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There is no multi-country/multi-language study testing a-priori multivariable associations between non-modifiable/modifiable factors and validated wellbeing/multidimensional mental health outcomes before/during the COVID-19 pandemic. Moreover, studies during COVID-19 pandemic generally do not report on representative/weighted non-probability samples. The Collaborative Outcomes study on Health and Functioning during Infection Times (COH-FIT) is a multi-country/multi-language survey conducting multivariable/LASSO-regularized regression models and network analyses to identify modifiable/non-modifiable factors associated with wellbeing (WHO-5)/composite psychopathology (P-score) change. It enrolled general population-representative/weighted-non-probability samples (26/04/2020-19/06/2022). Participants included 121,066 adults (age=42±15.9 years, females=64 %, representative sample=29 %) WHO-5/P-score worsened (SMD=0.53/SMD=0.74), especially initially during the pandemic. We identified 15 modifiable/nine non-modifiable risk and 13 modifiable/three non-modifiable protective factors for WHO-5, 16 modifiable/11 non-modifiable risk and 10 modifiable/six non-modifiable protective factors for P-score. The 12 shared risk/protective factors with highest centrality (network-analysis) were, for non-modifiable factors, country income, ethnicity, age, gender, education, mental disorder history, COVID-19-related restrictions, urbanicity, physical disorder history, household room numbers and green space, and socioeconomic status. For modifiable factors, we identified medications, learning, internet, pet-ownership, working and religion as coping strategies, plus pre-pandemic levels of stress, fear, TV, social media or reading time, and COVID-19 information. In multivariable models, for WHO-5, additional non-modifiable factors with |B|>1 were income loss, COVID-19 deaths. For modifiable factors we identified pre-pandemic levels of social functioning, hobbies, frustration and loneliness, and social interactions as coping strategy. For P-scores, additional non-modifiable/modifiable factors were income loss, pre-pandemic infection fear, and social interactions as coping strategy. COH-FIT identified vulnerable sub-populations and actionable individual/environmental factors to protect well-being/mental health during crisis times. Results inform public health policies, and clinical practice., Competing Interests: Conflict of interest Conflict of interest statements of all authors are detailed in eTable 12., (Copyright © 2024. Published by Elsevier B.V.)

About two-thirds of patients with major depressive disorder (MDD) fail to achieve symptom remission after the initial antidepressant treatment. Despite a role of genetic factors was proven, the specific underpinnings are not fully understood yet. Polygenic risk scores (PRSs), which summarise the additive effect of multiple risk variants across the genome, might provide insights into the underlying genetics. This study aims to investigate the possible association of PRSs for bipolar disorder, MDD, neuroticism, and schizophrenia (SCZ) with antidepressant non-response or non-remission in patients with MDD. PRSs were calculated at eight genome-wide P-thresholds based on publicly available summary statistics of the largest genome-wide association studies. Logistic regressions were performed between PRSs and non-response or non-remission in six European clinical samples, adjusting for age, sex, baseline symptom severity, recruitment sites, and population stratification. Results were meta-analysed across samples, including up to 3,637 individuals. Bonferroni correction was applied. In the meta-analysis, no result was significant after Bonferroni correction. The top result was found for MDD-PRS and non-remission (p = 0.004), with patients in the highest vs. lowest PRS quintile being more likely not to achieve remission (OR=1.5, 95% CI=1.11-1.98, p = 0.007). Nominal associations were also found between MDD-PRS and non-response (p = 0.013), as well as between SCZ-PRS and non-remission (p = 0.035). Although PRSs are still not able to predict non-response or non-remission, our results are in line with previous works; methodological improvements in PRSs calculation may improve their predictive performance and have a meaningful role in precision psychiatry., Competing Interests: Conflicts of Interest B.T. Baune: Advisory Board - Lundbeck, Janssen-Cilag; Consultant - National Health and Medical Research Council, Australia; Grant/Research Support - AstraZeneca, Fay Fuller Foundation, James & Diana Ramsay Foundation, National Health and Medical Research Council, Australia, German Research Council (DFG), Sanofi, Lundbeck; Honoraria - AstraZeneca, Bristol-Myers Squibb, Lundbeck, Pfizer, Servier Laboratories, Wyeth Pharmaceuticals, Takeda, Janssen, LivaNova PLC. K. Domschke is a member of the Steering Committee Neurosciences, Janssen Pharmaceuticals, Inc. P. Ferentinos received grants/research support, consulting fees and/or honoraria within the last three years from Angelini, Boehringer-Ingelheim, Janssen, Medochemie, Vianex, and Servier. S. Kasper received grants/research support, consulting fees and/or honoraria within the last three years from Angelini, AOP Orphan Pharmaceuticals AG, AstraZeneca, Eli Lilly, Janssen, KRKA-Pharma, Lundbeck, Neuraxpharm, Pfizer, Pierre Fabre, Schwabe, and Servier. E. Maron has received grant/research support from Lundbeck, Janssen, Sanofi and GlaxoSmithKline. S. Mendlewicz is a member of the board of the Lundbeck International Neuroscience Foundation and of the advisory board of Servier. S. Montgomery has been a consultant or served on advisory boards for Lundbeck. A. Serretti is or has been a consultant/speaker for Abbott, Abbvie, Angelini, AstraZeneca, Clinical Data, Boehringer, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Innovapharma, Italfarmaco, Janssen, Lundbeck, Naurex, Pfizer, Polifarma, Sanofi, and Servier. D. Souery has received grant/research support from GlaxoSmithKline and Lundbeck, and he has served as a consultant or on advisory boards for AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen, and Lundbeck. J. Zohar has received grant/research support from Lundbeck, Servier, and Pfizer; he has served as a consultant on the advisory boards for Servier, Pfizer, Solvay, and Actelion; and he has served on speakers’ bureaus for Lundbeck, GSK, Jazz, and Solvay. The other authors declare no conflict of interest., (Copyright © 2021 Elsevier B.V. and ECNP. All rights reserved.)

The global public health crisis caused by COVID-19 has lasted longer than many of us would have hoped and expected. With its high uncertainty and limited control, the COVID-19 pandemic has undoubtedly asked a lot from all of us. One important central question is: how resilient have we proved in face of the unprecedented and prolonged coronavirus pandemic? There is a vast and rapidly growing literature that has examined the impact of the pandemic on mental health both on the shorter (2020) and longer (2021) term. This not only concerns pandemic-related effects on resilience in the general population, but also how the pandemic has challenged stress resilience and mental health outcomes across more specific vulnerable population groups: patients with a psychiatric disorder, COVID-19 diagnosed patients, health care workers, children and adolescents, pregnant women, and elderly people. It is challenging to keep up to date with, and interpret, this rapidly increasing scientific literature. In this review, we provide a critical overview on how the COVID-19 pandemic has impacted mental health and how human stress resilience has been shaped by the pandemic on the shorter and longer term. The vast literature is dominated by a wealth of data which are, however, not always of the highest quality and heavily depend on online and self-report surveys. Nevertheless, it appears that we have proven surprisingly resilient over time, with fast recovery from COVID-19 measures. Still, vulnerable groups such as adolescents and health care personnel that have been severely impacted by the COVID-19 pandemic do exist. Large interindividual differences exist, and for future pandemics there is a clear need to comprehensively and integratively assess resilience from the start to provide personalized help and interventions tailored to the specific needs for vulnerable groups., Competing Interests: Conflicts of Interest There are no conflicts of interest, (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Given the high prevalence and considerable clinical and societal burden of anxiety disorders, preventive measures are urgently warranted to reduce their incidence and overall healthcare impact. Anxiety sensitivity (AS) - a key element in learning theories of anxiety disorders in the context of interoceptive conditioning - constitutes a malleable risk factor of particularly panic disorder and separation anxiety, which share developmental, nosological, epidemiological and pathomechanistic characteristics. The computer-assisted 'Cognitive Anxiety Sensitivity Treatment' (CAST) targeting interoceptive anxiety symptoms (cf. Schmidt et al., 2014) was translated, intensified and culturally adapted to German and evaluated in a sample of 105 healthy adult volunteers with elevated AS (mean ASI-3: 29.5) applying a randomized design. Success of the intervention was measured as a function of AS and separation anxiety (ASA-27) ∼6 weeks (T1) and ∼6 months (T2) after the intervention. As compared to waitlist, CAST resulted in a significant reduction of AS at both T1 and T2. Separation anxiety was not directly reduced by the intervention, but decreased mediated by a decline in AS. A composite interoceptive score capturing changes in sensitivity to respiratory symptoms during the baseline therapist-accompanied CAST session was shown to be predictive of overall response at T1. In sum, CAST-German Version was successfully established as an effective intervention reducing AS, while at the same time indirectly decreasing separation anxiety. A composite interoceptive score predicting treatment response might aid in further delineating risk markers informing targeted preventive interventions for anxiety disorders., Competing Interests: Declaration of Competing Interest KD is a member of the Janssen Pharmaceuticals, Inc. Steering Committee Neurosciences. All other authors declare that they have no potential conflicts of interest., (Copyright © 2021. Published by Elsevier B.V.)

Competing Interests: Declaration of Competing Interest KD is a member of the ‘Steering Committee Neurosciences’, Janssen Pharmaceuticals, Inc.

There is a recurring debate on the role of the serotonin transporter gene linked polymorphic region (5-HTTLPR) in the moderation of response to cognitive behavioral therapy (CBT) in anxiety disorders. Results, however, are still inconclusive. We here aim to perform a meta-analysis on the role of 5-HTTLPR in the moderation of CBT outcome in anxiety disorders. We investigated both categorical (symptom reduction of at least 50%) and dimensional outcomes from baseline to post-treatment and follow-up. Original data were obtained from ten independent samples (including three unpublished samples) with a total of 2,195 patients with primary anxiety disorder. No significant effects of 5-HTTLPR genotype on categorical or dimensional outcomes at post and follow-up were detected. We conclude that current evidence does not support the hypothesis of 5-HTTLPR as a moderator of treatment outcome for CBT in anxiety disorders. Future research should address whether other factors such as long-term changes or epigenetic processes may explain further variance in these complex gene-environment interactions and molecular-genetic pathways that may confer behavioral change following psychotherapy., Competing Interests: Conflict of Interest AR reports speaker honoraria and advisory board honoraria from Janssen, Servier, Medice, Shire and neuraxpharm. VA has received compensations for his contributions as member of advisory boards and for presentations for the following companies: Astra-Zeneca, Eli Lilly, Janssen-Cilag, Lundbeck, Otsuka, Sanofi, Servier, and Trommsdorff. TCE is part funded by a program grant from the UK Medical Research Council (MR/M021475/1), and the National Institute for Health Research (NIHR) Biomedical Research center at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. PP reports having received research funding from Volkswagenstiftung (A124277) and that he is shareholder of a commercial company (VTplus) that develops virtual reality research systems. KD is a member of the Janssen Pharmaceuticals, Inc. Steering Committee Neurosciences. All other authors reported no biomedical financial interests or potential conflicts of interest., (Copyright © 2021. Published by Elsevier B.V.)

A polymorphism in the gene encoding the serotonin (5-HT) transporter (5-HTT) has been shown to moderate the response to CO 2 inhalation, an experimental model for panic attacks (PAs). Recurrent, unpredictable PAs represent, together with anticipatory anxiety of recurring attacks, the core feature of panic disorder (PD) and significantly interfere with patients' daily life. In addition to genetic components, accumulating evidence suggests that epigenetic mechanisms, which regulate gene expression by modifying chromatin structure, also play a fundamental role in the etiology of mental disorders. However, in PD, epigenetic mechanisms have barely been examined to date. In the present study, we investigated the relationship between methylation at the regulatory region of the gene encoding the 5-HTT and the reactivity to a 35% CO 2 inhalation in PD patients. We focused on four specific CpG sites and found a significant association between the methylation level of one of these CpG sites and the fear response. This suggests that the emotional response to CO 2 inhalation might be moderated by an epigenetic mechanism, and underlines the implication of the 5-HT system in PAs. Future studies are needed to further investigate epigenetic alterations in PD and their functional consequences. These insights can increase our understanding of the underlying pathophysiology and support the development of new treatment strategies., (Copyright © 2020. Published by Elsevier B.V.)

The epidemic of the 2019 novel coronavirus SARS-CoV-2, causing the coronavirus disease 2019 (COVID-19) is a global public health emergency with multifaceted severe consequences for people's lives and their mental health. In this article, as members of the European College of Neuropsychopharmacology (ECNP) Resilience, we will discuss the urgent need for a focus on resilience during the current coronavirus pandemic. Resilience is pivotal to cope with stress and vital to stay in balance. We will discuss the importance of resilience at the individual and societal level, but also the implication for patients with a psychiatric condition and health care workers. We not only advocate for an increased focus on mental health during the coronavirus pandemic but also highlight the urgent need of augmenting our focus on resilience and on strategies to enhance it., (Copyright © 2020. Published by Elsevier B.V.)

In the DSM-5, separation anxiety disorder (SAD) is newly classified in the chapter on anxiety, renewing research efforts into its etiology. In this narrative review, we summarize the current literature on the genetic, endocrine, physiological, neural and neuropsychological underpinnings of SAD per se, SAD in the context of panic disorder, separation anxiety symptoms, and related intermediate phenotypes. SAD aggregates in families and has a heritability of ~43%. Variants in the oxytocin receptor, serotonin transporter, opioid receptor µ1, dopamine D4 receptor and translocator protein genes have all been associated with SAD. Dysregulation of the hypothalamus-pituitary-adrenal axis, dysfunctional cortico-limbic interaction and biased cognitive processing seem to constitute further neurobiological markers of separation anxiety. Hypersensitivity to carbon dioxide appears to be an endophenotype shared by SAD, panic disorder and anxiety sensitivity. The identification of biological risk markers and its multi-level integration hold great promise regarding the prediction of SAD risk, maintenance and course, and in the future may allow for the selection of indicated preventive and innovative, personalized therapeutic interventions., Competing Interests: Conflict of Interest DSB is a Medical Patron and Anxiety UK and Clinical Advisor to the UK National Clinical Audit of Anxiety and Depression. KD is a member of the Janssen Pharmaceuticals, Inc. Steering Committee Neurosciences. All other authors declare that they have no potential conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

Prevention is the most promising way to reduce the high personal, familial, societal, clinical and economic costs of mental disorders in Europe and worldwide. A complementary approach is to go beyond the prevention of mental ill health, to promote good mental health. This manuscript highlights the first European consortium fostering cutting-edge multidisciplinary research in these two areas. The ECNP-funded Network on the Prevention of Mental Disorders and Mental Health Promotion (ECNP PMD-MHP) brings together European sites of excellence with different expertise for translational research collaboration, including partnerships with the industry. The ECNP PMD-MHP Network adopts a transdiagnostic, lifespan, clinical staging model which cuts across different mental disorders and different methodologies. The main aims of the ECNP PMD-MHP Network are to facilitate multidisciplinary collaboration, enhance knowledge and data sharing, standardise core assessment and outcome measures, promote clinical research, apply for grant funding, and generate research reports. By supporting collaborative research, the ECNP PMD-MHP Network will be vital for fostering European psychiatry in the field of prevention of mental disorders and promotion of good mental health., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)

Panic disorder (PD) is frequently comorbid with major depressive disorder (MDD), which has been associated with impaired treatment response and recovery rates. Alterations in the serotonergic system may play a crucial role in the pathogenesis of PD and MDD and might constitute a shared biological trunk of both disorders. Epigenetic patterns such as hypermethylation of the serotonin transporter gene (SLC6A4) have been associated with various mental disorders including MDD, but, to date, no association with PD has been reported. In the present study, SLC6A4 promoter methylation was investigated in two independent samples of PD patients in a case-control design (sample 1: N = 120; sample 2: N = 118), while - given the reported high comorbidity of both disorders - taking into account the effect of comorbid MDD. The functional relevance of altered SLC6A4 promoter methylation was investigated by means of luciferase-based reporter gene assays. SLC6A4 promoter hypermethylation in PD patients relative to healthy controls was driven by comorbid diagnosis of MDD (p = 9 × 10 -6 ), whereas no altered methylation levels were observed in patients without comorbid MDD. This held true not only in comparison to healthy controls, but also in direct comparison between PD patients with and without comorbid MDD (p = .009). Functional analyses revealed increased methylation of the investigated region to confer decreased reporter gene activity. The present results suggest functionally relevant SLC6A4 promoter hypermethylation as a possibly specific epigenetic marker of MDD, but not of PD itself, and thus might constitute a selective biomarker informing differential diagnosis based on individual epigenetic profiles., (Copyright © 2019 Elsevier B.V. and ECNP. All rights reserved.)

The corticotropin releasing hormone receptor 1 (CRHR1) is crucially involved in the hypothalamic-pituitary-adrenal axis and thus a major regulator of the stress response. CRHR1 gene variation is associated with several mental disorders including anxiety disorders. Studies in rodents have demonstrated epigenetic regulation of CRHR1 gene expression to moderate response to stressful environment. In the present study, we investigated CRHR1 promoter methylation for the first time regarding its role in panic disorder applying a case-control approach (N=131 patients, N=131 controls). In an independent sample of healthy volunteers (N=255), CRHR1 methylation was additionally analyzed for association with the Beck Anxiety Inventory (BAI) score as a dimensional panic-related intermediate phenotype. The functional relevance of altered CRHR1 promoter methylation was investigated by means of luciferase-based reporter gene assays. In panic disorder patients, a significantly decreased CRHR1 methylation was discerned (p<0.001). Accordingly, healthy controls with high BAI scores showed significantly decreased CRHR1 methylation. Functional analyses revealed an increased gene expression in presence of unmethylated as compared to methylated pCpGl&#95;CRHR1 reporter gene vectors. The present study identified a potential role of CRHR1 hypomethylation - conferring increased CRHR1 expression - in panic disorder and a related dimensional intermediate phenotype. This up-regulation of CRHR1 gene expression driven by de-methylation might constitute a link between the stress response and panic disorder risk., (Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.)

Facilitated processing of interoceptive and exteroceptive information in the salience network is suggested to promote the development of anxiety and anxiety disorders. Here, it was investigated whether the adenosine 2 A receptor gene (ADORA2A) 1976T/C (rs5751876) variant - previously associated with anxiety disorders and anxiety-related phenotypes as well as general attentional efficiency -was involved in the regulation of this network. In detail, fMRI recordings of 65 healthy participants (female=35) were analyzed regarding ADORA2A genotype effects on brain connectivity related to (1) interoceptive processing in terms of functional connectivity resting-state fMRI, and (2) exteroceptive processing using dynamic causal modeling in task-based fMRI. In a subsample, cardiac interoceptive accuracy was furthermore measured via the Mental Tracking Task. ADORA2A genotype was found to modulate a fronto-insular network at rest (interoceptive processing) and while performing an executive control task (exteroceptive processing). Across both modalities, the ADORA2A TT risk genotype was associated with increased connectivity between the insula and the prefrontal cortex. The strength in connectivity correlated with interoceptive accuracy. It is concluded that alterations in fronto-insular connectivity are modulated by both the adenosinergic system and interoceptive accuracy. Thus, fronto-insular connectivity in synopsis with ADORA2A genotypic information could serve as combined biomarkers for personalized treatment approaches in anxiety disorders targeting exteroceptive and interoceptive dysfunction., (Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.)

In major depressive disorder (MDD), electrophysiological and imaging studies provide evidence for a reduced neural activity in parietal and dorsolateral prefrontal regions. In the present study, neural correlates and temporal dynamics of visual affective perception have been investigated in patients with unipolar depression in a pre/post treatment design using magnetoencephalography (MEG). Nineteen in-patients and 19 balanced healthy controls passed MEG measurement while passively viewing pleasant, unpleasant and neutral pictures. After a 4-week treatment with electroconvulsive therapy or 4-week waiting period without intervention respectively, 16 of these patients and their 16 corresponding controls participated in a second MEG measurement. Before treatment neural source estimations of magnetic fields evoked by the emotional scenes revealed a general bilateral parietal hypoactivation in depressed patients compared to controls predominately at early and mid-latency time intervals. Successful ECT treatment, as reflected by a decline in clinical scores (Hamilton Depression Scale; HAMD) led to a normalization of this distinct parietal hypoactivation. Effective treatment was also accompanied by relatively increased neural activation at right temporo-parietal regions. The present study indicates dysfunctional parietal information processing and attention processes towards emotional stimuli in MDD patients which can be returned to normal by ECT treatment. Since convergent neural hypoactivations and treatment effects have recently been shown in MDD patients before and after pharmacological therapy, this electrophysiological correlate might serve as a biomarker for objective treatment evaluation and thereby potentially advance treatment options and support the prediction of individual treatment responses., (Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.)

An excitatory-inhibitory neurotransmitter dysbalance has been suggested in pathogenesis of panic disorder. The neuropeptide S (NPS) system has been implicated in modulating GABA and glutamate neurotransmission in animal models and to genetically drive altered fear circuit function and an increased risk of panic disorder in humans. Probing a multi-level imaging genetic risk model of panic, in the present magnetic resonance spectroscopy (MRS) study brain glutamate+glutamine (Glx) levels in the bilateral anterior cingulate cortex (ACC) during a pharmacological cholecystokinin tetrapeptide (CCK-4) panic challenge were assessed depending on the functional neuropeptide S receptor gene (NPSR1) rs324981 A/T variant in a final sample of 35 healthy male subjects. The subjective panic response (Panic Symptom Scale; PSS) as well as cortisol and ACTH levels were ascertained throughout the experiment. CCK-4 injection was followed by a strong panic response. A significant time×genotype interaction was detected (p=.008), with significantly lower ACC Glx/Cr levels in T allele carriers as compared to AA homozygotes 5min after injection (p=.003). CCK-4 induced significant HPA axis stimulation, but no effect of genotype was discerned. The present pilot data suggests NPSR1 gene variation to modulate Glx levels in the ACC during acute states of stress and anxiety, with blunted, i.e. possibly maladaptive ACC glutamatergic reactivity in T risk allele carriers. Our results underline the notion of a genetically driven rapid and dynamic response mechanism in the neural regulation of human anxiety and further strengthen the emerging role of the NPS system in anxiety., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)

Anxiety disorders are among the most frequent psychiatric disorders. With regard to pharmacological treatment, antidepressants, the calcium modulator pregabalin and benzodiazepines are recommended according to current treatment guidelines. With regard to acute states of anxiety, so far practically only benzodiazepines provide an immediate anxiolytic effect. However, the risk of tolerance and dependency limits the use of this class of medication. Therefore, there is still a need for alternative pharmacologic strategies. Increasing evidence points towards anxiety-reducing properties of atypical antipsychotics, particularly quetiapine. Therefore, we aimed to evaluate the putative acute anxiolytic effects of this compound, choosing the induction of acute anxiety in patients with specific phobia as a model for the evaluation of ad-hoc anxiolytic properties in a proof-of-concept approach. In a randomized, double-blind, placebo-controlled study, 58 patients with arachnophobia were treated with a single dose of quetiapine XR or placebo prior to a virtual reality spider challenge procedure. Treatment effects were monitored using rating scales for acute anxiety as well as measurements of heart rate and skin conductance. Overall, quetiapine showed significant anxiolytic effects compared to placebo. However, effects were not seen on the primary outcome measure (VAS Anxiety), but were limited to somatic anxiety symptoms. Additionally, a significant reduction of skin conductance was observed. Further exploratory analyses hint towards a mediating role of the (COMT) val158met genotype on treatment response. The present results thus suggest a possible suitability of quetiapine in the acute treatment of anxiety, particularly with regard to somatic symptoms., (Copyright © 2013 Elsevier B.V. and ECNP. All rights reserved.)

Neuropeptide Y (NPY) has been found to play a role in the pathomechanism of both anxiety and depression. Thus, NPY is a promising candidate in the investigation of the clinical phenotype of "anxious depression". Five NPY gene variants were investigated for an influence on antidepressant treatment response in a sample of 256 patients with depression. Additionally, NPY gene impact on amygdala activation during facial emotion processing was analyzed in a subsample of 35 depressed patients. Particularly in anxious depression, the less active NPY rs16147 -399C allele conferred slow response after 2weeks and failure to achieve remission after four weeks of treatment. The rs16147 C allele was further associated with stronger bilateral amygdala activation in response to threatening faces in an allele-dose fashion. The present results point towards a possible influence of functional NPY gene variation on antidepressant treatment response in anxious depression, potentially conveyed by altered emotional processing., (2009 Elsevier B.V. and ECNP. All rights reserved.)

Two serotonin 2A receptor (HTR2A) SNPs recently reported to be associated with antidepressant treatment response in STARD (rs7997012; rs1928040) were analyzed for association with treatment response in two independent Caucasian samples of patients with a Major Depressive Episode. In the combined sample (n=637) SNP rs7997012 was significantly associated with remission after five weeks providing first replicative support for the initial finding, with, however, an inverse allelic association as compared to the STARD sample.

The endocannabinoid system has been implicated in the pathogenesis of depression and anxiety, the mediation of antidepressant drug effects in animal models and the neurobiology of emotion processing in healthy volunteers. Therefore, the impact of cannabinoid receptor 1 gene (CNR1) variants rs1049353 and rs12720071 on antidepressant treatment response was evaluated in 256 Caucasian patients with Major Depression. A subsample of 33 depressed patients was additionally scanned by fMRI under visual presentation of emotional faces. The CNR1 rs1049353 G allele conferred an increased risk of antidepressant treatment resistance, particularly in female patients with high comorbid anxiety. CNR1 rs1049353 G allele carriers also demonstrated weaker bilateral amygdala, putamen and pallidum activity as well as left lateralized caudate and thalamus activity in response to masked happy faces. This analysis provides preliminary support for a role of CNR1 gene variation in depression and anxiety, potentially mediated by subcortical hypo-responsiveness to social reward stimuli.