Publications by authors named "Katharina Domschke"

267 Publications

A Common Variant Is Associated with Low Agreeableness and Neural Responses to Working Memory Tasks in ADHD.

Genes (Basel) 2021 Aug 29;12(9). Epub 2021 Aug 29.

Division of Molecular Psychiatry, Center of Mental Health, University of Würzburg, 97080 Würzburg, Germany.

The cell-cell signaling gene is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression. regulates axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the gene in humans is sparse. Therefore, we tested for association of a functional intronic 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 is associated with personality traits and impacts neural processing during working memory tasks. Thus, might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD.
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http://dx.doi.org/10.3390/genes12091356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8471784PMC
August 2021

Social cognitive factors outweigh negative emotionality in predicting COVID-19 related safety behaviors.

Prev Med Rep 2021 Dec 16;24:101559. Epub 2021 Sep 16.

Department of Psychology, University of Würzburg, Germany.

Emotion-motivation models propose that behaviors, including health behaviors, should be predicted by the same variables that also predict negative affect since emotional reactions should induce a motivation to avoid threatening situations. In contrast, social cognitive models propose that safety behaviors are predicted by a different set of variables that mainly reflect cognitive and socio-structural aspects. Here, we directly tested these opposing hypotheses in young adults ( = 4134) in the context of COVID-19-related safety behaviors to prevent infections. In each participant, we collected measures of negative affect as well as cognitive and socio-structural variables during the lockdown in the first infection wave in Germany. We found a negative effect of the pandemic on emotional responses. However, this was not the main predictor for young adults' willingness to comply with COVID-19-related safety measures. Instead, individual differences in compliance were mainly predicted by cognitive and socio-structural variables. These results were confirmed in an independent data set. This study shows that individuals scoring high on negative affect during the pandemic are not necessarily more likely to comply with safety regulations. Instead, political measures should focus on cognitive interventions and the societal relevance of the health issue. These findings provide important insights into the basis of health-related concerns and feelings as well as behavioral adaptations.
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http://dx.doi.org/10.1016/j.pmedr.2021.101559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450590PMC
December 2021

The cognitive anxiety sensitivity treatment (CAST) in anxiety prevention - Focus on separation anxiety and interoception.

Eur Neuropsychopharmacol 2021 Sep 15;53:104-113. Epub 2021 Sep 15.

Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Center for Basics in Neuromodulation, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address:

Given the high prevalence and considerable clinical and societal burden of anxiety disorders, preventive measures are urgently warranted to reduce their incidence and overall healthcare impact. Anxiety sensitivity (AS) - a key element in learning theories of anxiety disorders in the context of interoceptive conditioning - constitutes a malleable risk factor of particularly panic disorder and separation anxiety, which share developmental, nosological, epidemiological and pathomechanistic characteristics. The computer-assisted 'Cognitive Anxiety Sensitivity Treatment' (CAST) targeting interoceptive anxiety symptoms (cf. Schmidt et al., 2014) was translated, intensified and culturally adapted to German and evaluated in a sample of 105 healthy adult volunteers with elevated AS (mean ASI-3: 29.5) applying a randomized design. Success of the intervention was measured as a function of AS and separation anxiety (ASA-27) ∼6 weeks (T1) and ∼6 months (T2) after the intervention. As compared to waitlist, CAST resulted in a significant reduction of AS at both T1 and T2. Separation anxiety was not directly reduced by the intervention, but decreased mediated by a decline in AS. A composite interoceptive score capturing changes in sensitivity to respiratory symptoms during the baseline therapist-accompanied CAST session was shown to be predictive of overall response at T1. In sum, CAST-German Version was successfully established as an effective intervention reducing AS, while at the same time indirectly decreasing separation anxiety. A composite interoceptive score predicting treatment response might aid in further delineating risk markers informing targeted preventive interventions for anxiety disorders.
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http://dx.doi.org/10.1016/j.euroneuro.2021.08.265DOI Listing
September 2021

Risk and protective factors for mental disorders beyond genetics: an evidence-based atlas.

World Psychiatry 2021 Oct;20(3):417-436

Early Psychosis: Interventions and Clinical-detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.

Decades of research have revealed numerous risk factors for mental disorders beyond genetics, but their consistency and magnitude remain uncer-tain. We conducted a "meta-umbrella" systematic synthesis of umbrella reviews, which are systematic reviews of meta-analyses of individual studies, by searching international databases from inception to January 1, 2021. We included umbrella reviews on non-purely genetic risk or protective factors for any ICD/DSM mental disorders, applying an established classification of the credibility of the evidence: class I (convincing), class II (highly suggestive), class III (suggestive), class IV (weak). Sensitivity analyses were conducted on prospective studies to test for temporality (reverse causation), TRANSD criteria were applied to test transdiagnosticity of factors, and A Measurement Tool to Assess Systematic Reviews (AMSTAR) was employed to address the quality of meta-analyses. Fourteen eligible umbrella reviews were retrieved, summarizing 390 meta-analyses and 1,180 associations between putative risk or protective factors and mental disorders. We included 176 class I to III evidence associations, relating to 142 risk/protective factors. The most robust risk factors (class I or II, from prospective designs) were 21. For dementia, they included type 2 diabetes mellitus (risk ratio, RR from 1.54 to 2.28), depression (RR from 1.65 to 1.99) and low frequency of social contacts (RR=1.57). For opioid use disorders, the most robust risk factor was tobacco smoking (odds ratio, OR=3.07). For non-organic psychotic disorders, the most robust risk factors were clinical high risk state for psychosis (OR=9.32), cannabis use (OR=3.90), and childhood adversities (OR=2.80). For depressive disorders, they were widowhood (RR=5.59), sexual dysfunction (OR=2.71), three (OR=1.99) or four-five (OR=2.06) metabolic factors, childhood physical (OR=1.98) and sexual (OR=2.42) abuse, job strain (OR=1.77), obesity (OR=1.35), and sleep disturbances (RR=1.92). For autism spectrum disorder, the most robust risk factor was maternal overweight pre/during pregnancy (RR=1.28). For attention-deficit/hyperactivity disorder (ADHD), they were maternal pre-pregnancy obesity (OR=1.63), maternal smoking during pregnancy (OR=1.60), and maternal overweight pre/during pregnancy (OR=1.28). Only one robust protective factor was detected: high physical activity (hazard ratio, HR=0.62) for Alzheimer's disease. In all, 32.9% of the associations were of high quality, 48.9% of medium quality, and 18.2% of low quality. Transdiagnostic class I-III risk/protective factors were mostly involved in the early neurodevelopmental period. The evidence-based atlas of key risk and protective factors identified in this study represents a benchmark for advancing clinical characterization and research, and for expanding early intervention and preventive strategies for mental disorders.
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http://dx.doi.org/10.1002/wps.20894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8429329PMC
October 2021

Spider Phobia: Neural Networks Informing Diagnosis and (Virtual/Augmented Reality-Based) Cognitive Behavioral Psychotherapy-A Narrative Review.

Front Psychiatry 2021 24;12:704174. Epub 2021 Aug 24.

Psychosomatic Medicine and Psychotherapy, Saarland University Medical Center, Homburg, Germany.

Recent fMRI studies on specific animal phobias, particularly spider phobia (arachnophobia), have identified a large variety of specific brain regions involved in normal and disturbed fear processing. Both functional and structural brain abnormalities have been identified among phobic patients. Current research suggests that both conscious and subconscious fear processing play a crucial role in phobic disorders. Cognitive behavioral therapy has been identified as an effective treatment for specific phobias and has been associated with neuroplastic effects which can be evaluated using current neuroimaging techniques. Recent research suggests that new approaches using virtual (VR) or augmented reality (AR) tend to be similarly effective as traditional "" therapy methods and could expand treatment options for different medical or individual scenarios. This narrative review elaborates on neural structures and particularities of arachnophobia. Current treatment options are discussed and future research questions are highlighted.
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http://dx.doi.org/10.3389/fpsyt.2021.704174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421596PMC
August 2021

Anti-MOG autoantibody-associated schizophreniform psychosis.

Acta Neuropsychiatr 2021 Sep 8:1-21. Epub 2021 Sep 8.

Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.

Objective: Autoimmune mechanisms are related to disease development in a subgroup of patients with psychosis. The contribution of immunoglobulin G (IgG) antibodies against myelin oligodendrocyte glycoprotein (MOG) is mainly unclear in this context.

Methods: Therefore, two patients with psychosis and anti-MOG antibodies-detected in fixed cell-based and live cell-based assays-are presented.

Results: Patient 1 suffered from late-onset psychosis with singular white matter lesions in MRI and intermittent EEG slowing. Patient 2 suffered from a chronic paranoid-hallucinatory disorder with intermittent confusional states, non-specific white matter alterations on MRI, a disorganized alpha rhythm on EEG and elevated cerebrospinal-fluid protein. Both patients had anti-MOG antibody titers of 1:320 in serum (reference<1:20).

Conclusion: The arguments for and against a causal role for anti-MOG antibodies are discussed. The antibodies could be relevant, but due to moderate titers, they may have caused a rather "subtle clinical picture" consisting of psychosis instead of "classical" MOG encephalomyelitis.
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http://dx.doi.org/10.1017/neu.2021.29DOI Listing
September 2021

Rumination about obsessive symptoms and mood maintains obsessive-compulsive symptoms and depressed mood: An experimental study.

J Abnorm Psychol 2021 Jul;130(5):435-442

Department of Psychology.

Rumination is common in individuals diagnosed with obsessive-compulsive disorder (OCD). We sought to clarify the causal role of rumination in the immediate and intermediate maintenance of obsessive-compulsive symptoms and depressed mood. In total, 145 individuals diagnosed with OCD were asked to read aloud their most distressing obsessive thought (OT). OT activation was followed by a thought-monitoring phase in which frequency of the OT was assessed. Participants were randomly allocated to one of three experimental conditions: rumination about obsessive-compulsive symptoms, rumination about mood, or distraction. Ratings of distress, urge to neutralize, and depressed mood and frequency ratings of the OTs were taken before and after the experimental manipulation. Obsessive-compulsive symptom severity and affect were assessed 2, 4, and 24 hr after the laboratory experiment using ecological momentary assessment. Compared to distraction, both types of rumination resulted in an immediate reduced decline of distress, urge to neutralize, depressed mood, and frequency of OTs, with medium to large effect sizes. Rumination about obsessive-compulsive symptoms did not have a stronger immediate effect than rumination about mood. Rumination about obsessive-compulsive symptoms increased obsessive-compulsive symptom severity and reduced positive affect compared to rumination about mood 24 hr later. Regarding negative affect, there was no difference in effect between the two types of rumination in the intermediate term. To conclude, rumination in OCD has an immediate and intermediate maintaining effect on obsessive-compulsive symptoms and mood and may require additional psychological interventions that supplement cognitive behavioral therapy. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/abn0000677DOI Listing
July 2021

Primary prevention of depression: An umbrella review of controlled interventions.

J Affect Disord 2021 Nov 31;294:957-970. Epub 2021 Jul 31.

Early Psychosis: Interventions and Clinical-detection (EPIC) Lab, Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK; National Institute for Health Research, Maudsley Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, London, UK; OASIS service, South London and Maudsley NHS Foundation Trust, London, UK; Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy. Electronic address:

Background: Primary prevention has the potential to modify the course of depression, but the consistency and magnitude of this effect are currently undetermined.

Methods: PRISMA and RIGHT compliant (PROSPERO:CRD42020179659) systematic meta-review, PubMed/Web of Science, up to June 2020. Meta-analyses of controlled interventions for the primary prevention of depressive symptoms [effect measures: standardized mean difference (SMD)] or depressive disorders [effect measure: relative risk (RR)] were carried out. Results were stratified by: (i) age range; (ii) target population (general and/or at-risk); (iii) intervention type. Quality (assessed with AMSTAR/AMSTAR-PLUS content) and credibility (graded as high/moderate/low) were assessed. USPSTF grading system was used for recommendations.

Results: Forty-six meta-analyses (k=928 individual studies, n=286,429 individuals, mean age=22.4 years, 81.1% female) were included. Effect sizes were: SMD=0.08-0.53; for depressive symptoms; RR=0.90-0.28 for depressive disorders. Sensitivity analyses including only RCTs did not impact the findings. AMSTAR median=9 (IQR=8-9); AMSTAR-PLUS content median=4.25 (IQR=4-5). Credibility of the evidence was insufficient/low in 43 (93.5%) meta-analyses, moderate in two (4.3%), and high in one (2.2%): reduction of depressive symptoms using psychosocial interventions for young adults only, and a combination of psychological and educational interventions in primary care had moderate credibility; preventive administration of selective serotonin reuptake inhibitors (SSRIs) for depressive disorders in individuals with a stroke had high credibility.

Limitations: Intervention heterogeneity and lack of long-term efficacy evaluation.

Conclusions: Primary preventive interventions for depression might be effective. Among them, clinicians may offer SSRIs post-stroke to prevent depressive disorders, and psychosocial interventions for children/adolescents/young adults with risk factors or during the prenatal/perinatal period.
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http://dx.doi.org/10.1016/j.jad.2021.07.101DOI Listing
November 2021

Efficacy of temporally intensified exposure for anxiety disorders: A multicenter randomized clinical trial.

Depress Anxiety 2021 Jul 22. Epub 2021 Jul 22.

Institute of Clinical Psychology & Psychotherapy, Technische Universität Dresden, Dresden, Germany.

Background: The need to optimize exposure treatments for anxiety disorders may be addressed by temporally intensified exposure sessions. Effects on symptom reduction and public health benefits should be examined across different anxiety disorders with comorbid conditions.

Methods: This multicenter randomized controlled trial compared two variants of prediction error-based exposure therapy (PeEx) in various anxiety disorders (both 12 sessions + 2 booster sessions, 100 min/session): temporally intensified exposure (PeEx-I) with exposure sessions condensed to 2 weeks (n = 358) and standard nonintensified exposure (PeEx-S) with weekly exposure sessions (n = 368). Primary outcomes were anxiety symptoms (pre, post, and 6-months follow-up). Secondary outcomes were global severity (across sessions), quality of life, disability days, and comorbid depression.

Results: Both treatments resulted in substantial improvements at post (PeEx-I: d  = 1.50, PeEx-S: d  = 1.78) and follow-up (PeEx-I: d  = 2.34; PeEx-S: d  = 2.03). Both groups showed formally equivalent symptom reduction at post and follow-up. However, time until response during treatment was 32% shorter in PeEx-I (median = 68 days) than PeEx-S (108 days; TR  = 0.68). Interestingly, drop-out rates were lower during intensified exposure. PeEx-I was also superior in reducing disability days and improving quality of life at follow-up without increasing relapse.

Conclusions: Both treatment variants focusing on the transdiagnostic exposure-based violation of threat beliefs were effective in reducing symptom severity and disability in severe anxiety disorders. Temporally intensified exposure resulted in faster treatment response with substantial public health benefits and lower drop-out during the exposure phase, without higher relapse. Clinicians can expect better or at least comparable outcomes when delivering exposure in a temporally intensified manner.
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http://dx.doi.org/10.1002/da.23204DOI Listing
July 2021

Pharmacotherapy, drug-drug interactions and potentially inappropriate medication in depressive disorders.

PLoS One 2021 22;16(7):e0255192. Epub 2021 Jul 22.

Vitos Hochtaunus, Friedrichsdorf, Germany.

Introduction: The aim of this study was to describe the number and type of drugs used to treat depressive disorders in inpatient psychiatry and to analyse the determinants of potential drug-drug interactions (pDDI) and potentially inappropriate medication (PIM).

Methods: Our study was part of a larger pharmacovigilance project funded by the German Innovation Funds. It included all inpatients with a main diagnosis in the group of depressive episodes (F32, ICD-10) or recurrent depressive disorders (F33) discharged from eight psychiatric hospitals in Germany between 1 October 2017 and 30 September 2018 or between 1 January and 31 December 2019.

Results: The study included 14,418 inpatient cases. The mean number of drugs per day was 3.7 (psychotropic drugs = 1.7; others = 2.0). Thirty-one percent of cases received at least five drugs simultaneously (polypharmacy). Almost one half of all cases received a combination of multiple antidepressant drugs (24.8%, 95% CI 24.1%-25.5%) or a treatment with antidepressant drugs augmented by antipsychotic drugs (21.9%, 95% CI 21.3%-22.6%). The most frequently used antidepressants were selective serotonin reuptake inhibitors, followed by serotonin and norepinephrine reuptake inhibitors and tetracyclic antidepressants. In multivariate analyses, cases with recurrent depressive disorders and cases with severe depression were more likely to receive a combination of multiple antidepressant drugs (Odds ratio recurrent depressive disorder: 1.56, 95% CI 1.41-1.70, severe depression 1.33, 95% CI 1.18-1.48). The risk of any pDDI and PIM in elderly patients increased substantially with each additional drug (Odds Ratio: pDDI 1.32, 95% CI: 1.27-1.38, PIM 1.18, 95% CI: 1.14-1.22) and severity of disease (Odds Ratio per point on CGI-Scale: pDDI 1.29, 95% CI: 1.11-1.46, PIM 1.27, 95% CI: 1.11-1.44), respectively.

Conclusion: This study identified potential sources and determinants of safety risks in pharmacotherapy of depressive disorders and provided additional data which were previously unavailable. Most inpatients with depressive disorders receive multiple psychotropic and non-psychotropic drugs and pDDI and PIM are relatively frequent. Patients with a high number of different drugs must be intensively monitored in the management of their individual drug-related risk-benefit profiles.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0255192PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297778PMC
July 2021

Upregulation of sICAM-1 and sVCAM-1 Levels in the Cerebrospinal Fluid of Patients with Schizophrenia Spectrum Disorders.

Diagnostics (Basel) 2021 Jun 22;11(7). Epub 2021 Jun 22.

Section for Experimental Neuropsychiatry, Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.

Immunological explanatory approaches are becoming increasingly important in schizophrenia research. In this context, the function of the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (BCSFB) plays an essential role. Different adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), are key elements in sustaining the integrity of the BBB and BCSFB. The objectives of this study were to (1) compare the levels of different cell adhesion molecules in the CSF of patients with schizophrenia spectrum disorders to those of patients with unipolar depression and (2) analyze their association with the established markers of the BBB/BCSFB function (CSF total protein and albumin quotient (AQ)). Therefore, a total of 40 patients with schizophrenia spectrum disorder and 39 age- and sex-matched control patients with unipolar depression were analyzed. The levels of soluble ICAM-1 (s-ICAM-1), soluble VCAM-1 (s-VCAM-1), and plasminogen activator inhibitor 1 (PAI-1) in the CSF were measured using a magnetic bead multiplexing immunoassay. The levels of sICAM-1 ( < 0.001), sVCAM-1 ( < 0.001), and PAI-1 ( < 0.001) in the CSF were significantly higher in patients with schizophrenia spectrum disorder than in patients with unipolar depression. In addition, a significant correlation of sVCAM-1 levels with total protein concentrations (r = 0.454, = 0.003) and AQ levels (r = 0.512, = 0.001) in patients with schizophrenia spectrum disorders was observed. The results revealed that sICAM-1 and sVCAM-1 levels in the CSF were higher in patients with schizophrenia spectrum disorder than in those with depression. These circulating signaling molecules may indicate endothelial dysfunction causing impaired BBB/BCSFB function in patients with schizophrenia spectrum disorders. Consistent with this view, a highly significant correlation of sVCAM-1 with CSF protein and AQs was detected. Upregulation of these cell adhesion molecules might be indicative of a proinflammatory immune response underlying the BBB/BCSFB disturbance in a subgroup of patients with schizophrenia spectrum disorders. The significance of the study is limited by its retrospective research design and by the absence of a healthy control group. The assay used was not previously established for the measurement of CSF. Further translational and controlled studies of the role of different cell adhesion molecules in schizophrenia are needed.
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http://dx.doi.org/10.3390/diagnostics11071134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8307568PMC
June 2021

An observational study on the association of anti-thyroid autoantibodies with clinical, EEG, MRI, FDG-PET, cerebrospinal fluid and anti-neuronal antibody findings in 530 patients with schizophreniform and affective disorders.

Psychoneuroendocrinology 2021 Sep 10;131:105320. Epub 2021 Jun 10.

Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address:

Introduction: Although the link between autoimmune thyroiditis and mental illnesses is well established, the precise underlying pathophysiology and the influence of anti-thyroid antibodies on diagnostic findings require further research.

Patients And Methods: A total of 530 patients with schizophreniform and affective syndromes were screened for anti-thyroid antibodies against thyroid peroxidase (TPO), thyroglobulin (TG), and thyroid-stimulating hormone receptor (TSH-R). The patient group analyzed here is a patient subgroup of a previously published cohort (Endres et al., 2020, Translational Psychiatry). The anti-thyroid antibody positive (N = 91) and negative (N = 439) patients were compared in terms of various clinical parameters, routine cerebrospinal fluid (CSF) findings, and the number of positive anti-neuronal antibodies in serum and/or CSF, as well as electroencephalography (EEG), magnetic resonance imaging (MRI), and fluorodeoxyglucose positron emission tomography (FDG-PET) findings.

Results: Anti-TPO antibodies were increased in 17%, anti-TG antibodies in 15%, and anti-TSH-R antibodies in 2% of all patients. In CSF, higher protein concentrations (p = 0.018) and albumin quotients (p = 0.008) were found in the anti-thyroid antibody positive patient group. Also, there were more patients with elevated age-corrected albumin quotients in this group (p = 0.031). FDG-PET hypometabolism was significantly more frequent and the number of positive anti-neuronal intracellular antibodies was significantly higher in patients with anti-thyroid antibodies (p = 0.048, N = 29 and p = 0.032, N = 497 respectively). In addition, there was a trend for higher white blood cell (WBC) counts in all patients with anti-thyroid antibodies (p = 0.090). In the patient subgroup with anti-TPO antibodies this difference was statistically significant (p = 0.027). No relevant differences were found in the other CSF routine parameters, the number of anti-neuronal antibodies against cell surface antigens in serum and/or CSF, EEG and MRI findings.

Discussion: The present study provides evidence of impaired blood CSF barrier (BCSFB) function in patients with anti-TPO and anti-TG antibodies. An influence of anti-TG antibodies on BCSFB structures has been shown in previous laboratory studies, which reported that the antibodies bind to vascular smooth muscle cells. Due to BCSFB breakdown anti-thyroid antibodies might lead to increased autoimmune susceptibility. The alterations in the FDG-PET, WBC count, and anti-neuronal antibody findings against intracellular structures indicate that it could be useful to extend diagnostic investigations in patients with anti-thyroid antibodies. Further studies should investigate whether anti-thyroid antibodies can also act as "drivers of disease".
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http://dx.doi.org/10.1016/j.psyneuen.2021.105320DOI Listing
September 2021

Polypharmacy and the risk of drug-drug interactions and potentially inappropriate medications in hospital psychiatry.

Pharmacoepidemiol Drug Saf 2021 Sep 24;30(9):1258-1268. Epub 2021 Jun 24.

Vitos Hochtaunus gemeinnutzige GmbH, Friedrichsdorf, Germany.

Purpose: The aim of this study was to analyze the epidemiology of polypharmacy in hospital psychiatry. Another aim was to investigate predictors of the number of drugs taken and the associated risks of drug-drug interactions and potentially inappropriate medications in the elderly.

Methods: Daily prescription data were obtained from a pharmacovigilance project sponsored by the Innovations Funds of the German Federal Joint Committee.

Results: The study included 47 071 inpatient hospital cases from eight different study centers. The mean number of different drugs during the entire stay was 6.1 (psychotropic drugs = 2.7; others = 3.4). The mean number of drugs per day was 3.8 (psychotropic drugs = 1.6; others = 2.2). One third of cases received at least five different drugs per day on average during their hospital stay (polypharmacy). Fifty-one percent of patients received more than one psychotropic drug simultaneously. Hospital cases with polypharmacy were 18 years older (p < 0.001), more likely to be female (52% vs. 40%, p < 0.001) and had more comorbidities (5 vs. 2, p < 0.001) than hospital cases without polypharmacy. The risks of drug-drug interactions (OR = 3.7; 95% CI = 3.5-3.9) and potentially inappropriate medication use in the elderly (OR = 2.2; CI = 1.9-2.5) substantially increased in patients that received polypharmacy.

Conclusion: Polypharmacy is frequent in clinical care. The number of used drugs is a proven risk factor of adverse drug reactions due to drug-drug interactions and potentially inappropriate medication use in the elderly. The potential interactions and the specific pharmacokinetics and -dynamics of older patients should always be considered when multiple drugs are used.
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http://dx.doi.org/10.1002/pds.5310DOI Listing
September 2021

Reducing Generalization of Conditioned Fear: Beneficial Impact of Fear Relevance and Feedback in Discrimination Training.

Front Psychol 2021 1;12:665711. Epub 2021 Jun 1.

Department of Psychology (Biological Psychology, Clinical Psychology, and Psychotherapy), Center of Mental Health, University of Würzburg, Würzburg, Germany.

Anxiety patients over-generalize fear, possibly because of an incapacity to discriminate threat and safety signals. Discrimination trainings are promising approaches for reducing such fear over-generalization. Here we investigated the efficacy of a fear-relevant vs. a fear-irrelevant discrimination training on fear generalization and whether the effects are increased with feedback during training. Eighty participants underwent two fear acquisition blocks, during which one face (conditioned stimulus, CS+), but not another face (CS-), was associated with a female scream (unconditioned stimulus, US). During two generalization blocks, both CSs plus four morphs (generalization stimuli, GS1-GS4) were presented. Between these generalization blocks, half of the participants underwent a fear-relevant discrimination training (discrimination between CS+ and the other faces) with or without feedback and the other half a fear-irrelevant discrimination training (discrimination between the width of lines) with or without feedback. US expectancy, arousal, valence ratings, and skin conductance responses (SCR) indicated successful fear acquisition. Importantly, fear-relevant vs. fear-irrelevant discrimination trainings and feedback vs. no feedback reduced generalization as reflected in US expectancy ratings independently from one another. No effects of training condition were found for arousal and valence ratings or SCR. In summary, this is a first indication that fear-relevant discrimination training and feedback can improve the discrimination between threat and safety signals in healthy individuals, at least for learning-related evaluations, but not evaluations of valence or (physiological) arousal.
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http://dx.doi.org/10.3389/fpsyg.2021.665711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203828PMC
June 2021

Event-related potentials in insomnia reflect altered perception of sleep.

Sleep 2021 Oct;44(10)

Medical Center - University of Freiburg, Department of Psychiatry and Psychotherapy, Section of Clinical Psychology and Psychophysiology, Freiburg, Germany.

Study Objectives: Insomnia is defined by the subjective complaint of poor sleep as well as daytime impairments. Since polysomnography (PSG) typically shows only modest sleep impairment, some still unidentified property of sleep, not mirrored in PSG, may be modified in insomnia.One possible mechanistic hypothesis is that insomnia patients may be more sensitive to inevitably occurring internal or external stimuli during the night, causing brief sleep disruptions then perceived as wake time.

Methods: Auditory event-related potentials (ERP) to low intensity (50 dB SPL) synthesized guitar tones played continuously throughout two nights of polysomnographically registered sleep were obtained in fifty patients with insomnia disorder (ID, without comorbidities) and 50 age- and sex-matched good sleeper controls (GSC) for each sleep stage and NREM/REM cycle. Phasic and tonic REM were treated as separate stages. Latencies and amplitudes of components P1, N1 and P2 were measured and analyzed by multivariate repeated-measures ANCOVA including effects of group, night, cycle, and age.

Results: ID showed reduced P2 amplitudes relative to GSC specifically in phasic REM sleep. The same reduction also correlated with the amount of sleep misperception across groups. Independent component analysis showed a frontal negativity to contribute most to this group difference.

Conclusions: The present finding can be interpreted as increased mismatch negativity (MMN) in ID, reflecting automated detection of change in the auditory system and a concomitant orienting response. Specifically phasic REM sleep appears to be vulnerable to sensory afferences in ID patients, possibly contributing to the perception of being awake.

Clinical Trial Information: Short name "PERSLEEP 2," URL https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00008965, Registration DRKS00008965.
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http://dx.doi.org/10.1093/sleep/zsab137DOI Listing
October 2021

Exploratory drive, fear, and anxiety are dissociable and independent components in foraging mice.

Transl Psychiatry 2021 05 26;11(1):318. Epub 2021 May 26.

Max Planck Institute of Psychiatry, Research Group Neuronal Plasticity, Kraepelinstr. 2-10, 80804, Munich, Germany.

Anxiety-like behavior of rodents is frequently accompanied by reduced exploration. Here, we identify dissociable components of anxiety, fear, and exploratory drive of sated and foraging mice. With the help of behavioral assays, including the open field task, elevated plus maze, dark-light transition task, and beetle mania task, we demonstrate a general increase in exploration by food restriction. Food-restricted mice bred for high anxiety behavior (HAB) showed ameliorated anxiety- but not fear-related behavior. By means of principal component analysis, we identified three independent components, which resemble the behavioral dimensions proposed by Gray's Reinforcement Sensitivity Theory (approach behavior, avoidance behavior, and decision making). Taken together, we demonstrate anxiolytic consequences of food restriction in a mouse model of anxiety disorders that can be dissociated from a general increase in foraging behavior.
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http://dx.doi.org/10.1038/s41398-021-01458-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155035PMC
May 2021

Increased GFAP concentrations in the cerebrospinal fluid of patients with unipolar depression.

Transl Psychiatry 2021 05 21;11(1):308. Epub 2021 May 21.

Department of Psychiatry and Psychotherapy, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, 79104 Freiburg, Germany.

Inflammatory processes involving altered microglial activity may play a relevant role in the pathophysiology of depressive disorders. Glial fibrillary acidic protein (GFAP) and calcium-binding protein S100B are considered microglial markers. To date, their role has been studied in the serum and tissue material of patients with unipolar depression but not in the cerebrospinal fluid (CSF). Therefore, the aim of the current study was to examine GFAP and S100B levels in the CSF of patients with major depression to better understand their role in affective disorders. In this retrospective study, 102 patients with unipolar depression and 39 mentally healthy controls with idiopathic intracranial hypertension were investigated. GFAP and S100B levels were measured using commercially available ELISA kits. CSF routine parameters were collected during routine clinical care. The mean values of GFAP and S100B were compared using age (and sex) corrected ANOVAs. Matched subgroups were analyzed by using an independent sample t-test. In addition, correlation analyses between GFAP/S100B levels and CSF routine parameters were performed within the patient group. Patients with unipolar depression had significantly higher levels of GFAP than controls (733.22 pg/ml vs. 245.56 pg/ml, p < 0.001). These results remained significant in a sub-analysis in which all controls were compared with patients suffering from depression matched 1:1 by age and sex (632.26 pg/ml vs. 245.56 pg/ml, p < 0.001). Levels of S100B did not differ significantly between patients and controls (1.06 ng/ml vs. 1.17 ng/ml, p = 0.385). GFAP levels correlated positively with albumin quotients (p < 0.050), S100B levels correlated positively with white blood cell counts (p = 0.001), total protein concentrations (p < 0.001), and albumin quotients (p = 0.001) in the CSF. The significance of the study is limited by its retrospective and open design, methodological aspects, and the control group with idiopathic intracranial hypertension. In conclusion, higher GFAP levels in patients with depression may be indicative of altered microglia activity, especially in astrocytes, in patients with unipolar depression. In addition, correlation analyses support the idea that S100B levels could be related to the integrity of the blood-brain/CSF barrier. Further multimodal and longitudinal studies are necessary to validate these findings and clarify the underlying biological processes.
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http://dx.doi.org/10.1038/s41398-021-01423-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8139962PMC
May 2021

Prevention in psychiatry: a role for epigenetics?

World Psychiatry 2021 Jun;20(2):227-228

Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, and Center for Basics in NeuroModulation, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

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http://dx.doi.org/10.1002/wps.20854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129863PMC
June 2021

Prevention in psychiatry: a role for epigenetics?

World Psychiatry 2021 Jun;20(2):227-228

Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, and Center for Basics in NeuroModulation, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

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http://dx.doi.org/10.1002/wps.20854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129863PMC
June 2021

Fear conditioning and stimulus generalization in association with age in children and adolescents.

Eur Child Adolesc Psychiatry 2021 May 13. Epub 2021 May 13.

Center of Mental Health, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany.

The aim of the study was to investigate age-related differences in fear learning and generalization in healthy children and adolescents (n = 133), aged 8-17 years, using an aversive discriminative fear conditioning and generalization paradigm adapted from Lau et al. (2008). In the current task, participants underwent 24 trials of discriminative conditioning of two female faces with neutral facial expressions, with (CS+) or without (CS-) a 95-dB loud female scream, presented simultaneously with a fearful facial expression (US). The discriminative conditioning was followed by 72 generalization trials (12 CS+, 12 GS1, 12 GS2, 12 GS3, 12 GS4, and 12 CS-): four generalization stimuli depicting gradual morphs from CS+ to CS- in 20%-steps were created for the generalization phases. We hypothesized that generalization in children and adolescents is negatively correlated with age. The subjective ratings of valence, arousal, and US expectancy (the probability of an aversive noise following each stimulus), as well as skin conductance responses (SCRs) were measured. Repeated-measures ANOVAs on ratings and SCR amplitudes were calculated with the within-subject factors stimulus type (CS+, CS-, GS1-4) and phase (Pre-Acquisition, Acquisition 1, Acquisition 2, Generalization 1, Generalization 2). To analyze the modulatory role of age, we additionally calculated ANCOVAs considering age as covariate. Results indicated that (1) subjective and physiological responses were generally lower with increasing age irrespective to the stimulus quality, and (2) stimulus discrimination improved with increasing age paralleled by reduced overgeneralization in older individuals. Longitudinal follow-up studies are required to analyze fear generalization with regard to brain maturational aspects and clarify whether overgeneralization of conditioned fear promotes the development of anxiety disorders or vice versa.
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http://dx.doi.org/10.1007/s00787-021-01797-4DOI Listing
May 2021

Inhibition of acid sphingomyelinase increases regulatory T cells in humans.

Brain Commun 2021 5;3(2):fcab020. Epub 2021 Mar 5.

Institute for Virology and Immunobiology, University of Würzburg, Würzburg 97078, Germany.

Genetic deficiency for acid sphingomyelinase or its pharmacological inhibition has been shown to increase Foxp3 regulatory T-cell frequencies among CD4 T cells in mice. We now investigated whether pharmacological targeting of the acid sphingomyelinase, which catalyzes the cleavage of sphingomyelin to ceramide and phosphorylcholine, also allows to manipulate relative CD4 Foxp3 regulatory T-cell frequencies in humans. Pharmacological acid sphingomyelinase inhibition with antidepressants like sertraline, but not those without an inhibitory effect on acid sphingomyelinase activity like citalopram, increased the frequency of Foxp3 regulatory T cell among human CD4 T cells . In an observational prospective clinical study with patients suffering from major depression, we observed that acid sphingomyelinase-inhibiting antidepressants induced a stronger relative increase in the frequency of CD4 Foxp3 regulatory T cells in peripheral blood than acid sphingomyelinase-non- or weakly inhibiting antidepressants. This was particularly true for CD45RA CD25 effector CD4 Foxp3 regulatory T cells. Mechanistically, our data indicate that the positive effect of acid sphingomyelinase inhibition on CD4 Foxp3 regulatory T cells required CD28 co-stimulation, suggesting that enhanced CD28 co-stimulation was the driver of the observed increase in the frequency of Foxp3 regulatory T cells among human CD4 T cells. In summary, the widely induced pharmacological inhibition of acid sphingomyelinase activity in patients leads to an increase in Foxp3 regulatory T-cell frequencies among CD4 T cells in humans both and .
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http://dx.doi.org/10.1093/braincomms/fcab020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054263PMC
March 2021

An observational study investigating cytokine levels in the cerebrospinal fluid of patients with schizophrenia spectrum disorders.

Schizophr Res 2021 05 19;231:205-213. Epub 2021 Apr 19.

Section for Experimental Neuropsychiatry, Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany; Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.

Introduction: The role of immunological mechanisms in the pathophysiology of mental disorders has been discussed with increasing frequency. In this context, especially schizophrenia has become the focus of attention after the discovery of autoimmune encephalitis, which might present with psychotic symptoms. Furthermore, multiple studies have identified associations between infections or autoimmune diseases and schizophreniform disorders. Cerebrospinal fluid (CSF) analysis plays a central role in identifying potential inflammatory processes in the central nervous system. Therefore, the rationale of this retrospective study was the analysis of different cytokines, including interleukin-8 (IL-8) levels, in the CSF of patients with schizophrenia spectrum disorders.

Methods: The authors examined the CSF of 40 patients with schizophrenia spectrum disorders, in comparison to the CSF of a mentally healthy control group of 39 patients with idiopathic intracranial hypertension (IIH). Magnetic bead multiplexing immunoassay was used to retrospectively determine different cytokines in the participants' CSF.

Results: Participants with schizophrenia spectrum disorders had significantly higher IL-8 levels in their CSF than controls (mean ± SD: 41.83 ± 17.50 pg/ml versus 21.40 ± 7.96 pg/ml; p < 0.001).

Conclusion: The main finding of this study is the presence of significantly higher IL-8 concentrations in the CSF of patients with schizophrenia spectrum disorders when compared to the control group. This supports the hypothesis that immunological processes may be involved in the pathophysiology of a subgroup of patients with schizophrenia spectrum disorders. However, the study's results are limited by the retrospective design, methodological aspects, and the control group with IIH.
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http://dx.doi.org/10.1016/j.schres.2021.03.022DOI Listing
May 2021

Targeted prevention of anxiety disorders.

Eur Neuropsychopharmacol 2021 May 10;46:49-51. Epub 2021 Apr 10.

Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Center for Basics in Neuromodulation, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.euroneuro.2021.03.021DOI Listing
May 2021

Predicting the risk of drug-drug interactions in psychiatric hospitals: a retrospective longitudinal pharmacovigilance study.

BMJ Open 2021 04 9;11(4):e045276. Epub 2021 Apr 9.

Waldkrankenhaus Köppern, Vitos Hospital Hochtaunus, Friedrichsdorf, Germany.

Objectives: The aim was to use routine data available at a patient's admission to the hospital to predict polypharmacy and drug-drug interactions (DDI) and to evaluate the prediction performance with regard to its usefulness to support the efficient management of benefits and risks of drug prescriptions.

Design: Retrospective, longitudinal study.

Setting: We used data from a large multicentred pharmacovigilance project carried out in eight psychiatric hospitals in Hesse, Germany.

Participants: Inpatient episodes consecutively discharged between 1 October 2017 and 30 September 2018 (year 1) or 1 January 2019 and 31 December 2019 (year 2).

Outcome Measures: The proportion of rightly classified hospital episodes.

Methods: We used gradient boosting to predict respective outcomes. We tested the performance of our final models in unseen patients from another calendar year and separated the study sites used for training from the study sites used for performance testing.

Results: A total of 53 909 episodes were included in the study. The models' performance, as measured by the area under the receiver operating characteristic, was 'excellent' (0.83) and 'acceptable' (0.72) compared with common benchmarks for the prediction of polypharmacy and DDI, respectively. Both models were substantially better than a naive prediction based solely on basic diagnostic grouping.

Conclusion: This study has shown that polypharmacy and DDI can be predicted from routine data at patient admission. These predictions could support an efficient management of benefits and risks of hospital prescriptions, for instance by including pharmaceutical supervision early after admission for patients at risk before pharmacological treatment is established.
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http://dx.doi.org/10.1136/bmjopen-2020-045276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043005PMC
April 2021

Transcranial Magnetic Stimulation in Psychiatry: Is There a Need for Electric Field Standardization?

Front Hum Neurosci 2021 9;15:639640. Epub 2021 Mar 9.

Department of Neuroanatomy, Institute of Anatomy and Cell Biology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Single-pulse and repetitive transcranial magnetic stimulation (rTMS) are used in clinical practice for diagnostic and therapeutic purposes. However, rTMS-based therapies that lead to a significant and sustained reduction in neuropsychiatric symptoms remain scarce. While it is generally accepted that the stimulation frequency plays a crucial role in producing the therapeutic effects of rTMS, less attention has been dedicated to determining the role of the electric field strength. Conventional threshold-based intensity selection approaches, such as the resting motor threshold, produce variable stimulation intensities and electric fields across participants and cortical regions. Insufficient standardization of electric field strength may contribute to the variability of rTMS effects and thus therapeutic success. Computational approaches that can prospectively optimize the electric field and standardize it across patients and cortical targets may overcome some of these limitations. Here, we discuss these approaches and propose that electric field standardization will be instrumental for translational science frameworks (e.g., multiscale modeling and basic science approaches) aimed at deciphering the subcellular, cellular, and network mechanisms of rTMS. Advances in understanding these mechanisms will be important for optimizing rTMS-based therapies in psychiatry.
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http://dx.doi.org/10.3389/fnhum.2021.639640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985083PMC
March 2021

Novel Neuronal Autoantibodies in Huntington's Disease.

Biol Psychiatry 2021 Mar 12. Epub 2021 Mar 12.

Section for Experimental Neuropsychiatry, Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Department of Psychiatry and Psychotherapy, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.biopsych.2020.12.032DOI Listing
March 2021

Impaired fear learning and extinction, but not generalization, in anxious and non-anxious depression.

J Psychiatr Res 2021 03 21;135:294-301. Epub 2021 Jan 21.

Center of Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Margarete-Höppel-Platz 1, 97080, Würzburg, Germany; Interdisciplinary Center for Clinical Research, University Hospital of Würzburg, Josef-Schneider-Str. 2, 97080, Würzburg, Germany; Comprehensive Heart Failure Center (CHFC), University Hospital of Würzburg, Am Schwarzenberg 15, 97078, Würzburg, Germany; Medical Park Chiemseeblick, Department of Psychosomatic Medicine and Psychotherapy, Rasthausstr. 25, 83233, Bernau am Chiemsee, Germany.

Fear conditioning and generalization are well-known mechanisms in the pathogenesis of anxiety disorders. Extinction of conditioned fear responses is crucial for the psychotherapeutic treatment of these diseases. Anxious depression as a subtype of major depression shares characteristics with anxiety disorders. We therefore aimed to compare fear learning mechanisms in patients with anxious versus non-anxious depression. Fear learning mechanisms in patients with major depression (n = 79; for subgroup analyses n = 41 patients with anxious depression and n = 38 patients with non-anxious depression) were compared to 48 healthy participants. We used a well-established differential fear conditioning paradigm investigating acquisition, generalization, and extinction. Ratings of valence, arousal and probability of expected threat were assessed as well as skin conductance response as an objective psychophysiological measure. Patients with major depression showed impaired acquisition of conditioned fear. In addition, depressed patients showed impaired extinction of conditioned fear responses after successful fear conditioning. Generalization was not affected. However, there was no difference between patients with anxious and non-anxious depression. Results differed between objective and subjective measures. Our findings show altered fear acquisition and extinction in major depression as compared to healthy controls, but they do not favor differential fear learning and extinction mechanisms in the pathogenesis of anxious versus non-anxious depression. The results of impaired extinction warrant future studies addressing extinction learning elements in the treatment of depression.
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http://dx.doi.org/10.1016/j.jpsychires.2021.01.034DOI Listing
March 2021

Therapygenetic effects of 5-HTTLPR on cognitive-behavioral therapy in anxiety disorders: A meta-analysis.

Eur Neuropsychopharmacol 2021 Mar 20;44:105-120. Epub 2021 Jan 20.

Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany; Center of Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Germany.

There is a recurring debate on the role of the serotonin transporter gene linked polymorphic region (5-HTTLPR) in the moderation of response to cognitive behavioral therapy (CBT) in anxiety disorders. Results, however, are still inconclusive. We here aim to perform a meta-analysis on the role of 5-HTTLPR in the moderation of CBT outcome in anxiety disorders. We investigated both categorical (symptom reduction of at least 50%) and dimensional outcomes from baseline to post-treatment and follow-up. Original data were obtained from ten independent samples (including three unpublished samples) with a total of 2,195 patients with primary anxiety disorder. No significant effects of 5-HTTLPR genotype on categorical or dimensional outcomes at post and follow-up were detected. We conclude that current evidence does not support the hypothesis of 5-HTTLPR as a moderator of treatment outcome for CBT in anxiety disorders. Future research should address whether other factors such as long-term changes or epigenetic processes may explain further variance in these complex gene-environment interactions and molecular-genetic pathways that may confer behavioral change following psychotherapy.
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http://dx.doi.org/10.1016/j.euroneuro.2021.01.004DOI Listing
March 2021

Stress impairs response to antidepressants via HPA axis and immune system activation.

Brain Behav Immun 2021 03 8;93:132-140. Epub 2021 Jan 8.

Center of Mental Health, Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Margarete-Höppel-Platz 1, 97080 Würzburg, Germany.

Childhood trauma as well as severe events occurring later in life have been associated with the development of major depressive disorder (MDD). However, the interaction of early and later occurring adverse events in patients with MDD is understudied. This study aims to disentangle this interaction by investigating the effects on two of the main stress-response systems of the body, the hypothalamic-pituitaryadrenal (HPA-) axis and the immune system in depressed patients. The function of the HPA-axis was assessed by measuring FKBP5, SGK1 and NR3C1 mRNA-expression in peripheral blood after an in vivo glucocorticoid receptor (GR) challenge with 1.5 mg dexamethasone in 150 depressed in-patients (47.4% females). Childhood trauma was evaluated using the Childhood Trauma Questionnaire (CTQ), severe life events occurring one year prior to hospital admission were assessed with the List of Threatening Experiences (LTE). Multiple childhood traumata, i.e. ≥ 3, were present in 68 (45.5%) patients, 59 (39.3%) experienced ≥ 3 severe recent life events. The history of ≥ 3 severe recent life events was associated with an impaired GR-induction of SGK1 (F = 10.455; df = 1; p = 0.002) and FKBP5 mRNA expression (F = 8.720; df = 1; p = 0.004), and with elevated measures of the immune system such as CRP and lymphocyte count. In addition, severe recent life events were associated with a substantially impaired treatment response to antidepressants (F = 7.456; df = 1; p = 0.008). These effects could not be observed in relation to childhood trauma. Severe life events occurring prior to MDD development substantially impaired the stress-response systems and the response to treatment with antidepressants. This finding may indicate the need to employ additional treatment options such as psychotherapy right at the beginning of treatment or immune-modulating approaches.
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http://dx.doi.org/10.1016/j.bbi.2020.12.033DOI Listing
March 2021

Transcranial direct current stimulation induces long-term potentiation-like plasticity in the human visual cortex.

Transl Psychiatry 2021 01 4;11(1):17. Epub 2021 Jan 4.

Department of Psychiatry and Psychotherapy, Medical Center, University of Freiburg-Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Transcranial direct current stimulation (tDCS) is increasingly used as a form of noninvasive brain stimulation to treat psychiatric disorders; however, its mechanism of action remains unclear. Prolonged visual stimulation (PVS) can enhance evoked EEG potentials (visually evoked potentials, VEPs) and has been proposed as a tool to examine long-term potentiation (LTP) in humans. The objective of the current study was to induce and analyze VEP plasticity and examine whether tDCS could either modulate or mimic plasticity changes induced by PVS. Thirty-eight healthy participants received tDCS, PVS, either treatment combined or neither treatment, with stimulation sessions being separated by one week. One session consisted of a baseline VEP measurement, one stimulation block, and six test VEP measurements. For PVS, a checkerboard reversal pattern was presented, and for tDCS, a constant current of 1 mA was applied via each bioccipital anodal target electrode for 10 min (Fig. S1). Both stimulation types decreased amplitudes of C1 compared to no stimulation (F = 10.1; p = 0.002) and led to a significantly smaller increase (PVS) or even decrease (tDCS) in N1 compared to no stimulation (F = 4.7; p = 0.034). While all stimulation types increased P1 amplitudes, the linear mixed effects model did not detect a significant difference between active stimulation and no stimulation. Combined stimulation induced sustained plastic modulation of C1 and N1 but with a smaller effect size than what would be expected for an additive effect. The results demonstrate that tDCS can directly induce LTP-like plasticity in the human cortex and suggest a mechanism of action of tDCS relying on the restoration of dysregulated synaptic plasticity in psychiatric disorders such as depression and schizophrenia.
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http://dx.doi.org/10.1038/s41398-020-01134-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791098PMC
January 2021
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