Cohort profile: BioMD-Y (biopsychosocial factors of major depression in youth) - a biobank study on the molecular genetics and environmental factors of depression in children and adolescents in Munich.

PURPOSE: BioMD-Y is a comprehensive biobank study of children and adolescents with major depression (MD) and their healthy peers in Germany, collecting a host of both biological and psychosocial information from the participants and their parents with the aim of exploring genetic and environmental risk and protective factors for MD in children and adolescents. PARTICIPANTS: Children and adolescents aged 8-18 years are recruited to either the clinical case group (MD, diagnosis of MD disorder) or the typically developing control group (absence of any psychiatric condition). FINDINGS TO DATE: To date, four publications on both genetic and environmental risk and resilience factors (including FKBP5, glucocorticoid receptor activation, polygenic risk scores, psychosocial and sociodemographic risk and resilience factors) have been published based on the BioMD-Y sample. FUTURE PLANS: Data collection is currently scheduled to continue into 2026. Research questions will be further addressed using available measures.

The associations of Positive and Negative Valence Systems, Cognitive Systems and Social Processes on disease severity in anxiety and depressive disorders.

Background: Anxiety and depressive disorders share common features of mood dysfunctions. This has stimulated interest in transdiagnostic dimensional research as proposed by the Research Domain Criteria (RDoC) approach by the National Institute of Mental Health (NIMH) aiming to improve the understanding of underlying disease mechanisms. The purpose of this study was to investigate the processing of RDoC domains in relation to disease severity in order to identify latent disorder-specific as well as transdiagnostic indicators of disease severity in patients with anxiety and depressive disorders. Methods: Within the German research network for mental disorders, 895 participants (n = 476 female, n = 602 anxiety disorder, n = 257 depressive disorder) were recruited for the Phenotypic, Diagnostic and Clinical Domain Assessment Network Germany (PD-CAN) and included in this cross-sectional study. We performed incremental regression models to investigate the association of four RDoC domains on disease severity in patients with affective disorders: Positive (PVS) and Negative Valance System (NVS), Cognitive Systems (CS) and Social Processes (SP). Results: The results confirmed a transdiagnostic relationship for all four domains, as we found significant main effects on disease severity within domain-specific models (PVS: ß = -0.35; NVS: ß = 0.39; CS: ß = -0.12; SP: ß = -0.32). We also found three significant interaction effects with main diagnosis showing a disease-specific association. Limitations: The cross-sectional study design prevents causal conclusions. Further limitations include possible outliers and heteroskedasticity in all regression models which we appropriately controlled for. Conclusion: Our key results show that symptom burden in anxiety and depressive disorders is associated with latent RDoC indicators in transdiagnostic and disease-specific ways.

Mapping Research Domain Criteria using a transdiagnostic mini-RDoC assessment in mental disorders: a confirmatory factor analysis.

This study aimed to build on the relationship of well-established self-report and behavioral assessments to the latent constructs positive (PVS) and negative valence systems (NVS), cognitive systems (CS), and social processes (SP) of the Research Domain Criteria (RDoC) framework in a large transnosological population which cuts across DSM/ICD-10 disorder criteria categories. One thousand four hundred and thirty one participants (42.1% suffering from anxiety/fear-related, 18.2% from depressive, 7.9% from schizophrenia spectrum, 7.5% from bipolar, 3.4% from autism spectrum, 2.2% from other disorders, 18.4% healthy controls, and 0.2% with no diagnosis specified) recruited in studies within the German research network for mental disorders for the Phenotypic, Diagnostic and Clinical Domain Assessment Network Germany (PD-CAN) were examined with a Mini-RDoC-Assessment including behavioral and self-report measures. The respective data was analyzed with confirmatory factor analysis (CFA) to delineate the underlying latent RDoC-structure. A revised four-factor model reflecting the core domains positive and negative valence systems as well as cognitive systems and social processes showed a good fit across this sample and showed significantly better fit compared to a one factor solution. The connections between the domains PVS, NVS and SP could be substantiated, indicating a universal latent structure spanning across known nosological entities. This study is the first to give an impression on the latent structure and intercorrelations between four core Research Domain Criteria in a transnosological sample. We emphasize the possibility of using already existing and well validated self-report and behavioral measurements to capture aspects of the latent structure informed by the RDoC matrix.

Effect of Minocycline on Depressive Symptoms in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial.

Importance: Insufficient treatment response and resulting chronicity constitute a major problem in depressive disorders. Remission rates range as low as 15% to 40% and treatment-resistant depression (TRD) is associated with low-grade inflammation, suggesting anti-inflammatory interventions as a rational treatment strategy. Minocycline, which inhibits microglial activation, represents a promising repurposing candidate in the treatment of TRD. Objective: To determine whether 6 weeks of minocycline as add-on to antidepressant treatment as usual can significantly reduce depressive symptoms in patients with TRD. Design, Setting, and Participants: The study was conducted in Germany and designed as a multicenter double-blind randomized clinical trial (RCT) of 200 mg/d minocycline treatment over a course of 6 weeks with a 6-month follow-up. Participants were recruited from January 2016 to August 2020 at 9 university hospitals that served as study sites. Key inclusion criteria were a diagnosis of major depressive disorder (according to Diagnostic and Statistical Manual of Mental Disorders [Fifth Edition] criteria), severity of depressive symptoms on the Hamilton Depression Rating Scale (HAMD-17) greater than or equal to 16 points, aged 18 to 75 years, body mass index 18 to 40, Clinical Global Impression Scale (CGI-S) greater than or equal to 4, failure to adequately respond to an initial antidepressant standard medication as per Massachusetts General Hospital Antidepressant Treatment History Questionnaire, and stable medication for at least 2 weeks. A total of 258 patients were screened, of whom 173 were randomized and 168 were included into the intention-to-treat population. Statistical analysis was performed from April to November 2020. Interventions: Participants were randomized (1:1) to receive adjunct minocycline (200 mg/d) or placebo for 6 weeks. Main Outcomes and Measures: Primary outcome measure was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to week 6 analyzed by intention-to-treat mixed model repeated measures. Secondary outcome measures were response, remission, and various other clinical rating scales. Results: Of 173 eligible and randomized participants (84 randomized to minocycline and 89 randomized to placebo), 168 formed the intention-to-treat sample (79 [47.0%] were women, 89 [53.0%] were men, 159 [94.6%] were White, 9 [6.4%] were of other race and ethnicity, including Asian and unknown ethnicity), with 81 in the minocycline group and 87 in the placebo group. The mean (SD) age was 46.1 (13.1) years, and the mean (SD) MADRS score at baseline was 26.5 (5.0). There was no difference in rates of completion between the minocycline (83.3% [70 of 81]) and the placebo group (83.1% [74 of 87]). Minocycline treatment did not alter the course of depression severity compared with placebo as assessed by a decrease in MADRS scores over 6 weeks of treatment (1.46 [-1.04 to 3.96], P = .25). Minocycline treatment also exhibited no statistically significant effect on secondary outcomes. Conclusions and Relevance: In this large randomized clinical trial with minocycline at a dose of 200 mg/d added to antidepressant treatment as usual for 6 weeks, minocycline was well tolerated but not superior to placebo in reducing depressive symptoms in patients with TRD. The results of this RCT emphasize the unmet need for therapeutic approaches and predictive biomarkers in TRD. Trial Registration: EU Clinical Trials Register Number: EudraCT 2015-001456-29.

Recurrent suicide attempts affect normalization of HPA axis dysregulation after recovery from major depression.

More than 700,000 people worldwide die by suicide every year, and the number of suicide attempts is estimated as 20 times higher, most of them being associated with psychiatric disorders, especially major depression. Knowledge about effective methods for preventing suicide attempts in individuals at high risk for suicide is still scarce. Dysregulation of the neuroendocrine stress response system, i.e., the hypothalamic-pituitary-adrenocortical (HPA) axis, is one of the most consistent neurobiological findings in both major depression and suicidality. While the HPA axis is mostly overactive in depression, individuals with a history of suicide attempts exhibit an attenuated hormonal response to stress. It is unknown, however, whether the HPA axis is constantly attenuated in repeated suicide attempters or whether it regains normal responsivity after recovery from depression. Using the combined dexamethasone suppression/corticotropin-releasing hormone (dex/CRH) test, we assessed HPA axis regulation in acute depression (N = 237) and after recovery with respect to previous suicide attempts. Patients without previous suicide attempts show normalization of the stress hormone response to the second dex/CRH (basal ACTH response and cortisol response) after recovery from acute depression, while patients with multiple previous SA show an increased ACTH response. The change in HPA axis responsivity in patients with only one previous SA lies between the response patterns of the other groups with no change in HPA axis reactivity. Our findings suggest that patients with a history of suicide attempts belong to a subgroup of individuals that exhibit a distinct pattern of stress hormone response during acute depression and after recovery. Future studies may extend our approach by investigating additional psychological stress tasks to gain a broader understanding of the stress pathology of recurrent suicide attempters.

Effects of stressful life-events on DNA methylation in panic disorder and major depressive disorder.

BACKGROUND: Panic disorder (PD) is characterized by recurrent panic attacks and higher affection of women as compared to men. The lifetime prevalence of PD is about 2-3% in the general population leading to tremendous distress and disability. Etiologically, genetic and environmental factors, such as stress, contribute to the onset and relapse of PD. In the present study, we investigated epigenome-wide DNA methylation (DNAm) in respond to a cumulative, stress-weighted life events score (wLE) in patients with PD and its boundary to major depressive disorder (MDD), frequently co-occurring with symptoms of PD. METHODS: DNAm was assessed by the Illumina HumanMethylation450 BeadChip. In a meta-analytic approach, epigenome-wide DNAm changes in association with wLE were first analyzed in two PD cohorts (with a total sample size of 183 PD patients and 85 healthy controls) and lastly in 102 patients with MDD to identify possible overlapping and opposing effects of wLE on DNAm. Additionally, analysis of differentially methylated regions (DMRs) was conducted to identify regional clusters of association. RESULTS: Two CpG-sites presented with p-values below 1 × 10-05 in PD: cg09738429 (p = 6.40 × 10-06, located in an intergenic shore region in next proximity of PYROXD1) and cg03341655 (p = 8.14 × 10-06, located in the exonic region of GFOD2). The association of DNAm at cg03341655 and wLE could be replicated in the independent MDD case sample indicating a diagnosis independent effect. Genes mapping to the top hits were significantly upregulated in brain and top hits have been implicated in the metabolic system. Additionally, two significant DMRs were identified for PD only on chromosome 10 and 18, including CpG-sites which have been reported to be associated with anxiety and other psychiatric phenotypes. CONCLUSION: This first DNAm analysis in PD reveals first evidence of small but significant DNAm changes in PD in association with cumulative stress-weighted life events. Most of the top associated CpG-sites are located in genes implicated in metabolic processes supporting the hypothesis that environmental stress contributes to health damaging changes by affecting a broad spectrum of systems in the body.

Hypothalamic stress systems in mood disorders.

Stress system dysfunction is a typical characteristic of acute depression and other mood disorders. The exact pattern of factors predisposing for stress-related mental disorders is yet to be unraveled. However, corticosteroid receptor function plays an important role for appropriate or dysfunctional neuroendocrine responses to stress exposure and hence in resilience or risk for the development and course of both, depression and anxiety disorders. Solid neuroscience data strongly support that both neuropeptides, corticotropin-releasing hormone (CRH) and vasopressin (AVP), are central in coordinating humoral and behavioral adaptation to stress. Other neuropeptides, including oxytocin, neuropeptide S, neuropeptide Y, and orexin, are also considered important contributors. Attempts to turn neuropeptide biology into treatments for stress-related disorders need to consider that neuropeptide receptors are specific drug targets for certain patient populations rather than universal targets for all patients, like biogenic amine systems. That is why most negative clinical trials testing neuropeptide receptor antagonists have been in fact failed trials by design, because no companion tests were used to identify which patients with depression are most likely to benefit from a specific neuropeptide receptor-targeting drug treatment. Therefore, the most important future research task is discovery and development of appropriate companion tests that will allow the successful transfer of the precious treasure of neuropeptide system-targeting drugs into clinics.

Effects of weariness of life, suicide ideations and suicide attempt on HPA axis regulation in depression.

The neuropathological mechanisms leading to suicidality are still unknown, which, in view of an annual toll of around 1 million completed suicides constitutes an urgent clinical and societal problem. Alterations of stress hormone (ACTH and cortisol, representing the activity of the hypothalamic-pituitary-adrenocortical, HPA axis) regulation has been repeatedly studied in context of suicidality. Following a suicide attempt, stress hormone activity seems to be blunted, while depressed patients with suicidal ideation often present with elevated HPA axis activity. METHODS: We investigated the effects of different forms of suicidality on HPA axis regulation in 568 hospitalized patients of the Munich Antidepressant Response Signature (MARS) project. All patients had a diagnosis of a depressive disorder; 62 patients reported a recent suicide attempt, 192 patients suicide ideation, and 171 patients expressed weariness of life as the weakest form of suicidality, the latter not being analyzed in studies so far. All patients participated in the combined dexamethasone/corticotropin releasing hormone (dex/CRH) test for assessing HPA axis regulation shortly after admission to the hospital. RESULTS: We found an increased ACTH and cortisol response following the dex/CRH-test in patients that were weary of life. In contrast, stress hormone response in suicide attempters and suicide ideators did not differ from non-suicidal patients. Further, repeated suicide attempts in patients' history were associated with more pronounced stress hormone attenuation. CONCLUSION: In this so far largest study analyzing the HPA axis with respect to suicidality, we could not confirm the assumption of a general attenuation of HPA axis response in depressed suicide ideators and attempters. Conversely, HPA axis appears to be influenced by divergent effects of a specific suicidal psychopathology as well as outlasting effects of previous suicide attempts. We discuss these findings in the light of recent concepts of suicidality, pointing to multifactorial effects of acute and predisposing conditions on HPA axis reactivity in depressed patients.

Identification of transdiagnostic psychiatric disorder subtypes using unsupervised learning.

Psychiatric disorders show heterogeneous symptoms and trajectories, with current nosology not accurately reflecting their molecular etiology and the variability and symptomatic overlap within and between diagnostic classes. This heterogeneity impedes timely and targeted treatment. Our study aimed to identify psychiatric patient clusters that share clinical and genetic features and may profit from similar therapies. We used high-dimensional data clustering on deep clinical data to identify transdiagnostic groups in a discovery sample (N = 1250) of healthy controls and patients diagnosed with depression, bipolar disorder, schizophrenia, schizoaffective disorder, and other psychiatric disorders. We observed five diagnostically mixed clusters and ordered them based on severity. The least impaired cluster 0, containing most healthy controls, showed general well-being. Clusters 1-3 differed predominantly regarding levels of maltreatment, depression, daily functioning, and parental bonding. Cluster 4 contained most patients diagnosed with psychotic disorders and exhibited the highest severity in many dimensions, including medication load. Depressed patients were present in all clusters, indicating that we captured different disease stages or subtypes. We replicated all but the smallest cluster 1 in an independent sample (N = 622). Next, we analyzed genetic differences between clusters using polygenic scores (PGS) and the psychiatric family history. These genetic variables differed mainly between clusters 0 and 4 (prediction area under the receiver operating characteristic curve (AUC) = 81%; significant PGS: cross-disorder psychiatric risk, schizophrenia, and educational attainment). Our results confirm that psychiatric disorders consist of heterogeneous subtypes sharing molecular factors and symptoms. The identification of transdiagnostic clusters advances our understanding of the heterogeneity of psychiatric disorders and may support the development of personalized treatments.

Genetic comorbidity between major depression and cardio-metabolic traits, stratified by age at onset of major depression.

It is imperative to understand the specific and shared etiologies of major depression and cardio-metabolic disease, as both traits are frequently comorbid and each represents a major burden to society. This study examined whether there is a genetic association between major depression and cardio-metabolic traits and if this association is stratified by age at onset for major depression. Polygenic risk scores analysis and linkage disequilibrium score regression was performed to examine whether differences in shared genetic etiology exist between depression case control status (N cases = 40,940, N controls = 67,532), earlier (N = 15,844), and later onset depression (N = 15,800) with body mass index, coronary artery disease, stroke, and type 2 diabetes in 11 data sets from the Psychiatric Genomics Consortium, Generation Scotland, and UK Biobank. All cardio-metabolic polygenic risk scores were associated with depression status. Significant genetic correlations were found between depression and body mass index, coronary artery disease, and type 2 diabetes. Higher polygenic risk for body mass index, coronary artery disease, and type 2 diabetes was associated with both early and later onset depression, while higher polygenic risk for stroke was associated with later onset depression only. Significant genetic correlations were found between body mass index and later onset depression, and between coronary artery disease and both early and late onset depression. The phenotypic associations between major depression and cardio-metabolic traits may partly reflect their overlapping genetic etiology irrespective of the age depression first presents.

Citalopram-induced pathways regulation and tentative treatment-outcome-predicting biomarkers in lymphoblastoid cell lines from depression patients.

Antidepressant therapy is still associated with delays in symptomatic improvement and low response rates. Incomplete understanding of molecular mechanisms underlying antidepressant effects hampered the identification of objective biomarkers for antidepressant response. In this work, we studied transcriptome-wide expression followed by pathway analysis in lymphoblastoid cell lines (LCLs) derived from 17 patients documented for response to SSRI antidepressants from the Munich Antidepressant Response Signatures (MARS) study upon short-term incubation (24 and 48 h) with citalopram. Candidate transcripts were further validated with qPCR in MARS LCLs from responders (n = 33) vs. non-responders (n = 36) and afterward in an independent cohort of treatment-resistant patients (n = 20) vs. first-line responders (n = 24) from the STAR*D study. In MARS cohort we observed significant associations of GAD1 (glutamate decarboxylase 1; p = 0.045), TBC1D9 (TBC1 Domain Family Member 9; p = 0.014-0.021) and NFIB (nuclear factor I B; p = 0.015-0.025) expression with response status, remission status and improvement in depression scale, respectively. Pathway analysis of citalopram-altered gene expression indicated response-status-dependent transcriptional reactions. Whereas in clinical responders neural function pathways were primarily up- or downregulated after incubation with citalopram, deregulated pathways in non-responders LCLs mainly involved cell adhesion and immune response. Results from the STAR*D study showed a marginal association of treatment-resistant depression with NFIB (p = 0.068) but not with GAD1 (p = 0.23) and TBC1D9 (p = 0.27). Our results propose the existence of distinct pathway regulation mechanisms in responders vs. non-responders and suggest GAD1, TBC1D9, and NFIB as tentative predictors for clinical response, full remission, and improvement in depression scale, respectively, with only a weak overlap in predictors of different therapy outcome phenotypes.

Acute Stress-Induced Coagulation Activation in Patients With Remitted Major Depression Versus Healthy Controls and the Role of Stress-Specific Coping.

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.

Chronotype is associated with psychological well-being depending on the composition of the study sample.

Past studies examining the effect of chronotype and social jetlag on psychological well-being have been inconsistent so far. Here, we recruited participants from the general population and enquired about their natural sleeping behavior, sleep quality, depressive symptoms, and perceived stress. Partial correlations were computed between sleep variables and indicators of psychological well-being, controlling for age and sex. Less sleep during work days was found a good indicator for impairments in psychological well-being. In exploratory follow-up analyses, the same correlations were calculated within groups of early, intermediate, and late chronotype. We observed that the composition of the sample in terms of chronotype influenced whether associations between sleep variables and psychological well-being could be observed, a finding that is advised to be taken into account in future studies.

Evidence for an enhanced procoagulant state in remitted major depression.

OBJECTIVES: 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. METHODS: 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. Standardised z-scores of plasma levels of these haemostatic factors were added to form a procoagulant index (PCI) as the primary outcome variable. Self-ratings of residual depressive symptoms and trait anxiety were also obtained. RESULTS: Compared with controls, remitted MDD patients had higher PCI (p = 0.013, Cohen's d = 0.69) and fibrinogen (p = 0.001, d = 0.91), controlling for age, sex, body mass index, smoking and C-reactive protein. There were no significant associations of the PCI and individual haemostatic molecules with age of MDD onset, time since the last MDD episode, the number of previous MDD episodes and residual depressive symptoms. Additional adjustment for anxiety symptoms did not change these results. CONCLUSIONS: Remitted MDD is associated with an enhanced procoagulant state. Hypercoagulability seems more a trait than a state characteristic of depression.

Treatment response classes in major depressive disorder identified by model-based clustering and validated by clinical prediction models.

The identification of generalizable treatment response classes (TRC[s]) in major depressive disorder (MDD) would facilitate comparisons across studies and the development of treatment prediction algorithms. Here, we investigated whether such stable TRCs can be identified and predicted by clinical baseline items. We analyzed data from an observational MDD cohort (Munich Antidepressant Response Signature [MARS] study, N = 1017), treated individually by psychopharmacological and psychotherapeutic means, and a multicenter, partially randomized clinical/pharmacogenomic study (Genome-based Therapeutic Drugs for Depression [GENDEP], N = 809). Symptoms were evaluated up to week 16 (or discharge) in MARS and week 12 in GENDEP. Clustering was performed on 809 MARS patients (discovery sample) using a mixed model with the integrated completed likelihood criterion for the assessment of cluster stability, and validated through a distinct MARS validation sample and GENDEP. A random forest algorithm was used to identify prediction patterns based on 50 clinical baseline items. From the clustering of the MARS discovery sample, seven TRCs emerged ranging from fast and complete response (average 4.9 weeks until discharge, 94% remitted patients) to slow and incomplete response (10% remitted patients at week 16). These proved stable representations of treatment response dynamics in both the MARS and the GENDEP validation sample. TRCs were strongly associated with established response markers, particularly the rate of remitted patients at discharge. TRCs were predictable from clinical items, particularly personality items, life events, episode duration, and specific psychopathological features. Prediction accuracy improved significantly when cluster-derived slopes were modelled instead of individual slopes. In conclusion, model-based clustering identified distinct and clinically meaningful treatment response classes in MDD that proved robust with regard to capturing response profiles of differently designed studies. Response classes were predictable from clinical baseline characteristics. Conceptually, model-based clustering is translatable to any outcome measure and could advance the large-scale integration of studies on treatment efficacy or the neurobiology of treatment response.

Polymorphisms in the BDNF and BDNFOS genes are associated with hypothalamus-pituitary axis regulation in major depression.

Major depression is a stress-related disorder with robust clinical and preclinical data implicating that both, dysregulation of the hypothalamus-pituitary-adrenocortical (HPA) axis and of the neurotrophin system of the brain are involved in the pathophysiology. Genetic variations within the brain-derived neurotrophic factor (BDNF) gene region, a major representative of the brain neurotrophins, are suggested to influence response to antidepressant treatment. Specifically, we recently identified two BDNF single nucleotide polymorphisms (SNP), rs2049046 and rs11030094, as associated with antidepressant treatment response in a large pharmacogenetic study of hospitalized patients. We now analyzed these two SNPs in a sub-sample for their association with HPA axis dysregulation using the combined dexamethasone suppression/corticotropin releasing hormone challenge (dex/CRH) test at hospital admission (N = 266) and at discharge (N = 190). Rs11030094, located 3' outside the coding region of BDNF, is also located in an intron of BDNFOS coding for a functional antagonist of BDNF. We further included the non-synonymous Val66Met (rs6265) polymorphism in our analysis, for which - albeit being extensively studied - conflicting results in respect to its role in antidepressant treatment response have been reported. Similar to the previous analysis, rs2049046 and rs11030094 showed a significant effect on antidepressant response. In a gene-dose dependent manner, we found significant lower cortisol responses to the dex/CRH test at discharge in carriers of the respective SNP alleles ('T' of rs2049046 and 'G' of rs11030094) that were associated with antidepressant response (beneficial alleles). These genetic effects on HPA axis regulation were independent of age, sex, medication and depressive symptomatology. Although not reaching statistical significance, the same direction of effect was observed for cortisol at admission, as well as the ACTH response at admission and discharge. An interaction analysis of both SNPs revealed highest cortisol levels in subjects that were non-carriers of both beneficial alleles. The Val66Met (rs6265) was neither associated with antidepressant response nor with HPA axis regulation. Our findings provide further evidence for an interaction of the HPA axis and the neurotrophin system in major depression. This study stresses the importance investigating BDNF variants beyond the extensively studied Val66Met polymorphism. In-depth analyses of both pathophysiologically relevant systems may point to possible new targets for pharmaceutical intervention and precision medicine of major depression in the future.

Remission in schizophrenia - What are we measuring? Comparing the consensus remission criteria to a CGI-based definition of remission and to remission in major depression.

BACKGROUND: Despite being recommended for use in clinical trials, the consensus remission criteria were found to leave patients with persisting symptoms, relevant areas of functional impairment and a decreased sense of wellbeing. Therefore, to evaluate the appropriateness of the schizophrenia consensus criteria, a definition of remission based on the Clinical Global Impression Scale (CGI) was developed and remitter subgroups were compared. METHODS: 239 patients with a schizophrenia spectrum disorder were evaluated regarding their remission status after inpatient treatment. Remission in schizophrenia was defined according to the symptom-severity component of the consensus criteria by Andreasen et al. and a CGI based definition was calculated using sensitivity and specificity using receiver operating curves (asymptomatic remitter). Both remitter groups (schizophrenia consensus versus asymptomatic remitters) were compared regarding different clinical variables at discharge as well as the likelihood to relapse within a 1-year follow-up period. Both schizophrenia remitter subgroups were compared to remitters in major depression as a reference value. RESULTS: Following the consensus criteria, 63% of the schizophrenia patients were in remission compared to only 18% following the asymptomatic criterion. The schizophrenia consensus remitters were less likely to be concurrent treatment responders (p < 0.0001), had a significantly greater illness severity (p < 0.0001) and less functioning (p = 0.0358) as well as a significantly greater risk to relapse (p = 0.0174) compared to the schizophrenia asymptomatic remitters as well as the depressed remitters. CONCLUSION: It should be critically re-evaluated if the currently proposed consensus criteria are adequate to measure what is traditionally understood to be remission.

Interactions between FKBP5 variation and environmental stressors in adolescent Major Depression.

OBJECTIVE: Major Depression (MD) results from a complex interplay between environmental stressors and biological factors. Previous studies in adults have shown that adverse life events interact with genetic variation in FKBP5, a gene implicated in the stress-response system, to predict depressive symptoms and MD. This is the first study to investigate interactions between FKBP5 variants and a range of environmental stressors in adolescents with a clinical diagnosis of MD. METHOD: 148 male and female adolescents with MD and 143 typically developing (TD) controls (13-18 years) were included in the present study. For self-reported environmental stressors, subjective severity was assessed to allow a classification of these factors as mild, moderate and severe. Sociodemographic stressors were assessed via parental-report. RESULTS: With a heightened number of sociodemographic, moderate and total number of stressors, participants carrying at least one copy of the FKBP5 CATT haplotype or at least one minor allele of various FKBP5 SNPs had the highest risk for being in the MD group. No genetic main effects were found. Sociodemographic stressors as well as self-reported mild, moderate, and severe stressors were more common in depressed than in TD adolescents. CONCLUSION: This is the first study to show interactions between genetic variation in FKBP5 and environmental stressors in a sample of clinically depressed adolescents. The current study provides important starting-points for preventive efforts and highlights the need for a fine-grained analysis of different forms and severities of environmental stressors and their interplay with genetic variation for understanding the complex etiology of (youth) MD.

Does sex hormone treatment reverse the sex-dependent stress regulation? A longitudinal study on hypothalamus-pituitary-adrenal (HPA) axis activity in transgender individuals.

BACKGROUND: Studies in mammals indicate a role for sex hormones in the regulation of hypothalamic-pituitary-adrenal (HPA)-axis reactivity. However, in humans, experimental paradigms investigating long-term exposure to sex hormones are sparse, limiting the understanding of the influence of sex hormones on HPA-axis activity. Gender-affirming hormone therapy (GAHT) in transgender persons enables to study the physiological role of sex steroids partially uncoupled from the distinct genetic background of men and women. METHODS: Ten transwomen (male genotype and female gender identity) and 15 transmen (female genotype and male gender identity) were investigated at baseline and following three months of GAHT by means of the combined dexamethasone (dex)/CRH-test. Linear mixed-effects model analysis was used to assess changes over time and to identify determinants of HPA-axis reactivity. RESULTS: In response to CRH, overall ACTH (+18%) as well as cortisol (+15%) output were increased in transwomen after 3-months of estrogen and antiandrogen treatment, while the opposite was the case for transmen after testosterone treatment (-15% and -58%, respectively). The ACTH/Cortisol-ratio indicated that testosterone attenuated sensitivity for ACTH at the adrenal level in transmen. Interestingly, copeptin levels before CRH administration were a strong predictor of overall cortisol secretion. CONCLUSIONS: This is the first study demonstrating long-term effects of a complete reversal of the sex-hormonal milieu on HPA-axis activity in humans. Our findings hereby expand the current knowledge of the physiology of HPA-axis regulation. and may be particularly relevant for transgender and cisgender people undergoing hormonal suppression or substitution therapies.

FKBP5 Gene Expression Predicts Antidepressant Treatment Outcome in Depression.

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.