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New findings in schizophrenia -

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Norman Swan: Some of these antibodies targeted at recently discovered genes may find a use in people with schizophrenia if findings from an Australian research group are proven right. Schizophrenia has always been a mystery but it's becoming less so as research ramps up.

For many years there's been a suspicion, for example, that the immune system is involved in some way. For example, people with schizophrenia are more likely to be born to mothers who conceived during the winter months, suggesting a maternal infection might play a role.

People with schizophrenia also sometimes show signs of an overactive immune system in their blood, and there have been hints of that in the brain. But this work from the Schizophrenia Research Institute is the first time that they've seen clear footprints of immune messengers at work in the brains of people with schizophrenia compared to the brains of people without it.

Professor Cyndi Shannon Weickert was the lead researcher.

Cyndi Shannon Weickert: What we found is evidence of cell demise, and that was indicated by gliosis. Microglia density increases and...

Norman Swan: So these are the supporting cells of nerve cells, but they are also thought to have an immune function in the brain.

Cyndi Shannon Weickert: Yes, that's correct.

Norman Swan: Using advanced gene sequencing techniques, the team at the Schizophrenia Research Institute were the first in the world to discover the immune messages being transmitted in the brains of people with schizophrenia. And what was happening at the centre of the resulting inflammation was that certain key nerve cells appeared to be dying.

Cyndi Shannon Weickert: What we were able to show is that this relates to reduction in inhibitory interneurons. So these are...

Norman Swan: So what does that mean in ordinary language?

Cyndi Shannon Weickert: Okay, well, there are two kinds of neurons…

Norman Swan: Neurons are nerve cells.

Cyndi Shannon Weickert: Yes, nerve cells, sorry. There are two kinds of neurons or nerve cells, cells within the brain that control the activity of the cortex that control things like our language, our thinking, our sociability. And there are excitatory cells and then inhibitory cells. So 'go' cells and 'stop' cells. And what happens in people with schizophrenia is those stop cells are diminished. So the go cells, if you will, are over-firing, they are overactive.

Norman Swan: Which gives the delusional behaviour and that sort of thing.

Cyndi Shannon Weickert: That's one theory about what the substrate of delusions and hallucinations is, and perhaps the feeling that patients have that they are bombarded by sensory stimulation, that they can't really get a handle on reality.

Norman Swan: Cindy Shannon Weickert.

The unanswered question is what comes first; an immune system which damages these nerve cells, or something else makes the cells die and the immune system overreacts?

It's a big debate at the moment because in autism, for example, researchers are saying that the primary problem may in fact be the immune system. And as we've covered in the past on the Health Report, a proportion of people diagnosed with schizophrenia may actually have antibodies to a receptor (a lock and key mechanism in the brain) caused by a tumour in the body, a potentially curable condition made tragic because it's often missed.

But back to other factors, like maternal infections.

Cyndi Shannon Weickert: Well, there's this idea that there would be perhaps immune priming that may be causative in schizophrenia. Certainly it increases the risk.

Norman Swan: So does your research come anywhere closer to cause and effect, as to which way around it is, the immune system mopping up the cells that have already died, or the immune system being activated first by something like an infection activating the immune system to cause the death?

Cyndi Shannon Weickert: Well, forgive me Dr Swan, but I don't think that's the right question. I actually think the right question is could this help us treat patients with schizophrenia, regardless of whether it's cause or effect? Is it an important part of the pathophysiology? Is it a step in the cascade where we could intervene and potentially reverse some of the symptoms? I think that's a more important question, because I think that the field gets all caught up in what's causative, and we've searched for genes and we've searched for environments and we've spent billions and billions of dollars trying to search for the cause when we know there's a variety of causes. Has it really lead to new treatments?

Norman Swan: So what might be the treatment here?

Cyndi Shannon Weickert: I think the things that are being trialled are a sledgehammer approach, they are trying to actually dampen the whole immune response. And I think if we do more targeted therapy, changing particular molecules within the immune activation...and now what we're talking about is identifying those people ahead of time that have immune activation, not necessarily in the brain but those individuals that have immune activation in the blood, and trialling therapies that have been developed by immunologists to target particularly pro-inflammatory cytokines individually and see if those bring about therapeutic benefit. Drugs that have been developed for treating autoimmune disorders or things like arthritis or...

Norman Swan: So these are the new antibodies to target chemical messengers that cause inflammation.

Cyndi Shannon Weickert: Precisely.

Norman Swan: Are there any trials of these going on?

Cyndi Shannon Weickert: We actually have a proposal in to do a clinical trial looking at that very thing where we are targeting a particular molecule in the immune system that is overactive in people with schizophrenia.

Norman Swan: And is there any anecdotal information (there have been plenty of trials now of these drugs in, say, rheumatoid arthritis and other autoimmune conditions) that people who have got a psychosis get better?

Cyndi Shannon Weickert: I think that it could be the other way around sometimes, that people who have different kinds of immune therapy can present with psychiatric symptoms. So it's really important that we get the balance of the immune system correct.

Norman Swan: Ah, so if it goes the wrong way you could actually make things worse in the brain.

Cyndi Shannon Weickert: Exactly. It's very early days and that's why we would proceed with a very small-scale proof of principle clinical trial initially, giving the brain a chance to repair itself perhaps. And the other kind of anecdotal information is that some of the antipsychotics may actually work by dampening down the immune system. We've known for a long time that clozapine, one of the side-effects actually is agranulocytosis, and typically we worry about that being a negative side-effect, but it may very well be that antipsychotics could bring about some of their therapeutic benefit by working through changing factors in the immune system and the immune response.

Norman Swan: Professor Cyndi Shannon Weickert from the Schizophrenia Research Institute.