Search

Introduction Pharmacogenetic testing is proposed to minimize adverse effects when considered in combination with pharmacological knowledge of the drug. As yet, limited studies in clinical settings have investigated the predictive value of pharmacokinetic (pk) gene variation on therapeutic drug levels as a probable mechanism of adverse effects, nor considered the combined effect of pk gene variation and drug level on antidepressant treatment response. Methods Two depression cohorts were investigated for the relationship between pk gene variation and antidepressant serum concentrations of amitriptyline, venlafaxine, mirtazapine and quetiapine, as well as treatment response. For the analysis, 519 patients (49% females; 46.6±14.1 years) were included. Results Serum concentration of amitriptyline was associated with CYP2D6 (higher concentrations in poor metabolizers compared to normal metabolizers), of venlafaxine with CYP2C19 (higher concentrations in intermediate metabolizers compared to rapid/ultrarapid metabolizers) and CYP2D6 (lower metabolite-to-parent ratio in poor compared to intermediate and normal metabolizers, and intermediate compared to normal and ultrarapid metabolizers). Pk gene variation did not affect treatment response. Discussion The present data support previous recommendations to reduce starting doses of amitriptyline and to guide dose-adjustments via therapeutic drug monitoring in CYP2D6 poor metabolizers. In addition, we propose including CYP2C19 in routine testing in venlafaxine-treated patients to improve therapy by raising awareness of the risk of low serum concentrations in CYP2C19 rapid/ultrarapid metabolizers. In summary, pk gene variation can predict serum concentrations, and thus the combination of pharmacogenetic testing and therapeutic drug monitoring is a useful tool in a personalized therapy approach for depression.

Heterogeneity in the clinical presentation of major depressive disorder and response to antidepressants limits clinicians’ ability to accurately predict a specific patient’s eventual response to therapy. Validated depressive symptom profiles may be an important tool for identifying poor outcomes early in the course of treatment. To derive these symptom profiles, we first examined data from 947 depressed subjects treated with selective serotonin reuptake inhibitors (SSRIs) to delineate the heterogeneity of antidepressant response using probabilistic graphical models (PGMs). We then used unsupervised machine learning to identify specific depressive symptoms and thresholds of improvement that were predictive of antidepressant response by 4 weeks for a patient to achieve remission, response, or nonresponse by 8 weeks. Four depressive symptoms (depressed mood, guilt feelings and delusion, work and activities and psychic anxiety) and specific thresholds of change in each at 4 weeks predicted eventual outcome at 8 weeks to SSRI therapy with an average accuracy of 77% (p = 5.5E-08). The same four symptoms and prognostic thresholds derived from patients treated with SSRIs correctly predicted outcomes in 72% (p = 1.25E-05) of 1996 patients treated with other antidepressants in both inpatient and outpatient settings in independent publicly-available datasets. These predictive accuracies were higher than the accuracy of 53% for predicting SSRI response achieved using approaches that (i) incorporated only baseline clinical and sociodemographic factors, or (ii) used 4-week nonresponse status to predict likely outcomes at 8 weeks. The present findings suggest that PGMs providing interpretable predictions have the potential to enhance clinical treatment of depression and reduce the time burden associated with trials of ineffective antidepressants. Prospective trials examining this approach are forthcoming.

Background A major research finding in the field of Biological Psychiatry is that symptom-based categories of mental disorders map poorly onto dysfunctions in brain circuits or neurobiological pathways. Many of the identified (neuro) biological dysfunctions are “transdiagnostic”, meaning that they do not reflect diagnostic boundaries but are shared by different ICD/DSM diagnoses. The compromised biological validity of the current classification system for mental disorders impedes rather than supports the development of treatments that not only target symptoms but also the underlying pathophysiological mechanisms. The Biological Classification of Mental Disorders (BeCOME) study aims to identify biology-based classes of mental disorders that improve the translation of novel biomedical findings into tailored clinical applications. Methods BeCOME intends to include at least 1000 individuals with a broad spectrum of affective, anxiety and stress-related mental disorders as well as 500 individuals unaffected by mental disorders. After a screening visit, all participants undergo in-depth phenotyping procedures and omics assessments on two consecutive days. Several validated paradigms (e.g., fear conditioning, reward anticipation, imaging stress test, social reward learning task) are applied to stimulate a response in a basic system of human functioning (e.g., acute threat response, reward processing, stress response or social reward learning) that plays a key role in the development of affective, anxiety and stress-related mental disorders. The response to this stimulation is then read out across multiple levels. Assessments comprise genetic, molecular, cellular, physiological, neuroimaging, neurocognitive, psychophysiological and psychometric measurements. The multilevel information collected in BeCOME will be used to identify data-driven biologically-informed categories of mental disorders using cluster analytical techniques. Discussion The novelty of BeCOME lies in the dynamic in-depth phenotyping and omics characterization of individuals with mental disorders from the depression and anxiety spectrum of varying severity. We believe that such biology-based subclasses of mental disorders will serve as better treatment targets than purely symptom-based disease entities, and help in tailoring the right treatment to the individual patient suffering from a mental disorder. BeCOME has the potential to contribute to a novel taxonomy of mental disorders that integrates the underlying pathomechanisms into diagnoses. Trial registration Retrospectively registered on June 12, 2019 on ClinicalTrials.gov (TRN: NCT03984084).

Maladaptive stress responses are important risk factors in the etiology of mood and anxiety disorders, but exact pathomechanisms remain to be understood. Mapping individual differences of acute stress-induced neurophysiological changes, especially on the level of neural activation and functional connectivity (FC), could provide important insights in how variation in the individual stress response is linked to disease risk.Using an established psychosocial stress task flanked by two resting states, we measured subjective, physiological, and brain responses to acute stress and recovery in 217 participants with and without mood and anxiety disorders. To estimate blockwise changes in stress-induced activation and FC, we used hierarchical mixed-effects models based on denoised time series within predefined stress-related regions. We predicted inter- and intraindividual differences in stress phases (anticipation vs. stress vs. recovery) and transdiagnostic dimensions of stress reactivity using elastic net and support vector machines.We identified four subnetworks showing distinct changes in FC over time. FC but not activation trajectories predicted the stress phase (accuracy = 70%, pSpatiotemporal dynamics of brain network reconfiguration induced by stress reflect individual differences in the psychopathology dimension of negative affectivity. These results support the idea that vulnerability for mood and anxiety disorders can be conceptualized best at the level of network dynamics, which may pave the way for improved prediction of individual risk.

Negative interpersonal experiences are a key contributor to psychiatric disorders. While previous research has shown that negative interpersonal experiences influence social cognition, less is known about the effects on participation in social interactions and the underlying neurobiology. To address this, we developed a new naturalistic version of a gaze-contingent paradigm using real video sequences of gaze behaviour that respond to the participants’ gaze in real-time in order to create a believable and continuous interactive social situation. Additionally, participants listened to two autobiographical audio-scripts that guided them to imagine a recent stressful and a relaxing situation and performed the gaze-based social interaction task before and after the presentation of either the stressful or the relaxing audio-script. Our results demonstrate that the social interaction task robustly recruits brain areas with known involvement in social cognition, namely the medial prefrontal cortex, bilateral temporoparietal junction, superior temporal sulcus as well as the precuneus. Imagery of negative interpersonal experiences compared to relaxing imagery led to a prolonged change in affective state and to increased brain responses during the subsequent social interaction paradigm in the temporoparietal junction, medial prefrontal cortex, anterior cingulate cortex, precuneus and inferior frontal gyrus. Taken together this study presents a new naturalistic social interaction paradigm suitable to study the neural mechanisms of social interaction and the results demonstrate that the imagery of negative interpersonal experiences affects social interaction on neural levels.

Dissection of the HPA axis using single-cell RNA sequencing uncovers adrenal ABCB1 as an important player of stress adaptation., Chronic activation and dysregulation of the neuroendocrine stress response have severe physiological and psychological consequences, including the development of metabolic and stress-related psychiatric disorders. We provide the first unbiased, cell type–specific, molecular characterization of all three components of the hypothalamic-pituitary-adrenal axis, under baseline and chronic stress conditions. Among others, we identified a previously unreported subpopulation of Abcb1b+ cells involved in stress adaptation in the adrenal gland. We validated our findings in a mouse stress model, adrenal tissues from patients with Cushing’s syndrome, adrenocortical cell lines, and peripheral cortisol and genotyping data from depressed patients. This extensive dataset provides a valuable resource for researchers and clinicians interested in the organism’s nervous and endocrine responses to stress and the interplay between these tissues. Our findings raise the possibility that modulating ABCB1 function may be important in the development of treatment strategies for patients suffering from metabolic and stress-related psychiatric disorders.

Depression is a debilitating disorder with high prevalence and socioeconomic cost, but the brain-physiological processes that are altered during depressive states are not well understood. Here, we build on recent findings in macaques that indicate a direct causal relationship between pupil dilation and anterior cingulate cortex mediated arousal during anticipation of reward. We translated these findings to human subjects with concomitant pupillometry/fMRI in a sample of unmedicated participants diagnosed with major depression and healthy controls. We could show that the upregulation and maintenance of arousal in anticipation of reward was disrupted in patients in a symptom-load dependent manner. We could further show that the failure to maintain reward anticipatory arousal showed state-marker properties, as it tracked the load and impact of depressive symptoms independent of prior diagnosis status. Further, group differences of anticipatory arousal and continuous correlations with symptom load were not traceable only at the level of pupillometric responses, but were mirrored also at the neural level within salience network hubs. The upregulation and maintenance of arousal during reward anticipation is a novel translational and well-traceable process that could prove a promising gateway to a physiologically informed patient stratification and targeted interventions.

Depression is a debilitating disorder with high prevalence and socioeconomic cost, but the central processes that are altered during depressive states remain largely elusive. Here, we build on recent findings in macaques that indicate a direct causal relationship between pupil dilation and anterior cingulate cortex mediated arousal during anticipation of reward. Using pupillometry and concurrent fMRI in a sample of unmedicated participants diagnosed with major depression and healthy controls, we observed reduced pupil dilation during reward anticipation in depressed participants with acute symptomatology. We further observed that individual differences in arousal during reward anticipation track the load and impact of depressive symptoms, a correlation that we replicated in a second sample of unmedicated depressed participants. Moreover, these group differences and correlations were mirrored at the neural level. The upregulation and maintenance of arousal during reward anticipation is a translational and well-traceable process that could prove a promising gateway to a physiologically informed patient stratification.

Background Depressed patients have an increased risk of myocardial infarction, for which acute stress is a frequent trigger. Prothrombotic changes could be one involved mechanism that can be modulated by psychological coping. Purpose We examined the effects of remitted major depression and situation-specific coping strategies on stress-induced coagulation activation. Methods Forty patients with remitted depression and 23 healthy controls underwent the Trier Social Stress Test, rating applied coping strategies thereafter. Blood was sampled at baseline and 15 and 45 min poststress to measure fibrinogen, von Willebrand factor (VWF) and D-dimer. Coagulation activation over time was quantified as area under the curve (AUC) with respect to baseline activity. Standardized z-scores of individual coagulation AUC measures were added up to a prothrombotic index. Results Stress provoked significant VWF (p = .024) and D-dimer (p = .002) responses. Remitted depressed patients used positive distraction coping more frequently than controls did (p = .030). Coagulation AUC measures were similar in both groups. In all participants, higher positive coping total (p = 0.009), driven by devaluation/defense (p = .022) and distraction (p = .004) coping, was associated with a lower prothrombotic index. In controls, but not in remitted depressed patients, higher positive coping total (p = .008), driven by higher devaluation/defense (p = .010) and distraction (p = .023) coping, was associated with lower VWF AUC. Conclusions Despite the use of favorable coping strategies in a specific stress situation, remitted depressed patients may benefit less from a positive effect of positive situational coping on coagulation activation than controls. Such a mechanism could partially explain the increased risk of myocardial infarction in depressed individuals.

Hypercoagulability is one mechanism to explain the increased risk of incident atherothrombotic disease in patients with major depressive disorder (MDD). We examined whether patients with remitted MDD show an enhanced procoagulant state.63 individuals (median age 35 years, 59% women), 40 with a DSM-IV diagnosis of remitted MDD, made by a clinical interview, and 23 healthy controls provided blood samples for the measurement of fibrinogen, D-dimer, von Willebrand factor, and plasminogen activator inhibitor-1. StandardisedCompared with controls, remitted MDD patients had higher PCI (Remitted MDD is associated with an enhanced procoagulant state. Hypercoagulability seems more a trait than a state characteristic of depression.

P-glycoprotein (P-gp), the gene product of ABCB1, is a drug transporter at the blood–brain barrier and could be a limiting factor for entrance of antidepressants into the brain, the target site of antidepressant action. Animal studies showed that brain concentrations of many antidepressants depend on P-gp. In humans, ABCB1 genotyping in the treatment of depression rests on the assumption that genetic variations in ABCB1 explain individual differences in antidepressant response via their effects on P-gp expression at the blood–brain barrier. High P-gp expression is hypothesized to lead to lower and often insufficient brain concentrations of P-gp substrate antidepressants. In this review, we summarize 32 studies investigating the question of whether ABCB1 polymorphisms predict clinical efficacy and/or tolerability of antidepressants in humans and evaluate the clinical application status of ABCB1 genotyping in depression treatment.

Adverse experiences and chronic stress are well-known risk factors for the development of major depression, and an impaired stress response regulation is frequently observed in acute depression. Impaired glucocorticoid receptor (GR) signalling plays an important role in these alterations, and a restoration of GR signalling appears to be a prerequisite of successful antidepressant treatment. Variants in genes of the stress response regulation contribute to the vulnerability to depression in traumatized subjects. Consistent findings point to an important role of FKBP5, the gene expressing FK506-binding protein 51 (FKBP51), which is a strong inhibitor of the GR, and thus, an important regulator of the stress response. We investigated the role of FKBP5 and FKB51 expression with respect to stress response regulation and antidepressant treatment outcome in depressed patients. This study included 297 inpatients, who participated in the Munich Antidepressant Response Signature (MARS) project and were treated for acute depression. In this open-label study, patients received antidepressant treatment according to the attending doctor’s choice. In addition to the FKBP5 genotype, changes in blood FKBP51 expression during antidepressant treatment were analyzed using RT-PCR and ZeptoMARKTM reverse phase protein microarray (RPPM). Stress response regulation was evaluated in a subgroup of patients using the combined dexamethasone (dex)/corticotropin releasing hormone (CRH) test. As expected, increased FKBP51 expression was associated with an impaired stress response regulation at baseline and after six weeks was accompanied by an elevated cortisol response to the combined dex/CRH test. Further, we demonstrated an active involvement of FKBP51 in antidepressant treatment outcome. While patients responding to antidepressant treatment had a pronounced reduction of FKBP5 gene and FKBP51 protein expression, increasing expression levels were observed in nonresponders. This effect was moderated by the genotype of the FKBP5 single nucleotide polymorphism (SNP) rs1360780, with carriers of the minor allele showing the most pronounced association. Our findings demonstrate that FKBP5 and, specifically, its expression product FKBP51 are important modulators of antidepressant treatment outcome, pointing to a new, promising target for future antidepressant drug development.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, whose core symptoms consist of deficits in social interaction and communication as well as restricted and repetitive behavior. Brain oxytocin (OXT) has been associated with various prosocial behaviors, and might, therefore, be involved in the pathogenesis of disorders associated with socio-emotional dysfunctions such as ASD. However, significant associations between central and peripheral OXT levels may only be present in response to physiological or stressful stimuli but were not shown under baseline conditions. In this study, we, therefore, investigated salivary and plasma OXT in response to physical exercise in adults with ASD (n ​= ​33, mean age: 36.8 ​± ​10.7 years) without intellectual impairment (IQ ​> ​70) and neurotypical controls (n ​= ​31, mean age: 31.0 ​± ​11.7 years). To stimulate the OXT system, we used rapid cycling and measured cortisol (CORT) concentrations to monitor the physiological stress response. When controlling for age, neither salivary OXT (p ​= ​.469), plasma OXT (p ​= ​.297) nor CORT (p ​= ​.667) concentrations significantly differed between groups at baseline. In addition, neither OXT nor CORT concentrations significantly differed between groups after physical exercise. Social anxiety traits were negatively correlated with plasma, but not saliva OXT concentrations in neurotypicals at baseline, while empathetic traits were positively correlated with saliva, but not plasma concentrations in autistic patients at baseline. No significant correlations between salivary and plasma OXT concentrations were found at any time point. Future studies including adult participants should investigate the effect of age on CORT and OXT concentrations in response to stress.

Chronic psychological stress is associated with accelerated aging and increased risk for aging-related diseases, but the underlying molecular mechanisms are unclear.We examined the effect of lifetime stressors on a DNA methylation-based age predictor, epigenetic clock. After controlling for blood cell-type composition and lifestyle parameters, cumulative lifetime stress, but not childhood maltreatment or current stress alone, predicted accelerated epigenetic aging in an urban, African American cohort (n = 392). This effect was primarily driven by personal life stressors, was more pronounced with advancing age, and was blunted in individuals with higher childhood abuse exposure. Hypothesizing that these epigenetic effects could be mediated by glucocorticoid signaling, we found that a high number (n = 85) of epigenetic clock CpG sites were located within glucocorticoid response elements. We further examined the functional effects of glucocorticoids on epigenetic clock CpGs in an independent sample with genome-wide DNA methylation (n = 124) and gene expression data (n = 297) before and after exposure to the glucocorticoid receptor agonist dexamethasone. Dexamethasone induced dynamic changes in methylation in 31.2 % (110/353) of these CpGs and transcription in 81.7 % (139/170) of genes neighboring epigenetic clock CpGs. Disease enrichment analysis of these dexamethasone-regulated genes showed enriched association for aging-related diseases, including coronary artery disease, arteriosclerosis, and leukemias.Cumulative lifetime stress may accelerate epigenetic aging, an effect that could be driven by glucocorticoid-induced epigenetic changes. These findings contribute to our understanding of mechanisms linking chronic stress with accelerated aging and heightened disease risk.

The efflux pump P-glycoprotein (P-gp), a gene product of the ABCB1 gene, plays a pivotal role in the transfer of various molecules across the blood–brain barrier. P-gp protects the brain by selectively extruding its substrates, including certain antidepressive drugs, thereby limiting their uptake into the brain. Uhr et al. [2008] first showed that ABCB1 variants predicted the remission to antidepressants with P-gp substrate properties in patients suffering from major depression (MD). Other studies investigating the influence of ABCB1 polymorphisms on antidepressant treatment response produced inconclusive results. In this meta-analysis, we systematically summarized 16 pharmacogenetic studies focused on the association of ABCB1 variants and antidepressant treatment outcome in patients with MD (overall n = 2695). We investigated the association of treatment outcome and six ABCB1 single nucleotide polymorphisms (SNPs): rs2032583, rs2235015, rs2235040, rs1045642, rs2032582, rs1128503. We stratified for admission status, ethnicity, and prescription of concomitant medication. SNP rs2032583 showed a nominally significant association across all studies (P = 0.035, SNP was studied in a total of 2,037 patients) and a significant Bonferroni-corrected association among inpatients (P = 1.5 × 10−05, n = 485). Also SNP rs2235015 was significantly associated with antidepressant treatment outcome withstanding Bonferroni correction (P = 3.0 × 10−04) among inpatients in a smaller subsample (n = 195). There were no significant associations of the other SNPs tested with antidepressant treatment outcome. Future pharmacogenetic association studies should focus on the role of the ABCB1 SNP rs2032583 in antidepressant outcome prediction. © 2015 Wiley Periodicals, Inc.

The aim of the study was to examine the modulating effects of coping style on the response to psychosocial stress in remitted major depression (MD) and healthy controls. Thirty-three participants with a lifetime history of MD, who were in remission, and 32 age- and gender-matched healthy controls were recruited from a longitudinal-epidemiological study, in which the presence or absence of mental disorders was prospectively ascertained. Participants (aged 30-41 years) underwent two consecutive Trier Social Stress Tests (TSSTs). Subjects with a lifetime history of MD showed larger plasma ACTH and cortisol concentrations in response to both TSSTs, confirming a disturbed hypothalamic-pituitary-adrenal (HPA) axis regulation. Moreover, the MD group reported less positive, adaptive coping strategies and more negative, maladaptive strategies than the control group. The amount of negative coping predicted the size of the plasma cortisol response in the combined group. Our results demonstrate the importance of psychological coping strategies for the investigation of HPA axis response in depression.

Background Traumatic experiences during childhood are considered a major risk factor for depression in adulthood. Childhood trauma may induce physiological dysregulation with long-term effects of increased allostatic load until adulthood, which may lead to depression. Thus, our aim was to investigate whether allostatic load – which represents a multi-system measure of physiological dysregulation – mediates the association between childhood trauma and adult depression. Methods The study sample consisted of 324 depressed inpatients participating in the Munich Antidepressant Response Signature (MARS) project and 261 mentally healthy control participants. The mediation analysis using a case-control approach included childhood trauma, i.e., physical and sexual abuse, as predictor variables and an allostatic load index comprised of 12 stress-related biomarkers as mediator. Age and sex were included as covariates. Results Mediation analyses revealed that the influence of physical abuse, but not sexual abuse, during childhood on depression in adulthood was mediated by allostatic load. This effect was moderated by age: particularly young (18–42 years) and middle-aged (43–54 years) adults with a history of physical abuse during childhood exhibited high allostatic load, which in turn was associated with increased rates of depression, but this was not the case for older participants (55–81 years). Conclusions Results support the theoretical assumption of allostatic load mediating the effect of physical abuse during childhood on depression in adulthood. This predominantly holds for younger participants, while depression in older participants was independent of physical abuse and allostatic load. The effect of sexual abuse on depression, however, was not mediated by allostatic load. Identifying allostatic load biomarkers prospectively in the developmental course of depression is an important target for future research.

Childhood trauma is one of the most well-established risk factors for the development of mental disorders. Due to the availability of new technologies, we are now beginning to understand how early trauma gets under the skin and exerts a sustained influence on various domains of psychological functioning and health. In the present review we will first briefly summarize what is currently known about the neurobiological effects of childhood trauma. We will then consider genetic and epigenetic factors as possible mechanisms mediating the biological embedding of childhood trauma. Der Zusammenhang zwischen frühen Traumatisierungen in der Kindheit und einem erhöhten psychischen Erkrankungsrisiko ist in der Fachliteratur seit Langem gut belegt. Erst in den letzten Jahren beginnen wir aufgrund technologischer Fortschritte zu verstehen, wie frühe Traumatisierungen körperlich niedergeschrieben werden und sich so ein Leben lang auf verschiedene Aspekte unseres Verhaltens und Erlebens auswirken können. In der vorliegenden Übersicht wird zunächst der aktuelle Erkenntnisstand zu den neurobiologischen Auswirkungen von Kindheitstraumata kurz zusammengefasst. Danach werden genetische und epigenetische Faktoren als mögliche Mechanismen der biologischen Einbettung betrachtet.

Information processing is a cognitive trait forming the basis of complex abilities like executive function. The Trail Making Test (TMT) is a well-established test of information processing with moderate to high heritability. Age of the individual also plays an important role. A number of genetic association studies with the TMT have been performed, which, however, did not consider age as a moderating factor. We report the results of genome-wide association studies (GWASs) on age-independent and age-dependent TMT performance in two population-representative community samples (Munich Antidepressant Response Signature, MARS: N1 = 540; Ludwig Maximilians University, LMU: N2 = 350). Age-dependent genome-wide findings were then evaluated in a third sample of healthy elderly subjects (Sydney Memory and Ageing Study, Sydney MAS: N3 = 448). While a meta-analysis on the GWAS findings did not reveal age-independent TMT associations withstanding correction for multiple testing, we found a genome-wide significant age-moderated effect between variants in the DSG1 gene region and TMT-A performance predominantly reflecting visual processing speed (rs2199301, Pmeta-analysis = 1.3 × 10−7). The direction of the interaction suggests for the minor allele a beneficial effect in younger adults turning into a detrimental effect in older adults. The detrimental effect of the missense single nucleotide polymorphism rs1426310 within the same DSG1 gene region could be replicated in Sydney MAS participants aged 70–79, but not in those aged 80 years and older, presumably a result of survivor bias. Our findings demonstrate opposing effects of DSG1 variants on information processing speed depending on age, which might be related to the complex processes that DSG1 is involved with, including cell adhesion and apoptosis.

Background: Neurosteroids are synthesized both in brain and peripheral steroidogenic tissue from cholesterol or steroidal precursors. Neurosteroids have been shown to be implicated in neural proliferation, differentiation, and activity. Preclinical and clinical studies also suggest a modulatory role of neurosteroids in anxiety-related phenotypes. However, little is known about the contribution of genetic variants in genes relevant for the neurosteroidogenesis to anxiety disorders. Methods: We performed an association analysis of single nucleotide polymorphisms (SNPs) in five genes related to the neurosteroidal pathway with emphasis on progesterone and allopregnanolone biosynthesis (steroid-5-alpha-reductase 1A (SRD5A1), aldo-keto reductase family 1 C1-C3 (AKR1C1-AKR1C3) and translocator protein 18 kDA (TSPO) with panic disorder (PD) and dimensional anxietyintwoGermanPDsamples(casesN =522,controlsN =1,115).Results: Case–control analysis for PD and SNPs in the five selected genes was negative

Leptin, a peptide hormone from adipose tissue and key player in weight regulation, has been suggested to be involved in sleep and cognition and to exert antidepressant-like effects, presumably via its action on the HPA-axis and hippocampal function. This led us to investigate whether genetic variants in the leptin gene, the level of leptin mRNA-expression and leptin serum concentrations are associated with response to antidepressant treatment. Our sample consisted of inpatients from the Munich Antidepressant Response Signature (MARS) project with weekly Hamilton Depression ratings, divided into two subsamples. In the exploratory sample (n=251) 17 single nucleotide polymorphisms (SNPs) covering the leptin gene region were genotyped. We found significant associations of several SNPs with impaired antidepressant treatment outcome and impaired cognitive performance after correction for multiple testing. The SNP (rs10487506) showing the highest association with treatment response (p=3.9×10(-5)) was analyzed in the replication sample (n=358) and the association could be verified (p=0.021) with response to tricyclic antidepressants. In an additional meta-analysis combining results from the MARS study with data from the Genome-based Therapeutic Drugs for Depression (GENDEP) and the Sequenced Treatment Alternatives to Relieve Depression (STAR(⁎)D) studies, nominal associations of several polymorphisms in the upstream vicinity of rs10487506 with treatment outcome were detected (p=0.001). In addition, we determined leptin mRNA expression in lymphocytes and leptin serum levels in subsamples of the MARS study. Unfavorable treatment outcome was accompanied with decreased leptin mRNA and leptin serum levels. Our results suggest an involvement of leptin in antidepressant action and cognitive function in depression with genetic polymorphisms in the leptin gene, decreased leptin gene expression and leptin deficiency in serum being risk factors for resistance to antidepressant therapy in depressed patients.

The FK506 binding protein 51 or FKBP5 has been implicated in the regulation of glucocorticoid receptor (GR) sensitivity, and genetic variants in this gene have been associated with mood and anxiety disorders. GR resistance and associated stress hormone dysregulation are among the most robust biological findings in major depression, the extent of which may be moderated by FKBP5 polymorphisms. FKBP5 mRNA expression in peripheral blood cells (baseline and following in vivo GR stimulation with 1.5 mg dexamethasone p.o.) was analyzed together with plasma cortisol, ACTH, dexamethasone levels and the FKBP5 polymorphism rs1360780 in 68 depressed patients and 87 healthy controls. We observed a significant (P = 0.02) interaction between disease status and FKBP5 risk allele carrier status (minor allele T) on GR-stimulated FKBP5 mRNA expression. Patients carrying the risk T allele, but not the CC genotype, showed a reduced induction of FKBP5 mRNA. This FKBP5 polymorphism by disease status interaction was paralleled by the extent of plasma cortisol and ACTH suppression following dexamethasone administration, with a reduced suppression only observed in depressed patients carrying the T allele. Only depressed patients carrying the FKBP5 rs1360780 risk allele showed significant GR resistance compared with healthy controls, as measured by dexamethasone-induced FKBP5 mRNA induction in peripheral blood cells and suppression of plasma cortisol and ACTH concentrations. This finding suggests that endocrine alterations in depressed patients are determined by genetic variants and may allow identification of specific subgroups.

The binding protein FKBP5 is an important modulator of the function of the glucocorticoid receptor, the main receptor of the stress hormone system. This turns the FKBP5 gene into a key candidate for gene-environment interactions, which are considered critical for pathogenesis of stress-related disorders. The authors explored gene-environment interactions between FKBP5 gene variants and adverse life events in predicting the first occurrence of a major depressive episode.The analyses were based on 884 Caucasians in a 10-year prospective community study. At baseline, they were 14-24 years old and did not fulfill criteria for a major depressive episode. The DSM-IV-based Munich Composite International Diagnostic Interview was used to assess adverse life events preceding baseline and major depressive episodes during follow-up. On the basis of previous findings, five single-nucleotide polymorphisms (SNPs) within the FKBP5 gene were selected for genotyping.While the authors did not observe genetic main effects, they found interactions between the five SNPs and traumatic (but not separation) events, with the strongest effect for severe trauma. The effect of trauma on incident major depressive episodes was evident among subjects homozygous for the minor alleles but not subjects with other genotypes. The findings were replicated in the U.K. Environmental Risk Longitudinal Twin Study.These hypothesis-driven results suggest that an interaction between FKBP5 genotype and trauma is involved in the onset of depression. Subjects homozygous for the minor alleles of the investigated FKBP5 SNPs seem to be particularly sensitive to effects of trauma exposure in terms of triggering depression onset.

Klengel T, Heck A, Pfister H, Bruckl T, Hennings JM, Menke A, Czamara D, Muller-Myhsok B, Ising M. Somatization in major depression - clinical features and genetic associations. Objective: To identify clinical variables and genetic variations within monoaminergic genes known to be implicated in pain perception that are associated with the occurrence of somatization symptoms in patients with major depression. Method: Somatization was evaluated using the respective subscale of the Symptom Checklist SCL-90-R. Six monoaminergic genes were identified showing an involvement in pain perception and somatization according to the literature: COMT, HTR2A, SLC6A2, SLC6A4, DRD4, and TPH1. One hundred and eighteen single nucleotide polymorphisms (SNPs) within these genes were genotyped using Illumina BeadChips in a sample of 398 at least moderately to severely depressed in-patients participating in the Munich Antidepressant Response Signature (MARS) project. Results: Thirty SNPs exhibit nominally significant associations with somatization. One SNP (rs9534505) located in intron 2 of the HTR2A gene withstood correction for multiple testing. Clinical data provide further evidence for strong impact of somatization on the presentation of depressive symptoms and description of a patient subgroup with unfavorable clinical outcome. Conclusion: Our results demonstrate the influence of a HTR2A polymorphism on aspects of somatization in major depression, which co-occurs with an unfavorable antidepressant treatment outcome. These results confirm and expand previous findings on somatization as a risk factor for treatment outcome in major depression.

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.

In a recent paper, a new type of graph to visualize the results from graphical models was proposed. Association chain graphs (ACGs) provide a richer visualization than conventional graphs (directed acyclic and recursive regression graphs) if the data can be described with only a small number of parameters. ACGs display not only which associations reach statistical significance, but also the magnitude of associations (confidence intervals for statistical main effects) as the contrast color to the background color of the graph. In this paper, the ACG visualization is extended especially for the case where all variables are binary by illustrating their relative frequencies. This shows the degrees of associations not only on the individual (as expressed by odds ratios or other indexes of association) but also on the community level. We applied the approach to an extensive example of birth and childhood factors for the onset of affective mental disorders using data from the EDSP (Early Developmental Stages of Psychopathology) Study.

P-glycoprotein, encoded by the ABCB1 gene, functions as an ATP-driven efflux pump in the blood-brain barrier, extruding its substrates and thereby limiting their passage into the brain. ABCB1 polymorphisms predicted antidepressant drug response: Minor allele carriers of SNPs rs2032583 and rs2235015 had higher remission rates than major allele homozygotes. The aim of the current study was to evaluate an ABCB1 genotype-dependent efficacy of a quick dose escalation strategy. Depressed inpatients (n = 73) treated with antidepressants that are P-glycoprotein substrates were randomly assigned to a standard or high dose condition for 28 days. HAM-D scores, adverse effects and plasma antidepressant concentration were measured weekly and tested among two intronic SNPs rs2032583 and rs2235015. A treatment as usual control sample (n = 128) was retrospectively matched to the study group by gender, age, and diagnosis. There was a significant interaction of genotype x plasma antidepressant concentration: Minor allele carriers of rs2032583 [F(1,65) = 7.221, p = 0.009] and rs2235015 [F(1,65) = 4.939, p = 0.030] whose plasma drug concentration were within recommended range had a greater symptom reduction at study endpoint which exceeded the therapeutic benefit of the treatment as usual group [for rs2032583: F(1,163) = 4.366, p = 0.038]. Minor allele carriers of rs2032583 with high plasma drug levels had more sleep-related side effects than major allele homozygotes with high plasma drug levels. The treatment of MDD can be optimized by ABCB1 genotyping combined with monitoring of plasma drug concentrations: For minor allele carriers of rs2032583 and rs2235015, plasma antidepressant levels should not exceed the recommended range in order to obtain optimal treatment outcome.

The P2RX7 gene is located within a region on chromosome 12q24.31 that has been identified as a susceptibility locus for affective disorders by linkage and association studies. P2RX7 is a purinergic ATP-binding calcium channel expressed in neurons as well as in microglial cells in various brain regions. We investigated 29 single nucleotide polymorphisms (SNPs) within the P2RX7 gene and adjacent genes in a sample of 1000 German Caucasian patients suffering from recurrent major depressive disorder (MDD). These were contrasted with diagnosed healthy Caucasian controls from the same population (n=1029). A non-synonymous coding SNP in the P2RX7 gene (rs2230912), previously found to be associated with bipolar disorder, was significantly associated (P=0.0019) with MDD. This polymorphism results in an amino acid exchange in the C-terminal cytosolic domain of the P2RX7 channel protein, suggesting that the observed P2RX7 polymorphism might play a causal role in the development of depression.

The “Early Developmental Stages of Psychopathology (EDSP)” study is a prospective-longitudinal study program in a community sample (Munich, Germany) of adolescents and young adults. The program was launched in 1994 to study the prevalence and incidence of psychopathological syndromes and mental disorders, to describe the natural course and to identify vulnerability and risk factors for onset and progression as well as psychosocial consequences. This paper reviews methods and core outcomes of this study program. The EDSP is based on an age-stratified random community sample of originally N = 3021 subjects aged 14–24 years at baseline, followed up over 10 years with up to 3 follow-up waves. The program includes a family genetic supplement and nested cohorts with lab assessments including blood samples for genetic analyses. Psychopathology was assessed with the DSM-IV/M-CIDI; embedded dimensional scales and instruments assessed vulnerability and risk factors. Beyond the provision of age-specific prevalence and incidence rates for a wide range of mental disorders, analyses of their patterns of onset, course and interrelationships, the program identified common and diagnosis-specific distal and proximal vulnerability and risk factors including critical interactions. The EDSP study advanced our knowledge on the developmental pathways and trajectories, symptom progression and unfolding of disorder comorbidity, highlighting the dynamic nature of many disorders and their determinants. The results have been instrumental for defining more appropriate diagnostic thresholds, led to the derivation of symptom progression models and were helpful to identify promising targets for prevention and intervention.

When assessing the association between a factor X and a subsequent outcome Y in observational studies, the question that arises is what are the variables to adjust for to reduce bias due to confounding for causal inference on the effect of X on Y. Disregarding such factors is often a source of overestimation because these variables may affect both X and Y. On the other hand, adjustment for such variables can also be a source of underestimation because such variables may be the causal consequence of X and part of the mechanism that leads from X to Y.In this paper, we present a simple method to compute control variables in the presence of age at onset data on both X and a set of other variables. Using these age at onset data, control variables are computed that adjust only for conditions that occur prior to X. This strategy can be used in prospective as well as in survival analysis. Our method is motivated by an argument based on the counterfactual model of a causal effect.The procedure is exemplified by examining of the relation between panic attack and the subsequent incidence of MDD.The results reveal that the adjustment for all other variables, irrespective of their temporal relation to X, can yield a false negative result (despite unconsidered confounders and other sources of bias).

BackgroundThe gene product of the ABCB1 gene, the P-glycoprotein, functions as a custodian molecule in the blood–brain barrier and regulates the access of most antidepressants into the brain. Previous studies showed that ABCB1 polymorphisms predicted the response to antidepressants that are substrates of the P-gp, while the response to nonsubstrates was not influenced by ABCB1 polymorphisms. The aim of the present study was to evaluate the clinical application of ABCB1 genotyping in antidepressant pharmacotherapy.MethodsData came from 58 depressed inpatients participating in the Munich Antidepressant Response Signature (MARS) project, whose ABCB1 gene test results were implemented into the clinical decision making process. Hamilton Depression Rating Scale (HAM-D) scores, remission rates, and duration of hospital stay were documented with dose and kind of antidepressant treatment.ResultsPatients who received ABCB1 genotyping had higher remission rates [χ2(1) = 6.596,p= 0.005, 1-sided] and lower Hamilton sores [t(111) = 2.091,p= 0.0195, 1-sided] at the time of discharge from hospital as compared to patients without ABCB1 testing. Among major allele homozygotes for ABCB1 single nucleotide polymorphisms (SNPs) rs2032583 and rs2235015 (TT/GG genotype), an increase in dose was associated with a shorter duration of hospital stay [rho(28) = –0.441,p= 0.009, 1-sided], whereas other treatment strategies (eg, switching to a nonsubstrate) showed no significant associations with better treatment outcome.DiscussionThe implementation of ABCB1 genotyping as a diagnostic tool influenced clinical decisions and led to an improvement of treatment outcome. Patients carrying the TT/GG genotype seemed to benefit from an increase in P-gp substrate dose.ConclusionResults suggest that antidepressant treatment of depression can be optimized by the clinical application of ABCB1 genotyping.

BackgroundData from clinical studies and results from animal models suggest an involvement of the neurotrophin system in the pathology of depression and antidepressant treatment response. Genetic variations within the genes coding for the brain-derived neurotrophic factor (BDNF) and its key receptor Trkb (NTRK2) may therefore influence the response to antidepressant treatment.MethodsWe performed a single and multi-marker association study with antidepressant treatment outcome in 398 depressed Caucasian inpatients participating in the Munich Antidepressant Response Signature (MARS) project. Two Caucasian replication samples (N = 249 and N = 247) were investigated, resulting in a total number of 894 patients. 18 tagging SNPs in the BDNF gene region and 64 tagging SNPs in the NTRK2 gene region were genotyped in the discovery sample; 16 nominally associated SNPs were tested in two replication samples.ResultsIn the discovery analysis, 7 BDNF SNPs and 9 NTRK2 SNPs were nominally associated with treatment response. Three NTRK2 SNPs (rs10868223, rs1659412 and rs11140778) also showed associations in at least one replication sample and in the combined sample with the same direction of effects (Pcorr = .018, Pcorr = .015 and Pcorr = .004, respectively). We observed an across-gene BDNF-NTRK2 SNP interaction for rs4923468 and rs1387926. No robust interaction of associated SNPs was found in an analysis of BDNF serum protein levels as a predictor for treatment outcome in a subset of 93 patients.Conclusions/limitationsAlthough not all associations in the discovery analysis could be unambiguously replicated, the findings of the present study identified single nucleotide variations in the BDNF and NTRK2 genes that might be involved in antidepressant treatment outcome and that have not been previously reported in this context. These new variants need further validation in future association studies.

Aims: The co-chaperone FKBP5 of hsp-90 is an important modulator of glucocorticoid receptor function. Associations between SNPs in the FKBP5 gene and a faster antidepressant treatment response and an increased recurrence of depressive episodes were shown by us previously. Since stressful life events also contribute to depression via effects on HPA axis, FKBP5 could be involved in gene-environment processes. Aim: To explore interaction and correlation effects between variations in the FKBP5 gene and adverse events in predicting the first onset of a major depressive episode (MDE) in a ten-years prospective-longitudinal community survey. Methods: Analyses are based on 884 caucasians without baseline MDE who participated during the whole study period. Data were assessed with the M-CIDI according to DSM-IV. Five SNPs within the FKBP5 gene were selected for genotyping. Results: Whereas no genetic main effects were observed, the effect of trauma on incident MDE was clearly evident only among subjects homozygous for the minor alleles, but not among subjects with the other genotypes. There was an interaction between the five SNPs and traumatic (but not separation) events with the strongest effect for severe trauma (min pcorrected>0.0000001). Variants in the five FKBP5 SNPs were not associated with any adverse event category. Conclusions: These hypothesis-generating results support a potential gene-trauma interaction for the first onset of depression.

Background Psychological stress is associated with accelerated cellular aging and increased risk for aging-related diseases, but the underlying molecular mechanisms are unclear. Methods We examined the effect of stress on a DNA methylation age predictor that was shown to correlate strongly with chronological age across human tissues (Horvath 2013). Genome-wide DNA methylation was measured in peripheral blood using the 450K Illumina array in three independent cohorts: the Grady Trauma Project/GTP (N=366); a panic disorder case/control sample recruited at the Max Planck Institute of Psychiatry/MPI-P (N=318); and the Conte Center for the Psychobiology of Early-Life Trauma/Conte (N=42). Age acceleration was calculated by subtracting chronological age from age predicted by DNA methylation. Psychiatric symptomatology and stressors were assessed using standard questionnaires. Results DNA methylation age strongly correlated with chronological age in all samples (r=0.9, p=2.5x10 -133 ). Cumulative lifetime stress but not childhood or current stress predicted age acceleration in GTP (p=0.012) and MPI-P (p=0.021). Moreover, epigenetic age acceleration predicted depression (GTP: p=0.002; Conte: p=0.014) and panic disorder (p=0.007). In secondary analyses, we examined the effect of lifetime stress on individual CpGs of the DNA methylation age predictor. After correcting for multiple comparisons, we identified in both GTP and MPI-P a stress-regulated CpG near MCAM , a gene implicated in aging-related diseases, including cardiovascular disease and cancers. Conclusions Cumulative lifetime stress, but not childhood or current stress, and psychiatric phenotypes are associated with accelerated epigenetic aging. Our findings may explain the accelerated cellular aging and increased disease risk associated with chronic stress and psychiatric disorders.

BACKGROUND: Polymorphisms in the FK506 binding protein 5 (FKBP5) gene have been shown to influence glucocorticoid receptor sensitivity, stress response regulation, and depression risk in traumatized subjects, with most consistent findings reported for the functional variant rs1360780. In the present study, we investigated whether the FKBP5 polymorphism rs1360780 and lifetime history of major depression are associated with DNA methylation and FKBP5 gene expression after psychosocial stress. METHODS: A total of 116 individuals with a positive (n = 61) and negative (n = 55) lifetime history of major depression participated in the Trier Social Stress Test. We assessed plasma cortisol concentrations, FKBP5 mRNA expression, and CpG methylation of FKBP5 intron 7 in peripheral blood cells. RESULTS: Genotype-dependent plasma cortisol response to psychosocial stress exposure was observed in healthy controls, with the highest and longest-lasting cortisol increase in subjects with the TT genotype of the FKBP5 polymorphism rs1360780, and healthy controls carrying the T risk allele responded with a blunted FKBP5 mRNA expression after psychosocial stress. No genotype effects could be found in remitted depression. CONCLUSIONS: The FKBP5 rs1360780 polymorphism is associated with plasma cortisol and FKBP5 mRNA expression after psychosocial stress in healthy controls but not in remitted depression. Preliminary results of the DNA methylation analysis suggest that epigenetic modifications could be involved.

The stress hormone-regulating hypothalamic-pituitary-adrenal (HPA) axis has been implicated in the causality as well as the treatment of depression. To investigate a possible association between genes regulating the HPA axis and response to antidepressants and susceptibility for depression, we genotyped single-nucleotide polymorphisms in eight of these genes in depressed individuals and matched controls. We found significant associations of response to antidepressants and the recurrence of depressive episodes with single-nucleotide polymorphisms in FKBP5, a glucocorticoid receptor-regulating cochaperone of hsp-90, in two independent samples. These single-nucleotide polymorphisms were also associated with increased intracellular FKBP5 protein expression, which triggers adaptive changes in glucocorticoid receptor and, thereby, HPA-axis regulation. Individuals carrying the associated genotypes had less HPA-axis hyperactivity during the depressive episode. We propose that the FKBP5 variant-dependent alterations in HPA-axis regulation could be related to the faster response to antidepressant drug treatment and the increased recurrence of depressive episodes observed in this subgroup of depressed individuals. These findings support a central role of genes regulating the HPA axis in the causality of depression and the mechanism of action of antidepressant drugs.