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 (Asn¹⁰⁷Ile) 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.
Anxiety disorders are common, complex psychiatric disorders with twin heritabilities of 30-60%. We conducted a genome-wide association study of Lifetime Anxiety Disorder (n
= 25 453, n
= 58 113) ...and an additional analysis of Current Anxiety Symptoms (n
= 19 012, n
= 58 113). The liability scale common variant heritability estimate for Lifetime Anxiety Disorder was 26%, and for Current Anxiety Symptoms was 31%. Five novel genome-wide significant loci were identified including an intergenic region on chromosome 9 that has previously been associated with neuroticism, and a locus overlapping the BDNF receptor gene, NTRK2. Anxiety showed significant positive genetic correlations with depression and insomnia as well as coronary artery disease, mirroring findings from epidemiological studies. We conclude that common genetic variation accounts for a substantive proportion of the genetic architecture underlying anxiety.
A genetic contribution to the pathogenesis of panic disorder has been demonstrated by clinical genetic studies. Molecular genetic studies have focused on candidate genes suggested by the molecular ...mechanisms implied in the action of drugs utilized for therapy or in challenge tests. One class of drugs effective in the treatment of panic disorder is represented by monoamine oxidase A inhibitors. Therefore, the monoamine oxidase A gene on chromosome X is a prime candidate gene. In the present study we investigated a novel repeat polymorphism in the promoter of the monoamine oxidase A gene for association with panic disorder in two independent samples (German sample, n = 80; Italian sample, n = 129). Two alleles (3 and 4 repeats) were most common and constituted >97% of the observed alleles. Functional characterization in a luciferase assay demonstrated that the longer alleles (3a, 4 and 5) were more active than allele 3. Among females of both the German and the Italian samples of panic disorder patients (combined, n = 209) the longer alleles (3a, 4 and 5) were significantly more frequent than among females of the corresponding control samples (combined, n = 190, χ2 = 10.27, df = 1, P = 0.001). Together with the observation that inhibition of monoamine oxidase A is clinically effective in the treatment of panic disorder these findings suggest that increased monoamine oxidase A activity is a risk factor for panic disorder in female patients.
Antidepressants are recommended for the treatment of chronic musculoskeletal pain; however, target serum concentrations based on therapeutic drug monitoring (TDM) have not been established. ...Therefore, the authors analyzed routine care TDM data of antidepressants in patients with chronic pain with and without depression in terms of treatment outcomes in an interdisciplinary multimodal pain treatment (IMPT) program.
Patients with chronic musculoskeletal pain and TDM for amitriptyline (n = 45) or duloxetine (n = 30) were retrospectively included. The German pain questionnaire for pain intensity and the Depression Anxiety Stress scale were applied at T0 and at the end of the IMPT program (T1). A relief of pain intensity score ≥2 was considered as a positive outcome. Comorbid depression was diagnosed based on ICD-10 criteria. Serum concentrations of antidepressants were measured for routine clinical care TDM.
After IMPT, stress improved in all subgroups, and depressive symptoms improved only in the duloxetine group. Overall, 40% and 27% of patients in the amitriptyline and duloxetine subgroup, respectively, were responders in terms of maximum pain score relief. Responders with comorbid depression were treated with a dose that led to a 1.7-fold higher serum concentration of the active moiety of amitriptyline (amitriptyline + nortriptyline) compared with nonresponders. Similarly, a 2.3-fold higher serum concentration was observed in depressed responders than in nondepressed responders (at minimum 131.5 ng/mL).
Dosing of antidepressants for chronic pain relief should specifically take comorbid depression into account. TDM may provide better outcomes of pain relief in an IMPT setting in patients with comorbid depression.
Major depressive disorder and the anxiety disorders are highly prevalent, disabling and moderately heritable. Depression and anxiety are also highly comorbid and have a strong genetic correlation (r
...≈ 1). Cognitive behavioural therapy is a leading evidence-based treatment but has variable outcomes. Currently, there are no strong predictors of outcome. Therapygenetics research aims to identify genetic predictors of prognosis following therapy. We performed genome-wide association meta-analyses of symptoms following cognitive behavioural therapy in adults with anxiety disorders (n = 972), adults with major depressive disorder (n = 832) and children with anxiety disorders (n = 920; meta-analysis n = 2724). We estimated the variance in therapy outcomes that could be explained by common genetic variants (h
) and polygenic scoring was used to examine genetic associations between therapy outcomes and psychopathology, personality and learning. No single nucleotide polymorphisms were strongly associated with treatment outcomes. No significant estimate of h
could be obtained, suggesting the heritability of therapy outcome is smaller than our analysis was powered to detect. Polygenic scoring failed to detect genetic overlap between therapy outcome and psychopathology, personality or learning. This study is the largest therapygenetics study to date. Results are consistent with previous, similarly powered genome-wide association studies of complex traits.
Traditionally, adversity was defined as the accumulation of environmental events (allostatic load). Recently however, a mismatch between the early and the later (adult) environment (mismatch) has ...been hypothesized to be critical for disease development, a hypothesis that has not yet been tested explicitly in humans. We explored the impact of timing of life adversity (childhood and past year) on anxiety and depression levels (N = 833) and brain morphology (N = 129). Both remote (childhood) and proximal (recent) adversities were differentially mirrored in morphometric changes in areas critically involved in emotional processing (i.e. amygdala/hippocampus, dorsal anterior cingulate cortex, respectively). The effect of adversity on affect acted in an additive way with no evidence for interactions (mismatch). Structural equation modeling demonstrated a direct effect of adversity on morphometric estimates and anxiety/depression without evidence of brain morphology functioning as a mediator. Our results highlight that adversity manifests as pronounced changes in brain morphometric and affective temperament even though these seem to represent distinct mechanistic pathways. A major goal of future studies should be to define critical time periods for the impact of adversity and strategies for intervening to prevent or reverse the effects of adverse childhood life experiences.
This multidisciplinary book includes current research papers and reviews in the areas of basic neuroscience, neural mechanisms underlying neurodegenerative disorders. It further includes new ...approaches for neuroprotective treatments, clinical, neurobiological and treatment aspects of psychiatric disorders. The book was conceived as a celebration of the professional life and work of Peter Riederer to mark the occasion of his retirement.
Smoking is among the leading causes of mortality worldwide. Discontinuing smoking can increase life expectancy to the presmoking level. Unaided attempts are often ineffective, strengthening the ...necessity of cognitive-behavioral therapy (CBT), nicotine replacement or pharmacotherapy. Still, relapse rates are high. Recently, a modulation of nicotine craving, which predicts relapse, through transcranial magnetic stimulation to the prefrontal cortex was shown. In a pilot study, we investigated whether 4 sessions of intermittent theta burst stimulation (iTBS) as add-on treatment to CBT reduces nicotine craving and improves long-term abstinence (at 3, 6 and 12 months). Smokers were randomly assigned to a treatment (n = 38) or a sham group (n = 36). Although we did not find reduced craving, we could show higher abstinence rates in the treatment group at 3 months. At 6 and 12 months abstinence rates did not differ significantly. Results at 12 months, however, have to be interpreted cautiously due to significant differences in the dropout rates between the two groups at this time point. We provide first evidence for a beneficial effect of additional iTBS on intermediate nicotine abstinence; however, the low number of iTBS sessions might have prevented longer effects. More lasting effects might be achieved by iTBS maintenance sessions in analogy to the treatment of depression.
Genome-Wide Association Study of Panic Disorder Forstner, Andreas J.; Awasthi, Swapnil; Wolf, Christiane ...
EUROPEAN NEUROPSYCHOPHARMACOLOGY,
2019, 2019-00-00, Volume:
29
Journal Article, Conference Proceeding
Peer reviewed
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 genetic variants contributing to PD are largely unknown, with only few and 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 9,900 individuals.
In our study, we generated genome-wide SNP data from 2,147 clinically well-characterized patients with PD and 7,760 ethnically matched controls. The samples originate from four different European countries (Denmark, Estonia, Germany and Sweden). Standard GWAS quality control procedures were performed on each dataset individually. Imputation was performed using the 1000 Genomes Project reference panel. Then a meta-analysis was performed using the Ricopili pipeline (https://sites.google.com/a/broadinstitute.org/ricopili/).
In our meta-analysis, we did not identify any genome-wide significant locus. 36 linkage disequilibrium independent SNPs had a p-value < 1e-05. Leave-one-out analyses demonstrated highly significant polygenetic risk scores with an explained variance of up to 3%. Using the recently published LD Score regression method on our GWAS data the estimated heritability for PD was 0.2923.
In this collaborative study with sample sizes being larger than any other PD GWAS published to date, we did not identify any genome-wide significant locus. However, our PD meta-analysis shows highly similar characteristics as similar sized GWAS previously conducted in schizophrenia. LD Score regression analysis provides the first SNP-based heritability estimate for PD based on genotype data of more than 9,900 individuals. Replication of our top findings in independent European datasets as well as further pathway analyses are currently underway and will be presented.
PDF
