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BACKGROUND: Inflammatory mechanisms are thought to contribute to the onset of psychosis in persons with an at-risk mental state (ARMS). We investigated whether the anti-inflammatory properties of minocycline and omega-3 polyunsaturated fatty acids (omega-3), alone or synergistically, would prevent transition to psychosis in ARMS in a randomised, double-blind, placebo-controlled trial in Pakistan. METHODS: 10,173 help-seeking individuals aged 16-35 years were screened using the Prodromal Questionaire-16. Individuals scoring 6 and over were interviewed using the Comprehensive Assessment of At-Risk Mental States (CAARMS) to confirm ARMS. Participants (n = 326) were randomised to minocycline, omega-3, combined minocycline and omega-3 or to double placebo for 6 months. The primary outcome was transition to psychosis at 12 months. FINDINGS: Forty-five (13.8 %) participants transitioned to psychosis. The risk of transition was greater in those randomised to omega-3 alone or in combination with minocycline (17.3.%), compared to 10.4 % in those not exposed to omega-3; a risk-ratio (RR) of 1.67, 95 % CI [0.95, 2.92] p = 0.07. The RR for transitions on minocycline vs. no minocycline was 0.86, 95 % CI [0.50, 1.49] p > 0.10. In participants who did not become psychotic, CAARMS and depression symptom scores were reduced at six and twelve months (mean CAARMS difference = 1.43; 95 % CI [0.33, 1.76] p < 0.01 in those exposed to omega-3. Minocycline did not affect CAARMS or depression scores. INTERPRETATION: In keeping with other studies, omega-3 appears to have beneficial effects on ARMS and mood symptom severity but it increased transition to psychosis, which may reflect metabolic or developmental consequences of chronic poor nutrition in the population. Transition to psychosis was too rare to reveal a preventative effect of minocycline but minocycline did not improve symptom severity. ARMS symptom severity and transition to psychosis appear to have distinct pathogeneses which are differentially modulated by omega-3 supplementation. FUNDING: The study was funded by the Stanley Research Medical Institute.
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Ácidos Grasos Omega-3 , Trastornos Psicóticos , Humanos , Antiinflamatorios/uso terapéutico , Método Doble Ciego , Ácidos Grasos Omega-3/uso terapéutico , Minociclina/uso terapéutico , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/diagnóstico , Adolescente , Adulto Joven , AdultoRESUMEN
Both early childhood traumatic experiences and current stress increase the risk of suicidal behaviour, in which immune activation might play a role. Previous research suggests an association between mood disorders and P2RX7 gene encoding P2X7 receptors, which stimulate neuroinflammation. We investigated the effect of P2RX7 variation in interaction with early childhood adversities and traumas and recent stressors on lifetime suicide attempts and current suicide risk markers. Overall, 1644 participants completed questionnaires assessing childhood adversities, recent negative life events, and provided information about previous suicide attempts and current suicide risk-related markers, including thoughts of ending their life, death, and hopelessness. Subjects were genotyped for 681 SNPs in the P2RX7 gene, 335 of which passed quality control and were entered into logistic and linear regression models, followed by a clumping procedure to identify clumps of SNPs with a significant main and interaction effect. We identified two significant clumps with a main effect on current suicidal ideation with top SNPs rs641940 and rs1653613. In interaction with childhood trauma, we identified a clump with top SNP psy_rs11615992 and another clump on hopelessness containing rs78473339 as index SNP. Our results suggest that P2RX7 variation may mediate the effect of early childhood adversities and traumas on later emergence of suicide risk.
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Experiencias Adversas de la Infancia , Enfermedades Neuroinflamatorias , Receptores Purinérgicos P2X7 , Preescolar , Humanos , Afecto , Genotipo , Enfermedades Neuroinflamatorias/genética , Receptores Purinérgicos P2X7/genética , Ideación SuicidaRESUMEN
BACKGROUND: Evidence from rodents indicated that after recent stress, reduced expression of tight junction protein claudin-5 may weaken the blood-brain barrier and allow interleukin-6 to induce depressive symptoms. Our aims were to prove this pathomechanism in humans. METHODS: We used a large population genetic database (UK Biobank, n = 277â 501) to test whether variation in the CLDN5 gene could modulate effects of the IL6 gene variant in stress-induced depression. Three-way interaction of functional polymorphisms, rs885985 of CLDN5, and rs1800795 of IL6 with recent stressful life events were tested on current depressive symptoms. Analyses were performed in male and female populations as well. RESULTS: The 3-way interaction including recent stress yielded highly significant results on current depressive symptoms in the UK Biobank sample, which was more pronounced in men and could be replicated on trend level in an independent cohort (NewMood, n = 1638). None of any other associations or interactions, including, for example, childhood stressors and lifetime depression as an outcome, yielded significance. CONCLUSIONS: These findings provide genetic evidence in humans for the interaction among interleukin-6, claudin-5, and recent stress, suggesting that inflammation is involved in the development of depression and that stress-connected brain entry of inflammatory molecules is a key factor in this pathomechanism. These genetic polymorphisms may help to identify people at higher risk for recent stress-induced depression.
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Barrera Hematoencefálica , Interleucina-6 , Humanos , Masculino , Femenino , Niño , Barrera Hematoencefálica/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Depresión/genética , Claudina-5/genética , Claudina-5/metabolismo , Inflamación/genética , Inflamación/metabolismoRESUMEN
BACKGROUND: Evidence suggests that cognitive subtypes exist in schizophrenia that may reflect different neurobiological trajectories. We aimed to identify whether IQ-derived cognitive subtypes are present in early-phase schizophrenia-spectrum disorder and examine their relationship with brain structure and markers of neuroinflammation. METHOD: 161 patients with recent-onset schizophrenia spectrum disorder (<5 years) were recruited. Estimated premorbid and current IQ were calculated using the Wechsler Test of Adult Reading and a 4-subtest WAIS-III. Cognitive subtypes were identified with k-means clustering. Freesurfer was used to analyse 3.0 T MRI. Blood samples were analysed for hs-CRP, IL-1RA, IL-6 and TNF-α. RESULTS: Three subtypes were identified indicating preserved (PIQ), deteriorated (DIQ) and compromised (CIQ) IQ. Absolute total brain volume was significantly smaller in CIQ compared to PIQ and DIQ, and intracranial volume was smaller in CIQ than PIQ (F(2, 124) = 6.407, p = 0.002) indicative of premorbid smaller brain size in the CIQ group. CIQ had higher levels of hs-CRP than PIQ (F(2, 131) = 5.01, p = 0.008). PIQ showed differentially impaired processing speed and verbal learning compared to IQ-matched healthy controls. CONCLUSIONS: The findings add validity of a neurodevelopmental subtype of schizophrenia identified by comparing estimated premorbid and current IQ and characterised by smaller premorbid brain volume and higher measures of low-grade inflammation (CRP).
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Esquizofrenia , Adulto , Humanos , Esquizofrenia/diagnóstico por imagen , Proteína C-Reactiva , Inteligencia , Cognición , Encéfalo/diagnóstico por imagen , BiomarcadoresRESUMEN
Glutamate and increased inflammation have been separately implicated in the pathophysiology of schizophrenia and the extent of clinical response to antipsychotic treatment. Despite the mechanistic links between pro-inflammatory and glutamatergic pathways, the relationships between peripheral inflammatory markers and brain glutamate in schizophrenia have not yet been investigated. In this study, we tested the hypothesis that peripheral levels of pro-inflammatory cytokines would be positively associated with brain glutamate levels in schizophrenia. Secondary analyses determined whether this relationship differed according to antipsychotic treatment response. The sample consisted of 79 patients with schizophrenia, of whom 40 were rated as antipsychotic responders and 39 as antipsychotic non-responders. Brain glutamate levels were assessed in the anterior cingulate cortex (ACC) and caudate using proton magnetic resonance spectroscopy (1H-MRS) and blood samples were collected for cytokine assay on the same study visit (IL-6, IL-8, IL-10, TNF- α and IFN-γ). Across the whole patient sample, there was a positive relationship between interferon-gamma (IFN-γ) and caudate glutamate levels (r = 0.31, p = 0.02). In the antipsychotic non-responsive group only, there was a positive relationship between interleukin-8 (IL-8) and caudate glutamate (r = 0.46, p = 0.01). These findings provide evidence to link specific peripheral inflammatory markers and caudate glutamate in schizophrenia and may suggest that this relationship is most marked in patients who show a poor response to antipsychotic treatment.
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Antipsicóticos , Encefalitis , Esquizofrenia , Humanos , Ácido Glutámico/metabolismo , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Antipsicóticos/uso terapéutico , Interleucina-8 , Encéfalo/metabolismo , Inflamación/metabolismo , Encefalitis/metabolismoRESUMEN
OBJECTIVE: Immune system dysfunction is hypothesised to contribute to structural brain changes through aberrant synaptic pruning in schizophrenia. However, evidence is mixed and there is a lack of evidence of inflammation and its effect on grey matter volume (GMV) in patients. We hypothesised that inflammatory subgroups can be identified and that the subgroups will show distinct neuroanatomical and neurocognitive profiles. METHODS: The total sample consisted of 1067 participants (chronic patients with schizophrenia n = 467 and healthy controls (HCs) n = 600) from the Australia Schizophrenia Research Bank (ASRB) dataset, together with 218 recent-onset patients with schizophrenia from the external Benefit of Minocycline on Negative Symptoms of Psychosis: Extent and Mechanism (BeneMin) dataset. HYDRA (HeterogeneitY through DiscRiminant Analysis) was used to separate schizophrenia from HC and define disease-related subgroups based on inflammatory markers. Voxel-based morphometry and inferential statistics were used to explore GMV alterations and neurocognitive deficits in these subgroups. RESULTS: An optimal clustering solution revealed five main schizophrenia groups separable from HC: Low Inflammation, Elevated CRP, Elevated IL-6/IL-8, Elevated IFN-γ, and Elevated IL-10 with an adjusted Rand index of 0.573. When compared with the healthy controls, the IL-6/IL-8 cluster showed the most widespread, including the anterior cingulate, GMV reduction. The IFN-γ inflammation cluster showed the least GMV reduction and impairment of cognitive performance. The CRP and the Low Inflammation clusters dominated in the younger external dataset. CONCLUSIONS: Inflammation in schizophrenia may not be merely a case of low vs high, but rather there are pluripotent, heterogeneous mechanisms at play which could be reliably identified based on accessible, peripheral measures. This could inform the successful development of targeted interventions.
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Esquizofrenia , Humanos , Interleucina-6 , Interleucina-8 , Imagen por Resonancia Magnética , Encéfalo/diagnóstico por imagen , Sustancia Gris , Aprendizaje Automático SupervisadoRESUMEN
Positron emission tomography (PET) imaging of the 18 kDa translocator protein (TSPO), which is upregulated in activated microglia, is a method for investigating whether immune activation is evident in the brain of adults with schizophrenia. This study aimed to measure TSPO availability in the largest patient group to date, and to compare it between patients with recent onset (ROS) and established (ES) schizophrenia. In total, 20 ROS patients (14 male), 21 ES (13 male), and 21 healthy controls completed the study. Patients were predominantly antipsychotic-medicated. Participants underwent a PET scan using the TSPO-specific radioligand [11C](R)-PK11195. The primary outcome was binding potential (BPND) in the anterior cingulate cortex (ACC). Secondary outcomes were BPND in six other regions. Correlations were investigated between TSPO availability and symptom severity. Data showed that mean BPND was higher in older (ES and controls) compared with younger (ROS and controls) individuals, but did not significantly differ between ROS or ES and their respective age-matched controls (ACC; ANOVA main effect of diagnosis: F1,58 = 0.407, p = 0.526). Compared with controls, BPND was lower in antipsychotic-free (n = 6), but not in medicated, ROS patients. BPND in the ES group was negatively correlated with positive symptoms, and positively correlated with negative symptom score. Our data suggest ageing is associated with higher TSPO but a diagnosis of schizophrenia is not. Rather, subnormal TSPO levels in drug-free recent-onset patients may imply impaired microglial development and/or function, which is counteracted by antipsychotic treatment. The development of novel radioligands for specific immune-mechanisms is needed for further clarification.
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Esquizofrenia , Adulto , Anciano , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Humanos , Masculino , Microglía/metabolismo , Enfermedades Neuroinflamatorias , Tomografía de Emisión de Positrones , Receptores de GABA/metabolismo , Esquizofrenia/diagnóstico por imagen , Esquizofrenia/tratamiento farmacológicoRESUMEN
BACKGROUND: Immune dysfunction has been implicated in negative symptoms of schizophrenia and also in depression. These disorders are frequently co-morbid, with some symptoms such as anhedonia and apathy common to both. The anti-inflammatory agent minocycline may be ineffective in schizophrenia, but more positive effects have been seen in depression. Our aim was to investigate the role of immune dysfunction in depression and sub-domains of negative symptoms in schizophrenia by investigating their intercorrelation and the influence of treatment with minocycline. METHODS: We analysed longitudinal data from 207 patients within 5 years of onset of schizophrenia, from the randomised double-blind, placebo-controlled trial of minocycline (BeneMin). Symptom ratings and circulating IL-6, C-reactive protein (CRP) and TNF-α concentrations were collected at baseline and repeated over twelve months. The sample was not stratified by CRP prior to randomisation. Positive and Negative Syndrome Scale composite ratings of avolition-apathy and diminished expression, Calgary Depression Scale total scores, and immune markers were examined cross-sectionally using Spearman's rank, and longitudinally by linear mixed effect models that included body mass index and minocycline. Additionally, post hoc analysis of the sample stratified by elevated CRP (>1 mg/l and <10 mg/l at baseline) was carried out to assess whether minocycline had any effect on specific symptoms in an immune active sub-group of patients. RESULTS: Depression and avolition-apathy were significantly positively related, and depression correlated weakly with IL-6 at baseline. Diminished expression was associated with increased TNF-α both cross-sectionally and longitudinally. CRP was unrelated to any symptom domain. Minocycline did not affect any individual symptom or sub-domain in the full sample or in the immune active sub-group. DISCUSSION: IL-6 may have some specificity to depression in early schizophrenia. TNF-α may be an indicator of immune dysfunction relevant to negative symptoms, and our longitudinal findings add to this evidence. However, minocycline continues to show very little promise as a treatment for any symptom dimension of early schizophrenia.
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Minociclina , Esquizofrenia , Anhedonia , Depresión/tratamiento farmacológico , Método Doble Ciego , Humanos , Minociclina/uso terapéutico , Esquizofrenia/tratamiento farmacológicoRESUMEN
Weight gain is a common consequence of treatment with antipsychotic drugs in early psychosis, leading to further morbidity and poor treatment adherence. Identifying tools that can predict weight change in early psychosis may contribute to better-individualised treatment and adherence. Recently we showed that proteomic profiling with sequential window acquisition of all theoretical fragment ion spectra (SWATH) mass spectrometry (MS) can identify individuals with pre-diabetes more likely to experience weight change in relation to lifestyle change. We investigated whether baseline proteomic profiles predicted weight change over time using data from the BeneMin clinical trial of the anti-inflammatory antibiotic, minocycline, versus placebo. Expression levels for 844 proteins were determined by SWATH proteomics in 83 people (60 men and 23 women). Hierarchical clustering analysis and principal component analysis of baseline proteomics data did not reveal distinct separation between the proteome profiles of participants in different weight change categories. However, individuals with the highest weight loss had higher Positive and Negative Syndrome Scale (PANSS) scores. Our findings imply that mode of treatment i.e. the pharmacological intervention for psychosis may be the determining factor in weight change after diagnosis, rather than predisposing proteomic dynamics.
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Identifying key neural substrates in addiction disorders for targeted drug development remains a major challenge for clinical neuroscience. One emerging target is the opioid system, where substance-dependent populations demonstrate prefrontal opioid dysregulation that predicts impulsivity and relapse. This may suggest that disturbances to the prefrontal opioid system could confer a risk for relapse in addiction due to weakened 'top-down' control over impulsive behaviour. Naltrexone is currently licensed for alcohol dependence and is also used clinically for impulse control disorders. Using a go/no-go (GNG) task, we examined the effects of acute naltrexone on the neural correlates of successful motor impulse control in abstinent alcoholics (AUD), abstinent polysubstance-dependent (poly-SUD) individuals and controls during a randomised double blind placebo controlled fMRI study. In the absence of any differences on GNG task performance, the AUD group showed a significantly greater BOLD response compared to the control group in lateral and medial prefrontal regions during both placebo and naltrexone treatments; effects that were positively correlated with alcohol abstinence. There was also a dissociation in the positive modulating effects of naltrexone in the orbitofrontal cortex (OFC) and anterior insula cortex (AIC) of the AUD and poly-SUD groups respectively. Self-reported trait impulsivity in the poly-SUD group also predicted the effect of naltrexone in the AIC. These results suggest that acute naltrexone differentially amplifies neural responses within two distinct regions of a salience network during successful motor impulse control in abstinent AUD and poly-SUD groups, which are predicted by trait impulsivity in the poly-SUD group.
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Abstinencia de Alcohol , Disuasivos de Alcohol/uso terapéutico , Alcoholismo/diagnóstico por imagen , Conducta Impulsiva/fisiología , Naltrexona/uso terapéutico , Desempeño Psicomotor/fisiología , Adulto , Disuasivos de Alcohol/farmacología , Alcoholismo/tratamiento farmacológico , Método Doble Ciego , Femenino , Humanos , Conducta Impulsiva/efectos de los fármacos , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Naltrexona/farmacología , Desempeño Psicomotor/efectos de los fármacos , Trastornos Relacionados con Sustancias/diagnóstico por imagen , Trastornos Relacionados con Sustancias/tratamiento farmacológico , Adulto JovenRESUMEN
Comorbidity patterns have become a major source of information to explore shared mechanisms of pathogenesis between disorders. In hypothesis-free exploration of comorbid conditions, disease-disease networks are usually identified by pairwise methods. However, interpretation of the results is hindered by several confounders. In particular a very large number of pairwise associations can arise indirectly through other comorbidity associations and they increase exponentially with the increasing breadth of the investigated diseases. To investigate and filter this effect, we computed and compared pairwise approaches with a systems-based method, which constructs a sparse Bayesian direct multimorbidity map (BDMM) by systematically eliminating disease-mediated comorbidity relations. Additionally, focusing on depression-related parts of the BDMM, we evaluated correspondence with results from logistic regression, text-mining and molecular-level measures for comorbidities such as genetic overlap and the interactome-based association score. We used a subset of the UK Biobank Resource, a cross-sectional dataset including 247 diseases and 117,392 participants who filled out a detailed questionnaire about mental health. The sparse comorbidity map confirmed that depressed patients frequently suffer from both psychiatric and somatic comorbid disorders. Notably, anxiety and obesity show strong and direct relationships with depression. The BDMM identified further directly co-morbid somatic disorders, e.g. irritable bowel syndrome, fibromyalgia, or migraine. Using the subnetwork of depression and metabolic disorders for functional analysis, the interactome-based system-level score showed the best agreement with the sparse disease network. This indicates that these epidemiologically strong disease-disease relations have improved correspondence with expected molecular-level mechanisms. The substantially fewer number of comorbidity relations in the BDMM compared to pairwise methods implies that biologically meaningful comorbid relations may be less frequent than earlier pairwise methods suggested. The computed interactive comprehensive multimorbidity views over the diseasome are available on the web at Co=MorNet: bioinformatics.mit.bme.hu/UKBNetworks.
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Teorema de Bayes , Comorbilidad , Depresión/epidemiología , Trastornos Mentales/metabolismo , Modelos Estadísticos , Modelos de Riesgos Proporcionales , Simulación por Computador , Interpretación Estadística de Datos , Minería de Datos/métodos , Depresión/diagnóstico , Humanos , Incidencia , Síndrome del Colon Irritable/epidemiología , Enfermedades Metabólicas/epidemiología , Trastornos Migrañosos/epidemiología , Enfermedades Neurodegenerativas/epidemiología , Reconocimiento de Normas Patrones Automatizadas/métodos , Reproducibilidad de los Resultados , Medición de Riesgo/métodos , Sensibilidad y EspecificidadRESUMEN
Relapse after initially successful treatment is a significant problem facing the treatment of opioid dependence. Evidence suggests craving elicited by re-exposure to drug cues may precipitate relapse. Attempts to identify neural biomarkers of cue-elicited craving have yielded inconsistent findings. We aimed to apply a novel continuous functional magnetic resonance imaging technique to follow the minute-to-minute evolution of brain responses, which correlate with the waxing and waning of craving. Newly detoxified male opioid-dependent patients and healthy control participants attended two separate, counterbalanced, functional magnetic resonance imaging scanning sessions during which they viewed a 10-minute video (drug cue or neutral cue) followed by 5 minutes of fixation. Participants rated the intensity of their craving throughout each session. We hypothesized that subcortical/ventral prefrontal cortex (PFC) regions and dorsal PFC regions would show different associations with craving reflecting their putative roles in appetitive processing versus cognitive control. Compared with controls, drug cue (minus neutral cue) video recruited the left amygdala and was temporally correlated with craving. In contrast, dorsal anterior cingulate blood-oxygen-level-dependent signal time course was higher than controls only during a period after cue exposure when craving levels were declining. Against expectations, neither the ventral striatum nor ventral PFC was significantly recruited by drug cue exposure. Findings suggest that the amygdala has a central role in craving, whereas the dorsal anterior cingulate may control craving in treatment-seeking patients. Time course analysis yielded new insights into the neural substrates of craving that could objectively validate development of psychological and pharmacological approaches to sustained abstinence.
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Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Ansia/efectos de los fármacos , Ansia/fisiología , Trastornos Relacionados con Opioides/fisiopatología , Adulto , Mapeo Encefálico/métodos , Señales (Psicología) , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Vías Nerviosas/diagnóstico por imagen , Vías Nerviosas/efectos de los fármacos , Vías Nerviosas/fisiopatología , RecurrenciaRESUMEN
Naltrexone, an opioid receptor antagonist, is commonly used as a relapse prevention medication in alcohol and opiate addiction, but its efficacy and the mechanisms underpinning its clinical usefulness are not well characterized. In the current study, we examined the effects of 50-mg naltrexone compared with placebo on neural network changes associated with substance dependence in 21 alcohol and 36 poly-drug-dependent individuals compared with 36 healthy volunteers. Graph theoretic and network-based statistical analysis of resting-state functional magnetic resonance imaging (MRI) data revealed that alcohol-dependent subjects had reduced functional connectivity of a dispersed network compared with both poly-drug-dependent and healthy subjects. Higher local efficiency was observed in both patient groups, indicating clustered and segregated network topology and information processing. Naltrexone normalized heightened local efficiency of the neural network in alcohol-dependent individuals, to the same levels as healthy volunteers. Naltrexone failed to have an effect on the local efficiency in abstinent poly-substance-dependent individuals. Across groups, local efficiency was associated with substance, but no alcohol exposure implicating local efficiency as a potential premorbid risk factor in alcohol use disorders that can be ameliorated by naltrexone. These findings suggest one possible mechanism for the clinical effects of naltrexone, namely, the amelioration of disrupted network topology.
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Disuasivos de Alcohol/farmacología , Alcoholismo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Naltrexona/farmacología , Adulto , Alcoholismo/fisiopatología , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Femenino , Neuroimagen Funcional , Voluntarios Sanos , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Vías Nerviosas , Trastornos Relacionados con Sustancias/diagnóstico por imagen , Trastornos Relacionados con Sustancias/fisiopatología , Adulto JovenRESUMEN
PURPOSE: Glutathione (GSH) is an important intracellular antioxidant in the brain. A number of studies report its measurement by localized 1 H spectroscopy using PRESS and STEAM. This study evaluates the reliability and accuracy of GSH measurements from PRESS at 3 Tesla (T) and compares the results to those obtained with MEGA-PRESS. METHODS: Phantoms containing brain metabolites, identical except for variable GSH concentration between 0 and 24 mM, were scanned using PRESS (echo time (TE) = 35 ms) and MEGA-PRESS (optimized TE = 130 ms) at 3 T. Spectra of the anterior cingulate cortex and occipital cortex in seven healthy volunteers were also acquired. RESULTS: Phantom GSH concentrations from 0 to 3mM were unreliably quantified using PRESS, although at 4 mM and above there was a linear relationship between measured and true concentrations (R2 = 0.99). Using MEGA-PRESS, there was no signal detected at 0 mM GSH, plus a linear relationship (R2 = 0.99) over the full range from 0-24 mM. In brain, concentrations calculated from MEGA-PRESS and PRESS were significantly different in occipital cortex (P < 0.001). Moreover, only MEGA-PRESS reported significant differences in GSH between the two brain regions (P = 0.003). CONCLUSION: Due to uncertainties in GSH quantification raised by the study, the authors conclude that physiological concentrations (<4 mM) of GSH cannot be reliably quantified from PRESS (TE = 35 ms) spectra at 3 T. Magn Reson Med 78:1257-1266, 2017. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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Química Encefálica/fisiología , Encéfalo/diagnóstico por imagen , Glutatión/análisis , Imagen por Resonancia Magnética/métodos , Adulto , Encéfalo/metabolismo , Femenino , Glutatión/metabolismo , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Fantasmas de Imagen , Procesamiento de Señales Asistido por Computador , Adulto JovenRESUMEN
There is a concerted research effort to investigate brain mechanisms underlying addiction processes that may predicate the development of new compounds for treating addiction. One target is the brain's opioid system, because of its role in the reinforcing effects of substances of abuse. Substance-dependent populations have increased numbers of the mu opioid receptor (MOR) in fronto-striatal regions that predict drug relapse, and demonstrate disturbances in these regions during the processing of non-drug rewards. Naltrexone is currently licensed for alcohol and opiate dependence, and may remediate such disturbances through the blockade of MORs in fronto-striatal reward circuitry. Therefore, we examined the potential acute modulating effects of naltrexone on the anticipation of, and instrumental responding for, non-drug rewards in long-term abstinent alcoholics, alcoholic poly substance-dependent individuals and controls using a monetary incentive delay (MID) task during a randomized double blind placebo controlled functional MRI study. We report that the alcoholic poly substance-dependent group exhibited slower and less accurate instrumental responding compared to alcoholics and controls that was less evident after acute naltrexone treatment. However, naltrexone treatment was unable to remediate disturbances within fronto-striatal regions during reward anticipation and 'missed' rewards in either substance-dependent group. While we have not been able to identify the underlying neural mechanisms for improvement observed with naltrexone in the alcoholic poly-substance dependent group, we can confirm that both substance-dependent groups exhibit substantial neural deficits during an MID task, despite being in long-term abstinence.
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Alcoholismo/fisiopatología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/fisiopatología , Descuento por Demora/fisiología , Naltrexona/farmacología , Antagonistas de Narcóticos/farmacología , Adulto , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Motivación , Recompensa , Trastornos Relacionados con Sustancias/fisiopatología , Reino UnidoRESUMEN
Background and Hypothesis: Oxidative stress pathways may play a role in schizophrenia through direct neuropathic actions, microglial activation, inflammation, and by interfering with NMDA neurotransmission. N-acetylcysteine (NAC) has been shown to improve negative symptoms of schizophrenia, however, results from trials of other compounds targeting NMDA neurotransmission have been mixed. This may reflect poor target engagement but also that risk mechanisms act in parallel. Sodium Benzoate (NaB) could have an additive with NAC to act on several pathophysiological mechanisms implicated in schizophrenia. Study Design: A multicenter, 12 weeks, 2â ×â 2 factorial design, randomized double-blind placebo-controlled feasibility trial of NaB and NAC added to standard treatment in 68 adults with early schizophrenia. Primary feasibility outcomes included recruitment, retention, and completion of assessments as well as acceptability of the study interventions. Psychosis symptoms, functioning, and cognitive assessments were also assessed. Study Results: We recruited our desired sample (nâ =â 68) and retained 78% (nâ =â 53) at 12 weeks, supporting the feasibility of recruitment and retention. There were no difficulties in completing clinical outcome schedules. Medications were well tolerated with no dropouts due to side effects. This study was not powered to detect clinical effect and as expected no main effects were found on the majority of clinical outcomes. Conclusions: We demonstrated feasibility of conducting a clinical trial of NaB and NAC. Given the preliminary nature of this study, we cannot draw firm conclusions about the clinical efficacy of either agent, and a large-scale trial is needed to examine if significant differences between treatment groups emerge. Trial Registration: ClinicalTrials.gov: NCT03510741.
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It is well known that schizophrenia is associated with cognitive impairment, reduced cortical grey matter and increased circulating concentrations of inflammatory cytokines. However, the relationship between these findings is not clear. We outline the influential neuroinflammatory hypotheses that raised cytokines provoke a damaging immune response in microglia that results in reduced grey matter and associated cognitive performance. We investigated whether such an interaction might be detectable in the prodromal period as illness emerges from the Clinical High Risk for Psychosis (CHR-P). Meta-analyses suggest that compared with controls, impaired cognition and reduced grey matter are already present by the prodrome and that greater decrements are present in those who later develop symptoms. In contrast, the few cytokine studies report no abnormalities in CHR-P except that interleukin-6 (IL-6) levels were raised versus controls and to a greater extent in the future patients, in one study. We noted that cognitive impairment and less cortical grey matter are more severe in schizophrenia than in affective disorders, but that increased cytokine levels are similarly prevalent across disorders. We found no studies correlating cytokine levels with cognitive impairment in CHR-P but such correlations seem unlikely given the minimal relationship reported in a recent meta-analysis of the many cytokine-cognition studies in established illness. From this and other evidence, we conclude that neuroinflammation is not a core feature of schizophrenia nor a substrate for reduced grey matter volume or cognitive function. We draw attention instead to the emerging evidence that brain-resident immune cells and signalling molecules such as Tregs and IL-6, which are influenced by schizophrenia risk genes, regulate and are necessary for the development and function of neuron-glia interaction. We suggest that cognitive impairment in schizophrenia can be seen as a convergence of genetic and immune-neurodevelopmental dysregulation whereas raised cytokines are a consequence of impaired Tregs control of systemic inflammation.
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Trastornos Psicóticos , Esquizofrenia , Humanos , Interleucina-6 , Esquizofrenia/complicaciones , Cognición , CitocinasRESUMEN
Manipulation of intake of serotonin precursor tryptophan has been exploited to rapidly induce and alleviate depression symptoms. While studies show that this latter effect is dependent on genetic vulnerability to depression, the effect of habitual tryptophan intake in the context of predisposing genetic factors has not been explored. Our aim was to investigate the effect of habitual tryptophan intake on mood symptoms and to determine the effect of risk variants on depression in those with high and low tryptophan intake in the whole genome and specifically in serotonin and kynurenine pathways. 63,277 individuals in the UK Biobank with data on depressive symptoms and tryptophan intake were included. We compared two subpopulations defined by their habitual diet of a low versus a high ratio of tryptophan to other large amino acids (TLR). A modest protective effect of high dietary TLR against depression was found. NPBWR1 among serotonin genes and POLI in kynurenine pathway genes were significantly associated with depression in the low but not in the high TLR group. Pathway-level analyses identified significant associations for both serotonin and kynurenine pathways only in the low TLR group. In addition, significant association was found in the low TLR group between depressive symptoms and biological process related to adult neurogenesis. Our findings demonstrate a markedly distinct genetic risk profile for depression in groups with low and high dietary TLR, with association with serotonin and kynurenine pathway variants only in case of habitual food intake leading to low TLR. Our results confirm the relevance of the serotonin hypothesis in understanding the neurobiological background of depression and highlight the importance of understanding its differential role in the context of environmental variables such as complexity of diet in influencing mental health, pointing towards emerging possibilities of personalised prevention and intervention in mood disorders in those who are genetically vulnerable.
Asunto(s)
Aminoácidos Neutros , Triptófano , Adulto , Humanos , Triptófano/metabolismo , Quinurenina/metabolismo , Depresión/genética , Serotonina , DietaRESUMEN
Dysfunction of glutamate neurotransmission has been implicated in the pathophysiology of schizophrenia and may be particularly relevant in severe, treatment-resistant symptoms. The underlying mechanism may involve hypofunction of the NMDA receptor. We investigated whether schizophrenia-related pathway polygenic scores, composed of genetic variants within NMDA receptor encoding genes, are associated with cortical glutamate in schizophrenia. Anterior cingulate cortex (ACC) glutamate was measured in 70 participants across 4 research sites using Proton Magnetic Resonance Spectroscopy (1H-MRS). Two NMDA receptor gene sets were sourced from the Molecular Signatories Database and NMDA receptor pathway polygenic scores were constructed using PRSet. The NMDA receptor pathway polygenic scores were weighted by single nucleotide polymorphism (SNP) associations with treatment-resistant schizophrenia, and associations with ACC glutamate were tested. We then tested whether NMDA receptor pathway polygenic scores with SNPs weighted by associations with non-treatment-resistant schizophrenia were associated with ACC glutamate. A higher NMDA receptor complex pathway polygenic score was significantly associated with lower ACC glutamate (ß = -0.25, 95 % CI = -0.49, -0.02, competitive p = 0.03). When SNPs were weighted by associations with non-treatment-resistant schizophrenia, there was no association between the NMDA receptor complex pathway polygenic score and ACC glutamate (ß = 0.05, 95 % CI = -0.18, 0.27, competitive p = 0.79). These results provide initial evidence of an association between common genetic variation implicated in NMDA receptor function and ACC glutamate levels in schizophrenia. This association was specific to when the NMDA receptor complex pathway polygenic score was weighted by SNP associations with treatment-resistant schizophrenia.
Asunto(s)
Esquizofrenia , Humanos , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/genética , Esquizofrenia/metabolismo , Ácido Glutámico/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Encéfalo , Herencia Multifactorial , Espectroscopía de Protones por Resonancia Magnética , Giro del CínguloRESUMEN
Elevated brain glutamate has been implicated in non-response to antipsychotic medication in schizophrenia. Biomarkers that can accurately predict antipsychotic non-response from the first episode of psychosis (FEP) could allow stratification of patients; for example, patients predicted not to respond to standard antipsychotics could be fast-tracked to clozapine. Using proton magnetic resonance spectroscopy (1H-MRS), we examined the ability of glutamate and Glx (glutamate plus glutamine) in the anterior cingulate cortex (ACC) and caudate to predict response to antipsychotic treatment. A total of 89 minimally medicated patients with FEP not meeting symptomatic criteria for remission were recruited across two study sites. 1H-MRS and clinical data were acquired at baseline, 2 and 6 weeks. Response was defined as >20% reduction in Positive and Negative Syndrome Scale (PANSS) Total score from baseline to 6 weeks. In the ACC, baseline glutamate and Glx were higher in Non-Responders and significantly predicted response (P < 0.02; n = 42). Overall accuracy was greatest for ACC Glx (69%) and increased to 75% when symptom severity at baseline was included in the model. Glutamate metabolites in the caudate were not associated with response, and there was no significant change in glutamate metabolites over time in either region. These results add to the evidence linking elevations in ACC glutamate metabolites to a poor antipsychotic response. They indicate that glutamate may have utility in predicting response during early treatment of first episode psychosis. Improvements in accuracy may be made by combining glutamate measures with other response biomarkers.