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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.
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.
Background: Some studies suggest a mood-congruent attentional bias in bipolar patients. However, for euthymic patients, especially in dependence on the predominant polarity, there is little and inconsistent data. A clearer understanding of emotion-related attentional biases and their relationship to dysfunctional emotion regulation could help improving the diagnostics and treatment of bipolar disorder (BD). Twenty bipolar patients in a depressive state (BP-acute-D), 32 euthymic patients with manic (BP-euth-M) or depressive (BP-euth-D) predominant polarity, and 20 healthy control participants (HC) performed a dot-probe task (DPT) with happy and sad faces presented for 250 ms or 1250 ms in two different runs. Emotion regulation strategies were assessed with two questionnaires.
Results: In the short presentation condition of the DPT, BP-euth-M showed less attention for happy faces than HC (p = .03, r = − 0.48). BP-acute-D scored lower in cognitive reappraisal and putting into perspective and higher in suppression, catastrophizing, and rumination than HC. BP-euth-M scored higher in rumination and BP-euth-D lower in putting into perspective and higher in catastrophizing than HC. In BP-euth-D and HC, bias scores for sad faces in the longer presentation condition and reappraisal scores correlated positively.
Conclusions: Results of the DPT suggest an avoidance of happy faces for BP-euth-M which we interpret as a protection mechanism for triggers of mania. That individuals who apply more reappraisal show more selective attention to sad faces could on the one hand reflect a mental effort in reevaluating the sad emotional input and on the other hand a greater tolerance for it.
Background: Panic disorder is common (5% prevalence) and females are twice as likely to be affected as males. The heritable component of panic disorder is estimated at 48%. Glutamic acid dehydrogenase GAD1, the key enzyme for the synthesis of the inhibitory and anxiolytic neurotransmitter GABA, is supposed to influence various mental disorders, including mood and anxiety disorders. In a recent association study in depression, which is highly comorbid with panic disorder, GAD1 risk allele associations were restricted to females.
Methodology/Principal Findings: Nineteen single nucleotide polymorphisms (SNPs) tagging the common variation in GAD1 were genotyped in two independent gender and age matched case-control samples (discovery sample n = 478; replication sample n = 584). Thirteen SNPs passed quality control and were examined for gender-specific enrichment of risk alleles associated with panic disorder by using logistic regression including a genotype×gender interaction term. The latter was found to be nominally significant for four SNPs (rs1978340, rs3762555, rs3749034, rs2241165) in the discovery sample; of note, the respective minor/risk alleles were associated with panic disorder only in females. These findings were not confirmed in the replication sample; however, the genotype×gender interaction of rs3749034 remained significant in the combined sample. Furthermore, this polymorphism showed a nominally significant association with the Agoraphobic Cognitions Questionnaire sum score.
Conclusions/Significance: The present study represents the first systematic evaluation of gender-specific enrichment of risk alleles of the common SNP variation in the panic disorder candidate gene GAD1. Our tentative results provide a possible explanation for the higher susceptibility of females to panic disorder.
Predominant polarity in bipolar disorder and validation of the polarity index in a German sample
(2014)
Background: A large number of patients with bipolar disorder (BD) can be characterized by predominant polarity (PP), which has important implications for relapse prevention. Recently, Popovic et al. (EUR NEUROPSYCHOPHARM 22(5): 339¿346, 2012) proposed the Polarity Index (PI) as a helpful tool in the maintenance treatment of BD. As a numeric expression, it reflects the efficacy of drugs used in treatment of BD. In the present retrospective study, we aimed to validate this Index in a large and well characterized German bipolar sample.
Methods: We investigated 336 bipolar patients (BP) according to their PP and calculated the PI for each patient in order to prove if maintenance treatment differs according to their PP. Furthermore, we analysed whether PP is associated with demographic and clinical characteristics of BP.
Results: In our sample, 63.9% of patients fulfilled criteria of PP: 169 patients were classified as depressive predominant polarity (DPP), 46 patients as manic predominant polarity (MPP). The two groups differed significantly in their drug regime: Patients with DPP were more often medicated with lamotrigine and antidepressants, patients with MPP were more often treated with lithium, valproate, carbamazepine and first generation antipsychotics. However, patients with DPP and MPP did not differ significantly with respect to the PI, although they received evidence-based and guideline-driven treatment.
Conclusion: The reason for this negative finding might well be that for several drugs, which were used frequently, no PI value is available. Nevertheless we suggest PP as an important concept in the planning of BD maintenance treatment.
Background: Recently, RBFOX1, a gene encoding an RNA binding protein, has consistently been associated with aggressive and antisocial behavior. Several loci in the gene have been nominally associated with aggression in genome-wide association studies, the risk alleles being more frequent in the general population. We have hence examined the association of four RBFOX1 single nucleotide polymorphisms, previously found related to aggressive traits, with aggressiveness, personality, and alcohol use disorder in birth cohort representative samples.
Methods: We used both birth cohorts of the Estonian Children Personality Behavior and Health Study (ECPBHS; original n = 1,238). Aggressiveness was assessed using the Buss–Perry Aggression Questionnaire and the Lifetime History of Aggressiveness structured interview at age 25 (younger cohort) or 33 (older cohort). Big Five personality at age 25 was measured with self-reports and the lifetime occurrence of alcohol use disorder assessed with the MINI interview. RBFOX1 polymorphisms rs809682, rs8062784, rs12921846, and rs6500744 were genotyped in all participants. Given the restricted size of the sample, correction for multiple comparisons was not applied.
Results: Aggressiveness was not significantly associated with the RBFOX1 genotype. RBFOX1 rs8062784 was associated with neuroticism and rs809682 with extraversion. Two out of four analyzed RBFOX1 variants, rs8062784 and rs12921846, were associated with the occurrence of alcohol use disorder.
Conclusions: In the birth cohort representative sample of the ECPBHS, no association of RBFOX1 with aggressiveness was found, but RBFOX1 variants affected basic personality traits and the prevalence of alcohol use disorder. Future studies on RBFOX1 should consider the moderating role of personality and alcohol use patterns in aggressiveness.
The 14-3-3 protein family are molecular chaperones involved in several biological functions and neurological diseases. We previously pinpointed YWHAZ (encoding 14-3-3ζ) as a candidate gene for autism spectrum disorder (ASD) through a whole-exome sequencing study, which identified a frameshift variant within the gene (c.659-660insT, p.L220Ffs*18). Here, we explored the contribution of the seven human 14-3-3 family members in ASD and other psychiatric disorders by investigating the: (i) functional impact of the 14-3-3ζ mutation p.L220Ffs*18 by assessing solubility, target binding and dimerization; (ii) contribution of common risk variants in 14-3-3 genes to ASD and additional psychiatric disorders; (iii) burden of rare variants in ASD and schizophrenia; and iv) 14-3-3 gene expression using ASD and schizophrenia transcriptomic data. We found that the mutant 14-3-3ζ protein had decreased solubility and lost its ability to form heterodimers and bind to its target tyrosine hydroxylase. Gene-based analyses using publicly available datasets revealed that common variants in YWHAE contribute to schizophrenia (p = 6.6 × 10−7), whereas ultra-rare variants were found enriched in ASD across the 14-3-3 genes (p = 0.017) and in schizophrenia for YWHAZ (meta-p = 0.017). Furthermore, expression of 14-3-3 genes was altered in post-mortem brains of ASD and schizophrenia patients. Our study supports a role for the 14-3-3 family in ASD and schizophrenia.
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.
Highlights
• Up-to-date overview on developing new medications including candidates with novel bioloigical targets for the treatment of anxiety disorders and PTSD.
• Targeting glutamatergic, cholinergic and neurosteroid mechanisms can produce acute anxiolytic effects.
• Drugs, including psychedelics, are hypothesized to produce neuroplasticity to cause enduring clinical effects.
• Combining medication with psychological approaches may augment therapeutic efficacy.
• Advances in circuit neuroscience can be leveraged to inform the design of rationale drug targets.
Abstract
Psychiatric disorders associated with psychological trauma, stress and anxiety are a highly prevalent and increasing cause of morbidity worldwide. Current therapeutic approaches, including medication, are effective in alleviating symptoms of anxiety disorders and posttraumatic stress disorder (PTSD), at least in some individuals, but have unwanted side-effects and do not resolve underlying pathophysiology. After a period of stagnation, there is renewed enthusiasm from public, academic and commercial parties in designing and developing drug treatments for these disorders. Here, we aim to provide a snapshot of the current state of this field that is written for neuropharmacologists, but also practicing clinicians and the interested lay-reader. After introducing currently available drug treatments, we summarize recent/ongoing clinical assessment of novel medicines for anxiety and PTSD, grouped according to primary neurochemical targets and their potential to produce acute and/or enduring therapeutic effects. The evaluation of putative treatments targeting monoamine (including psychedelics), GABA, glutamate, cannabinoid, cholinergic and neuropeptide systems, amongst others, are discussed. We emphasize the importance of designing and clinically assessing new medications based on a firm understanding of the underlying neurobiology stemming from the rapid advances being made in neuroscience. This includes harnessing neuroplasticity to bring about lasting beneficial changes in the brain rather than – as many current medications do – produce a transient attenuation of symptoms, as exemplified by combining psychotropic/cognitive enhancing drugs with psychotherapeutic approaches. We conclude by noting some of the other emerging trends in this promising new phase of drug development.
Trotz der Relevanz des Themas Suizidalität und gut bekannter Risikofaktoren gibt es bisher keine deutsche Leitlinie zur Suizidalität im Erwachsenenalter. In diesem Beitrag werden zunächst die Geschichte und die Hintergründe der Arbeit mit Leitlinien beschrieben. Der aktuelle Stand der Leitlinien für psychische Erkrankungen in Deutschland wird dargestellt und auf suizidpräventive Inhalte hin untersucht. Die Notwendigkeit evidenzbasierter Suizidprävention und einer spezifischen Leitlinie zur Suizidprävention bei Erwachsenen wird diskutiert.
Nur durch gezielte Suizidpräventionsstrategien und Interventionen für die jeweiligen Risikogruppen und unter Beachtung von Alters- und Geschlechtsspezifität kann für alle Betroffenen eine flächendeckende, gut erreichbare, bedarfs- und versorgungsgerechte, finanzierbare sowie nachhaltige medizinische Versorgung auf einem hohen Niveau sichergestellt werden. Dies gilt für den ambulanten und den stationären Bereich sowie für deren Schnittstellen. Bei Suizidalität handelt es sich um ein diagnoseübergreifendes, in unterschiedlichen Versorgungskontexten auftretendes Syndrom mit komplexem Behandlungsbedarf, weshalb intersektorale und multiprofessionelle Aspekte in einer entsprechenden Leitlinie besonders zu adressieren sind. Wissenschaftliche Evidenz und interdisziplinärer Konsens unter Expertinnen und Experten zum Umgang mit suizidalem Verhalten in der medizinischen Versorgung können dazu beitragen, Morbidität und Mortalität im Zusammenhang mit Suizidalität zu reduzieren. Im August 2021 wurde die Finanzierung einer S3-Leitlinie „Umgang mit Suizidalität“ vom Innovationsfonds des Gemeinsamen Bundesausschusses bewilligt.
Highlights
• Suicides which occurred in a biologics trial targeting the IL-17R are revisited.
• High IL-17 levels are found in depression by the majority of reports.
• Results from studies regarding IL-17 and psychosis are mixed.
• Very few psychiatric studies investigated IL-17 signalling in suicidality.
• Potential mechanisms how IL-17 influences neuro-inflammation are described.
Abstract:
Interleukin 17 (IL-17) is a potent pro-inflammatory cytokine which plays a role in autoimmune disorders, such as psoriasis and multiple sclerosis, and is important for the defense against pathogens, particularly in the gut. However, IL-17 has recently also gained attention in association with suicidal behavior. In this review, we review the literature regarding IL-17 in psychiatric disorders and suicidality. We also take a closer look at the suicides which occurred in the clinical trial for psoriasis with brodalumab, a monoclonal antibody targeting the IL-17 receptor. Lastly, we discuss potential working mechanisms relevant to neuroinflammation and the possible involvement of IL-17.
Most research on human fear conditioning and its generalization has focused on adults whereas only little is known about these processes in children. Direct comparisons between child and adult populations are needed to determine developmental risk markers of fear and anxiety. We compared 267 children and 285 adults in a differential fear conditioning paradigm and generalization test. Skin conductance responses (SCR) and ratings of valence and arousal were obtained to indicate fear learning. Both groups displayed robust and similar differential conditioning on subjective and physiological levels. However, children showed heightened fear generalization compared to adults as indexed by higher arousal ratings and SCR to the generalization stimuli. Results indicate overgeneralization of conditioned fear as a developmental correlate of fear learning. The developmental change from a shallow to a steeper generalization gradient is likely related to the maturation of brain structures that modulate efficient discrimination between danger and (ambiguous) safety cues.
Background: Understanding which factors influence dietary intake, particularly in daily life, is crucial given the impact diet has on physical as well as mental health. However, a factor might influence whether but not how much an individual eats and vice versa or a factor’s importance may differ across these two facets. Distinguishing between these two facets, hence, studying dietary intake as a dual process is conceptually promising and not only allows further insights, but also solves a statistical issue. When assessing the association between a predictor (e.g. momentary affect) and subsequent dietary intake in daily life through ecological momentary assessment (EMA), the outcome variable (e.g. energy intake within a predefined time-interval) is semicontinuous. That is, one part is equal to zero (i.e. no dietary intake occurred) and the other contains right-skewed positive values (i.e. dietary intake occurred, but often only small amounts are consumed). However, linear multilevel modelling which is commonly used for EMA data to account for repeated measures within individuals cannot be applied to semicontinuous outcomes. A highly informative statistical approach for semicontinuous outcomes is multilevel two-part modelling which treats the outcome as generated by a dual process, combining a multilevel logistic/probit regression for zeros and a multilevel (generalized) linear regression for nonzero values. Methods: A multilevel two-part model combining a multilevel logistic regression to predict whether an individual eats and a multilevel gamma regression to predict how much is eaten, if an individual eats, is proposed. Its general implementation in R, a widely used and freely available statistical software, using the R-package brms is described. To illustrate its practical application, the analytical approach is applied exemplary to data from the Eat2beNICE-APPetite-study. Results: Results highlight that the proposed multilevel two-part model reveals process-specific associations which cannot be detected through traditional multilevel modelling. Conclusions: This paper is the first to introduce multilevel two-part modelling as a novel analytical approach to study dietary intake in daily life. Studying dietary intake through multilevel two-part modelling is conceptually as well as methodologically promising. Findings can be translated to tailored nutritional interventions targeting either the occurrence or the amount of dietary intake.
Background: Diet and physical activity (PA) have a major impact on physical and mental health. However, there is a lack of effective strategies for sustaining these health-protective behaviors. A shift to a microtemporal, within-person approach is needed to capture dynamic processes underlying eating behavior and PA, as they change rapidly across minutes or hours and differ among individuals. However, a tool that captures these microtemporal, within-person processes in daily life is currently not present.
Objective: The APPetite-mobile-app is developed for the ecological momentary assessment of microtemporal, within-person processes of complex dietary intake, objectively recorded PA, and related factors. This study aims to evaluate the feasibility and usability of the APPetite-mobile-app and the validity of the incorporated APPetite-food record.
Methods: The APPetite-mobile-app captures dietary intake event-contingently through a food record, captures PA continuously through accelerometers, and captures related factors (eg, stress) signal-contingently through 8 prompts per day. Empirical data on feasibility (n=157), usability (n=84), and validity (n=44) were collected within the Eat2beNICE-APPetite-study. Feasibility and usability were examined in healthy participants and psychiatric patients. The relative validity of the APPetite-food record was assessed with a subgroup of healthy participants by using a counterbalanced crossover design. The reference method was a 24-hour recall. In addition, the energy intake was compared with the total energy expenditure estimated from accelerometry.
Results: Good feasibility, with compliance rates above 80% for prompts and the accelerometer, as well as reasonable average response and recording durations (prompt: 2.04 min; food record per day: 17.66 min) and latencies (prompts: 3.16 min; food record: 58.35 min) were found. Usability was rated as moderate, with a score of 61.9 of 100 on the System Usability Scale. The evaluation of validity identified large differences in energy and macronutrient intake between the two methods at the group and individual levels. The APPetite-food record captured higher dietary intakes, indicating a lower level of underreporting, compared with the 24-hour recall. Energy intake was assessed fairly accurately by the APPetite-food record at the group level on 2 of 3 days when compared with total energy expenditure. The comparison with mean total energy expenditure (2417.8 kcal, SD 410) showed that the 24-hour recall (1909.2 kcal, SD 478.8) underestimated habitual energy intake to a larger degree than the APPetite-food record (2146.4 kcal, SD 574.5).
Conclusions: The APPetite-mobile-app is a promising tool for capturing microtemporal, within-person processes of diet, PA, and related factors in real time or near real time and is, to the best of our knowledge, the first of its kind. First evidence supports the good feasibility and moderate usability of the APPetite-mobile-app and the validity of the APPetite-food record. Future findings in this context will build the foundation for the development of personalized lifestyle modification interventions, such as just-in-time adaptive interventions.
Structural brain morphometry as classifier and predictor of ADHD and reward-related comorbidities
(2022)
Attention deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, and around two-thirds of affected children report persisting problems in adulthood. This negative trajectory is associated with high comorbidity with disorders like obesity, depression, or substance use disorder (SUD). Decreases in cortical volume and thickness have also been reported in depression, SUD, and obesity, but it is unclear whether structural brain alterations represent unique disorder-specific profiles. A transdiagnostic exploration of ADHD and typical comorbid disorders could help to understand whether specific morphometric brain changes are due to ADHD or, alternatively, to the comorbid disorders. In the current study, we studied the brain morphometry of 136 subjects with ADHD with and without comorbid depression, SUD, and obesity to test whether there are unique or common brain alterations. We employed a machine-learning-algorithm trained to classify subjects with ADHD in the large ENIGMA-ADHD dataset and used it to predict the diagnostic status of subjects with ADHD and/or comorbidities. The parcellation analysis demonstrated decreased cortical thickness in medial prefrontal areas that was associated with presence of any comorbidity. However, these results did not survive correction for multiple comparisons. Similarly, the machine learning analysis indicated that the predictive algorithm grouped most of our ADHD participants as belonging to the ADHD-group, but no systematic differences between comorbidity status came up. In sum, neither a classical comparison of segmented structural brain metrics nor an ML model based on the ADHD ENIGMA data differentiate between ADHD with and without comorbidities. As the ML model is based in part on adolescent brains, this might indicate that comorbid disorders and their brain changes are not captured by the ML model because it represents a different developmental brain trajectory.
Neuronal nitric oxide synthase (NOS-I) impacts on fear/anxiety-like behavior in animals. In humans, the short (S) allele of a functional promotor polymorphism of NOS1 (NOS1 ex1f-VNTR) has been shown to be associated with higher anxiety and altered fear conditioning in healthy subjects in the amygdala and hippocampus (AMY/HIPP). Here, we explore the role of NOS1 ex1f-VNTR as a pathophysiological correlate of panic disorder and agoraphobia (PD/AG). In a sub-sample of a multicenter cognitive behavioral therapy (CBT) randomized controlled trial in patients with PD/AG (n = 48: S/S-genotype n=15, S/L-genotype n=21, L/L-genotype n=12) and healthy control subjects, HS (n = 34: S/S-genotype n=7, S/L-genotype n=17, L/L-genotype=10), a differential fear conditioning and extinction fMRI-paradigm was used to investigate how NOS1 ex1f-VNTR genotypes are associated with differential neural activation in AMY/HIPP. Prior to CBT, L/L-allele carriers showed higher activation than S/S-allele carriers in AMY/HIPP. A genotype × diagnosis interaction revealed that the S-allele in HS was associated with a pronounced deactivation in AMY/HIPP, while patients showed contrary effects. The interaction of genotype × stimulus type (CS+, conditioned stimulus associated with an aversive stimulus vs. CS-, unassociated) showed effects on differential learning in AMY/HIPP. All effects were predominately found during extinction. Genotype associated effects in patients were not altered after CBT. Low statistical power due to small sample size in each subgroup is a major limitation. However, our findings provide first preliminary evidence for dysfunctional neural fear conditioning/extinction associated with NOS1 ex1f-VNTR genotype in the context of PD/AG, shedding new light on the complex interaction between genetic risk, current psychopathology and treatment-related effects.
Einführung: Seit 20 Jahren ist die Vagusnervstimulation (VNS) eine europaweit zugelassene invasive Therapieoption für therapieresistente Depressionen (TRD). Im Gegensatz zu geläufigeren Behandlungen wie EKT sind Kenntnisse über VNS sowohl in der Allgemeinbevölkerung als auch in Fachkreisen gering.
Methoden: In diesem narrativen Review geben wir eine klinisch und wissenschaftlich fundierte Übersicht über die VNS. Hypothesen zum Wirkmechanismus sowie die aktuelle Evidenzlage zur Wirksamkeit werden dargestellt. Das perioperative Management, das Nebenwirkungsprofil und die Nachbetreuung einschließlich Dosistitration werden beschrieben. Ein Vergleich über internationale Leitlinienempfehlungen zur VNS findet sich ebenfalls. Ferner formulieren wir Kriterien, die bei der Auswahl geeigneter Patienten hilfreich sind.
Ergebnisse: Die elektrischen Impulse werden über den N. vagus afferent weitergeleitet und stimulieren über verschiedene Wege ein neuromodulatorisches zerebrales Netzwerk. Viele Studien und Fallserien zeigten die Wirksamkeit von VNS als adjuvantes Verfahren bei TRD. Der Effekt tritt mit einer Latenz von 3 bis 12 Monaten ein und steigt möglicherweise mit der Dauer der VNS. Unter der Beachtung der Stimulationsempfehlungen sind die Nebenwirkungen für die meisten Patienten tolerabel.
Fazit: Die VNS ist eine zugelassene, wirksame und gut verträgliche Langzeittherapie für chronische und therapieresistente Depressionen. Weitere Sham-kontrollierte Studien über einen längeren Beobachtungszeitraum sind zur Verbesserung der Evidenz wünschenswert.
The consequences of the current COVID-19 pandemic for mental health remain unclear, especially regarding the effects on suicidal behaviors. To assess changes in the pattern of suicide attempt (SA) admissions and completed suicides (CS) in association with the COVID-19 pandemic. As part of a longitudinal study, SA admissions and CS are systematically documented and analyzed in all psychiatric hospitals in Frankfurt/Main (765.000 inhabitants). Number, sociodemographic factors, diagnoses and methods of SA and CS were compared between the periods of March–December 2019 and March–December 2020. The number of CS did not change, while the number of SA significantly decreased. Age, sex, occupational status, and psychiatric diagnoses did not change in SA, whereas the percentage of patients living alone while attempting suicide increased. The rate and number of intoxications as a SA method increased and more people attempted suicide in their own home, which was not observed in CS. Such a shift from public places to home is supported by the weekday of SA, as the rate of SA on weekends was significantly lower during the pandemic, likely because of lockdown measures. Only admissions to psychiatric hospitals were recorded, but not to other institutions. As it seems unlikely that the number of SA decreased while the number of CS remained unchanged, it is conceivable that the number of unreported SA cases increased during the pandemic. Our data suggest that a higher number of SA remained unnoticed during the pandemic because of their location and the use of methods associated with lower lethality.
Der Eintrag starker anorganischer Säuren in Wälder führte zu tiefen pH-Werten und hohen Al3+-Konzentrationen im Boden. Dem versuchte man in Deutschland seit den 1980er Jahren durch Kalkung unter Verwendung dolomitischer Kalke zu begegnen. In den ersten Jahren nach Kalkung werden organische Auflagen abgebaut und die darin enthaltenen Nährstoffe, v. a. Stickstoff (N), mobilisiert und teils im humosen Oberboden gespeichert, teils aufgenommen, teils ins Grundwasser ausgewaschen. Die Bodenvegetation reagiert auf Kalkungmit einer Zunahme an nährstoff- und stickstoffliebenden Arten, Azidophyten gehen zurück. Die Artenzusammensetzung von Mykorrhizapilzen und Bodenfauna verändern sich vollständig. Die Baumwurzeln ziehen sich in den mineralischen Oberboden zurück. Bis die basischen Kationen eine Tiefe von 30 cm erreichen, vergehen viele Jahre. Seit 1990 gingen die Depositionen an Schwefel (S) stark zurück, doch der N-Eintrag blieb bis heute auf hohem Niveau. In Nadelbaumbeständen ist der N-Eintrag wesentlich höher als in Laubwäldern oder im Freiland. Hohe N-Einträge tragen zur fortdauernden Bodenversauerung bei, zugleich eutrophieren sie Waldökosysteme, welche von Natur aus N-limitiert sind. Das verstärkte Wachstum der Waldbestände zieht einen erhöhten Bedarf an anderen Nährstoffen nach sich. In vielen Wäldern wird die kritische Belastungsgrenze („critical load“) des Eintrags von ca. 10 bis 20 kg N ha-1 a-1 überschritten. Solche Wälder werden mit N übersättigt und geben überschüssiges Nitrat, das nicht im Humus eingebaut oder von der Waldvegetation aufgenommen wird, ans Grundwasser ab. Bis heute werden in Baden-Württemberg, Rheinland-Pfalz, Hessen, Niedersachsen, Sachsen, Nordrhein-Westfalen, Thüringen und neuerdings Sachsen-Anhalt große Waldflächen mit drei bis vier Tonnen dolomitischem Kalk pro Hektar und Jahrzehnt gekalkt. Ziel ist es, eine weitere säurebedingte Verwitterung von Tonmineralen zu verhindern und die Vitalität der Waldbestände zu erhöhen. Oftmals werden dem Kalk auch Phosphor- (P) und/oder Kaliumverbindungen (K) beigemengt. Bayern, Brandenburg und Mecklenburg-Vorpommern verzichten auf Waldkalkungen oder wenden sie nur in sehr spezifischen Fällen an. Die mitteleuropäischen Hauptbaumarten Buche, Fichte, Wald-Kiefer, Tanne und Eichen sind dort ähnlich vital, da diese edaphisch eine weite ökologische Amplitude besitzen. Analysen von Blatt- und Nadelspiegeln belegen eine geringe, doch ausreichende Nährelementversorgung selbst auf den sauersten Waldböden. Heute stellt nicht Bodenversauerung, sondern N-Eutrophierung (und Klimawandel) die Hauptgefährdung der Waldökosysteme dar. Eutrophierung gefährdet die Lebensgemeinschaften auf schwach gepufferten Böden in besonderem Maße, insbesondere oligotrophe Kiefern- und Eichenwälder. Kalkung in eutrophierten Wäldern wirkt der Versauerung entgegen und führt langfristig zu tieferer Durchwurzelung. Zugleich jedoch verbessert sie angesichts hohen N-Eintrags die Verfügbarkeit limitierender Nährstoffe und verstärkt dadurch die Auswirkungen der Eutrophierung. Daher fällt die Bewertung der Kalkung ambivalent aus. Nur eine Reduzierung des N-Eintrags stellt eine wirklich gute Lösung dar. Aus Naturschutzsicht besonders bedenklich ist Waldkalkung auf natürlich basenarmen Substraten und ihren oligotraphenten Lebensgemeinschaften. Deren Habitate müssen durch Pufferzonen und angepasste Verabreichungstechniken gegen Kalkeinträge geschützt werden. Auf bestimmten mesotrophen, aber versauerungsanfälligen Lehmböden kann Kalkung fallweise toleriert werden. Die Anreicherung mit P und K entspricht einer Düngung und ist daher nicht akzeptabel. Um die Auswirkungen von Waldkalkung abwägen zu können, sollten ausreichend große ungekalkte Kontrollflächen ausgewiesen werden. Angesichts eines heute relativ hohen Waldwachstums sollte eine weitere Förderung von Waldkalkung überdacht werden.