The cognitive anxiety sensitivity treatment (CAST) in anxiety prevention - Focus on separation anxiety and interoception.

Given the high prevalence and considerable clinical and societal burden of anxiety disorders, preventive measures are urgently warranted to reduce their incidence and overall healthcare impact. Anxiety sensitivity (AS) - a key element in learning theories of anxiety disorders in the context of interoceptive conditioning - constitutes a malleable risk factor of particularly panic disorder and separation anxiety, which share developmental, nosological, epidemiological and pathomechanistic characteristics. The computer-assisted 'Cognitive Anxiety Sensitivity Treatment' (CAST) targeting interoceptive anxiety symptoms (cf. Schmidt et al., 2014) was translated, intensified and culturally adapted to German and evaluated in a sample of 105 healthy adult volunteers with elevated AS (mean ASI-3: 29.5) applying a randomized design. Success of the intervention was measured as a function of AS and separation anxiety (ASA-27) ∼6 weeks (T1) and ∼6 months (T2) after the intervention. As compared to waitlist, CAST resulted in a significant reduction of AS at both T1 and T2. Separation anxiety was not directly reduced by the intervention, but decreased mediated by a decline in AS. A composite interoceptive score capturing changes in sensitivity to respiratory symptoms during the baseline therapist-accompanied CAST session was shown to be predictive of overall response at T1. In sum, CAST-German Version was successfully established as an effective intervention reducing AS, while at the same time indirectly decreasing separation anxiety. A composite interoceptive score predicting treatment response might aid in further delineating risk markers informing targeted preventive interventions for anxiety disorders.

Oxytocin Receptor Gene DNA Methylation: A Biomarker of Treatment Response in Obsessive-Compulsive Disorder?

INTRODUCTION: Obsessive-compulsive disorder (OCD) is associated with high chronicity and treatment resistance, indicating the need for early therapy response markers enabling fast and personalized treatment adaptations. Although epigenetic mechanisms such as DNA methylation of the oxytocin receptor (OXTR) gene have previously been linked to OCD pathogenesis, epigenetic markers as predictors of treatment success have not yet been investigated in OCD. OBJECTIVE: For the first time, this therapyepigenetic study aimed to investigate the role of OXTR methylation as a treatment response marker in OCD. METHODS: In total, 113 inpatients with OCD (57 females) were compared to 113 age- and sex-matched healthy controls. Patients were investigated over a 10-week course of standardized, OCD-specific cognitive-behavioral psychotherapy. Clinical response was measured using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) at baseline, before in vivo exposure, and after therapy. OXTR exon III methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. RESULTS: Relative OXTR hypermethylation was observed in OCD patients compared to healthy controls. In OCD, higher baseline OXTR methylation was found to predict impaired treatment response at both categorical (responders vs. nonresponders) and dimensional (relative Y-BOCS reduction) levels, whereas lower baseline methylation was related to treatment response and greater symptom improvements. Analysis of Y-BOCS subdimensions revealed that the association between OXTR hypermethylation with impaired treatment response applied especially to symptoms related to obsessions, but not compulsions. CONCLUSIONS: OXTR hypermethylation may constitute a predictive marker of impaired treatment response in OCD and thus carries great potential for future personalized treatment efforts in OCD.

Epigenetics Underlying Susceptibility and Resilience Relating to Daily Life Stress, Work Stress, and Socioeconomic Status.

Susceptibility and resilience to mental disorders result from a complex choreography of gene-environment interactions with epigenetics at the intersection of external psychological stressors and internal biological systems. Increasing awareness of the growing disease burden influenced by daily life stress ("daily hassles"), work-related stress, and low socioeconomic status (SES) has resulted in a novel interest into their underlying molecular signatures. This review offers a brief outline of psychiatric epigenetics and a comprehensive overview of recent findings exploring the relationship of various occupational stressors and DNA methylation in epigenome-wide association studies (EWAS) and in candidate gene studies including the serotonin transporter (SLC6A4; 5-HTTLPR), melatonin receptor 1A (MTNR1A), brain-derived neurotrophic factor (BDNF), tyrosine hydroxylase (TH), and the protein family of DNA methyltransferases (DNMTs). Conceptual and methodological challenges of epigenetic investigations with a special focus on gene-environment interactions are highlighted and discussed. The findings are integrated into a pathophysiological framework featuring epigenetic plasticity factors and work-related stress as a possible central detrimental component targetable by workplace interventions. Finally, the potential of dynamic epigenetic biomarkers of treatment response to pharmacotherapy or psychotherapy is expanded upon.

The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention.

Mental disorders are highly complex and multifactorial in origin, comprising an elaborate interplay of genetic and environmental factors. Epigenetic mechanisms such as DNA modifications (e.g. CpG methylation), histone modifications (e.g. acetylation) and microRNAs function as a translator between genes and the environment. Indeed, environmental influences such as exposure to stress shape epigenetic patterns, and lifetime experiences continue to alter the function of the genome throughout the lifespan. Here, we summarize the recently burgeoning body of research regarding the involvement of aberrant epigenetic signatures in mediating an increased vulnerability to a wide range of mental disorders. We review the current knowledge of epigenetic changes to constitute useful markers predicting the clinical response to psychotherapeutic interventions, and of psychotherapy to alter - and potentially reverse - epigenetic risk patterns. Given first evidence pointing to a transgenerational transmission of epigenetic information, epigenetic alterations arising from successful psychotherapy might be transferred to future generations and thus contribute to the prevention of mental disorders. Findings are integrated into a multi-level framework highlighting challenges pertaining to the mechanisms of action and clinical implications of epigenetic research. Promising future directions regarding the prediction, prevention, and personalized treatment of mental disorders in line with a 'precision medicine' approach are discussed.

Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes.

Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10-7), particularly in the female subsample (p = 9.8 × 10-9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10-4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system.

Temporal proteomic profiling of postnatal human cortical development.

Healthy cortical development depends on precise regulation of transcription and translation. However, the dynamics of how proteins are expressed, function and interact across postnatal human cortical development remain poorly understood. We surveyed the proteomic landscape of 69 dorsolateral prefrontal cortex samples across seven stages of postnatal life and integrated these data with paired transcriptome data. We detected 911 proteins by liquid chromatography-mass spectrometry, and 83 were significantly associated with postnatal age (FDR < 5%). Network analysis identified three modules of co-regulated proteins correlated with age, including two modules with increasing expression involved in gliogenesis and NADH metabolism and one neurogenesis-related module with decreasing expression throughout development. Integration with paired transcriptome data revealed that these age-related protein modules overlapped with RNA modules and displayed collinear developmental trajectories. Importantly, RNA expression profiles that are dynamically regulated throughout cortical development display tighter correlations with their respective translated protein expression compared to those RNA profiles that are not. Moreover, the correspondence between RNA and protein expression significantly decreases as a function of cortical aging, especially for genes involved in myelination and cytoskeleton organization. Finally, we used this data resource to elucidate the functional impact of genetic risk loci for intellectual disability, converging on gliogenesis, myelination and ATP-metabolism modules in the proteome and transcriptome. We share all data in an interactive, searchable companion website. Collectively, our findings reveal dynamic aspects of protein regulation and provide new insights into brain development, maturation, and disease.

Cerebrospinal Fluid Concentrations of Neuronal Proteins Are Reduced in Primary Angiitis of the Central Nervous System.

Primary angiitis of the central nervous system (PACNS) is a rare autoimmune vasculitis limited to the CNS often causing substantial disability. Understanding of this disease is impaired by the lack of available biomaterial. Here, we collected cerebrospinal fluid (CSF) from patients with PACNS and matched controls and performed unbiased proteomics profiling using ion mobility mass spectrometry to identify novel disease mechanisms and candidate biomarkers. We identified 14 candidate proteins, including amyloid-beta A4 protein (APP), with reduced abundance in the CSF of PACNS patients and validated APP by Enzyme-linked Immunosorbent Assay (ELISA) in an extended cohort of patients with PACNS. Subsequent functional annotation surprisingly suggested neuronal pathology rather than immune activation in PACNS. Our study is the first to employ mass spectrometry to local immune reactions in PACNS and it identifies candidates such as APP with pathogenic relevance in PACNS to improve patient care in the future.

Oxytocin and Anxiety Disorders.

In the present chapter, we review the literature focusing on oxytocin (OT)-centered research in anxiety spectrum conditions, comprising separation anxiety disorder, specific phobias, social anxiety disorder (SAD), panic disorder, generalized anxiety disorder, and anxiety-related endophenotypes (e.g., trust behavior, behavioral inhibition, neuroticism, and state/trait anxiety). OT receptor gene (OXTR) polymorphisms have been implicated in gene-environment interactions with attachment style and childhood maltreatment and to influence clinical outcomes, including SAD intensity and limbic responsiveness. Epigenetic OXTR DNA methylation patterns have emerged as a link between categorical, dimensional, neuroendocrinological, and neuroimaging SAD correlates, highlighting them as potential peripheral surrogates of the central oxytocinergic tone. A pathophysiological framework of OT integrating the dynamic nature of epigenetic biomarkers and the summarized genetic and peripheral evidence is proposed. Finally, we emphasize opportunities and challenges of OT as a key network node of social interaction and fear learning in social contexts. In conjunction with multi-level investigations incorporating a dimensional understanding of social affiliation and avoidance in anxiety spectrum disorders, these concepts will help to promote research for diagnostic, state, and treatment response biomarkers of the OT system, advancing towards indicated preventive interventions and personalized treatment approaches.

Genetics of generalized anxiety disorder and related traits.

This review serves as a systematic guide to the genetics of generalized anxiety disorder (GAD) and further focuses on anxiety-relevant endophenotypes, such as pathological worry fear of uncertainty, and neuroticism. We inspect clinical genetic evidence for the familialityl heritability of GAD and cross-disorder phenotypes based on family and twin studies. Recent advances of linkage studies, genome-wide association studies, and candidate gene studies (eg, 5-HTT, 5-HT1A, MAOA, BDNF) are outlined. Functional and structural neuroimaging and neurophysiological readouts relating to peripheral stress markers and psychophysiology are further integrated, building a multilevel disease framework. We explore etiologic factors in gene-environment interaction approaches investigating childhood trauma, environmental adversity, and stressful life events in relation to selected candidate genes (5-HTT, NPSR1, COMT, MAOA, CRHR1, RGS2), Additionally, the pharmacogenetics of selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor treatment are summarized (5-HTT, 5-HT2A, COMT, CRHR1). Finally, GAD and trait anxiety research challenges and perspectives in the field of genetics, including epigenetics, are discussed.

Esta revisión propone una orientación sistemática para la genética del trastorno de ansiedad generalizada (TAG) y además se enfoca en los endofenotipos relevantes para la ansiedad, como las preocupaciones patológicas, el temor por la incertidumbre y el neuroticismo. Se revisan las evidencias clínico genéticas del carácter familiar/hereditario del TAG y los fenotipos de los trastornos cruzados en base a estudios familiares y de gemelos. Hay avances recientes de estudios de ligamiento, estudios de asociaciones de todo el genoma y de genes candidatos (por ejemplo, 5-HTT, 5-HT1A, MAOA, BDNF) que se han integrado en el contexto de neuroimágenes funcionales y estructurales, y de lecturas neurofisiológicas relacionadas con marcadores periféricos de estrés y psicofisiológicos. Los efectos del trauma infantil, la adversidad ambiental y los acontecimientos de vida estresantes son explorados desde la perspectiva de la interacción genes-ambiente (5-HTT, NPSR1, COMT, MAOA, CRHR1, RGS2). Además se resume la farmacogenética del tratamiento con ISRS y ISRN (5-HTT, 5-HT2A, COMT, CRHR1). Por último, se discuten los problemas y las perspectivas de la investigación en el campo de la genética, incluyendo la epigenética, del TAG y de los rasgos de ansiedad.

Cet article, qui se propose comme recommandation systématique pour la génétique des troubles anxieux généralisés (TAG), se concentre ensuite sur les endophénotypes pertinents pour l'anxiété, comme les craintes pathologiques, la peur de l'inconnu et le neuroticisme. Nous analysons les données génétiques cliniques, basées sur des études familiales ou de jumeaux, montrant le caractère familial/héréditaire des TAG et des phénotypes d'anxiété présents dans d'autres troubles. Les progrès récents des études de couplage, d'association pangénomique et de gènes candidats (par ex. 5-HTT, 5-HT1A, MAOA, BDNF) sont soulignés dans le contexte de la neuro-imagerie fonctionnelle et structurale et des lectures neurophysiologiques liées aux marqueurs de stress périphériques et à la psychophysiologie. Les traumatismes subis pendant l'enfance, l'adversité environnementale, et les événements stressants de la vie sont étudiés à l'aide d'approches d'interaction gène-environnement (5-HTT, NPSR1, COMT, MAOA, CRHR1, RGS2). De plus, nous résumons la pharmacogénétique des traitements inhibiteurs sélectifs de la recapture de la sérotonine/ inhibiteurs de la recapture de la sérotonine et de la noradrénaline (5-HTT, 5-HT2A, COMT, CRHR1). Enfin, nous analysons les problèmes et les perspectives de recherche dans le domaine de la génétique, y compris de l'épigénétique, du TAG et du caractère anxieux.

Lithium reverses behavioral and axonal transport-related changes associated with ANK3 bipolar disorder gene disruption.

Ankyrin 3 (ANK3) has been implicated as a genetic risk factor for bipolar disorder (BD), however the resulting pathophysiological and treatment implications remain elusive. In a preclinical systems biological approach, we aimed to characterize the behavioral and proteomic effects of Ank3 haploinsufficiency and chronic mood-stabilizer treatment in mice. Psychiatric-related behavior was evaluated with the novelty-suppressed feeding (NSF) paradigm, elevated plus maze (EPM) and a passive avoidance task (PAT). Tandem mass spectrometry (MSE) was employed for hippocampal proteome profiling. A functional enrichment approach based on protein-protein interactions (PPIs) was performed to outline which biological processes in the hippocampus were affected by Ank3 haploinsufficiency and lithium treatment. Proteomic abundance changes as detected by MSE or highlighted by PPI network modelling were followed up by targeted selected reaction monitoring (SRM). Increased psychiatric-related behavior in Ank3+/- mice was ameliorated by lithium in all assessments (NSF, EPM, PAT). MSE followed by modular PPI clustering and functional annotation enrichment pointed towards kinesin-related axonal transport and glutamate signaling as mediators of Ank3+/- pathophysiology and lithium treatment. SRM validated this hypothesis and further confirmed abundance changes of ANK3 interaction partners. We propose that psychiatric-related behavior in Ank3+/- mice is connected to a disturbance of the kinesin cargo system, resulting in a dysfunction of neuronal ion channel and glutamate receptor transport. Lithium reverses this molecular signature, suggesting the promotion of anterograde kinesin transport as part of its mechanism of action in ameliorating Ank3-related psychiatric-related behavior.

Proteomic systems evaluation of the molecular validity of preclinical psychosis models compared to schizophrenia brain pathology.

Pharmacological and genetic rodent models of schizophrenia play an important role in the drug discovery pipeline, but quantifying the molecular similarity of such models with the underlying human pathophysiology has proved difficult. We developed a novel systems biology methodology for the direct comparison of anterior prefrontal cortex tissue from four established glutamatergic rodent models and schizophrenia patients, enabling the evaluation of which model displays the greatest similarity to schizophrenia across different pathophysiological characteristics of the disease. Liquid chromatography coupled tandem mass spectrometry (LC-MSE) proteomic profiling was applied comparing healthy and "disease state" in human post-mortem samples and rodent brain tissue samples derived from models based on acute and chronic phencyclidine (PCP) treatment, ketamine treatment or NMDA receptor knockdown. Protein-protein interaction networks were constructed from significant abundance changes and enrichment analyses enabled the identification of five functional domains of the disease such as "development and differentiation", which were represented across all four rodent models and were thus subsequently used for cross-species comparison. Kernel-based machine learning techniques quantified that the chronic PCP model represented schizophrenia brain changes most closely for four of these functional domains. This is the first study aiming to quantify which rodent model recapitulates the neuropathological features of schizophrenia most closely, providing an indication of face validity as well as potential guidance in the refinement of construct and predictive validity. The methodology and findings presented here support recent efforts to overcome translational hurdles of preclinical psychiatric research by associating functional dimensions of behaviour with distinct biological processes.

Novel developments in genetic and epigenetic mechanisms of anxiety.

PURPOSE OF REVIEW: The present review aims to deliver a systematic overview of current developments and trends in (epi)genetics of anxiety and to identify upcoming challenges and opportunities. RECENT FINDINGS: Genes related to peptide and hormone signaling have been suggested for anxiety-related phenotypes, e.g., the NPSR1 gene, which has been associated predominantly with panic disorder in women, and shown to interact with environmental factors and to influence psychometric, neurophysiological, and neuroimaging correlates of anxiety. Similar multi-level results have been reported for genetic and epigenetic variation in the OXTR gene, especially in social anxiety disorder (SAD), and for CRHR1 gene variation in women with panic disorder. Variants in RGS2 and ASIC1 genes were linked to panic disorder, with the latter also being implicated in SAD treatment response. Finally, monoaminergic 'risk' genes (SLC6A4, MAOA, HTR1A) were related to SAD, generalized anxiety disorder and women with panic disorder, anxiety traits and response to psychopharmacological and psychotherapeutic interventions. SUMMARY: Converging evidence for potential genetic and epigenetic risk markers has been gathered and future studies call for independent replications and multi-level integration of dimensional approaches, environmental factors, and biological readouts, while considering sex-specific substratification. Particularly, epigenetic variation appears promising for disease course and treatment response predictions.

Targeted multiplexed selected reaction monitoring analysis evaluates protein expression changes of molecular risk factors for major psychiatric disorders.

BACKGROUND: Extensive research efforts have generated genomic, transcriptomic, proteomic, and functional data hoping to elucidate psychiatric pathophysiology. Selected reaction monitoring, a recently developed targeted proteomic mass spectrometric approach, has made it possible to evaluate previous findings and hypotheses with high sensitivity, reproducibility, and quantitative accuracy. METHODS: Here, we have developed a labelled multiplexed selected reaction monitoring assay, comprising 56 proteins previously implicated in the aetiology of major psychiatric disorders, including cell type markers or targets and effectors of known psychopharmacological interventions. We analyzed postmortem anterior prefrontal cortex (Brodmann area 10) tissue of patients diagnosed with schizophrenia (n=22), bipolar disorder (n=23), and major depressive disorder with (n=11) and without (n=11) psychotic features compared with healthy controls (n=22). RESULTS: Results agreed with several previous studies, with the finding of alterations of Wnt-signalling and glutamate receptor abundance predominately in bipolar disorder and abnormalities in energy metabolism across the neuropsychiatric disease spectrum. Calcium signalling was predominantly affected in schizophrenia and affective psychosis. Interestingly, we were able to show a decrease of all 4 tested oligodendrocyte specific proteins (MOG, MBP, MYPR, CNPase) in bipolar disorder and to a lesser extent in schizophrenia and affective psychosis. Finally, we provide new evidence linking ankyrin 3 specifically to affective psychosis and the 22q11.2 deletion syndrome-associated protein septin 5 to schizophrenia. CONCLUSIONS: Our study highlights the potential of selected reaction monitoring to evaluate the protein abundance levels of candidate markers of neuropsychiatric spectrum disorders, providing a high throughput multiplex platform for validation of putative disease markers and drug targets.

Applications of blood-based protein biomarker strategies in the study of psychiatric disorders.

Major psychiatric disorders such as schizophrenia, major depressive and bipolar disorders are severe, chronic and debilitating, and are associated with high disease burden and healthcare costs. Currently, diagnoses of these disorders rely on interview-based assessments of subjective self-reported symptoms. Early diagnosis is difficult, misdiagnosis is a frequent occurrence and there are no objective tests that aid in the prediction of individual responses to treatment. Consequently, validated biomarkers are urgently needed to help address these unmet clinical needs. Historically, psychiatric disorders are viewed as brain disorders and consequently only a few researchers have as yet evaluated systemic changes in psychiatric patients. However, promising research has begun to challenge this concept and there is an increasing awareness that disease-related changes can be traced in the peripheral system which may even be involved in the precipitation of disease onset and course. Converging evidence from molecular profiling analysis of blood serum/plasma have revealed robust molecular changes in psychiatric patients, suggesting that these disorders may be detectable in other systems of the body such as the circulating blood. In this review, we discuss the current clinical needs in psychiatry, highlight the importance of biomarkers in the field, and review a representative selection of biomarker studies to highlight opportunities for the implementation of personalized medicine approaches in the field of psychiatry. It is anticipated that the implementation of validated biomarker tests will not only improve the diagnosis and more effective treatment of psychiatric patients, but also improve prognosis and disease outcome.

The use of proteomic biomarkers for improved diagnosis and stratification of schizophrenia patients.

Schizophrenia is characterized by a wide spectrum of clinical manifestations, including strong effects on mood and behavior. Patients can also suffer from serious comorbidities including immune system or metabolic abnormalities. Recent advances using proteomic profiling approaches have increased our understanding of these molecular effects and have laid the groundwork for unraveling the heterogeneity of this broadly defined disease. These findings could lead to improved diagnosis and stratification of patients through identification of biochemically different disease subtypes and personalized medicine approaches. The inclusion of molecular signatures in psychiatry will be an important leap forward in providing more effective treatment of patients suffering from this debilitating disorder.

Proteomic enrichment analysis of psychotic and affective disorders reveals common signatures in presynaptic glutamatergic signaling and energy metabolism.

BACKGROUND: Although genetic studies suggest an overlap in risk alleles across the major psychiatric disorders, disease signatures reflecting overlapping symptoms have not been found. Profiling studies have identified candidate protein markers associated with specific disorders of the psychoaffective spectrum, but this has always been done in a selective fashion without accounting for the entire proteome composition of the system under investigation. METHODS: Employing an orthogonal system-based proteomic enrichment approach based on label-free liquid chromatography mass spectrometry, we analyzed anterior prefrontal human post-mortem brain tissue of patients affected by schizophrenia (n = 23), bipolar disorder (n = 23), major depressive disorder with (n = 12) and without psychotic features (n = 11), and healthy controls (n = 23). Labeled selected reaction monitoring (SRM) was used to validate these findings on a pathway level. Independent in silico analyses of biological annotations revealed common pathways across the diseases, associated with presynaptic glutamatergic neurotransmission and energy metabolism. We validated the proteomic findings using SRM and confirmed that there were no effects of post-mortem confounders. RESULTS: Schizophrenia and affective psychosis were linked to a hypoglutamatergic state and hypofunction of energy metabolism, while bipolar disorder and major depressive disorder were linked to a hyperglutamatergic state and hyperfunction of energy metabolism. CONCLUSIONS: These findings support recent investigations, which have focused on the therapeutic potential of glutamatergic modulation in psychotic and affective disorders. We suggest a disease model in which disturbances of the glutamatergic system and ensuing adaptations of neuronal energy metabolism are linked to distinct psychiatric symptom dimensions, delivering novel evidence for targeted treatment approaches.

Estudos traducionais de neuropsiquiatria e esquizofrenia: modelos animais genéticos e de neurodesenvolvimento / Translational neuropsychiatry of genetic and neurodevelopmental animal models of schizophrenia

Sintomas psiquiátricos são subjetivos por natureza e tendem a se sobrepor entre diferentes desordens. Sendo assim, a criação de modelos de uma desordem neuropsiquiátrica encontra desafios pela falta de conhecimento dos fundamentos da fisiopatologia e diagnósticos precisos. Modelos animais são usados para testar hipóteses de etiologia e para representar a condição humana tão próximo quanto possível para aumentar nosso entendimento da doença e avaliar novos alvos para a descoberta de drogas. Nesta revisão, modelos animais genéticos e de neurodesenvolvimento de esquizofrenia são discutidos com respeito a achados comportamentais e neurofisiológicos e sua associação com a condição clínica. Somente modelos animais específicos de esquizofrenia podem, em último caso, levar a novas abordagens diagnósticas e descoberta de drogas. Argumentamos que biomarcadores moleculares são importantes para aumentar a tradução de animais a humanos, já que faltam a especificidade e a fidelidade necessárias às leituras comportamentais para avaliar sintomas psiquiátricos humanos

Psychiatric symptoms are subjective by nature and tend to overlap between different disorders. The modelling of a neuropsychiatric disorder therefore faces challenges because of missing knowledge of the fundamental pathophysiology and a lack of accurate diagnostics. Animal models are used to test hypotheses of aetiology and to represent the human condition as close as possible to increase our understanding of the disease and to evaluate new targets for drug discovery. In this review, genetic and neurodevelopmental animal models of schizophrenia are discussed with respect to behavioural and neurophysiological findings and their association with the clinical condition. Only specific animal models of schizophrenia may ultimately lead to novel diagnostic approaches and drug discovery. We argue that molecular biomarkers are important to improve animal to human translation since behavioural readouts lack the necessary specificity and reliability to assess human psychiatric symptoms