Significance: Early life stress (ELS) is an important risk factor for schizophrenia. Our study shows that ELS in mice increases the levels of histone-deacetylase (HDAC) 1 in brain and blood. Although altered Hdac1 expression in response to ELS is widespread, increased Hdac1 levels in the prefrontal cortex are responsible for the development of schizophrenia-like phenotypes. In turn, administration of an HDAC inhibitor ameliorates ELS-induced schizophrenia-like phenotypes. We also show that Hdac1 levels are increased in the brains of patients with schizophrenia and in blood from patients who suffered from ELS, suggesting that the analysis of Hdac1 expression in blood could be used for patient stratification and individualized therapy.

Telomere shortening is a normal age-related process. However, premature shortening of telomeres in leukocytes – as has been reported in depression – may increase the risk for age-related diseases. While previous studies investigated telomere length in peripheral blood mononuclear cells (PBMCs) as a whole, this study investigated specific changes in the clonal composition of white blood cells of the adaptive immune system (CD4+ helper and CD8+ cytotoxic T lymphocytes, and CD20+ B lymphocytes). Forty-four females with a history of unipolar depression were investigated and compared to fifty age-matched female controls. Telomere lengths were compared between three groups: 1) individuals with a history of depression but currently no clinically relevant depressive symptoms, 2) individuals with a history of depression with relevant symptoms of depression, and 3) healthy age-matched controls. Telomere length was assessed using quantitative fluorescence in situ hybridization (qFISH). Both groups with a history of unipolar depression (with and without current depressive symptoms) showed significantly shorter telomeres in all three lymphocyte subpopulations. The effect was stronger in CD8+ and CD20+ cells than in CD4+ cells. Individuals with a history of depression and with (without) current symptoms exhibited a CD8+ telomere length shortening corresponding to an age differential of 27.9 (25.3) years. A history of depression is associated with shortened telomeres in the main effector populations of the adaptive immune system. Shorter telomeres seem to persist in individuals with lifetime depression independently of the severity of depressive symptoms. CD8+ cytotoxic T cells and CD20+ B cells seem to be particularly affected in depression. The total number of depressive episodes did not influence telomere length in the investigated adaptive immune cell populations.

Background: Whether Borna disease virus (BDV-1) is a human pathogen remained controversial until recent encephalitis cases showed BDV-1 infection could even be deadly. This called to mind previous evidence for an infectious contribution of BDV-1 to mental disorders. Pilot open trials suggested that BDV-1 infected depressed patients benefitted from antiviral therapy with a licensed drug (amantadine) which also tested sensitive in vitro. Here, we designed a double-blind placebo-controlled randomized clinical trial (RCT) which cross-linked depression and BDV-1 infection, addressing both the antidepressant and antiviral efficacy of amantadine. Methods: The interventional phase II RCT (two 7-weeks-treatment periods and a 12-months follow-up) at the Hannover Medical School (MHH), Germany, assigned currently depressed BDV-1 infected patients with either major depression (MD; N = 23) or bipolar disorder (BD; N = 13) to amantadine sulphate (PK-Merz®; twice 100 mg orally daily) or placebo treatment, and contrariwise, respectively. Clinical changes were assessed every 2–3 weeks by the 21-item Hamilton rating scale for depression (HAMD) (total, single, and combined scores). BDV-1 activity was determined accordingly in blood plasma by enzyme immune assays for antigens (PAG), antibodies (AB) and circulating immune complexes (CIC). Results: Primary outcomes (≥25% HAMD reduction, week 7) were 81.3% amantadine vs. 35.3% placebo responder (p = 0.003), a large clinical effect size (ES; Cohen’s d) of 1.046, and excellent drug tolerance. Amantadine was safe reducing suicidal behaviour in the first 2 weeks. Pre-treatment maximum infection levels were predictive of clinical improvement (AB, p = 0.001; PAG, p = 0.026; HAMD week 7). Respective PAG and CIC levels correlated with AB reduction (p = 0,001 and p = 0.034, respectively). Follow-up benefits (12 months) correlated with dropped cumulative infection measures over time (p < 0.001). In vitro, amantadine concentrations as low as 2.4–10 ng/mL (50% infection-inhibitory dose) prevented infection with human BDV Hu-H1, while closely related memantine failed up to 100,000-fold higher concentration (200 μg/mL). Conclusions: Our findings indicate profound antidepressant efficacy of safe oral amantadine treatment, paralleling antiviral effects at various infection levels. This not only supports the paradigm of a link of BDV-1 infection and depression. It provides a novel possibly practice-changing low cost mental health care perspective for depressed BDV-1-infected patients addressing global needs. Trial registration: The trial was retrospectively registered in the German Clinical Trials Registry on 04th of March 2015. The trial ID is DRKS00007649; https://www.drks.de/drks_web/setLocale_EN.do

Objective: Memory processes, as reflected by ‘old/new’ effects of event-related potentials (ERPs), have been shown to be impaired in depressed patients. This variability might be partly explained by biological factors. S100B is a glial calcium-binding protein with neuroplastic properties; S100B serum levels have been shown to be increased in depressive patients. The pathophysiologic role of S100B in depression, however, is not yet sufficiently understood. Methods: In the present study, ERPs recorded in a visual continuous word recognition paradigm were therefore investigated in patients with remitted major depression in relation to S100B serum levels. Results: Patients with moderately increased S100B serum levels (n = 6) showed a normal old/new effect in contrast to a reduced old/new effect in patients with normal S100B levels (n = 6) compared to aged-matched controls. Conclusions: These findings provide evidence of an association between S100B levels and memory processes in patients with recurrent depression and further suggest a neuroprotective role of moderately increased S100B serum levels in the course of affective disorders.

Adverse childhood experiences (ACE) contribute significantly to mental disorders. While existing research has primarily focused on specific diagnostic categories, a comprehensive understanding of how childhood trauma interacts with biological factors, symptom severity and functioning requires a broader perspective. Therefore, this study adopted a cross-diagnostic approach to examine the impact of ACE on quality of life (QoL), psychosocial functioning, and symptom burden by analyzing data from the PsyCourse Study, a longitudinal, multicenter research project conducted in Germany and Austria. We used multivariate linear regression models and cluster analysis to evaluate data from 725 participants with affective and psychotic disorders and healthy controls who completed the self-assessed Childhood Trauma Screener (CTS) during the course of the study. The results showed that across diagnoses, QoL was significantly impacted by ACE, particularly emotional neglect. An ablation study revealed that 2.3 % to 6.2 % of the variability in QoL domains could be attributed to ACE. Across diagnoses, symptoms of depression were significantly associated with ACE, especially emotional abuse, but psychotic and manic symptoms were not. Polygenic risk scores (PRS) did not emerge as significant predictors for any examined outcomes. Cluster analysis revealed distinct symptom profiles: Averaged over time, patients with less trauma exposure were rather in the subclinical than in the clinically ill clusters. We conclude that the pervasive influence of ACE on disease severity should be considered when evaluating and treating patients with affective and psychotic disorders.