High-Throughput Screening Of The Genome And Proteome In Postmortem CNS From Subjects With Schizophrenia
Funder
National Health and Medical Research Council
Funding Amount
$553,190.00
Summary
Schizophrenia is a serious psychiatric illness that effects ~1% of the Australia population. The underlying pathology of the illness remains unknown. This application seeks funding to use new technologies to screen approximately 60% of the expressed human genome and proteome to determine which genes are being differentially expressed in two regions thought to be important in generating the symptoms of the illness, the frontal cortex and hippocampus. This project will generate a large amount of d ....Schizophrenia is a serious psychiatric illness that effects ~1% of the Australia population. The underlying pathology of the illness remains unknown. This application seeks funding to use new technologies to screen approximately 60% of the expressed human genome and proteome to determine which genes are being differentially expressed in two regions thought to be important in generating the symptoms of the illness, the frontal cortex and hippocampus. This project will generate a large amount of data, however by comparing the data from subjects with schizophrenia to that from control subjects and subjects with bipolar disorder who were psychotic and being treated with antipsychotic drugs close to death will allow us to identify changes that are specific to schizophrenia. Genes that are expressing different levels of mRNA and protein will become prime targets for future investigations as they are likely to be central to the pathology of the illness.Read moreRead less
A Double-blind Placebo Controlled Trial Of Transcranial Magnetic Stimulation In The Treatment Of Depression.
Funder
National Health and Medical Research Council
Funding Amount
$366,775.00
Summary
Depression is a severe and often disabling illness that occurs frequently in the general population. Depression is a treatable illness and the majority of patients will respond to anti-depressant medication, a form of psychotherapy or a combination of these. However, a significant percentage of patients with depression fail to respond to these therapies and currently require electroconvulsive therapy (ECT). This entails the complications and costs of multiple anaesthetics, memory impairment and ....Depression is a severe and often disabling illness that occurs frequently in the general population. Depression is a treatable illness and the majority of patients will respond to anti-depressant medication, a form of psychotherapy or a combination of these. However, a significant percentage of patients with depression fail to respond to these therapies and currently require electroconvulsive therapy (ECT). This entails the complications and costs of multiple anaesthetics, memory impairment and substantial social stigma. Transcranial magnetic stimulation is being researched as a potential alternative for these patients. It is administered to patients who are awake and alert and appears to have fewer side effects. TMS uses the unique properties of a magnetic field to produce or disrupt electrical activity in superficial areas of the brain, targeted to the areas thought to be involved in the cause of depression. Our research study will compare the two most promising types of TMS with an inactive or placebo condition. This is important to establish that the effects of TMS arise from the actual stimulation and to investigate whether one of two types of TMS administered is superior. We will administer this treatment for between 2 and 4 weeks and assess the response. We anticipate that our research will contribute to the development of TMS as a treatment methodology for this important patient group. It is crucial that a new treatment be thoroughly evaluated prior to wide dissemination of it in clinical practice. We will help define the effectiveness of this treatment and the most appropriate way in which it can be administered.Read moreRead less
Understanding The Molecular Basis Of Bipolar Affective Disorder
Funder
National Health and Medical Research Council
Funding Amount
$812,250.00
Summary
Bipolar disorder (manic depressive illness) is a severe mood disorder, with a lifetime prevalence of up to 1.6%. The illness is characterised by aberrant mood swings resulting in periods of mania and depression with reversion to normal behaviour between episodes. The condition has a severe impact on sufferers, being demonstrated to be the sixth most disabling disorder in the WHO Global Burden of Disease report and increasing the risk of suicide fifteen-fold. There is a pressing need to define mo ....Bipolar disorder (manic depressive illness) is a severe mood disorder, with a lifetime prevalence of up to 1.6%. The illness is characterised by aberrant mood swings resulting in periods of mania and depression with reversion to normal behaviour between episodes. The condition has a severe impact on sufferers, being demonstrated to be the sixth most disabling disorder in the WHO Global Burden of Disease report and increasing the risk of suicide fifteen-fold. There is a pressing need to define more clearly the biological basis of bipolar disorder as a necessary prerequisite to improved diagnosis and treatment. The underlying causes of bipolar disorder remain unknown. However, family studies reveal the high heritability of bipolar disorder and this familial clustering provides an opportunity to use genetic approaches to identify the predisposing genes. The long-term aim of our research is to investigate the biology of those genes that either cause or predispose to bipolar disorder. We have previously reported strong evidence for a novel bipolar disorder susceptibility gene on chromosome 4, a finding which has subsequently been reproduced in several independent studies. Consequently, we hypothesise that there is a gene located on chromosome 4 that predisposes to bipolar disorder. The aim of this proposal is to identify the chromosome 4 bipolar susceptibility gene and understand how the gene causes bipolar disorder. Identifying the genes responsible for bipolar disorder will allow us to define and understand the biological basis of this severe psychiatric condition. This will ultimately lead to major improvements in the ability to diagnose, treat and prevent the illness.Read moreRead less
Longitudinal Brain Changes In First-episode Psychosis: A 10 Year Follow-up MRI Study
Funder
National Health and Medical Research Council
Funding Amount
$165,250.00
Summary
It is now widely accepted that schizophrenia is associated with changes in the structure of the brain. Until recently these structural changes were considered to predate the onset of illness and to remain static. However, our own work has suggested an alternative model, which relates schizophrenia to brain changes at specific life stages. In order to demonstrate this, we intend to acquire repeat brain images on 100 patients who were initially scanned 10 years ago at the start of their psychotic ....It is now widely accepted that schizophrenia is associated with changes in the structure of the brain. Until recently these structural changes were considered to predate the onset of illness and to remain static. However, our own work has suggested an alternative model, which relates schizophrenia to brain changes at specific life stages. In order to demonstrate this, we intend to acquire repeat brain images on 100 patients who were initially scanned 10 years ago at the start of their psychotic illness. This would be the largest follow-up study of first episode psychosis in the world, with the longest interval between the first and second brain scan. Further, for a proportion of patients we will have 3 MRI scans, at illness onset, 2-4 years post-onset, followed by a third scan at 10 years, thereby providing unique follow-up brain imaging data. Based on our own and other research, we intend to explore the relationship between progressive brain change over a ten year period and: (i) the diagnosis of the patient (schizophrenia or other disorder), (ii) the clinical and functional outcome of the patient (still chronically ill or with no further episode of psychosis), and (iii) the cognitive state of the patient (their ability to perform well on tests of memory, planning and so on). We are able to conduct this study because of the existence of an infrastructure developed to follow-up patients, with a recontact rate of 70% of those patients admitted in 1992 and 1993. In this study we seek to implement these strategies for the patients identified after 1994. The results of this study will test our ideas derived from our model of the major psychotic illnesses and may identify the structural brain changes which are associated with the development of chronic schizophrenia and other psychoses. A further novel outcome will be the inclusion of patients who have remained well and identiifying the structural correlates of a good prognosis.Read moreRead less
Anti-Estrogens - A Potential Treatment For Bipolar Affective Disorder In Women?
Funder
National Health and Medical Research Council
Funding Amount
$239,250.00
Summary
Bipolar Affective Disorder (BPAD) or Manic-Depressive Illness is a serious mental illness with high morbidity and mortality. The cause of the illness is still unclear and the underlying neurochemical changes are different for the manic phase compared with the depressive phase. The current treatments for BPAD are limited in scope and not biochemically well understood. There are gender differences in the presentation and outcomes for BPAD which adds to the complexity of the illness. We are proposi ....Bipolar Affective Disorder (BPAD) or Manic-Depressive Illness is a serious mental illness with high morbidity and mortality. The cause of the illness is still unclear and the underlying neurochemical changes are different for the manic phase compared with the depressive phase. The current treatments for BPAD are limited in scope and not biochemically well understood. There are gender differences in the presentation and outcomes for BPAD which adds to the complexity of the illness. We are proposing a study to develop a new type of treatment for the manic phase of BPAD and are exploring the use of anti-estrogens in women with mania. The background to our proposed study comes from a few case reports suggesting that anti-estrogen agents such as progesterone and tamoxifen may be useful adjuncts to treatment. We conducted a small pilot study comparing the addition of oral tamoxifen with oral progesterone and placebo in 10 women with mania and found that the women who received tamoxifen made significantly better improvements in their manic symptoms over a 28-day trial. The research study we are now proposing is a larger, three-arm, double blind, placebo controlled, 28-day adjunctive study in women with mania to expand and clarify our pilot study findings. Patients in our proposed study would receive either 40mg per day tamoxifen or 20mg per day progesterone or placebo in addition to standardised lithium medication. We will measure enzyme activity (protein kinase C) and estrogen-progesterone levels to understand more about the mechanisms of action by these new hormone treatments. BPAD is a crippling disorder and if we are successful, then tamoxifen treatment may be an important new treatment. This proposed study will also shed new light on some of the neurochemical mechanisms underlying BPAD as well as opening up the new area of hormone treatments for serious mental illness.Read moreRead less
Advanced Paternal Age: Behavioural, Neuroanatomical And Genomic Correlates In The Offspring Of Older Fathers
Funder
National Health and Medical Research Council
Funding Amount
$501,565.00
Summary
The offspring of older fathers have an increased risk of developing disorders such as autism and schizophrenia. This is thought to be due to mutations in the developing sperm. Our group has shown in a mouse model that the offspring of older fathers have changes in brain shape and in behaviour, similar to some findings in autism. In this grant we will refine this animal model and explore the brain, behavioural and genetic correlates of advanced paternal age.
Depressive Illness And The Heart: Identifying The Relation Between Affective Disorders And Coronary Heart Disease
Funder
National Health and Medical Research Council
Funding Amount
$503,625.00
Summary
Major depression is ranked fourth among the 10 leading causes of the global burden of disease and, if epidemiological projections are correct, by 2020 it will reach second place. Patients with depression are at increased risk of developing coronary heart disease. This elevated risk is independent of conventional risk factors such as smoking, obesity, hyperlipidaemia, diabetes and hypertension. Also conclusively demonstrated is the adverse effect of depression in patients following myocardial inf ....Major depression is ranked fourth among the 10 leading causes of the global burden of disease and, if epidemiological projections are correct, by 2020 it will reach second place. Patients with depression are at increased risk of developing coronary heart disease. This elevated risk is independent of conventional risk factors such as smoking, obesity, hyperlipidaemia, diabetes and hypertension. Also conclusively demonstrated is the adverse effect of depression in patients following myocardial infarction (MI), which materially increases mortality. The mechanism of increased cardiac risk attributable to depressive illness is at present uncertain but activation of the sympathetic nervous system, exaggerated platelet reactivity and-or altered baroreflex function are likely to be of prime importance. Preliminary data from our laboratory indicates that whole body and cardiac sympathetic nervous activity and cardiac baroreflex sensitivity are modified following antidepressant therapy. Identifying the underlying neurochemical mechanisms responsible for alterations in affective behaviour, and quantifying cardiac and whole body sympathetic activity directly and indirectly, and testing whether therapeutic and behavioural interventions can influence brain neurotransmitter turnover and modify cardiac sympathetic tone, platelet reactivity, and baroreflex function in a fashion likely to reduce cardiac risk, will be an important step forward in alleviating the burden of depressive illness on the community.Read moreRead less