Research Programs

The distinguished scientific contributors to APRN unanimously propose that the network should have a thematic and strategic approach to discovery of molecular pathways involved in schizophrenia and bipolar disorder, and that this should be integrated into a larger set of research themes that allow translation of fundamental research into better outcomes for people with psychotic illness.

Our challenge is to articulate a common theme that can be applied to all levels of research and has enough specificity to offer a driving principle to discovery. The proposal is that we build the Network research around the role of genes as risk factors for psychotic illness.

Why Genes?

To date, no other descriptive and predictive hypothesis for the root cause of psychosis other than those implicating genes has been advanced. This is not to say that there are not many ideas regarding the causes of psychosis, but that many of them involve hypotheses that are difficult to test in a range of experimental paradigms.

By focussing on genes, we are able to envisage a range of cellular and molecular studies, studies on postmortem brain tissue, studies using animal models including transgenics, epidemiological studies, brain imaging studies and potential drug development studies.

Are we really certain as to which genes may be involved in the etiology of psychosis? No! But one of the more exciting developments in schizophrenia research in the past couple of years has been the success of microarray approaches using postmortem human tissue and transgenic animal models, and from the identification by positional cloning of several candidate genes from genetic linkage studies.

Of great interest has been the convergence of these two approaches where it now appears that genes involved in synaptic communication, especially presynaptic communication, are critically involved as either genetic risk factors or as causal or consequential changes in brain tissue.

Susceptibility genes for psychosis have been identified by positional cloning of candidate genetic loci, and a number of others by direct candidate selection. In addition, two genes have been identified as marking a cytogenetic breakpoint in a schizophrenia pedigree.

Equivalent susceptibility genes have not yet been published for bipolar disorder, although several groups have strong candidates identified through linkage studies and positional cloning approaches.

These results make testable hypotheses that can be validated or refuted and that can lead to other research questions being formulated. It is the concept of success in the areas of genes and molecules rather than the specific research results to date that is most important. Indeed, it is likely that even today, many of the currently claimed ‘genes’ will not be validated, but more importantly these claims are now testable.

The following is an outline of the APRN research proposals. A fully detailed report in PDF form may be downloaded by clicking here: <Final Report>

1. CELLULAR AND MOLECULAR NEUROSCIENCE PROGRAM

The neuroscience centres proposed for inclusion in this national program are:

• Mental Health Research Institute Victoria (MHRIV)
• The Howard Florey Institute; Brain Sciences, University of NSW
• Neuroscience Institute of Schizophrenia and Allied Disorders (NISAD) and its NSW affiliated research centres (located at the Universities of Sydney, Wollongong, Newcastle, and Garvan Institute of Medical Research)
• The Prince of Wales Medical Research Institute
• Hunter Medical Research Institute
• Queensland Brain Institute
• Queensland Institute of Medical Research
• Queensland Centre for Mental Health Research
• Centre for Molecular Neurobiology, Griffith University
• Flinders University
• Centre for Clinical Research in Neuropsychiatry, University of Western
  Australia

Major advances in treatment have rarely occurred without understanding the pathophysiology of a disease. Adequate descriptions of the cellular, subcellular and molecular abnormalities do not exist for the psychotic disorders. This lack of knowledge limits research at all levels because the relevance of candidate susceptibility genes cannot readily be assessed, animal models cannot be validated, functional imaging studies cannot be precisely targeted biochemically, and specific molecular targets for drug design are lacking. The breadth of this field demands that molecular or functional targets be specified for productive applied research.

To this end, the Cellular and Molecular Neuroscience program will carry out two types of studies: one type investigating human postmortem brain tissue and the other type developing and investigating animals that have been genetically designed to ‘model’ an aspect of psychotic disorder (animal models).

1a: Human postmortem brain tissue studies

It is essential to carry out research directly on human brain tissue because only humans develop schizophrenia or bipolar disorder. This research is fundamental to achieving a full phenotypic description of the diseases which is necessary for valid selection of animal models.

APRN proposes that the collaborative research program on human postmortem brain tissue determine protein and mRNA levels for each of the susceptibility genes in schizophrenia, using high-throughput technologies (proteomic and microarray-based) to create large databases for protein and gene expression for future investigation of other pathways, in addition to building on existing lines of research.

1b: Studies of human cell lines

A variety of cells can be derived from biopsy of patients and healthy controls. Biopsies can be made in well characterised patients without some of the problems associated with postmortem tissue and variable cause of death.

APRN proposes treated cellular preparation studies (with susceptibility gene product ligands; psychotogenic and antipsychotic agents) to determine changes in protein and mRNA levels for each of the susceptibility genes, using high-throughput technologies (proteomic- and microarray-based) to create large databases for protein and gene expression for future investigation of other pathways.

1c: Animal treatment studies

Studies of the effects of treatment of animals, mainly rodents, with psychotogenic and anti-psychotic agents can be used to determine changes in protein and mRNA levels using high-throughput proteomic- and microarraybased approaches. These experiments complement the human postmortem and cell line studies and lead to the creation of large databases of protein and gene expression for future investigation of other pathways. Future experiments can be directed to similar approaches using animals with altered expression (eg knockout) of identified susceptibility genes or treatment of animals with novel ligands that may inhibit or enhance the actions of susceptibility gene products.

APRN proposes treated animal studies (with susceptibility gene product ligands; psychotogenic and antipsychotic agents) to determine changes in protein and mRNA levels for each of the susceptibility genes, using highthroughput technologies (proteomic- and microarray-based) to create large databases for protein and gene expression for future investigation of other pathways.

1d: Transgenic and other animal models

Relatively few transgenic animal models of psychosis have been proposed, largely because until recently, very few candidate genes had been identified. However, the NMDA receptor R1 subunit knockdown model of Mohn et al. has been an important advance as this model supported both the synaptic transmission hypothesis and resulted in mice with behavioural traits that were reversed by anti-psychotic medications. As susceptibility genes have been identified, pre-existing knockout mice have also been used to provide supportive data; for example, neuregulin knockout hypomorphs have been used to support the discovery of neuregulin as a schizophrenia susceptibility gene.

Schizophrenia and bipolar disorder are certainly the result of interactions between genes and the developmental environment. Probably multiple gene pathways are involved. Animal models that investigate possible environmental risk factors include prenatal infection, prenatal hypoxia, prenatal hypovitaminosis D, and exposure to cannabinoids during brain maturation. Such models are open to interrogation via behavioural, structural and microarray-based approaches. Candidate gene-environment interactions can be explored using a combination of transgenic and environmental models.

APRN proposes that transgenic studies, as they become available (including transgenes, knockout’s, conditional knockout’s, knockdown’s, etc), be used to determine the function of susceptibility genes, and to compare the resulting animal phenotypes with the findings from postmortem tissue from patients with psychosis.

2. HIGH FIELD MAGNETIC RESONANCE PROGRAM

The high field MRI centres proposed for inclusion in this national program are:

• Centre for Magnetic Resonance, University of Queensland (4 Tesla)
• The Prince of Wales Medical Research Institute MRI centre (3T)
• Brain Research Institute, Austin Hospital, Melbourne (3T)

Over the last decade, advances in the development and application of magnetic resonance (MR) technology have provided unprecedented opportunities for conducting non-invasive in vivo investigations of human brain structure and metabolism.

Recently, there has been considerable interest in using genetic information to interrogate MRI data. Success has already been achieved in terms of identifying genetic influences upon brain development and function in healthy adolescents and adults. A genetic predisposition to psychosis has been demonstrated to produce reliable differences in fMRI measures, therefore specific hypotheses concerning candidate genes and their relationships with brain structure and metabolism may be developed and tested in vivo.

APRN proposes to add funding to two or three Collaborative High Field MRI Research Centres, as a separate initiative to the clinical neuroimaging of the large samples proposed in the Genetic Epidemiology Program (see next section). This high field MRI initiative is essential because it is the only way to bridge the scale of measurement gap between in vivo imaging and in vitro cellular research.

It is intended that identical protocols be developed, established and conducted at each centre, with regular assessments using phantoms for quality assurance. This will provide essential data concerning replicability of results, a problematic area for MRI studies of psychosis, and the potential of pooling data to achieve sufficient sample sizes.

3. GENETIC EPIDEMIOLOGY PROGRAM

Genetic epidemiology is the study of the genetic determinants of specific characteristics of individuals (phenotypes) in a population. Defining relevant phenotypes for the psychotic disorders is not straightforward. Unlike diseases caused by a single gene, psychotic disorders involve multiple gene variants that interact with one another and the environment to produce disease. Many decades of studying the pattern of aggregation of diagnosable psychotic disorder in families has demonstrated that these disorders have strong genetic backgrounds - at least 80% of the risk for these disorders being due to genetic factors.

Family history is currently the only reliable means of identifying risk (and such studies are in progress in several overseas centres), but the majority of cases of schizophrenia do not have a family history.

If a risk-screening instrument applicable to large populations of young people can be devised, follow-up therapy through the period of highest risk for psychosis onset is likely to reduce the severity and term of the disability.

Clinical research centres in Perth, Melbourne, Sydney, Newcastle and Brisbane are proposed for involvement in three studies aimed at developing a risk-screening instrument:

3a: Within family case-control study: cross-sectional assessments

APRN proposes to recruit 1,600 nuclear families across multiple centres. Each family will comprise a proband, at least one sibling and two parents. Diagnoses of the probands will be schizophrenia (N=800) and bipolar disorder (N=800). These samples will be assessed diagnostically, neurocognitively, genetically, electrophysiologically and by MRI measurement, and on a battery of personality and endophenotypic characteristics (eg, neurological soft signs, minor physical anomalies).

We acknowledge the work of Professor Assen Jablensky and his colleagues in
drafting the core study and thank them for allowing it to be included as part of
the APRN proposals.

3b: Within family case-control study: longitudinal follow-up of siblings

Probands under the age of 26 years (clinical cases diagnosed as either schizophrenia or bipolar disorder) will be recruited shortly after their first presentation to a mental health service for treatment. Based on the assumption that the probands will be the first member of their sibship to develop a psychotic illness, we can expect that ten percent of the sibling sample recruited will develop a psychotic illness, and many of these cases will emerge within a few years of the proband’s illness. Hence the regular assessment of the siblings longitudinally will map out the evolution of the onset of psychotic illness as well as enable comparison of those siblings who develop illness with those that do not, on a range of assessments of risk. In addition, this study will provide valuable information to base the design of a risk assessment battery for use in school-aged children and adolescents.

3c: Development of a screening instrument for the identification of young people at risk

It is not yet feasible to conduct a population-based longitudinal study of children and adolescents at high risk for schizophrenia and related disorders. Instead it is proposed to develop a screening instrument for the identification of young people at risk and determine the prevalence of risk factors in a population of year 4-5 (9-10-year old) children and year 9-10 (14-15-year old) adolescents.

The development of the screening instrument is anticipated to take three to five years. Thereafter this instrument will be able to be applied to the selection of a sample of school aged children at high risk of developing psychotic disorder for longitudinal assessment and follow-up.

4. DRUG DEVELOPMENT PROGRAM

Information from other aspects of APRN research will lead to the identification of genes that are up or down regulated in particular psychotic conditions. The primary target of the drug development program will be those genes that are up-regulated, and the strategy will be to develop chemical antagonists of these targets.

Although the Drug Development Program will be coordinated with activities in the other levels of research, unlike other levels of research it will be mainly led by one centre, and conducted principally at the University of Queensland in the Institute for Molecular Bioscience (IMB) and the School of Biomedical Sciences - utilising the high field NMR spectrometer there.

APRN proposes to direct seeding funding towards the early stage of the drug discovery process and this will be used to leverage funds for further development. In particular, we anticipate that leads identified in this discovery program will be further developed in partnership with biotechnology or pharmaceutical companies.

5. NOVEL THERAPEUTICS, PSYCHOSOCIAL INTERVENTION AND REHABILITATION PROGRAM

Research consistently indicates that treatment outcomes in schizophrenia and related disorders are suboptimal. For example, a recent follow up study of first onset patients found consistent recovery in less than 15% of patients at 5 years after the onset of symptoms.

Whilst antipsychotic medications, including more recently developed agents, are successful in the alleviation of positive symptoms in a significant number of patients, they have limited effects on negative and cognitive symptoms, do not abolish the occurrence of relapse, and the degree of long term psychosocial recovery of many patients remains quite poor. Even when patients are able to return to life roles, they often remain symptomatic and with impaired quality of life.

APRN proposes to establish a collaborative network of clinical trials centres (CTC) to support two inter-related research programs on novel therapeutics, and psychosocial intervention and rehabilitation.

5a: Novel Therapeutics

Interventions to enhance outcomes in psychotic disorders should be carefully linked to the type of discovery projects to be undertaken within this overall research proposal. These are targeted at the discovery and development of new and innovative biological compounds. This may arise from a variety of the research streams but the most promising possibility will be the generation of agents based on the identification and characterization of specific genotypes in groups or sub-groups of patients. There will be a direct need for the testing of these agents through a series of phase I, II and III clinical trials.

5b: Psychosocial Interventions and Rehabilitation

In addition to the testing of novel biological agents, there is a pressing need for the development and evaluation of established and new psychosocial interventions. There is available research evidence for the efficacy of a number of well defined psychosocial interventions in schizophrenia.

For example, the Schizophrenia Patient Outcomes Research Team (PORT) made 9 treatment recommendations relating to specific individual and group treatments (including behavioural and cognitive skills training), family treatments, vocational rehabilitation and service systems (Lehman & Steinwachs, 1998). However, much less is known about which psychosocial interventions are helpful, since some treatments have not been adequately evaluated. Little systematic research points to the superiority of one strategy over others across all outcome measures (Huxley et al 2000).

In addition to the real world evaluation of established interventions, there is considerable scope for the development, evaluation and distribution of new psychosocial treatment tools, especially targeting areas of unmet need. Examples of this might include interventions to address social isolation, in-vivo skills training and consumer and peer support initiatives to rebuild social relationships and meaningful occupation.

5c: Collaborative Clinical Trial Centres

APRN proposes to support the development and implementation of a collaborative network of clinical trial centres (CTC) with the goal of facilitating and conducting a variety of clinical trial activities in psychotic disorders in Australia. This will include:

A CTC will be funded in each region, which will be required to develop a core set of resources and expertise. This will be supported by two national lead sites each of which will provide a coordinating role in one of either trials of novel agents or psychosocial/rehabilitation: that is, there will be one ‘novel agents’ and one ‘psychosocial/rehabilitation’ lead site nationally.

Individual CTCs may either focus on one of the two trial areas or develop expertise in both, liaising with the national lead centres. It is anticipated that separate CTCs in the two different streams may be more viable in states with larger more concentrated populations although the composition of CTCs is likely to be primarily determined by local expertise.

The clinical research centres proposed for consideration as lead CTCs are: Melbourne (novel therapeutics and rehabilitation), Newcastle (psychosocial intervention and rehabilitation) and Brisbane (psychosocial intervention).

The above is an outline only of the APRN research proposals. A fully detailed report in PDF form may be downloaded by clicking here: <Final Report>

6. RESEARCH INTO PRACTICE PROGRAM

There is a substantial delay between therapeutic discovery and its incorporation into clinical practice. The translational research pathway is completed by ensuring full and rapid uptake of existing and new treatments in the clinic. Processes to achieve this step now come under the rubric of Research into Practice, and include clinician and manager education and training.

The Cancer Council of Australia has applied these processes in the management of cancer by drafting best practice treatment protocols for early detection and optimal staged care.

APRN proposes to adopt these procedures in relation to the management of psychotic disorders. Nationally coordinated development of evidence based treatment protocols for dissemination and implementation in services participating in our network will be initiated.

The selection of clinical research centres for inclusion in this program will be made by competitive tendering.

7. COLLABORATIVE SENIOR RESEARCH FELLOWSHIP PROGRAM

A network that is multi-levelled, multi-disciplinary, and nationally distributed will require considerable collaborative ‘glue’ to keep it together. It is considered essential that some of this glue take the form of ‘flesh and blood’.

APRN proposes to fund a number of highly competitive senior research fellowships. Such fellowships will secure the network’s future scientific leadership of collaborative researchers into psychotic disorders, and recruit researchers most likely to attract competitive funding.