Generalization of Conditioned Contextual Anxiety and the Modulatory Effects of Anxiety Sensitivity

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

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 1,370 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=3.3x10-8; rs191260602, p=3.9x10-8). We followed up on this finding in a larger dimensional ACQ sample (N=2,547) and in independent samples with a dichotomous AG phenotype based on the Symptoms Checklist (SCL-90; N=3,845) and a case control sample with the categorical phenotype PD/AG (Ncombined =1,012) obtaining highly significant p-values also for GLRB single nucleotide variants rs17035816 (p=3.8x10-4) and rs7688285 (p=7.6x10-5). 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 withthe 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, though functional GLRB gene polymorphisms may predispose to PD by increasing startle response and agoraphobic cognitions.PostprintPeer reviewe

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

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 Original data were obtained from ten independent samples (including three unpublished samples) with a total of 2,195 patients with primary anxiety disorder.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

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

Predominant polarity in bipolar disorder and validation of the polarity index in a German sample

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

A neurobiological framework of separation anxiety and related phenotypes

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.</p

DNA hypomethylation of the Krüppel-like factor 11 (KLF11) gene promoter: a putative biomarker of depression comorbidity in panic disorder and of non-anxious depression?

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

Oxytocin receptor gene variation, behavioural inhibition, and adult separation anxiety – role in complicated grief

Objectives: complicated grief (CG) following bereavement significantly increases the risk for mood and anxiety disorders. The severity of grief reactions may be interactively influenced by temperamental and psychological factors such as behavioural inhibition (BI) and separation anxiety (SA) as well as biological factors. Given its central role in attachment and stress processing, a genetic variant in the oxytocin receptor (OXTR) gene was thus investigated in order to elucidate the direction of association as well as its interaction with BI and SA in the moderation of CG severity.Methods: ninety-three patients with mood and anxiety disorders were evaluated for CG by means of the Inventory of Complicated Grief (ICG), for BI using the Retrospective Self-Report of Inhibition (RSRI), and for symptoms of SA during adulthood using the Adult Separation Anxiety Scale (ASA-27). All patients were genotyped for OXTR rs2254298.Results: OXTR genotype interacted with BI and, on a trend-level, with adult SA, to increase CG. Specifically, higher levels on the RSRI and ASA-27 scales, respectively, were related to higher ICG scores in GG genotype carriers.Conclusions: the present study for the first time suggests a gene-environment interaction effect of an OXTR gene variant with behavioural inhibition and possibly also symptoms of adult separation anxiety in the moderation of vulnerability for complicated grief.<br/

Developmental aspects of fear: comparing the acquisition and generalization of conditioned fear in children and adults

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