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Primary schizophreniform psychoses are thought to be caused by complex gene–environment interactions. Secondary forms are based on a clearly identifiable organic cause, in terms of either an etiological or a relevant pathogenetic factor. The secondary or “symptomatic” forms of psychosis have reentered the focus stimulated by the discovery of autoantibody (Ab)-associated autoimmune encephalitides (AEs), such as anti-NMDA-R encephalitis, which can at least initially mimic variants of primary psychosis. These newly described secondary, immune-mediated schizophreniform psychoses typically present with the acute onset of polymorphic psychotic symptoms. Over the course of the disease, other neurological phenomena, such as epileptic seizures, movement disorders, or reduced levels of consciousness, usually arise. Typical clinical signs for AEs are the acute onset of paranoid hallucinatory symptoms, atypical polymorphic presentation, psychotic episodes in the context of previous AE, and additional neurological and medical symptoms such as catatonia, seizure, dyskinesia, and autonomic instability. Predominant psychotic courses of AEs have also been described casuistically. The term autoimmune psychosis (AP) was recently suggested for these patients. Paraclinical alterations that can be observed in patients with AE/AP are inflammatory cerebrospinal fluid (CSF) pathologies, focal or generalized electroencephalographic slowing or epileptic activity, and/or suspicious “encephalitic” imaging findings. The antibody analyses in these patients include the testing of the most frequently found Abs against cell surface antigens (NMDA-R, CASPR2, LGI1, AMPA-R, GABAB-R), intracellular antigens (Hu, Ri, Yo, CV2/CRMP5, Ma2 [Ta], amphiphysin, GAD65), thyroid antigens (TG, TPO), and antinuclear Abs (ANA). Less frequent antineuronal Abs (e.g., against DPPX, GABAA-R, glycine-R, IgLON5) can be investigated in the second step when first step screening is negative and/or some specific clinical factors prevail. Beyond, tissue-based assays on brain slices of rodents may detect previously unknown antineuronal Abs in some cases. The detection of clinical and/or paraclinical pathologies (e.g., pleocytosis in CSF) in combination with antineuronal Abs and the exclusion of alternative causes may lead to the diagnosis of AE/AP and enable more causal therapeutic immunomodulatory opportunities.

Major depression is a debilitating psychiatric illness that is typically associated with low mood and anhedonia. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximize sample size, we meta-analyzed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 genesets associated with depression, including both genes and gene pathways associated with synaptic structure and neurotransmission. An enrichment analysis provided further evidence of the importance of prefrontal brain regions. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant after multiple testing correction. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding etiology and developing new treatment approaches.The authors conducted a genetic meta-analysis of depression and found 269 associated genes. These genes highlight several potential drug repositioning opportunities, and relationships with depression were found for neuroticism and smoking.

Obsessive-compulsive disorder (OCD) is a highly disabling mental illness that can be divided into frequent primary and rarer organic secondary forms. Its association with secondary autoimmune triggers was introduced through the discovery of Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal infection (PANDAS) and Pediatric Acute onset Neuropsychiatric Syndrome (PANS). Autoimmune encephalitis and systemic autoimmune diseases or other autoimmune brain diseases, such as multiple sclerosis, have also been reported to sometimes present with obsessive-compulsive symptoms (OCS). Subgroups of patients with OCD show elevated proinflammatory cytokines and autoantibodies against targets that include the basal ganglia. In this conceptual review paper, the clinical manifestations, pathophysiological considerations, diagnostic investigations, and treatment approaches of immune-related secondary OCD are summarized. The novel concept of “autoimmune OCD” is proposed for a small subgroup of OCD patients, and clinical signs based on the PANDAS/PANS criteria and from recent experience with autoimmune encephalitis and autoimmune psychosis are suggested. Red flag signs for “autoimmune OCD” could include (sub)acute onset, unusual age of onset, atypical presentation of OCS with neuropsychiatric features (e.g., disproportionate cognitive deficits) or accompanying neurological symptoms (e.g., movement disorders), autonomic dysfunction, treatment resistance, associations of symptom onset with infections such as group A streptococcus, comorbid autoimmune diseases or malignancies. Clinical investigations may also reveal alterations such as increased levels of anti-basal ganglia or dopamine receptor antibodies or inflammatory changes in the basal ganglia in neuroimaging. Based on these red flag signs, the criteria for a possible, probable, and definite autoimmune OCD subtype are proposed.

Anxiety-like behavior of rodents is frequently accompanied by reduced exploration. Here, we identify dissociable components of anxiety, fear, and exploratory drive of sated and foraging mice. With the help of behavioral assays, including the open field task, elevated plus maze, dark–light transition task, and beetle mania task, we demonstrate a general increase in exploration by food restriction. Food-restricted mice bred for high anxiety behavior (HAB) showed ameliorated anxiety- but not fear-related behavior. By means of principal component analysis, we identified three independent components, which resemble the behavioral dimensions proposed by Gray’s Reinforcement Sensitivity Theory (approach behavior, avoidance behavior, and decision making). Taken together, we demonstrate anxiolytic consequences of food restriction in a mouse model of anxiety disorders that can be dissociated from a general increase in foraging behavior.

Depression is more frequent among individuals exposed to traumatic events. Both trauma exposure and depression are heritable. However, the relationship between these traits, including the role of genetic risk factors, is complex and poorly understood. When modelling trauma exposure as an environmental influence on depression, both gene-environment correlations and gene-environment interactions have been observed. The UK Biobank concurrently assessed Major Depressive Disorder (MDD) and self-reported lifetime exposure to traumatic events in 126,522 genotyped individuals of European ancestry. We contrasted genetic influences on MDD stratified by reported trauma exposure (final sample size range: 24,094–92,957). The SNP-based heritability of MDD with reported trauma exposure (24%) was greater than MDD without reported trauma exposure (12%). Simulations showed that this is not confounded by the strong, positive genetic correlation observed between MDD and reported trauma exposure. We also observed that the genetic correlation between MDD and waist circumference was only significant in individuals reporting trauma exposure (rg = 0.24, p = 1.8 × 10−7 versus rg = −0.05, p = 0.39 in individuals not reporting trauma exposure, difference p = 2.3 × 10−4). Our results suggest that the genetic contribution to MDD is greater when reported trauma is present, and that a complex relationship exists between reported trauma exposure, body composition, and MDD.

Single-pulse and repetitive transcranial magnetic stimulation (rTMS) are used in clinical practice for diagnostic and therapeutic purposes. However, rTMS-based therapies that lead to a significant and sustained reduction in neuropsychiatric symptoms remain scarce. While it is generally accepted that the stimulation frequency plays a crucial role in producing the therapeutic effects of rTMS, less attention has been dedicated to determining the role of the electric field strength. Conventional threshold-based intensity selection approaches, such as the resting motor threshold, produce variable stimulation intensities and electric fields across participants and cortical regions. Insufficient standardization of electric field strength may contribute to the variability of rTMS effects and thus therapeutic success. Computational approaches that can prospectively optimize the electric field and standardize it across patients and cortical targets may overcome some of these limitations. Here, we discuss these approaches and propose that electric field standardization will be instrumental for translational science frameworks (e.g., multiscale modeling and basic science approaches) aimed at deciphering the subcellular, cellular, and network mechanisms of rTMS. Advances in understanding these mechanisms will be important for optimizing rTMS-based therapies in psychiatry.

Transcranial direct current stimulation (tDCS) is increasingly used as a form of noninvasive brain stimulation to treat psychiatric disorders; however, its mechanism of action remains unclear. Prolonged visual stimulation (PVS) can enhance evoked EEG potentials (visually evoked potentials, VEPs) and has been proposed as a tool to examine long-term potentiation (LTP) in humans. The objective of the current study was to induce and analyze VEP plasticity and examine whether tDCS could either modulate or mimic plasticity changes induced by PVS. Thirty-eight healthy participants received tDCS, PVS, either treatment combined or neither treatment, with stimulation sessions being separated by one week. One session consisted of a baseline VEP measurement, one stimulation block, and six test VEP measurements. For PVS, a checkerboard reversal pattern was presented, and for tDCS, a constant current of 1 mA was applied via each bioccipital anodal target electrode for 10 min (Fig. S1). Both stimulation types decreased amplitudes of C1 compared to no stimulation (F = 10.1; p = 0.002) and led to a significantly smaller increase (PVS) or even decrease (tDCS) in N1 compared to no stimulation (F = 4.7; p = 0.034). While all stimulation types increased P1 amplitudes, the linear mixed effects model did not detect a significant difference between active stimulation and no stimulation. Combined stimulation induced sustained plastic modulation of C1 and N1 but with a smaller effect size than what would be expected for an additive effect. The results demonstrate that tDCS can directly induce LTP-like plasticity in the human cortex and suggest a mechanism of action of tDCS relying on the restoration of dysregulated synaptic plasticity in psychiatric disorders such as depression and schizophrenia.

Panic disorder (PD) has a lifetime prevalence of 2–4% and heritability estimates of 40%. The contributory genetic variants remain largely unknown, with few and inconsistent loci having been reported. The present report describes the largest genome-wide association study (GWAS) of PD to date comprising genome-wide genotype data of 2248 clinically well-characterized PD patients and 7992 ethnically matched controls. The samples originated from four European countries (Denmark, Estonia, Germany, and Sweden). Standard GWAS quality control procedures were conducted on each individual dataset, and imputation was performed using the 1000 Genomes Project reference panel. A meta-analysis was then performed using the Ricopili pipeline. No genome-wide significant locus was identified. Leave-one-out analyses generated highly significant polygenic risk scores (PRS) (explained variance of up to 2.6%). Linkage disequilibrium (LD) score regression analysis of the GWAS data showed that the estimated heritability for PD was 28.0–34.2%. After correction for multiple testing, a significant genetic correlation was found between PD and major depressive disorder, depressive symptoms, and neuroticism. A total of 255 single-nucleotide polymorphisms (SNPs) with p < 1 × 10−4 were followed up in an independent sample of 2408 PD patients and 228,470 controls from Denmark, Iceland and the Netherlands. In the combined analysis, SNP rs144783209 showed the strongest association with PD (pcomb = 3.10  × 10−7). Sign tests revealed a significant enrichment of SNPs with a discovery p-value of <0.0001 in the combined follow up cohort (p = 0.048). The present integrative analysis represents a major step towards the elucidation of the genetic susceptibility to PD.

Inflammatory processes involving altered microglial activity may play a relevant role in the pathophysiology of depressive disorders. Glial fibrillary acidic protein (GFAP) and calcium-binding protein S100B are considered microglial markers. To date, their role has been studied in the serum and tissue material of patients with unipolar depression but not in the cerebrospinal fluid (CSF). Therefore, the aim of the current study was to examine GFAP and S100B levels in the CSF of patients with major depression to better understand their role in affective disorders. In this retrospective study, 102 patients with unipolar depression and 39 mentally healthy controls with idiopathic intracranial hypertension were investigated. GFAP and S100B levels were measured using commercially available ELISA kits. CSF routine parameters were collected during routine clinical care. The mean values of GFAP and S100B were compared using age (and sex) corrected ANOVAs. Matched subgroups were analyzed by using an independent sample t-test. In addition, correlation analyses between GFAP/S100B levels and CSF routine parameters were performed within the patient group. Patients with unipolar depression had significantly higher levels of GFAP than controls (733.22 pg/ml vs. 245.56 pg/ml, p < 0.001). These results remained significant in a sub-analysis in which all controls were compared with patients suffering from depression matched 1:1 by age and sex (632.26 pg/ml vs. 245.56 pg/ml, p < 0.001). Levels of S100B did not differ significantly between patients and controls (1.06 ng/ml vs. 1.17 ng/ml, p = 0.385). GFAP levels correlated positively with albumin quotients (p < 0.050), S100B levels correlated positively with white blood cell counts (p = 0.001), total protein concentrations (p < 0.001), and albumin quotients (p = 0.001) in the CSF. The significance of the study is limited by its retrospective and open design, methodological aspects, and the control group with idiopathic intracranial hypertension. In conclusion, higher GFAP levels in patients with depression may be indicative of altered microglia activity, especially in astrocytes, in patients with unipolar depression. In addition, correlation analyses support the idea that S100B levels could be related to the integrity of the blood–brain/CSF barrier. Further multimodal and longitudinal studies are necessary to validate these findings and clarify the underlying biological processes.

The COVID-19 pandemic and associated countermeasures had an immensely disruptive impact on people’s lives. Due to the lack of systematic pre-pandemic data, however, it is still unclear how individuals’ psychological health has been affected across this incisive event. In this study, we analyze longitudinal data from two healthy samples ( N  = 307) to provide quasi-longitudinal insight into the full trajectory of psychological burden before (baseline), during the first peak, and at a relative downturn of the COVID-19 pandemic. Our data indicated a medium rise in psychological strain from baseline to the first peak of the pandemic ( d  = 0.40). Surprisingly, this was overcompensated by a large decrease of perceived burden until downturn ( d  =  − 0.93), resulting in a positive overall effect of the COVID-19 pandemic on mental health ( d  = 0.44). Accounting for this paradoxical positive effect, our results reveal that the post-pandemic increase in mental health is driven by individuals that were already facing psychological challenges before the pandemic. These findings suggest that coping with acute challenges such as the COVID-19 pandemic can stabilize previously impaired mental health through reframing processes.