Epigenetics and biomarkers in the staging of neuropsychiatric disorders.
ABSTRACT Epigenetics, or alterations in the phenotype or gene expression due to mechanisms other than changes in the underlying DNA sequence, reflects the sensitivity and responsiveness of human and animal brains in constantly varying circumstances regulating gene expression profiles that define the biomarkers and present the ultimate phenotypical outcomes, such as cognition and emotion. Epigenetics is associated with functionally relevant alterations to the genome in such a fashion that under the particular conditions of early, adolescent, and adult life, environmental signals may activate intracellular pathways that remodel the "epigenome," triggering changes in gene expression and neural function. Thus, genetic influences in neuropsychiatric disorders that are subject to clinical staging, epigenetics in schizophrenia, epigenetic considerations in the expression of sensorimotor gating resulting from disease conditions, biomarkers of drug use and addiction, current notions on the role of dopamine in schizophrenia spectrum disorders, and the discrete interactions of biomarkers in persistent memory were to greater or lesser extents reflected upon. The relative contributions of endophenotypes and epistasis for mediating epigenetic phenomena and the outcomes as observed in the analysis of biomarkers appear to offer a multitude of interactive combinations to further complicate the labyrinthine machinations of diagnosis, intervention, and prognosis.
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ABSTRACT: The concept of staging of disease in psychiatry has developed over the past years. A neglected component of this model pertains to people in the advanced stages of a mental illness, who remain symptomatic and functionally impaired despite treatment. These patients are often high service utilizers, receiving complex multimodal treatments where the balance of risk and benefit shifts perceptibly. In this paper, we argue the need to adopt 'palliative' models of care for some individuals, and consider changing the therapeutic goals to follow care pathways similar to those used in other chronic and refractory medical illnesses. Data was sourced by a literature search using Medline and a hand search of scientific journals. Relevant articles were selected. Clinical staging can help us better define subgroups of patients who will benefit from different goals and treatment. In the most advanced stage group, we find patients with persistent symptoms and treatment resistance. In these situations, it may be preferable to follow some of the principles of palliative care, which include the setting of attainable goals, reduction of side-effects, limited symptom control, targeting identified psychological and social problems, and attempting to attain the best quality of life for these patients and their families. It is in the interest of those in the advanced phases of a disorder that clinicians acknowledge the limitations of treatment and actively attempt to plan treatment utilizing alternate models. It is essential to be clear that such approaches do not equate to the abandonment of care, but rather to the reconceptualizing of feasible and personalized treatment goals, a rebalancing of the risks and benefits of intervention, the management of illness behaviour, and the approaches that allow the patient to live gainfully within their limitations.Australian and New Zealand Journal of Psychiatry 02/2012; 46(2):92-9. DOI:10.1177/0004867411432072 · 3.77 Impact Factor
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ABSTRACT: Neurodevelopmental risk factors have assumed a critical role in prevailing notions concerning the etiopathogenesis of neuropsychiatric disorders. Staging, diagnostic elements at which phase of disease is determined, provides a means of conceptualizing the degree and extent of factors affecting brain development trajectories, but is concurrently specified through the particular interactions of genes and environment unique to each individual case. For present purposes, staging perspectives in neurodevelopmental aspects of the disease processes are considered from conditions giving rise to neurodevelopmental staging in affective states, adolescence, dopamine disease states, and autism spectrum disorders. Three major aspects influencing the eventual course of individual developmental trajectories appear to possess an essential determinant influence upon outcome: (i) the type of agent that interferes with brain development, whether chemical, immune system activating or absent (anoxia/hypoxia), (ii) the phase of brain development at which the agent exerts disruption, whether prenatal, postnatal, or adolescent, and (iii) the age of expression of structural and functional abnormalities. Clinical staging may be assumed at any or each developmental phase. The present perspective offers both a challenge to bring further order to diagnosis, intervention, and prognosis and a statement regarding the extreme complexities and interwoven intricacies of epigenetic factors, biomarkers, and neurobehavioral entities that aggravate currents notions of the neuropsychiatric disorders.Neurotoxicity Research 03/2010; 18(3-4):287-305. DOI:10.1007/s12640-010-9162-6 · 3.15 Impact Factor
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ABSTRACT: Illnesses which develop in a complex way are best described in stages, and those stages will describe not only a particular point in the course of the disease but also the appropriate treatment for that stage. This approach has, over the years, proved to be very appropriate for planning the treatment of various cancers. It is suggested that in the same way, it can be very important in planning the treatment of a complex illness such as schizophrenia. We aim to describe the staging model of schizophrenia, show the neuroimaging and clinical evidence for it, and discuss its implications for treatment. We propose that the development of schizophrenia can be described in at least three stages; the prodrome, the first episode, and the chronic phase. In order to describe these stages, we will use data derived wherever possible from literature published in Europe, and we will compare this with data produced from other continents of the world, notably Australia. This is done by reference to and examination of the original published literature, in order that this evidence may be tested against criteria for evidence of a staging model which we propose. There is much data, from clinical studies which show that schizophrenia develops over time and that its presentation can be described in at least three stages in the development of a schizophrenic illness; the prodrome, the first episode, and the long term chronic phase. It is also true that there is a pre-morbid phase before the prodrome, where it is possible to identify delays in such signs of early neurodevelopment as early paediatric milestones which may suggest an increased risk of schizophrenia in the future. This is mirrored in descriptions of the MRI findings, with loss of gray matter beginning in the prodrome, as well as in changes in cognition which develop as the illness develops over time. It follows from this model that treatment is different in all these three stages, and that the expected outcome of treatment will be different in each of the various stages of the illness. In all the phases of the illness, evidence based psychological interventions, including psycho-education, cognitive therapy, family interventions, and other interventions to prevent relapse work together with medication in order to optimise treatment. Consequently, any attempt to optimise treatment in schizophrenia must take into account the different stages of the illness, and target outcomes must be appropriate for these stages. The treatments, both pharmacological and psychological must be appropriate to the stage of the disease. The application of treatment protocols which are inappropriate to the stage of the disease may lead to sub-optimal outcomes, and even to iatrogenic harm.Psychiatria Danubina 06/2010; 22(2):211-20. · 0.65 Impact Factor