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Abstract The global impact of SARS-CoV-2 infection has raised concerns about secondary diseases beyond acute illness. This review explores the significance and potential underlying mechanisms of how SARS-CoV-2 infection might elicit an immune response targeting N-methyl-D-aspartate (NMDA) receptors, and its implications for autoimmune-driven neuropsychiatric manifestations. We identified 19 published case reports of NMDA receptor encephalitis associated with SARS-CoV-2 infection or vaccination by a systematic literature search. The significance of these reports was limited since it is not clear if a coincidental or causal relationship exists between SARS-CoV-2 infection or vaccination and manifestation of NMDA receptor encephalitis. The included studies were hampered by difficulties in establishing if these patients had pre-existing NMDA receptor antibodies which entered the brain by infection- or vaccination-associated transient blood-brain barrier leakage. In addition, four cases had comorbid ovarian teratoma, which is a known trigger for development of NMDA receptor encephalitis. Considering that billions of people have contracted COVID-19 or have been vaccinated against this virus, the publication of only 19 case reports with a possible link to NMDA receptor encephalitis, indicates that it is rare. In conclusion, these findings do not support the case that SARS-CoV-2 infection or vaccination led to an increase of existing or de novo encephalitis mediated by an autoimmune response targeting NMDA receptor function. Nevertheless, this work underscores the importance of ongoing vigilance in monitoring viral outbreaks and their potential impact on the central nervous system through basic, epidemiological and translational research.

BackgroundNeuronal nicotinic acetylcholine receptors (nAChRs) are abundant in the central nervous system (CNS), playing critical roles in brain function. Antigenicity of nAChRs has been well demonstrated with antibodies to ganglionic AChR subtypes (i.e., subunit α3 of α3β4-nAChR) and muscle AChR autoantibodies, thus making nAChRs candidate autoantigens in autoimmune CNS disorders. Antibodies to several membrane receptors, like NMDAR, have been identified in autoimmune encephalitis syndromes (AES), but many AES patients have yet to be unidentified for autoantibodies. This study aimed to develop of a cell-based assay (CBA) that selectively detects potentially pathogenic antibodies to subunits of the major nAChR subtypes (α4β2- and α7-nAChRs) and its use for the identification of such antibodies in “orphan” AES cases.MethodsThe study involved screening of sera derived from 1752 patients from Greece, Turkey and Italy, who requested testing for AES-associated antibodies, and from 1203 “control” patients with other neuropsychiatric diseases, from the same countries or from Germany. A sensitive live-CBA with α4β2-or α7-nAChR–transfected cells was developed to detect antibodies against extracellular domains of nAChR major subunits. Flow cytometry (FACS) was performed to confirm the CBA findings and indirect immunohistochemistry (IHC) to investigate serum autoantibodies’ binding to rat brain tissue.ResultsThree patients were found to be positive for serum antibodies against nAChR α4 subunit by CBA and the presence of the specific antibodies was quantitatively confirmed by FACS. We detected specific binding of patient‐derived serum anti‐nAChR α4 subunit antibodies to rat cerebellum and hippocampus tissue. No serum antibodies bound to the α7-nAChR-transfected or control-transfected cells, and no control serum antibodies bound to the transfected cells. All patients positive for serum anti‐nAChRs α4 subunit antibodies were negative for other AES-associated antibodies. All three of the anti‐nAChR α4 subunit serum antibody-positive patients fall into the AES spectrum, with one having Rasmussen encephalitis, another autoimmune meningoencephalomyelitis and another being diagnosed with possible autoimmune encephalitis.ConclusionThis study lends credence to the hypothesis that the major nAChR subunits are autoimmune targets in some cases of AES and establishes a sensitive live-CBA for the identification of such patients.

The sudden appearance and devastating effects of the COVID-19 pandemic resulted in the need for multiple adaptive changes in societies, business operations and healthcare systems across the world. This review describes the development and increased use of digital technologies such as chat bots, electronic diaries, online questionnaires and even video gameplay to maintain effective treatment standards for individuals with mental health conditions such as depression, anxiety and post-traumatic stress syndrome. We describe how these approaches have been applied to help meet the challenges of the pandemic in delivering mental healthcare solutions. The main focus of this narrative review is on describing how these digital platforms have been used in diagnostics, patient monitoring and as a treatment option for the general public, as well as for frontline medical staff suffering with mental health issues.

Numerous studies have now implicated a role for inflammation in schizophrenia. However, many aspects surrounding this aspect of the disease are still controversial. This controversy has been driven by conflicting evidence on the role of both pro-and anti-inflammatory factors and by often contentious findings concerning cytokine and immune cell profiles in the central nervous system and periphery. Current evidence supports the point that interleukin-6 is elevated in CSF, but does not support activation of microglia, resident macrophage-like cells in the brain. Furthermore, the mechanisms involving transit of the peripheral immune system factors across the blood brain barrier to central parenchyma have still not been completely elucidated. This process appears to involve perivascular macrophages and accompanying dendritic cells retained in the parenchyma by the chemokine and cytokine composition of the surrounding milieu. In addition, a number of studies have shown that this can be modulated by infection with viruses such as herpes simplex virus type I which may disrupt antigen presentation in the perivascular space, with long-lasting consequences. In this review article, we discuss the role of inflammation and viral infection as potential disease modifiers in schizophrenia. The primary viral hit may occur in the fetus in utero, transforming the immune response regulatory T-cells or the virus may secondarily remain latent in immune cells or neurons and modify further immune responses in the developing individual. It is hoped that unraveling this pathway further and solidifying our understanding of the pathophysiological mechanisms involved will pave the way for future studies aimed at identification and implementation of new biomarkers and drug targets. This may facilitate the development of more effective personalized therapies for individuals suffering with schizophrenia.

Nicotinic acetylcholine receptors (nAChRs) are widely expressed in many and diverse cell types, participating in various functions of cells, tissues and systems. In this review, we focus on the autoimmunity against neuronal nAChRs, the specific autoantibodies and their mechanisms of pathological action in selected autoimmune diseases. We summarize the current relevant knowledge from human diseases as well as from experimental models of autoimmune neurological disorders related to antibodies against neuronal nAChR subunits. Despite the well-studied high immunogenicity of the muscle nAChRs where autoantibodies are the main pathogen of myasthenia gravis, autoimmunity to neuronal nAChRs seems infrequent, except for the autoantibodies to the ganglionic receptor, the α3 subunit containing nAChR (α3-nAChR), which are detected and are likely pathogenic in Autoimmune Autonomic Ganglionopathy (AAG). We describe the detection, presence and function of these antibodies and especially the recent development of a cell-based assay (CBA) which, contrary to until recently available assays, is highly specific for AAG. Rare reports of autoantibodies to the other neuronal nAChR subtypes include a few cases of antibodies to α7 and/or α4β2 nAChRs in Rasmussen encephalitis, schizophrenia, autoimmune meningoencephalomyelitis, and in some myasthenia gravis patients with concurrent CNS symptoms. Neuronal-type nAChRs are also present in several non-excitable tissues, however the presence and possible role of antibodies against them needs further verification. It is likely that the future development of more sensitive and disease-specific assays would reveal that neuronal nAChR autoantibodies are much more frequent and may explain the mechanisms of some seronegative autoimmune diseases.

IntroductionTreatment of severe mental illness (SMI) symptoms, especially negative symptoms and cognitive dysfunction in schizophrenia, remains a major unmet need. There is good evidence that SMIs have a strong genetic background and are characterized by multiple biological alterations, including disturbed brain circuits and connectivity, dysregulated neuronal excitation-inhibition, disturbed dopaminergic and glutamatergic pathways, and partially dysregulated inflammatory processes. The ways in which the dysregulated signaling pathways are interconnected remains largely unknown, in part because well-characterized clinical studies on comprehensive biomaterial are lacking. Furthermore, the development of drugs to treat SMIs such as schizophrenia is limited by the use of operationalized symptom-based clusters for diagnosis.MethodsIn line with the Research Domain Criteria initiative, the Clinical Deep Phenotyping (CDP) study is using a multimodal approach to reveal the neurobiological underpinnings of clinically relevant schizophrenia subgroups by performing broad transdiagnostic clinical characterization with standardized neurocognitive assessments, multimodal neuroimaging, electrophysiological assessments, retinal investigations, and omics-based analyzes of blood and cerebrospinal fluid. Moreover, to bridge the translational gap in biological psychiatry the study includes in vitro investigations on human-induced pluripotent stem cells, which are available from a subset of participants.ResultsHere, we report on the feasibility of this multimodal approach, which has been successfully initiated in the first participants in the CDP cohort; to date, the cohort comprises over 194 individuals with SMI and 187 age and gender matched healthy controls. In addition, we describe the applied research modalities and study objectives.DiscussionThe identification of cross-diagnostic and diagnosis-specific biotype-informed subgroups of patients and the translational dissection of those subgroups may help to pave the way toward precision medicine with artificial intelligence-supported tailored interventions and treatment. This aim is particularly important in psychiatry, a field where innovation is urgently needed because specific symptom domains, such as negative symptoms and cognitive dysfunction, and treatment-resistant symptoms in general are still difficult to treat.

Background: Disruptions of neuronal macro- and microcircuits in schizophrenia (SCZ) have been attributed to pathologies of neuronal connectivity. We hypothesized that during acute psychosis structural damage to axons and synapses occurs in a subset of patients, rendering them more susceptible to poor treatment outcomes or relapse. Methods: Neurofilament light-chain protein (NfL), a marker of axonal and synaptic damage, was quantified in sera of acutely ill unmedicated schizophrenia patients (SCZ, n=98) at hospital admission (T0) and after 6 weeks of inpatient treatment (T6), compared to healthy controls (HC, n=132). Additionally, we analyzed blood cell counts, the levels of 171 serum biomarkers, clinical symptomatology and functioning relapse occurrences requiring hospitalisation during the 5-year follow-up. Univariate analysis and support vector machine learning were employed to identify SCZ with increased NfL, interrogate the relationship between biological factors and NfL and examine whether NfL and associated biological factors can predict treatment outcome or likelihood of relapse. Results: NfL was increased in SCZ versus HC (p=0.014), correlated positively with positive and negative syndrome scale-positive scores (rho=0.265, P=0.019) and inversely with global assessment of functioning-scores (rho=-0.365, P

Abstract Background We recently reported increased levels of neutrophils, monocytes and C-reactive protein (CRP) correlated with symptom severity in acute schizophrenia. Here, we investigated if a similar pattern of innate immune system activation occurs in major depression (MD). Methods We assessed differential blood counts, CRP, depression symptoms (HAMD-21) and psychosocial functioning (GAF) in controls (n = 129) and patients with first (FEMD: n = 82) or recurrent (RMD: n = 47) disease episodes of MD at baseline (T0; hospital admission) and after 6-weeks treatment (T6). Results Considering smoking, BMI and gender as covariates, neutrophils (FEMD: p = 0.034, RMD: p = 0.034) and CRP (FEMD: p

Abstract Approximately 30% of individuals with severe SARS-CoV-2 infections also develop neurological and psychiatric complaints. In rare cases, the occurrence of autoimmune encephalitis has been reported after SARS-CoV-2 infection. In this systematic review, we have identified eight SARS-CoV-2-associated cases of anti-NMDA receptor encephalitis. All had cerebrospinal fluid antibodies against the NMDA receptor and a recent onset of working memory deficits, altered mental status, or psychiatric symptoms, such as confusion, agitation, auditory hallucination, catatonia and speech dysfunction. All patients received high-dose steroid and immunoglobulin therapeutics and conditions improved in each case. These findings suggest that clinical attention should be paid to warning signs of autoimmune encephalitis in severe COVID-19 cases. If characteristic features of autoimmune encephalitis are present, autoantibody diagnostics should be performed and confirmed cases should be treated with immunotherapy to minimize neurological impairments.

GDP-Mannose Pyrophosphorylase B (GMPPB) is a key enzyme for glycosylation. Previous studies suggested a dysregulation of GMPBB and mannose in depression. Evidence, however, was sporadic and interventions to reverse these changes are unknown. Here, we show that GMPPB protein, but not RNA abundance is increased in the postmortem prefrontal cortex (PFC) of depressed patients and the chronic variable stress (CVS) mouse-model. This is accompanied by higher plasma mannose levels. Importantly, a single dose of intraperitoneally administered vitamin B12, which has previously been shown to rapidly reverse behavioral symptoms and molecular signatures of chronic stress in mice, normalized GMPPB plasma mannose levels and elevated GDP-mannose abundance. In summary, these data underline metabolic dysregulation in chronic stress and depression and provide further support for rapid effects of vitamin B12 on chronic stress.

Based on current implications of the SARS-CoV-2 pandemic with regards to mental health, we show that biological links exist between inflammation and mental illness in addition to psychoreactive effects. We describe key principles of the biological interaction of the immune system and the mind, as well as the possible routes of viral entry into the brain. In addition, we provide a stepwise scheme for the diagnosis and therapy of autoimmune-encephalitis with schizophrenia-like symptomatology as a general guide for clinical practice and in the specialized scenario of infections, such as those caused by the SARS-CoV-2 virus.

Objectives: The paper presents the results of the statistical analyses of completed suicides in the Tri-City area, Poland from 1980 to 2009. The main objective of this study was to evaluate the trait dynamics of completed suicides in the context of drastic political and socioeconomic transformations. Methods: Statistical analysis of approximately 30,000 autopsy cases, including 3885 suicides, was performed. All data were evaluated using the STATISTICA version 10 software. Results: The analyses revealed an increasing number of suicide completers. Men committed suicide more frequently and were younger than female suicide committers. We observed also an increase in the mean age of suicide completers. More suicides occurred in the spring and summer compared to autumn and winter seasons. The most common method of suicide was hanging. Conclusions: The results of this study suggest temporal changes in trends, methods and social profile of suicide attempters related to political and socioeconomic changes in Poland in the years 1980–2009. These included the activity of the opposition movement “Solidarity”, the introduction of martial law in December 1981, the fall of communism and democratization processes, and the shifting from the system of a centrally planned economy to a neoliberal capitalism.

Abstract Growing data point to the overlap between psychosis and pathological processes associated with immunological dysregulation as well as inflammation. Notably, the recent discovery of antibodies against synaptic and neuronal cell membrane proteins such as anti-N-methyl-d-aspartate receptor provides more direct evidence of the etiological connection between autoimmunity and subsequent hazard of psychosis. Here, we advocate the use of term “autoimmune psychosis,” as this term suggests that autoimmune disorders can masquerade as drug-resistant primary psychosis, and this subtype of psychosis has anatomical and immunological footprints in the brain, despite the frequent absence of structural abnormalities on conventional brain MRI. Furthermore, this term might serve as a reminder not to overlook appropriate neurological workup such as neuroimaging and EEG testing, as well as CSF analysis, for cases with acute or subacute atypical onset of neuropsychiatric presentations including those dominated by acute psychotic symptoms. We propose etiologically and serologically oriented subclassification as well as multi-modal diagnostic approach to address some of the challenges inherent to early diagnosis of patients presenting with atypical and refractory new-onset psychotic symptoms of autoimmune origin. This is particularly relevant to the diagnosis of seronegative but probable autoimmune psychosis (SPAP) that might masquerade as antipsychotic drug-resistant primary psychotic disorder. This distinction is therapeutically important as autoimmune-related psychotic symptomatology can frequently respond well to timely treatment with proper immune modulatory therapies.

Background: Ketamine is receiving increasing attention as a rapid-onset antidepressant in patients suffering from major depressive disorder (MDD) with treatment resistance or severe suicidal ideation. Ketamine modulates several neurotransmitter systems, including norepinephrine via the norepinephrine transporter (NET), both peripherally and centrally. The locus coeruleus (LC), which has high NET concentration, has been attributed to brain networks involved in depression. Thus we investigated the effects of single-dose of racemic ketamine on the LC using resting state functional MRI. Methods: Fifty-nine healthy participants (mean age 25.57 ± 4.72) were examined in a double-blind, randomized, placebo-controlled study with 7 Tesla MRI. We investigated the resting state functional connectivity (rs-fc) of the LC before and one hour after subanesthetic ketamine injection (0.5 mg/kg), as well as associations between its rs-fc and a common polymorphism in the NET gene (rs28386840). Results: A significant interaction of drug and time was revealed, and post hoc testing showed decreased rs-fc between LC and the thalamus after ketamine administration compared with baseline levels, including the mediodorsal, ventral anterior, ventral lateral, ventral posterolateral and centromedian nuclei. The rs-fc reduction was more pronounced in NET rs28386840 [AA] homozygous subjects than in [T] carriers. Conclusions: We demonstrated acute rs-fc changes after ketamine administration in the central node of the norepinephrine pathway. These findings may contribute to understanding the antidepressant effect of ketamine at the system level, supporting modes of action on networks subserving aberrant arousal regulation in depression. Keywords: Ketamine, Locus coeruleus (LC), Norepinephrine transporter (NET), Attention networks, Pharmacogenetics, Major depressive disorder (MDD)

Abstract Genome-wide association studies (GWAS) and proteomic studies have provided convincing evidence implicating alterations in immune/inflammatory processes in schizophrenia. However, despite the convergence of evidence, direct links between the genetic and proteomic findings are still lacking for schizophrenia. We investigated associations between single nucleotide polymorphisms (SNPs) from the custom-made PsychArray and the expression levels of 190 multiplex immunoassay profiled serum proteins in 149 schizophrenia patients and 198 matched controls. We identified associations between 81 SNPs and 29 proteins, primarily involved in immune/inflammation responses. Significant SNPxDiagnosis interactions were identified for eight serum proteins including Factor-VII[rs555212], Alpha-1-Antitrypsin[rs11846959], Interferon-Gamma Induced Protein 10[rs4256246] and von-Willebrand-Factor[rs12829220] in the control group; Chromogranin-A[rs9658644], Cystatin-C[rs2424577] and Vitamin K-Dependent Protein S[rs6123] in the schizophrenia group; Interleukin-6 receptor[rs7553796] in both the control and schizophrenia groups. These results suggested that the effect of these SNPs on expression of the respective proteins varies with diagnosis. The combination of patient-specific genetic information with blood biomarker data opens a novel approach to investigate disease mechanisms in schizophrenia and other psychiatric disorders. Our findings not only suggest that blood protein expression is influenced by polymorphisms in the corresponding gene, but also that the effect of certain SNPs on expression of proteins can vary with diagnosis.

Abstract Background Precision medicine is a new and important topic in psychiatry. Psychiatry has not yet benefited from the advanced diagnostic and therapeutic technologies that form an integral part of other clinical specialties. Thus, the vision of precision medicine as applied to psychiatry – ‘precision psychiatry’ – promises to be even more transformative than in other fields of medicine, which have already lessened the translational gap. Discussion Herein, we describe ‘precision psychiatry’ and how its several implications promise to transform the psychiatric landscape. We pay particular attention to biomarkers and to how the development of new technologies now makes their discovery possible and timely. The adoption of the term ‘precision psychiatry’ will help propel the field, since the current term ‘precision medicine’, as applied to psychiatry, is impractical and does not appropriately distinguish the field. Naming the field ‘precision psychiatry’ will help establish a stronger, unique identity to what promises to be the most important area in psychiatry in years to come. Conclusion In summary, we provide a wide-angle lens overview of what this new field is, suggest how to propel the field forward, and provide a vision of the near future, with ‘precision psychiatry’ representing a paradigm shift that promises to change the landscape of how psychiatry is currently conceived.

This is the first study to identify lipidomic markers in plasma associated with response of acutely ill schizophrenia patients in response to specific antipsychotic treatments. The study population included 54 schizophrenia patients treated with antipsychotics for 6 weeks. Treatment led to significant improvement in positive and negative symptoms for 34 patients with little or no improvement for 20 patients. In addition, 37 patients showed an increase in body mass index after the 6 week treatment period, consistent with effects on metabolism and the association of such effects with symptom improvement. Profiling of plasma samples taken prior to therapy using liquid chromatography tandem mass spectrometry (LC-MS/MS) resulted in identification of 38, 10, and 52 compounds associated with the olanzapine, risperidone, and quetiapine treatment groups, which could be used to distinguish responders from non-responders. Limitations include the retroactive active nature of the study and the small sample size. Further investigations with larger sample sets could lead to the development of a molecular test that could be used to help psychiatrists determine the best treatment options for each patient.

We describe the validation of a serum-based test developed by Rules-Based Medicine which can be used to help confirm the diagnosis of schizophrenia. In preliminary studies using multiplex immunoassay profiling technology, we identified a disease signature comprised of 51 analytes which could distinguish schizophrenia (n = 250) from control (n = 230) subjects. In the next stage, these analytes were developed as a refined 51-plex immunoassay panel for validation using a large independent cohort of schizophrenia (n = 577) and control (n = 229) subjects. The resulting test yielded an overall sensitivity of 83% and specificity of 83% with a receiver operating characteristic area under the curve (ROC-AUC) of 89%. These 51 immunoassays and the associated decision rule delivered a sensitive and specific prediction for the presence of schizophrenia in patients compared to matched healthy controls.

BACKGROUND: In schizophrenia, sex specific dimorphisms related to age of onset, course of illness and response to antipsychotic treatment may be mirrored by sex-related differences in the underlying molecular pathways. METHODOLOGY/PRINCIPAL FINDINGS: Here, we have carried out multiplex immunoassay profiling of sera from 4 independent cohorts of first episode antipsychotic naive schizophrenia patients (n = 133) and controls (n = 133) to identify such sex-specific illness processes in the periphery. The concentrations of 16 molecules associated with hormonal, inflammation and growth factor pathways showed significant sex differences in schizophrenia patients compared with controls. In female patients, the inflammation-related analytes alpha-1-antitrypsin, B lymphocyte chemoattractant BLC and interleukin-15 showed negative associations with positive and negative syndrome scale (PANSS) scores. In male patients, the hormones prolactin and testosterone were negatively associated with PANSS ratings. In addition, we investigated molecular changes in a subset of 33 patients before and after 6 weeks of treatment with antipsychotics and found that treatment induced sex-specific changes in the levels of testosterone, serum glutamic oxaloacetic transaminase, follicle stimulating hormone, interleukin-13 and macrophage-derived chemokine. Finally, we evaluated overlapping and distinct biomarkers in the sex-specific molecular signatures in schizophrenia, major depressive disorder and bipolar disorder. CONCLUSIONS/SIGNIFICANCE: We propose that future studies should investigate the common and sex-specific aetiologies of schizophrenia, as the current findings suggest that different therapeutic strategies may be required for male and female patients.

INTRODUCTION: Former studies have investigated the potential of serum biomarkers for diseases affecting the human brain. In particular the glial protein S100B, a neuro- and gliotrophin inducing plasticity, seems to be involved in the pathogenesis and treatment of psychiatric diseases such as major depression and schizophrenia. Neuron-specific enolase (NSE) is a specific serum marker for neuronal damage. However, the specificity of these biomarkers for cell type and brain region has not been investigated in vivo until now. METHODS: We acquired two magnetic resonance imaging parameters sensitive to changes in gray and white matter (T(1)-weighted/diffusion tensor imaging) and obtained serum S100B and NSE levels of 41 healthy subjects. Additionally, we analyzed whole brain gene expressions of S100B in another male cohort of three subjects using the Allen Brain Atlas. Furthermore, a female post mortal brain was investigated using double immunofluorescence labelling with oligodendrocyte markers. RESULTS: We show that S100B is specifically related to white matter structures, namely the corpus callosum, anterior forceps and superior longitudinal fasciculus in female subjects. This effect was observed in fractional anisotropy and radial diffusivity - the latest an indicator of myelin changes. Histological data confirmed a co-localization of S100B with oligodendrocyte markers in the human corpus callosum. S100B was most abundantly expressed in the corpus callosum according to the whole genome Allen Human Brain Atlas. In addition, NSE was related to gray matter structures, namely the amygdala. This effect was detected across sexes. CONCLUSION: Our data demonstrates a very high S100B expression in white matter tracts, in particular in human corpus callosum. Our study is the first in vivo study validating the specificity of the glial marker S100B for the human brain, and supporting the assumption that radial diffusivity represents a myelin marker. Our results open a new perspective for future studies investigating major neuropsychiatric disorders.

Sex is an important factor in the prevalence, incidence, progression, and response to treatment of many medical conditions, including autoimmune and cardiovascular diseases and psychiatric conditions. Identification of molecular differences between typical males and females can provide a valuable basis for exploring conditions differentially affected by sex.Using multiplexed immunoassays, we analyzed 174 serum molecules in 9 independent cohorts of typical individuals, comprising 196 males and 196 females. Sex differences in analyte levels were quantified using a meta-analysis approach and put into biological context using k-means to generate clusters of analytes with distinct biological functions. Natural sex differences were established in these analyte groups and these were applied to illustrate sexually dimorphic analyte expression in a cohort of 22 males and 22 females with Asperger syndrome. Reproducible sex differences were found in the levels of 77 analytes in serum of typical controls, and these comprised clusters of molecules enriched with distinct biological functions. Analytes involved in fatty acid oxidation/hormone regulation, immune cell growth and activation, and cell death were found at higher levels in females, and analytes involved in immune cell chemotaxis and other indistinct functions were higher in males. Comparison of these naturally occurring sex differences against a cohort of people with Asperger syndrome indicated that a cluster of analytes that had functions related to fatty acid oxidation/hormone regulation was associated with sex and the occurrence of this condition.Sex-specific molecular differences were detected in serum of typical controls and these were reproducible across independent cohorts. This study extends current knowledge of sex differences in biological functions involved in metabolism and immune function. Deviations from typical sex differences were found in a cluster of molecules in Asperger syndrome. These findings illustrate the importance of investigating the influence of sex on medical conditions.

Glutamatergic mechanisms and resting state functional connectivity alterations have been recently described as factors contributing to Major Depressive Disorder (MDD). Furthermore, the pregenual anterior cingulate cortex (pgACC) seems to play an important role for major depressive symptoms such as anhedonia and impaired emotion processing. We investigated 22 MDD patients and 22 healthy subjects using a combined Magnetic Resonance Spectroscopy (MRS) and Resting State functional Magnetic Resonance Imaging (fMRI) approach. Severity of depression was rated using the 21-item Hamilton Depression Scale (HAMD) and patients were divided into severely and mildly depressed subgroups according to HAMD scores. Because of their hypothesized role in depression we investigated the functional connectivity between pgACC and left anterior insular cortex (AI). The sum of Glutamate and Glutamine (Glx) in the pgACC, but not in left AI, predicted the resting state functional connectivity between the two regions exclusively in depressed patients. Furthermore, functional connectivity between these regions was significantly altered in the subgroup of severely depressed patients (HAMD>15) compared to healthy subjects and mildly depressed patients. Similarly the Glx ratios, relative to Creatine, in the pgACC were lowest in severely depressed patients. These findings support the involvement of glutamatergic mechanisms in severe MDD which are related to the functional connectivity between pgACC and AI and depression severity.