45 years German Society of Biological Psychiatry (DGBP).

The foundation of a German Society of Biological Psychiatry (DGBP) was initiated at the Second World Congress of Biological Psychiatry of the WFSBP in Barcelona in 1978. Its mission was and is to promote interdisciplinary research on the biology of mental disorders and to translate results of biological research into clinical practice. During the presidency of Peter Falkai, its tasks were defined to improve the quality and support of biologically oriented research in Germany by the DFG (Deutsche Forschungsgemeinschaft; German Research Foundation), BMBF (Bundesministerium für Bildung und Forschung) and EU (European Union), to promote young researchers doing biologically oriented research, to improve on the diagnosis and therapy of mental disorders and to advise policy makers by taking part in legal processes. The DGBP has been a corporate member of the WFSBP from its beginning, became a cooperative member of the DGPPN (Deutsche Gesellschaft für Psychiatrie und Psychotherapie, Psychosomatik und Nervenheilkunde), later of the German Brain Council, and fostered relationships with other scientific societies. Over the past 45 years, more than twenty congresses were held in Germany and neighboring countries. Emerging from the pandemic, the DGBP is ready to continue its mission to promote interdisciplinary research on the biology of mental disorders with a focus on the development of young scientists and to translate results of biological research into clinical practice, with regard to pharmacotherapy in close cooperation with the Arbeitsgemeinschaft Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP). In this sense, this article also aims to stimulate the cooperation of the society with other national and international partners and to foster new relationships with young scientists and professionals interested in the aims and goals of the DGBP.

[ZSE-DUO - dual guidance structure at the centre for rare diseases]. / ZSE-DUO ­ duale Lotsenstruktur im Zentrum für Seltene Erkrankungen.

BACKGROUND: Patients with an unclear diagnosis and suspected rare disease pose special challenges to physicians, among others. AIM OF THE STUDY (RESEARCH QUESTION): The ZSE-DUO project aims to establish whether patient care under the joint supervision of a somatic expert and a mental health expert can improve diagnostic efficacy and precision, as well as shorten the time to diagnosis. MATERIAL AND METHODS: ZSE-DUO has successfully recruited more than 1000 patients at eleven national centres for rare diseases in a control and an intervention group. The findings are being analysed by three evaluating institutions. RESULTS AND DISCUSSION: The study is currently in its final phase. The results will be published in further papers.

BNST and amygdala activation to threat: Effects of temporal predictability and threat mode.

Recent animal and human studies highlight the uncertainty about the onset of an aversive event as a crucial factor for the involvement of the centromedial amygdala (CM) and bed nucleus of the stria terminalis (BNST) activity. However, studies investigating temporally predictable or unpredictable threat anticipation and confrontation processes are rare. Furthermore, the few existing fMRI studies analyzing temporally predictable and unpredictable threat processes used small sample sizes or limited fMRI paradigms. Therefore, we measured functional brain activity in 109 predominantly female healthy participants during a temporally predictable-unpredictable threat paradigm, which aimed to solve limited aspects of recent studies. Results showed higher BNST activity compared to the CM during the cue indicating that the upcoming confrontation is aversive relative to the cue indicating an upcoming neutral confrontation. Both the CM and BNST showed higher activity during the confrontation with unpredictable and aversive stimuli, but the reaction to aversive confrontation relative to neutral confrontation was stronger in the CM compared to the BNST. Additional modulation analyses by NPSR1 rs324981 genotype revealed higher BNST activity relative to the CM in unpredictable anticipation relative to predictable anticipation in T-carriers compared to AA carriers. Our results indicate that during the confrontation with aversive or neutral stimuli, temporal unpredictability modulates CM and BNST activity. Further, there is a differential activity concerning threat processing, as BNST is more involved when focussing on fear-related anticipation processes and CM is more involved when focussing on threat confrontation.

A major role for common genetic variation in anxiety disorders.

Anxiety disorders are common, complex psychiatric disorders with twin heritabilities of 30-60%. We conducted a genome-wide association study of Lifetime Anxiety Disorder (ncase = 25 453, ncontrol = 58 113) and an additional analysis of Current Anxiety Symptoms (ncase = 19 012, ncontrol = 58 113). The liability scale common variant heritability estimate for Lifetime Anxiety Disorder was 26%, and for Current Anxiety Symptoms was 31%. Five novel genome-wide significant loci were identified including an intergenic region on chromosome 9 that has previously been associated with neuroticism, and a locus overlapping the BDNF receptor gene, NTRK2. Anxiety showed significant positive genetic correlations with depression and insomnia as well as coronary artery disease, mirroring findings from epidemiological studies. We conclude that common genetic variation accounts for a substantive proportion of the genetic architecture underlying anxiety.

Individual differences in human fear generalization-pattern identification and implications for anxiety disorders.

Previous research indicates that anxiety disorders are characterized by an overgeneralization of conditioned fear as compared with healthy participants. Therefore, fear generalization is considered a key mechanism for the development of anxiety disorders. However, systematic investigations on the variance in fear generalization are lacking. Therefore, the current study aims at identifying distinctive phenotypes of fear generalization among healthy participants. To this end, 1175 participants completed a differential fear conditioning phase followed by a generalization test. To identify patterns of fear generalization, we used a k-means clustering algorithm based on individual arousal generalization gradients. Subsequently, we examined the reliability and validity of the clusters and phenotypical differences between subgroups on the basis of psychometric data and markers of fear expression. Cluster analysis reliably revealed five clusters that systematically differed in mean responses, differentiation between conditioned threat and safety, and linearity of the generalization gradients, though mean response levels accounted for most variance. Remarkably, the patterns of mean responses were already evident during fear acquisition and corresponded most closely to psychometric measures of anxiety traits. The identified clusters reliably described subgroups of healthy individuals with distinct response characteristics in a fear generalization test. Following a dimensional view of psychopathology, these clusters likely delineate risk factors for anxiety disorders. As crucial group characteristics were already evident during fear acquisition, our results emphasize the importance of average fear responses and differentiation between conditioned threat and safety as risk factors for anxiety disorders.

Influence of two functional polymorphisms in NOS1 on baseline cortisol and working memory in healthy subjects.

INTRODUCTION: The neuronal isoform of the nitric oxide synthase (NOS-I) encoded by NOS1 is the main source of nitric oxide (NO) in the brain. Reduced NO signaling in the prefrontal cortex has been linked to schizophrenia and cognitive processes while reduced striatal NOS1 expression has been associated with impulsive behavior. METHODS: To evaluate the effect of two functional polymorphisms in alternative first exons of NOS1, ex1f-VNTR and ex1c-SNP rs41279104, on the HPA stress axis and neurocognitive abilities, 280 healthy subjects were genotyped, had their salivary cortisol levels measured and were assessed in verbal memory, verbal fluency, working memory and verbal IQ by using the California Verbal Learning Test (CVLT), the Regensburger test of verbal fluency (RWT), a n-back task and subscales of the Wechsler Adult Intelligence Scale III (WAIS-III). RESULTS: Schizophrenia risk (A)-allele carriers of NOS1 ex1c-SNP rs41279104 displayed significantly lower baseline cortisol levels (p = 0.004). NOS1 ex1f-VNTR genotype carriers showed differences in working memory performance (p = 0.05) in a gene-dose effect manner, with homozygous carriers of the short impulsivity-risk allele committing most commission errors. Finally, A-allele carriers of the NOS1 ex1c-SNP rs41279104 tended to react faster during the working memory task (p = 0.065). CONCLUSION: For the first time, we demonstrated an influence of the NOS1 ex1c-SNP rs41279104 on salivary cortisol levels and additionally implicate the A-allele in an enhanced reaction time during a working memory task. Regarding the NOS1 ex1f-VNTR our study supports the previously reported influence on impulsivity, lending further support to the hypothesis that this genetic variant underlies impulsive behavior.

Variations in cardiovascular risk factors in people with and without migration background in Germany - Results from the STAAB cohort study.

BACKGROUND: About 20% of the German population have a migration background which might influence prevalence of preventable cardiovascular risk factors (CVRF). METHODS: We report data of the prospective Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression (STAAB) cohort study investigating a representative sample of inhabitants of the City of Würzburg, Germany, aged 30 to 79 years. Individuals without migration background were defined as follows: German as native language, no other native language, and/or born in Germany. All other participants were defined as individuals with migration background. RESULTS: Of 2473 subjects (51% female, mean age 54 ±â€¯12 years), 291 (12%) reported a migration background: n = 107 (37%) from a country within the EU, n = 117 (40%) from Russia, and n = 67 (23%) from other countries. Prevalence of hypertension, atherosclerotic disease, and diabetes mellitus was similar in individuals with and without migration background. By contrast, prevalence of obesity and metabolic syndrome was significantly higher in individuals with migration background, with the least favourable profile apparent in individuals from Russia (individuals without vs. with migration background: obesity 19 vs. 24%, p < 0.05; odds ratio: EU: 1.6, Russia: 2.2*, other countries: 0.6; metabolic syndrome 18 vs. 21%, p < 0.05; odds ratio: EU: 1.2, Russia: 1.7*, other countries: 1.5; *p < 0.05). CONCLUSION: Individuals with migration background in Germany might exhibit a higher CVRF burden due to a higher prevalence of obesity and metabolic syndrome. Strategies for primary prevention of heart failure may benefit from deliberately considering the migration background.

A functional genetic variation of SLC6A2 repressor hsa-miR-579-3p upregulates sympathetic noradrenergic processes of fear and anxiety.

Increased sympathetic noradrenergic signaling is crucially involved in fear and anxiety as defensive states. MicroRNAs regulate dynamic gene expression during synaptic plasticity and genetic variation of microRNAs modulating noradrenaline transporter gene (SLC6A2) expression may thus lead to altered central and peripheral processing of fear and anxiety. In silico prediction of microRNA regulation of SLC6A2 was confirmed by luciferase reporter assays and identified hsa-miR-579-3p as a regulating microRNA. The minor (T)-allele of rs2910931 (MAFcases = 0.431, MAFcontrols = 0.368) upstream of MIR579 was associated with panic disorder in patients (pallelic = 0.004, ncases = 506, ncontrols = 506) and with higher trait anxiety in healthy individuals (pASI = 0.029, pACQ = 0.047, n = 3112). Compared to the major (A)-allele, increased promoter activity was observed in luciferase reporter assays in vitro suggesting more effective MIR579 expression and SLC6A2 repression in vivo (p = 0.041). Healthy individuals carrying at least one (T)-allele showed a brain activation pattern suggesting increased defensive responding and sympathetic noradrenergic activation in midbrain and limbic areas during the extinction of conditioned fear. Panic disorder patients carrying two (T)-alleles showed elevated heart rates in an anxiety-provoking behavioral avoidance test (F(2, 270) = 5.47, p = 0.005). Fine-tuning of noradrenaline homeostasis by a MIR579 genetic variation modulated central and peripheral sympathetic noradrenergic activation during fear processing and anxiety. This study opens new perspectives on the role of microRNAs in the etiopathogenesis of anxiety disorders, particularly their cardiovascular symptoms and comorbidities.

CRP genetic variants are associated with mortality and depressive symptoms in chronic heart failure patients.

OBJECTIVE: Heart failure (HF) is a complex medical condition with a multitude of genetic and other factors being involved in the pathogenesis. Emerging evidence points to an involvement of inflammatory mechanisms at least in subgroups of patients. The same is true for depression and depressive symptoms, which have a high prevalence in HF patients and are risk factors for the development and outcomes of cardiovascular disease. METHODS: In 936 patients of the Interdisciplinary Network Heart Failure (INH) program, CRP and IL-6 protein blood levels were measured and genetic variants (single nucleotide polymorphisms) of the CRP and IL6 gene analyzed regarding their influence on mortality. RESULTS: Less common recessive genotypes of two single nucleotide polymorphisms in the CRP gene (rs1800947 and rs11265263) were associated with significantly higher mortality risk (p < 0.006), higher CRP levels (p = 0.029, p = 0.006) and increased depressive symptoms in the PHQ-9 (p = 0.005, p = 0.003). Variants in the IL-6 gene were not associated with mortality. CONCLUSION: Our results hint towards an association of less common CRP genetic variants with increased mortality risk, depressive symptoms and peripheral CRP levels in this population of HF patients thereby suggesting a possible role of the inflammatory system as link between poor prognosis in HF and depressive symptoms.

[Pharmacogenetics in psychiatry: state of the art]. / Pharmakogenetik in der Psychiatrie: eine Standortbestimmung.

In this article, the current literature on pharmacogenetics of antidepressants, antipsychotics and lithium are summarized by the section of Neurobiology and Genetics of the German Society of Psychiatry, Psychotherapy and Neurology (DGPPN). The publications of international expert groups and regulatory authorities are reviewed and discussed. In Germany, a statement on pharmacogenetics was also made by the gene diagnostics committee of the Ministry of Health. The DGPPN supports two recommendations: 1) to perform CYP2D6 genetic testing prior to prescription of tricyclic antidepressants and 2) to determine the HLA-B*1502 genotype in patients of Asian origin before using carbamazepine. The main obstacle for a broad application of pharmacogenetic tests in psychiatry remains the lack of large prospective studies, for both single gene-drug pair and cobinatorial pharmacogenetic tests, to evaluate the benefits of genetic testing. Psychiatrists, geneticists and funding agencies are encouraged to increase their efforts for the future benefit of psychiatric patients.

Consensus Guidelines for Therapeutic Drug Monitoring in Neuropsychopharmacology: Update 2017.

Therapeutic drug monitoring (TDM) is the quantification and interpretation of drug concentrations in blood to optimize pharmacotherapy. It considers the interindividual variability of pharmacokinetics and thus enables personalized pharmacotherapy. In psychiatry and neurology, patient populations that may particularly benefit from TDM are children and adolescents, pregnant women, elderly patients, individuals with intellectual disabilities, patients with substance abuse disorders, forensic psychiatric patients or patients with known or suspected pharmacokinetic abnormalities. Non-response at therapeutic doses, uncertain drug adherence, suboptimal tolerability, or pharmacokinetic drug-drug interactions are typical indications for TDM. However, the potential benefits of TDM to optimize pharmacotherapy can only be obtained if the method is adequately integrated in the clinical treatment process. To supply treating physicians and laboratories with valid information on TDM, the TDM task force of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) issued their first guidelines for TDM in psychiatry in 2004. After an update in 2011, it was time for the next update. Following the new guidelines holds the potential to improve neuropsychopharmacotherapy, accelerate the recovery of many patients, and reduce health care costs.

Increased fear learning, spatial learning as well as neophobia in Rgs2-/- mice.

Anxiety disorders result from a complex interplay of genetic and environmental factors such as stress. On the level of cellular signaling, regulator of G protein signaling 2 (Rgs2) has been implicated in human and rodent anxiety. However, there is limited knowledge about the role of Rgs2 in fear learning and reactivity to stress. In this study, Rgs2-/- mice showed increased fear learning, male mice displayed increased contextual and cued fear learning, while females showed selectively enhanced cued fear learning. Male Rgs2-/- mice displayed increased long-term-contextual fear memory, but increased cued fear extinction. Learning in spatial non-aversive paradigms was also increased in Rgs2-/- mice. Female, but not male mice show increased spatial learning in the Barnes maze, while male mice showed enhanced place preference in the IntelliCage, rendering enhanced cognitive function non-specific for aversive stimuli. Consistent with the previous results, Rgs2 deletion resulted in increased innate anxiety, including neophobic behavior expressed as hypolocomotion, in three different tests based on the approach-avoidance conflict. Acute electric foot shock stress provoked hypolocomotion in several exploration-based tests, suggesting fear generalization in both genotypes. Rgs2 deletion was associated with reduced monoaminergic neurotransmitter levels in the hippocampus and prefrontal cortex and disturbed corresponding GPCR expression of the adrenergic, serotonergic, dopaminergic and neuropeptide Y system. Taken together, Rgs2 deletion promotes improved cognitive function as well as increased anxiety-like behavior, but has no effect on acute stress reactivity. These effects may be related to the observed disruption of the monoaminergic systems.

Modulation of defensive reactivity by GLRB allelic variation: converging evidence from an intermediate phenotype approach.

Representing a phylogenetically old and very basic mechanism of inhibitory neurotransmission, glycine receptors have been implicated in the modulation of behavioral components underlying defensive responding toward threat. As one of the first findings being confirmed by genome-wide association studies for the phenotype of panic disorder and agoraphobia, allelic variation in a gene coding for the glycine receptor beta subunit (GLRB) has recently been associated with increased neural fear network activation and enhanced acoustic startle reflexes. On the basis of two independent healthy control samples, we here aimed to further explore the functional significance of the GLRB genotype (rs7688285) by employing an intermediate phenotype approach. We focused on the phenotype of defensive system reactivity across the levels of brain function, structure, and physiology. Converging evidence across both samples was found for increased neurofunctional activation in the (anterior) insular cortex in GLRB risk allele carriers and altered fear conditioning as a function of genotype. The robustness of GLRB effects is demonstrated by consistent findings across different experimental fear conditioning paradigms and recording sites. Altogether, findings provide translational evidence for glycine neurotransmission as a modulator of the brain's evolutionary old dynamic defensive system and provide further support for a strong, biologically plausible candidate intermediate phenotype of defensive reactivity. As such, glycine-dependent neurotransmission may open up new avenues for mechanistic research on the etiopathogenesis of fear and anxiety disorders.

GLRB allelic variation associated with agoraphobic cognitions, increased startle response and fear network activation: a potential neurogenetic pathway to panic disorder.

The molecular genetics of panic disorder (PD) with and without agoraphobia (AG) are still largely unknown and progress is hampered by small sample sizes. We therefore performed a genome-wide association study with a dimensional, PD/AG-related anxiety phenotype based on the Agoraphobia Cognition Questionnaire (ACQ) in a sample of 1370 healthy German volunteers of the CRC TRR58 MEGA study wave 1. A genome-wide significant association was found between ACQ and single non-coding nucleotide variants of the GLRB gene (rs78726293, P=3.3 × 10-8; rs191260602, P=3.9 × 10-8). We followed up on this finding in a larger dimensional ACQ sample (N=2547) and in independent samples with a dichotomous AG phenotype based on the Symptoms Checklist (SCL-90; N=3845) and a case-control sample with the categorical phenotype PD/AG (Ncombined =1012) obtaining highly significant P-values also for GLRB single-nucleotide variants rs17035816 (P=3.8 × 10-4) and rs7688285 (P=7.6 × 10-5). GLRB gene expression was found to be modulated by rs7688285 in brain tissue, as well as cell culture. Analyses of intermediate PD/AG phenotypes demonstrated increased startle reflex and increased fear network, as well as general sensory activation by GLRB risk gene variants rs78726293, rs191260602, rs17035816 and rs7688285. Partial Glrb knockout mice demonstrated an agoraphobic phenotype. In conjunction with the clinical observation that rare coding GLRB gene mutations are associated with the neurological disorder hyperekplexia characterized by a generalized startle reaction and agoraphobic behavior, our data provide evidence that non-coding, although functional GLRB gene polymorphisms may predispose to PD by increasing startle response and agoraphobic cognitions.

Cognitive remediation for bipolar patients with objective cognitive impairment: a naturalistic study.

BACKGROUND: Many bipolar patients (BP) are affected by cognitive impairments and reduced psychosocial function even after complete remission. In the present naturalistic study, we developed a tailored cognitive remediation program (CR) to evaluate the effect on objective and subjective neuropsychological performance, psychosocial functioning and quality of life. METHODS: The CR program used a cognitive training software combined with group sessions to educate cognitive skills. 102 BP were screened by a neuropsychological test battery. Of those, 39 BP showed distinct cognitive impairments and 26 patients of them participated in the CR program for 12 weeks and then were retested. A matched control group consisting of 10 BP was measured at baseline and follow-up after three months (treatment as usual). RESULTS: Within the training group, a significant improvement of cognitive performance after CR was observed in working memory (p = .043), problem solving (p = .031) and divided attention (trend, p = .065). The control group did not improve in any test measure. In addition, we detected a significant reduction of sub-depressive symptoms (p = .011) after the CR program. However, there was no change in psychosocial functioning and quality of life. Subjective cognitive complaints were not associated with objective test performance. LIMITATIONS: As we included exclusively BP with objectively assessed neurocognitive deficits, recruitment was difficult and subsequently we had a small sample size and were not able to implement a randomized group design. CONCLUSIONS: Our results suggest that BP with objective cognitive impairments could benefit from CR potentially with regard to executive functioning. Furthermore, there is preliminary evidence that CR could have a positive effect on subthreshold residual symptoms. However, to fully identify the possible implications of CR in bipolar disorder, larger randomized-controlled trials are needed in this new field of research.

MAOA gene hypomethylation in panic disorder-reversibility of an epigenetic risk pattern by psychotherapy.

Epigenetic signatures such as methylation of the monoamine oxidase A (MAOA) gene have been found to be altered in panic disorder (PD). Hypothesizing temporal plasticity of epigenetic processes as a mechanism of successful fear extinction, the present psychotherapy-epigenetic study for we believe the first time investigated MAOA methylation changes during the course of exposure-based cognitive behavioral therapy (CBT) in PD. MAOA methylation was compared between N=28 female Caucasian PD patients (discovery sample) and N=28 age- and sex-matched healthy controls via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. MAOA methylation was furthermore analyzed at baseline (T0) and after a 6-week CBT (T1) in the discovery sample parallelized by a waiting time in healthy controls, as well as in an independent sample of female PD patients (N=20). Patients exhibited lower MAOA methylation than healthy controls (P<0.001), and baseline PD severity correlated negatively with MAOA methylation (P=0.01). In the discovery sample, MAOA methylation increased up to the level of healthy controls along with CBT response (number of panic attacks; T0-T1: +3.37±2.17%), while non-responders further decreased in methylation (-2.00±1.28%; P=0.001). In the replication sample, increases in MAOA methylation correlated with agoraphobic symptom reduction after CBT (P=0.02-0.03). The present results support previous evidence for MAOA hypomethylation as a PD risk marker and suggest reversibility of MAOA hypomethylation as a potential epigenetic correlate of response to CBT. The emerging notion of epigenetic signatures as a mechanism of action of psychotherapeutic interventions may promote epigenetic patterns as biomarkers of lasting extinction effects.

[Guideline-oriented inpatient psychiatric psychotherapeutic/psychosomatic treatment of anxiety disorders : How many personnel are need?]. / Leitliniengerechte stationäre psychiatrisch-psychotherapeutische/psychosomatische Behandlung von Angsterkrankungen : Wieviel Personal ist erforderlich?

BACKGROUND/OBJECTIVES: The reimbursement of inpatient psychiatric psychotherapeutic/psychosomatic hospital treatment in Germany is regulated by the German personnel ordinance for psychiatric hospitals (Psych-PV), which has remained unchanged since 1991. The aim of this article was to estimate the personnel requirements for guideline-adherent psychiatric psychotherapeutic hospital treatment. METHODS: A normative concept for the required psychotherapeutic "dose" for anxiety disorders was determined based on a literature review. The required staffing contingent was compared to the resources provided by the Psych-PV based on category A1. RESULTS: According to the German policy guidelines for outpatient psychotherapy, a quota of 25 sessions of 50 min each (as a rule plus 5 probatory sessions) is reimbursed. This approach is supported by studies on dose-response relationships. As patients undergoing inpatient treatment for anxiety disorders are usually more severely ill than outpatients, a contingent of 30 sessions for the average treatment duration of 5 weeks seems appropriate in order to fully exploit the costly inpatient treatment time (300 min per patient and week). In contrast, only 70 min are reimbursed according to the Psych-PV. The total personnel requirement for the normative concept is 624 min per patient and week. The Psych-PV only covers 488 min (78 %). CONCLUSION: Currently, the time contingents for evidence-based psychiatric psychotherapeutic/psychosomatic hospital care are nowhere near sufficient. In the development of future reimbursement systems this needs to be corrected.