Application of meta-analysis methods for identifying proteomic expression level differences.

We present new statistical approaches for identification of proteins with expression levels that are significantly changed when applying meta-analysis to two or more independent experiments. We showed that the Euclidean distance measure has reduced risk of false positives compared to the rank product method. Our Ψ-ranking method has advantages over the traditional fold-change approach by incorporating both the fold-change direction as well as the p-value. In addition, the second novel method, Π-ranking, considers the ratio of the fold-change and thus integrates all three parameters. We further improved the latter by introducing our third technique, Σ-ranking, which combines all three parameters in a balanced nonparametric approach.

Molecular validation of the acute phencyclidine rat model for schizophrenia: identification of translational changes in energy metabolism and neurotransmission.

Administration of the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine (PCP) to rodents is widely used as preclinical model for schizophrenia. Most studies on this model employ methods investigating behavior and brain abnormalities. However, little is known about the corresponding peripheral effects. In this study, we analyzed changes in brain and serum molecular profiles, together with alterations in behavior after acute PCP treatment of rats. Furthermore, abnormalities in peripheral protein expression of first and recent onset antipsychotic free schizophrenia patients were assessed for comparison with the preclinical model. PCP treatment induced hyperlocomotion and stereotypic behavior, which have been related to positive symptoms of schizophrenia. Multiplex immunoassay profiling of serum revealed molecular abnormalities similar to those seen in first and recent onset, antipsychotic free schizophrenia patients. Also, increased insulin levels were detected after administration of a glucose tolerance test (GTT), consistent with previous studies showing changes in insulin signaling in patients with schizophrenia. Finally, schizophrenia-relevant alterations in brain molecules were found in the hippocampus and to a lesser extent in the frontal cortex using liquid-chromatography mass spectrometry and (1)H nuclear magnetic resonance spectroscopy. In conclusion, this study identified behavioral and molecular alterations in the acute PCP rat model, which are also observed in human schizophrenia. We propose that the corresponding changes in serum in both animals and patients may have utility as surrogate markers in this model to facilitate discovery and development of novel drugs for treatment of certain pathological features of schizophrenia.

Shared Immune and Repair Markers During Experimental Toxoplasma Chronic Brain Infection and Schizophrenia.

Chronic neurologic infection with Toxoplasma gondii is relatively common in humans and is one of the strongest known risk factors for schizophrenia. Nevertheless, the exact neuropathological mechanisms linking T gondii infection and schizophrenia remain unclear. Here we utilize a mouse model of chronic T gondii infection to identify protein biomarkers that are altered in serum and brain samples at 2 time points during chronic infection. Furthermore, we compare the identified biomarkers to those differing between "postmortem" brain samples from 35 schizophrenia patients and 33 healthy controls. Our findings suggest that T gondii infection causes substantial and widespread immune activation indicative of neural damage and reactive tissue repair in the animal model that partly overlaps with changes observed in the brains of schizophrenia patients. The overlapping changes include increases in C-reactive protein (CRP), interleukin-1 beta (IL-1ß), interferon gamma (IFNγ), plasminogen activator inhibitor 1 (PAI-1), tissue inhibitor of metalloproteinases 1 (TIMP-1), and vascular cell adhesion molecule 1 (VCAM-1). Potential roles of these factors in the pathogenesis of schizophrenia and toxoplasmosis are discussed. Identifying a defined set of markers shared within the pathophysiological landscape of these diseases could be a key step towards understanding their specific contributions to pathogenesis.

Translating potential biomarker candidates for schizophrenia and depression to animal models of psychiatric disorders.

Schizophrenia and major depressive disorder are severe mental illnesses, which are diagnosed based on patient interviews. Despite many years of extensive research, scientists have not yet fully deciphered how genetic and environmental factors interact to cause these illnesses. Biomarker tests that can confirm diagnoses of schizophrenia or depression are only now beginning to emerge, and could result in a paradigm shift in this field. These tests will help to evaluate the validity of animal models of psychiatric disorders, which are currently characterized based on behavioral measures. In this article, we explore the utility of translating both behavioral and molecular phenotypes of such models to the corresponding human disorders. This approach may help to provide construct validity to animal models and could lead to the identification of models corresponding to defined subtypes of neuropsychiatric disorders based on molecular profiles. Here, we review the molecular and biological pathway alterations that have been found in animal models of schizophrenia and depression and focus on those that are mirrored by similar abnormalities in human patients. Such parallels may provide insight into the validity of specific animal models and therefore help to provide more valuable and accurate tools for the discovery and development of improved psychiatric medications.

Proteomic changes induced by anaesthesia and muscle relaxant treatment prior to electroconvulsive therapy.

PURPOSE: Electroconvulsive therapy (ECT) is a psychiatric treatment in which seizures are electrically induced in patients. Prior to treatment, patients are usually given short-acting anaesthetics and muscle relaxants to avoid harm, e.g. musculoskeletal injury, during the convulsions. However, most molecular studies investigating the mechanism of action of ECT have not explored the potential effects of the pre-treatment with anaesthetic and/ or muscle relaxant. EXPERIMENTAL DESIGN: We have carried out a targeted proteome analysis using multiplex immunoassay platform of serum samples before and 10 min after initiating the administration of the anaesthetic methohexital(®) and the muscle relaxant succinylcholine(®) to eight major depressive disorder patients undergoing ECT. RESULTS: Twenty-six out of 142 analysed molecules showed significant differences in abundance after the methohexital/succinylcholine treatment. Importantly, eight of these molecules (fatty acid-binding protein, insulin, interleukin (IL)1ß, IL-10, IL-4, prolactin, S100 calcium-binding protein B and tumor necrosis factor α) have been associated previously with effects of ECT. CONCLUSIONS AND CLINICAL RELEVANCE: These findings indicate that caution should be used when interpreting results in existing and future proteome-based biomarkers studies on the effects of ECT in neuropsychiatric disease or the use of anaesthetic/muscle relaxant in major surgical operations related to different therapeutic areas.

Behavioral and molecular biomarkers in translational animal models for neuropsychiatric disorders.

Modeling neuropsychiatric disorders in animals poses a significant challenge due to the subjective nature of diverse often overlapping symptoms, lack of objective biomarkers and diagnostics, and the rudimentary understanding of the pathophysiology. Successful translational research requires animal models that can inform about disease mechanisms and therapeutic targets. Here, we review behavioral and neurobiological findings from selected animal models, based on presumed etiology and risk factors, for schizophrenia, bipolar disorder, and major depressive disorder. We focus on the use of appropriate statistical tools and newly developed Research Domain Criteria (RDoC) to link biomarkers from animal models with the human disease. We argue that this approach will lead to development of only the most robust animal models for specific psychiatric disorders and may ultimately lead to better understanding of the pathophysiology and identification of novel biomarkers and therapeutic targets.