Stripping down Schizophrenia

Imagine your brain is being bombarded by information, coming in through all of your senses including hearing.  You start hearing voices that other people can't, you can't filter them out.  Your brain does its job and tries to make sense of them, tries to rationalise them...

Squeaky Gate Male -   My voices make me think I am someone that I don’t want to be.  They tell me that I love somebody else instead of my wife.

Squeaky Gate Female -   They're all looking at me.

Hannah -   You’re not sleeping, your thoughts become more and more disorganised and confused.  Your perception of the world around you has changed.   You don’t want to socialise as much and the voices escalate and amplify, becoming more frequent and more insistent.  Hallucinations, hearing things that aren't really there.  You start to experience delusions as a result, strong beliefs in something that may not be true, causing you to act in a particular way. 

Squeaky Gate Male Two -   I thought they were trying to kill me and so, I ran away with my 4-year-old son.

Hannah -   That were students at the local mental health charity, Squeaky Gate, speaking about their experiences.  We’ll be finding out about the genetics and brain biology of Schizophrenia, a thought disorder that affects 1 in every 100 people worldwide.  In order to do this, I visited Edinburgh University to talk to Cathy and Stephen. 

Cathy was diagnosed with Schizophrenia over 30 years ago.  It can be a debilitating disorder.  40 % of patients will attempt to suicide and up to 10 % of them succeed.  These shocking statistics indicate that the medications currently on offer are not effective for every person, and it’s difficult to know which medication to put which patient on.  So, more research is desperately required in this field.  Cathy now volunteers for studies with Stephen Lawrie, Professor and Head of Psychiatry at Edinburgh University.  They are trying to find out more about Schizophrenia to help improve treatments for the future.  Cathy speaks with Stephen about her condition.

Cathy -   Hello. This is my side as a patient.  I actually had to be told, “You are ill.”  I didn’t know I was ill.  It took up to the age of 24 from age 18, to be told it was a Schizophrenic illness, and even then the psychiatrist diagnosed said that there's just looking in my case and they’ll give it that label because it helps the medical students to understand that it’s just a survey case. 

I very rarely recall it but when the voices first started to talk to me they were accent less and they would penetrate in my eardrum and I was - got sick with fear.  That is why I was put on medicine.

Stephen -   So, can we talk about the voices a little bit because they're probably quite interesting for people to hear about?

Cathy -   Yes.

Stephen -   What sort of things do they say to you?

Cathy -   Well, they give me an insight into just what humanity is all about.  I am getting guided by voices.  The UFOs got in touch with me.  It was in the presence of a human form, and they were talking to me in my room for up to 4 months before I was admitted to the Royal Edinburgh Hospital with a suspected mental illness. 

Because I hear them and nobody else does, what does that mean?  I'm not imagining it.  I'm on medication and I take the medication, and I still hear the voices.  The medication does stop the voice from penetrating my eardrum to a point which is discomfort, and the voices go along with this

Hannah -   That was Stephen, finding out from Cathy her experiences of Schizophrenia and the difficulties she had, getting diagnosed, and finding the correct treatment over the last 30 years. 

And we’ll be speaking Professor Stephen Lawrie again shortly to discover what his research has told us so far.  But first, I go in to search of a genetic contribution to Schizophrenia.  I met with Professor David Porteous from Edinburgh University who tells me about some of his work, unravelling the role of genes in this disorder.

David -   Some years ago, in fact in 2000, just at the turn of the Century, we were able to report that we’d identified a very unusual new gene, a gene that we knew nothing about before – that when it was damaged, led to a very high probability that individuals inheriting that damaged version of gene would develop a number of different possible types of psychiatric illness.  So, some of the individuals within the same family developed Schizophrenia, some bipolar disorder, and others are a recurrent form of major depression.

Hannah -   And what were the percentage risks for developing these psychiatric disorders then with this gene change?

David -   About 2/3 of the individuals carrying the gene change developed a profound, clinically important psychiatric disorder, but a third didn’t.  Now, that's quite interesting in itself.  It reminds us that it’s not all to do with the genes.  It reminds us also that the genes are important and not just for a particular type of psychiatric illness, but perhaps for a spectrum of illness.  How might we understand that?  Well, perhaps that's just chance, but perhaps more scientifically, perhaps it’s because there are other genes that were affecting whether or not you develop a very severe form of illness by Schizophrenia or a milder form like depression. 

The other things that we have to take into account is that each individual is an individual with the different life experiences, with different life exposures.  And that could also influence how a liability to a major mental illness actually develops over their life course.

Hannah -   So, what's the role of this gene that you're working on?  What does it do within the brain?

David -   Well, that's a really interesting and very difficult question to answer because we’re actually still working out exactly what it does.  But the thing that's very exciting about this particular gene which we call disrupted in Schizophrenia because that's what we’ve observed – is that it encodes for a protein, a building block in the brain, but that protein works with lots of other proteins in a way that it sticks them together and forms what we call ‘functional complexes’.  And what those complexes do is help to determine how the brain develops in the very early stages of life, but also, how the brain signals one neuron to another, later on in life.  So, it’s got this double feature to it.  First, it is important in how the brain develops, and second, it’s important in how cells within the brain, the neurons signal one to another in adults.

Hannah -   So, Schizophrenia has a neurodevelopmental origin, is that what you're saying and it’s also, there's some problem with communication from one nerve cell to another?

David -   That's a very good way of summarising it.  Yes, indeed, we have this notion that individuals at risk of Schizophrenia are born with that risk, but actually, the signs and symptoms tend not to develop until late adolescence and early adulthood.  And so, they have a predisposition which is what we call neurodevelopmental in nature.  Our hypothesis is that there are changes going on in the brain very early in life, but they are not manifest until later in life, and crucially at, and around the time of adolescence and early adulthood, and we have to try and explain that.  And we think that in the discovery of this gene DISC1, and all the things that it does and regulates, that we’ve got a way to explain that.

Hannah -   And you mentioned that families that have a history of DISC1 disruption in their genes, 2/3 of them will then go on to show some signs of psychiatric disorder.  But how many people with Schizophrenia actually have this change in DISC1?

David -   The answer to that is actually remarkably few and that’s been a bit of a puzzle, and it’s why some people have asked the question:  Well, how important is all of these?  And I think there are two answers to that.  One answer is, actually, when you look at DISC1 alone, it perhaps only explains a small percentage of Schizophrenia, but when you look at the proteins, the other building blocks of the brain, the other signalling components of the brain that are influenced by DISC1, then the list gets much longer.  And we’ve done some studies to suggest that perhaps as much as 5% of all of the risk of Schizophrenia could be ascribed either directly or indirectly to DISC1.  So, when we think that 1% of the world’s population have a lifetime risk of Schizophrenia and we think that perhaps 5% of that 1% might be due to this one gene, that is a very, very large number of individuals.  It’s more than that of course because this gene not only influences the risk of Schizophrenia, but also of bipolar disorder and of major depression.  Now major depression carries about a lifetime risk of about 1 in 6.  So we are talking about potentially a very profound influence on the risk of developing these illnesses in a very large number of individuals.

Hannah -   That was Professor David Porteous from Edinburgh University, speaking about how genetic studies are telling us more about what's happening in the brain to give rise to Schizophrenia.  These findings may be of help for patients in the future so they wouldn’t have to wait so long to get the right diagnosis and treatments as Cathy did.  We now return to Professor Stephen Lawrie who describes what his studies with Cathy have helped to tell us so far.

Stephen -   The research that we and other groups are doing has for example shown that we can predict Schizophrenia in those at high genetic risk because they come from multiple infected families, 2 or 3 years before people get the condition, because of changes in brain structure, reductions in the volume of particularly parts of the temporal lobe, 2 or 3 years before onset. 

In terms of distinguishing features, Schizophrenia versus bipolar disorder, that looks like there might be simple differences in the volume of a structure called the amygdala which is an almond-shape structure at the front of your temporal lobe.  But there are probably even more striking differences in terms of the appearances one gets on functional MRI, when one asks people to do a task in a scanner, you can get a variety of different patterns of blood flow in the two different conditions that look very promising in terms of being able to tease the conditions apart. 

Of course, what you really want to be able to do is to use that kind of information to predict treatment response, who would need treatment, who’s getting it better anyway, who would need a particular type of treatment.  And that work is really just getting started now.

Hannah -   How sensitive are your techniques at the moment, particularly for differentiating between the different disorders of Schizophrenia or bipolar?

Stephen - They're about 70 to 80 % powerful in terms of being able to predict whether an individual who is going to go on to get Schizophrenia or in distinguishing groups of people with Schizophrenia from groups of people with bipolar disorder.

Hannah -   So, given that we do seem to be getting there in terms of identifying scientific markers or biological markers for psychiatry, should these markers, these genes that David Porteous was talking about or the brain structure and activity changes that Stephen was talking about, or perhaps a combination of them all, should they be used to help screen people and start treating them even before they develop symptoms? 

It’s a question that’s come in to play for breast cancer screening here in the UK recently and we discussed the ethical implications for this for psychiatry with David Porteous, getting his thoughts on the topic.

David -   You're asking a question that often comes up and I'm actually rather on the side against this kind of approach even though I am very much a card-carrying geneticist.  My view is that genetics is most important for trying to give us clues as to what might be going wrong in the brain, to understand better what’s going wrong in the brain, and then to be thinking about ways in which we might be able to think about the better use of medicines available to us today, and the way to make better medicines in the future. 

But let’s not duck the question because this is an important one.  So let’s use the example of identical twins.  If we look at identical twin pairs and we have one presenting with a clinical diagnosis of Schizophrenia or bipolar disorder and we ask, “Well, what's the diagnosis in the co-twin?”  And the answer is somewhere between 60 to 80% of the co-twins will have the same diagnosis, but not 100%. 

So, are we thinking about treating an individual who might be at risk, but is not going to develop the illness?  I think we’ve got to be very cautious about that and we’ve got to be very sure that the treatment really would be entirely harmless and also, fully protective. 

I would rather see us thinking about more intelligent ways of making better medicines and have them available at the first sign of signs and symptoms.  So, in order to try to dampen down the development of the illness and perhaps most importantly of all, one of the great problems we have in psychiatry is that the individual that turns up with the diagnosis will be put on the medicine that was last used that seem to work.  And unfortunately, that choice is not always the best choice.  So for many patients, not only does it take a long time to establish clearly what their diagnosis is, but also, it often takes a long time to find the medicine that’s best for them.  If we could do that earlier, that would be a huge, huge advantage.

Hannah -   That was Professor David Porteous and Professor Stephen Lawrie, and Cathy from Edinburgh discussing current gaps in knowledge of psychiatry and where science could help patients for the future.