@article{KopfGloecknerAlthenetal.2023, author = {Kopf, Juliane and Gl{\"o}ckner, Stefan and Althen, Heike and Cevada, Thais and Schecklmann, Martin and Dresler, Thomas and Kittel-Schneider, Sarah and Reif, Andreas}, title = {Neural responses to a working memory task in acute depressed and remitted phases in bipolar patients}, series = {Brain Sciences}, volume = {13}, journal = {Brain Sciences}, number = {5}, issn = {2076-3425}, doi = {10.3390/brainsci13050744}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-313509}, year = {2023}, abstract = {(1) Cognitive impairments such as working memory (WM) deficits are amongst the most common dysfunctions characterizing bipolar disorder (BD) patients, severely contributing to functional impairment. We aimed to investigate WM performance and associated brain activation during the acute phase of BD and to observe changes in the same patients during remission. (2) Frontal brain activation was recorded using functional near-infrared spectroscopy (fNIRS) during n-back task conditions (one-back, two-back and three-back) in BD patients in their acute depressive (n = 32) and remitted (n = 15) phases as well as in healthy controls (n = 30). (3) Comparison of BD patients during their acute phase with controls showed a trend (p = 0.08) towards lower dorsolateral prefrontal cortex (dlPFC) activation. In the remitted phase, BD patients showed lower dlPFC and ventrolateral prefrontal cortex (vlPFC) activation (p = 0.02) compared to controls. No difference in dlPFC and vlPFC activation between BD patients' phases was found. (4) Our results showed decreased working memory performance in BD patients during the working memory task in the acute phase of disease. Working memory performance improved in the remitted phase of the disease but was still particularly attenuated for the more demanding conditions.}, language = {en} } @article{KittelSchneiderDavidovaKaloketal.2022, author = {Kittel-Schneider, Sarah and Davidova, Petra and Kalok, Miriam and Essel, Corina and Ahmed, Fadia Ben and Kingeter, Yasmina and Matentzoglu, Maria and Leutritz, Anna and Kersken, Katharina and Koreny, Carolin and Weber, Heike and Kollert, Leoniee and McNeill, Rihannon V. and Reif, Andreas and Bahlmann, Franz and Trautmann-Villalba, Patricia}, title = {A pilot study of multilevel analysis of BDNF in paternal and maternal perinatal depression}, series = {Archives of Women's Mental Health}, volume = {25}, journal = {Archives of Women's Mental Health}, number = {1}, issn = {1435-1102}, doi = {10.1007/s00737-021-01197-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-268849}, pages = {237-249}, year = {2022}, abstract = {Depression in the perinatal period is common in mothers worldwide. Emerging research indicates that fathers are also at risk of developing perinatal depression. However, knowledge regarding biological risk factors and pathophysiological mechanisms of perinatal depression is still scarce, particularly in fathers. It has been suggested that the neurotrophin BDNF may play a role in maternal perinatal depression; however, there is currently no data regarding paternal perinatal depression. For this pilot study, 81 expecting parents were recruited and assessed at several time points. We screened for depression using EPDS and MADRS, investigated several psychosocial variables, and took blood samples for BDNF val66met genotyping, epigenetic, and protein analysis. Between pregnancy and 12 months postpartum (pp), we found that 3.7 to 15.7\% of fathers screened positive for depression, and 9.6 to 24\% of mothers, with at least a twofold increased prevalence in both parents using MADRS compared with EPDS. We also identified several psychosocial factors associated with perinatal depression in both parents. The data revealed a trend that lower BDNF levels correlated with maternal depressive symptoms at 3 months pp. In the fathers, no significant correlations between BDNF and perinatal depression were found. Pregnant women demonstrated lower BDNF methylation and BDNF protein expression compared with men; however, these were found to increase postpartum. Lastly, we identified correlations between depressive symptoms and psychosocial/neurobiological factors. The data suggest that BDNF may play a role in maternal perinatal depression, but not paternal.}, language = {en} } @article{BrunkhorstKanaanTrautmannSchreiberetal.2021, author = {Brunkhorst-Kanaan, Nathalie and Trautmann, Sandra and Schreiber, Yannick and Thomas, Dominique and Kittel-Schneider, Sarah and Gurke, Robert and Geisslinger, Gerd and Reif, Andreas and Tegeder, Irmgard}, title = {Sphingolipid and endocannabinoid profiles in adult attention deficit hyperactivity disorder}, series = {Biomedicines}, volume = {9}, journal = {Biomedicines}, number = {9}, issn = {2227-9059}, doi = {10.3390/biomedicines9091173}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-246080}, year = {2021}, abstract = {Genes encoding endocannabinoid and sphingolipid metabolism pathways were suggested to contribute to the genetic risk towards attention deficit hyperactivity disorder (ADHD). The present pilot study assessed plasma concentrations of candidate endocannabinoids, sphingolipids and ceramides in individuals with adult ADHD in comparison with healthy controls and patients with affective disorders. Targeted lipid analyses of 23 different lipid species were performed in 71 mental disorder patients and 98 healthy controls (HC). The patients were diagnosed with adult ADHD (n = 12), affective disorder (major depression, MD n = 16 or bipolar disorder, BD n = 6) or adult ADHD with comorbid affective disorders (n = 37). Canonical discriminant analysis and CHAID analyses were used to identify major components that predicted the diagnostic group. ADHD patients had increased plasma concentrations of sphingosine-1-phosphate (S1P d18:1) and sphinganine-1-phosphate (S1P d18:0). In addition, the endocannabinoids, anandamide (AEA) and arachidonoylglycerol were increased. MD/BD patients had increased long chain ceramides, most prominently Cer22:0, but low endocannabinoids in contrast to ADHD patients. Patients with ADHD and comorbid affective disorders displayed increased S1P d18:1 and increased Cer22:0, but the individual lipid levels were lower than in the non-comorbid disorders. Sphingolipid profiles differ between patients suffering from ADHD and affective disorders, with overlapping patterns in comorbid patients. The S1P d18:1 to Cer22:0 ratio may constitute a diagnostic or prognostic tool.}, language = {en} } @article{FernandezCastilloCabanaDominguezKappeletal.2021, author = {Fern{\`a}ndez-Castillo, No{\`e}lia and Cabana-Dom{\´i}nguez, Judit and Kappel, Djenifer B. and Torrico, B{\`a}rbara and Weber, Heike and Lesch, Klaus-Peter and Lao, Oscar and Reif, Andreas and Cormand, Bru}, title = {Exploring the contribution to ADHD of genes involved in Mendelian disorders presenting with hyperactivity and/or inattention}, series = {Genes}, volume = {13}, journal = {Genes}, number = {1}, issn = {2073-4425}, doi = {10.3390/genes13010093}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-252346}, year = {2021}, abstract = {Attention-deficit hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder characterized by hyperactivity, impulsivity, and/or inattention, which are symptoms also observed in many rare genetic disorders. We searched for genes involved in Mendelian disorders presenting with ADHD symptoms in the Online Mendelian Inheritance in Man (OMIM) database, to curate a list of new candidate risk genes for ADHD. We explored the enrichment of functions and pathways in this gene list, and tested whether rare or common variants in these genes are associated with ADHD or with its comorbidities. We identified 139 genes, causal for 137 rare disorders, mainly related to neurodevelopmental and brain function. Most of these Mendelian disorders also present with other psychiatric traits that are often comorbid with ADHD. Using whole exome sequencing (WES) data from 668 ADHD cases, we found rare variants associated with the dimension of the severity of inattention symptoms in three genes: KIF11, WAC, and CRBN. Then, we focused on common variants and identified six genes associated with ADHD (in 19,099 cases and 34,194 controls): MANBA, UQCC2, HIVEP2, FOPX1, KANSL1, and AUH. Furthermore, HIVEP2, FOXP1, and KANSL1 were nominally associated with autism spectrum disorder (ASD) (18,382 cases and 27,969 controls), as well as HIVEP2 with anxiety (7016 cases and 14,475 controls), and FOXP1 with aggression (18,988 individuals), which is in line with the symptomatology of the rare disorders they are responsible for. In conclusion, inspecting Mendelian disorders and the genes responsible for them constitutes a valuable approach for identifying new risk genes and the mechanisms of complex disorders.}, language = {en} } @article{PostemaHoogmanAmbrosinoetal.2021, author = {Postema, Merel C. and Hoogman, Martine and Ambrosino, Sara and Asherson, Philip and Banaschewski, Tobias and Bandeira, Cibele E. and Baranov, Alexandr and Bau, Claiton H.D. and Baumeister, Sarah and Baur-Streubel, Ramona and Bellgrove, Mark A. and Biederman, Joseph and Bralten, Janita and Brandeis, Daniel and Brem, Silvia and Buitelaar, Jan K. and Busatto, Geraldo F. and Castellanos, Francisco X. and Cercignani, Mara and Chaim-Avancini, Tiffany M. and Chantiluke, Kaylita C. and Christakou, Anastasia and Coghill, David and Conzelmann, Annette and Cubillo, Ana I. and Cupertino, Renata B. and de Zeeuw, Patrick and Doyle, Alysa E. and Durston, Sarah and Earl, Eric A. and Epstein, Jeffery N. and Ethofer, Thomas and Fair, Damien A. and Fallgatter, Andreas J. and Faraone, Stephen V. and Frodl, Thomas and Gabel, Matt C. and Gogberashvili, Tinatin and Grevet, Eugenio H. and Haavik, Jan and Harrison, Neil A. and Hartman, Catharina A. and Heslenfeld, Dirk J. and Hoekstra, Pieter J. and Hohmann, Sarah and H{\o}vik, Marie F. and Jernigan, Terry L. and Kardatzki, Bernd and Karkashadze, Georgii and Kelly, Clare and Kohls, Gregor and Konrad, Kerstin and Kuntsi, Jonna and Lazaro, Luisa and Lera-Miguel, Sara and Lesch, Klaus-Peter and Louza, Mario R. and Lundervold, Astri J. and Malpas, Charles B and Mattos, Paulo and McCarthy, Hazel and Namazova-Baranova, Leyla and Nicolau, Rosa and Nigg, Joel T. and Novotny, Stephanie E. and Oberwelland Weiss, Eileen and O'Gorman Tuura, Ruth L. and Oosterlaan, Jaap and Oranje, Bob and Paloyelis, Yannis and Pauli, Paul and Picon, Felipe A. and Plessen, Kerstin J. and Ramos-Quiroga, J. Antoni and Reif, Andreas and Reneman, Liesbeth and Rosa, Pedro G.P. and Rubia, Katya and Schrantee, Anouk and Schweren, Lizanne J.S. and Seitz, Jochen and Shaw, Philip and Silk, Tim J. and Skokauskas, Norbert and Soliva Vila, Juan C. and Stevens, Michael C. and Sudre, Gustavo and Tamm, Leanne and Tovar-Moll, Fernanda and van Erp, Theo G.M. and Vance, Alasdair and Vilarroya, Oscar and Vives-Gilabert, Yolanda and von Polier, Georg G. and Walitza, Susanne and Yoncheva, Yuliya N. and Zanetti, Marcus V. and Ziegler, Georg C. and Glahn, David C. and Jahanshad, Neda and Medland, Sarah E. and Thompson, Paul M. and Fisher, Simon E. and Franke, Barbara and Francks, Clyde}, title = {Analysis of structural brain asymmetries in attention-deficit/hyperactivity disorder in 39 datasets}, series = {Journal of Child Psychology and Psychiatry}, volume = {62}, journal = {Journal of Child Psychology and Psychiatry}, number = {10}, doi = {10.1111/jcpp.13396}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239968}, pages = {1202 -- 1219}, year = {2021}, abstract = {Objective Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium. Methods We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries. Results There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen's d from -0.18 to 0.18) and would not survive study-wide correction for multiple testing. Conclusion Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.}, language = {en} } @article{ZieglerEhlisWeberetal.2021, author = {Ziegler, Georg C. and Ehlis, Ann-Christine and Weber, Heike and Vitale, Maria Rosaria and Z{\"o}ller, Johanna E. M. and Ku, Hsing-Ping and Schiele, Miriam A. and K{\"u}rbitz, Laura I. and Romanos, Marcel and Pauli, Paul and Kalisch, Raffael and Zwanzger, Peter and Domschke, Katharina and Fallgatter, Andreas J. and Reif, Andreas and Lesch, Klaus-Peter}, title = {A Common CDH13 Variant is Associated with Low Agreeableness and Neural Responses to Working Memory Tasks in ADHD}, series = {Genes}, volume = {12}, journal = {Genes}, number = {9}, issn = {2073-4425}, doi = {10.3390/genes12091356}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-245220}, year = {2021}, abstract = {The cell—cell signaling gene CDH13 is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression. CDH13 regulates axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of CDH13 on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the CDH13 gene in humans is sparse. Therefore, we tested for association of a functional intronic CDH13 SNP rs2199430 with ADHD in a sample of 998 adult patients and 884 healthy controls. The Big Five personality traits were assessed by the NEO-PI-R questionnaire. Assuming that altered neural correlates of working memory and cognitive response inhibition show genotype-dependent alterations, task performance and electroencephalographic event-related potentials were measured by n-back and continuous performance (Go/NoGo) tasks. The rs2199430 genotype was not associated with adult ADHD on the categorical diagnosis level. However, rs2199430 was significantly associated with agreeableness, with minor G allele homozygotes scoring lower than A allele carriers. Whereas task performance was not affected by genotype, a significant heterosis effect limited to the ADHD group was identified for the n-back task. Heterozygotes (AG) exhibited significantly higher N200 amplitudes during both the 1-back and 2-back condition in the central electrode position Cz. Consequently, the common genetic variation of CDH13 is associated with personality traits and impacts neural processing during working memory tasks. Thus, CDH13 might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD.}, language = {en} } @article{GrimmWeberKittelSchneideretal.2020, author = {Grimm, Oliver and Weber, Heike and Kittel-Schneider, Sarah and Kranz, Thorsten M. and Jacob, Christian P. and Lesch, Klaus-Peter and Reif, Andreas}, title = {Impulsivity and Venturesomeness in an Adult ADHD Sample: Relation to Personality, Comorbidity, and Polygenic Risk}, series = {Frontiers in Psychiatry}, volume = {11}, journal = {Frontiers in Psychiatry}, issn = {1664-0640}, doi = {10.3389/fpsyt.2020.557160}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-219751}, year = {2020}, abstract = {While impulsivity is a basic feature of attention-deficit/hyperactivity disorder (ADHD), no study explored the effect of different components of the Impulsiveness (Imp) and Venturesomeness (Vent) scale (IV7) on psychiatric comorbidities and an ADHD polygenic risk score (PRS). We used the IV7 self-report scale in an adult ADHD sample of 903 patients, 70\% suffering from additional comorbid disorders, and in a subsample of 435 genotyped patients. Venturesomeness, unlike immediate Impulsivity, is not specific to ADHD. We consequently analyzed the influence of Imp and Vent also in the context of a PRS on psychiatric comorbidities of ADHD. Vent shows a distinctly different distribution of comorbidities, e.g., less anxiety and depression. PRS showed no effect on different ADHD comorbidities, but correlated with childhood hyperactivity. In a complementary analysis using principal component analysis with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition ADHD criteria, revised NEO Personality Inventory, Imp, Vent, and PRS, we identified three ADHD subtypes. These are an impulsive-neurotic type, an adventurous-hyperactive type with a stronger genetic component, and an anxious-inattentive type. Our study thus suggests the importance of adventurousness and the differential consideration of impulsivity in ADHD. The genetic risk is distributed differently between these subtypes, which underlines the importance of clinically motivated subtyping. Impulsivity subtyping might give insights into the organization of comorbid disorders in ADHD and different genetic background.}, language = {en} } @article{PalladinoChiocchettiFranketal.2020, author = {Palladino, Viola Stella and Chiocchetti, Andreas G. and Frank, Lukas and Haslinger, Denise and McNeill, Rhiannon and Radtke, Franziska and Till, Andreas and Haupt, Simone and Br{\"u}stle, Oliver and G{\"u}nther, Katharina and Edenhofer, Frank and Hoffmann, Per and Reif, Andreas and Kittel-Schneider, Sarah}, title = {Energy metabolism disturbances in cell models of PARK2 CNV carriers with ADHD}, series = {Journal of Clinical Medicine}, volume = {9}, journal = {Journal of Clinical Medicine}, number = {12}, issn = {2077-0383}, doi = {10.3390/jcm9124092}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-220074}, year = {2020}, abstract = {The main goal of the present study was the identification of cellular phenotypes in attention-deficit-/hyperactivity disorder (ADHD) patient-derived cellular models from carriers of rare copy number variants (CNVs) in the PARK2 locus that have been previously associated with ADHD. Human-derived fibroblasts (HDF) were cultured and human-induced pluripotent stem cells (hiPSC) were reprogrammed and differentiated into dopaminergic neuronal cells (mDANs). A series of assays in baseline condition and in different stress paradigms (nutrient deprivation, carbonyl cyanide m-chlorophenyl hydrazine (CCCP)) focusing on mitochondrial function and energy metabolism (ATP production, basal oxygen consumption rates, reactive oxygen species (ROS) abundance) were performed and changes in mitochondrial network morphology evaluated. We found changes in PARK2 CNV deletion and duplication carriers with ADHD in PARK2 gene and protein expression, ATP production and basal oxygen consumption rates compared to healthy and ADHD wildtype control cell lines, partly differing between HDF and mDANs and to some extent enhanced in stress paradigms. The generation of ROS was not influenced by the genotype. Our preliminary work suggests an energy impairment in HDF and mDAN cells of PARK2 CNV deletion and duplication carriers with ADHD. The energy impairment could be associated with the role of PARK2 dysregulation in mitochondrial dynamics.}, language = {en} } @article{BaaderKianiBrunkhorstKanaanetal.2020, author = {Baader, Anna and Kiani, Behnaz and Brunkhorst-Kanaan, Nathalie and Kittel-Schneider, Sarah and Reif, Andreas and Grimm, Oliver}, title = {A within-sample comparison of two innovative neuropsychological tests for assessing ADHD}, series = {Brain Sciences}, volume = {11}, journal = {Brain Sciences}, number = {1}, issn = {2076-3425}, doi = {10.3390/brainsci11010036}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-220089}, year = {2020}, abstract = {New innovative neuropsychological tests in attention deficit hyperactivity disorder ADHD have been proposed as objective measures for diagnosis and therapy. The current study aims to investigate two different commercial continuous performance tests (CPT) in a head-to-head comparison regarding their comparability and their link with clinical parameters. The CPTs were evaluated in a clinical sample of 29 adult patients presenting in an ADHD outpatient clinic. Correlational analyses were performed between neuropsychological data, clinical rating scales, and a personality-based measure. Though inattention was found to positively correlate between the two tests (r = 0.49, p = 0.01), no association with clinical measures and inattention was found for both tests. While hyperactivity did not correlate between both tests, current ADHD symptoms were positively associated with Nesplora Aquarium's motor activity (r = 0.52 to 0.61, p < 0.05) and the Qb-Test's hyperactivity (r = 0.52 to 0.71, p < 0.05). Conclusively, the overall comparability of the tests was limited and correlation with clinical parameters was low. While our study shows some interesting correlation between clinical symptoms and sub-scales of these tests, usage in clinical practice is not recommended.}, language = {en} } @article{LeopoldBauerBechdolfetal.2020, author = {Leopold, Karolina and Bauer, Michael and Bechdolf, Andreas and Correll, Christoph U. and Holtmann, Martin and Juckel, Georg and Lambert, Martin and Meyer, Thomas D. and Pfeiffer, Steffi and Kittel-Schneider, Sarah and Reif, Andreas and Stamm, Thomas J. and Rottmann-Wolf, Maren and Mathiebe, Josephine and Kellmann, Eva L. and Ritter, Philipp and Kr{\"u}ger-{\"O}zg{\"u}rdal, Seza and Karow, Anne and Sondergeld, Lene-Marie and Roessner, Veit and Sauer, Cathrin and Pfennig, Andrea}, title = {Efficacy of cognitive-behavioral group therapy in patients at risk for serious mental illness presenting with subthreshold bipolar symptoms: Results from a prespecified interim analysis of a multicenter, randomized, controlled study}, series = {Bipolar Disorders}, volume = {22}, journal = {Bipolar Disorders}, number = {5}, doi = {10.1111/bdi.12894}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-215469}, pages = {517 -- 529}, year = {2020}, abstract = {Objective Most patients with bipolar disorders (BD) exhibit prodromal symptoms before a first (hypo)manic episode. Patients with clinically significant symptoms fulfilling at-risk criteria for serious mental illness (SMI) require effective and safe treatment. Cognitive-behavioral psychotherapy (CBT) has shown promising results in early stages of BD and in patients at high risk for psychosis. We aimed to investigate whether group CBT can improve symptoms and functional deficits in young patients at risk for SMI presenting with subthreshold bipolar symptoms. Method In a multicenter, randomized, controlled trial, patients at clinical risk for SMI presenting with subthreshold bipolar symptoms aged 15-30 years were randomized to 14 weeks of at-risk for BD-specific group CBT or unstructured group meetings. Primary efficacy endpoints were differences in affective symptomatology and psychosocial functioning at 14 weeks. At-risk status was defined as a combination of subthreshold bipolar symptomatology, reduction of psychosocial functioning and a family history for (schizo)affective disorders. A prespecified interim analysis was conducted at 75\% of the targeted sample. Results Of 128 screened participants, 75 were randomized to group CBT (n = 38, completers = 65.8\%) vs unstructured group meetings (n = 37, completers = 78.4\%). Affective symptomatology and psychosocial functioning improved significantly at week 14 (P < .001) and during 6 months (P < .001) in both groups, without significant between-group differences. Findings are limited by the interim character of the analysis, the use of not fully validated early detection interviews, a newly adapted intervention manual, and the substantial drop-outs. Conclusions Results suggest that young patients at-risk for SMI presenting with subthreshold bipolar symptoms benefit from early group sessions. The degree of specificity and psychotherapeutic interaction needed requires clarification.}, language = {en} } @article{BiereKranzMaturaetal.2020, author = {Biere, Silvia and Kranz, Thorsten M. and Matura, Silke and Petrova, Kristiyana and Streit, Fabian and Chiocchetti, Andreas G. and Grimm, Oliver and Brum, Murielle and Brunkhorst-Kanaan, Natalie and Oertel, Viola and Malyshau, Aliaksandr and Pfennig, Andrea and Bauer, Michael and Schulze, Thomas G. and Kittel-Schneider, Sarah and Reif, Andreas}, title = {Risk Stratification for Bipolar Disorder Using Polygenic Risk Scores Among Young High-Risk Adults}, series = {Frontiers in Psychiatry}, volume = {11}, journal = {Frontiers in Psychiatry}, doi = {10.3389/fpsyt.2020.552532}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-214976}, year = {2020}, abstract = {Objective: Identifying high-risk groups with an increased genetic liability for bipolar disorder (BD) will provide insights into the etiology of BD and contribute to early detection of BD. We used the BD polygenic risk score (PRS) derived from BD genome-wide association studies (GWAS) to explore how such genetic risk manifests in young, high-risk adults. We postulated that BD-PRS would be associated with risk factors for BD. Methods: A final sample of 185 young, high-risk German adults (aged 18-35 years) were grouped into three risk groups and compared to a healthy control group (n = 1,100). The risk groups comprised 117 cases with attention deficit hyperactivity disorder (ADHD), 45 with major depressive disorder (MDD), and 23 help-seeking adults with early recognition symptoms [ER: positive family history for BD, (sub)threshold affective symptomatology and/or mood swings, sleeping disorder]. BD-PRS was computed for each participant. Logistic regression models (controlling for sex, age, and the first five ancestry principal components) were used to assess associations of BD-PRS and the high-risk phenotypes. Results: We observed an association between BD-PRS and combined risk group status (OR = 1.48, p < 0.001), ADHD diagnosis (OR = 1.32, p = 0.009), MDD diagnosis (OR = 1.96, p < 0.001), and ER group status (OR = 1.7, p = 0.025; not significant after correction for multiple testing) compared to healthy controls. Conclusions: In the present study, increased genetic risk for BD was a significant predictor for MDD and ADHD status, but not for ER. These findings support an underlying shared risk for both MDD and BD as well as ADHD and BD. Improving our understanding of the underlying genetic architecture of these phenotypes may aid in early identification and risk stratification.}, language = {en} } @article{RaynerColemanPurvesetal.2019, author = {Rayner, Christopher and Coleman, Jonathan R. I. and Purves, Kirstin L. and Hodsoll, John and Goldsmith, Kimberley and Alpers, Georg W. and Andersson, Evelyn and Arolt, Volker and Boberg, Julia and B{\"o}gels, Susan and Creswell, Cathy and Cooper, Peter and Curtis, Charles and Deckert, J{\"u}rgen and Domschke, Katharina and El Alaoui, Samir and Fehm, Lydia and Fydrich, Thomas and Gerlach, Alexander L. and Grocholewski, Anja and Hahlweg, Kurt and Hamm, Alfons and Hedman, Erik and Heiervang, Einar R. and Hudson, Jennifer L. and J{\"o}hren, Peter and Keers, Robert and Kircher, Tilo and Lang, Thomas and Lavebratt, Catharina and Lee, Sang-hyuck and Lester, Kathryn J. and Lindefors, Nils and Margraf, J{\"u}rgen and Nauta, Maaike and Pan{\´e}-Farr{\´e}, Christiane A. and Pauli, Paul and Rapee, Ronald M. and Reif, Andreas and Rief, Winfried and Roberts, Susanna and Schalling, Martin and Schneider, Silvia and Silverman, Wendy K. and Str{\"o}hle, Andreas and Teismann, Tobias and Thastum, Mikael and Wannem{\"u}ller, Andre and Weber, Heike and Wittchen, Hans-Ulrich and Wolf, Christiane and R{\"u}ck, Christian and Breen, Gerome and Eley, Thalia C.}, title = {A genome-wide association meta-analysis of prognostic outcomes following cognitive behavioural therapy in individuals with anxiety and depressive disorders}, series = {Translational Psychiatry}, volume = {9}, journal = {Translational Psychiatry}, number = {150}, doi = {10.1038/s41398-019-0481-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-225048}, pages = {1-13}, year = {2019}, abstract = {Major depressive disorder and the anxiety disorders are highly prevalent, disabling and moderately heritable. Depression and anxiety are also highly comorbid and have a strong genetic correlation (r(g) approximate to 1). Cognitive behavioural therapy is a leading evidence-based treatment but has variable outcomes. Currently, there are no strong predictors of outcome. Therapygenetics research aims to identify genetic predictors of prognosis following therapy. We performed genome-wide association meta-analyses of symptoms following cognitive behavioural therapy in adults with anxiety disorders (n = 972), adults with major depressive disorder (n = 832) and children with anxiety disorders (n = 920; meta-analysis n = 2724). We (h(SNP)(2)) and polygenic scoring was used to examine genetic associations between therapy outcomes and psychopathology, personality and estimated the variance in therapy outcomes that could be explained by common genetic variants learning. No single nucleotide polymorphisms were strongly associated with treatment outcomes. No significant estimate of h(SNP)(2) could be obtained, suggesting the heritability of therapy outcome is smaller than our analysis was powered to detect. Polygenic scoring failed to detect genetic overlap between therapy outcome and psychopathology, personality or learning. This study is the largest therapygenetics study to date. Results are consistent with previous, similarly powered genome-wide association studies of complex traits.}, language = {en} } @article{EversVeehMcNeilletal.2019, author = {Evers, Ann-Kristin and Veeh, Julia and McNeill, Rhiannon and Reif, Andreas and Kittel-Schneider, Sarah}, title = {C-reactive protein concentration in bipolar disorder: association with genetic variants}, series = {International Journal of Bipolar Disorders}, volume = {7}, journal = {International Journal of Bipolar Disorders}, doi = {10.1186/s40345-019-0162-z}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-202289}, pages = {26}, year = {2019}, abstract = {Background Several recent studies have investigated the role of C-reactive protein (CRP) in bipolar disorder (BD), but few studies have directly investigated the interaction between CRP genetic variants and peripheral CRP concentration across different phases of BD. In this study, we aimed to replicate previous findings that demonstrated altered CRP levels in BD, and to investigate whether there is an association of peripheral protein expression with genetic variants in the CRP gene. Methods 221 patients were included in the study, of which 183 (all episodes, 46 not medicated, 174 medicated) were genotyped for CRP single-nucleotide polymorphisms (SNPs) shown to influence peripheral CRP protein expression (rs1800947, rs2808630, rs1417938, rs1205). Results There were no differences in CRP levels associated with the genotypes, only regarding the rs1205 SNP there were significantly different CRP protein expression between the genotypes when taking body mass index, age, BD polarity, subtype and leukocyte number into account. However, we could show significantly elevated CRP protein expression in manic patients compared to euthymic and depressed patients, independent from genotype. Medication was found to have no effect on CRP protein expression. Conclusions These results indicate that low grade inflammation might play a role in mania and might be rather a state than a trait marker of bipolar disorder.}, language = {en} } @article{KittelSchneiderWolffQueiseretal.2019, author = {Kittel-Schneider, Sarah and Wolff, Sarah and Queiser, Kristin and Wessendorf, Leonie and Meier, Anna Maria and Verdenhalven, Moritz and Brunkhorst-Kanaan, Nathalie and Grimm, Oliver and McNeill, Rhiannon and Grabow, Sascha and Reimertz, Christoph and Nau, Christoph and Klos, Michelle and Reif, Andreas}, title = {Prevalence of ADHD in accident victims: results of the PRADA study}, series = {Journal of Clinical Medicine}, volume = {8}, journal = {Journal of Clinical Medicine}, number = {10}, issn = {2077-0383}, doi = {10.3390/jcm8101643}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-193293}, pages = {1643}, year = {2019}, abstract = {Background: Recent research has shown an increased risk of accidents and injuries in ADHD patients, which could potentially be reduced by stimulant treatment. Therefore, the first aim of our study was to evaluate the prevalence of adult ADHD in a trauma surgery population. The second aim was to investigate accident mechanisms and circumstances which could be specific to ADHD patients, in comparison to the general population. Methods: We screened 905 accident victims for ADHD using the ASRS 18-item self-report questionnaire. The basic demographic data and circumstances of the accidents were also assessed. Results: Prevalence of adult ADHD was found to be 6.18\% in our trauma surgery patient sample. ADHD accident victims reported significantly higher rates of distraction, stress and overconfidence in comparison to non-ADHD accident victims. Overconfidence and being in thoughts as causal mechanisms for the accidents remained significantly higher in ADHD patients after correction for multiple comparison. ADHD patients additionally reported a history of multiple accidents. Conclusion: The majority of ADHD patients in our sample had not previously been diagnosed and were therefore not receiving treatment. The results subsequently suggest that general ADHD screening in trauma surgery patients may be useful in preventing further accidents in ADHD patients. Furthermore, psychoeducation regarding specific causal accident mechanisms could be implemented in ADHD therapy to decrease accident incidence rate}, language = {en} } @article{SchieleZieglerKollertetal.2018, author = {Schiele, Miriam A. and Ziegler, Christiane and Kollert, Leonie and Katzorke, Andrea and Schartner, Christoph and Busch, Yasmin and Gromer, Daniel and Reif, Andreas and Pauli, Paul and Deckert, J{\"u}rgen and Herrmann, Martin J. and Domschke, Katharina}, title = {Plasticity of Functional MAOA Gene Methylation in Acrophobia}, series = {International Journal of Neuropsychopharmacology}, volume = {21}, journal = {International Journal of Neuropsychopharmacology}, number = {9}, doi = {10.1093/ijnp/pyy050}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-228571}, pages = {822-827}, year = {2018}, abstract = {Epigenetic mechanisms have been proposed to mediate fear extinction in animal models. Here, MAOA methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells before and after a 2-week exposure therapy in a sample of n = 28 female patients with acrophobia as well as in n = 28 matched healthy female controls. Clinical response was measured using the Acrophobia Questionnaire and the Attitude Towards Heights Questionnaire. The functional relevance of altered MAOA methylation was investigated by luciferase-based reporter gene assays. MAOA methylation was found to be significantly decreased in patients with acrophobia compared with healthy controls. Furthermore, MAOA methylation levels were shown to significantly increase after treatment and correlate with treatment response as reflected by decreasing Acrophobia Questionnaire/Attitude Towards Heights Questionnaire scores. Functional analyses revealed decreased reporter gene activity in presence of methylated compared with unmethylated pCpGfree_MAOA reporter gene vector constructs. The present proof-of-concept psychotherapy-epigenetic study for the first time suggests functional MAOA methylation changes as a potential epigenetic correlate of treatment response in acrophobia and fosters further investigation into the notion of epigenetic mechanisms underlying fear extinction.}, language = {en} } @article{OezkurMagyarThomasetal.2018, author = {Oezkur, Mehmet and Magyar, Atilla and Thomas, Phillip and Reif, Andreas and St{\"o}rk, Stefan and Heuschmann, Peter U. and Leyh, Rainer G. and Wagner, Martin}, title = {The COMT-polymorphism is not associated with the incidence of acute kidney injury after cardiac surgery - a prospective cohort study}, series = {BMC Nephrology}, volume = {19}, journal = {BMC Nephrology}, number = {34}, doi = {10.1186/s12882-018-0820-x}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-175529}, year = {2018}, abstract = {Background: The Catechol-O-methyltransferase (COMT) represents the key enzyme in catecholamine degradation. Recent studies suggest that the COMT rs4680 polymorphism is associated with the response to endogenous and exogenous catecholamines. There are, however, conflicting data regarding the COMT Met/Met phenotype being associated with an increased risk of acute kidney injury (AKI) after cardiac surgery. The aim of the current study is to prospectively investigate the impact of the COMT rs4680 polymorphism on the incidence of AKI in patients undergoing cardiac surgery. Methods: In this prospective single center cohort study consecutive patients hospitalized for elective cardiac surgery including cardiopulmonary-bypass (CPB) were screened for participation. Demographic clinical data, blood, urine and tissue samples were collected at predefined time points throughout the clinical stay. AKI was defined according to recent recommendations of the Kidney Disease Improving Global Outcome (KDIGO) group. Genetic analysis was performed after patient enrolment was completed. Results: Between April and December 2014, 150 patients were recruited. The COMT genotypes were distributed as follows: Val/Met 48.7\%, Met/Met 29.3\%, Val/Val 21.3\%. No significant differences were found for demography, comorbidities, or operative strategy according to the underlying COMT genotype. AKI occurred in 35 patients (23.5\%) of the total cohort, and no differences were evident between the COMT genotypes (20.5\% Met/Met, 24.7\% Val/Met, 25.0\% Val/Val, p = 0.66). There were also no differences in the post-operative period, including ICU or in-hospital stay. Conclusions: We did not find statistically significant variations in the risk for postoperative AKI, length of ICU or in-hospital stay according to the underlying COMT genotype.}, language = {en} } @article{KatzorkeZellerMuelleretal.2017, author = {Katzorke, Andrea and Zeller, Julia B. M. and M{\"u}ller, Laura D. and Lauer, Martin and Polak, Thomas and Reif, Andreas and Deckert, J{\"u}rgen and Herrmann, Martin J.}, title = {Reduced activity in the right inferior frontal gyrus in elderly APOE-E4 carriers during a verbal fluency task}, series = {Frontiers in Human Neuroscience}, volume = {11}, journal = {Frontiers in Human Neuroscience}, doi = {10.3389/fnhum.2017.00046}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-171892}, year = {2017}, abstract = {Apolipoprotein-E4 (APOE-E4) is a major genetic risk factor for developing Alzheimer's disease (AD). The verbal fluency task (VFT), especially the subtask category fluency, has shown to provide a good discrimination between cognitively normal controls and subjects with AD. Interestingly, APOE-E4 seems to have no effect on the behavioral performance during a VFT in healthy elderly. Thus, the purpose of the present study was to reveal possible compensation mechanisms by investigating the effect of APOE-E4 on the hemodynamic response in non-demented elderly during a VFT by using functional near-infrared spectroscopy (fNIRS). We compared performance and hemodynamic response of high risk APOE-E4/E4, -E3/E4 carriers with neutral APOE-E3/E3 non-demented subjects (N = 288; 70-77 years). No difference in performance was found. APOE-E4/E4, -E3/E4 carriers had a decreased hemodynamic response in the right inferior frontal junction (IFJ) with a corresponding higher response in the left middle frontal gyrus (MFG) during category fluency. Performance was correlated with the hemodynamic response in the MFG. We assume a compensation of decreased IFJ brain activation by utilizing the MFG during category fluency and thus resulting in no behavioral differences between APOE-groups during the performance of a VFT.}, language = {en} } @article{KingslakeDiasDawsonetal.2017, author = {Kingslake, Jonathan and Dias, Rebecca and Dawson, Gerard R. and Simon, Judit and Goodwin, Guy M. and Harmer, Catherine J. and Morriss, Richard and Brown, Susan and Guo, Boliang and Dourish, Colin T. and Ruh{\´e}, Henricus G. and Lever, Anne G. and Veltman, Dick J. and van Schaik, Anneke and Deckert, J{\"u}rgen and Reif, Andreas and St{\"a}blein, Michael and Menke, Andreas and Gorwood, Philip and Voegeli, G{\´e}raldine and Perez, Victor and Browning, Michael}, title = {The effects of using the PReDicT Test to guide the antidepressant treatment of depressed patients: study protocol for a randomised controlled trial}, series = {Trials}, volume = {18}, journal = {Trials}, doi = {10.1186/s13063-017-2247-2}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173012}, year = {2017}, abstract = {Background Antidepressant medication is commonly used to treat depression. However, many patients do not respond to the first medication prescribed and improvements in symptoms are generally only detectable by clinicians 4-6 weeks after the medication has been initiated. As a result, there is often a long delay between the decision to initiate an antidepressant medication and the identification of an effective treatment regimen. Previous work has demonstrated that antidepressant medications alter subtle measures of affective cognition in depressed patients, such as the appraisal of facial expression. Furthermore, these cognitive effects of antidepressants are apparent early in the course of treatment and can also predict later clinical response. This trial will assess whether an electronic test of affective cognition and symptoms (the Predicting Response to Depression Treatment Test; PReDicT Test) can be used to guide antidepressant treatment in depressed patients and, therefore, hasten treatment response compared to a control group of patients treated as usual. Methods/design The study is a randomised, two-arm, multi-centre, open-label, clinical investigation of a medical device, the PReDicT Test. It will be conducted in five European countries (UK, France, Spain, Germany and the Netherlands) in depressed patients who are commencing antidepressant medication. Patients will be randomised to treatment guided by the PReDicT Test (PReDicT arm) or to Treatment as Usual (TaU arm). Patients in the TaU arm will be treated as per current standard guidelines in their particular country. Patients in the PReDicT arm will complete the PReDicT Test after 1 (and if necessary, 2) weeks of treatment. If the test indicates non-response to the treatment, physicians will be advised to immediately alter the patient's antidepressant therapy by dose escalation or switching to another compound. The primary outcome of the study is the proportion of patients showing a clinical response (defined as 50\% or greater decrease in baseline scores of depressionmeasured using the Quick Inventory of Depressive Symptoms - Self-Rated questionnaire) at week 8. Health economic and acceptability data will also be collected and analysed. Discussion This trial will test the clinical efficacy, cost-effectiveness and acceptability of using the novel PReDicT Test to guide antidepressant treatment selection in depressed patients. Trial registration ClinicalTrials.gov, ID: NCT02790970. Registered on 30 March 2016.}, language = {en} } @article{GruenewaldLangeWerneretal.2017, author = {Gr{\"u}newald, Benedikt and Lange, Maren D and Werner, Christian and O'Leary, Aet and Weishaupt, Andreas and Popp, Sandy and Pearce, David A and Wiendl, Heinz and Reif, Andreas and Pape, Hans C and Toyka, Klaus V and Sommer, Claudia and Geis, Christian}, title = {Defective synaptic transmission causes disease signs in a mouse model of juvenile neuronal ceroid lipofuscinosis}, series = {eLife}, volume = {6}, journal = {eLife}, number = {e28685}, doi = {10.7554/eLife.28685}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-170004}, year = {2017}, abstract = {Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease) caused by mutations in the CLN3 gene is the most prevalent inherited neurodegenerative disease in childhood resulting in widespread central nervous system dysfunction and premature death. The consequences of CLN3 mutation on the progression of the disease, on neuronal transmission, and on central nervous network dysfunction are poorly understood. We used Cln3 knockout (Cln3\(^{Δex1-6}\)) mice and found increased anxiety-related behavior and impaired aversive learning as well as markedly affected motor function including disordered coordination. Patch-clamp and loose-patch recordings revealed severely affected inhibitory and excitatory synaptic transmission in the amygdala, hippocampus, and cerebellar networks. Changes in presynaptic release properties may result from dysfunction of CLN3 protein. Furthermore, loss of calbindin, neuropeptide Y, parvalbumin, and GAD65-positive interneurons in central networks collectively support the hypothesis that degeneration of GABAergic interneurons may be the cause of supraspinal GABAergic disinhibition.}, language = {en} } @article{EngeFleischhauerGaertneretal.2016, author = {Enge, S{\"o}ren and Fleischhauer, Monika and G{\"a}rtner, Anne and Reif, Andreas and Lesch, Klaus-Peter and Kliegel, Matthias and Strobel, Alexander}, title = {Brain-Derived Neurotrophic Factor (Val66Met) and Serotonin Transporter (5-HTTLPR) Polymorphisms Modulate Plasticity in Inhibitory Control Performance Over Time but Independent of Inhibitory Control Training}, series = {Frontiers in Human Neuroscience}, volume = {10}, journal = {Frontiers in Human Neuroscience}, number = {370}, doi = {10.3389/fnhum.2016.00370}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-165176}, year = {2016}, abstract = {Several studies reported training-induced improvements in executive function tasks and also observed transfer to untrained tasks. However, the results are mixed and there is a large interindividual variability within and across studies. Given that training-related performance changes would require modification, growth or differentiation at the cellular and synaptic level in the brain, research on critical moderators of brain plasticity potentially explaining such changes is needed. In the present study, a pre-post-follow-up design (N = 122) and a 3-weeks training of two response inhibition tasks (Go/NoGo and Stop-Signal) was employed and genetic variation (Val66Met) in the brain-derived neurotrophic factor (BDNF) promoting differentiation and activity-dependent synaptic plasticity was examined. Because Serotonin (5-HT) signaling and the interplay of BDNF and 5-HT are known to critically mediate brain plasticity, genetic variation in the 5-HTT gene-linked polymorphic region (5-HTTLPR) was also addressed. The overall results show that the kind of training (i.e., adaptive vs. non-adaptive) did not evoke genotype-dependent differences. However, in the Go/NoGo task, better inhibition performance (lower commission errors) were observed for BDNF Val/Val genotype carriers compared to Met-allele ones supporting similar findings from other cognitive tasks. Additionally, a gene-gene interaction suggests a more impulsive response pattern (faster responses accompanied by higher commission error rates) in homozygous l-allele carriers relative to those with the s-allele of 5-HTTLPR. This, however, is true only in the presence of the Met-allele of BDNF, while the Val/Val genotype seems to compensate for such non-adaptive responding. Intriguingly, similar results were obtained for the Stop-Signal task. Here, differences emerged at post-testing, while no differences were observed at T1. In sum, although no genotype-dependent differences between the relevant training groups emerged suggesting no changes in the trained inhibition function, the observed genotype-dependent performance changes from pre- to post measurement may reflect rapid learning or memory effects linked to BDNF and 5-HTTLPR. In line with ample evidence on BDNF and BDNF-5-HT system interactions to induce (rapid) plasticity especially in hippocampal regions and in response to environmental demands, the findings may reflect genotype-dependent differences in the acquisition and consolidation of task-relevant information, thereby facilitating a more adaptive responding to task-specific requirements.}, language = {en} }