Norman Swan: One of the reasons the Young and Well Cooperative Research Centre is involved in that survey is that most mental health problems begin when we're young, especially schizophrenia and psychotic illnesses.

Research here and overseas has been trying to find the earliest signs of issues which may indicate a person is at risk. That's been the project of Diana Perkins, who's Professor of Psychiatry at the University of North Carolina, Chapel Hill.

Diane Perkins: I've been interested in better ways of identifying people very early on in the course of developing schizophrenia, in fact even preventing schizophrenia in people who are at high risk. Part of the rationale is we know that the earlier we treat people, the better off they do. So that was sort of what drove our interest in studying people, not just when they first become psychotic but even before.

Norman Swan: So describe the people that you pick up early on.

Diane Perkins: So those are criteria that were actually pioneered by Pat McGorry in Australia, and modified slightly here in the US. But basically it is people who are having symptoms that sort of look like psychosis but aren’t severe enough. For example, a person who is having hallucinations, hearing voices that aren't there or seeing visions that aren't there, that's a full-blown psychotic symptom.

An attenuated psychosis symptom would be seeing things out of the corner of your eyes, seeing shadows, looking at, say, a tree and thinking you see a face in that tree. Most of us have had those kind of experiences. We're in the shower, we hear the phone ring or we think we hear the phone ring and then we realise it was our mind playing tricks on us. The difference here is that it is happening very frequently, several times a week, maybe several times a day. So that is the perceptual abnormalities. Or they maybe have disruption in their thought process. So, for example, starting to make connections between things…

Norman Swan: That are spurious.

Diane Perkins: Yes, spurious or based on irrelevant details, having disorganised thinking, so thoughts coming in their head that are totally irrelevant. Like a person will be sitting there watching TV and they'll just think, 'The sugar is in the cupboard.' Like, where did that come from? Or becoming suspicious, thinking people are talking about them or laughing at them, and they know that it's really not true, but it sort of seems like it could be happening.

Norman Swan: To what extent do these people come forward, because they are often going to be quite young, 15, 16 years old, and often male more than females because females have it later. How is this revealed, because they often keep it to themselves.

Diane Perkins: We screen clinics, so it turns out that a lot of adolescents and young adults who are experiencing these symptoms will also be having trouble at school or at work, having trouble with depression, and so they may be help-seeking for those kind of problems.

Norman Swan: But not necessarily admitting to the scary symptoms that you've just described.

Diane Perkins: Yes, or not being asked, they just may not be understanding that this is something that should be important because the clinicians are not asking about it. We also put ads in the bus, 'something not quite right', 'is your mind playing tricks on you' kind of thing.

Norman Swan: So how many of these young people have you collected over the years?

Diane Perkins: I'm part of a consortium of researchers in the US and Canada, and we've been working together for a decade now. And so in our most recent prospective study where we identified people and then now we've followed them, identified about 795 individuals that are having these high-risk symptoms. Some of them were lost to follow-up. In the end about 94 ended up developing psychosis.

Norman Swan: So in fact getting these symptoms, most people are going to do quite well.

Diane Perkins: Absolutely. If you look at the published literature, how many people will convert to psychosis over two years varies. In some studies it has been as high as 40%, in other studies it's been as low as 14%. So somewhere in that ballpark, but it's probably closer to the 14% to 25% rather than the higher end. So most people that are having these perceptual abnormalities, alterations in thought process, are not on their way to developing a psychotic illness.

I think about this, as a person is developing physically sometimes they get a little clumsy and one part of their body grows a little too fast or something like that, well maybe that's what's happening in the brain during this adolescence and early adulthood, that's a very dynamic process for brain maturation. So maybe it's just gets a little bit out of sync.

Norman Swan: And presumably you collect information about whether they've been smoking dope too much.

Diane Perkins: Absolutely, yes. That's pretty controversial. Most studies show that marijuana use increases vulnerability for schizophrenia. It's been harder for us to find that in our data.

Norman Swan: And just before we get onto some of the fascinating findings that you've made in this group, do you intervene with them at all or do you just watch them?

Diane Perkins: So it is part of the research study. We do not intervene, that's an observational study. But when patients come to see us for the research evaluation we will let them know about our outpatient treatment program and refer them there. In fact often people come to our outpatient treatment program for a clinical evaluation and then if we think they meet criteria we will refer them to the study.

In the clinical program, the kind of interventions we offer them are those where there is an evidence base, so psychotherapy with a cognitive behavioural stress resiliency sort of emphasis. There is some evidence that omega-three fatty ashes, fish oil, can be preventative. And so those are the sorts of things we do.

We do not give antipsychotics, and I have great concern about clinicians giving antipsychotics to patients where four out of five of them are not on their way to developing a psychotic illness, because we do not know the impact of antipsychotics on a healthy developing brain.

Norman Swan: And is that happening much?

Diane Perkins: It's happening a lot. It is not unusual for me to get a person coming in on an antipsychotic for these early warning signs and symptoms, and that's all. I can understand why clinicians would do that because it kind of looks like psychosis, but what they really need to be aware of is that most people are not on their way to get a psychosis. And in fact if you just look at general population studies of adolescents, there is a relatively high proportion where they at least have transiently their mind playing tricks on them. These symptoms alone do not warrant antipsychotic intervention.

Norman Swan: So you've been looking at them to see whether or not you can predict the kids who are going to go on to have a course that's more unfortunate, and you've been doing blood tests on them. Tell me what are the sort of things that you found, both behaviourally, psychosocially and physically that might predict this course isn't going to be so good.

Diane Perkins: There's a lot of people that are getting interventions that they don't need, so we would like to do better. It is also hard to do a clinical trial when only one out of five is going to actually convert. So that's why we were very interested in biomarkers that are going to increase our ability within this clinical group to get psychosis. I've been looking at blood biomarkers, and there's a literature now with schizophrenia that for some people who develop schizophrenia there may be an inflammatory process or a process that involves oxidative damage.

Norman Swan: Biological rusting.

Diane Perkins: Right. The way I explain it to patient is oxidants generally are not good, they are molecules that are highly reactive. They have an unpaired electron and no molecule likes having an unpaired electron. So this molecule seeks out another molecule that it can share that electron with, and they will do that with any protein or fat or DNA, nucleic acid, or RNA that they run into. And so that's how these free radicals damage our DNA or RNA, our cell membranes, our protein.

We produce free radicals all the time, our bodies have defence systems to neutralise them. And it may be that in schizophrenia these defence systems don't work so well, or it may be that there is some fault in how their mitochondria work or little organelles that are producing energy and also producing free radicals may be a little bit faulty. So whatever the cause, people with schizophrenia produce more free radicals, have more free radical damage. And it's like premature ageing. So that's one thing that we looked at, and in fact we did find that marker of oxidative damage in these young people meaningfully predicted psychosis risk.

Similarly, markers of inflammation, this is the kind of inflammation that you see with heart disease. Elevations in those was also part of the blood based biomarker that was predicting psychosis risk. And in the group that we tested this in, it was able to double our predictive capacity. So instead of it…

Norman Swan: So it's not everybody but it does increase the likelihood of an individual going on a poor course.

Diane Perkins: If the test is bad, you have a pretty high risk. But the thing is that schizophrenia, psychosis is a heterogeneous disease. There are many, many reasons, we don't know them all, we don't know any of them really.

Norman Swan: So you're just on one of the many pathways.

Diane Perkins: Yes. We think inflammation and oxidative damage is an important pathway. So that's sort of one that at least this blood based biomarker was able to identify. And we still need to replicate that and we are planning on replicating it.

Norman Swan: And in the other people who go on to develop schizophrenia, what are you finding in them?

Diane Perkins: We have found other biomarkers are predictive of risk. For example, I mentioned a little bit a few minutes ago about how the brain is developing during late adolescence and early adulthood. What's happening is that in the parts of the brain that are maturing, you're actually getting pruning of connections between the brain…

Norman Swan: This is the normal process of an adolescent growing up. The brain nerves edit themselves so that you get a much more refined function of the brain.

Diane Perkins: Absolutely. And what you'll see is that the brain shrinks and that's normal. What we found was an acceleration, a relatively dramatic acceleration of that process.

Norman Swan: It was over-edited.

Diane Perkins: Over-editing, right, and it is in that pre-frontal cortex, the front part of your brain…

Norman Swan: Which controls your behaviour and other things.

Diane Perkins: Yes, and some other regions, these were the areas that we were seeing shrinking more rapidly. And so that may end up being a biomarker. We've had biomarkers looking at the electroencephalogram, the EEG, we are seeing abnormalities in connectivity between…that's what we think that these EEG has measured. And so again, that was predicting who was going to go on to develop psychosis. We found elevations of salivary cortisol were also predictive of development of psychosis.

Norman Swan: And that relates to what is well known, which is that people with schizophrenia are incredibly sensitive to stress. You put them in a stressful situation, they can actually have a relapse.

Diane Perkins: Yes, and in fact the stress resiliency may be one of the common factors, is that there is impairments in stress resiliency which are leading to the person being basically overstressed with the elevations in the cortisol. For some people it leads to a pro-inflammatory state, a state of oxidative stress, and these may be the pathways that end up leading to the endpoint of psychosis.

Norman Swan: So two things arise, one is whether it leads to any treatments to interrupt the way, and we'll come back to that in a moment. The other is to cause, because work done in Australia, Scotland and elsewhere has suggested that one of the risk factors for a child developing schizophrenia is maternal infection during pregnancy. And the indications which you are alluding to are also that there's something funny going on immune wise in the brain, there's something wrong with the immune system in the brain with people with schizophrenia. Does it illuminate the cause of schizophrenia in some situations?

Diane Perkins: The only situation where we really think we have it nailed is something called NMDA receptor autoantibody syndrome. So this is something where a person may develop an autoimmune disease…

Norman Swan: It's incredibly rare, we've had that on the Health Report.

Diane Perkins: It's incredibly rare yes, incredibly rare…

Norman Swan: So you've got this this vestigial tissue in the ovary of a teratoma, which produces these abnormal hormones and you get this florid psychosis.

Diane Perkins: Yes, that's like one example where probably there have been people in the past who were misdiagnosed as schizophrenia and that's really what they had. But it's very rare. And so there may be other kinds of autoimmune types of illness, we just don't know the right antibodies to look for.

Norman Swan: And what about interventions? Does it tell you anything? Because antioxidants have been desperately disappointing wherever they've been tried, in heart disease and dementia and anywhere else, they basically don't work.

Diane Perkins: Yes, but they work in schizophrenia.

Norman Swan: Do they?

Diane Perkins: In the brain one of the most important intracellular antioxidants is glutathione. Glutathione is made up of three amino acids—glycine, glutamate and cysteine—and a way to increase your brain's glutathione is by eating more cysteine. You can't eat glutathione because you just digest it into the three amino acids, but cysteine is the rate limiting amino acid.

And so N-acetylcysteine or NAC, many people may be familiar with NAC as an antioxidant, is available over the counter, and in doses of 1,200 milligrams twice a day, there has now been three double-blind clinical trials that showed it improved symptoms in people with schizophrenia as an adjunctive treatment. I've been using it in my first episode treatment program and it has been I think kind of remarkable.

So we have an evidence base for N-acetylcysteine, and we have the theory behind it, that there's something going on with this oxidative damage. That may not be the mechanism by which N-acetylcysteine is working, maybe there's other possibilities, but I think it's pretty intriguing that yes, we have an antioxidant that actually can ameliorate residual schizophrenia symptoms.

But what you're alluding to is I think the really exciting place that medicine is going right now, and that is wouldn't it be great if we could target a person saying, yes, you have elevated markers of oxidative stress, this is the intervention that we should be doing, and if we lower these biomarkers you can go on to be less likely to develop psychosis. We were doing this in the first episode treatment program that I have, we are developing a psychotherapy that is actually aimed at improving stress resiliency, and we think the mechanism is going to be through some of these biomarkers, that's what we going to be testing as well, not just does it work but who it works on.

Norman Swan: Diana Perkins, who's Professor of Psychiatry at the University of North Carolina, Chapel Hill.