Current Pharmaceutical Design - Volume 18, Issue 4, 2012

The recent decade has been characterized by a resurging interest for socio-environmental determinants of psychotic disorders, largely as a result of findings from studies of migration and psychotic disorders. This contribution reviews recent meta-analytic findings which confirm higher incidence rates of schizophrenia and related disorders among first- and second-generation immigrants than in nonimmigrant populations, as well as substantial risk variation according to both ethnic minority groups and host society contexts. The relevance of social contexts in the onset of psychosis is also suggested by incidence variation according to the neighbourhood level ethnic density. While limited, an emerging literature suggests potential variations in psychotic-like experiences and at-risk mental states according to ethnic minority status. We then discuss the meaning of findings from migrant studies, as well as integrative models that attempt to account for ethnic variations in the incidence of psychosis and psychotic-like phenomena. In conclusion, there remain numerous gaps in our understanding of the relation between migration, ethnicity, social contexts and the onset of psychosis and we propose future research avenues to address these. In particular, there is a need for multilevel approaches integrating disciplines and methodologies across the psychosis continuum.

Stress plays a role in most conceptualizations of the etiology of psychotic disorders. This is based on extensive research showing an association between the incidence of psychosis and psychosocial stress exposure (e.g., stressful life events and trauma) both in childhood and the weeks preceding a psychotic episode. There is also evidence of increased sensitivity to stressful events and dysregulation of biological stress systems. To better understand the relation of stress with the initial emergence of psychosis, research has increasingly focused on the psychosis prodrome, the period of functional decline that precedes clinical illness. Preliminary results suggest that increased incidence of early childhood trauma, heightened sensitivity to psychosocial stress, and dysregulation of biological stress response systems are present in the prodrome and associated with the onset and severity of psychosis. The current paper reviews this research and discusses the possible mechanisms responsible for these associations. This discussion includes the possible effect of stress on the hypothalamic-pituitary-adrenal [HPA] axis and hippocampus, and the role adolescent developmental changes may play in mediating this effect. Further longitudinal research combining clinical and biological measures of stress with techniques designed to assess developmental change in neural structure and function, cellular mechanisms, and genetic and epigenetic factors are critical for elucidating the role stress plays in the pathophysiology of psychotic illness.

Background: The aim of cognitive remediation is to target the cognitive impairments of patients with psychosis, including attentional deficits, memory problems, and limitations in planning and problem solving. It is hoped that by addressing these deficits, patients will be more able to take advantage of other interventions and will be more able to function in social and other domains. Many results in controlled trials of cognitive remediation in adult patients affected by schizophrenia have demonstrated its effectiveness on different cognitive domains and on patient's functioning. Some researchers speculate that deficits in cognition are more amenable to remediation during earlier phases of illness than when chronicity has developed. For these reasons cognitive rehabilitation should be a key component of early intervention programs, seeking to produce durable functional changes in the early course of schizophrenia. Although there is strong evidence that cognitive remediation is effective in adult schizophrenia, there is little evidence about its efficacy and long-term generalized effectiveness in the early course of the disease, and its possible application in the prodromal phase of the disease. Purpose Of Review: The aim of this paper is to review the available literature on cognitive remediation in the prodromal phase and in the early course of schizophrenia. This review summarizes especially findings of cognitive changes induced in the early course or in the prodromal phases of schizophrenia by different remediation methods. Controlled studies of cognitive training are discussed in more detail. Conclusion: Few studies on the effects of cognitive training programs have been conducted in first episode or in early schizophrenia and only one study has been conducted in the prodromal phase of the disease. Although preliminary positive results have been achieved, more empirical research is needed to confirm the efficacy of cognitive remediation in the early course of schizophrenia, and future studies should address the issue of the usefulness of cognitive remediation in the prodromes of psychosis.

Cannabis is the most widely used illicit substance in the world and due to the high levels of use observed among young people with psychosis, most research has focused on the causal relationship between cannabis use and mental health problems. Despite a large interest in developing intervention models to target this group, there are as yet no established and effective methods of prevention and intervention focusing on cannabis use. In this paper we present the available evidence for the effectiveness of substance use treatments in patients with co-morbid severe mental illness, as well as exploring the prevention and early intervention initiatives for substance use in the general population.

Over the last couple of decades, the treatment of psychoses has much advanced; yet, despite all progress, the individual and societal burden associated with psychosis and particularly schizophrenia has largely remained unchanged. Therefore, much hope is currently placed on indicated prevention as a mean to fight these burdens before they set in. Though the number of studies investigating pharmacological interventions is still limited, encouraging results have been reported from the pioneering trials, despite several methodological limitations. Furthermore, it has become clear that persons characterized by the at-risk criteria are already ill and do not only need preventive intervention, but also treatment. In consequence, outcome criteria have to be broadened to cover the current needs of the patients. As is indicated by a recent study successfully using Omega-3 fatty acids for both purposes, it may be promising to develop and investigate interventions especially for the at-risk state, independent of their effectiveness in manifest disease states. Treatment studies may become promoted by the proposed introduction of a new disorder category into DSM-V. Future prevention studies, however, need to solve the challenge of changing immediate transition rates, demanding for new risk enrichment strategies as a prerequisite for feasible trial designs.

There is a strong impetus in the psychosis research field to develop interventions that aim to prevent the onset of psychotic disorders. Over the past 15 years there has been a tremendous development in the work aimed at understanding the pre-psychotic period. More recently there has been a focus on developing and testing treatments both pharmacological and psychological that could potentially prevent or delay the onset of psychosis. One of the psychological treatments that has received the most attention is cognitive behavioral therapy (CBT). Relatively few trials have been completed and this paper reviews the existing trials. Implications of these trials for the treatment of this early phase as well as for designing future studies are discussed.

Pychoeducation is a useful and required intervention in subjects with elevated-risk state of psychosis. Psychoeducation is, however, an under-investigated area in the field of early identification and prevention. Psychoeducation with this particular patient group needs to adapt to several unique features, e.g. the diagnostic uncertainty (“say it only in subjunctive”) and problems of stigmatization. More research regarding the subjective psychoeducational needs of individuals at elevated risk for psychosis as well as more explicit provision and evaluation of psychoeducation in the elevated-risk state is strongly desirable.

Objectives: To investigate if low-dose lithium may counteract the microstructural and metabolic brain changes proposed to occur in individuals at ultra-high risk (UHR) for psychosis. Methods: Hippocampal T2 relaxation time (HT2RT) and proton magnetic resonance spectroscopy (1H-MRS) measurements were performed prior to initiation and following three months of treatment in 11 UHR patients receiving low-dose lithium and 10 UHR patients receiving treatment as usual (TAU). HT2RT and 1H-MRS percentage change scores between scans were compared using repeated measures ANOVA and correlated with behavioural change scores. Results: Low-dose lithium significantly reduced HT2RT compared to TAU (p=0.018). No significant group by time effects was seen for any brain metabolites as measured with 1H-MRS, although myo-inositol, creatine, choline-containing compounds and NAA increased in the group receiving low-dose lithium and decreased or remained unchanged in subjects receiving TAU. Conclusions: This pilot study suggests that low-dose lithium may protect the microstructure of the hippocampus in UHR states as reflected by significantly decreasing HT2RT. Larger scale replication studies in UHR states using T2 relaxation time as a proxy for emerging brain pathology seem a feasible mean to test neuroprotective strategies such as low-dose lithium as potential treatments to delay or even prevent the progression to full-blown disorder.

The role of polyunsaturated fatty acids and their metabolites for the cause and treatment of psychotic disorders are widely discussed. The efficacy as an augmenting agent in chronic schizophrenia seems to be small or not present, however epidemiological data, as well as some recent controlled studies in emerging psychosis point towards possible preventive effects of long-chain polyunsaturated fatty acids in early and very early stages of psychotic disorders and some potential secondary or tertiary beneficial long-term effects in later, more chronic stages, in particular for metabolic or extra-pyramidal side effects. In this comprehensive review, we describe the physiology and metabolism of polyunsaturated fatty acids, phospholipases, epidemiological evidence and the effect of these fatty acids on the brain and neurodevelopment. Furthermore, we examine the available evidence in indicated prevention in emerging psychosis, monotherapy, add-on therapy and tolerability. The neuroprotective potential of n-3 LC-PUFAs for indicated prevention, i.e. delaying transition to psychosis in high-risk populations needs to be further explored.

Background: Whilst there is a growing body of evidence relating to the effectiveness of early detection and early intervention services there have been relatively few studies which have provided information on whether they are cost-effective. Aim: The aim of this paper is to review the cost-effectiveness evidence for early detection and early intervention in psychosis. Methods: Full economic evaluations, cost studies, and studies which do not report costs but do provide important resource use information were included in the review. Results: All cost effectiveness analysis to date suggest that it is possible to offer help early in the development of psychosis in a cost effective manner. Conclusions: The potential longer term economic benefits of early detection and early intervention are required.

In this paper we try to examine some of the philosophical issues that arise from the clinical and scientific study of the prodromal phase of psychotic illness. These issues can be broadly grouped in to ethical concerns and those relating to the philosophy of psychology and science. Specifically, we discuss the notion of the prodrome as a discrete disorder as opposed to being a segment of the continuum of psychosis, and whether we can define psychopathology purely via the use of neuroscientific variables and concepts. We argue that many psychopathological terms have definitions that rely on normative notions that themselves may not be able to be reduced to terms in cognitive neuroscience and hence a purely neuroscientific conception of psychopathology and of the prodromal phase of psychosis may be unachievable. Ethical concerns arise around the treatment of ‘false positives’, that is, those who may clinically look to be at risk but do not develop psychosis, and the reification of a subtle research category into a DSM-5 diagnosis. More subtle issues lie in the clinical encounter where one has to balance communicating risk about developing psychosis with attempts to normalize experiences and decrease anxiety. We conclude by noting that studying the brain solely will not enable us to comprehensively understand prodromal phase of psychosis: a close attention to continua and normativity is also required and that several important clinical and ethical issues arise in both indentifying and intervening in this high risk group, and that these are now cast sharply in to focus with the inclusion of the risk syndrome in the draft DSM-5.

The last 15 years have witnessed a shift in schizophrenia research with increasing interest in earlier stages of illness with the hope of early intervention and ultimately prevention of psychotic illness. Large-scale longitudinal studies have identified clinical and biological risk factors associated with increased risk of psychotic conversion, which together with symptomatic and demographic risk factors may improve the power of prediction algorithms for psychotic transition. Despite these advances, 45-70% of at risk subjects in most samples do not convert to frank psychosis, but continue to function well below their age matched counterparts. The issue is of utmost importance in light of the upcoming DSM-V and the possible inclusion of the attenuated psychotic symptoms syndrome (APSS) diagnosis, with clinical and ethical implications. Clinical considerations include feasibility of reliably diagnosing the at risk state in non-academic medical centers, variable psychotic conversion rates, a non-uniform definition of conversion and extensive debate about treatment for individuals with an ill-defined outcome. On the ethical side, diagnosing APSS could lead to unnecessary prescribing of antipsychotics with long-term deleterious consequences, slow research by providing a false sense of comfort in the diagnosis, and have psychosocial implications for those who receive a diagnosis. Thus it may be prudent to engage at risk populations early and to use broad-spectrum treatments with low risk benefit ratios to relieve functional impairments, while simultaneously studying all subsets of the at risk population.