1194th General Meeting

“Schizophrenia: from neuropathology to new treatments”

Professor Cyndi Shannon Weickert, Macquarie Group Foundation Chair of Schizophrenia Research, Neuroscience Research Australia and UNSW, and Professor, School of Psychiatry, UNSW

Wednesday 3 August 2011 at 6.30 pm

Seminar Room 102, New Law Building, University of Sydney

Is schizophrenia caused by genes or environment? This question was posed by Professor Cyndi Shannon Weickert at the 1194th ordinary general meeting of the Society. 

Schizophrenia was first formally classified in 1887. Despite extensive pathological investigation there was no clear distinction identified between the brains of people who have schizophrenia and those who do not. Until 1930s it was considered to be primarily a behavioural disorder put down to bad mothering. But in the 1930s treatments involving insulin and shock therapy were shown to be somewhat effective. There was a breakthrough in 1952 when D2R blockers were introduced and found to be effective against some of the symptoms. However, it was not until 1988 that the first definite genetic link was established by progress was swift and in the last decade it has been shown that there may be several hundred genes involved in the disorder. Because of the large number of genes that are implicated, identifying treatments that target these genes is extraordinarily complex. Most researchers in the field now believe that the disease has both environmental and genetic origins. 

The approach taken by Professor Shannon Weickert’s group is to attempt to identify the pathology of various genetic pathways to the disease, in particular identifying molecules that can be new drug targets. Once these have been postulated, the aim is to use existing drugs which are either known to or believed to affect those targets and then to test their effect in clinical trials. This approach has the advantage of using drugs that have already been approved for use in humans thereby avoiding the necessity for time- consuming and expensive early-stage clinical trials that establish general parameters such as toxicity and dosage levels. 

One notable aspect of schizophrenia is that it is virtually never found in children prior to adolescence. Most cases of schizophrenia are diagnosed from mid-teens to the early 20s but, interestingly, there is a second peak among women at menopause. This suggests that sex hormones could be an important part of the mechanism causing the disorder. Oestrogen receptors are found in the human cortex and act as “transcription factors”, that is, they transport proteins across the cell membrane into the nucleus of the neuron. On investigating oestrogen receptor proteins a mutation specific to schizophrenia has been found in a transcription factor protein called ESR1. This protein cannot bind to oestrogen and hence cannot pass hormonal signals into the nucleus of the cell. Hence, the cell cannot activate important genes that produce their normal proteins and this may cause some of the symptoms of schizophrenia.

 An existing drug, raloxifene, has already been approved as a selective oestrogen receptor modulator for treating various disorders in postmenopausal women. Raloxifene has been found to stimulate the oestrogen receptor and overcome the mutant effect in the ESR1 gene. However, the great variability of genes means that the drug effect on one specific mutation is likely to be masked, so there needs to careful design of clinical trials to make the effect apparent. One such trial is currently being conducted by Professor Shannon Weickert’s group and involves a double-blind trial in which patients and control groups are treated in two stages, with all trial participants receiving the drug in one or other of the stages. This clinical trial is still under way and is expected to be completed towards the end of this year. If successful it may be a major step in establishing personalised drug treatments for the 1% of the human population that currently suffers the debilitating effects of schizophrenia. [The May 2009 edition of the ABC’s Australian Story was on Professor Shannon Weickert’s work and is available at http://www.abc.net.au/austory/specials/allinyourmind/default.htm. Anyone interested in the clinical trial may be interested to read the transcript or to view it.]