Staging model in psychiatry: Review of the evolution of electroencephalography abnormalities in major psychiatric disorders.

AIM: Clinical staging in psychiatry aims to classify patients according to the severity of their symptoms, from stage 0 (increased risk, asymptomatic) to stage 4 (severe illness), enabling adapted treatment at each stage of the illness. The staging model would gain specificity if one or more quantifiable biological markers could be identified. Several biomarkers reflecting possible causal mechanisms and/or consequences of the pathophysiology are candidates for integration into the clinical staging model of psychiatric illnesses. METHODS: This review covers the evolution (from stage 0 to stage 4) of the most important brain functioning impairments as measured with electroencephalography (EEG), in psychosis spectrum and in severe mood disorders. RESULTS: The present review of the literature demonstrates that it is currently not possible to draw any conclusion with regard to the state or trait character of any of the EEG impairments in both major depressive disorder and bipolar disorder. As for schizophrenia, the most promising markers of the stage of the illness are the pitch mismatch negativity as well as the p300 event-related potentials, as these components seem to deteriorate with increasing severity of the illness. CONCLUSIONS: Given the complexity of major psychiatric disorders, and that not a single impairment can be observed in all patients, future research should most likely consider combinations of markers in the quest for a better identification of the stages of the psychiatric illnesses.

Biomarkers and clinical staging in psychiatry.

Personalized medicine is rapidly becoming a reality in today's physical medicine. However, as yet this is largely an aspirational goal in psychiatry, despite significant advances in our understanding of the biochemical, genetic and neurobiological processes underlying major mental disorders. Preventive medicine relies on the availability of predictive tools; in psychiatry we still largely lack these. Furthermore, our current diagnostic systems, with their focus on well-established, largely chronic illness, do not support a pre-emptive, let alone a preventive, approach, since it is during the early stages of a disorder that interventions have the potential to offer the greatest benefit. Here, we present a clinical staging model for severe mental disorders and discuss examples of biological markers that have already undergone some systematic evaluation and that could be integrated into such a framework. The advantage of this model is that it explicitly considers the evolution of psychopathology during the development of a mental illness and emphasizes that progression of illness is by no means inevitable, but can be altered by providing appropriate interventions that target individual modifiable risk and protective factors. The specific goals of therapeutic intervention are therefore broadened to include the prevention of illness onset or progression, and to minimize the risk of harm associated with more complex treatment regimens. The staging model also facilitates the integration of new data on the biological, social and environmental factors that influence mental illness into our clinical and diagnostic infrastructure, which will provide a major step forward in the development of a truly pre-emptive psychiatry.

At the heart of an early psychosis centre: the core components of the 2014 Early Psychosis Prevention and Intervention Centre model for Australian communities.

OBJECTIVE: To describe the core components of the Early Psychosis Prevention and Intervention Centre service model as the template agreed with the Australian Federal Government for national upscaling. The Early Psychosis Prevention and Intervention Centre model of early intervention has two main goals: to reduce the period of time between the onset of psychosis and the commencement of treatment and to bring about symptomatic recovery and restore the normal developmental trajectory as early as possible. CONCLUSIONS: The Early Psychosis Prevention and Intervention Centre comprises three elements of service provision for young people experiencing a first episode of psychosis: (i) early detection; (ii) acute care during and immediately following a crisis; (iii) recovery-focused continuing care, featuring multimodal interventions to enable the young person to maintain or regain their social, academic and/or career trajectory during the critical first 2-5 years following the onset of a psychotic illness. It does this via a combination of 16 core components, which provide a flexible, comprehensive, integrated service that is able to respond quickly, appropriately and consistently to the individual needs of the young person and their family. Innovative service reforms, such as Early Psychosis Prevention and Intervention Centre, that recognise the value of early intervention are crucial to reducing the impact of serious mental illness on young people and their families and, ultimately, on our society.

Cultures for mental health care of young people: an Australian blueprint for reform.

Mental ill health is now the most important health issue facing young people worldwide. It is the leading cause of disability in people aged 10-24 years, contributing 45% of the overall burden of disease in this age group. Despite their manifest need, young people have the lowest rates of access to mental health care, largely as a result of poor awareness and help-seeking, structural and cultural flaws within the existing care systems, and the failure of society to recognise the importance of this issue and invest in youth mental health. We outline the case for a specific youth mental health stream and describe the innovative service reforms in youth mental health in Australia, using them as an example of the processes that can guide the development and implementation of such a service stream. Early intervention with focus on the developmental period of greatest need and capacity to benefit, emerging adulthood, has the potential to greatly improve the mental health, wellbeing, productivity, and fulfilment of young people, and our wider society.

Improving mental health in young people.

The gap between unmet need and access to care for mental ill-health is wider for adolescents and young people aged 12-25 years than any other age group worldwide. This age group is the peak time of onset for many mental disorders including mood, substance abuse and psychotic disorders. Effective interventions in primary or specialist care are likely to be most cost-effective at this age. Yet in most countries there are few opportunities for young people and their families to gain access to treatment and care for mental ill-health and preventive interventions. This is especially important for young people exposed to trauma and adversity. Few countries give sufficient attention to safeguarding and improving the mental health of young people and few have developed policies and programs to support this. Policy and practice changes suitable for each country have two essential starting points: improved understanding of youth mental health within communities; and involving young people and their families in decisions that affect them. Using information technology to assist care is another desirable feature of modern service development suitable for any environment. New directions and models of care to respond to better awareness and help-seeking and new approaches to health promotion are being developed in several countries, and psychiatrists have a central role in supporting these developments.

Palliative models of care for later stages of mental disorder: maximizing recovery, maintaining hope, and building morale.

BACKGROUND: 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. METHOD: Data was sourced by a literature search using Medline and a hand search of scientific journals. Relevant articles were selected. RESULTS: 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. CONCLUSIONS: 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.

Is this normal? Assessing mental health in young people.

BACKGROUND: Mental ill-health is a key health issue facing young Australians today. While the physical health of young people has improved in recent decades, their mental health appears to have worsened. Mental health and substance use disorders now account for over 50% of the burden of disease in the 15-25 years age group, and 75% of mental health disorders that will affect people across the lifespan will have emerged for the first time by the age of 25 years. OBJECTIVE: This article provides the general practitioner with key factors in assessing the young person with a mental illness: when to worry and what the early stages of mental illness look like; and provides guidance and tips for effective treatment. DISCUSSION: Mental ill-health in young people is all too often accepted as a 'normal' feature of adolescence. However, the short and long term consequences of mental illness include impaired social functioning, poor educational achievement, substance abuse, self harm, suicide and violence. Distinguishing between what represents transitory and normative changes in behaviour and disturbances that may represent the early signs of the onset of a potentially serious mental illness is difficult, particularly in young people, where emotional disturbance and distress is such a common experience. The primary goal of initial assessment is not to make a definitive diagnosis but rather to assess risk and the need for clinical care. The GP has an important role to play in longitudinal assessment and ongoing review, and facilitating access to treatment and mobilising support networks.

Age of onset and timing of treatment for mental and substance use disorders: implications for preventive intervention strategies and models of care.

PURPOSE OF REVIEW: To provide an update of the recent studies on the age of onset of the major mental illnesses, with a special focus on the prospects for prevention and early intervention. RECENT FINDINGS: The studies reviewed here confirm previous reports on the age of onset of the major mental disorders. While the behaviour disorders, and certain anxiety disorders, emerge during childhood, most of the high prevalence disorders (anxiety, mood and substance use) emerge during adolescence and early adulthood, as do the psychotic disorders. Early age of onset has been shown to be associated with a longer duration of untreated illness and poorer clinical and functional outcomes. SUMMARY: Although the onset of most mental disorders usually occurs during the first three decades of life, effective treatment is typically not initiated until a number of years later. Although there is increasing evidence to suggest that intervention during the early stages of a disorder may help reduce the severity and/or the persistence of the initial or primary disorder and prevent secondary disorders, additional research is needed into appropriate treatment for early stage cases as well as the long-term effects of early intervention, and to appropriate service design for those in the early stages of a mental illness. This will mean not only the strengthening and re-engineering of existing systems but also, crucially, the construction of new streams of care for young people in transition to adulthood.

Clinical staging: a heuristic and practical strategy for new research and better health and social outcomes for psychotic and related mood disorders.

Most mental illnesses emerge during adolescence and early adulthood, with considerable associated distress and functional decline appearing during this critical developmental phase. Our current diagnostic system lacks therapeutic validity, particularly for the early stages of mental disorders when symptoms are still emerging and intensifying and have not yet stabilized sufficiently to fit the existing syndromal criteria. While this is, in part, due to the difficulty of distinguishing transient developmental or normative changes from the early symptoms of persistent and disabling mental illness, these factors have contributed to a growing movement for the reform of our current diagnostic system to more adequately inform the choice of therapeutic strategy, particularly in the early stages of a mental illness. The clinical staging model, which defines not only the extent of progression of a disorder at a particular point in time but also where a person lies currently along the continuum of the course of an illness, is particularly useful as it differentiates early, milder clinical phenomena from those that accompany illness progression and chronicity. This will not only enable clinicians to select treatments relevant to earlier stages of an illness, where such interventions are likely to be more effective and less harmful than treatments delivered later in the course of illness, but also allow a more efficient integration of our rapidly expanding knowledge of the biological, social, and psychological vulnerability factors involved in the development of mental illness into a useful diagnostic framework.

Investigating the effectiveness, safety and tolerability of quetiapine in the treatment of anorexia nervosa in young people: a pilot study.

To investigate the safety and tolerability of the atypical antipsychotic quetiapine in anorexia nervosa patients, and to determine the effect of quetiapine treatment on anorexic psychopathology and other key outcome measures including weight and body image, we conducted a naturalistic, open-label, 12-week randomized controlled trial of low-dose (100-400 mg/day) quetiapine treatment versus treatment as usual in 33 anorexia nervosa patients from our Eating Disorder Clinics. To monitor the effects of treatment over the medium term, the participants were then followed up with assessment visits at 6 and 12 months after the end of the treatment phase. Low-dose quetiapine treatment resulted in both psychological and physical improvements, with minimal associated side-effects. Given the overall trend toward improvement that we observed, quetiapine appears to be a promising candidate for the treatment of anorexia nervosa. Further large-scale placebo-controlled clinical trials will be necessary to fully evaluate the benefits of quetiapine treatment for this disorder.

Tip1/CLIP-170 protein is required for correct chromosome poleward movement in fission yeast.

The plus-end microtubule binding proteins (+TIPs) play an important role in the regulation of microtubule stability and cell polarity during interphase. In S. pombe, the CLIP-170 like protein Tip1, together with the kinesin Tea2, moves along the microtubules towards their plus ends. Tip1 also requires the EB1 homolog Mal3 to localize to the microtubule tips. Given the requirement for Tip1 for microtubule stability, we have investigated its role during spindle morphogenesis and chromosome movement. Loss of Tip1 affects metaphase plate formation and leads to the activation of the spindle assembly checkpoint. In the absence of Tip1 we also observed the appearance of lagging chromosomes, which do not influence the normal rate of spindle elongation. Our results suggest that S. pombe Tip1/CLIP170 is directly or indirectly required for correct chromosome poleward movement independently of Mal3/EB1.

Sister kinetochore recapture in fission yeast occurs by two distinct mechanisms, both requiring Dam1 and Klp2.

In eukaryotic cells, proper formation of the spindle is necessary for successful cell division. We have studied chromosome recapture in the fission yeast Schizosaccharomyces pombe. We show by live cell analysis that lost kinetochores interact laterally with intranuclear microtubules (INMs) and that both microtubule depolymerization (end-on pulling) and minus-end-directed movement (microtubule sliding) contribute to chromosome retrieval to the spindle pole body (SPB). We find that the minus-end-directed motor Klp2 colocalizes with the kinetochore during its transport to the SPB and contributes to the effectiveness of retrieval by affecting both end-on pulling and lateral sliding. Furthermore, we provide in vivo evidence that Dam1, a component of the DASH complex, also colocalizes with the kinetochore during its transport and is essential for its retrieval by either of these mechanisms. Finally, we find that the position of the unattached kinetochore correlates with the size and orientation of the INMs, suggesting that chromosome recapture may not be a random process.

Dynein participates in chromosome segregation in fission yeast.

BACKGROUND INFORMATION: In eukaryotic cells, proper formation of the spindle is necessary for successful cell division. For faithful segregation of sister chromatids, each sister kinetochore must attach to microtubules that extend to opposite poles (chromosome bi-orientation). At the metaphase-anaphase transition, cohesion between sister chromatids is removed, and each sister chromatid is pulled to opposite poles of the cell by microtubule-dependent forces. RESULTS: We have studied the role of the minus-end-directed motor protein dynein by analysing kinetochore dynamics in fission yeast cells deleted for the dynein heavy chain (Dhc1) or the light chain (Dlc1). In these mutants, we found an increased frequency of cells showing defects in chromosome segregation, which leads to the appearance of lagging chromosomes and an increased rate of chromosome loss. By following simultaneously kinetochore dynamics and localization of the checkpoint protein Mad2, we provide evidence that dynein function is not necessary for spindle-assembly checkpoint inactivation. Instead, we have demonstrated that loss of dynein function alters chromosome segregation and activates the Mad2-dependent spindle-assembly checkpoint. CONCLUSIONS: These results show an unexpected role for dynein in the control of chromosome segregation in fission yeast, most probably operating during the process of bi-orientation during early mitosis.

The fission yeast spindle orientation checkpoint: a model that generates tension?

In all eukaryotes, the alignment of the mitotic spindle with the axis of cell polarity is essential for accurate chromosome segregation as well as for the establishment of cell fate, and thus morphogenesis, during development. Studies in invertebrates, higher eukaryotes and yeast suggest that astral microtubules interact with the cell cortex to position the spindle. These microtubules are thought to impose pushing or pulling forces on the spindle poles to affect the rotation or movement of the spindle. In the fission yeast model, where cell division is symmetrical, spindle rotation is dependent on the interaction of astral microtubules with the cortical actin cytoskeleton. In these cells, a bub1-dependent mitotic checkpoint, the spindle orientation checkpoint (SOC), is activated when the spindles fail to align with the cell polarity axis. In this paper we review the mechanism that orientates the spindle during mitosis in fission yeast, and discuss the consequences of misorientation on metaphase progression.

Pluripotent cell division cycles are driven by ectopic Cdk2, cyclin A/E and E2F activities.

Pluripotent cells of embryonic origin proliferate at unusually rapid rates and have a characteristic cell cycle structure with truncated gap phases. To define the molecular basis for this we have characterized the cell cycle control of murine embryonic stem cells and early primitive ectoderm-like cells. These cells display precocious Cdk2, cyclin A and cyclin E kinase activities that are conspicuously cell cycle independent. Suppression of Cdk2 activity significantly decreased cycling times of pluripotent cells, indicating it to be rate-limiting for rapid cell division, although this had no impact on cell cycle structure and the establishment of extended gap phases. Cdc2-cyclin B was the only Cdk activity that was identified to be cell cycle regulated in pluripotent cells. Cell cycle regulation of cyclin B levels and Y(15) regulation of Cdc2 contribute to the temporal changes in Cdc2-cyclin B activity. E2F target genes are constitutively active throughout the cell cycle, reflecting the low activity of pocket proteins such as p107 and pRb and constitutive activity of pRb-kinases. These results show that rapid cell division cycles in primitive cells of embryonic origin are driven by extreme levels of Cdk activity that lack normal cell cycle periodicity.