Editorial

The First Australian Schizophrenia Prevention Conference was convened to develop a consensual framework within which to carry out research into the primary prevention of schizophrenia. A focus to the proceedings was provided by a core objective, which was considering the feasibility of designing screening procedures to identify young people at risk of schizophrenia before the onset of illness. The Scientific Committee accepts responsibility for the section structure of the conference, which was intended to give the endeavour an epidemiological and developmental perspective. All contributions to the proceedings were by invitation. The Scientific Committee was encouraged by the willing participation of so many eminent scientists and clinicians from Australia and overseas. The committee was also grateful for the opportunity to facilitate broad interdisciplinary scientific exchange around the common theme of advancing preventive mental health and, in particular, the prevention of schizophrenia.

Professor Raphael opens the proceedings by reminding us of the foundations laid by the late David Maddison for prevention in mental health in Australia. Professor Maddison's legacy includes the pioneering work of researchers whom he influenced, who include both Professor Raphael and Professor McGorry. Professor Raphael's paper is a landmark review of outstanding Australasian contributions to the international literature while, inter alia, eloquently summarising the many background issues related to research into the prevention of schizophrenia. In an accompanying paper, Professor McGorry describes the opportunities and challenges related to applying a preventive approach to schizophrenia, many of which he himself has addressed in the pioneering work of the internationally recognised centre of excellence, the Early Psychosis Prevention and Intervention Centre (EPPIC). Professor McGorry draws the reader's attention to those aspects of the nature of schizophrenia that indicate the potential for early intervention and prevention. Importantly, the evidence that the early course of schizophrenia is malleable and that the Kraepelinian concept of schizophrenia as an unrelenting and unmodifiable deteriorating disease is challenged by the literature and the experience amassed at EPPIC. This work has provided much of the confidence for proceeding to the next stage of developing interventions for schizophrenia, namely, preclinical intervention aiming, in time, at primary prevention.

But how do we move from detecting people early in the course of a psychotic illness, or perhaps even prodromally, to identifying people who merely show risk factors or precursors before the disease is apparent? In the third paper of the introductory section, Professor McConaghy, another pioneering Australian schizophrenia researcher, illuminates the path forward by describing a dimensional, generally applicable model of risk factors associated with schizophrenia. In his paper, Professor McConaghy describes the series of original studies that provided the first psychometric evidence that Bleulerian ‘loosening of the associations’ is not a disorder specific to schizophrenia but is, in fact, a dimension of normal conceptual thinking. If allusive thinking is present to a marked degree, it may reflect a genetically transmitted risk factor for schizophrenia and other related adolescent-onset mental disorders. The model advanced by Professor McConaghy provides a basis for detecting markers of risk in people who may be predisposed to schizophrenia. The likely dimensional character of risk factors for schizophrenia is a theme that is taken up in other sections of the proceedings from, in turn, an epidemiological, genetic and clinical perspective.

The epidemiology of schizophrenia is then reviewed, spanning incidence, prevalence, measurement issues and screening. Professor Jablensky reviews the incidence and prevalence of schizophrenia spectrum disorders, particularly informed by the Australian Study of Low Prevalence Psychotic Disorders as part of the National Survey of Mental Health and Wellbeing that he recently supervised. Dr Rosenman reminds the audience of the difficulties and the prospects of accurate measurement, and Dr O'Toole presents the theory of screening as it applies to low-prevalence disorders such as schizophrenia. From the mathematics, it is clear that a major challenge will be to identify those people who are at high risk for later psychotic disorders without incurring a large number of false positives, while, at the same time, not missing a substantial number of people who are actually at high risk.

In the next section of the proceedings, Professors Hallmayer and Schofield leave the reader in no doubt that we should not wait for geneticists to provide most of the answers to understanding and preventing schizophrenia. Despite the well-established genetic contribution to the causes of schizophrenia, no single gene has been implicated in the disease. Professor Hallmayer informs the reader that the mode of genetic transmission of schizophrenia is complex and molecular genetics studies are already indicating that multiple genetic mutations are likely to be involved in most cases of schizophrenia. With the completion of at least 11 genome-wide scans, no loci of major effect have been identified. By contrast, at least six loci scattered throughout the genome are under investigation as the sites of susceptibility genes of small effect. These genetic findings are entirely consistent with the view that dimensional risk factors for schizophrenia are relatively widely distributed in the general population, compared to the prevalence of narrowly defined schizophrenia.

In the section titled ‘Prenatal, perinatal and developmental factors’, Professor McGrath's seminal paper alerts us to the possibilities of universal preventive approaches to schizophrenia that potentially offer the greatest power to reduce the incidence of schizophrenia on a population basis. Professor McGrath reviews the evidence that modifying antenatal and perinatal factors may be the most effective way of preventing schizophrenia. Professor McNeil's paper provides a fascinating review of the literature on obstetric risk factors and the substantial evidence on minor physical anomalies that indicate that the differences in development associated with schizophrenia are not restricted to the brain. Professor McNeil's paper demonstrates the value of applying an epidemiological approach to careful clinical observation and measurement, and is presented with the insights one would expect of a researcher who has been at the forefront of his field for many years.

The former sections lead naturally to the coverage of the considerable research into the characterisation and measurement of phenotypic markers that can be assessed as part of screening procedures to identify people genetically predisposed to schizophrenia. A phenotypic marker of risk is a measure of behaviour or biology that can significantly distinguish unaffected biological relatives of patients with schizophrenia from healthy controls unrelated to a patient with schizophrenia. A family history of diagnosable schizophrenia is the classical phenotypic marker most commonly used in genetic linkage studies. Unfortunately, the diagnosis of schizophrenia has turned out to be an imprecise phenotype and because only one in 10 patients have a family history, it does not have great diagnostic accuracy in discriminating relatives of patients with schizophrenia from unrelated healthy controls. As Faraone et al. argue, phenotypic markers need to be found for use in genetic studies and for inclusion in risk factor assessment protocols with superior diagnostic accuracy over that provided by a family history of schizophrenia, that is, greater than one in 10 [1]. In the first paper of this section, Professor Michie describes the range of neurocognitive measures that may meet the criteria of Faraone et al. and presents convincing evidence that measures of performance on the Continuous Performance Test may be the most suitable neurocognitive marker of risk for schizophrenia. Professor McNeil follows on with a similar review of the evidence concerning neuromotor anomalies as phenotypic markers and potential measures of risk in identifying people who may be predisposed to schizophrenia, with or without a family history of schizophrenia. The contrast between the extremely low frequency of abnormal neurological signs noted on routine physical examination of patients with schizophrenia and the prevalence of neuromotor anomalies detected on the assessments used by Professor McNeil should be of considerable interest to clinicians. Lee and Williams provide a review of the literature on eye movement anomalies and indicate the potential value of their measurements in risk factor assessment. Dr Catts reviews the literature concerning psychometrically and clinically assessed schizotypy traits and recommends that these assessments be included in a risk factor evaluation.

Professor Copolov and Crook take up the important issue of whether there are any biological markers that have sufficient diagnostic accuracy to be considered in an assessment of risk to schizophrenia. Although these authors conclude that no measures currently available are worthy of inclusion in such an assessment at this stage, they provide a succinct and valuable review of biological differences found in patients with schizophrenia and their relatives. Dr Velakoulis and colleagues have contributed a fascinating review of imaging studies of the hippocampus in schizophrenia and propose a staged model of the development of schizophrenia that could potentially lead to preventive intervention in the future. Professor Ward completes this section with a number of critical insights into the interpretation of structural neuroimaging studies.

In order to prevent the first episode of psychosis it will be necessary to identify those individuals who are at highest risk before they succumb to the illness and, given the peak age of onset, this must occur in people who are young and living in the community. This seems best accomplished through agencies that have a general and community focus, of which general medical practice is the most obvious. Professor Harris reviews the realities of general practice in order to highlight the tasks that confront any effort to identify individuals in the prodromal stages. He emphasises the need to incorporate incentives for GPs that assist them in dealing with patients who may be suspected to be at high risk. These incentives are based on good medical practice: GPs need to know what to look for and, most importantly, what to do when they encounter people who raise their ‘index of suspicion’. The need for extensive support and backup for individual GPs is clear, especially because GPs may only have limited experience of individuals with psychosis and there will be many GPs who never see conversion to psychosis in their practices. Professor Falloon then describes the prevention efforts mounted in the UK, outlining the integration of mental health workers with general practice in a well-defined region and the extensive program that examined the feasibility of mounting a prevention effort. Ms Penrose-Wall provides an insightful commentary on local Australian conditions that may enhance or inhibit the early detection of individuals at high risk of later breakdown. Professor McGorry reinforces the urgency to detect these individuals early, as he presents evidence on the effects of reducing the duration of untreated psychosis and the importance of early detection in the course and outcome of the disorder.

However, early detection of people in the prodromal phase requires accurate measurement. Dr Halpin and Professor Carr showed that this can be accomplished by using quantitative rating scales, while Professor Andrews discusses standardised diagnostic interviews. However, the difficulties should not be under-estimated. We were fortunate in having representatives from strong early intervention programs in several Australian states and the lessons learned from the Personal Assistance and Crisis Evaluation (PACE) clinic outlined by Drs Phillips and Yung and Professor McGorry in Melbourne, and the Psychological Assistance Service (PAS) clinics outlined by Professor Carr and colleagues in Newcastle are invaluable.

If, for a moment, we assumed that we could successfully identify young people at high risk of schizophrenia before illness-onset, or had sufficient resources to expose all young people (for example, at school) to an intervention, are there any candidate preventive strategies currently available? The substantial evidence that neuroleptic medication prevents relapse after the first episode of psychosis suggests that preventive pharmacological prevention may be possible. The much-reduced risk of tardive dyskinesia associated with second generation antipsychotics [2] is reassuring in terms of the safety of low-dose neuroleptics as long-term prophylaxis. Of relevance to this issue are preliminary data from a study using very low dose risperidone in apparently well relatives of patients with schizophrenia. This study indicated that this intervention produced measurable improvements in neurocognitive function [3]. The neuroprotective and neurotrophic actions of the newer anticonvulsants also suggest that these drugs are potential candidate preventive treatments for high risk subjects.

However, the section titled ‘Preventive strategies in schizophrenia’ focuses on psychosocial approaches as both primary and secondary preventive interventions. Professor Birchwood opens this section by describing research supportive of the notion that the early course of schizophrenia is a ‘critical period’ when intervention can limit and prevent disability. Importantly, Professor Birchwood draws the clinician's attention to the formulation of vulnerability as a long-term phenomenon irrespective of successful early intervention and argues for ongoing management of vulnerability for a minimum of 3 years or perhaps, in some patients, indefinitely. Professor Falloon describes the evidence for the efficiency of training patients and carers in problem solving techniques for preventing illness relapse and secondary disability. Professor Falloon takes this research forward to its logical conclusion by posing the question of whether the power of such simple training is sufficient to warrant a trial of this intervention as a universal prevention strategy for young people. In an insightful paper, Patterson and associates describe research on the developmental aspects of expressed emotion (EE) in relatives of patients with serious mental illness. Patterson and associates advance their hypothesis that early feelings of loss, grief and guilt are key determinants of subsequent high EE in relatives. This proposal suggests feasible preventive intervention that should be urgently evaluated.

Finally, the important place of the consumer is reinforced by eloquent discussions by Mitchell and Peterson, who note that, perhaps contrary to professional concerns, people who are afflicted by the disease appreciate accurate and timely assessment, do not necessarily fear the naming of their problem if it leads to help, and identify the need for understanding and support. That screening and the uncertainty produced by slow production of results can be extremely difficult for the individuals who are being assessed is underlined by Professor Turner's reporting of experiences with other genetically based screening programs and points to the need for accurate, timely and sympathetic processes to be in place before any widespread screening is offered. Dr Rosen sums up the ethical difficulties produced by errors of labelling, by overriding individuals' right not to know, and the problems of less than perfect test accuracy. The challenges are great indeed.

In summary, these proceedings, for the first time, bring together a diverse range of literature relevant to research into the prevention of schizophrenia in a comprehensive and integrated manner. The theme may seem almost futuristic to those workers trying to provide timely optimal treatment to patients with advanced disease. The Scientific Committee hope that these proceedings will stimulate research that will, in time, allow those workers to spend increasing amounts of time in a preventive mode. The fact is that there are severe limits to the amount of disability that can be prevented by early intervention after the onset of psychosis. The World Health Organization's Determinants of Outcome Study demonstrated that early course accounts for no more than one-third of the variance of measured long-term disability [4]. Perhaps one of the reasons for this limitation is that, on average, disabling, non-psychotic symptoms have their onset at least 5 years before most patients are seen [5],[6]. Even if the diagnostic accuracy of the best risk factor assessment protocol is not sufficient to warrant intervention preclinically, such assessments may create the opportunity to identify adolescents early in this very long, prepsychotic deteriorative stage, possibly increasing the power of early intervention strategies [7].

The Scientific Committee formed the opinion that we must prepare for success. Let us make the assumption that within 10 years, a range of susceptibility genes for schizophrenia have been identified (the first locus may have already been found [8]). How will the decision be made to intervene in people carrying susceptibility genes? The committee's view is that only via immediate research into the assessment procedures described herein will we be prepared to effectively identify early phenotypic expression and developmental precursors. And only by identifying these will we be able to give informed advice concerning intervention to individuals genetically predisposed, and have the capacity to monitor the impact of preventive intervention.

The editors would like to thank the Scientific Program Committee (Assoc. Prof. Scott Clark, Prof. Mark Harris, Dr Maryanne O'Donnell, Dr Alan Rosen, Dr Brian O'Toole and Dr Stanley Catts), the speakers at the conference, the sponsors (South Western Sydney Area Health Service, New South Wales Centre for Mental Health, Janssen-Cilag, Eli Lilly, Pfizer, Novartis and Lundbeck), our advertisers (South Western Sydney Area Health Service, Janssen-Cilag, Eli Lilly, Pfizer, Novartis, Lundbeck and AstraZeneca), Ms Susan Daly and Ms Barbara Liebert.

Our host organisation, the Neuroscience Institute of Schizophrenia and Allied Disorders (NISAD), views the conference and these proceedings as but one of the first steps in the contribution of NISAD to finding the causes of schizophrenia and, ultimately, the means for its prevention.