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Depressive patients suffer from a complex of symptoms of varying intensity compromising their mood, emotions, self-concept, neurocognition, and somatic function. Due to a mosaic of aetiologies involved in developing depression, such as somatic, neurobiological, (epi-)genetic factors, or adverse life events, patients often experience recurrent depressive episodes. About 20–30% of these patients develop difficult-to-treat depression. Here, we describe the design of the GEParD (Genetics and Epigenetics of Pharmaco- and Psychotherapy in acute and recurrent Depression) cohort and the DaCFail (Depression-associated Cardiac Failure) case–control protocol. Both protocols intended to investigate the incremental utility of multimodal biomarkers including cardiovascular and (epi-)genetic markers, functional brain and heart imaging when evaluating the response to antidepressive therapy using comprehensive psychometry. From 2012 to 2020, 346 depressed patients (mean age 45 years) were recruited to the prospective, observational GEParD cohort protocol. Between 2016 and 2020, the DaCFail case–control protocol was initiated integrating four study subgroups to focus on heart-brain interactions and stress systems in patients > 50 years with depression and heart failure, respectively. For DaCFail, 120 depressed patients (mean age 60 years, group 1 + 2), of which 115 also completed GEParD, and 95 non-depressed controls (mean age 66 years) were recruited. The latter comprised 47 patients with heart failure (group 3) and 48 healthy subjects (group 4) of a population-based control group derived from the Characteristics and Course of Heart Failure Stages A–B and Determinants of Progression (STAAB) cohort study. Our hypothesis-driven, exploratory study design may serve as an exemplary roadmap for a standardized, reproducible investigation of personalized antidepressant therapy in an inpatient setting with focus on heart comorbidities in future multicentre studies.

The etio-pathophysiology of obsessive-compulsive disorder (OCD) can be explained using a biopsychosocial model. Little is known about obsessive-compulsive symptoms (OCS) in the context of chromosomal disorders involving the X chromosome.Case studies of two patients with chromosomal disorders involving the X chromosome (Patient 1 with a variant of Turner syndrome and Patient 2 with triple X syndrome).Both patients were treated due to severe OCS. In the research MRI analysis, the most pronounced MRI change in both patients was a gray matter volume loss in the orbitofrontal cortex. Patient 1 additionally showed left mesiotemporal changes. Patient 2 presented with global gray matter volume reduction, slowing in EEG, and a reduced intelligence quotient.OCS could occur in the context of Turner syndrome or triple X syndrome. The detected MRI changes would be compatible with dysfunction of the cortico-striato-thalamo-cortical loops involved in OCD pathophysiology. Further studies with larger patient groups should investigate whether this association can be validated.

AIM: This study aimed to investigate whether separation anxiety (SA) constitutes a dimension related to age at onset of panic disorder (PD), in homogeneous subgroups of outpatients with PD, based on their age of onset and symptom severity.METHODS: A sample of 232 outpatients with PD was assessed with the Panic Disorder Severity Scale (PDSS) and the Sheehan Disability Scale (SDS) for functional impairments. Separation anxiety was evaluated using structured interviews and questionnaires. We applied a K-Means Cluster Analysis based on the standardized "PD age of onset" and "the PDSS total score" to identify distinct but homogeneous groups.RESULTS: We identified three groups of patients: group 1 ("PD early onset/severe", N = 97, 42%, onset 23.2 ± 6.7 years), group 2 ("PD early onset/not severe", N = 76, 33%, onset 23.4 ± 6.0 years) and group 3 ("PD adult onset/not severe", N = 59, 25%, onset 42.8 ± 7.0 years). Patients with early onset/severe PD had significantly higher scores on all SA measures than PD late-onset/not severe. Regression analyses showed that SA scores, but not PDSS scores, were predictive of impairment in SDS work/school, social life, and family functioning domains.CONCLUSIONS: Our data indicate a significant relationship between SA and PD with an earlier age of onset and an impact on individual functioning. This may have important implications for implementing preventive interventions targeting early risk factors for the subsequent onset of PD.

Abstract: Fear-, anxiety- and stress-related disorders are among the most frequent mental disorders. Given substantial rates of insufficient treatment response and often a chronic course, a better under-standing of the pathomechanisms of fear-, anxiety- and stress-related disorders is urgently warranted. Epigenetic mechanisms such as histone modifications - positioned at the interface between the biological and the environmental level in the complex pathogenesis of mental disorders - might be highly informative in this context. The current state of knowledge on histone modifications, chromatin-related pharmacology and animal models modified for genes involved in the histone-related epigenetic ma-chinery will be reviewed with respect to fear-, anxiety- and stress-related states. Relevant studies, published until 30th June 2022, were identified using a multi-step systematic literature search of the Pub-Med and Web of Science databases. Animal studies point towards histone modifications (e.g., H3K4me3, H3K9me1/2/3, H3K27me2/3, H3K9ac, H3K14ac and H4K5ac) to be dynamically and mostly brain region-, task- and time-dependently altered on a genome-wide level or gene-specifically (e.g., Bdnf) in models of fear conditioning, retrieval and extinction, acute and (sub-)chronic stress. Singular and underpowered studies on histone modifications in human fear-, anxiety- or stress-related phenotypes are currently restricted to the phenotype of PTSD. Provided consistent validation in human phenotypes, epigenetic biomarkers might ultimately inform indicated preventive interventions as well as personalized treatment approaches, and could inspire future innovative pharmacological treatment options targeting the epigenetic machinery improving treatment response in fear-, anxiety- and stress related disorders.

Obsessive-compulsive disorder (OCD) can rarely be associated with immunological etiologies, most notably in Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections and possibly in autoimmune encephalitis. As cerebrospinal fluid (CSF) analysis is a sensitive method for assessing neuroinflammation, this retrospective study analyzed basic CSF parameters and well-characterized as well as novel neuronal autoantibodies in OCD to screen for signs of autoimmunity.Basic CSF findings of 54 adult OCD patients suspected of an organic etiology were retrospectively compared to a control group of mentally healthy patients (N = 39) with idiopathic intracranial hypertension. Further subgroup analysis included testing for well-characterized neuronal IgG autoantibodies and tissue-based assays using indirect immunofluorescence to screen for novel brain autoantibodies.Elevated protein in the CSF of OCD patients compared to the control group (p = 0.043) were identified. Inflammatory markers (pleocytosis/oligoclonal bands/increased IgG-index) were detected in 7% of all patients with OCD. Well-characterized neuronal autoantibodies were not found in any OCD patient, whereas 6/18 (33%) CSF samples showed binding on mouse brain sections in tissue-based assays (binding to neuropil in the basal ganglia/brainstem, cilia of granule cells, blood vessels, nuclear/perinuclear structures).While elevated CSF protein is merely a weak indicator of blood CSF barrier dysfunction, the presence of inflammatory CSF changes and novel brain autoantibodies in CSF may indicate OCD subtypes with inflammatory pathomechanism and supports the hypothesis of a rare 'autoimmune OCD' subtype.

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.

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 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.

Symptoms of obsessive–compulsive disorder (OCD) may rarely occur in the context of genetic syndromes. So far, an association between obsessive–compulsive symptoms (OCS) and ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome has not been described as yet. A thoroughly phenotyped patient with OCS and ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome is presented. The 25-year-old male patient was admitted to in-patient psychiatric care due to OCD. A whole-exome sequencing analysis was initiated as the patient also showed an autistic personality structure, below average intelligence measures, craniofacial dysmorphia signs, sensorineural hearing loss, and sinus cavernoma as well as subtle cardiac and ophthalmological alterations. The diagnosis of Baraitser-Winter cerebrofrontofacial syndrome type 2 was confirmed by the detection of a heterozygous likely pathogenic variant in the ACTG1 gene [c.1003C > T; p.(Arg335Cys), ACMG class 4]. The automated analysis of magnetic resonance imaging (MRI) revealed changes in the orbitofrontal, parietal, and occipital cortex of both sides and in the right mesiotemporal cortex. Electroencephalography (EEG) revealed intermittent rhythmic delta activity in the occipital and right temporal areas. Right mesiotemporal MRI and EEG alterations could be caused by a small brain parenchymal defect with hemosiderin deposits after a cavernomectomy. This paradigmatic case provides evidence of syndromic OCS in ACTG1-associated Baraitser-Winter cerebrofrontofacial syndrome. The MRI findings are compatible with a dysfunction of the cortico-striato-thalamo-cortical loops involved in OCD. If a common pathophysiology is confirmed in future studies, corresponding patients with Baraitser-Winter cerebrofrontofacial syndrome type 2 should be screened for OCS. The association may also contribute to a better understanding of OCD pathophysiology.

Obsessive-compulsive disorder (OCD) is a frequent mental disorder that leads to an enormous impairment in the quality of life. Cognitive-behavioral explanatory approaches are well established. Scientific research on the underlying neurobiology has increased in recent years.This article reviews current research findings and the etiopathophysiological considerations derived from them.An overview of the genetic, epigenetic, structural, functional, and neurochemical alterations in OCD is presented. Additionally, the possible organic causes that can trigger obsessive-compulsive symptoms are summarized.With respect to OCD a moderate heritability is assumed. On a molecular level, genetic variants and epigenetic variations in the serotonergic, dopaminergic and glutamatergic systems in particular seem to play a role in the pathogenesis of the disease and affect the corresponding neurotransmission. Cortico-striatal-thalamo-cortical loops are neurochemically modulated, and predominance of the activity of the direct excitatory pathway is hypothesized in OCD. Recent research also provides evidence for the involvement of frontoparietal and frontolimbic networks. Obsessive-compulsive symptoms may also have different organic (e.g., immunological) causes.The neurobiology of OCD is partially understood and categorized in an integrative neurobiological model. For the rare secondary immunological causes the concept of "autoimmune OCD" has recently been proposed. The better understanding of the neurobiology of OCD might allow for individualized, personalized treatment approaches in the future.HINTERGRUND: Die Zwangsstörung ist eine häufige psychische Störung, die zu einer enormen Einschränkung in der Lebensqualität führt. Kognitiv-behaviorale Erklärungsmodelle sind gut etabliert. Die zugrunde liegende Neurobiologie wurde in den letzten Jahren vermehrt wissenschaftlich untersucht.Übersicht über die aktuellen Forschungsbefunde und davon abgeleitete ätiopathophysiologische Überlegungen.Überblick über genetische, epigenetische, strukturelle, funktionelle und neurochemische Veränderungen bei der Zwangsstörung sowie über mögliche organische Ursachen, die Symptome einer Zwangsstörung auslösen können.Hinsichtlich der Zwangsstörung wird eine moderate Heritabilität angenommen. Auf molekularer Ebene scheinen genetische Varianten und epigenetische Veränderungen, vor allem in den serotonergen, dopaminergen und glutamatergen Systemen, an der Krankheitsentstehung beteiligt zu sein und die entsprechende Neurotransmission zu beeinflussen. Die kortiko-striato-thalamo-kortikalen Schleifensysteme werden neurochemisch moduliert, wobei ein Überwiegen des direkten, exzitatorischen „Pathway“ bei Zwangsstörungen angenommen wird. Neue Studienergebnisse geben auch Hinweise auf eine Beteiligung frontoparietaler und frontolimbischer Netzwerke. Symptome einer Zwangsstörung können zudem ursächlich organisch und so beispielsweise immunologisch bedingt sein.Die Neurobiologie der Zwangsstörung ist partiell verstanden und wird in ein integratives neurobiologisches Modell eingeordnet. Für die seltenen sekundären, immunologischen Ursachen wurde kürzlich das Konzept der „autoimmunen Zwangsstörung“ vorgeschlagen. Ein zunehmend besseres Verständnis der Neurobiologie von Zwangsstörungen kann zukünftig im Optimalfall eine individualisierte, personalisierte Behandlung ermöglichen.

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.

Praventive Masnahmen wie universelle und targetierte – d. h. selektive und indizierte – Interventionen konnen die Inzidenz von Angsterkrankungen wirksam reduzieren und somit zu einer Senkung der hohen individuellen und soziookonomischen Kosten von Angsterkrankungen beitragen. Diese Ubersichtsarbeit gibt einen Uberblick uber international etablierte Praventionsprogramme im Kindes- und Jugendalter sowie fur Erwachsene. Weiterhin werden die Wirksamkeit und Kosteneffektivitat praventiver Interventionen diskutiert. Dabei sind universell eingesetzte Masnahmen aufgrund ihrer grosen Zielgruppe zwar kostenintensiv und organisatorisch aufwendig, konnen aber bereits mit kleinen Effekten eine hohe Anzahl klinisch manifester Erkrankungen verhindern oder deren klinische Auspragung reduzieren. Selektive praventive Masnahmen wenden sich an Personen mit einem hohen Risiko fur Angsterkrankungen (z. B. hohe Angstsensitivitat, gehemmtes Verhalten, pessimistische Grundannahmen, Angsterkrankungen bei Familienangehorigen). Die indizierte Pravention bei Hochrisikopersonen mit bereits ersten, subklinischen Angstsymptomen zeigt signifikante Erfolge bei der Verhinderung der Manifestation klinisch relevanter Angsterkrankungen und stellt die wahrscheinlich kosteneffektivste praventive Masnahme dar. Ausblickend werden biologische, d. h. genetische, bildgebende oder neurophysiologische Faktoren bzw. deren kombinierte Bestimmung als vielversprechende Marker fur die selektive bzw. indizierte Pravention von Angsterkrankungen diskutiert.

In the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) separation anxiety disorder has been included in the chapter on anxiety disorders, thereby removing the age of onset restriction that previously required first onset during childhood or adolescence. Separation anxiety disorder has a lifetime prevalence of 4.8% and onset often occurs after the age of 18 years. Despite the high prevalence, separation anxiety disorder is often underdiagnosed and subsequently remains untreated. This narrative review summarizes the etiology, clinical features, diagnostic criteria as well as important differential diagnostic aspects, common comorbidity profiles and treatment implications of separation anxiety disorder. Furthermore, relevant implications for everyday practice and future perspectives for treatment and research are discussed.

There is an emerging role of autoimmune causes related to severe mental disorders (SMD). The clinical approach in patients with chronic SMD and novel anti-central nervous system antibodies is complex.Two corresponding cumulative cases are presented. Cerebrospinal fluid (CSF) and serum were investigated using tissue-based assays.Both patients suffered from chronic SMD and were negative for well-characterized neuronal antibodies. Patient 1 suffered from a dysexecutive and neurocognitive syndrome with mild abnormalities in automated electroencephalography analysis, elevated CSF protein levels, several serum autoantibodies (including antibodies against endothelial cells), and novel antibodies with a 'dotted/scalloped' binding against cytoplasmic structures in CSF. Patient 2 with obsessive-compulsive disorder had left temporal abnormalities on automated magnetic resonance imaging analysis, an elevated CSF/serum albumin quotient, and novel atypical cytoplasmic 'spotted' antibody staining in the serum. Patient 1 improved with immunotherapy using high-dose steroids, but patient 2 did not improve under the same treatment.The detection of autoantibodies in CSF of chronic SMD may be beneficial in selecting some patients for immunotherapy. The possible impact of novel anti-cytoplasmic antibodies in this context is critically discussed. Further research is needed to establish the underlying pathophysiological processes as well as their diagnostic and therapeutic implications.

Background Previous work on gene-environment (GxE) interplay concerning anxiety has focused on the interaction of 5-HTTLPR with childhood adversities or traumatic events whereas the impact of recent stressors is understudied, as is the integration of resilience. The current study aimed to investigate the interactive effect of 5-HTTLPR and recent stress on anxiety in adolescents considering resilience as buffer of a GxE risk constellation. Method In a random population-based sample of 14-21 years old from Dresden, Germany, (N = 1180; genotyped = 942) recent stress (Daily Hassles [DH] Scale, Perceived Stress Scale, Screening Scale of the Trier Inventory for the Assessment of Chronic Stress), resilience (Connor-Davidson resilience scale) and anxiety (Patient Reported Outcome Measurement Information System Anxiety Short Form) were assessed via questionnaire in 2015 or 2016. Results Fractional regression models revealed that resilience interacted with recent stress in form of DH as well as recent chronic stress and 5-HTTLPR regarding anxiety. Participants carrying the more active LA LA genotype reported consistently higher levels of anxiety when experiencing more DH or more recent chronic stress and having low levels of resilience. When the resilience scores were high, LA LA carriers reported the lowest anxiety scores despite DH or recent chronic stress. Conclusion Findings revealed an interactive relationship between 5-HTTLPR genotype and recent stress suggesting resilience to function as an additional dimension buffering the impact of a GxE risk constellation. Early interventions to build resilience may be useful to prevent an escalation of distress and associated unfavorable health outcomes.

Introduction: Obsessive-compulsive disorder (OCD) is associated with high chronicity and treatment resistance, indicating the need for early therapy response markers enabling fast and personalized treatment adaptations. Although epigenetic mechanisms such as DNA methylation of the oxytocin receptor (OXTR) gene have previously been linked to OCD pathogenesis, epigenetic markers as predictors of treatment success have not yet been investigated in OCD. Objective: For the first time, this therapyepigenetic study aimed to investigate the role of OXTR methylation as a treatment response marker in OCD. Methods: In total, 113 inpatients with OCD (57 females) were compared to 113 age- and sex-matched healthy controls. Patients were investigated over a 10-week course of standardized, OCD-specific cognitive-behavioral psychotherapy. Clinical response was measured using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) at baseline, before in vivo exposure, and after therapy. OXTR exon III methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. Results: Relative OXTR hypermethylation was observed in OCD patients compared to healthy controls. In OCD, higher baseline OXTR methylation was found to predict impaired treatment response at both categorical (responders vs. nonresponders) and dimensional (relative Y-BOCS reduction) levels, whereas lower baseline methylation was related to treatment response and greater symptom improvements. Analysis of Y-BOCS subdimensions revealed that the association between OXTR hypermethylation with impaired treatment response applied especially to symptoms related to obsessions, but not compulsions. Conclusions: OXTR hypermethylation may constitute a predictive marker of impaired treatment response in OCD and thus carries great potential for future personalized treatment efforts in OCD.

Panic disorder (PD) is one of the most common anxiety disorders and often occurs comorbidly with major depressive disorder (MDD). Altered methylation of the monoamine oxidase A (MAOA) gene has been implicated in the etiology of both PD and MDD. The Krüppel-like factor 11 (KLF11; alias TIEG2), an activating transcription factor of the MAOA gene, has been found to be increased in MDD, but has not yet been investigated in PD. In an effort to further delineate the effects of the KLF11–MAOA pathway in anxiety and affective disorders, KLF11 promoter methylation was analyzed via pyrosequencing of sodium bisulfite-treated DNA isolated from human peripheral blood in two independent samples of PD patients with or without comorbid MDD in a case–control design (sample 1: N = 120) as well as MDD patients with and without anxious depression (sample 2: N = 170). Additionally, in sample 1, KLF11 methylation was correlated with Beck Depression Inventory (BDI-II) scores. No overall association of KLF11 promoter methylation with PD was detected. However, PD patients with comorbid MDD showed significant hypomethylation relative to both healthy controls (p = 0.010) and PD patients without comorbid MDD (p = 0.008). Furthermore, KLF11 methylation was negatively correlated with BDI-II scores in PD patients (p = 0.013). MDD patients without anxious features showed nominally decreased KLF11 methylation in comparison to MDD patients with anxious depression (p = 0.052). The present results suggest KLF11 promoter hypomethylation as a potential epigenetic marker of MDD comorbidity in PD or of non-anxious depression, respectively, possibly constituting a differential pathomechanism in anxiety and mood disorders.

BackgroundThe general understanding of the ‘vulnerability–stress model’ of mental disorders neglects the modifying impact of resilience-increasing factors such as coping ability.AimsProbing a conceptual framework integrating both adverse events and coping factors in an extended ‘vulnerability–stress–coping model’ of mental disorders, the effects of functional neuropeptide S receptor gene (NPSR1) variation (G), early adversity (E) and coping factors (C) on anxiety were addressed in a three-dimensional G × E × C model.MethodIn two independent samples of healthy probands (discovery: n = 1403; replication: n = 630), the interaction of NPSR1 rs324981, childhood trauma (Childhood Trauma Questionnaire, CTQ) and general self-efficacy as a measure of coping ability (General Self-Efficacy Scale, GSE) on trait anxiety (State-Trait Anxiety Inventory) was investigated via hierarchical multiple regression analyses.ResultsIn both samples, trait anxiety differed as a function of NPSR1 genotype, CTQ and GSE score (discovery: β = 0.129, P = 3.938 × 10−8; replication: β = 0.102, P = 0.020). In A allele carriers, the relationship between childhood trauma and anxiety was moderated by general self-efficacy: higher self-efficacy and childhood trauma resulted in low anxiety scores, and lower self-efficacy and childhood trauma in higher anxiety levels. In turn, TT homozygotes displayed increased anxiety as a function of childhood adversity unaffected by general self-efficacy.ConclusionsFunctional NPSR1 variation and childhood trauma are suggested as prime moderators in the vulnerability–stress model of anxiety, further modified by the protective effect of self-efficacy. This G × E × C approach – introducing coping as an additional dimension further shaping a G × E risk constellation, thus suggesting a three-dimensional ‘vulnerability–stress–coping model’ of mental disorders – might inform targeted preventive or therapeutic interventions strengthening coping ability to promote resilient functioning.

In the DSM-5, separation anxiety disorder (SAD) is newly classified in the chapter on anxiety, renewing research efforts into its etiology. In this narrative review, we summarize the current literature on the genetic, endocrine, physiological, neural and neuropsychological underpinnings of SAD per se, SAD in the context of panic disorder, separation anxiety symptoms, and related intermediate phenotypes. SAD aggregates in families and has a heritability of ~43%. Variants in the oxytocin receptor, serotonin transporter, opioid receptor µ1, dopamine D4 receptor and translocator protein genes have all been associated with SAD. Dysregulation of the hypothalamus-pituitary-adrenal axis, dysfunctional cortico-limbic interaction and biased cognitive processing seem to constitute further neurobiological markers of separation anxiety. Hypersensitivity to carbon dioxide appears to be an endophenotype shared by SAD, panic disorder and anxiety sensitivity. The identification of biological risk markers and its multi-level integration hold great promise regarding the prediction of SAD risk, maintenance and course, and in the future may allow for the selection of indicated preventive and innovative, personalized therapeutic interventions.

Background Epigenetic markers such as DNA methylation of the monoamine oxidase A (MAOA) gene have previously been shown to be altered in anxiety- and stress-related disorders and to constitute a potential mechanism of action of psychotherapeutic interventions such as cognitive behavioral therapy in these disorders. The present study for the first time, to our knowledge, investigated MAOA methylation in patients with obsessive-compulsive disorder applying a longitudinal psychotherapy-epigenetic approach. Methods The present sample comprised 14 unmedicated female patients with primary obsessive-compulsive disorder and 14 age- and sex-matched healthy controls. MAOA promoter methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from whole blood before and after an 8- to 10-week semi-standardized, obsessive-compulsive disorder–specific cognitive behavioral therapy. Clinical response was assessed by means of the Yale-Brown Obsessive Compulsive Scale. Results Significantly lower MAOA promoter methylation was discerned in obsessive-compulsive disorder patients relative to healthy controls. Data were available for 12 patients with obsessive-compulsive disorder and 14 controls. Furthermore, following cognitive behavioral therapy, clinical improvement, i.e., decreases in obsessive-compulsive disorder symptoms as indicated by lower scores on the Yale-Brown Obsessive Compulsive Scale was found to be significantly correlated with increases in MAOA methylation levels in patients (data available for n = 7). Conclusions The present pilot data suggest MAOA hypomethylation as a potential risk marker of obsessive-compulsive disorder and an increase in MAOA methylation levels as a possible mechanistic correlate of response to cognitive behavioral therapy in obsessive-compulsive disorder.

Objectives: Temperamental traits as ascertained by the Temperament Evaluation of Memphis, Pisa, Paris and San Diego Auto-Questionnaire (TEMPS-A) have been suggested as promising intermediate phenotypes of mental disorders. In anxiety disorders, however, TEMPS scales and their genetic underpinnings are still understudied.Methods: TEMPS-A scores in 109 patients with panic disorder (PD) were compared to a sample of 536 healthy probands. All participants were genotyped for serotonin transporter gene variation (5-HTTLPR/rs25531).Results: PD patients displayed significantly increased scores on the dysthymic, cyclothymic, irritable and anxious subscales, and lower scores on the hyperthymic subscale, respectively (all ps < 0.001) compared to healthy probands. In the total sample, the less active 5-HTTLPR/rs25531 S/LG alleles were associated with higher scores on the dysthymic, cyclothymic, irritable and anxious temperaments (all ps < 0.01), but not the hyperthymic subscale. Mediation analyses revealed anxious temperament in particular to mediate the relationship between 5-HTT genotype and PD.Conclusions: Dysthymic, cyclothymic, irritable and notably anxious temperament could serve as valuable intermediate phenotypes in efforts to unravel neurobiological, particularly serotonin system related genetic pathomechanisms associated with PD and potentially contribute to a panel of vulnerability markers guiding early targeted preventive interventions.

Anxiety patients overgeneralize fear responses, possibly because they cannot distinguish between cues never been associated with a threat (i.e., safe) and threat-associated cues. However, as contexts and not cues are discussed as the relevant triggers for prolonged anxiety responses characterizing many anxiety disorders, we speculated that it is rather overgeneralization of contextual anxiety, which constitutes a risk factor for anxiety disorders. To this end, we investigated generalization of conditioned contextual anxiety and explored modulatory effects of anxiety sensitivity, a risk factor for anxiety disorders. Fifty-five participants underwent context conditioning in a virtual reality paradigm. On Day 1 (acquisition), participants received unpredictable mildly painful electric stimuli (unconditioned stimulus, US) in one virtual office (anxiety context, CTX+), but never in a second office (safety context, CTX−). Successful acquisition of conditioned anxiety was indicated by aversive ratings and defensive physiological responses (i.e., SCR) to CTX+ vs CTX−. On Day 2 (generalization), participants re-visited both the anxiety and the safety contexts plus three generalization contexts (G-CTX), which were gradually dissimilar to CTX+ (from 75 to 25%). Generalization of conditioned anxiety was evident for ratings, but less clear for physiological responses. The observed dissociation between generalization of verbal and physiological responses suggests that these responses depend on two distinct context representations, likely elemental and contextual representations. Importantly, anxiety sensitivity was positively correlated with the generalization of reported contextual anxiety. Thus, this study demonstrates generalization gradients for conditioned contextual anxiety and that anxiety sensitivity facilitates such generalization processes suggesting the importance of generalization of contextual anxiety for the development of anxiety disorders. Electronic supplementary material The online version of this article (10.1007/s13311-020-00831-8) contains supplementary material, which is available to authorized users.

Alterations in fear learning/generalization are considered to be relevant mechanisms engendering the development of anxiety disorders being the most prevalent mental disorders. Although anxiety disorders almost exclusively have their first onset in childhood and adolescence, etiological research focuses on adult individuals. In this study, we evaluated findings of a recent meta-analysis of genome-wide association studies in adult anxiety disorders with significant associations of four single nucleotide polymorphisms (SNPs) in a large cohort of 347 healthy children (8–12 years) characterized for dimensional anxiety. We investigated the modulation of anxiety parameters by these SNPs in a discriminative fear conditioning and generalization paradigm in the to-date largest sample of children. Results extended findings of the meta-analysis showing a genomic locus on 2p21 to modulate anxious personality traits and arousal ratings. These SNPs might, thus, serve as susceptibility markers for a shared risk across pathological anxiety, presumably mediated by alterations in arousal. Electronic supplementary material The online version of this article (10.1007/s00787-019-01458-7) contains supplementary material, which is available to authorized users.

Autoimmune obsessive-compulsive disorder (OCD) in the context of pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) has been observed for decades. The first cases of autoimmune OCD in adulthood were recently described. An association between obsessive-compulsive symptoms (OCS) and systemic autoimmune diseases in the form of connective tissue disease has also been reported. However, whether an association exists between OCD and sarcoidosis is unknown.Here, the authors present an end 20-year-old female patient with symptoms of OCD in whom an advanced diagnostic work-up revealed inflammatory cerebrospinal fluid (CSF) changes (elevated IgG index, CSF-specific oligoclonal bands, intrathecal IgG synthesis, and a positive MRZ reaction). In tissue-based assays using unfixed mouse brain sections, both serum and CSF showed a distinct antinuclear antibody pattern with perinuclear staining. Electroencephalography identified frontocentral theta spindles. Upon endobronchial-guided lymph node biopsy demonstrating non-caseating lymph nodes in further work-up, sarcoidosis was diagnosed. Levels of the sarcoidosis parameters IL-2-R and neopterin were increased. Under immunotherapy for sarcoidosis, the OCS seemed to improve.This case study is paradigmatic, as an association between sarcoidosis and OCD has not been previously reported. After exclusion of alternative causes, the inflammatory CSF changes would be compatible with an inflammatory brain involvement of sarcoidosis. Autoimmune OCD may occur more frequently than is thought, probably also in the context of neurosarcoidosis. This could open up new opportunities through immunotherapies in rare cases with OCD.

Obsessive-compulsive disorder (OCD) is a heritable disorder, but no definitive, replicated OCD susceptibility loci have yet been identified by any genome-wide association study (GWAS). Here, we report results from a GWAS in the largest OCD case-control sample (N = 14,140 OCD cases and N = 562,117 controls) to date. We explored the genetic architecture of OCD, including its genetic relationships to other psychiatric and non-psychiatric phenotypes. In the GWAS analysis, we identified one SNP associated with OCD at a genome-wide significant level. Subsequent gene-based analyses identified additional two genes as potentially implicated in OCD pathogenesis. All SNPs combined explained 16% of the heritability of OCD. We show sub-stantial positive genetic correlations between OCD and a range of psychiatric disorders, including anxiety disorders, anorexia nervosa, and major depression. We thus for the first time provide evidence of a genome-wide locus implicated in OCD and strengthen previous literature suggesting a polygenic nature of this disorder.

Objectives: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 magnetic resonance imaging (MRI) and intermittent electroencephalography (EEG) slowing. Patient 2 suffered from a chronic paranoid–hallucinatory disorder with intermittent confusional states, non-specific white matter alterations on MRI, a disorganised alpha rhythm on EEG, and elevated cerebrospinal fluid protein. Both patients had anti-MOG antibody titres of 1 : 320 in serum (reference < 1 : 20).Conclusions:The arguments for and against a causal role for anti-MOG antibodies are discussed. The antibodies could be relevant, but due to moderate titres, they may have caused a rather ‘subtle clinical picture’ consisting of psychosis instead of ‘classical’ MOG encephalomyelitis.