Please could you give us a brief introduction to schizophrenia?
Schizophrenia is the most disabling disease impacting youth today. It impacts 1% of the total population and typically causes withdrawal from society, loss in IQ, disordered thought and speech, hallucinations and delusions.
Current treatments are based on a single chance discovery made 60 years ago, do not restore people to normal function, and can cause serious side effects including obesity and diabetes.
What was previously known about the causes of schizophrenia?
We know that schizophrenia has both genetic and environmental risk factors. After the chance discovery that a chemical compound could reduce anxiety and quiet hallucinations of people with schizophrenia, it was discovered that this chemical blocked a particular brain receptor, the dopamine receptor.
This observation lead to the theory that schizophrenia could be caused by an excess of dopamine in the brain, a theory that has received some strong support. However, it also raised the question: why would there be too much dopamine in the first place?
More modern theories suggest that the cerebral cortex, that normally controls the dopamine neurons, is weak and that the disease really begins in the cortex.
In the past, neuropathologists looking at the cortex thought that there was no evidence of weakness or cell damage anywhere in the brain.
One of the most exciting discoveries of modern neuropathology is that there are in fact cells that are damaged, but they are small inhibitory neurons in the cortex and may have been missed by earlier investigators. The fact that cortical inhibitory neurons are damaged is the most agreed-upon finding in the field today.
How did your research originate?
We were drilling down and examining molecules made by cells to search for even more specific neuropathology, trying to uncover the possible causes of the demise of inhibitory neurons.
We wanted to use the most current technology to examine thousands of molecules at once with extreme sensitivity to see what the brains themselves could tell us about how the molecular environment of the cortex may be different in schizophrenia compared to controls.
We coupled this discovery-driven approach with a hypothesis driven approach. We re-examined an old theory that there was no gliosis in the brains of people with schizophrenia (as would be predicted if there was cell death and neuronal damage). We used modern staining approaches and the largest number of samples ever studied and hypothesized that if we looked in the right way we would in fact detect gliosis.
What did your research find?
First, that there was indeed evidence of gliosis in the cortex. In fact, it was the small glia, the microglia, that were elevated in the brains of people with schizophrenia. These glial cells are the resident immune cells of the brain and an increase suggests that they are reacting to neuronal damage.
Second, we found several types of molecules typically produced by immune cells, known as cytokines, to be greatly increased in the cortex of people with schizophrenia.
Both these lines of evidence suggest that there is an active process of cortical damage occurring in the brains of people who suffer from schizophrenia. We found a large proportion, around 40%, of the people with schizophrenia fell into this high inflammation group.
What implications does your research have for the treatment of schizophrenia?
Among the many implications, one is that schizophrenia does indeed have a biological basis. Our findings mean that increases in cytokines reported in the blood of people with schizophrenia may be linked to increased cytokines and immune activation in the brain.
We may now be able to develop a blood based biomarker to identify those with neuroinflammation as part of the pathophysiology of this disease. Importantly, treatments being developed to treat neuroinflammation may provide novel therapies for people with schizophrenia.
Since the response to neuroimmune therapies can be dramatic, we may see restoration of function and some people “cured”.
How do you think new treatments for schizophrenia will compare to immune suppressants that are already available for different conditions – for example those used as anti-rejection drugs in post-transplant patients?
I am not sure that global immune suppressants are going to be a way for treating schizophrenia. We need to learn more about the process that is going on in the brain and how to best define which aspect of a very complicated immune system has gone wrong.
It is also likely that there will be different reasons for neuroimmune dysregualtion in different people with schizophrenia and we should be thinking about developing ways to distinguish these and to target treatment.
So, I would suggest user a laser guided, instead of a sledge-hammer, approach. Also, we as people interested in treating those suffering from schizophrenia, have a lot to learn from other scientists and doctors who have already been treating neuroimmune disorders, such as neurologists and immunologists; but at least we are starting to have the conversations across the traditional divides of medicine.
What plans do you have for further research into this field?
I plan to start a clinical trial aimed at the immune system. What I will do differently than ones that have gone before, is to first select the participants to enter the trial based on a positive immune profile in the blood and to use a more targeted approach.
How do you think the future of schizophrenia treatment will develop?
We will move towards a more personalized, preventative approach to treating people with psychiatric problems.
As our biological understanding grows, we will be able to reposition more drugs to trial in schizophrenia. We will develop biomarkers to help tailor treatments and eventually we will be able to develop, not one, but many cures.
What do you think about the current DSM IV definition of schizophrenia? Do you think that the classic subtypes of schizophrenia should be removed from the DSM V definition?
I think we should use biological information to classify the subtypes of schizophrenia as that will be most informative to understanding what is going on in each case and to get the right medicine for the right person.
Would you like to make any further comments?
While I am grateful for the support of Neuroscience Research Australia (NeuRA), the Macquarie Group Foundation, Schizophrenia Research Institute, University of New South Wales, New South Wales Health, and the National Health and Medical Research Council for supporting my research, more funds are desperately needed if we are to quickly advance these new and exciting discoveries into new treatments.
Using modern tools, building on recent advances in our biological understanding of schizophrenia, and with visionary leadership in place, I believe cures to this devastating disorder are possible in our lifetime. Now is the time to make a serious investment.
Where can readers find more information?
News story on NeuRA website: https://neura.edu.au/
NeuRA blog article on the study: http://blog.neura.edu.au/2012/08/07/schizophrenia-and-the-immune-system-an-inflammatory-topic/
Cyndi’s research group at NeuRA: https://neura.edu.au/researchers/prof-cyndi-shannon-weickert
Schizophrenia Research Institute
About Prof Cyndi Shannon Weickert
Prof Cyndi Shannon Weickert is the Macquarie Group Foundation Chair of Schizophrenia Research, a joint venture of Neuroscience Research Australia, University of New South Wales, Schizophrenia Research Institute and Macquarie Group Foundation, and supported by New South Wales.
Cyndi's research is focused on the molecular developmental neurobiology of schizophrenia. She earned a PhD in Biomedical Science at Mount Sinai School of Medicine, New York City and completed postdoctoral training at the National Institute of Mental Health rising to the level of Unit Chief of Molecules in the Neurobiology and Development of Schizophrenia Unit.
She currently holds the Macquare Group Foundation Chair of Schizophrenia Research. Her awards include the Eli Lilly Young Investigator Award, NIH Fellows Award for Research Excellence, Independent Investigator Award and two Young Investigator Awards from NARSAD and an NH&MRC Senior Research Fellowship. She has lectured throughout the world and contributed to over 110 primary research publications.
New insights into the genetics of schizophrenia