DNA methylation of FKBP5 and response to exposure-based psychological therapy.

Differential DNA methylation of the hypothalamic-pituitary-adrenal axis related gene FKBP5 has recently been shown to be associated with varying response to environmental influences and may play a role in how well people respond to psychological treatments. Participants (n = 111) received exposure-based cognitive behavioural therapy (CBT) for agoraphobia with or without panic disorder, or specific phobias. Percentage DNA methylation levels were measured for the promoter region and intron 7 of FKBP5. The association between percentage reduction in clinical severity and change in DNA methylation was tested using linear mixed models. The effect of genotype (rs1360780) was tested by the inclusion of an interaction term. The association between change in DNA methylation and FKBP5 expression was examined. Change in percentage DNA methylation at one CpG site of intron 7 was associated with percentage reduction in severity (ß = -4.26, p = 3.90 × 10-4 ), where a decrease in DNA methylation was associated with greater response to therapy. An interaction was detected between rs1360780 and changes in DNA methylation in the promoter region of FKBP5 on treatment outcome (p = .045) but did not survive correction for multiple testing. Changes in DNA methylation were not associated with FKBP5 expression. Decreasing DNA methylation at one CpG site of intron 7 of FKBP5 was strongly associated with decreasing anxiety severity following exposure-based CBT. In addition, there was suggestive evidence that allele-specific methylation at the promoter region may also be associated with treatment response. The results of this study add to the growing literature demonstrating the role of biological processes such as DNA methylation in response to environmental influences.

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

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

Therapygenetics: anterior cingulate cortex-amygdala coupling is associated with 5-HTTLPR and treatment response in panic disorder with agoraphobia.

Variation in the 5'-flanking promoter region of the serotonin transporter gene SLC6A4, the 5-HTT-linked polymorphic region (5-HTTLPR) has been inconclusively associated with response to cognitive-behavioural therapy (CBT). As genomic functions are stronger related to neural than to behavioural markers, we investigated the association of treatment response, 5-HTTLPR and functional brain connectivity in patients with panic disorder with agoraphobia (PD/AG). Within the national research network PANIC-NET 231 PD/AG patients who provided genetic information underwent a manualized exposure-based CBT. A subset of 41 patients participated in a functional magnetic resonance imaging (fMRI) add-on study prior to treatment applying a differential fear conditioning task. Neither the treatment nor the reduced fMRI sample showed a direct effect of 5-HTTLPR on treatment response as defined by a reduction in the Hamilton Anxiety Scale score ≥50 % from baseline to post assessment. On a neural level, inhibitory anterior cingulate cortex (ACC)-amygdala coupling during fear conditioning that had previously been shown to characterize treatment response in this sample was driven by responders with the L/L genotype. Building upon conclusive evidence from basic and preclinical findings on the association of the 5-HTTLPR polymorphism with emotion regulation and related brain connectivity patterns, present findings translate these to a clinical sample of PD/AG patients and point towards a potential intermediate connectivity phenotype modulating response to exposure-based CBT.

5HTT is associated with the phenotype psychological flexibility: results from a randomized clinical trial.

Adaption to changing environments is evolutionarily advantageous. Studies that link genetic and phenotypic expression of flexible adjustment to one's context are largely lacking. In this study, we tested the importance of psychological flexibility, or goal-related context sensitivity, in an interaction between psychotherapy outcome for panic disorder with agoraphobia (PD/AG) and a genetic polymorphism. Given the established role of the 5HTT-LPR polymorphism in behavioral flexibility, we tested whether this polymorphism (short group vs. long group) impacted therapy response as a function of various endophenotypes (i.e., psychological flexibility, panic, agoraphobic avoidance, and anxiety sensitivity). Patients with PD/AG were recruited from a large multicenter randomized controlled clinical trial on cognitive-behavioral therapy. Pre- to post-treatment changes by 5HTT polymorphism were analyzed. 5HTT polymorphism status differentiated pre- to post-treatment changes in the endophenotype psychological flexibility (effect size difference d = 0.4, p < 0.05), but none of the specific symptom-related endophenotypes consistently for both the intent-to-treat sample (n = 228) and the treatment completers (n = 194). Based on the consistency of these findings with existing theory on behavioral flexibility, the specificity of the results across phenotypes, and the consistency of results across analyses (i.e., completer and intent to treat), we conclude that 5HTT polymorphism and the endophenotype psychological flexibility are important variables for the treatment of PD/AG. The endophenotype psychological flexibility may help bridge genetic and psychological literatures. Despite the limitation of the post hoc nature of these analyses, further study is clearly warranted.

MicroRNA hsa-miR-4717-5p regulates RGS2 and may be a risk factor for anxiety-related traits.

Regulator of G-protein Signaling 2 (RGS2) is a key regulator of G-protein-coupled signaling pathways involved in fear and anxiety. Data from rodent models and genetic analysis of anxiety-related traits and disorders in humans suggest down-regulation of RGS2 expression to be a risk factor for anxiety. Here we investigated, whether genetic variation in microRNAs mediating posttranscriptional down-regulation of RGS2 may be a risk factor for anxiety as well. 75 microRNAs predicted to regulate RGS2 were identified by four bioinformatic algorithms and validated experimentally by luciferase reporter gene assays. Specificity was confirmed for six microRNAs (hsa-miR-1271-5p, hsa-miR-22-3p, hsa-miR-3591-3p, hsa-miR-377-3p, hsa-miR-4717-5p, hsa-miR-96-5p) by disrupting their seed sequence at the 3' untranslated region of RGS2. Hsa-miR-4717-5p showed the most robust effect on RGS2 and regulated two other candidate genes of anxiety disorders (CNR1 and IKBKE) as well. Two SNPs (rs150925, rs161427) within and 1,000 bp upstream of the hostgene of hsa-miR-4717-5p (MIR4717) show a minor allele frequency greater than 0.05. Both were in high linkage disequilibrium (r(2) = 1, D' = 1) and both major (G) alleles showed a trend for association with panic disorder with comorbid agoraphobia in one of two patient/control samples (combined n(patients) = 497). Dimensional anxiety traits, as described by Anxiety Sensitivity Index (ASI) and Agoraphobic Cognitions Questionnaire (ACQ) were significantly higher among carriers of both major (G) alleles in a combined patient/control sample (n(combined) = 831). Taken together, data indicate that MIR4717 regulates human RGS2 and contributes to the genetic risk towards anxiety-related traits.

The structure of genetic and environmental risk factors for fears and phobias.

BACKGROUND: Although prior genetic studies of interview-assessed fears and phobias have shown that genetic factors predispose individuals to fears and phobias, they have been restricted to the DSM-III to DSM-IV aggregated subtypes of phobias rather than to individual fearful and phobic stimuli. METHOD: We examined the lifetime history of fears and/or phobias in response to 21 individual phobic stimuli in 4067 personally interviewed twins from same-sex pairs from the Virginia Adult Twin Study of Psychiatric and Substance Abuse Disorders (VATSPSUD). We performed multivariate statistical analyses using Mx and Mplus. RESULTS: The best-fitting model for the 21 phobic stimuli included four genetic factors (agora-social-acrophobia, animal phobia, blood-injection-illness phobia and claustrophobia) and three environmental factors (agora-social-hospital phobia, animal phobia, and situational phobia). CONCLUSIONS: This study provides the first view of the architecture of genetic and environmental risk factors for phobic disorders and their subtypes. The genetic factors of the phobias support the DSM-IV and DSM-5 constructs of animal and blood-injection-injury phobias but do not support the separation of agoraphobia from social phobia. The results also do not show a coherent genetic factor for the DSM-IV and DSM-5 situational phobia. Finally, the patterns of co-morbidity across individual fears and phobias produced by genetic and environmental influences differ appreciably.

Neuropeptide S receptor gene -- converging evidence for a role in panic disorder.

Animal studies have suggested neuropeptide S (NPS) and its receptor (NPSR) to be involved in the pathogenesis of anxiety-related behavior. In this study, a multilevel approach was applied to further elucidate the role of NPS in the etiology of human anxiety. The functional NPSR A/T (Asn¹°7Ile) variant (rs324981) was investigated for association with (1) panic disorder with and without agoraphobia in two large, independent case-control studies, (2) dimensional anxiety traits, (3) autonomic arousal level during a behavioral avoidance test and (4) brain activation correlates of anxiety-related emotional processing in panic disorder. The more active NPSR rs324981 T allele was found to be associated with panic disorder in the female subgroup of patients in both samples as well as in a meta-analytic approach. The T risk allele was further related to elevated anxiety sensitivity, increased heart rate and higher symptom reports during a behavioral avoidance test as well as decreased activity in the dorsolateral prefrontal, lateral orbitofrontal and anterior cingulate cortex during processing of fearful faces in patients with panic disorder. The present results provide converging evidence for a female-dominant role of NPSR gene variation in panic disorder potentially through heightened autonomic arousal and distorted processing of anxiety-relevant emotional stimuli.

Re-examining the differential familial liability of agoraphobia and panic disorder.

BACKGROUND: Controversy surrounds the question of whether agoraphobia (AG) exists as an independent diagnostic entity apart from panic. In favor of this position, AG without panic disorder (PD) in parents was found being unrelated to offsprings' risk for AG or PD, albeit it may enhance the familial transmission of PD (Nocon et al., Depress Anxiety 2008;25:422-434). However, a recent behavioral genetic analysis (Mosing et al., Depress Anxiety 2009;26:1004-1011) found an increased risk for both PD and AG in siblings of those with AG without PD, casting doubt on whether AG exists independently of PD. Convincing evidence for either position notably requires considering also other anxiety disorders to establish the position of AG relative to the panic/anxiety spectrum. METHODS: Familial transmission of panic attacks (PAs), PD, and AG was examined in a 10-year prospective-longitudinal community study of 3,021 adolescents and young adults including completed direct and indirect information on parental psychopathology. Standardized diagnostic assessments using the Munich-Composite International Diagnostic Interview allowed generating exclusive diagnostic groups independent from diagnostic hierarchy rules. RESULTS: Parental PD without AG was associated with an increased risk for PA and PD+AG, but not for PD without AG or AG without PD in offspring. Parental AG without PD was unrelated to the offsprings' risk for PA, exclusive PD or AG, or PD+AG. Findings were largely unaffected by adjustment for other offspring or parental anxiety disorders. CONCLUSIONS: Findings provide further evidence for the independence of AG apart from the PD spectrum.

Rare variants in TMEM132D in a case-control sample for panic disorder.

Genome-wide association studies have identified common variants associated with common diseases. Most variants, however, explain only a small proportion of the estimated heritability, suggesting that rare variants might contribute to a larger extent to common diseases than assumed to date. Here, we use next-generation sequencing to test whether such variants contribute to the risk for anxiety disorders by re-sequencing 40 kb including all exons of the TMEM132D locus which we have previously shown to be associated with panic disorder and anxiety severity measures. DNA from 300 patients suffering from anxiety disorders, mostly panic disorder (84.7%), and 300 healthy controls was screened for the presence of genetic variants using next-generation re-sequencing in a pooled approach. Results were verified by individual re-genotyping. We identified 371 variants of which 247 had not been reported before, including 15 novel non-synonymous variants. The majority, 76% of these variants had a minor allele frequency less than 5%. While we did not identify additional common variants in TMEM132D associated with panic disorders, we observed an overrepresentation of presumably functional coding variants in healthy controls as compared to cases as well as a higher rate of private coding variants in cases, with one non-synonymous coding variant present in four patients but not in any of the matched controls nor in over 5,500 individuals of different ethnic origins from publicly available re-sequencing datasets. Our data suggest that not only common but also putatively functional and/or rare variants within TMEM132D might contribute to the risk to develop anxiety disorders.

Separation anxiety disorder in OCD.

BACKGROUND: A history of separation anxiety disorder (SAD) is frequently reported by patients with obsessive-compulsive disorder (OCD). The purpose of this study was to determine if there are clinical differences between OCD-affected individuals with, versus without, a history of SAD. METHODS: Using data collected during the OCD Collaborative Genetic Study, we studied 470 adult OCD participants; 80 had a history of SAD, whereas 390 did not. These two groups were compared as to onset and severity of OCD, lifetime prevalence of Axis I disorders, and number of personality disorder traits. RESULTS: OCD participants with a history of SAD were significantly younger than the non-SAD group (mean, 34.2 versus 42.2 years; P<.001). They had an earlier age of onset of OCD symptoms (mean, 8.0 versus 10.5 years; P<.003) and more severe OCD, as measured by the Yale-Brown Obsessive Compulsive Scale (mean, 27.5 versus 25.0; P<.005). In addition, those with a history of SAD had a significantly greater lifetime prevalence of agoraphobia (odds ratio (OR) = 2.52, 95% confidence interval (CI) = 1.4-4.6, P<.003), panic disorder (OR = 1.84, CI = 1.03-3.3 P<.04), social phobia (OR = 1.69, CI 1.01-2.8, P<.048), after adjusting for age at interview, age at onset of OCD, and OCD severity in logistic regression models. There was a strong relationship between the number of dependent personality disorder traits and SAD (adjusted OR = 1.42, CI = 1.2-1.6, P<.001). CONCLUSIONS: A history of SAD is associated with anxiety disorders and dependent personality disorder traits in individuals with OCD.

Life events in panic disorder-an update on "candidate stressors".

Studies on gene-environment interactions in mental disorders are characterized by powerful genetic techniques and well defined "candidate genes," whereas a definition of "candidate stressors," in most cases assessed in the form of life events (LEs), is inconsistent or not even provided. This review addresses this problem, with particular attention to the clinical phenotype of panic disorder (PD), by providing an overview and critical discussion for which life events are known to contribute to the etiology of the disease and how they may be conceptualized. There is converging evidence for a significant impact of cumulative as well as specific life events, such as threat, interpersonal and health-related events in adulthood, and abuse or loss/separation experiences in childhood, respectively, on the pathogenesis of panic disorder with some overlapping effect across the anxiety disorder spectrum as well as on comorbid major depression. Besides genetic vulnerability factors, personality and behavioral characteristics, such as anxiety sensitivity, neuroticism, and cognitive appraisal might moderate the influence of LEs on the development of panic disorder. The present state of knowledge regarding the specification and conceptualization of LEs in PD within a more complex multifactorial model, involving mediating and moderating factors in between genes and the clinical phenotype, is hoped to aid in informing future gene-environment interaction studies in panic disorder.

Neural correlates of NOS1 ex1f-VNTR allelic variation in panic disorder and agoraphobia during fear conditioning and extinction in fMRI.

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.

Association analysis of Rgs7 variants with panic disorder.

Following our recent finding of Rgs2 playing a role in the development of human panic disorder (PD), we examine another positional and functional candidate from the functionally interwoven Rgs (regulator of G-protein signaling) family, Rgs7, in the pathogenesis of PD. A German PD sample (N = 224) was compared with matched controls (N = 224) for seven SNPs within and flanking the gene. The intronic SNP3 (rs11805657) and its corresponding haplotypes were found to be associated with PD, particularly PD with comorbid agoraphobia (PDAgP), with the effect originating from the female subgroup (P values 0.008-0.047). The rare A-allele was underrepresented in patients, suggesting a protective effect with carriers possessing an about 2-fold lower risk for developing the disorder compared to G/G homozygotes. Our results argue against a major role of Rgs7 gene variants in the pathogenesis of PD, but are consistent with a minor gender-specific effect on PD, particularly PDAgP.

Genetic and environmental influences on the co-morbidity between depression, panic disorder, agoraphobia, and social phobia: a twin study.

BACKGROUND: Major depression (MD) and anxiety disorders such as panic disorder (PD), agoraphobia (AG), and social phobia (SP) are heritable and highly co-morbid. However, the relative importance of genetic and environmental etiology of the covariation between these disorders, particularly the relationship between PD and AG, is less clear. METHODS: This study measured MD, PD, and AG in a population sample of 5,440 twin pairs and 1,245 single twins, about 45% of whom were also scored for SP. Prevalences, within individual co-morbidity and twin odds ratios for co-morbidity, are reported. A behavioral genetic analysis of the four disorders using the classical twin design was conducted. RESULTS: Odds ratios for MD, PD, AG, and SP in twins of individuals diagnosed with one of the four disorders were increased. Heritability estimates under a threshold-liability model for MD, PD, AG, and SP respectively were .33 (CI: 0.30-0.42), .38 (CI: 0.24-0.55), .48 (CI: 0.37-0.65), and .39 (CI: 0.16-0.65), with no evidence for any variance explained by the common environment shared by twins. We find that a common genetic factor explains a moderate proportion of variance in these four disorders. The genetic correlation between PD and AG was .83. CONCLUSION: MD, PD, AG, and SP strongly co-aggregate within families and common genetic factors explain a moderate proportion of variance in these four disorders. The high genetic correlation between PD and AG and the increased odds ratio for PD and AG in siblings of those with AG without PD suggests a common genetic etiology for PD and AG.

Association of NPSR1 gene variation and neural activity in patients with panic disorder and agoraphobia and healthy controls.

INTRODUCTION: The neurobiological mechanisms behind panic disorder with agoraphobia (PD/AG) are not completely explored. The functional A/T single nucleotide polymorphism (SNP) rs324981 in the neuropeptide S receptor gene (NPSR1) has repeatedly been associated with panic disorder and might partly drive function respectively dysfunction of the neural "fear network". We aimed to investigate whether the NPSR1 T risk allele was associated with malfunctioning in a fronto-limbic network during the anticipation and perception of agoraphobia-specific stimuli. METHOD: 121 patients with PD/AG and 77 healthy controls (HC) underwent functional magnetic resonance imaging (fMRI) using the disorder specific "Westphal-Paradigm". It consists of neutral and agoraphobia-specific pictures, half of the pictures were cued to induce anticipatory anxiety. RESULTS: Risk allele carriers showed significantly higher amygdala activation during the perception of agoraphobia-specific stimuli than A/A homozygotes. A linear group x genotype interaction during the perception of agoraphobia-specific stimuli showed a strong trend towards significance. Patients with the one or two T alleles displayed the highest and HC with the A/A genotype the lowest activation in the inferior orbitofrontal cortex (iOFC). DISCUSSION: The study demonstrates an association of the NPSR1rs324981 genotype and the perception of agoraphobia-specific stimuli. These results support the assumption of a fronto-limbic dysfunction as an intermediate phenotype of PD/AG.

Association of rs7688285 allelic variation coding for GLRB with fear reactivity and exposure-based therapy in patients with panic disorder and agoraphobia.

The gene coding for glycine receptor ß subunits (GLRB) has been found to be related to panic disorder and agoraphobia (PD/AG) and to be associated with altered insular BOLD activation during fear conditioning, as an intermediate phenotype of defensive system reactivity in healthy subjects. In a multicenter clinical trial on PD/AG patients we investigated in three sub-samples whether GLRB allelic variation (A/G; A-allele identified as «risk¼) in the single nucleotide polymorphism rs7688285 was associated with autonomic (behavioral avoidance test BAT; n = 267 patients) and neural (differential fear conditioning; n = 49 patients, n = 38 controls) measures, and furthermore with responding towards exposure-based cognitive behavioral therapy (CBT, n = 184 patients). An interaction of genotype with current PD/AG diagnosis (PD/AG vs. controls; fMRI data only) and their modification after CBT was tested as well. Exploratory fMRI results prior to CBT, revealed A-allele carriers irrespective of diagnostic status to show overall higher BOLD activation in the hippocampus, motor cortex (MC) and insula. Differential activation in the MC, anterior cingulate cortex (ACC) and insula was found in the interaction genotype X diagnosis. Differential activation in ACC and hippocampus was present in differential fear learning. ACC activation was modified after treatment, while no overall rs7688285 dependent effect on clinical outcomes was found. On the behavioral level, A-allele carriers showed pronounced fear reactivity prior to CBT which partially normalized afterwards. In sum, rs7688285 variation interacts in a complex manner with PD/AG on a functional systems level and might be involved in the development of PD/AG but not in their treatment.

Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes.

Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10-7), particularly in the female subsample (p = 9.8 × 10-9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10-4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.

Differential familial liability of panic disorder and agoraphobia.

To examine the familial liability of panic disorder (PD) and agoraphobia (AG) in a community sample, namely the effect of parental PD and AG on the offspring's risk to develop either or both conditions in adolescence or adulthood. A representative community sample of N=3,021 adolescents and young adults aged 14-24 years at baseline was followed up over a period of 10 years in up to four waves. Family information was assessed by either direct interviews with at least one parent or by using subjects' family history information at either wave (N=3,014). Diagnoses and selected symptoms were assessed in both, parents and subjects, by using a standardized diagnostic interview (DSM-IV M-CIDI) with its respective family history module. (1) Parental panic attacks (PA), PD, and AG were all shown to be associated with an increased risk of offspring to also develop PA, PD, and AG. (2) Associations of parental PD were present irrespective of parental AG, whereas parental AG without PD was not associated with an increased offspring risk. (3) Outcome risk was particularly elevated in offspring of parents with PD+AG. (4) Parental PD or AG was not associated with an earlier age of onset of any syndrome in the offspring. We confirmed and expanded previous results from clinical samples that comorbid PD and AG aggregate in families. AG without PD is not familial, but it might enhance the familial transmission of PD.

Panic disorder with nocturnal panic attacks: symptoms and comorbidities.

The aim of this study was to determine the relationship between nocturnal panic attacks and comorbidities, clinical variables and panic attack symptoms. One hundred and six consecutive patients with DSM-IV panic disorder were enrolled in the study. The patients were divided into two groups depending on the presence of nocturnal panic attacks. Comorbidities were diagnosed with the help of SCID-I and SCID-II. The groups were compared using the Beck Depression Inventory, State-Trait Anxiety Inventory and Symptom Checklist. Nocturnal panic attacks were not related to comorbidities or age at the onset of the disease. The scores from the Beck Depression Inventory, general scores from the Symptom Checklist, somatization, obsession-compulsion, interpersonal sensitivity and anger-hostility sub-scale scores were higher in the nocturnal panic attack group. Patients with nocturnal panic attacks experience more frequent respiratory symptoms, suggesting that nocturnal panic attacks may be related to respiratory symptoms. Our findings demonstrate that patients with nocturnal panic attacks have more respiratory symptoms of panic, depressive and other psychiatric symptoms than the no nocturnal panic group.

Low extraversion and high neuroticism as indices of genetic and environmental risk for social phobia, agoraphobia, and animal phobia.

OBJECTIVE: The authors examined the extent to which two major personality dimensions (extraversion and neuroticism) index the genetic and environmental risk for three phobias (social phobia, agoraphobia, and animal phobia) in twins ascertained from a large, population-based registry. METHOD: Lifetime phobias and personality traits were assessed through diagnostic interview and self-report questionnaire, respectively, in 7,800 twins from female-female, male-male, and opposite-sex pairs. Sex-limited trivariate Cholesky structural equation models were used to decompose the correlations among extraversion, neuroticism, and each phobia. RESULTS: In the best-fitting models, genetic correlations were moderate and negative between extraversion and both social phobia and agoraphobia, and that between extraversion and animal phobia was effectively zero. Genetic correlations were high and positive between neuroticism and both social phobia and agoraphobia, and that between neuroticism and animal phobia was moderate. All of the genetic risk factors for social phobia and agoraphobia were shared with those that influence extraversion and neuroticism; in contrast, only a small proportion of the genetic risk factors for animal phobia (16%) was shared with those that influence personality. Shared environmental experiences were not a source of correlations between personality traits and phobias, and unique environmental correlations were relatively modest. CONCLUSION: Genetic factors that influence individual variation in extraversion and neuroticism appear to account entirely for the genetic liability to social phobia and agoraphobia, but not animal phobia. These findings underline the importance of both introversion (low extraversion) and neuroticism in some psychiatric disorders.