Home > Benefactors
Benefactors
The Mental Health Research Institute of Victoria
The vision of the Mental Health Research Institute (MHRI) is to lead cutting edge research focused upon improving the diagnosis, treatment and prevention of major mental disorders.
Based in Melbourne , Australia , MHRI concentrates its efforts towards understanding:
One In Five Research Project
One In Five Research Project
Update by research director, Suresh Sundram
May 2010
Psychiatric disorders are the major cause of health morbidity in Australia despite treatment being available. This is in part due to the treatments being only partially effective; variably tolerated; and only addressing symptoms rather than the causes of the disorders. They do, nevertheless, work in a proportion of people and this provides a valuable clue as to the nature of these disorders. By understanding the brain mechanisms by which medicines used to treat psychiatric disorders work it may be possible to identify both the causes of the disorders and better ways of treating them.
Using this principle we investigated how the medicines used to treat psychotic disorders may work in the brain. Psychotic disorders are a set of serious psychiatric illnesses including schizophrenia, bipolar disorder and the most severe type of major depression. The class of treatments are known as antipsychotic drugs (APD) and have been in use for about 60 years. They are all roughly equal and effective for some symptoms in about 60% of cases. For the remaining patients and those with only a partial response there is only one option – clozapine. Clozapine is also an APD but is unique in that it is effective in cases where other APD are ineffective but it is also highly toxic meaning that it is reserved as a treatment of last resort. We have been trying to work out how clozapine is able to do this in order to gain insights into the neurobiology of psychotic disorders and new, more effective and less toxic ways of treating them.
We focussed on a pathway called the MAPK/ERK cascade that in neurons (brain cells) is central to brain development and neuronal communication in adults, processes thought to be involved in psychotic disorders. We demonstrated that clozapine did, unlike other APD, activate the ERK cascade in neurons and also in brains from animals treated with it. We then showed that it was not through the normal mechanisms that APD are thought to act. Finally and most importantly we established that the effect of clozapine on the ERK cascade required another brain signalling system, the EGF (epidermal growth factor) system. Ours was the first demonstration that APD might recruit alternative signalling pathways and was significant enough for us to receive funding in 2010 from the National Health and Medical Research Council (NHMRC) to further explore this interaction.
We subsequently have identified key downstream targets of the ERK activation involved in gene regulation and are currently attempting to elucidate the mechanism (transactivation) by which clozapine is able to recruit the EGF system and in particular the EGF receptor. This would be a critical step forward. Our work has three major streams forward: characterising the transactivation process and signalling pathways in neurons initiated by the clozapine-EGF interaction; determining the role of the EGF system in the pathology of psychotic disorders; and exploring if markers of the EGF system can be used to develop blood tests to predict which patients will and won’t respond to clozapine. The results of these studies could potentially transform our understanding of psychotic disorders and open the way for entirely new ways of treating these devastating illnesses.
This research is led by Associate Professor Sundram who is Head of the Institute’s Molecular Psychopharmacology research program, Clinical Director at the Northern Area Mental Health Service and a Fellow of the World Congress of Biological Psychiatry.
