Understanding The Role Of Muscarinic Receptors In The Pathophysiology Of Depression And Bipolar Disorder
Funder
National Health and Medical Research Council
Funding Amount
$480,074.00
Summary
The causes of bipolar disorder and major depressive disorder, which effect many Australians, remain unknown. We have recently shown decreases in muscarinic receptors in the brain of people with bipolar disorder and major depressive disorder. Muscarinic receptors are important in maintaining the functions of the brain that seem to be affected in people with bipolar disorder and major depressive disorder. Here we seek to understand how changes in muscarinic receptors occur in both disorders.
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
New research with scanning techniques has confirmed older ideas about the complementary functions of the two hemispheres of the human brain. One major contrast between the two hemispheres concerns their cognitive and emotional styles. The left hemisphere plans and confidently smooths over discrepancies that do not fit the plan while the right hemisphere looks at all possibilities and cautiously highlights the discrepancies. This research project studies the switch between the two hemispheres tha ....New research with scanning techniques has confirmed older ideas about the complementary functions of the two hemispheres of the human brain. One major contrast between the two hemispheres concerns their cognitive and emotional styles. The left hemisphere plans and confidently smooths over discrepancies that do not fit the plan while the right hemisphere looks at all possibilities and cautiously highlights the discrepancies. This research project studies the switch between the two hemispheres that alternately activates these contrasting, but equally valid, viewpoints. The switch is studied directly by optical recording from animal brains. The switch can also be studied in humans using a recent discovery from our laboratory:- that the perceptual rivalries are mediated by a hemispheric switch mechanism. Perceptual rivalry is a phenomenon where continuous, but ambiguous, stimulation leads to a back-and-forth alternation of complementary percepts, a phenomenon that fascinated Salvador Dali and is featured in many of his paintings. The nature of the perceptual switch during rivalry has been debated for centuries. New experiments link perceptual rivalry to the switch of attention between the hemispheres. Using perceptual rivalry as an indirect way to monitor hemispheric switching in humans, we discovered a remarkable feature. The back-and-forth switching process of perceptual rivalry is significantly slower in subjects with bipolar disorder (manic depression), even when they are between episodes and their mood is normal. The timing of the switching process is very stable in an individual, and appears to be similar in identical twins. The speed of the switch mechanism may therefore be inherited. Altered neural rhythms may underly the predisposition, known to run in familes, from which bipolar disorder can be triggered. The aim of the project is to test these propositions about the basis of this common disorder, affecting 1-2% of the population..Read moreRead less
Cloning And Characterisation Of A Bipolar Disorder Susceptibility Gene On Chromosome 15q
Funder
National Health and Medical Research Council
Funding Amount
$347,621.00
Summary
Bipolar disorder is a severe mood disorder, characterised by aberrant mood swings resulting in periods of mania and depression. We need to define more clearly the biological basis of bipolar disorder to improve diagnosis and treatment. Bipolar disorder is highly heritabile allowing the use of genetics to identify the predisposing genes. Our aim is to identify a bipolar susceptibility gene on chromosome 15 and to understand how this gene contributes to the risk of developing bipolar disorder.
Trajectories Between Childhood Internalising Behaviour Problems And Adolescent Depressive Symptoms
Funder
National Health and Medical Research Council
Funding Amount
$55,000.00
Summary
Depressive symptoms are known to escalate sharply through the adolescent years. Adolescents who experience an episode of depression are very likely to experience further mental illness as adults. Efforts to prevent depressive illness may be advanced by research delineating the factors and processes implicated in the early emergence of depressive symptoms. To advance such an understanding this project will analyse data collected, in part, through NHMRC support to Australian Temperament Project (A ....Depressive symptoms are known to escalate sharply through the adolescent years. Adolescents who experience an episode of depression are very likely to experience further mental illness as adults. Efforts to prevent depressive illness may be advanced by research delineating the factors and processes implicated in the early emergence of depressive symptoms. To advance such an understanding this project will analyse data collected, in part, through NHMRC support to Australian Temperament Project (ATP) researchers. The ATP data will be used to examine factors associated with the development and progression of depressive symptoms from childhood to adolescence. The ATP data set includes detailed longitudinal data collected from multiple sources (parents, teachers and youth) concerning child and adolescent temperament, behavioural problems, mother-child relations, health, depressive symptoms, school achievement, school adjustment, social skills, peer relationships, parenting practices, stressful life events, and sociodemographic factors. Of an original sample of 2443 enrolled in the cohort in 1983 (aged 4-8 months) a subsample of 1,350 adolescents should complete the data collection due in 2000 (age 17-18). Through the analysis of ATP data proposed in this application, models will be developed to explain the risk and resiliency processes in childhood and early adolescence influencing the development and course of adolescent depression, for different subgroups of adolescents. To achieve this objective, analyses will: 1. identify groups who have differing trajectories from childhood internalising behaviour problems to adolescent depressive symptoms; 2. compare groups to identify factors that contribute to the progression from internalising behaviour problems to depressive symptoms, while also identifying factors which appear to impede such progression and; 3. compare groups to identify factors associated with transient versus persistent depressive symptoms in adolescence.Read moreRead less
A Double-blind Sham Controlled Trial Of RTMS In Treatment Resistant Major Depression
Funder
National Health and Medical Research Council
Funding Amount
$371,491.00
Summary
Treatment Resistant Depression is clearly a major health issue - depression is common, results in marked morbidity and mortality and a large percentage of patients do not respond to, or cannot tolerate standard treatment. The development of new treatments for this condition is undoubtedly required. International efforts are underway to try and establish the efficacy of high frequency left Transcranial Magnetic Stimulation (HFL-TMS) to the point where the technique may be approved by regulatory a ....Treatment Resistant Depression is clearly a major health issue - depression is common, results in marked morbidity and mortality and a large percentage of patients do not respond to, or cannot tolerate standard treatment. The development of new treatments for this condition is undoubtedly required. International efforts are underway to try and establish the efficacy of high frequency left Transcranial Magnetic Stimulation (HFL-TMS) to the point where the technique may be approved by regulatory authorities and clinically introduced. However, clearly the response rate to HFL-TMS is suboptimal for its widespread use. The overall goal of this research program is to develop repetitive TMS (rTMS) methods to the point at which they are highly relevant and applicable to clinical practice. None of the substantial international studies is focusing on novel applications such as sequential bilateral rTMS (SBrTMS). The planned outcome of this study is that it may change the focus of rTMS application and practice nationally and internationally. If we can follow our well received initial study of this technique with a substantial comparative trial as planned here, it will provide enough evidence for the more widespread adoption and testing of SBrTMS as a viable alternative to HFL-TMS. Ultimately, this or a modification of it, may become the rTMS administration method of choice. Additionally, we will have a sufficient sample size to start to explore meaningful predictors of clinical response including biological, psychosocial-personality variable predictors.Read moreRead less
THE EFFECTS OF TRANSCRANIAL MAGNETIC STIMULATION (TMS) ON RAT MODELS OF DEPRESSION
Funder
National Health and Medical Research Council
Funding Amount
$204,274.00
Summary
Repetitive Transcranial Magnetic Stimulation (rTMS) is the direct stimulation of the brain by using high field magnetic pulses. It is a new technique that has been demonstrated to have some potential as a treatment of depressive illness and possibly other neuropsychiatric disorders. At this early stage of its investigation, the parameters of stimulation that are most likely to be therapeutic, and its mechanisms of action, are not known. Published studies vary in the frequency, duration and exten ....Repetitive Transcranial Magnetic Stimulation (rTMS) is the direct stimulation of the brain by using high field magnetic pulses. It is a new technique that has been demonstrated to have some potential as a treatment of depressive illness and possibly other neuropsychiatric disorders. At this early stage of its investigation, the parameters of stimulation that are most likely to be therapeutic, and its mechanisms of action, are not known. Published studies vary in the frequency, duration and extent of stimulation, with no firm guidelines about optimal parameters. Empirical study of the relative effects of stimulation at different frequencies, at different numbers of stimuli and for different durations is therefore important for the future development of this treatment. Such an investigation is best carried out in an animal model of depression for both ethical and practical reasons, as such studies in patients would possibly take many years and be extremely difficult to conduct. We propose such a study in rat models of depression which have demonstrated validity and utility in drug research. Rat models have a long track record in developing psychiatric treatments and are cost-effective and of proven value. We also plan to investigate the neuroanatomy of the immediate-early genes induced by TMS and compare it with electroconvulsive shock (ECS) and a tricyclic antidepressant, two established treatments of depression. The results will have implications for future human studies in guiding us toward the optimal parameters for therapeutic effects. They will also enhance our understanding of the mechanism of action of TMS in depression.Read moreRead less
A Double-blind Controlled Trial Of RTMS In The Treatment Of Bipolar Depression
Funder
National Health and Medical Research Council
Funding Amount
$401,605.00
Summary
Bipolar affective disorder (BPAD) is a serious mental illness of substantive impact but there has been relatively sparse investigation of treatments for it. One of the only substantially new treatments developed for depression in recent years has been rTMS. Repetitive TMS has been evaluated in over 30 trials conducted, but no substantive trials have explored its use in bipolar depression. We propose to do this, conducting a large scale clinical trial.