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Introduction The neuronal isoform of the nitric oxide synthase (NOS-I) encoded by NOS1 is the main source of nitric oxide (NO) in the brain. Reduced NO signaling in the prefrontal cortex has been linked to schizophrenia and cognitive processes while reduced striatal NOS1 expression has been associated with impulsive behavior. Methods To evaluate the effect of two functional polymorphisms in alternative first exons of NOS1, ex1f-VNTR and ex1c-SNP rs41279104, on the HPA stress axis and neurocognitive abilities, 280 healthy subjects were genotyped, had their salivary cortisol levels measured and were assessed in verbal memory, verbal fluency, working memory and verbal IQ by using the California Verbal Learning Test (CVLT), the Regensburger test of verbal fluency (RWT), a n-back task and subscales of the Wechsler Adult Intelligence Scale III (WAIS-III). Results Schizophrenia risk (A)-allele carriers of NOS1 ex1c-SNP rs41279104 displayed significantly lower baseline cortisol levels (p = 0.004). NOS1 ex1f-VNTR genotype carriers showed differences in working memory performance (p = 0.05) in a gene-dose effect manner, with homozygous carriers of the short impulsivity-risk allele committing most commission errors. Finally, A-allele carriers of the NOS1 ex1c-SNP rs41279104 tended to react faster during the working memory task (p = 0.065). Conclusion For the first time, we demonstrated an influence of the NOS1 ex1c-SNP rs41279104 on salivary cortisol levels and additionally implicate the A-allele in an enhanced reaction time during a working memory task. Regarding the NOS1 ex1f-VNTR our study supports the previously reported influence on impulsivity, lending further support to the hypothesis that this genetic variant underlies impulsive behavior.

About 20% of the German population have a migration background which might influence prevalence of preventable cardiovascular risk factors (CVRF).We report data of the prospective Characteristics and Course of Heart Failure Stages A-B and Determinants of Progression (STAAB) cohort study investigating a representative sample of inhabitants of the City of Würzburg, Germany, aged 30 to 79 years. Individuals without migration background were defined as follows: German as native language, no other native language, and/or born in Germany. All other participants were defined as individuals with migration background.Of 2473 subjects (51% female, mean age 54 ± 12 years), 291 (12%) reported a migration background: n = 107 (37%) from a country within the EU, n = 117 (40%) from Russia, and n = 67 (23%) from other countries. Prevalence of hypertension, atherosclerotic disease, and diabetes mellitus was similar in individuals with and without migration background. By contrast, prevalence of obesity and metabolic syndrome was significantly higher in individuals with migration background, with the least favourable profile apparent in individuals from Russia (individuals without vs. with migration background: obesity 19 vs. 24%, p 0.05; odds ratio: EU: 1.6, Russia: 2.2*, other countries: 0.6; metabolic syndrome 18 vs. 21%, p 0.05; odds ratio: EU: 1.2, Russia: 1.7*, other countries: 1.5; *p 0.05).Individuals with migration background in Germany might exhibit a higher CVRF burden due to a higher prevalence of obesity and metabolic syndrome. Strategies for primary prevention of heart failure may benefit from deliberately considering the migration background.

Purpose of review The present review complements previous reviews on prediction research in anxiety disorders with a focus on clinical, imaging and genetic as well as epigenetic factors and aims to provide recommendations for the design of future integrative studies in adults as well as children. Recent findings Clinical factors predicting worse outcome such as a diagnosis of social anxiety disorder, comorbid depression and certain cognitive, behavioral and personality traits as well as low socioeconomic status were confirmed in large clinical studies. Imaging factors focusing on the fear and anxiety network were repeatedly described as predicting therapy response in small exploratory studies. The plethora of candidate gene studies has now been complemented by large genome-wide association studies and small epigenetic investigations with the need for replication in larger samples. Summary The present status of research on predictors for therapy response in anxiety disorders, in particular on imaging and genetic factors, is still fragmentary. Some clinical factors for poorer outcome, though, have been consistently replicated and should be considered in the revision of therapy guidelines. There is a definite need for large integrative studies at the national and international level integrating multiple levels of biomarkers at different stages of development.

Recent animal and human studies highlight the uncertainty about the onset of an aversive event as a crucial factor for the involvement of the centromedial amygdala (CM) and bed nucleus of the stria terminalis (BNST) activity. However, studies investigating temporally predictable or unpredictable threat anticipation and confrontation processes are rare. Furthermore, the few existing fMRI studies analyzing temporally predictable and unpredictable threat processes used small sample sizes or limited fMRI paradigms. Therefore, we measured functional brain activity in 109 predominantly female healthy participants during a temporally predictable-unpredictable threat paradigm, which aimed to solve limited aspects of recent studies. Results showed higher BNST activity compared to the CM during the cue indicating that the upcoming confrontation is aversive relative to the cue indicating an upcoming neutral confrontation. Both the CM and BNST showed higher activity during the confrontation with unpredictable and aversive stimuli, but the reaction to aversive confrontation relative to neutral confrontation was stronger in the CM compared to the BNST. Additional modulation analyses by NPSR1 rs324981 genotype revealed higher BNST activity relative to the CM in unpredictable anticipation relative to predictable anticipation in T-carriers compared to AA carriers. Our results indicate that during the confrontation with aversive or neutral stimuli, temporal unpredictability modulates CM and BNST activity. Further, there is a differential activity concerning threat processing, as BNST is more involved when focussing on fear-related anticipation processes and CM is more involved when focussing on threat confrontation.

Translational Psychiatry 10(1), 406 (2020). doi:10.1038/s41398-020-01085-w, Published by Nature Publishing Group, London

Background Many bipolar patients (BP) are affected by cognitive impairments and reduced psychosocial function even after complete remission. In the present naturalistic study, we developed a tailored cognitive remediation program (CR) to evaluate the effect on objective and subjective neuropsychological performance, psychosocial functioning and quality of life. Methods The CR program used a cognitive training software combined with group sessions to educate cognitive skills. 102 BP were screened by a neuropsychological test battery. Of those, 39 BP showed distinct cognitive impairments and 26 patients of them participated in the CR program for 12 weeks and then were retested. A matched control group consisting of 10 BP was measured at baseline and follow-up after three months (treatment as usual). Results Within the training group, a significant improvement of cognitive performance after CR was observed in working memory (p = .043), problem solving (p = .031) and divided attention (trend, p = .065). The control group did not improve in any test measure. In addition, we detected a significant reduction of sub-depressive symptoms (p = .011) after the CR program. However, there was no change in psychosocial functioning and quality of life. Subjective cognitive complaints were not associated with objective test performance. Limitations As we included exclusively BP with objectively assessed neurocognitive deficits, recruitment was difficult and subsequently we had a small sample size and were not able to implement a randomized group design. Conclusions Our results suggest that BP with objective cognitive impairments could benefit from CR potentially with regard to executive functioning. Furthermore, there is preliminary evidence that CR could have a positive effect on subthreshold residual symptoms. However, to fully identify the possible implications of CR in bipolar disorder, larger randomized-controlled trials are needed in this new field of research. Electronic supplementary material The online version of this article (doi:10.1186/s40345-017-0079-3) contains supplementary material, which is available to authorized users.

Previous research indicates that anxiety disorders are characterized by an overgeneralization of conditioned fear as compared with healthy participants. Therefore, fear generalization is considered a key mechanism for the development of anxiety disorders. However, systematic investigations on the variance in fear generalization are lacking. Therefore, the current study aims at identifying distinctive phenotypes of fear generalization among healthy participants. To this end, 1175 participants completed a differential fear conditioning phase followed by a generalization test. To identify patterns of fear generalization, we used a k-means clustering algorithm based on individual arousal generalization gradients. Subsequently, we examined the reliability and validity of the clusters and phenotypical differences between subgroups on the basis of psychometric data and markers of fear expression. Cluster analysis reliably revealed five clusters that systematically differed in mean responses, differentiation between conditioned threat and safety, and linearity of the generalization gradients, though mean response levels accounted for most variance. Remarkably, the patterns of mean responses were already evident during fear acquisition and corresponded most closely to psychometric measures of anxiety traits. The identified clusters reliably described subgroups of healthy individuals with distinct response characteristics in a fear generalization test. Following a dimensional view of psychopathology, these clusters likely delineate risk factors for anxiety disorders. As crucial group characteristics were already evident during fear acquisition, our results emphasize the importance of average fear responses and differentiation between conditioned threat and safety as risk factors for anxiety disorders.

Background Depression is frequent in heart failure (HF) and associated with adverse clinical outcomes. The randomized MOOD-HF trial showed that in depressed patients with systolic heart failure (HF) the selective serotonin reuptake inhibitor escitalopram (E) improved neither survival nor depression compared to placebo (P). The hypothalamic-pituitary-adrenocortical axis is known to be altered in depression or HF. This MOOD-HF substudy aimed to clarify whether circadian salivary cortisol levels (SCL) were predictive of adverse events in depressed MOOD-HF participants and whether outcomes differed according to treatment with E. Methods MOOD-HF participants (all suffering from symptomatic systolic HF with left ventricular ejection fraction (LVEF) Results In the total study cohort (146 patients on E, 147 on P) median morning SCL at BL was 0.210 μg/dL (IQR 0.141–0.338 μg/dL) and median evening (pm) SCL 0.067 μg/dL (0.036–0.128 μg/dL, p During 12 months follow-up the composite endpoint (all-cause death or rehospitalization) occurred least in E-treated patients with low pm-SCL and most often in E-treated patients with high pm-SCL (HR 2.02, 95% CI 1.12–3.65, p=0.010); patients on P had comparable event rates irrespective of BL pm-SCL (Figure A). Thus, numerically patients on E with low BL pm-SCL had lower event rates compared with corresponding P-treated patients (HR 0.76 (0.41–1.40, p=0.796)), while patients with high BL pm-SCL had higher event rates (HR 1.29 (0.74–2.24, p=0.799)) than corresponding P-treated patients. Patients with circadian SCL changes above the median receiving P experienced the composite primary endpoint least, while both subgroups with circadian SCL changes below the median and also patients with circadian SCL changes above the median on E had higher event rates (HR 0.66 (0.45–0.97, p=0.039), Figure B). Conclusion In depressed patients with systolic HF high pm-SCL are associated with more severe disease (depression and cardiac dysfunction). Extending primary MOOD-HF results indicating unfavourable outcomes related to E, the current findings suggest a SCL x treatment interaction with higher event rates in (sicker) patients with high pm-SCL and lower event rates in (less sick) patients with low pm-SCL when treated with the antidepressant. Low circadian changes of SCL were always associated with higher event rates. Acknowledgement/Funding BMBF (Grant 01 KG0702) and Lundbeck A/S Denmark

Background: Previous research showed inconsistent results concerning a possible association between solute carrier family 6 member 3 (SLC6A3) gene polymorphisms and dopamine symptoms of posttraumatic stress disorder (PTSD). Several studies also indicate that the myelin basic protein (MBP) gene is of importance in the etiology of several psychiatric disorders. The aim of this study was to investigate the relation of distinct SLC6A3 and MBP gene polymorphisms with PTSD and whether SLC6A3 and MBP genotypes contribute to PTSD symptom severity. Subjects and methods: The study included 719 individuals who had experienced war trauma in the South Eastern Europe (SEE). Genotypes of variable number tandem repeat (VNTR) polymorphism within the SLC6A3 gene were assessed in 696 participants, and the single nucleotide polymorphism (SNP) rs12458282 located within the MBP gene region was genotyped in a total of 703 subjects. The Mini International Neuropsychiatric Interview, the Clinical Administrated PTSD Scale (CAPS) and Brief Symptom Inventory (BSI), were used for data collection. Results: No significant differences concerning the investigated SLC6A3 and MBP polymorphisms was identifiable between PTSD and non PTSD participants. Also we could not detect significant influence of these distinct SLC6A3 and MBP alleles on the severity of PTSD symptoms (CAPS) or BSI scores. However, the results of MBP rs12458282 within the patients with lifetime PTSD may point to a possible correlation of the major allele (T) with elevated CAPS scores. Conclusions: Our results do not support an association of the analysed SLC6A3 and MBP gene polymorphisms with PTSD in war traumatized individuals. We found that there is a possibility for a correlation of the T allele rs12458282 within the MBP gene with higher CAPS scores in lifetime PTSD patients which would need to be tested in a sample providing more statistical power.

Post-traumatic stress disorder (PTSD) is a common and debilitating disorder. The risk of PTSD following trauma is heritable, but robust common variants have yet to be identified by genome-wide association studies (GWAS). We have collected a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls. We first demonstrate significant genetic correlations across 60 PTSD cohorts to evaluate the comparability of these phenotypically heterogeneous studies. In this largest GWAS meta-analysis of PTSD to date we identify a total of 6 genome-wide significant loci, 4 in European and 2 in African-ancestry analyses. Follow-up analyses incorporated local ancestry and sex-specific effects, and functional studies. Along with other novel genes, a non-coding RNA (ncRNA) and a Parkinson’s Disease gene,PARK2, were associated with PTSD. Consistent with previous reports, SNP-based heritability estimates for PTSD range between 10-20%. Despite a significant shared liability between PTSD and major depressive disorder, we show evidence that some of our loci may be specific to PTSD. These results demonstrate the role of genetic variation contributing to the biology of differential risk for PTSD and the necessity of expanding GWAS beyond European ancestry.

Heart failure (HF) is a complex medical condition with a multitude of genetic and other factors being involved in the pathogenesis. Emerging evidence points to an involvement of inflammatory mechanisms at least in subgroups of patients. The same is true for depression and depressive symptoms, which have a high prevalence in HF patients and are risk factors for the development and outcomes of cardiovascular disease.In 936 patients of the Interdisciplinary Network Heart Failure (INH) program, CRP and IL-6 protein blood levels were measured and genetic variants (single nucleotide polymorphisms) of the CRP and IL6 gene analyzed regarding their influence on mortality.Less common recessive genotypes of two single nucleotide polymorphisms in the CRP gene (rs1800947 and rs11265263) were associated with significantly higher mortality risk (p 0.006), higher CRP levels (p = 0.029, p = 0.006) and increased depressive symptoms in the PHQ-9 (p = 0.005, p = 0.003). Variants in the IL-6 gene were not associated with mortality.Our results hint towards an association of less common CRP genetic variants with increased mortality risk, depressive symptoms and peripheral CRP levels in this population of HF patients thereby suggesting a possible role of the inflammatory system as link between poor prognosis in HF and depressive symptoms.

Epigenetic signatures such as methylation of the monoamine oxidase A (MAOA) gene have been found to be altered in panic disorder (PD). Hypothesizing temporal plasticity of epigenetic processes as a mechanism of successful fear extinction, the present psychotherapy-epigenetic study for we believe the first time investigated MAOA methylation changes during the course of exposure-based cognitive behavioral therapy (CBT) in PD. MAOA methylation was compared between N=28 female Caucasian PD patients (discovery sample) and N=28 age- and sex-matched healthy controls via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. MAOA methylation was furthermore analyzed at baseline (T0) and after a 6-week CBT (T1) in the discovery sample parallelized by a waiting time in healthy controls, as well as in an independent sample of female PD patients (N=20). Patients exhibited lower MAOA methylation than healthy controls (PMAOA methylation (P=0.01). In the discovery sample, MAOA methylation increased up to the level of healthy controls along with CBT response (number of panic attacks; T0–T1: +3.37±2.17%), while non-responders further decreased in methylation (−2.00±1.28%; P=0.001). In the replication sample, increases in MAOA methylation correlated with agoraphobic symptom reduction after CBT (P=0.02–0.03). The present results support previous evidence for MAOA hypomethylation as a PD risk marker and suggest reversibility of MAOA hypomethylation as a potential epigenetic correlate of response to CBT. The emerging notion of epigenetic signatures as a mechanism of action of psychotherapeutic interventions may promote epigenetic patterns as biomarkers of lasting extinction effects.

Representing a phylogenetically old and very basic mechanism of inhibitory neurotransmission, glycine receptors have been implicated in the modulation of behavioral components underlying defensive responding toward threat. As one of the first findings being confirmed by genome-wide association studies for the phenotype of panic disorder and agoraphobia, allelic variation in a gene coding for the glycine receptor beta subunit (GLRB) has recently been associated with increased neural fear network activation and enhanced acoustic startle reflexes. On the basis of two independent healthy control samples, we here aimed to further explore the functional significance of the GLRB genotype (rs7688285) by employing an intermediate phenotype approach. We focused on the phenotype of defensive system reactivity across the levels of brain function, structure, and physiology. Converging evidence across both samples was found for increased neurofunctional activation in the (anterior) insular cortex in GLRB risk allele carriers and altered fear conditioning as a function of genotype. The robustness of GLRB effects is demonstrated by consistent findings across different experimental fear conditioning paradigms and recording sites. Altogether, findings provide translational evidence for glycine neurotransmission as a modulator of the brain’s evolutionary old dynamic defensive system and provide further support for a strong, biologically plausible candidate intermediate phenotype of defensive reactivity. As such, glycine-dependent neurotransmission may open up new avenues for mechanistic research on the etiopathogenesis of fear and anxiety disorders.

The pathogenesis of anxiety disorders is considered to be multifactorial with a complex interaction of genetic factors and individual environmental factors. Therefore, the aim of this study was to examine gene-by-environment interactions of the genes coding for catechol-O-methyltransferase (COMT) and monoamine oxidase A (MAOA) with life events on measures related to anxiety. A sample of healthy subjects (N = 782; thereof 531 women; mean age M = 24.79, SD = 6.02) was genotyped for COMT rs4680 and MAOA-uVNTR (upstream variable number of tandem repeats), and was assessed for childhood adversities [Childhood Trauma Questionnaire (CTQ)], anxiety sensitivity [Anxiety Sensitivity Index (ASI)] and anxious apprehension [Penn State Worry Questionnaire (PSWQ)]. Main and interaction effects of genotype, environment and gender on measures related to anxiety were assessed by means of regression analyses. Association analysis showed no main gene effect on either questionnaire score. A significant interactive effect of childhood adversities and COMT genotype was observed: Homozygosity for the low-active met allele and high CTQ scores was associated with a significant increment of explained ASI variance [R2 = 0.040, false discovery rate (FDR) corrected P = 0.04]. A borderline interactive effect with respect to MAOA-uVNTR was restricted to the male subgroup. Carriers of the low-active MAOA allele who reported more aversive experiences in childhood exhibited a trend for enhanced anxious apprehension (R2 = 0.077, FDR corrected P = 0.10). Early aversive life experiences therefore might increase the vulnerability to anxiety disorders in the presence of homozygosity for the COMT 158met allele or low-active MAOA-uVNTR alleles.

In 2000, Gorman et al. published a widely acknowledged revised version of their 1989 neuroanatomical hypothesis of panic disorder (PD). Herein, a 'fear network' was suggested to mediate fear- and anxiety-related responses: panic attacks result from a dysfunctional coordination of 'upstream' (cortical) and 'downstream' (brainstem) sensory information leading to heightened amygdala activity with subsequent behavioral, autonomic and neuroendocrine activation. Given the emergence of novel imaging methods such as fMRI and the publication of numerous neuroimaging studies regarding PD since 2000, a comprehensive literature search was performed regarding structural (CT, MRI), metabolic (PET, SPECT, MRS) and functional (fMRI, NIRS, EEG) studies on PD, which will be reviewed and critically discussed in relation to the neuroanatomical hypothesis of PD. Recent findings support structural and functional alterations in limbic and cortical structures in PD. Novel insights regarding structural volume increase or reduction, hyper- or hypoactivity, laterality and task-specificity of neural activation patterns emerged. The assumption of a generally hyperactive amygdala in PD seems to apply more to state than trait characteristics of PD, and involvement of further areas in the fear circuit, such as anterior cingulate and insula, is suggested. Furthermore, genetic risk variants have been proposed to partly drive fear network activity. Thus, the present state of knowledge generally supports limbic and cortical prefrontal involvement as originally proposed in the neuroanatomical hypothesis. Some modifications might be suggested regarding a potential extension of the fear circuit, genetic factors shaping neural network activity and neuroanatomically informed clinical subtypes of PD potentially guiding future treatment decisions.

The monoamine oxidase A (MAOA) gene has been suggested as a prime candidate in the pathogenesis of panic disorder. In the present study, DNA methylation patterns in the MAOA regulatory and exon 1/intron 1 region were investigated for association with panic disorder with particular attention to possible effects of gender and environmental factors. Sixty-five patients with panic disorder (44 females, 21 males) and 65 healthy controls were analysed for DNA methylation status at 42 MAOA CpG sites via direct sequencing of sodium bisulfate treated DNA extracted from blood cells. The occurrence of recent positive and negative life events was ascertained. Male subjects showed no or only very minor methylation with some evidence for relative hypomethylation at one CpG site in intron 1 in patients compared to controls. Female patients exhibited significantly lower methylation than healthy controls at 10 MAOA CpG sites in the promoter as well as in exon/intron 1, with significance surviving correction for multiple testing at four CpG sites (p?0.001). Furthermore, in female subjects the occurrence of negative life events was associated with relatively decreased methylation, while positive life events were associated with increased methylation. The present pilot data suggest a potential role of MAOA gene hypomethylation in the pathogenesis of panic disorder particularly in female patients, possibly mediating a detrimental influence of negative life events. Future studies are warranted to replicate the present finding in independent samples, preferably in a longitudinal design.

BACKGROUND AND PURPOSE Prolonged wakefulness impairs sustained vigilant attention, measured with the psychomotor vigilance task (PVT), and induces a compensatory increase in sleep intensity in recovery sleep, quantified by slow-wave activity (SWA) in the sleep electroencephalogram (EEG). These effects of sleep deprivation are counteracted by the adenosine receptor antagonist caffeine, implying involvement of the adenosine neuromodulator/receptor system. To examine a role for adenosine A2A receptors, we investigated whether variation of the A2A receptor gene (ADORA2A) modified effects of caffeine on PVT and SWA after sleep deprivation. EXPERIMENTAL APPROACH A haplotype analysis of eight single-nucleotide polymorphisms of ADORA2A was performed in 82 volunteers. In 45 young men carrying five different allele combinations, we investigated the effects of prolonged waking and 2 × 200 mg caffeine or 2 × 100 mg modafinil on psychomotor vigilance, sleepiness, and the waking and sleep EEG. KEY RESULTS Throughout extended wakefulness, the carriers of haplotype HT4 performed faster on the PVT than carriers of non-HT4 haplotype alleles. In haplotype HT4, caffeine failed to counteract the waking-induced impairment of PVT performance and the rebound of SWA in recovery sleep. However, caffeine was effective in non-HT4 allele carriers, and modafinil reduced the consequences of prolonged waking, independently of ADORA2A haplotype. CONCLUSIONS AND IMPLICATIONS Common genetic variation of ADORA2A is an important determinant of psychomotor vigilance in rested and sleep-deprived state. It also modulates individual responses to caffeine after sleep deprivation. These findings demonstrate a role for adenosine A2A receptors in the effects of prolonged wakefulness on vigilant attention and the sleep EEG.

Recent studies highlighted the great potential of newly established theta burst stimulation (TBS) protocols for non‐invasive human brain stimulation studies using transcranial magnetic stimulation (TMS). While intermittent TBS over the primary motor cortex was found to potentiate motor evoked potentials, continuous TBS led to profound attenuations. Although numerous studies investigated the impact of TBS on motor cortex function, yet, only few imaging studies focused on its effects in other brain areas. Particularly for the prefrontal cortex, it is unclear whether TBS has similar effects compared to application over motor areas. In the current study continuous TBS was applied to either the left or right dorsolateral prefrontal cortex in a sample of healthy subjects. Changes in prefrontal oxygenation were measured during an emotional Stroop task by means of functional multi‐channel near‐infrared spectroscopy (fNIRS) before and after stimulation. Results showed bilaterally decreased prefrontal oxygenation following inhibitory stimulation of the left prefrontal cortex but no behavioral effect. No such alterations were observed following right‐hemispheric or sham stimulation. The results of the current study are in line with earlier findings and additionally demonstrate that also prefrontal oxygenation can be impaired by continuous TBS. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.

Citalopram (CIT) is a widely used antidepressant which acts by a selective serotonin reuptake inhibition. It is considered to be safer than tricyclic antidepressants at therapeutic levels, but also with respect to intoxications. We report the case of a 46-year-old woman, who ingested in suicidal intention 1400 mg CIT. During the following inpatient treatment repeatedly ECGs and determinations of the serum level of CIT were performed. Initially the patient’s serum level of CIT was 1231 ng/mL and QTc interval was 541.60 ms. It took 12 days until the serum level of CIT fell below the upper threshold of the recommended therapeutic range (130 ng/mL). The QTc interval on the sixth day after the intoxication for the first time was below 500 ms. The QTc interval correlated significantly with the serum level of CIT after intoxication (r=0.943; p

Duloxetine is a dual acting antidepressant (selective serotonin and norepinephrine reuptake inhibitor). Existing data suggest that the advisable therapeutic serum level of duloxetine ranges between 20 and 80 ng/mL. In a naturalistic setting we determined duloxetine serum levels within a steady state in a sample of depressive inpatients by high performance liquid chromatography (HPLC). The mean serum levels in 28 patients at the time of the first TDM analysis were 52.0+/-67 ng/mL. Eight of the patients were smokers and showed a considerably lower serum level of 24.3+/-18.8 ng/mL. In the further course of treatment the difference was compensated by application of higher doses in smokers. These findings suggest that smoking is associated with lower duloxetine serum levels due to an induction of CYP1A2 by polycylic hydrocarbons which are contained in tobacco smoke. Therefore in smokers higher doses of duloxetine (about 15%) seem to be necessary to reach adequate serum levels.

Social anxiety has been suggested to be promoted by an insecure attachment style. Oxytocin is discussed as a mediator of trust and social bonding as well as a modulator of social anxiety. Applying a gene-environment (G × E) interaction approach, in the present pilot study the main and interactive effects of attachment styles and oxytocin receptor (OXTR) gene variation were probed in a combined risk factor model of social anxiety in healthy probands.Participants (N = 388; 219 females, 169 males; age 24.7 ± 4.7 years) were assessed for anxiety in social situations (Social Phobia and Anxiety Inventory) depending on attachment style (Adult Attachment Scale, AAS) and OXTR rs53576 A/G genotype.A less secure attachment style was significantly associated with higher social anxiety. This association was partly modulated by OXTR genotype, with a stronger negative influence of a less secure attachment style on social anxiety in A allele carriers as compared to GG homozygotes.The present pilot data point to a strong association of less secure attachment and social anxiety as well as to a gene-environment interaction effect of OXTR rs53576 genotype and attachment style on social anxiety possibly constituting a targetable combined risk marker of social anxiety disorder.

Anxiety disorders result from a complex interplay of genetic and environmental factors such as stress. On the level of cellular signaling, regulator of G protein signaling 2 (Rgs2) has been implicated in human and rodent anxiety. However, there is limited knowledge about the role of Rgs2 in fear learning and reactivity to stress. In this study, Rgs2-/- mice showed increased fear learning, male mice displayed increased contextual and cued fear learning, while females showed selectively enhanced cued fear learning. Male Rgs2-/- mice displayed increased long-term-contextual fear memory, but increased cued fear extinction. Learning in spatial non-aversive paradigms was also increased in Rgs2-/- mice. Female, but not male mice show increased spatial learning in the Barnes maze, while male mice showed enhanced place preference in the IntelliCage, rendering enhanced cognitive function non-specific for aversive stimuli. Consistent with the previous results, Rgs2 deletion resulted in increased innate anxiety, including neophobic behavior expressed as hypolocomotion, in three different tests based on the approach-avoidance conflict. Acute electric foot shock stress provoked hypolocomotion in several exploration-based tests, suggesting fear generalization in both genotypes. Rgs2 deletion was associated with reduced monoaminergic neurotransmitter levels in the hippocampus and prefrontal cortex and disturbed corresponding GPCR expression of the adrenergic, serotonergic, dopaminergic and neuropeptide Y system. Taken together, Rgs2 deletion promotes improved cognitive function as well as increased anxiety-like behavior, but has no effect on acute stress reactivity. These effects may be related to the observed disruption of the monoaminergic systems.

Background Panic disorder (PD) is one of the most common anxiety disorders with a lifetime prevalence of about 4%. The disorder is characterized by recurrent episodes of abrupt intense fear accompanied by additional physiological or cognitive symptoms. Although PD shows moderate heritability estimates of 30-54%, the specific genetic variants contributing to PD are largely unknown, with few and somewhat inconsistent loci reported to date. To address the challenge of underpowered individual studies, we conducted the largest genome-wide association study of PD to date comprising more than 8,700 individuals. Methods In our study we generated genome-wide SNP data from > 2,000 clinically well-characterized patients with PD and > 6,700 ethnically matched controls. The samples originate from five different European countries (Denmark, Estonia, Finland, Germany and Sweden). Standard GWAS quality control procedures were performed on each dataset individually. Imputation was performed using the 1000 Genomes Project reference panel. Only SNPs present in all datasets were kept for the meta-analysis using METASOFT. Results In the single-marker analysis we identified several SNPs with PD association on the significance level of p Discussion In this collaborative study with sample sizes being larger than any other PD GWAS published to date, we identified PD associated loci across different European samples. LD Score regression analysis of our GWAS data provides robust evidence for a polygenic contribution of common SNPs to PD heritability. Replication of our top findings as well as further pathway and eQTL analyses are currently underway and will be presented.

Variation in the serotonin transporter gene ( 5-HTT; SERT; SLC6A4 ) has been suggested to pharmacogenetically drive interindividual differences in antidepressant treatment response. In the present analysis, a ‘pharmaco-epigenetic’ approach was applied by investigating the influence of DNA methylation patterns in the 5-HTT transcriptional control region on antidepressant treatment response. Ninety-four patients of Caucasian descent with major depressive disorder (MDD) ( f = 61) were analysed for DNA methylation status at nine CpG sites in the 5-HTT transcriptional control region upstream of exon 1A via direct sequencing of sodium bisulfite treated DNA extracted from blood cells. Patients were also genotyped for the functional 5-HTTLPR /rs25531 polymorphisms. Clinical response to treatment with escitalopram was assessed by intra-individual changes of HAM-D-21 scores after 6 wk of treatment. Lower average 5-HTT methylation across all nine CpGs was found to be associated with impaired antidepressant treatment response after 6 wk ( p = 0.005). This effect was particularly conferred by one individual 5-HTT CpG site (CpG2 (GRCh37 build, NC_000017.10 28.563.102; p = 0.002). 5-HTTLPR /rs25531 haplotype was neither associated with 5-HTT DNA methylation nor treatment response. This analysis suggests that DNA hypomethylation of the 5-HTT transcriptional control region – possibly via increased serotonin transporter expression and consecutively decreased serotonin availability – might impair antidepressant treatment response in Caucasian patients with MDD. This pharmaco-epigenetic approach could eventually aid in establishing epigenetic biomarkers of treatment response and thereby a more personalized treatment of MDD.

Summary: Recurrent panic attacks, anticipatory anxiety and phobic avoidance characterise panic disorder. The influence of genetic factors on liability to the disease has been the object of several linkage and association studies and appears to relate to an oligo-or polygenic rather than a monogenic mode of inheritance. Recently, an excess of high activity monoamine oxidase A (MAO-A) gene promoter alleles was found in female patients with panic disorder. An analysis of possible synergistic effects of the MAO-A gene promoter variant and the short serotonin transporter (5-HTT) gene promoter variant in panic disorder was performed in a German and an Italian sample (combined panic disorder n = 144, combined controls n = 175). There was no significant difference in odds ratios, suggesting that the observed increase of genetic liability by the long MAO-A gene promoter allele is not modified by the 5-HTT gene promoter polymorphism.