Volume 190 · Issue 4 · Supplement

New approaches to schizophrenia research and policy can provide a substantive basis for early intervention and better care

Ian B Hickie MD, FRANZCP · Patrick D McGorry MD, FRCP, FRANZCP

New primary data and systematic reviews have prompted the review of some long-held views about the epidemiology of schizophrenia. The incidence and prevalence of schizophrenia show prominent variation between locations. Males are more likely to develop schizophrenia than females (1.4 : 1). Migrant status, urban birth or residence, and advanced paternal age are associated with an increased risk of developing schizophrenia. Prenatal infection and nutrition are associated with an increased risk of schizophrenia. Individuals with schizophrenia have a 2–3-fold increased mortality risk compared with the general population. This differential mortality gap may have worsened in recent decades. Epidemiology is good for generating candidate exposures but poor at proving them. Cross-disciplinary projects between epidemiology and neuroscience may help us understand the pathways leading to schizophrenia.

John J McGrath MD, PhD, FRANZCP · Ezra S Susser MD, MPH, DrPH

Neuroimaging studies of individuals at risk of psychosis have the potential to identify markers predictive of illness onset and features that progress with transition. To date, reduced brain volumes have shown weak predictive value for onset of psychotic illness. All published longitudinal studies of the transition to psychosis show progressive brain changes that are not seen in at-risk individuals who do not develop the disorder. Although the cause of these changes is unclear, they challenge the conventional neurodevelopmental model of schizophrenia.

Stephen J Wood PhD · Christos Pantelis MD, FRANZCP · Alison R Yung PhD, FRANZCP · Dennis Velakoulis FRANZCP · Patrick D McGorry MD, FRCP, FRANZCP

During adolescence, about 30% of the synapses formed during childhood in the dorsolateral prefrontal cortex (DLPC) are lost; in patients with schizophrenia, the synapse loss is about 60%. Studies of synapse loss in the neuromuscular junction have provided insights into the molecular basis of synapse formation and regression, thereby providing a paradigm for investigations of synapse loss in the DLPC. Research into some of these molecules in the DLPC has shown that they are crucial to synapse formation and regression. Further research in this field could examine when synapse loss in the DLPC of patients with schizophrenia occurs, and further elucidate how these molecules are involved in the development of schizophrenia.

Maxwell R Bennett BEng, DSc, FAA

Postnatal infection may represent a preventable risk factor for onset of psychotic disorders in adolescence and early adulthood. The mechanism of action is likely to involve site-directed triggering of the brain’s innate immune system, mediated principally through localised activation of microglial cells. This triggering may occur in response to systemic inflammatory stimuli, without direct involvement of the central nervous system. Microglial activation can represent a primary response or a secondary phenomenon at sites made vulnerable by prior injury; that is, areas containing previously activated microglia will respond more strongly to a new stimulus. The presence of activated microglia is indicative of a recent insult or active disease. It is not characteristic of long-established neurodevelopmental abnormalities. Activated microglia, acting through a variety of cytokine and other signal systems, have the capacity to significantly interfere with synaptic turnover and thus, over time, alter synaptic architecture and function. This pathophysiological path should be investigated more systematically as it may explain a novel “neuroprotective” mode of action for some existing antipsychotic compounds.

Ian B Hickie MD, FRANZCP · Richard Banati MD, PhD · Claire H Stewart PhD · Andrew R Lloyd MD, FRACP

The aetiology of schizophrenia remains complex, although proposed models have identified genetic markers and environmental pathogens as important risk factors. Researchers have found no large-effect or unique genetic elements, and only a small number of putative environmental agents have been identified. Use of amphetamine-type stimulants (ATSs) is an exemplar environmental pathogen, as it is known to trigger schizophrenia-like illness and other psychotic and manic episodes. To date, the ATS model of illness onset has been under-utilised. It has the potential to reveal key neurobiological elements of schizophrenia and related psychoses. The model proposed here has the capacity to inform detection of those at risk of ATS-related psychoses, and therefore help develop early intervention strategies. It is possible that the same approach may be used in young people known to be at risk of schizophrenia and related disorders, by informing models that involve other environmental or genetic risks.

Daniel F Hermens BSc, GDipSci, PhD · Dan I Lubman PhD, FRANZCP, FAChAM · Philip B Ward BMedSc, PhD · Sharon L Naismith BA, DPsych, CCN · Ian B Hickie MD, FRANZCP, AM

We propose that various measures of brain structure or function, gene expression and proteomic technologies can be used to guide better treatment of schizophrenia and other psychotic disorders. These measures are not used to establish a specific diagnosis. Their purpose is to predict variations in underlying illness activity that predict severity, course of clinical illness, or other morbidity. We propose a new instrument that uses a composite scoring system of systemic biomarkers of illness-related changes in health status: the Brain and Mind Research Institute Biomarker Index. This may permit comparison of biological dysfunction among patients who are at similar points in their illness or have similar clinical features. A specific example of the use of a novel positron emission tomography marker of progressive brain disease in patients with schizophrenia is described.

Richard Banati MD, PhD · Ian B Hickie MD, FRANZCP, AM

A fundamental shift in the design of clinical trials for psychotic disorders is desirable and feasible. Priority should be placed on evaluation of the efficacy of interventions targeting different phases of illness. A range of traditional therapeutic approaches needs to be augmented by an increased emphasis on the potential benefits of informational, e-health, behavioural and neuroprotective strategies. A new national clinical trials platform, based on headspace, the National Youth Mental Health Foundation, is outlined. It provides the opportunity for conducting large multisite clinical trials in young people with emerging major mental disorders.

Patrick D McGorry MD, FRCP, FRANZCP · Alison R Yung MB BS, MPM, FRANZCP · Christos Pantelis MD, FRANZCP · Ian B Hickie MD, FRANZCP, AM

The oestrogen protection hypothesis proposes that oestrogen has a protective effect against onset of schizophrenia. In support of this: Epidemiological studies have shown that young women are less likely to develop schizophrenia than men of the same age, and women are more likely to develop late-onset schizophrenia after menopause. Clinical studies have shown higher psychotic symptoms in perimenopausal women, and women at the low oestrogen phase of the menstrual cycle. Animal studies provide further evidence in support of the oestrogen protection hypothesis. Three randomised double-blind placebo-controlled trials and an open-label study showed that adding oestradiol to women’s usual antipsychotic medications was associated with significant abatement of schizophrenia symptoms. A small study of men with schizophrenia who received oral oestradiol valerate also showed a significant abatement in psychotic symptoms. Although oestrogen appears to be a useful treatment for schizophrenia, further research is required to determine the correct dose and duration of use of oestradiol. New types of oestrogen compounds may provide a safer, non-feminising approach for the treatment of schizophrenia.

Jayashri Kulkarni MB BS, FRANZCP, PhD

Patients with schizophrenia have a wide range of risk factors for cardiometabolic disease, at rates 1.5–5 times greater than the general population. Despite the provision of many sets of guidelines and protocols for screening and monitoring of cardiometabolic risks, morbidity and mortality rates for those with psychotic illnesses remain excessive and premature. Surveys of mental health practitioners reveal a clear acknowledgement of the importance of managing cardiometabolic risks and subsequent comorbidity. However, inadequate screening rates of patients with antipsychotic-treated mental illnesses suggest “knowing is not doing”. Surmountable barriers (at service, patient and illness levels) to adequate integrated health care are not being adequately challenged for this population. Recommendations to improve the situation include service reorganisation, communication enhancement, improved training and education, better incentives, accreditation rigour, and government leadership.

Tim J R Lambert MB BS, PhD, FRANZCP · John W Newcomer MD

Over the past 15 years, governments have agreed to a series of National Mental Health Plans. These national strategies and plans have set goals and discussed the importance of monitoring and evaluation. Despite this ongoing national collaborative framework, Australia’s mental health policy lacks real accountability and relies largely on limited mental health service systems data. The lack of outcome data represents a critical gap in knowledge for mental health policy, planning and practice. Resistance from current stakeholders and a lack of investment in research and monitoring capacity are preventing more rigorous ongoing monitoring of mental health policy. The new Rudd Government appears to be shifting the emphasis towards measuring the outcomes of national policy in health, housing and employment. Measuring such outcomes will guide government decision making and ultimately improve mental health services.

David W Crosbie BA, DipEd, GradDipSpecEd