Shitij kapur

Proton magnetic resonance spectroscopy ((1)H MRS) studies in schizophrenia patients generally report decreased levels of N-acetyl-aspartate (NAA), glutamate and glutathione, particularly in frontal cortex. However, these data are inconsistent in part due to confounds associated with clinical samples. The lack of validated diagnostic biomarkers also hampers analysis of the neurodevelopmental trajectory of neurochemical abnormalities. Rodent models are powerful tools to address these issues, particularly when combined with (1)H MRS (clinically comparable technology)...

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Neuroinflammation is increasingly implicated in the pathogenesis of Schizophrenia (SCZ). In addition, there is increasing evidence for a relationship between the dose and duration of antipsychotic drug (APD) treatment and reductions in grey matter volume. The potential contribution of microglia to these phenomena is however not yet defined. Adult rats were treated with a common vehicle, haloperidol (HAL, 2 mg/kg/day) or olanzapine (OLZ, 10 mg/kg/day) for 8 weeks via an osmotic mini-pump implanted subcutaneously...

Current approaches to the management of severe mental illness have four major limitations: 1) symptom reporting is intermittent and subject to problems with reliability; 2) service users report feelings of disengagement from their care planning; 3) late detection of symptoms delay interventions and increase the risk of relapse; and 4) care systems are held back by the costs of unscheduled hospital admissions that could have been avoided with earlier detection and intervention. The ClinTouch system was developed to close the loop between service users and health professionals...

The mechanisms underlying neurodegeneration and loss of dopaminergic signalling in Parkinson's disease are still only partially understood. Phosphodiesterase 10A (PDE10A) is a basal ganglia expressed dual substrate enzyme, which regulates cAMP and cGMP signalling cascades, thus having a key role in the regulation of dopaminergic signalling in striatal pathways, and in promoting neuronal survival. This study aimed to assess in vivo the availability of PDE10A in patients with Parkinson's disease using positron emission tomography molecular imaging with (11)C-IMA107, a highly selective PDE10A radioligand...

BACKGROUND: The UK, like some other countries, carries out a periodic review of research quality in universities and the most recent Research Excellence Framework (REF) reported a doubling (103% increase) in its "world leading" or so-called "4*" research outputs in the areas of life sciences and medicine between 2008 and 2014. This is a remarkable improvement in six years and if validated internationally could have profound implications for health sciences. METHODS: We compared the reported changes in 4* quality to bibliometric measures of quality for the 56,639 articles submitted to the RAE 2008 and the 50,044 articles submitted to the REF 2014 to Panel A, which assesses the life sciences, including medicine...

There is an urgent need for early biomarkers and novel disease-modifying therapies in Huntington's disease. Huntington's disease pathology involves the toxic effect of mutant huntingtin primarily in striatal medium spiny neurons, which highly express phosphodiesterase 10A (PDE10A). PDE10A hydrolyses cAMP/cGMP signalling cascades, thus having a key role in the regulation of striatal output, and in promoting neuronal survival. PDE10A could be a key therapeutic target in Huntington's disease. Here, we used combined positron emission tomography (PET) and multimodal magnetic resonance imaging to assess PDE10A expression in vivo in a unique cohort of 12 early premanifest Huntington's disease gene carriers with a mean estimated 90% probability of 25 years before the predicted onset of clinical symptoms...

Delusional experiences can be considered on a range of dimensions including conviction, distress, preoccupation, and disruption, which have been shown to be related to depression and anxiety. This study aimed to test the hypotheses that delusional conviction is less responsive to antipsychotic treatment than delusional distress and preoccupation, and that depression and anxiety reduce alongside improvements in delusional dimensions. Forty acutely ill inpatients with delusions were assessed during their early stage of antipsychotic treatment...

Emerging data from on imaging and genetic studies have generated interest in "clinically significant" biomarkers to predict response and prognosis. What constitutes "clinical significance" and how a biomarker would reach that threshold are unclear. To develop a benchmark we reviewed different approaches for defining "clinical significance" applied in schizophrenia research and identified that an improvement of 15 points on the PANSS Total is considered meaningful in clinical settings. Using this benchmark and we simulated thousands of schizophrenia trials, using characteristics derived from the NEWMEDS database with over 8000 patients with schizophrenia, to the kind of imaging, genetic, and other biomarkers that could attain clinical significance...

RATIONALE: Cognitive impairment associated with schizophrenia is a key predictor of functional outcomes. The FDA-accepted MATRICS Consensus Cognitive Battery (MCCB) is held to be the gold standard measure but there are concerns about its ease of administration, reliance on language causing problems with translation and possible practice effects. The CogState Schizophrenia Battery (SB) is suggested as a non-language-based alternative but there is no substantial, independent comparison...

Several efforts to develop pharmacological treatments with a beneficial effect on cognition in schizophrenia are underway, while cognitive remediation has shown modest effects on cognitive performance. Our goal was to test if pharmacological augmentation of cognitive training would result in enhancement of training-induced learning. We chose modafinil as the pharmacological augmenting agent, as it is known to have beneficial effects on learning and cognition. 49 participants with chronic schizophrenia were enroled in a double-blind, placebo-controlled study across two sites and were randomised to either modafinil (200mg/day) or placebo...

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BACKGROUND: Most of the 13 542 trials contained in the Cochrane Schizophrenia Group's register just tested the general efficacy of pharmacological or psychosocial interventions. Studies on the subsequent treatment steps, which are essential to guide clinicians, are largely missing. This knowledge gap leaves important questions unanswered. For example, when a first antipsychotic failed, is switching to another drug effective? And when should we use clozapine? The aim of this article is to review the efficacy of switching antipsychotics in case of nonresponse...

Successful treatment of first-episode psychosis is one of the major factors that impacts long-term prognosis. Currently, there are no satisfactory biological markers (biomarkers) to predict which patients with a first-episode psychosis will respond to which treatment. In addition, a non-negligible rate of patients does not respond to any treatment or may develop side effects that affect adherence to the treatments as well as negatively impact physical health. Thus, there clearly is a pressing need for defining biomarkers that may be helpful to predict response to treatment and sensitivity to side effects in first-episode psychosis...

BACKGROUND: Benzodiazepine prescribing for schizophrenia occurs in clinical practice and antipsychotic trials. This review examined the clinical outcomes for benzodiazepines in schizophrenia. METHOD: A systematic search identified randomised controlled trials that evaluated benzodiazepines in comparison with placebo or antipsychotics, and also as adjuncts to antipsychotics. Relevant clinical outcome data was extracted. RESULTS: Twenty six studies were included with some reporting multiple comparisons...

BACKGROUND: The hypothesis that cortical dopaminergic alterations underlie aspects of schizophrenia has been highly influential. AIMS: To bring together and evaluate the imaging evidence for dopaminergic alterations in cortical and other extrastriatal regions in schizophrenia. METHOD: Electronic databases were searched for in vivo molecular studies of extrastriatal dopaminergic function in schizophrenia. Twenty-three studies (278 patients and 265 controls) were identified...

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Despite five decades of search for clinically meaningful 'biomarkers' in schizophrenia there are still no common tests to inform diagnosis or treatment. Our aim was to understand why it has been so difficult to convert biological findings into clinical tests. We categorized all PubMed-indexed articles investigating psychosis-related biomarkers to date (over 3200). Studies showed an evident publication bias, a confusing array of terminology, and few systematic efforts at longitudinal evaluation or external validation...

The clinical expression of schizophrenia is generally reported to be expressed by three to five different factors (i.e. positive, negative, disorganization, excitability, anxiety-depression symptoms). It is often claimed that antipsychotic medications are particularly helpful for positive symptoms, but not for the others, suggesting a differential efficacy for different aspects of the disorder. We formally tested this claim. Using Structural Equation Modeling in two large [1884 patients] clinical trials in schizophrenia, we compared the model of a common general effect of antipsychotics to models whereby the antipsychotics have multiple and differential effects on the different factors of the illness...

BACKGROUND: Response to antipsychotics in schizophrenia is highly variable, and determinants are not well understood or used to design clinical trials. OBJECTIVE: We aimed to understand determinants of response to antipsychotic treatment. METHOD: Supported by the Innovative Medicines Initiative, as part of a large public-private collaboration (NEWMEDS), we assembled the largest dataset of individual patient level information from randomized placebo-controlled trials of second-generation antipsychotics conducted in adult schizophrenia patients by 5 large pharmaceutical companies...