aspartate receptor (NMDAR) NR1 subunit cause a severe and common form of encephalitis. To better understand their generation, we aimed to characterize and identify human germinal centres actively participating in NMDAR-specific autoimmunization by sampling patient blood, CSF, ovarian teratoma tissue and, directly from the putative site of human CNS lymphatic drainage, cervical lymph nodes. From serum, both NR1-IgA and NR1-IgM were detected more frequently in NMDAR-antibody encephalitis patients versus controls (both P < 0.0001). Within patients, ovarian teratoma status was associated with a higher frequency of NR1-IgA positivity in serum (OR = 3.1; P < 0.0001) and CSF (OR = 3.8, P = 0.047), particularly early in disease and before ovarian teratoma resection. Consistent with this immunoglobulin class bias, ovarian teratoma samples showed intratumoral production of both NR1-IgG and NR1-IgA and, by single cell RNA sequencing, contained expanded highly-mutated IgA clones with an ovarian teratoma-restricted B cell population. Multiplex histology suggested tertiary lymphoid architectures in ovarian teratomas with dense B cell foci expressing the germinal centre marker BCL6, CD21+ follicular dendritic cells, and the NR1 subunit, alongside lymphatic vessels and high endothelial vasculature. Cultured teratoma explants and dissociated intratumoral B cells secreted NR1-IgGs in culture. Hence, ovarian teratomas showed structural and functional evidence of NR1-specific germinal centres. On exploring classical secondary lymphoid organs, B cells cultured from cervical lymph nodes of patients with NMDAR-antibody encephalitis produced NR1-IgG in 3/7 cultures, from patients with the highest serum NR1-IgG levels (P < 0.05). By contrast, NR1-IgG secretion was observed neither from cervical lymph nodes in disease controls nor in patients with adequately resected ovarian teratomas. Our multimodal evaluations provide convergent anatomical and functional evidence of NMDAR-autoantibody production from active germinal centres within both intratumoral tertiary lymphoid structures and traditional secondary lymphoid organs, the cervical lymph nodes. Furthermore, we develop a cervical lymph node sampling protocol that can be used to directly explore immune activity in health and disease at this emerging neuroimmune interface.

Melatonin In Acute Mania Investigation (MIAMI-UK). A randomized controlled trial of add-on melatonin in bipolar disorder.

OBJECTIVES: Current options for treating emergent episodes of hypomania and mania in bipolar disorder are limited. Our objective was to compare the effectiveness and safety of add-on melatonin in hypomania or mania over 3 weeks as a well-tolerated therapy. METHODS: A randomized, double-blind, parallel-group, 3-week comparison of modified release melatonin (n = 21) vs placebo (n = 20) in adult bipolar patients aged 18-65 years. Permuted block randomization was used with participants and investigators masked to treatment allocation. Trial registration is ISRCTN28988273 and EUdraCT2008-000281-23. Approved by the South Central National Research Ethics Service (Oxford REC A) ref: 09/H0604/63. RESULTS: The trial was negative as there was no significant difference between melatonin and placebo on the primary outcome-mean Young Mania Rating Scale (YMRS) score at Day 21: (mean difference [MD] -1.77 ([95% CI: -6.39 to 2.85]; P = .447). Significantly fewer patients on melatonin scored 10 or more on the Altman Self Rating Mania Scale: (odds ratio [OR] 0.164 [95% CI: 0.0260-1.0002]; P = .05). Quick Inventory of Depression Symptomatology Clinician Version-16 (QIDS-C16) scores were not significantly different. (OR 1.77 [95% CI: 0.43-7.29]; P = .430). The proportion of patients scoring less than or equal to 5 on the self-report QIDS-SR16 at end-point was greater for the melatonin group (OR 8.35 [95% CI: 1.04-67.23]; P = .046). CONCLUSIONS: In this small trial, melatonin did not effectively treat emerging hypomania or mania as there was no significant difference on the primary outcome. The sample size limitation and secondary outcomes suggest further investigation of melatonin treatment in mood episodes is indicated.

Schizophrenia delays and alters maturation of the brain in adolescence.

Early-onset schizophrenia appears to be clinically more severe than the adult-onset form of the disease. In a previous study, we showed that anatomically related grey and white matter abnormalities found in adolescents patients were larger and more widespread than what had been reported in the literature on adult schizophrenia. Particularly, we found novel structural abnormalities in the primary sensorimotor and premotor systems. Here, we tested alternative hypotheses: either this striking sensorimotor-related pattern is an artefact due to a better sensitivity of the methods, or apparent greater structural abnormalities in the early-onset population are specifically associated with earlier disease onset. Then, if we were to find such characteristic structural pattern, we would test whether these anatomical abnormalities would remain static or, conversely, show dynamic changes in the still developing brain. To address these questions, we combined a cross-sectional study of brain structure for adolescent-onset patients (n = 25) and adult-onset patients (n = 35) and respective matched healthy subjects with a longitudinal study of adolescent-onset patients (n = 12, representative subset of the cross-sectional group) and matched healthy controls for >2 years. Looking at differences between adolescent and adult patients' grey matter volume and white matter microstructure abnormalities, we first confirmed the specificity (especially in motor-related areas) and the greater severity of structural abnormalities in the adolescent patients. Closer examination revealed, however, that such greater anomalies seemed to arise because adolescent patients fail to follow the same developmental time course as the healthy control group. Longitudinal analysis of a representative subset of the adolescent patient and matched healthy populations corroborated the delayed and altered maturation in both grey and white matters. Structural abnormalities specific to adolescent-onset schizophrenia in the sensori-motor cortices and corticospinal tract were less marked or even disappeared within the longitudinal period of observation, grey matter abnormalities in adolescent patients evolving towards the adult-onset pattern as defined by recent meta-analyses of adult schizophrenia. Combining cross-sectional adolescent and adult datasets with longitudinal adolescent dataset allowed us to find a unique, abnormal trajectory of grey matter maturation regardless of the age at onset of symptoms and of disease duration, with a lower and later peak than for healthy subjects. Taken together, these results suggest common aetiological mechanisms for adolescent- and adult-onset schizophrenia with an altered neurodevelopmental time course in the schizophrenic patients that is particularly salient in adolescence.

Evidence for the association of the DAOA (G72) gene with schizophrenia and bipolar disorder but not for the association of the DAO gene with schizophrenia.

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 (chi2 = 5.824 p = 0.016) and bipolar disorder (chi2 = 4.293 p = 0.038). A trend towards association with schizophrenia was observed for two other DAOA markers rs3916967 (M14, chi2 = 3.675 p = 0.055) and rs1421292 (M24; chi2 = 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.

GWAS of Suicide Attempt in Psychiatric Disorders and Association With Major Depression Polygenic Risk Scores.

OBJECTIVE: More than 90% of people who attempt suicide have a psychiatric diagnosis; however, twin and family studies suggest that the genetic etiology of suicide attempt is partially distinct from that of the psychiatric disorders themselves. The authors present the largest genome-wide association study (GWAS) on suicide attempt, using cohorts of individuals with major depressive disorder, bipolar disorder, and schizophrenia from the Psychiatric Genomics Consortium. METHODS: The samples comprised 1,622 suicide attempters and 8,786 nonattempters with major depressive disorder; 3,264 attempters and 5,500 nonattempters with bipolar disorder; and 1,683 attempters and 2,946 nonattempters with schizophrenia. A GWAS on suicide attempt was performed by comparing attempters to nonattempters with each disorder, followed by a meta-analysis across disorders. Polygenic risk scoring was used to investigate the genetic relationship between suicide attempt and the psychiatric disorders. RESULTS: Three genome-wide significant loci for suicide attempt were found: one associated with suicide attempt in major depressive disorder, one associated with suicide attempt in bipolar disorder, and one in the meta-analysis of suicide attempt in mood disorders. These associations were not replicated in independent mood disorder cohorts from the UK Biobank and iPSYCH. No significant associations were found in the meta-analysis of all three disorders. Polygenic risk scores for major depression were significantly associated with suicide attempt in major depressive disorder (R2=0.25%), bipolar disorder (R2=0.24%), and schizophrenia (R2=0.40%). CONCLUSIONS: This study provides new information on genetic associations and demonstrates that genetic liability for major depression increases risk for suicide attempt across psychiatric disorders. Further collaborative efforts to increase sample size may help to robustly identify genetic associations and provide biological insights into the etiology of suicide attempt.

Confirmation of the genetic association between the U2AF homology motif (UHM) kinase 1 (UHMK1) gene and schizophrenia on chromosome 1q23.3.

UHMK1 has previously been implicated as a susceptibility gene for schizophrenia in the 1q23.3 region by significant evidence of allelic and haplotypic association between schizophrenia and several genetic markers at UHMK1 in a London-based case-control sample. Further fine mapping of the UHMK1 gene locus in the University College London schizophrenia case-control sample was carried out with tagging SNPs. Two additional SNPs were found to be associated with schizophrenia (rs6604863 P = 0.02, rs10753578 P = 0.017). Tests of allelic and haplotypic association were then carried out in a second independent sample from Aberdeen consisting of 858 individuals with schizophrenia and 591 controls. Two of these SNPs also showed association in the Aberdeen sample (rs7513662 P = 0.0087, rs10753578 P = 0.022) and several haplotypes were associated (global permutation P = 0.0004). When the UCL and Aberdeen samples were combined three SNPs (rs7513662 P = 0.0007, rs6427680 P = 0.0252, rs6694863 P = 0.015) and several haplotypes showed association (eg HAP-A, HAP-B, HAP-C permutation P = 0.00005). The finding of allelic association with markers in the UHMK1 gene might help explain why it has not been possible, despite great effort, to satisfactorily confirm previously reported associations between schizophrenia and the genes RGS4 and NOS1AP/CAPON. These genes flank UHMK1 and all three loci are within a 700 kb region showing linkage to schizophrenia. The confirmation of association between UHMK1 and schizophrenia, rather than RGS4 and NOS1AP in the London sample, points to the possibility that previous efforts to accurately fine map a gene in the 1q23.3 region have lacked accuracy or may have suffered from methodological flaws.

Fine mapping by genetic association implicates the chromosome 1q23.3 gene UHMK1, encoding a serine/threonine protein kinase, as a novel schizophrenia susceptibility gene.

BACKGROUND: Linkage studies by us and others have confirmed that chromosome 1q23.3 is a susceptibility locus for schizophrenia. Based on this information, several research groups have published evidence that markers within both the RGS4 and CAPON genes, which are 700 kb apart, independently showed allelic association with schizophrenia. Tests of allelic association with both of these genes in our case control sample were negative. Therefore, we carried out further fine mapping between the RGS4 and CAPON genes. METHODS: Twenty-nine SNP and microsatellite markers in the 1q23.3 region were genotyped in the United Kingdom based sample of 450 cases and 450 supernormal control subjects. RESULTS: We detected positive allelic association after the eighth marker was genotyped and found that three microsatellite markers (p = .011, p = .014, p = .049) and two SNPs (p = .004, p = .043) localized in the 700 kb region between the RGS4 and CAPON genes, within the UHMK1 gene, were associated with schizophrenia. Tests of significance for marker rs10494370 remained significant following Bonferroni correction (alpha = .006) for multiple tests. Tests of haplotypic association were also significant for UHMK1 (p = .009) using empirical permutation tests, which make it unnecessary to further correct for both multiple alleles and multiple markers. CONCLUSIONS: These results provide preliminary evidence that the UHMK1 gene increases susceptibility to schizophrenia. Further confirmation in adequately powered samples is needed. UHMK1 is a serine threonine kinase nuclear protein and is highly expressed in regions of the brain implicated in schizophrenia.

Failure to confirm allelic and haplotypic association between markers at the chromosome 6p22.3 dystrobrevin-binding protein 1 (DTNBP1) locus and schizophrenia.

BACKGROUND: Previous linkage and association studies may have implicated the Dystrobrevin-binding protein 1 (DTNBP1) gene locus or a gene in linkage disequilibrium with DTNBP1 on chromosome 6p22.3 in genetic susceptibility to schizophrenia. METHODS: We used the case control design to test for of allelic and haplotypic association with schizophrenia in a sample of four hundred and fifty research subjects with schizophrenia and four hundred and fifty ancestrally matched supernormal controls. We genotyped the SNP markers previously found to be significantly associated with schizophrenia in the original study and also other markers found to be positive in subsequent studies. RESULTS: We could find no evidence of allelic, genotypic or haplotypic association with schizophrenia in our UK sample. CONCLUSION: The results suggest that the DTNBP1 gene contribution to schizophrenia must be rare or absent in our sample. The discrepant allelic association results in previous studies of association between DTNBP1 and schizophrenia could be due population admixture. However, even positive studies of European populations do not show any consistent DTNBP1 alleles or haplotypes associated with schizophrenia. Further research is needed to resolve these issues. The possible confounding of linkage with association in family samples already showing linkage at 6p22.3 might be revealed by testing genes closely linked to DTNBP1 for allelic association and by restricting family based tests of association to only one case per family.

Genetic association and brain morphology studies and the chromosome 8p22 pericentriolar material 1 (PCM1) gene in susceptibility to schizophrenia.

CONTEXT: There is evidence of linkage to a schizophrenia susceptibility locus on chromosome 8p21-22 found by several family linkage studies. OBJECTIVES: To fine map and identify a susceptibility gene for schizophrenia on chromosome 8p22 and to investigate the effect of this genetic susceptibility on an endophenotype of abnormal brain structure using magnetic resonance imaging. DESIGN: Fine mapping and identification of a chromosome 8p22 susceptibility gene was carried out by finding linkage disequilibrium between genetic markers and schizophrenia in multiply affected families, a case-control sample, and a trio sample. Variation in brain morphology associated with pericentriolar material 1 (PCM1) alleles was examined using voxel-based morphometry and statistical parametric mapping with magnetic resonance imaging. Setting and Patients A family sample of 13 large families multiply affected with schizophrenia, 2 schizophrenia case-control samples from the United Kingdom and Scotland, and a sample of schizophrenic trios from the United States containing parents and 1 affected child with schizophrenia. MAIN OUTCOME MEASURES: Tests of transmission disequilibrium between PCM1 locus polymorphisms and schizophrenia using a family sample and tests of allelic association in case-control and trio samples. Voxel-based morphometry using statistical parametric mapping. RESULTS: The family and trio samples both showed significant transmission disequilibrium between marker D85261 in the PCM1 gene locus and schizophrenia. The case-control sample from the United Kingdom also found significant allelic association between PCM1 gene markers and schizophrenia. Voxel-based morphometry of cases who had inherited a PCM1 genetic susceptibility showed a significant relative reduction in the volume of orbitofrontal cortex gray matter in comparison with patients with non-PCM1-associated schizophrenia, who, by contrast, showed gray matter volume reduction in the temporal pole, hippocampus, and inferior temporal cortex. CONCLUSIONS: The PCM1 gene is implicated in susceptibility to schizophrenia and is associated with orbitofrontal gray matter volumetric deficits.

Actigraphic features of bipolar disorder: A systematic review and meta-analysis.

Sleep disruptions represent a core feature of bipolar disorders and have been widely studied through the use of actigraphy, which is an objective measure of motor activity and sleep. Finding objective outcomes, which reliably measure sleep in bipolar disorders, is essential in developing better therapies and improving follow-up monitoring strategies. Our aim is to understand the role of actigraphy as an objective measure of sleep in bipolar disorder. We undertook a systematic review and meta-analysis on studies using actigraphy to detect changes in activity and sleep patterns in bipolar patients versus healthy controls. The primary outcome measures were the analyses of 'activity mean' and 'sleep duration'. As secondary outcomes we analysed 'sleep onset latency', 'sleep efficiency', and 'time awake after sleep onset'. Thirteen studies comprising 821 subjects met quality criteria for inclusion. The results show a decrease in activity mean and an altered pattern of sleep in bipolar patients. Further analyses suggest that the results might be generalized to a bipolar condition which underlies manic and depressed episodes as well as euthymic phases. This study highlights the role of actigraphy as an important objective tool for the ambulatory monitoring of sleep and activity in bipolar disorders.

Failure to confirm allelic association between markers at the CAPON gene locus and schizophrenia in a British sample.

BACKGROUND: Linkage studies have confirmed that chromosome 1q23.3 is a susceptibility locus for schizophrenia. It was then claimed that markers at the carboxyl-terminal PDZ ligand of neuronal nitric oxide synthase (CAPON) gene showed allelic association with schizophrenia in Canadian families. A second Chinese study found a base pair polymorphism at the CAPON gene also associated with schizophrenia. METHODS: We attempted replication using eight markers from the Canadian study in a UK based sample of 450 cases and 450 supernormal controls. RESULTS: We found no evidence for allelic or haplotypic association with schizophrenia for any of the markers found to be associated in the Canadian sample. CONCLUSIONS: The negative results might reflect genetic heterogeneity between the Canadian, Chinese and UK samples or be due to methodological problems. The present finding weakens the evidence that mutations or variation in the CAPON gene are causing genetic susceptibility to schizophrenia in European populations.

The use of actigraphy in the monitoring of sleep and activity in ADHD: A meta-analysis.

Attention deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder of childhood. There is an increasing need to find objective measures and markers of the disorder in order to assess the efficacy of the therapies and to improve follow-up strategies. Actigraphy is an objective method for recording motor activity and sleep parameters that has been used in many studies in ADHD. Our meta-analysis aimed to assess the current evidence on the role of actigraphy in both the detection of changes in motor activity and in sleep patterns in ADHD. A systematic review was carried out to find studies comparing children with unmedicated ADHD versus controls, using actigraphic measures as an outcome. The primary outcome measures were "sleep duration" and daytime "activity mean". As secondary outcome measures we analyzed "sleep onset latency", "sleep efficiency" and "wake after sleep onset". Twenty-four studies comprising 2179 children were included in this review. We show evidence that ADHD compared to typically developing children present a higher mean activity during structured sessions, a similar sleep duration, and a moderately altered sleep pattern. This study highlights the role of actigraphy as an objective tool for the ambulatory monitoring of sleep and activity in ADHD.

Presynaptic dopaminergic dysfunction in schizophrenia: a positron emission tomographic [18F]fluorodopa study.

CONTEXT: The dopamine overactivity hypothesis of schizophrenia remains one of the most influential theories of the pathophysiology of the illness. Radiotracer brain imaging studies are now directly testing aspects of the overactivity hypothesis. OBJECTIVE: To assess presynaptic dopaminergic function in a large cohort of patients with schizophrenia by means of [18F]fluorodopa uptake and a high-sensitivity 3-dimensional positron emission tomograph. We predicted elevations in striatal [18F]fluorodopa uptake and reductions in prefrontal cortical [18F]fluorodopa uptake in patients with schizophrenia. DESIGN: Case-control study. SETTING: Research institute investigation recruiting hospital outpatients. PATIENTS: Sixteen male medicated hospital outpatients with a DSM-IV diagnosis of schizophrenia (mean age, 38 years) and 12 age-matched male volunteers free of psychiatric and neurologic illness. INTERVENTION: [18F]fluorodopa positron emission tomographic scanning. MAIN OUTDOME MEASURE: [18F]fluorodopa uptake constant Ki measured with statistical parametric mapping and region-of-interest analyses. RESULTS: Statistical parametric mapping (P<.05 corrected) and region-of-interest analyses (P<.01) showed increased [18F]fluorodopa uptake, confined primarily to the ventral striatum in patients with schizophrenia. No reductions in prefrontal cortical [18F]fluorodopa uptake Ki were seen in the statistical parametric mapping and region-of-interest analyses, although dorsal anterior cingulate [18F]fluorodopa Ki correlated with performance on the Stroop Color-Word Test in both groups. CONCLUSIONS: As in studies in unmedicated patients, presynaptic striatal dopamine dysfunction is present in medicated schizophrenic patients, adding further in vivo support for dopamine overactivity in the illness.

A novel polymorphism in exon 11 of the WKL1 gene, shows no association with schizophrenia.

A missense mutation in exon 11 of the WKL1 gene on chromosome 22 was found to be associated with cases of catatonic schizophrenia in a single large pedigree. We have screened exon 11 of the WKL1 gene in 174 cases of schizophrenia, including cases of 22 cases of catatonic schizophrenia, but could not detect the previously reported mis-sense mutation. However in exon 11, we observed an insertion/deletion polymorphism, one-missense substitution and two synonymous substitutions. In addition, we also identified a nucleotide substitution in intron 11. All these polymorphisms appeared to be in complete linkage disequilibrium with one another. The polymorphisms were also identified in a UK pedigree with schizophrenia, however the polymorphisms did not segregate with the disease. To test for potential association between these polymorphisms and schizophrenia we sequenced an equal number of UK control individuals who were free of all psychiatric symptoms and had negative family histories for mental illness; the frequency of the insertion/deletion polymorphism was not significantly different in schizophrenia cases (42 out of 348 chromosomes, allele frequency 12%) compared to normal controls (40 out of 356 chromosomes, allele frequency 11%). The insertion/deletion was found to be in Hardy Weinberg equilibrium in both the schizophrenic and control groups. The insertion/deletion is composed of repeated sequence from exon 11 and intron 11 and is predicted to affect WKL1 protein structure.

A positron emission tomography study of the 5-HT1A receptor in schizophrenia and during clozapine treatment.

Several post-mortem studies have identified increases of 5-HT1A receptor density in frontal cortical areas in schizophrenic patients, and one has found increases in the cerebellar vermis. Clozapine has moderate affinity at the 5-HT1A receptor, and this may be of therapeutic importance. This positron emission tomography (PET) study attempted to replicate the post-mortem findings in vivo and sought an occupancy effect of clozapine at the 5-HT1A receptor. We recruited healthy controls, and patients with schizophrenia who were divided into those receiving clozapine and those receiving neuroleptics lacking 5-HT1A receptor affinity. Each volunteer received a PET scan, using the 5-HT1A receptor radioligand [carbonyl-11C]WAY-100635, and a magnetic resonance imaging scan. The cerebellar vermis was examined by comparing time-activity data between groups. For other brain regions (the raphe and subdivisions of the cerebral cortex), binding potential images were generated to reflect receptor density, then analysed using 'region of interest' and voxel-by-voxel methods. No significant changes of 5-HT1A receptor density were found in schizophrenic patients compared to controls. Two other PET studies, containing drug naïve rather than medicated schizophrenic patients, have also reported no increase in 5-HT1A receptor density in the frontal cortex. The results obtained in vivo bring into question the importance of the receptor in the pathophysiology of the illness. Clozapine did not occupy the 5-HT1A receptor at clinical doses. This is consistent with recent related PET results: 5-HT1A agonists do not appear to measurably block the binding of antagonist radiotracers in man at doses that are pharmacologically active but which are limited by tolerability.

Is lateral bias anomalous in early-onset schizophrenia? Selected comparisons with normal populations.

The aim of this study was to investigate lateral bias in patients with early-onset schizophrenia. Hand, eye, and foot preferences and relative hand skill were examined in early-onset patients (n=44) and matched controls (n=39), and were compared with population estimates. Patients demonstrated a significant excess in mixed handedness (20.5% vs. 8.5%) relative to population estimates and reduced relative hand skill on a pegboard task compared with controls. Left eye preference was significantly less common in schizophrenic patients relative to population estimates. Crossed eye-hand and eye-foot preferences were not significantly increased in the patient group as a whole but were present, respectively, in four of nine and five of nine mixed-handed patients but in none of five mixed-handed controls. These findings are consistent with the view that lateralisation is anomalous in schizophrenia early in the course of illness.

The use of actigraphy in the monitoring of methylphenidate versus placebo in ADHD: a meta-analysis.

Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder of childhood. There is an increasing need to find objective measures and markers of the disorder in order to assess the efficacy of the therapy and to improve follow-up strategies. Actigraphy is an objective method for recording motor activity and sleep parameters using small, computerized, watch-like devices worn on the body, and it has been used in many clinical trials to assess methylphenidate efficacy and adverse effects in ADHD. Our article aim is to systematically review and perform a meta-analysis of the current evidence on the role of actigraphy in both the detection of changes in activity and in sleep patterns in randomized clinical trials that compared methylphenidate against placebo in the treatment of ADHD. A comprehensive literature search of PubMed/MEDLINE, Scopus, Embase, Cochrane Library, CINHAL and PsycINFO databases was carried out to find randomized clinical trials comparing methylphenidate versus placebo in children with ADHD, using actigraphic measures as an outcome. No start date limit was used and the search was updated until June 2013. The primary outcome measures were 'total sleep time' and daytime 'activity mean'. As secondary outcomes, we analyzed 'sleep onset latency', 'sleep efficiency' and 'wake after sleep onset'. Eight articles comprising 393 patients were included in the analysis. Children with ADHD using MPH compared to placebo have a significant difference of a large effect with a diminishing value in the activity mean. For the total sleep time, we found a significant and large effect in the decrease in sleep in MPH group. This study shows that MPH may effectively reduce mean activity in ADHD children, but it may negatively affect total sleep time.

Case-case genome-wide association analysis shows markers differentially associated with schizophrenia and bipolar disorder and implicates calcium channel genes.

OBJECTIVE: There are theoretical reasons why comparing marker allele frequencies between cases of different diseases, rather than with controls, may offer benefits. The samples may be better matched, especially for background risk factors common to both diseases. Genetic loci may also be detected which influence which of the two diseases occurs if common risk factors are present. METHOD: We used samples of UK bipolar and schizophrenic cases that had earlier been subject to genome-wide association studies and compared marker allele frequencies between the two samples. When these differed for a marker, we compared the case sample allele frequencies with those of a control sample. RESULTS: Eight markers were significant at P value of less than 10(-5). Of these, the most interesting finding was for rs17645023, which was significant at P value of less than 10(-6) and which lies 36 kb from CACNG5. Control allele frequencies for this marker were intermediate between those for bipolar and schizophrenic cases. CONCLUSION: The application of this approach suggests that it does have some merits. The finding for CACNG5, taken together with the earlier implication of CACNA1C and CACNA1B, strongly suggests a key role for voltage-dependent calcium channel genes in the susceptibility to bipolar disorder and/or schizophrenia.