Disrupted white matter integrity in treatment-resistant schizophrenia

Treatment response in schizophrenia is heterogeneous and has been posited to divide into three distinct subcategories: treatment-responsive (first-line responders; FLR), treatment-resistant (TRS, responding to clozapine), and ultra-treatment-resistant schizophrenia (UTRS, requiring augmented antipsychotic therapy). Previous work suggests that white matter abnormalities drive antipsychotic resistance but little work has been carried out to identify differences between those with TRS and those with UTRS. The current study aimed to establish whether differences in white matter structure are present across both treatment-resistant subtypes of schizophrenia or if UTRS is distinct from TRS. Diffusion-weighted images were acquired for 18 individuals with TRS, 14 with UTRS, 18 FLR and 20 healthy controls. Measures of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and parallel diffusivity (PD) were obtained using tract-based spatial statistics. Analysis of variance (ANOVA) and post-hoc between-groups t-tests interrogating differences were conducted for each white matter measure. Those with TRS had lower FA than healthy controls across widespread regions of the brain, including the superior longitudinal fasciculus, corpus callosum, thalamic radiation, corticospinal tract, internal capsule, corona radiata and fronto-occipital fasciculus (p<.05 FWE-corrected). Lower FA was also observed in those with TRS compared with UTRS in the superior longitudinal fasciculus (p<.05 FWE-corrected). However, post-hoc tests failed to survive corrections for multiple comparisons across the 12 post-hoc contrasts. No differences in MD, PD or RD were observed between groups. These data suggest that TRS is distinct from UTRS and that lower FA could act as a biomarker of treatment resistance in people with schizophrenia

Aberrant white matter microstructure in treatment-resistant schizophrenia

Treatment response in schizophrenia divides into three subcategories: treatment-responsive (first-line responders; FLR), treatment-resistant (TRS), and ultra-treatment-resistant schizophrenia (UTRS). White matter abnormalities could drive antipsychotic resistance but little work has investigated differences between TRS and UTRS. The current study aimed to establish whether differences in white matter structure are present across both treatment-resistant subtypes or if UTRS is distinct from TRS. Diffusion-weighted images were acquired for 18 individuals with TRS, 14 with UTRS, 18 FLR and 20 healthy controls. Measures of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD) and axial diffusivity (AD) were obtained using tract-based spatial statistics. Analysis of variance and post-hoc t-tests were conducted for each measure. Those with TRS had lower FA than healthy controls in superior longitudinal fasciculus, corpus callosum, thalamic radiation, corticospinal tract, internal capsule, corona radiata and fronto-occipital fasciculus (p<.05 FWE-corrected). Lower FA was also observed in TRS compared with UTRS in the superior longitudinal fasciculus (p<.05 FWE-corrected). No post-hoc tests survived corrections for multiple comparisons and no differences in MD, AD or RD were observed. These data suggest that microstructural deficits in white matter could contribute to TRS but suggest that other mechanisms may be more relevant for UTRS

Functional network dysconnectivity as a biomarker of treatment resistance in schizophrenia.

Schizophrenia may develop from disruptions in functional connectivity regulated by neurotransmitters such as dopamine and acetylcholine. The modulatory effects of these neurotransmitters might explain how antipsychotics attenuate symptoms of schizophrenia and account for the variable response to antipsychotics observed in clinical practice. Based on the putative mechanisms of antipsychotics and evidence of disrupted connectivity in schizophrenia, we hypothesised that functional network connectivity, as assessed using network-based statistics, would exhibit differences between treatment response subtypes of schizophrenia and healthy controls. Resting-state functional MRI data were obtained from 17 healthy controls as well as individuals with schizophrenia who responded well to first-line atypical antipsychotics (first-line responders; FLR, n=18), had failed at least two trials of antipsychotics but responded to clozapine (treatment-resistant schizophrenia; TRS, n=18), or failed at least two trials of antipsychotics and a trial of clozapine (ultra-treatment-resistant schizophrenia; UTRS, n=16). Data were pre-processed using the Advanced Normalization Toolkit and BrainWavelet Toolbox. Network connectivity was assessed using the Network-Based Statistics toolbox in Matlab. ANOVA revealed a significant difference in functional connectivity between groups that extended between cerebellar and parietal regions to the frontal cortex (p<0.05). Post-hoc t-tests revealed weaker network connectivity in individuals with UTRS compared with healthy controls but no other differences between groups. Results demonstrated distinct differences in functional connectivity between individuals with UTRS and healthy controls. Future work must determine whether these changes occur prior to the onset of treatment and if they can be used to predict resistance to antipsychotics during first-episode psychosis

Multinational evidence-based recommendations for the diagnosis and management of gout: integrating systematic literature review and expert opinion of a broad panel of rheumatologists in the 3e initiative

We aimed to develop evidence-based multinational recommendations for the diagnosis and management of gout. Using a formal voting process, a panel of 78 international rheumatologists developed 10 key clinical questions pertinent to the diagnosis and management of gout. Each question was investigated with a systematic literature review. Medline, Embase, Cochrane CENTRAL and abstracts from 2010-2011 European League Against Rheumatism and American College of Rheumatology meetings were searched in each review. Relevant studies were independently reviewed by two individuals for data extraction and synthesis and risk of bias assessment. Using this evidence, rheumatologists from 14 countries (Europe, South America and Australasia) developed national recommendations. After rounds of discussion and voting, multinational recommendations were formulated. Each recommendation was graded according to the level of evidence. Agreement and potential impact on clinical practice were assessed. Combining evidence and clinical expertise, 10 recommendations were produced. One recommendation referred to the diagnosis of gout, two referred to cardiovascular and renal comorbidities, six focused on different aspects of the management of gout (including drug treatment and monitoring), and the last recommendation referred to the management of asymptomatic hyperuricaemia. the level of agreement with the recommendations ranged from 8.1 to 9.2 (mean 8.7) on a 1-10 scale, with 10 representing full agreement. Ten recommendations on the diagnosis and management of gout were established. They are evidence-based and supported by a large panel of rheumatologists from 14 countries, enhancing their utility in clinical practice.AbbVieAustralian National Health and Medical Research Council (NHMRC)Hosp Gen Univ Elda, Dept Reumatol, Elda 03600, SpainHosp Gen Univ Alicante, Dept Reumatol, Alicante, SpainUniv Camilo Jose Cela, Fac Ciencias Salud, Madrid, SpainUniv British Columbia, Div Rheumatol, Vancouver, BC V5Z 1M9, CanadaRoyal Melbourne Hosp, Parkville, Vic 3050, AustraliaUniv Hosp Southampton NHS Fdn Trust, Southampton, Hants, EnglandNIHR Wellcome Trust Clin Res Facil, Southampton, Hants, EnglandCtr Hosp Univ Liege, Liege, BelgiumMaastricht Univ, Med Ctr, Dept Internal Med Rheumatol, Maastricht, NetherlandsAtrium Med Ctr, Heerlen, NetherlandsUniv Toronto, Div Rheumatol, Toronto, ON, CanadaRepatriat Gen Hosp, Rheumatol Res Unit, Adelaide, SA, AustraliaFlinders Univ S Australia, Adelaide, SA 5001, AustraliaMed Univ Vienna, Dept Internal Med 3, Div Rheumatol, Vienna, AustriaUniv Toronto, Dept Hlth Policy Management & Evaluat, Toronto, ON, CanadaMt Sinai Hosp, Univ Hlth Network, Toronto Gen Res Inst, Div Clin Decis Making & Hlth Care, Toronto, ON M5G 1X5, CanadaCabrini Hosp, Monash Dept Clin Epidemiol, Malvern, Vic, AustraliaMonash Univ, Dept Epidemiol & Prevent Med, Malvern, Vic, AustraliaUniv Amsterdam, Acad Med Ctr, Dept Clin Immunol & Rheumatol, NL-1105 AZ Amsterdam, NetherlandsUniv Med Ctr Utrecht, Dept Rheumatol & Clin Immunol, Utrecht, NetherlandsUniv Nova Lisboa, Fac Ciencias Med, CEDOC, P-1200 Lisbon, PortugalEPE Hosp Egas Moniz, CHLO, Dept Rheumatol, Lisbon, PortugalHosp Gen Mexico City, Rheumatol Unit, Mexico City, DF, MexicoKarolinska Univ Hosp, Dept Rheumatol, Stockholm, SwedenKarolinska Inst, Stockholm, SwedenGhent Univ Hosp, Dept Rheumatol, Ghent, BelgiumUniversidade Federal de São Paulo, Div Rheumatol, São Paulo, BrazilSt Georges Healthcare NHS Trust, Dept Rheumatol, London, EnglandState Hosp Stockerau, Ctr Rheumatol, Lower Austria, Stockerau, AustriaUniv Pavia, IRCCS Policlin S Matteo, Cattedra Reumatol, I-27100 Pavia, ItalyUniv Giessen, Kerckhoff Klin, Dept Rheumatol & Clin Immunol, Bad Nauheim, GermanyCopenhagen Univ Hosp, Ctr Rheumatol & Spine Dis, Copenhagen Ctr Arthrit Res, Glostrup, DenmarkMenzies Res Inst Tasmania, Hobart, Tas, AustraliaColumbia Univ, Med Ctr, New York, NY USALeiden Univ, Med Ctr, Leiden, NetherlandsUniversidade Federal de São Paulo, Div Rheumatol, São Paulo, BrazilWeb of Scienc

The coexistence of peace and conflict in South America: toward a new conceptualization of types of peace

South America's predominant democratic regimes and its increasing interdependence on regional trade have not precluded the emergence of militarized crises between Colombia and Venezuela or the revival of boundary claims between Chile and Peru. This way, how can we characterize a zone that, in spite of its flourishing democracy and dense economic ties, remain involved in territorial disputes for whose resolution the use of force has not yet been discarded? This article contends that existing classifications of zones of peace are not adequate to explain this unusual coexistence. Thus, its main purpose is to develop a new analytical category of regional peace for assessing this phenomenon: the hybrid peace. It aims to research the evolution of security systems in South America during the previous century and build a new, threefold classification of peace zones: negative peace zones, hybrid peace zones, and positive peace zones

Quantitative EEG and Low-Resolution Electromagnetic Tomography (LORETA) Imaging of Patients Undergoing Methadone Treatment for Opiate Addiction

Methadone maintenance treatment (MMT) has been used as a treatment for opiate dependence since the mid-1960s. Evidence suggests that methadone binds to mu opiate receptors as do other opiates and induces changes in neurophysiological function. However, little is known, about how neural activity within the higher frequency gamma band (>30 Hz) while at rest changes in those stabilized on MMT despite its association with the excitation-inhibition balance within pyramidal-interneuron networks. Our study investigated differences in resting gamma power (37-41 Hz) between patients undergoing MMT for opiate dependence, illicit opiate users, and healthy controls subjects. Electroencephalographic data were recorded from 26 sites according to the international 10-20 system. Compared with the healthy controls subjects, people either undergoing MMT (mean difference [MD] = 0.32, 95% CI = 0.09-0.55, P <.01) or currently using illicit opiates (MD = 0.31, 95% CI = 0.06-0.56, P =.01) exhibited significant increased gamma power. The sLORETA (standardized low-resolution electromagnetic tomography) between-group comparison revealed dysfunctional neuronal activity in the occipital, parietal, and frontal lobes in the patients undergoing MMT. A more severe profile of dysfunction was observed in those using illicit opiates. Our findings suggest that long-term exposure to opioids is associated with disrupted resting state network, which may be reduced after MMT

Auditory event-related potentials in methadone substituted opiate users

The effects of methadone maintenance treatment (MMT) on neurophysiological function are unclear. Using an auditory oddball paradigm, event-related potential (ERP) amplitudes and latencies were measured in 32 patients undertaking MMT, 17 opiate users who were addicted but not receiving substitution treatment and 25 healthy control subjects. Compared with healthy control subjects, the MMT and opiate user groups showed an increased P200 amplitude in response to target stimuli. The opiate user group also exhibited a decreased amplitude and an increased latency of N200, and a greater number of task-related errors than either healthy control subjects or patients undertaking MMT. There were no significant group differences in the P300 amplitude. However, it is noteworthy that the frontal P300 amplitude of the MMT group was greater than that of opiate users or healthy controls. Our findings suggest that altered sensory information processing associated with a history of opiate use remains in patients undertaking MMT. However, there are less marked ERP abnormalities in those receiving MMT than in active opiate users. The deficits in information processing associated with illicit opiate use are likely to be reduced during MMT