Predictors Of Response To Antidepressants: Utility Of Behavioural, Neuroimaging And Genetics Data
Funder
National Health and Medical Research Council
Funding Amount
$310,071.00
Summary
Major depressive disorder (MDD) is projected to cause the second greatest global burden of disease by 2020, highlighting the urgent need for valid predictors of effective treatment response. Currently, there are no accurate predictors of response to antidepressants in MDD, and successful treatment relies greatly on 'trial and error'. This process is demanding on health resources, and may be a factor in the high suicide rates in depressed patients. Previous research on treatment response has been ....Major depressive disorder (MDD) is projected to cause the second greatest global burden of disease by 2020, highlighting the urgent need for valid predictors of effective treatment response. Currently, there are no accurate predictors of response to antidepressants in MDD, and successful treatment relies greatly on 'trial and error'. This process is demanding on health resources, and may be a factor in the high suicide rates in depressed patients. Previous research on treatment response has been limited by recruitment of small, heterogeneous patient samples, lack of placebo control, and a failure to examine task related activity in brain imaging studies. Perhaps one of the more troubling aspects of research that aims to predict treatment response to antidepressant medications is the use of commonly used outcome measures such as the Hamilton Rating Depression Scale (HAM-D), which were developed long before current classification systems of depression came into use. The US Federal Drug Administration has recently identified what they call a translational gap such that behavioural and biological measures are the most robust for detection of disorders such as depression, yet these measures remain to be translated into clinical tools that can be used to evaluate treatment. The aim of the current study therefore is to determine whether genetic variability is related to treatment outcome as defined by a more objective outcome measure (facial expression perception) using a randomised controlled design. The study will also determine whether brain measures (fMRI, EEG) enhance the prediction of SSRI response to both clinical and behavioural measures, over and above the genetic contribution.Read moreRead less
PIPK2A, A Candidate Gene For Schizophrenia: Impact Of DNA Polymorphisms On Gene- And Protein Expression And -function
Funder
National Health and Medical Research Council
Funding Amount
$454,023.00
Summary
Schizophrenia is a devastating mental disorder with severe impact not only on the individual, but also on families and communities. Prevalence of the illness is worldwide about 0.5% for all populations. More than 200,000 Australians suffer from schizophrenia, costing the Australian community nearly $2 billion each year. The causes for schizophrenia are still unclear. There is now agreement that nature (genetic factors) and nurture (environmental influences) play a role in the development of the ....Schizophrenia is a devastating mental disorder with severe impact not only on the individual, but also on families and communities. Prevalence of the illness is worldwide about 0.5% for all populations. More than 200,000 Australians suffer from schizophrenia, costing the Australian community nearly $2 billion each year. The causes for schizophrenia are still unclear. There is now agreement that nature (genetic factors) and nurture (environmental influences) play a role in the development of the disorder. Evidence for genetic factors has been obtained and consistently confirmed by family-, twin-, and adoption studies. After many years of research, evidence for several genes, conferring susceptibility to schizophrenia, has been obtained by gene finding approaches applied to large family samples with multiple affected members. However, these genes have to be considered as candidates until more is known about their impact on brain function resulting in schizophrenic disorders. We have dissected a gene locus on chromosome 10p detected by linkage analysis by several groups including ourselves. We obtained statistical evidence for association of DNA sequence variants in the gene encoding the enzyme phosphatidyl-4-phosphate 5-kinase with schizophrenia. This enzyme is a critical component of the phosphoinositide pathways, which are involved in cell signalling. Our aim is to identify a possible dysfunction in the pathways. We will search for mutations involved in function or dysfunction of the enzyme. We will investigate gene- and protein expression and enzyme function in lymphoblast cell cultures and in post mortem brain tissue. Our ultimate goal is to characterise the possible impairment of intracellular cell signalling and thus identify molecular targets for development of novel and specific pharmacological treatments that have the potential to replace the currently available medication which is symptom-oriented and usually accompanied by severe adverse effects.Read moreRead less
Chronic or extreme reactions to stress can lead to pathological conditions such as long term anxiety states, depression and panic disorders. Stress related disease also contributes to other major health problems such as heart disease and disorders of the immune system. These disease states include some of the major medical problems of our times. This proposal is to define genes which may be involved in stress responsiveness, to further understand and treat stress related disease.
Heroin Dependence In WA: Identification Of Candidate Genes Involved In Susceptibility And Treatment Outcome
Funder
National Health and Medical Research Council
Funding Amount
$560,797.00
Summary
We will address identification of genetic factors which are important for the development of heroin addiction. In addition, we will correlate variation in genes involved in metabolism of heroin as well as the drugs used to treat heroin addiction with treatment outcome. Once these genetic factors are identified it will allow earlier intervention for treatment. In addition, it will allow identifying which treatment option might be most successful for the single individual.
The Role Of Proteases In Deafness; Generation Of A Knockout Mouse For Tmprss3 As A Model Of Autosomal Recessive Deafness
Funder
National Health and Medical Research Council
Funding Amount
$70,880.00
Summary
Age-related hearing loss is the most common type of human hearing impairment, affecting approximately half the population by the age of 80. The interaction of predisposing genetic factors with environmental factors is responsible for most age-related hearing loss. Genes underlying genetically inherited hearing impairment also affect susceptibility to age-related hearing loss. Approximately 1-1000 children are born deaf and ~50% of these cases have a genetic cause. Autosomal recessively-inherited ....Age-related hearing loss is the most common type of human hearing impairment, affecting approximately half the population by the age of 80. The interaction of predisposing genetic factors with environmental factors is responsible for most age-related hearing loss. Genes underlying genetically inherited hearing impairment also affect susceptibility to age-related hearing loss. Approximately 1-1000 children are born deaf and ~50% of these cases have a genetic cause. Autosomal recessively-inherited defects are responsible for most cases of genetic deafness (70%) and patients have no other medical problems, indicating that only the inner ear is affected. Genes previously identified for genetic forms of deafness can be broadly classified as either ion channels (e.g. connexins) or structural proteins (e.g. myosins and collagens). We recently identified a novel gene, a transmembrane serine protease, TMPRSS3, which is mutated both in familial and sporadic cases of deafness. Different classes of mutations may cause either deafness from birth or childhood onset deafness. Thus, reduced expression or abnormal function of TMPRSS3 may be involved in age-related hearing loss. This discovery was the first description of a protease involved in hearing loss and the first gene family involved in congenital deafness for which a ready hypothesis for involvement in age-related hearing loss can be made. We will generate and characterize a mouse model to investigate the role of TMPRSS3 in inner ear function and development. We will also isolate and characterize additional members of the transmembrane protease gene family to investigate further the role of proteases in both genetic and age-related hearing loss. This may lead to a greater understanding of the function of the auditory system and, eventually, to new therapeutic protocols.Read moreRead less