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Estrogen Link in Mental Illness

Researchers are homing in on the molecular causes of schizophrenia.

From The Australian | Leigh Dayton | 2 August 2008

When she was a teenager, Cyndi Shannon Weickert's twin brother showed the first signs of schizophrenia.

"It was very frightening to observe," she recalls. No doubt. Yet like the budding young scientist she was, Shannon Weickert watched carefully as her brother's devastating mental illness progressed.

She saw first-hand many of the distressing symptoms of schizophrenia, from delusions and hallucinations to depression, social withdrawal and a loss of motivation, drive and initiative. Today, she is a neurobiologist, dedicated to unravelling the complex causes of his disease. "I saw it unfold and that helped me understand it," she says.

Little wonder then that Shannon Weickert now heads a schizophrenia research project, jointly initiated by the Prince of Wales Medical Research Institute, the University of NSW and the Schizophrenia Research Institute. The SRI is a "virtual" collaboration of Australian biomedical researchers.

The ambition is to untangle many of the baffling genetic and biochemical threads driving the developmental brain disorder. While there are many scientific tacks to take, Shannon Weickert's search is shaped by her expertise in brain development.

"I think of mechanisms that change with adolescence," she explains. What changes? Hormones, of course, such as the so-called female hormone estrogen. That "of course" moment led Shannon Weickert and colleagues to look for genes implicated in estrogen's business in the brain.

They hit paydirt. They discovered that mutations in a gene called the estrogen receptor alpha gene (ESR1) are linked to schizophrenia (Human Molecular Genetics 2008 17(15):2293-2309).

Now her group is looking for 80 volunteers, men and women, with schizophrenia willing to trial a drug used to regulate estrogen in the brain, along with their own medication. The trial drug was designed to treat osteoporosis and cancer, but Shannon Weickert suspects it will help modify the "negative" symptoms of schizophrenia -- the antisocial, loss of get-up-and-go emotional states.

"We hope people will be more comfortable socially, be a little better motivated and have their thinking become clearer," she explains.

Shannon Wieckert's research illustrates how various branches of science are converging on causes of and cures for schizophrenia. This week, for instance, the journal Nature published reports from three enormous international consortia -- two with Australian participants -- that had scanned the genes of people with and without the illness, looking for more clues to its genetic underpinning.

As evolutionary biologist Simon Easteal notes, there are no immediate clinical implications of the findings. "But these papers appear to provide some evidence for possible clinical subtypes of schizophrenia and the lack of clear demarcation from (the intense mood swings of) bipolar disorder," concludes Easteal, deputy director of the John Curtin School of Medical Research at Canberra's Australian National University.

In other words, the ability to trawl through vast swathes of the human genome has allowed researchers to confirm that there's no single gene driving schizophrenia. Instead, it's a jumble of genetic glitches that ultimately come together to produce the terrible symptoms. Just how, why and where those glitches merge remains the unsolved mystery.

Enter scientists such as molecular biologist Murray Cairns, with Newcastle University in NSW and the SRI. He's exploring the role tiny snippets of genetic material called micro ribonucleic acids (miRNAs) play in turning genes on or off. Because miRNAs themselves are influenced by non-genetic pressures, from diet to stress, they are a link between nature and nurture. They must be central to those troublesome paths to schizophrenia.

"I thought it could have something to do with how the genes (for schizophrenia) are regulated, rather than a series of genetic mutations," he says of his recent discovery that miRNAs do indeed "disregulate" gene activity in the brains of people with schizophrenia. It's a finding Cairns claims points to new "targets" for drug development.

University of Melbourne psychiatrist Michael Berk agrees that genetic work promises to help reveal which biochemical events are "upstream" and "downstream" in the biochemical pathway to schizophrenia.

Meanwhile, Berk -- also with Barwon Health, The Geelong Clinic and the Orygen Research Centre -- is exploring trails to near-term treatments. One exploits fundamental research about the damage so-called free radicals cause to body cells and DNA. Along with US and Swiss colleagues, Berk tried out the idea that battling free radicals by boosting levels of a powerful antioxidant called glutathione might, like estrogen, reduce the "negative" symptoms of schizophrenia.

It does. A trial, with 83 people, reported last May in the journal Biological Psychiatry, showed that that a dietary supplement -- N-acetyl cysteine (NAC) -- taken by muscle-bound bodybuilders and partygoers to cure a hangover did, indeed, boost glutathione and reduce symptoms. "We know we're on to something," says Berk, who is beginning trials of NAC with people with bipolar disorder.

And proving that Shannon Weickert doesn't have a monopoly on a good idea, Berk's also involved in a three-centre trial in Victoria that uses estrogen to treat men and women. Instead of inspiration from developmental biology, though, this work's based on insights for epidemiological, clinical and animal studies.

"The evidence is very clear that estrogen in the brain has a very powerful antipsychotic effect," says team leader Jayashri Kulkarni, a psychiatrist with Monash University and The Alfred Psychiatry Research Centre.

Along with Victorian colleagues, Kulkarni reported seven years ago that estrogen helped female patients (Schizophrenia Research 2001;48:137-144). New

confirmatory results will be published soon in the Archives of General Psychiatry.

"It has a direct impact on dopamine and serotonin systems," she says, pointing to two well-known paths to the hallucinations and delusions of schizophrenia -- disruption of those neurotransmitters in the brain.

In fact, those pathways work alongside one involving another neurotransmitter, acetylcholine, which is the target of chlorpromazine. Developed in 1950, it was the first drug developed for schizophrenia. As clinicians such as Berk and Kulkarni note, chlorpromazine and daughter drugs manage the psychotic symptoms of schizophrenia, hence the push for ways to help with negative symptoms.

Shannon Weickert couldn't agree more: "That's our real goal. Novel treatments to help these patients today." Patients such as her brother.

Any patients with schizophrenia aged between 18 and 40 years and on a stable medication program who may be interested in participating in the hormonal modulator program should contact Kristy Dunlop at 02 9399 1142, email: k.dunlop@unsw.edu.au for more information.

Click her for an interview with Prof. Cyndi Shannon Weickert from SKY News on 3 August 2008.

August 2008