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2.
J Psychiatr Res ; 135: 294-301, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33524676

RESUMO

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.

3.
Eur Neuropsychopharmacol ; 44: 105-120, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33483252

RESUMO

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.

4.
J Psychiatr Res ; 132: 18-22, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33035761

RESUMO

Treatment resistance is common in obsessive-compulsive disorder (OCD) and associated with a significant burden for the individual patient. Accordingly, the identification of biomarkers as early predictors of the clinical response has become a central goal in the search for more efficacious and personalized treatments. Epigenetic mechanisms such as DNA methylation of the serotonin transporter gene (SLC6A4) have been suggested to predict therapy outcome in mental disorders closely related to OCD, but have not yet been investigated as such in OCD. The present therapy-epigenetic study therefore sought to address the potential role of SLC6A4 promoter methylation in the prediction of treatment response for the first time in OCD. Overall, 112 patients with primary OCD were investigated over the course of 8-10-week OCD-specific, cognitive behavioral therapy (CBT) comprising exposure and response prevention/management (phase I) and in vivo exposure exercises ('flooding', phase II). OCD symptoms were measured using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) at baseline as well as before and after the in vivo exposure phase. SLC6A4 promoter methylation at baseline was analyzed via pyrosequencing of sodium bisulfite-treated DNA extracted from blood cells. Lower baseline SLC6A4 promoter methylation predicted impaired treatment response (defined as reduction in Y-BOCS scores) in phase II (but not phase I) of CBT (ß = -0.359, p = .002). SLC6A4 methylation may thus constitute a potential early biomarker predicting biologically mediated clinical changes elicited specifically by exposure treatment. These results carry promise for clinical application and in the future could aid in early treatment modification and personalized treatment efforts.

5.
Int J Mol Sci ; 21(22)2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-33203140

RESUMO

Complex neuropsychiatric-cardiac syndromes can be genetically determined. For the first time, the authors present a syndromal form of short QT syndrome in a 34-year-old German male patient with extracardiac features with predominant psychiatric manifestation, namely a severe form of secondary high-functioning autism spectrum disorder (ASD), along with affective and psychotic exacerbations, and severe dental enamel defects (with rapid wearing off his teeth) due to a heterozygous loss-of-function mutation in the CACNA1C gene (NM_000719.6: c.2399A > C; p.Lys800Thr). This mutation was found only once in control databases; the mutated lysine is located in the Cav1.2 calcium channel, is highly conserved during evolution, and is predicted to affect protein function by most pathogenicity prediction algorithms. L-type Cav1.2 calcium channels are widely expressed in the brain and heart. In the case presented, electrophysiological studies revealed a prominent reduction in the current amplitude without changes in the gating behavior of the Cav1.2 channel, most likely due to a trafficking defect. Due to the demonstrated loss of function, the p.Lys800Thr variant was finally classified as pathogenic (ACMG class 4 variant) and is likely to cause a newly described Cav1.2 channelopathy.

6.
Fluids Barriers CNS ; 17(1): 67, 2020 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-33176794

RESUMO

BACKGROUND: The importance of cerebrospinal fluid (CSF) diagnostics for psychiatry is growing. The CSF/blood albumin quotient (QAlb) is considered to be a measure of the blood-CSF barrier function. Recently, systematically higher QAlb in males than in females was described in neurological patients. The aim of this study was to investigate whether a sex difference could also be detected in a well-characterized psychiatric cohort. METHODS: The patient cohort comprised 989 patients, including 545 females and 444 males with schizophreniform and affective syndromes who underwent CSF diagnostics, including QAlb measurement. The basic CSF findings and antineuronal autoantibody data of this cohort have already been published. This re-analysis employed analysis of covariance with age correction for QAlb mean values and chi2-testing for the number of increased age-corrected QAlb levels to investigate sex differences in QAlb. RESULTS: The QAlb levels were elevated above reference levels by 18% across all patients, and a comparison between male and female patients revealed a statistically significant sex difference, with increased values in 26% of male patients and a corresponding rate of only 10% in female patients (chi2 = 42.625, p < 0.001). The mean QAlb values were also significantly higher in males (6.52 ± 3.69 × 10-3) than in females (5.23 ± 2.56 × 10-3; F = 52.837, p < 0.001). DISCUSSION: The main finding of this study was a significantly higher QAlb level in male compared to female patients with psychiatric disorders, complementing previously described sex differences in neurological patient cohorts. This result indicates bias from some general factors associated with sex and could be partly explained by sex differences in body height, which is associated with spine length and thus a longer distance for CSF flow within the subarachnoid space down the spine from the occipital area to the lumbar puncture site in males compared to females. Hormonal influences caused by different estrogen levels and other sex-specific factors could also play a relevant role. The significance of the study is limited by its retrospective design, absence of a healthy control group, and unavailability of exact measures of spine length.

7.
Depress Anxiety ; 2020 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-33058370

RESUMO

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.

8.
Psychother Psychosom ; : 1-7, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32920561

RESUMO

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.

9.
J Neural Transm (Vienna) ; 127(11): 1539-1546, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32524199

RESUMO

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.

10.
J Neural Transm (Vienna) ; 127(11): 1527-1537, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32468273

RESUMO

While DNA methylation patterns have been studied for a role in the pathogenesis of anxiety disorders, the role of the enzymes establishing DNA methylation-DNA methyltransferases (DNMTs)-has yet to be investigated. In an effort to investigate DNMT genotype-specific effects on dimensional anxiety traits in addition to the categorical phenotype of panic disorder, 506 panic disorder patients and 3112 healthy participants were assessed for anxiety related cognition [Agoraphobic Cognitions Questionnaire (ACQ)], anxiety sensitivity [Anxiety Sensitivity Index (ASI)] as well as pathological worry [Penn State Worry Questionnaire (PSWQ)] and genotyped for five single nucleotide polymorphisms (SNPs) in the DNMT3A (rs11683424, rs1465764, rs1465825) and DNMT3B (rs2424932, rs4911259) genes, which have previously been found associated with clinical and trait-related phenotypes. There was no association with the categorical phenotype panic disorder. However, a significant association was discerned between DNMT3A rs1465764 and PSWQ scores in healthy participants, with the minor allele conveying a protective effect. In addition, a marginally significant association between questionnaire scores (PSWQ, ASI) in healthy participants and DNMT3B rs2424932 was detected, again with the minor allele conveying a protective effect. The present results suggest a possible minor role of DNMT3A and DNMT3B gene variation in conveying resilience towards anxiety disorders. As the observed associations indicated a protective effect of two SNPs particularly with pathological worry, future studies are proposed to explore these variants in generalized anxiety disorder rather than panic disorder.

11.
Br J Psychiatry ; 217(5): 645-650, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32321595

RESUMO

BACKGROUND: The general understanding of the 'vulnerability-stress model' of mental disorders neglects the modifying impact of resilience-increasing factors such as coping ability. AIMS: Probing 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. METHOD: In 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. RESULTS: In both samples, trait anxiety differed as a function of NPSR1 genotype, CTQ and GSE score (discovery: ß = 0.129, P = 3.938 × 10-8; replication: ß = 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. CONCLUSIONS: Functional 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.

12.
Front Psychiatry ; 11: 163, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32265751

RESUMO

Susceptibility and resilience to mental disorders result from a complex choreography of gene-environment interactions with epigenetics at the intersection of external psychological stressors and internal biological systems. Increasing awareness of the growing disease burden influenced by daily life stress ("daily hassles"), work-related stress, and low socioeconomic status (SES) has resulted in a novel interest into their underlying molecular signatures. This review offers a brief outline of psychiatric epigenetics and a comprehensive overview of recent findings exploring the relationship of various occupational stressors and DNA methylation in epigenome-wide association studies (EWAS) and in candidate gene studies including the serotonin transporter (SLC6A4; 5-HTTLPR), melatonin receptor 1A (MTNR1A), brain-derived neurotrophic factor (BDNF), tyrosine hydroxylase (TH), and the protein family of DNA methyltransferases (DNMTs). Conceptual and methodological challenges of epigenetic investigations with a special focus on gene-environment interactions are highlighted and discussed. The findings are integrated into a pathophysiological framework featuring epigenetic plasticity factors and work-related stress as a possible central detrimental component targetable by workplace interventions. Finally, the potential of dynamic epigenetic biomarkers of treatment response to pharmacotherapy or psychotherapy is expanded upon.

13.
Clin Psychol Rev ; 77: 101830, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32163803

RESUMO

Mental disorders are highly complex and multifactorial in origin, comprising an elaborate interplay of genetic and environmental factors. Epigenetic mechanisms such as DNA modifications (e.g. CpG methylation), histone modifications (e.g. acetylation) and microRNAs function as a translator between genes and the environment. Indeed, environmental influences such as exposure to stress shape epigenetic patterns, and lifetime experiences continue to alter the function of the genome throughout the lifespan. Here, we summarize the recently burgeoning body of research regarding the involvement of aberrant epigenetic signatures in mediating an increased vulnerability to a wide range of mental disorders. We review the current knowledge of epigenetic changes to constitute useful markers predicting the clinical response to psychotherapeutic interventions, and of psychotherapy to alter - and potentially reverse - epigenetic risk patterns. Given first evidence pointing to a transgenerational transmission of epigenetic information, epigenetic alterations arising from successful psychotherapy might be transferred to future generations and thus contribute to the prevention of mental disorders. Findings are integrated into a multi-level framework highlighting challenges pertaining to the mechanisms of action and clinical implications of epigenetic research. Promising future directions regarding the prediction, prevention, and personalized treatment of mental disorders in line with a 'precision medicine' approach are discussed.

14.
Int J Neuropsychopharmacol ; 23(5): 319-323, 2020 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-32133483

RESUMO

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.

15.
Eur Neuropsychopharmacol ; 33: 45-57, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32046934

RESUMO

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.

16.
Neurotherapeutics ; 17(3): 1239-1252, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-31933066

RESUMO

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.

17.
World J Biol Psychiatry ; : 1-7, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-31852378

RESUMO

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.

18.
Eur Child Adolesc Psychiatry ; 29(9): 1301-1310, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31865460

RESUMO

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.


Assuntos
Transtornos de Ansiedade/psicologia , Cromossomos Humanos Par 2/genética , Medo/psicologia , Generalização Psicológica/fisiologia , Polimorfismo de Nucleotídeo Único/genética , Criança , Feminino , Técnicas de Genotipagem , Humanos , Masculino
19.
Transl Psychiatry ; 9(1): 314, 2019 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-31754096

RESUMO

In panic disorder (PD), epigenetic mechanisms such as DNA methylation of candidate genes have been suggested to play a key role at the intersection of genetic and environmental factors. On an epigenome-wide level, however, only two studies in PD patients have been published so far, while to date no study has intra-individually analyzed dynamic epigenetic correlates of treatment-response in PD on a DNA methylome level. Here, an epigenome-wide association study (EWAS) was performed in a sample of 57 PD patients and matched healthy controls using the Illumina MethylationEPIC BeadChip, along with a longitudinal approach assessing changes on the DNA methylome level corresponding to clinical effects of a manualized six-week cognitive-behavioral therapy (CBT) in PD. While no epigenome-wide significant hits could be discerned, top suggestive evidence was observed for decreased methylation in PD at cg19917903 in the Cilia and Flagella Associated Protein 46 (CFAP46) gene, and for an increase in methylation after CBT at cg06943668 in the Interleukin 1 Receptor Type 1 (IL1R1) gene in treatment responders to CBT. Additional exploratory analyses based on biological validity and a combined statistical/biological ranking point to further new potential PD risk genes such as the CCL4L1 or GMNN genes, and suggest dynamic methylation of, e.g., the ZFP622 and the SLC43A2 genes along with response to CBT. These EWAS and first longitudinal epigenome-wide pilot data in PD add to the emerging candidate gene-based body of evidence for epigenetic mechanisms to be involved in PD pathogenesis and to possibly constitute dynamic biological correlates of therapeutic interventions.


Assuntos
Terapia Cognitivo-Comportamental , Metilação de DNA , Transtorno de Pânico/genética , Adulto , Estudos de Casos e Controles , Ilhas de CpG , Epigênese Genética , Feminino , Redes Reguladoras de Genes , Estudo de Associação Genômica Ampla , Humanos , Estudos Longitudinais , Masculino , Transtorno de Pânico/terapia , Adulto Jovem
20.
J Neural Transm (Vienna) ; 126(12): 1653-1665, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31630255

RESUMO

Covariation bias, defined as an overestimation of the relationship between fear-relevant stimuli and aversive consequences, is a well-investigated cognitive bias in anxiety disorders. As patients with affective disorders also show biased information processing, the aim of the present study was to investigate whether depressed patients also display a covariation bias between negative stimuli and aversive consequences. Covariation estimates of 62 inpatients with a current severe depressive episode were assessed at admission (n = 31) or after 6 weeks of treatment (n = 31) and were compared in a between-group design with 31 age- and sex-matched healthy controls. All participants showed a covariation bias for the relationship between negative stimuli and aversive consequences. Moreover, covariation bias at admission was significantly associated with various clinician- and self-reported dimensional measures of treatment response assessed 6 weeks later (Global Assessment of Functioning, Clinical Global Impression Scale, and Beck Depression Inventory), i.e., patients with a stronger bias showed greater impairment after 6 weeks of treatment. Categorical analyses revealed that overall, treatment non-responders-but not responders-were characterized by a covariation bias. The naturalistic study design without standardized pharmacological and psychotherapeutic treatments is a central limitation. We conclude that the covariation bias may constitute a possible marker in the field of emotional information processing in the search for effective predictors of therapy outcome.


Assuntos
Depressão/tratamento farmacológico , Depressão/psicologia , Adulto , Antidepressivos/uso terapêutico , Emoções , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
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