Clinical trials of potential cognitive-enhancing drugs in schizophrenia: what have we learned so far?

In light of the number of studies conducted to examine the treatment of cognitive impairment associated with schizophrenia (CIAS), we critically reviewed recent CIAS trials. Trials were identified through searches of the website "www.clinicaltrials.gov" using the terms "schizophrenia AND cognition," "schizophrenia AND neurocognition," "schizophrenia AND neurocognitive tests," "schizophrenia AND MATRICS," "schizophrenia AND MCCB," "schizophrenia AND BACS," "schizophrenia AND COGSTATE," and "schizophrenia AND CANTAB" and "first-episode schizophrenia AND cognition." The cutoff date was 20 April 2011. Included trials were conducted in people with schizophrenia, the effects on cognition were either a primary or secondary outcome, and the effect of a pharmacologically active substance was examined. Drug challenge, pharmacokinetic, pharmacodynamic, or prodrome of psychosis studies were excluded. We identified 118 trials, with 62% using an add-on parallel group design. The large majority of completed trials were underpowered to detect moderate effect sizes, had ≤8 weeks duration, and were performed in samples of participants with chronic stable schizophrenia. The ongoing add-on trials are longer, have larger sample sizes (with a number of them being adequately powered to detect moderate effect sizes), and are more likely to use a widely accepted standardized cognitive battery (eg, the MATRICS Consensus Cognitive Battery) and MATRICS guidelines. Ongoing studies performed in subjects with recent onset schizophrenia may help elucidate which subjects are most likely to show an effect in cognition. New insights into the demands of CIAS trial design and methodology may help increase the probability of identifying treatments with beneficial effect on cognitive impairment in schizophrenia

What are the top 10 physical activity research questions in schizophrenia?

Purpose: Research has only recently started to consider the applicability of physical activity (PA) for people with schizophrenia. Although there is increasing evidence for the benefits of physical activity, this population remains generally physically inactive and sedentary. The aim of the current study is to highlight 10 pertinent physical activity research questions in people with schizophrenia. Method: The International Organisation of Physical Therapy in Mental Health (IOPTMH) executed a consultation of its National Organisations (n=13) to identify the most salient questions relevant to guide clinical practice on physical activity in people with schizophrenia. Results: We identified the following 10 questions: (1) What are the benefits of physical activity for people with schizophrenia? (2) What are the mechanisms of the physical activity effects in people with schizophrenia? (3) What are the most prominent safety issues for physical activity prescription in people with schizophrenia? (4) What is the most optimal physical activity prescription for people with schizophrenia? (5) What are the key barriers for engaging people with schizophrenia in physical activity? (6) What are the most effective motivational interventions for physical activity adoption and maintenance in people with schizophrenia? (7) How do we translate physical activity research into clinical and community practice? (8) How can we ensure integration of physical therapists within the multidisciplinary mental health treatment team? (9) How can we prevent sedentary behaviour in people with schizophrenia? (10) What is the most appropriate physical activity assessment method in clinical practice? Conclusions: Addressing these questions is critical for developing evidence-based approaches for promoting and sustaining an active lifestyle in people with schizophrenia. Ultimately, achieving this will improve the quality of life of this population. Implications for Rehabilitation: · Investigation of behaviour change interventions for people with schizophrenia is critical · A low cost, easy to use, clinical, valid physical activity questionnaire is urgently needed

Motor deficits in schizophrenia quantified by nonlinear analysis of postural sway.

Motor dysfunction is a consistently reported but understudied aspect of schizophrenia. Postural sway area was examined in individuals with schizophrenia under four conditions with different amounts of visual and proprioceptive feedback: eyes open or closed and feet together or shoulder width apart. The nonlinear complexity of postural sway was assessed by detrended fluctuation analysis (DFA). The schizophrenia group (n = 27) exhibited greater sway area compared to controls (n = 37). Participants with schizophrenia showed increased sway area following the removal of visual input, while this pattern was absent in controls. Examination of DFA revealed decreased complexity of postural sway and abnormal changes in complexity upon removal of visual input in individuals with schizophrenia. Additionally, less complex postural sway was associated with increased symptom severity in participants with schizophrenia. Given the critical involvement of the cerebellum and related circuits in postural stability and sensorimotor integration, these results are consistent with growing evidence of motor, cerebellar, and sensory integration dysfunction in the disorder, and with theoretical models that implicate cerebellar deficits and more general disconnection of function in schizophrenia

The Misunderstanding between Schizophrenia and Clairaudience

This research focuses on Schizophrenia and Clairaudience that is part of doctoral research for a Doctorate of Metaphysical Sciences at the University of Metaphysics. The mental illness known as Schizophrenia has been known for centuries. There are various symptoms associated with this mental illness upon which a diagnosis is based. The exact causes of the mental illness Schizophrenia remain unknown, as does the actual part of the individual which is effect by the illness. The most prominent and definable symptom of Schizophrenia remains to be auditory hallucinations. Another explanation for individual's being able to hear voices, is that of clairaudience, a psychic ability. Clairaudient ability has a positive connotation upon the ability to hear voices, whereas the diagnosis of Schizophrenia is most commonly treated with pharmaceutical drugs to reduce or eliminate symptoms. This paper involves information about Schizophrenia, how it is perceived and treated. It also discusses various views of clairaudience, and how it is effective and manageable. A new approach is required to the medical industry when individuals are being treated for a diagnosis of Schizophrenia

The C/C Genotype of the C957T Polymorphism of the Dopamine D2 Receptor is Associated with Schizophrenia

The T allele of the human dopamine D2 receptor (DRD2) gene C957T polymorphism is associated with reduced mRNA translation and stability. This results in decreased dopamine induced DRD2 upregulation and decreased in-vivo D2 dopamine binding. Conversely, the C allele of the C957T polymorphism is not associated with such changes in mRNA leading to increased DRD2 expression. PET and post-mortem binding studies show that schizophrenia is often associated with increased DRD2 availability. We report that on the basis of comparing the frequencies of the C/C and T/T genotypes of 153 patients with schizophrenia and 148 controls that schizophrenia is associated with the C/C genotype. The C957T shows a population attributable risk for schizophrenia of 24% and an attributable risk in those with schizophrenia of 42%. Increased expression of D2 receptors associated with the C allele is likely to be important in the underlying pathophysiology of at least some forms of schizophrenia. Enhanced understanding of schizophrenia afforded by this finding may lead to advances in treatment and prevention

Schizophrenia and the Dysfunctional Brain

Scientists, philosophers, and even the lay public commonly accept that schizophrenia stems from a biological or internal ‘dysfunction.’ However, this assessment is typically accompanied neither by well-defined criteria for determining that something is dysfunctional nor empirical evidence that schizophrenia satisfies those criteria. In the following, a concept of biological function is developed and applied to a neurobiological model of schizophrenia. It concludes that current evidence does not warrant the claim that schizophrenia stems from a biological dysfunction, and, in fact, that unusual neural structures associated with schizophrenia may have functional or adaptive significance. The fact that current evidence is ambivalent between these two possibilities (dysfunction versus adaptive function) implies that schizophrenia researchers should be much more cautious in using the ‘dysfunction’ label than they currently are. This has implications for both psychiatric treatment as well as public perception of mental disorders

Morbidity burden and community-based palliative care are associated with rates of hospital use by people with schizophrenia in the last year of life: A population-based matched cohort study

Objective: People with schizophrenia face an increased risk of premature death from chronic diseases and injury. This study describes the trajectory of acute care health service use in the last year of life for people with schizophrenia and how this varied with receipt of community based specialist palliative care and morbidity burden. Method: A population-based retrospective matched cohort study of people who died from 01/01/ 2009 to 31/12/2013 with and without schizophrenia in Western Australia. Hospital inpatient, emergency department, death and community-based care data collections were linked at the person level. Rates of emergency department presentations and hospital admissions over the last year of life were estimated. Results: Of the 63508 decedents, 1196 (1.9%) had a lifetime history of schizophrenia. After adjusting for confounders and averaging over the last year of life there was no difference in the overall rate of ED presentation between decedents with schizophrenia and the matched cohort (HR 1.09; 95%CI 0.99–1.19). However, amongst the subset of decedents with cancer, choking or intentional self-harm recorded on their death certificate, those with schizophrenia presented to ED more often. Males with schizophrenia had the highest rates of emergency department use in the last year of life. Rates of hospital admission for decedents with schizophrenia were on average half (HR 0.53, 95%CI 0.44–0.65) that of the matched cohort although this varied by cause of death. Of all decedents with cancer, 27.5% of people with schizophrenia accessed community-based specialist palliative care compared to 40.4% of the matched cohort (p\u3c0.001). Rates of hospital admissions for decedents with schizophrenia increased 50% (95% CI: 10%-110%) when enrolled in specialist palliative care. Conclusion: In the last year of life, people with schizophrenia were less likely to be admitted to hospital and access community-based speciality palliative care, but more likely to attend emergency departments if male. Community-based specialist palliative care was associated with increased rates of hospital admissions

Grey-matter texture abnormalities and reduced hippocampal volume are distinguishing features of schizophrenia

Neurodevelopmental processes are widely believed to underlie schizophrenia. Analysis of brain texture from conventional magnetic resonance imaging (MRI) can detect disturbance in brain cytoarchitecture. We tested the hypothesis that patients with schizophrenia manifest quantitative differences in brain texture that, alongside discrete volumetric changes, may serve as an endophenotypic biomarker. Texture analysis (TA) of grey matter distribution and voxel-based morphometry (VBM) of regional brain volumes were applied to MRI scans of 27 patients with schizophrenia and 24 controls. Texture parameters (uniformity and entropy) were also used as covariates in VBM analyses to test for correspondence with regional brain volume. Linear discriminant analysis tested if texture and volumetric data predicted diagnostic group membership (schizophrenia or control). We found that uniformity and entropy of grey matter differed significantly between individuals with schizophrenia and controls at the fine spatial scale (filter width below 2 mm). Within the schizophrenia group, these texture parameters correlated with volumes of the left hippocampus, right amygdala and cerebellum. The best predictor of diagnostic group membership was the combination of fine texture heterogeneity and left hippocampal size. This study highlights the presence of distributed grey-matter abnormalities in schizophrenia, and their relation to focal structural abnormality of the hippocampus. The conjunction of these features has potential as a neuroimaging endophenotype of schizophrenia

Dysregulated protocadherin-pathway activity as an intrinsic defect in induced pluripotent stem cell-derived cortical interneurons from subjects with schizophrenia.

We generated cortical interneurons (cINs) from induced pluripotent stem cells derived from 14 healthy controls and 14 subjects with schizophrenia. Both healthy control cINs and schizophrenia cINs were authentic, fired spontaneously, received functional excitatory inputs from host neurons, and induced GABA-mediated inhibition in host neurons in vivo. However, schizophrenia cINs had dysregulated expression of protocadherin genes, which lie within documented schizophrenia loci. Mice lacking protocadherin-α showed defective arborization and synaptic density of prefrontal cortex cINs and behavioral abnormalities. Schizophrenia cINs similarly showed defects in synaptic density and arborization that were reversed by inhibitors of protein kinase C, a downstream kinase in the protocadherin pathway. These findings reveal an intrinsic abnormality in schizophrenia cINs in the absence of any circuit-driven pathology. They also demonstrate the utility of homogenous and functional populations of a relevant neuronal subtype for probing pathogenesis mechanisms during development