Uncoupling the widespread occurrence of anti-NMDAR1 autoantibodies from neuropsychiatric disease in a novel autoimmune model.

Autoantibodies of the IgG class against N-methyl-D-aspartate-receptor subunit-NR1 (NMDAR1-AB) were considered pathognomonic for anti-NMDAR encephalitis. This view has been challenged by the age-dependent seroprevalence (up to >20%) of functional NMDAR1-AB of all immunoglobulin classes found in >5000 individuals, healthy or affected by different diseases. These findings question a merely encephalitogenic role of NMDAR1-AB. Here, we show that NMDAR1-AB belong to the normal autoimmune repertoire of dogs, cats, rats, mice, baboons, and rhesus macaques, and are functional in the NMDAR1 internalization assay based on human IPSC-derived cortical neurons. The age dependence of seroprevalence is lost in nonhuman primates in captivity and in human migrants, raising the intriguing possibility that chronic life stress may be related to NMDAR1-AB formation, predominantly of the IgA class. Active immunization of ApoE-/- and ApoE+/+ mice against four peptides of the extracellular NMDAR1 domain or ovalbumin (control) leads to high circulating levels of specific AB. After 4 weeks, the endogenously formed NMDAR1-AB (IgG) induce psychosis-like symptoms upon MK-801 challenge in ApoE-/- mice, characterized by an open blood-brain barrier, but not in their ApoE+/+ littermates, which are indistinguishable from ovalbumin controls. Importantly, NMDAR1-AB do not induce any sign of inflammation in the brain. Immunohistochemical staining for microglial activation markers and T lymphocytes in the hippocampus yields comparable results in ApoE-/- and ApoE+/+ mice, irrespective of immunization against NMDAR1 or ovalbumin. These data suggest that NMDAR1-AB of the IgG class shape behavioral phenotypes upon access to the brain but do not cause brain inflammation on their own.

Violent aggression predicted by multiple pre-adult environmental hits.

Early exposure to negative environmental impact shapes individual behavior and potentially contributes to any mental disease. We reported previously that accumulated environmental risk markedly decreases age at schizophrenia onset. Follow-up of matched extreme group individuals (≤1 vs. ≥3 risks) unexpectedly revealed that high-risk subjects had >5 times greater probability of forensic hospitalization. In line with longstanding sociological theories, we hypothesized that risk accumulation before adulthood induces violent aggression and criminal conduct, independent of mental illness. We determined in 6 independent cohorts (4 schizophrenia and 2 general population samples) pre-adult risk exposure, comprising urbanicity, migration, physical and sexual abuse as primary, and cannabis or alcohol as secondary hits. All single hits by themselves were marginally associated with higher violent aggression. Most strikingly, however, their accumulation strongly predicted violent aggression (odds ratio 10.5). An epigenome-wide association scan to detect differential methylation of blood-derived DNA of selected extreme group individuals yielded overall negative results. Conversely, determination in peripheral blood mononuclear cells of histone-deacetylase1 mRNA as 'umbrella mediator' of epigenetic processes revealed an increase in the high-risk group, suggesting lasting epigenetic alterations. Together, we provide sound evidence of a disease-independent unfortunate relationship between well-defined pre-adult environmental hits and violent aggression, calling for more efficient prevention.

Implementing a Need-Adapted Stepped-Care Model for Mental Health of Refugees: Preliminary Data of the State-Funded Project "RefuKey".

Introduction: Refugees have been shown to be a rather vulnerable population with increased psychiatric morbidity and lack of access to adequate mental health care. By expanding regional psychosocial and psychiatric-psychotherapeutic care structures and adapting psychiatric routine care to refugees' needs, the state-funded project "refuKey" based in Lower Saxony, Germany, pursues to ease access to mental health care and increase service quality for refugees. A stepped-care treatment model along with intercultural opening of mental health care services is proposed. Methods: The project is subject to a four-part evaluation study. The first part investigates the state of psychiatric routine care for refugees in Lower Saxony by requesting data from all psychiatric clinics, participating and non-participating ones, regarding the numbers of refugee patients, their diagnoses, settings of treatment, etc. The second part explores experiences and work satisfaction of mental health care professionals treating refugees in refuKey cooperation clinics. The third part consists of interviews and focus group discussions with experts regarding challenges in mental health care of refugees and expectations for improvement through refuKey. The fourth part compares mental health parameters like depression, anxiety, traumatization, somatization, psychoticism, quality of life, as well as "pathways-to-care" of refuKey-treated refugees before and after treatment and, in a follow-up, to a non-refuKey-treated refugee control group. Results: RefuKey-treated refugees reported many mental health problems and estimated their mental health burden as high. The symptoms decreased significantly over the course of treatment. Mental health in the refuKey sample was strongly linked to post-migration stressors. Discussion: The state of mental health care for refugees is discussed. Implications for the improvement and the need for adaptation of routine mental health care services are drawn.