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      No association between cortical dopamine D2 receptor availability and cognition in antipsychotic-naive first-episode psychosis

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          Abstract

          Cognitive impairment is an important predictor of disability in schizophrenia. Dopamine neurotransmission in cortical brain regions has been suggested to be of importance for higher-order cognitive processes. The aim of this study was to examine the relationship between extrastriatal dopamine D2-R availability and cognitive function, using positron emission tomography and the high-affinity D2-R radioligand [ 11C]FLB 457, in an antipsychotic-naive sample of 18 first-episode psychosis patients and 16 control subjects. We observed no significant associations between D2-R binding in the dorsolateral prefrontal cortex or hippocampus ( β = 0.013–0.074, partial r = −0.037–0.273, p = 0.131–0.841). Instead, using Bayesian statistics, we found moderate support for the null hypothesis of no relationship (BF H0:H1 = 3.3–8.2). Theoretically, our findings may suggest a lack of detrimental effects of D2-R antagonist drugs on cognition in schizophrenia patients, in line with clinical observations.

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          Biological Insights From 108 Schizophrenia-Associated Genetic Loci

          Summary Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here, we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain providing biological plausibility for the findings. Many findings have the potential to provide entirely novel insights into aetiology, but associations at DRD2 and multiple genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that play important roles in immunity, providing support for the hypothesized link between the immune system and schizophrenia.
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            Using Bayes to get the most out of non-significant results

            No scientific conclusion follows automatically from a statistically non-significant result, yet people routinely use non-significant results to guide conclusions about the status of theories (or the effectiveness of practices). To know whether a non-significant result counts against a theory, or if it just indicates data insensitivity, researchers must use one of: power, intervals (such as confidence or credibility intervals), or else an indicator of the relative evidence for one theory over another, such as a Bayes factor. I argue Bayes factors allow theory to be linked to data in a way that overcomes the weaknesses of the other approaches. Specifically, Bayes factors use the data themselves to determine their sensitivity in distinguishing theories (unlike power), and they make use of those aspects of a theory’s predictions that are often easiest to specify (unlike power and intervals, which require specifying the minimal interesting value in order to address theory). Bayes factors provide a coherent approach to determining whether non-significant results support a null hypothesis over a theory, or whether the data are just insensitive. They allow accepting and rejecting the null hypothesis to be put on an equal footing. Concrete examples are provided to indicate the range of application of a simple online Bayes calculator, which reveal both the strengths and weaknesses of Bayes factors.
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              The MATRICS Consensus Cognitive Battery, part 2: co-norming and standardization.

              The consensus cognitive battery developed by the National Institute of Mental Health's (NIMH's) Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative includes 10 independently developed tests that are recommended as the standard battery for clinical trials of cognition-enhancing interventions for schizophrenia. To facilitate interpretation of results from the MATRICS Consensus Cognitive Battery using a common scaling across tests, normative data were obtained from a single representative U.S. community sample with the battery administered as a unit. The MATRICS Consensus Cognitive Battery was administered to 300 individuals from the general community at five sites in differing geographic regions. For each site, recruitment was stratified by age, gender, and education. A scientific survey sampling method was used to help avoid sampling bias. The battery was administered in a standard order to each participant in a single session lasting approximately 60 minutes. Descriptive data were generated, and age, gender, and education effects on performance were examined. Prominent age and education effects were observed across tests. The results for gender differed by measure, suggesting the need for age and gender corrections in clinical trials. The MATRICS Consensus Cognitive Battery components were co-normed, with allowance for demographic corrections. Co-norming a battery such as the MATRICS Consensus Cognitive Battery, comprising tests from independent test developers each with their own set of norms, facilitates valid interpretation of test scores and communication of findings across studies. These normative data will aid in estimating the magnitude of change during clinical trials of cognition-enhancing agents and make it possible to derive more directly interpretable composite scores.
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                Author and article information

                Contributors
                maria.lee@ki.se
                Journal
                NPJ Schizophr
                NPJ Schizophr
                NPJ Schizophrenia
                Nature Publishing Group UK (London )
                2334-265X
                21 September 2021
                21 September 2021
                2021
                : 7
                : 46
                Affiliations
                [1 ]GRID grid.4714.6, ISNI 0000 0004 1937 0626, Centre for Psychiatry Research, Department of Clinical Neuroscience, , Karolinska Institutet, & Stockholm Health Care Services, Region Stockholm, ; Stockholm, Sweden
                [2 ]GRID grid.4973.9, ISNI 0000 0004 0646 7373, Department Neurology and Neurobiology Research Unit, , Copenhagen University Hospital, ; Rigshospitalet, Denmark
                [3 ]GRID grid.4714.6, ISNI 0000 0004 1937 0626, Department of Physiology and Pharmacology, , Karolinska Institutet, ; SE- 171 77 Stockholm, Sweden
                [4 ]GRID grid.8993.b, ISNI 0000 0004 1936 9457, Department of Neuroscience, Psychiatry, , Uppsala University, ; Uppsala, Sweden
                Author information
                http://orcid.org/0000-0003-4080-4030
                http://orcid.org/0000-0003-1297-0816
                http://orcid.org/0000-0001-8103-6977
                Article
                176
                10.1038/s41537-021-00176-x
                8455597
                34548499
                7b709d0e-aaba-4182-898b-c07022eb62f6
                © The Author(s) 2021

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 12 April 2021
                : 26 August 2021
                Funding
                Funded by: ALF Payment for Clinical Research (Karolinska Institutet and Stockholm County Council)
                Funded by: FundRef https://doi.org/10.13039/501100003748, Svenska Sällskapet för Medicinsk Forskning (Swedish Society for Medical Research);
                Funded by: FundRef https://doi.org/10.13039/501100003554, Lundbeckfonden (Lundbeck Foundation);
                Funded by: FundRef https://doi.org/10.13039/501100004359, Vetenskapsrådet (Swedish Research Council);
                Award ID: 2017-00875
                Award ID: 09114
                Award ID: 523-2014-3467
                Award Recipient :
                Funded by: FundRef https://doi.org/10.13039/100007464, Torsten Söderbergs Stiftelse (Torsten Söderberg Foundation);
                Categories
                Article
                Custom metadata
                © The Author(s) 2021

                schizophrenia,working memory,molecular neuroscience
                schizophrenia, working memory, molecular neuroscience

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