RESUMEN
Antidepressant treatment for major depressive disorder remains suboptimal with response rates of just over 50%. Although treatment guidelines, algorithms and clinical keys are available to assist the clinician, the process of finding an effective pharmacotherapy to maximise benefit for the individual patient is largely by "trial and error" and remains challenging. This highlights a clear need to identify biomarkers of treatment response to help guide personalised treatment strategies. We have carried out the largest multiplex immunoassay based longitudinal study to date, examining up to 258 serum markers involved in immune, endocrine and metabolic processes as potential biomarkers associated with treatment response in 332 depression patients recruited from four independent clinical centres. We demonstrated for the first time that circulating Apolipoprotein A-IV, Endoglin, Intercellular Adhesion Molecule 1, Tissue Inhibitor of Metalloproteinases 1, Plasminogen Activator Inhibitor 1, Thrombopoietin, Complement C3, Hepatocyte Growth Factor and Insulin-like Growth Factor-Binding Protein 2 were associated with response to different antidepressants. In addition, we showed that specific sets of immune-endocrine proteins were associated with response to Venlafaxine (serotonin-norepinephrine reuptake inhibitor), Imipramine (tricyclic antidepressant) and other antidepressant drugs. However, we were not able to reproduce the literature findings on BDNF and TNF-α, two of the most commonly reported candidate treatment response markers. Despite the need for extensive validation studies, our preliminary findings suggest that a pre-treatment immune-endocrine profile may help to determine a patient's likelihood to respond to specific antidepressant and/or alternative treatments such as anti-inflammatory drugs, providing hope for future personalised treatment approaches.
Asunto(s)
Antidepresivos/uso terapéutico , Biomarcadores/sangre , Trastorno Depresivo Mayor , Adulto , Anciano , Anciano de 80 o más Años , Apolipoproteínas A/sangre , Complemento C3/metabolismo , Citocinas/sangre , Trastorno Depresivo Mayor/sangre , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/inmunología , Endoglina/sangre , Femenino , Humanos , Inmunoensayo , Factor II del Crecimiento Similar a la Insulina/metabolismo , Molécula 1 de Adhesión Intercelular/sangre , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Inhibidor Tisular de Metaloproteinasa-1/sangreRESUMEN
RATIONALE: A substantial number of patients suffering from major depressive disorder (MDD) do not respond to multiple trials of anti-depressants, develop a chronic course of disease and become treatment resistant. Most of the studies investigating molecular changes in treatment-resistant depression (TRD) have only examined a limited number of molecules and genes. Consequently, biomarkers associated with TRD are still lacking. OBJECTIVES: This study aimed to use recently advanced high-throughput proteomic platforms to identify peripheral biomarkers of TRD defined by two staging models, the Thase and Rush staging model (TRM) and the Maudsley Staging Model (MSM). METHODS: Serum collected from an inpatient cohort of 65 individuals suffering from MDD was analysed using two different mass spectrometric-based platforms, label-free liquid chromatography mass spectrometry (LC-MS(E)) and selective reaction monitoring (SRM), as well as a multiplex bead based assay. RESULTS: In the LC-MS(E) analysis, proteins involved in the acute phase response and complement activation and coagulation were significantly different between the staging groups in both models. In the multiplex bead-based assay analysis TNF-α levels (log(odds) = -4.95, p = 0.045) were significantly different in the TRM comparison. Using SRM, significant changes of three apolipoproteins A-I (ß = 0.029, p = 0.035), M (ß = -0.017, p = 0.009) and F (ß = -0.031, p = 0.024) were associated with the TRM but not the MSM. CONCLUSION: Overall, our findings suggest that proteins, which are involved in immune and complement activation, may represent potential biomarkers that could be used by clinicians to identify high-risk patients. Nevertheless, given that the molecular changes between the staging groups were subtle, the results need to be interpreted cautiously.
Asunto(s)
Trastorno Depresivo Mayor/sangre , Trastorno Depresivo Resistente al Tratamiento/sangre , Proteómica , Adulto , Antidepresivos/uso terapéutico , Biomarcadores/sangre , Coagulación Sanguínea , Cromatografía Liquida , Estudios de Cohortes , Activación de Complemento , Citocinas/sangre , Reparación de la Incompatibilidad de ADN , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/metabolismo , Trastorno Depresivo Resistente al Tratamiento/tratamiento farmacológico , Trastorno Depresivo Resistente al Tratamiento/metabolismo , Femenino , Humanos , Modelos Logísticos , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Factor de Necrosis Tumoral alfa/sangreRESUMEN
BACKGROUND: Dipeptidyl peptidase 4 (DPP4; EC 3.4.14.5; CD26) is a membrane-bound or shedded serine protease that hydrolyzes dipeptides from the N-terminus of peptides with either proline or alanine at the penultimate position. Substrates of DPP4 include several stress-related neuropeptides implicated in anxiety, depression and schizophrenia. A decline of DPP4-like activity has been reported in sera from depressed patient, but not fully characterized regarding DPP4-like enzymes, therapeutic interventions and protein. METHODS: Sera from 16 melancholic- and 16 non-melancholic-depressed patients were evaluated for DPP4-like activities and the concentration of soluble DPP4 protein before and after treatment by anti-depressive therapies. Post-translational modification of DPP4-isoforms and degradation of NPY, Peptide YY (PYY), Galanin-like peptide (GALP), Orexin B (OrxB), OrxA, pituitary adenylate cyclase-activating polypeptide (PACAP) and substance P (SP) were studied in serum and in ex vivo human blood. N-terminal truncation of biotinylated NPY by endothelial membrane-bound DPP4 versus soluble DPP4 was determined in rat brain perfusates and spiked sera. RESULTS: Lower DPP4 activities in depressed patients were reversed by anti-depressive treatment. In sera, DPP4 contributed to more than 90% of the overall DPP4-like activity and correlated with its protein concentration. NPY displayed equal degradation in serum and blood, and was equally truncated by serum and endothelial DPP4. In addition, GALP and rat OrxB were identified as novel substrates of DPP4. CONCLUSION: NPY is the best DPP4-substrate in blood, being truncated by soluble and membrane DPP4, respectively. The decline of soluble DPP4 in acute depression could be reversed upon anti-depressive treatment. Peptidases from three functional compartments regulate the bioactivity of NPY in blood.
Asunto(s)
Trastorno Depresivo/sangre , Trastorno Depresivo/enzimología , Dipeptidil Peptidasa 4/sangre , Neuropéptido Y/sangre , Estrés Psicológico/sangre , Adulto , Animales , Antidepresivos/uso terapéutico , Trastorno Depresivo/tratamiento farmacológico , Endotelio/metabolismo , Femenino , Humanos , Hidrólisis , Isoenzimas/sangre , Masculino , Persona de Mediana Edad , Orexinas/sangre , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/sangre , Procesamiento Proteico-Postraduccional , Proteolisis , Ratas , Sustancia P/sangreRESUMEN
BACKGROUND: Schizophrenia can be conceptualized as a form of dysconnectivity between brain regions.To investigate the neurobiological foundation of dysconnectivity, one approach is to analyze white matter structures, such as the pathology of fiber tracks. S100B is considered a marker protein for glial cells, in particular oligodendrocytes and astroglia, that passes the blood brain barrier and is detectable in peripheral blood. Earlier Studies have consistently reported increased S100B levels in schizophrenia. In this study, we aim to investigate associations between S100B and structural white matter abnormalities. METHODS: We analyzed data of 17 unmedicated schizophrenic patients (first and recurrent episode) and 22 controls. We used voxel based morphometry (VBM) to detect group differences of white matter structures as obtained from T1-weighted MR-images and considered S100B serum levels as a regressor in an age-corrected interaction analysis. RESULTS: S100B was increased in both patient subgroups. Using VBM, we found clusters indicating significant differences of the association between S100B concentration and white matter. Involved anatomical structures are the posterior cingulate bundle and temporal white matter structures assigned to the superior longitudinal fasciculus. CONCLUSIONS: S100B-associated alterations of white matter are shown to be existent already at time of first manifestation of psychosis and are distinct from findings in recurrent episode patients. This suggests involvement of S100B in an ongoing and dynamic process associated with structural brain changes in schizophrenia. However, it remains elusive whether increased S100B serum concentrations in psychotic patients represent a protective response to a continuous pathogenic process or if elevated S100B levels are actively involved in promoting structural brain damage.
RESUMEN
Adverse environmental factors including prenatal maternal infection are capable of inducing long-lasting behavioral and neural alterations which can enhance the risk to develop schizophrenia. It is so far not clear whether supportive postnatal environments are able to modify such prenatally-induced alterations. In rodent models, environmental enrichment influences behavior and cognition, for instance by affecting endocrinologic, immunologic, and neuroplastic parameters. The current study was designed to elucidate the influence of postnatal environmental enrichment on schizophrenia-like behavioral alterations induced by prenatal polyI:C immune stimulation at gestational day 9 in mice. Adult offspring were tested for amphetamine-induced locomotion, social interaction, and problem-solving behavior as well as expression of dopamine D1 and D2 receptors and associated molecules, microglia density and adult neurogenesis. Prenatal polyI:C treatment resulted in increased dopamine sensitivity and dopamine D2 receptor expression in adult offspring which was not reversed by environmental enrichment. Prenatal immune activation prevented the effects of environmental enrichment which increased exploratory behavior and microglia density in NaCl treated mice. Problem-solving behavior as well as the number of immature neurons was affected by neither prenatal immune stimulation nor postnatal environmental enrichment. The behavioral and neural alterations that persist into adulthood could not generally be modified by environmental enrichment. This might be due to early neurodevelopmental disturbances which could not be rescued or compensated for at a later developmental stage.
Asunto(s)
Ambiente , Conducta Exploratoria/fisiología , Microglía/patología , Efectos Tardíos de la Exposición Prenatal/enfermería , Efectos Tardíos de la Exposición Prenatal/patología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Factores de Edad , Anfetamina/farmacología , Análisis de Varianza , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Estimulantes del Sistema Nervioso Central/farmacología , Corticosterona/sangre , Modelos Animales de Enfermedad , Conducta Exploratoria/efectos de los fármacos , Femenino , Expresión Génica/efectos de los fármacos , Inductores de Interferón/toxicidad , Masculino , Memoria/efectos de los fármacos , Ratones , Microglía/efectos de los fármacos , Poli I-C/toxicidad , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Solución de Problemas/efectos de los fármacos , Receptores Dopaminérgicos/metabolismo , Conducta Social , Conducta Estereotipada/efectos de los fármacosRESUMEN
BACKGROUND: Bipolar disorder (BD) is a costly, devastating and life shortening mental disorder that is often misdiagnosed, especially on initial presentation. Misdiagnosis frequently results in ineffective treatment. We investigated the utility of a biomarker panel as a diagnostic test for BD. METHODS AND FINDINGS: We performed a meta-analysis of eight case-control studies to define a diagnostic biomarker panel for BD. After validating the panel on established BD patients, we applied it to undiagnosed BD patients. We analysed 249 BD, 122 pre-diagnostic BD, 75 pre-diagnostic schizophrenia and 90 first onset major depression disorder (MDD) patients and 371 controls. The biomarker panel was identified using ten-fold cross-validation with lasso regression applied to the 87 analytes available across the meta-analysis studies. We identified 20 protein analytes with excellent predictive performance [area under the curve (AUC)⩾0.90]. Importantly, the panel had a good predictive performance (AUC 0.84) to differentiate 12 misdiagnosed BD patients from 90 first onset MDD patients, and a fair to good predictive performance (AUC 0.79) to differentiate between 110 pre-diagnostic BD patients and 184 controls. We also demonstrated the disease specificity of the panel. CONCLUSIONS: An early and accurate diagnosis has the potential to delay or even prevent the onset of BD. This study demonstrates the potential utility of a biomarker panel as a diagnostic test for BD.
Asunto(s)
Trastorno Bipolar/sangre , Trastorno Bipolar/diagnóstico , Adulto , Biomarcadores/sangre , Estudios de Casos y Controles , Trastorno Depresivo Mayor/sangre , Trastorno Depresivo Mayor/diagnóstico , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esquizofrenia/sangre , Esquizofrenia/diagnóstico , Sensibilidad y EspecificidadRESUMEN
Traditional schizophrenia pharmacotherapy remains a subjective trial and error process involving administration, titration and switching of drugs multiple times until an adequate response is achieved. Despite this time-consuming and costly process, not all patients show an adequate response to treatment. As a consequence, relapse is a common occurrence and early intervention is hampered. Here, we have attempted to identify candidate blood biomarkers associated with drug response in 121 initially antipsychotic-free recent-onset schizophrenia patients treated with widely-used antipsychotics, namely olanzapine (n=40), quetiapine (n=23), risperidone (n=30) and a mixture of these drugs (n=28). Patients were recruited and investigated as two separate cohorts to allow biomarker validation. Data analysis showed the most significant relationship between pre-treatment levels of heart-type fatty acid binding protein (H-FABP) and response to olanzapine (p=0.008, F=8.6, ß=70.4 in the discovery cohort and p=0.003, F=15.2, ß=24.4 in the validation cohort, adjusted for relevant confounding variables). In a functional follow-up analysis of this finding, we tested an independent cohort of 10 patients treated with olanzapine and found that baseline levels of plasma H-FABP and expression of the binding partner for H-FABP, fatty acid translocase (CD36), on monocytes predicted the reduction of psychotic symptoms (p=0.040, F=6.0, ß=116.3 and p=0.012, F=11.9, ß=-0.0054, respectively). We also identified a set of serum molecules changed after treatment with antipsychotic medication, in particular olanzapine. These molecules are predominantly involved in cellular development and metabolism. Taken together, our findings suggest an association between biomarkers involved in fatty acid metabolism and response to olanzapine, while other proteins may serve as surrogate markers associated with drug efficacy and side effects.
Asunto(s)
Antipsicóticos/uso terapéutico , Benzodiazepinas/uso terapéutico , Antígenos CD36/sangre , Proteínas de Unión a Ácidos Grasos/sangre , Esquizofrenia/sangre , Esquizofrenia/tratamiento farmacológico , Adulto , Estudios de Cohortes , Proteína 3 de Unión a Ácidos Grasos , Femenino , Humanos , Interleucina-10/sangre , Masculino , Persona de Mediana Edad , Olanzapina , Fumarato de Quetiapina/uso terapéutico , Risperidona/uso terapéutico , Adulto JovenRESUMEN
The bioactivity of neuropeptide Y (NPY) is either N-terminally modulated with respect to receptor selectivity by dipeptidyl peptidase 4 (DP4)-like enzymes or proteolytic degraded by neprilysin or meprins, thereby abrogating signal transduction. However, neither the subcellular nor the compartmental differentiation of these regulatory mechanisms is fully understood. Using mass spectrometry, selective inhibitors and histochemistry, studies across various cell types, body fluids, and tissues revealed that most frequently DP4-like enzymes, aminopeptidases P, secreted meprin-A (Mep-A), and cathepsin D (CTSD) rapidly hydrolyze NPY, depending on the cell type and tissue under study. Novel degradation of NPY by cathepsins B, D, L, G, S, and tissue kallikrein could also be identified. The expression of DP4, CTSD, and Mep-A at the median eminence indicates that the bioactivity of NPY is regulated by peptidases at the interphase between the periphery and the CNS. Detailed ex vivo studies on human sera and CSF samples recognized CTSD as the major NPY-cleaving enzyme in the CSF, whereas an additional C-terminal truncation by angiotensin-converting enzyme could be detected in serum. The latter finding hints to potential drug interaction between antidiabetic DP4 inhibitors and anti-hypertensive angiotensin-converting enzyme inhibitors, while it ablates suspected hypertensive side effects of only antidiabetic DP4-inhibitors application. The bioactivity of neuropeptide Y (NPY) is either N-terminally modulated with respect to receptor selectivity by dipeptidyl peptidase 4 (DP4)-like enzymes or proteolytic degraded by neprilysin or meprins, thereby abrogating signal transduction. However, neither the subcellular nor the compartmental differentiation of these regulatory mechanisms is fully understood. Using mass spectrometry, selective inhibitors and histochemistry, studies across various cell types, body fluids, and tissues revealed that most frequently DP4-like enzymes, aminopeptidases P, secreted meprin-A (Mep-A), and cathepsin D (CTSD) rapidly hydrolyze NPY, depending on the cell type and tissue under study. Novel degradation of NPY by cathepsins B, D, L, G, S, and tissue kallikrein could also be identified. The expression of DP4, CTSD, and Mep-A at the median eminence indicates that the bioactivity of NPY is regulated by peptidases at the interphase between the periphery and the CNS. Detailed ex vivo studies on human sera and CSF samples recognized CTSD as the major NPY-cleaving enzyme in the CSF, whereas an additional C-terminal truncation by angiotensin-converting enzyme could be detected in serum. The latter finding hints to potential drug interaction between antidiabetic DP4 inhibitors and anti-hypertensive angiotensin-converting enzyme inhibitors, while it ablates suspected hypertensive side effects of only antidiabetic DP4-inhibitors application.
Asunto(s)
Sistema Nervioso Central/citología , Dipeptidil Peptidasa 4/metabolismo , Neuroglía/metabolismo , Neuronas/metabolismo , Neuropéptido Y/metabolismo , Sistema Nervioso Periférico/citología , Animales , Proteína C-Reactiva/líquido cefalorraquídeo , Catepsina D/líquido cefalorraquídeo , Células Cultivadas , Dipeptidil Peptidasa 4/genética , Interacciones Farmacológicas , Femenino , Humanos , Hidrólisis/efectos de los fármacos , Masculino , Neuroglía/efectos de los fármacos , Neuronas/efectos de los fármacos , Fragmentos de Péptidos/metabolismo , Proteolisis/efectos de los fármacos , Ratas , Ratas Endogámicas F344 , Ratas TransgénicasRESUMEN
BACKGROUND: There is an ongoing search for biomarkers in psychiatry, for example, as diagnostic tools or predictors of treatment response. The neurotrophic factor S100 calcium binding protein B (S100B) has been discussed as a possible predictor of antidepressant response in patients with major depression, but also as a possible biomarker of an acute depressive state. The aim of the present study was to study the association of serum S100B levels with antidepressant treatment response and depression severity in melancholically depressed inpatients. METHODS: After a wash-out period of 1 week, 40 inpatients with melancholic depression were treated with either venlafaxine or imipramine. S100B levels and Hamilton Depression Rating Scale (HAM-D) scores were assessed at baseline, after 7 weeks of treatment, and after 6 months. RESULTS: Patients with high S100B levels at baseline showed a markedly better treatment response defined as relative reduction in HAM-D scores than those with low baseline S100B levels after 7 weeks (P=.002) and 6 months (P=.003). In linear regression models, S100B was a significant predictor for treatment response at both time points. It is of interest to note that nonresponders were detected with a predictive value of 85% and a false negative rate of 7.5%. S100B levels were not associated with depression severity and did not change with clinical improvement. CONCLUSIONS: Low S100B levels predict nonresponse to venlafaxine and imipramine with high precision. Future studies have to show which treatments are effective in patients with low levels of S100B so that this biomarker will help to reduce patients' burden of nonresponding to frequently used antidepressants.
Asunto(s)
Antidepresivos/uso terapéutico , Trastorno Depresivo/sangre , Trastorno Depresivo/tratamiento farmacológico , Imipramina/uso terapéutico , Subunidad beta de la Proteína de Unión al Calcio S100/sangre , Clorhidrato de Venlafaxina/uso terapéutico , Adulto , Anciano , Biomarcadores/sangre , Análisis Químico de la Sangre , Trastorno Depresivo/diagnóstico , Reacciones Falso Negativas , Femenino , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Pronóstico , Escalas de Valoración Psiquiátrica , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
The calcium-binding protein S100B has been shown to support neuron proliferation, migration and neurite growth in vitro, while the significance of S100B for neuronal development in vivo is controversial. We have investigated the effect of S100B deficiency on cerebellar development in S100B knockout mice at an age of 5 and 10 days after birth (P5 and P10). This time range covers important developmental steps in the cerebellum such as granule cell proliferation and migration, as well as dendritic growth of Purkinje cells. Bergmann glial cells contain a particularly high concentration of S100B and serve as scaffold for both migrating granule cells and growing Purkinje cell dendrites. This renders the postnatal cerebellum ideal as a model system to study the importance of S100B for glial and neuronal development. We measured the length of Bergmann glial processes, the width of the external granule cell layer as a measure of granule cell proliferation, the decrease in width of the external granule cell layer between P5 and P10 as a measure of granule cell migration, and the length of Purkinje cell dendrites in wild-type and S100B knockout mice. None of these parameters showed significant differences between wild-type and knockout mice. In addition, wild-type and knockout mice performed equally in locomotor behaviour tests. The results indicate that S100B-deficient mice have normal development of the cerebellum and no severe impairment of motor function.
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Cerebelo/crecimiento & desarrollo , Cerebelo/fisiología , Actividad Motora/fisiología , Subunidad beta de la Proteína de Unión al Calcio S100/deficiencia , Animales , Animales Recién Nacidos , Astrocitos/citología , Astrocitos/fisiología , Western Blotting , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Cerebelo/citología , Dendritas/fisiología , Inmunohistoquímica , Ratones Noqueados , Células de Purkinje/citología , Células de Purkinje/fisiología , Subunidad beta de la Proteína de Unión al Calcio S100/genéticaRESUMEN
Schizophrenia is a heterogeneous disorder normally diagnosed using the Diagnostic and Statistical Manual of Mental Disorders criteria. However, these criteria do not necessarily reflect differences in underlying molecular abnormalities of the disorder. Here, we have used multiplexed immunoassay analyses to measure immune molecules, growth factors, and hormones important to schizophrenia in acutely ill antipsychotic-naive patients (n = 180) and matched controls (n = 398). We found that using the resulting molecular profiles, we were capable of separating schizophrenia patients into 2 significantly distinct subgroups with predominant molecular abnormalities in either immune molecules or growth factors and hormones. These molecular profiles were tested using an independent cohort, and this showed the same separation into 2 subgroups. This suggests that distinct abnormalities occur in specific molecular pathways in schizophrenia patients. This may be of relevance for intervention studies that specifically target particular molecular mechanisms and could be a first step to further define the complex schizophrenia syndrome based on molecular profiles.
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Citocinas/inmunología , Hormonas/metabolismo , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Esquizofrenia/inmunología , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Inmunoensayo , Masculino , Esquizofrenia/clasificación , Esquizofrenia/metabolismo , Adulto JovenRESUMEN
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 (nâ=â133) and controls (nâ=â133) 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.
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Esquizofrenia/sangre , Caracteres Sexuales , Adulto , Antipsicóticos/administración & dosificación , Biomarcadores/sangre , Quimiocina CXCL13/sangre , Femenino , Humanos , Interleucina-13/sangre , Interleucina-15/sangre , Masculino , Persona de Mediana Edad , Prolactina/sangre , Esquizofrenia/tratamiento farmacológico , Testosterona/sangre , alfa 1-Antiquimotripsina/sangreRESUMEN
Genetic variants as well as increased serum levels of the neurotrophic factor S100B are associated with different psychiatric disorders. However, elevated S100B levels are also related to a better therapeutic outcome in psychiatric patients. The functional role of elevated S100B in psychiatric disorders is still unclear. Hence, this study was designed in order to elucidate the differential effects of S100B overexpression in interaction with chronic social stress during adolescence on emotional behavior and adult neurogenesis. S100B transgenic and wild-type mice were housed either in socially stable or unstable environments during adolescence, between postnatal days 28 and 77. In adulthood, anxiety-related behavior in the open field, dark-light, and novelty-induced suppression of feeding test as well as survival of proliferating hippocampal progenitor cells were assessed. S100B transgenic mice revealed significantly reduced anxiety-related behavior in the open field compared to wild-types when reared in stable social conditions. In contrast, when transgenic mice grew up in unstable social conditions, their level of anxiety-related behavior was comparable to the levels of wild-type mice. In addition, S100B overexpressing mice from unstable housing conditions displayed higher numbers of surviving newborn cells in the adult hippocampus which developed into mature neurons. In conclusion, elevated S100B levels increase the susceptibility to environmental stimuli during adolescence resulting in more variable behavioral and neural phenotypes in adulthood. In humans, this increased plasticity might lead to both, enhanced risk for psychiatric disorders in negative environments and improved therapeutic outcome in positive environments.
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Ambiente , Conducta Exploratoria/fisiología , Regulación del Desarrollo de la Expresión Génica/genética , Plasticidad Neuronal/genética , Subunidad beta de la Proteína de Unión al Calcio S100/metabolismo , Medio Social , Factores de Edad , Animales , Animales Recién Nacidos , Ansiedad/genética , Ansiedad/fisiopatología , Peso Corporal/genética , Corticosterona/metabolismo , Adaptación a la Oscuridad/genética , Conducta Alimentaria/fisiología , Humanos , Masculino , Ratones , Ratones Transgénicos , Subunidad beta de la Proteína de Unión al Calcio S100/genética , Estrés Psicológico/genética , Estrés Psicológico/metabolismoRESUMEN
Electroconvulsive therapy (ECT) is mainly used to treat medication resistant major depressive disorder (MDD) patients, with a remission rate of up to 90%. However, little is known about the serum molecular changes induced by this treatment. Understanding the mechanisms of action of ECT at the molecular level could lead to identification of response markers and potential new drug targets for more effective antidepressant treatments. We have carried out a pilot study which analysed serum samples of MDD patients who received a series of ECT treatments over 4 weeks. Patients received only ECT treatments over the first two weeks and a combination of ECT and antidepressant drugs (AD) over the subsequent two weeks. Blood serum analyses were carried out using a combination of multiplex Human MAP® immunoassay and liquid-chromatography mass spectrometry (LC-MS(E)) profiling. This showed that ECT had a predominant acute effect on the levels of serum proteins and small molecules, with changes at the beginning of ECT treatment and after administration of the ECT+AD combination treatment. This suggested a positive interaction between the two types of treatment. Changed molecules included BDNF, CD40L, IL-8, IL-13, EGF, IGF-1, pancreatic polypeptide, SCF, sortilin-1 and others which have already been implicated in MDD pathophysiology. We conclude that ECT appears to exert mainly acute effects on serum molecules.
Asunto(s)
Trastorno Depresivo Mayor/sangre , Trastorno Depresivo Mayor/terapia , Terapia Electroconvulsiva , Proteínas Adaptadoras del Transporte Vesicular/sangre , Adulto , Antidepresivos/uso terapéutico , Biomarcadores/sangre , Factor Neurotrófico Derivado del Encéfalo/sangre , Cromatografía Líquida de Alta Presión , Terapia Combinada , Citocinas/sangre , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/inmunología , Manual Diagnóstico y Estadístico de los Trastornos Mentales , Terapia Electroconvulsiva/efectos adversos , Factor de Crecimiento Epidérmico/sangre , Femenino , Humanos , Inmunoensayo , Factor I del Crecimiento Similar a la Insulina/análisis , Masculino , Espectrometría de Masas , Persona de Mediana Edad , Proyectos Piloto , Proteómica/métodos , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSIONS/SIGNIFICANCE: 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.
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Suero/metabolismo , Caracteres Sexuales , Adulto , Síndrome de Asperger/sangre , Análisis por Conglomerados , Femenino , Redes Reguladoras de Genes , Humanos , Masculino , Metaanálisis como Asunto , Persona de Mediana Edad , Análisis de Componente Principal , Adulto JovenRESUMEN
Most proteomic studies to date have attempted to identify changes in protein levels without considering the effects of post-translational modifications (PTM). However, characteristic changes of PTM such as phosphorylation could be biologically informative, as these can give insights into disease and drug mechanisms of action at the functional level. With this in mind, we have conducted a comparative proteomic and phosphoproteomic analysis of blood sera from 20 antipsychotic-naïve schizophrenia patients and 20 matched healthy controls. We used immobilised metal ion affinity chromatography (IMAC) for enrichment of phosphoproteins combined with label-free liquid chromatography-mass spectrometry (LC-MS(E)) for identification and measurement of protein and phosphoprotein levels. The LC-MS(E) analysis of both IMAC-fractions resulted in identification of 35 proteins with altered levels in schizophrenia. Analysis of the enriched fraction resulted in identification of 72 phosphoproteins with altered phosphorylation patterns. Of these, 59 showed changes in phosphorylation only, with no overall change in protein levels. This study provided evidence that schizophrenia patients feature serum abnormalities in phosphorylation of proteins involved in acute phase response and coagulation pathways. Further studies of such phosphorylation-specific changes could lead to a better understanding of the molecular aetiology of schizophrenia, and provide a means of biomarker identification for clinical studies. This article is part of a Special Issue entitled: Integrated omics.
Asunto(s)
Fosfoproteínas/sangre , Esquizofrenia/sangre , Adulto , Biomarcadores/sangre , Cromatografía de Afinidad/métodos , Cromatografía Líquida de Alta Presión/métodos , Femenino , Cromatografía de Gases y Espectrometría de Masas/métodos , Humanos , Masculino , Fosforilación , Proteómica/métodosRESUMEN
Atypical antipsychotic drugs, such as olanzapine, have been shown to alleviate the positive, negative and, to a lesser degree, the cognitive symptoms of schizophrenia in many patients. However, the detailed mechanisms of action of these drugs have yet to be elucidated. We have carried out the first investigation aimed at evaluating the effects of olanzapine treatment on the glycosylation of serum proteins in schizophrenia patients. Olanzapine treatment resulted in increased levels of a disialylated biantennary glycan and reduced levels of a number of disialylated bi- and triantennary glycans on whole serum glycoproteins. These changes were not observed on a low-abundance serum protein fraction. α1 acid glycoprotein was identified as a carrier of some of the detected altered oligosaccharides. In addition, glycan analysis of haptoglobin, transferrin, and α1 antitrypsin reported similar findings, although these changes did not reach significance. Exoglycosidase digestion analysis showed that olanzapine treatment increased galactosylation and sialylation of whole serum proteins, suggesting increased activity of specific galactosyltransferases and increased availability of galactose residues for sialylation. Taken together, these findings indicate that olanzapine treatment results in altered glycosylation of serum proteins.
Asunto(s)
Antipsicóticos/farmacología , Benzodiazepinas/farmacología , Glicoproteínas/sangre , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Esquizofrenia Paranoide/sangre , Enfermedad Aguda , Adulto , Antipsicóticos/uso terapéutico , Benzodiazepinas/uso terapéutico , Cromatografía Liquida , Femenino , Glicómica , Glicoproteínas/aislamiento & purificación , Glicoproteínas/metabolismo , Glicosilación , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Masculino , Persona de Mediana Edad , Olanzapina , Orosomucoide/metabolismo , Polisacáridos/sangre , Esquizofrenia Paranoide/tratamiento farmacológico , Adulto Joven , alfa 1-Antitripsina/sangreRESUMEN
The process of protein phosphorylation in cells is well studied in the context of a wide range of biologic functions such as signalling, cell cycle, cell growth and differentiation, and others. In contrast, little progress has been made in the investigation of protein phosphorylation specifically in blood. Here, we focussed on the phosphoproteome in human blood serum to study its extent and characteristics, and to explore the potential clinical utility. Immobilised metal ion affinity chromatography (IMAC) for the enrichment of intact phosphorylated proteins and label-free liquid chromatography-mass spectrometry (LC-MS(E)) were used for the molecular analysis of a large number of serum samples. To obtain high-confidence results, phosphorylated peptides had to be detected in at least 2 out of 3 technical replicates per sample and in >70% of the serum samples drawn from 80 volunteers. Individual analysis of these 80 non-pooled samples resulted in the detection of 5825 unique phosphorylated peptides after filtering, which corresponded to 502 unique proteins. The results provided evidence that blood serum may be an untapped source of phosphoproteins suitable for potential use in understanding disease pathophysiology and for identification of disease and drug response biomarkers. This article is part of a Special Issue entitled: Integrated omics.
Asunto(s)
Proteínas Sanguíneas/metabolismo , Cromatografía de Afinidad/métodos , Fosfoproteínas/sangre , Adulto , Biomarcadores/análisis , Biomarcadores/sangre , Proteínas Sanguíneas/análisis , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fosfoproteínas/análisisRESUMEN
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.