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SRF Interviews Robin Murray

Posted on 17 Oct 2005

Robin Murray has seen patients and studied mental illness since the early 1970s, for most of that time in London. A leader in European schizophrenia research and care, Murray currently is professor of psychiatry at the Institute of Psychiatry at Maudsley Hospital, Kings College, and University of London; and consultant psychiatrist at the Maudsley. Murray's research interests range widely, but he is perhaps best known for helping establish the neurodevelopmental hypothesis of schizophrenia and for environmental risk factors for schizophrenia such as obstetric events and cannabis use. At the Psychosis Research Group, the largest of its kind at any center outside the U.S., Murray oversees a group of more than 100 researchers working in epidemiology, molecular genetics, neuropsychiatry, neuroimaging, neurodevelopment, neuropharmacology and related fields. Murray also runs a clinical team at the National Psychosis Unit.

SRF: I'm delighted to speak with you for this inaugural interview for Schizophrenia Research Forum. Part of the mission of this website is to educate scientific newcomers to the field, or basic scientists who are becoming interested in the disease and who find the terminology and symptomatology overwhelming initially, so I'll ask some basic questions. I'll also ask about some of your research, and about differences between schizophrenia research in Europe and the United States.

First off: How frequent is schizophrenia? The number of 1 percent of the population gets batted around in casual conversation, but others call that an overstatement. What are the best current numbers?

RM: The traditional broad diagnosis made by clinicians produces numbers that average out to about 1 percent of the population having schizophrenia at some point in their life. However, when you apply operational criteria, such as the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) or the International Classification of Diseases (ICD-10), then the numbers drop to about 0.5 percent. It's a function of using different diagnostic systems. It's also the case that, although we frequently use these as average figures, the incidence and the lifetime prevalence of schizophrenia vary quite dramatically in different settings.

SRF: Such as?

RM: Oddly, many psychiatrists believe that the incidence of schizophrenia is the same everywhere in the world. This partly arises from a study by the World Health Organization (WHO), where they looked at incidence across nine centers in different countries. When they used a narrow definition of schizophrenia, they were unable to find statistical differences among these centers in the incidence. In fact, the study didn't have enough power to address this question properly.

When you look at incidence carefully, you find, for example, that people who live in cities have a higher incidence than people who live in the country. Its a graded phenomenon so that people in large cities have a higher incidence than people in small cities, and people in small cities have a higher incidence than people living in towns and so on. You also find that men have a higher incidence than women, and that migrants have a much higher incidence. Perhaps the most remarkable finding is that in the U.K., migrants from the Caribbean have an incidence which numerous studies have shown is at least six times that of the host white population (Sharpley et al., 2001).

So the old idea, which many psychiatrists still believe, that schizophrenia has a universal incidence, is just nonsense. It's obviously nonsense because there are no diseases that occur at the same incidence in all populations around the world; it would be extraordinary if schizophrenia was the one exception to this rule.

SRF: Generally, neither genetic nor environmental diseases are the same everywhere.

RM: You only get that sort of comparability when you have syndromes like mental handicap or epilepsy, where there's a whole range of causes and you can't distinguish one from the other. If you lump together all the causes of mental handicap across the world, or all the causes of epilepsy, then they can average out, even though in different countries the causes of these syndromes may be different.

SRF: How heterogeneous is the disease from person to person? Do patients tend to fall into particular groups of symptom combinations or is the disease pretty uniform?

RM: It's extremely heterogeneous, both in terms of the symptoms that are presented and in terms of the outcome. Some people present with an insidious onset and severe negative symptoms, and they tend to have a poor outcome. Other people present with an acute onset, with florid hallucinations and delusions, and lots of disturbance. By and large, the more acute the onset, the better the outcome so, ironically, it's better if you take your clothes off or cause a scene in public at the onset of your illness.

SRF: What is the outcome when you talk about better or worse? What are the outcomes for this chronic disease?

RM: It's not necessarily a chronic disease. The data are weak, but I estimate that 10 percent of people have one episode of schizophrenia and then recover without having another one. This depends on your definition. To become schizophrenic in America, you have to be ill for 6 months. To become schizophrenic under ICD-10 criteria, you have to be psychotic for 1 month. So naturally, people who meet criteria for 1 month are more likely to recover. People who meet criteria for 6 months are more likely to become chronic because they only get the diagnosis if they're already a bit chronic.

So among those who meet the ICD-10 criteria, approximately 10 percent won't need continuing psychiatric treatment to function in society, though they may appear odd or eccentric. Then around 30 percent will have relapses but recover well each time. The next 50 percent will also have relapses and remissions but with each episode, they will tend to become more damaged psychologically and socially. Sadly, 10 percent will not recover from their first episode.

SRF: Do people who have a more severe course of the disease have a normal life expectancy?

RM: No. People with schizophrenia are more likely to die sooner than the general population. First, they're more likely to kill themselves. The traditional figure is 10 percent, but I think that's too high. They also have an unhealthy lifestyle. Many sit around doing nothing but listening to their voices, they smoke a lot, they get fat; indeed, we give them drugs that make them fat. Therefore, they have a high frequency of coronary artery disease, diabetes, and related conditions.

SRF: Is there also a high co-morbidity with addiction other than smoking?

RM: Certainly. In the States, many psychiatrists believe that schizophrenia causes people to abuse illicit drugs. In Europe, we tend to think that the drugs contribute to the onset of schizophrenia.

SRF: We'll expand on the issue of drug use. First, though, let's clarify a basic point of confusion for scientists approaching schizophrenia: Is it a single disorder or a group, a syndrome? Is there one pathophysiology with different symptom combinations, or are there several separate pathophysiologies with overlapping symptoms?

RM: Nobody knows. I regard schizophrenia as a syndrome. That is to say that people present with a characteristic pattern of symptoms. Many people believe schizophrenia is a disease, but personally, I don't. Those who do follow Emil Kraepelin, who invented the term dementia praecox, the disorder that became schizophrenia. He regarded it as an adult-onset deteriorating disease, a bit like Alzheimer disease. Alzheimer disease had been discovered in his department, and he used it as a model for people with schizophrenia. He believed they had a disease that caused pathological changes in their brains, which progressed in a characteristic way.

I don't think that's true. We define schizophrenia on the basis of signs and symptoms, and that is why there is such heterogeneity. We have no way of validating the signs and symptoms. You go to see a physician with a pain in your chest. The physician says this could be pneumonia or it could be hiatus hernia, or it could be a myocardial infarction, and so the physician does some tests to find out which. The problem with schizophrenia is that it's like pain or breathlessness. It's purely a symptomatic diagnosis. There are no external validating criteria for it. I think it's a syndrome, and there is a range of ways that you can develop the combination of symptoms that we call schizophrenia.

SRF: Is that a European view?

RM: Perhaps it's a minority view even in Europe, and certainly in America where most psychiatrists believe schizophrenia is a progressive disease.

SRF: Alzheimer disease is clearly progressive and there, unlike in schizophrenia, at least a rough molecular physiologic pathway exists that a majority of the field believe operates in most patients. Even so, the question of single disease or syndrome has been debated in the Alzheimer research field for years. From what you tell me, it sounds like the schizophrenia field sorely needs biomarkers or accepted surrogate markers that tell you that a person actually has schizophrenia.

RM: If it even exists. Let me give you the example of dropsy. Dropsy was a Victorian diagnosis over a hundred years ago, where people had breathlessness, ankle swelling, and retained fluid—they were water-logged. The diagnosis was dropsy. We don't make that diagnosis because now we can do tests and show that dropsy can arise because of renal failure or because of cardiac failure or from a range of other conditions. I bet that schizophrenia is like dropsy; the diagnosis is based on the symptoms that people present, but it's only when you understand the pathophysiology that you can make good distinctions.

SRF: To basic biologists interested in schizophrenia, the present distinctions and their terminology can be bewildering. Can you define them, and explain where affective and psychotic symptoms fit in?

RM: Basically, we still differentiate between dementia praecox and manic depression, the two conditions conceptualized by Kraepelin, though now we call them schizophrenia and bipolar disorder. Schizophrenia is primarily psychotic and bipolar is primarily affective; that's one big distinction. But it's not absolute, because many people with schizophrenia also have affective symptoms. Lots of people with schizophrenia get depressed and miserable and you can understand why. Likewise, a proportion of people who have bipolar disorder hear voices or have delusions. Nevertheless, it is still a useful distinction in clinical practice.

So the traditional categorical distinction is between schizophrenia and bipolar disorder. Then within schizophrenia, factor analytic studies distinguish between positive symptoms, which are hallucinations and delusions, and a negative factor that includes cognitive difficulties, poverty of thought, lack of motivation, emotional bluntness. The third factor is called disorganization or disorder of thought. Whenever you do a factor analysis on schizophrenic symptoms, you get these positive, negative, and disorganization factors. And then, you also get depressed or manic factors, although they tend to be less in schizophrenia than in bipolar disorder.

SRF: Maybe the overlap explains why these classifications are hard to grasp. For example, last May you published a study on executive function that found more similarities between people with schizophrenia showing positive symptoms and bipolar patients in a manic episode on the one hand, and schizophrenics with negative symptoms and bipolar patients with depression on the other hand, than between people with schizophrenia with positive or with negative symptoms. The study seemed to be one of many in the literature that calls into question the classification you just outlined. How useful is it really in this day?

RM: At the extremes, it's easy to diagnose somebody with classical schizophrenia, and it's easy to diagnose somebody with classical bipolar disorder, and these sorts of people tend to come back into the hospital showing the same picture. But in the middle, we see a huge range of people who have psychotic and affective symptoms, and these are the people who pose the problems for the classification system. This is why the term schizoaffective was invented in the 1930s.

In my clinical practice, it's not uncommon for me to see somebody who has been admitted to hospital many times; maybe five times they had a diagnosis of schizophrenia, three times they had a diagnosis of a schizoaffective disorder, and a couple of times, they've had a diagnosis of bipolar disorder. The resident doctor presents the case to me, and I say, "It's absolutely clear this is bipolar disorder. Who are the idiots that diagnosed schizophrenia in the past?" And at this point I notice that the resident is smiling, and discover that I was one of those "idiots" who diagnosed schizophrenia in the past!

SRF: That's because the diagnosis depends on the symptom combination a person presented with at any particular day, and that combination changes with time?

RM: Yes. Consider our study of the co-twins of patients with schizophrenia. If you take identical pairs, in about 10 percent of cases, the co-twin has presented with manic symptoms at some time in his/her life. It's not as common as presenting with schizophrenic symptoms, but it still occurs (Cardno et al., 2002).

We also have a set of identical triplets where one looked like chronic schizophrenia, one looked like bipolar disorder, and one looked like schizoaffective disorder, even though they have the same genes. So it's not just that psychiatrists are stupid and can't make the distinction. These conditions do overlap in terms of symptoms, genetic predisposition, brain imaging, and in drug response (Murray et al., 2004).

SRF: Is the field trapped in descriptive symptomatology because there is no obvious pathology to guide the geneticist? In Alzheimer's and Parkinson's, by comparison, pathologists define the diseases by the nature of cell loss and protein deposits, and that has driven human genetic studies with quite a bit of success. John Hardy, the British neurogeneticist, proclaims that the pathologist be king in sorting out the mess of heterogeneous symptoms. In schizophrenia, there does not seem to be a clear pathology.

RM: No, and that has been the great problem. There is no characteristic pathology at the neuropathological level. Everybody in our field knows the ancient quote that schizophrenia is a graveyard of neuropathologists, because there has been such difficulty in replicating findings.

We now have reliable diagnoses. There's no doubt that DSM diagnoses can be applied in New York, London, Moscow, or anywhere else, and will pick the same sort of people. The question is: Do the diagnoses have real validity or are they artificial constructs applied to a certain group of mentally ill people? I usually give the analogy of hamburgers: Everybody can recognize a McDonald's hamburger. It's highly reliable in New York or Moscow or wherever, though a bit different from a Burger King hamburger. However, you do not know whether a hamburger is an artificial construct, or whether it actually has real meat in it. It's the same with schizophrenia. There are different definitions of schizophrenia, and there is argument about which is the best; is the ICD-10 better than the DSM-IV? However, just as with hamburgers, you do not know whether schizophrenia, however defined, has any biological reality at its core. For schizophrenia, you can't use neuropathology to validate the diagnosis: It is the clinical definition that identifies the core schizophrenic group. It's circular and that is the problem.

We have made some progress. We know that, on average, people with schizophrenia are more likely to have brain structural abnormalities, impaired neuropsychology, and deviant neurophysiology. So we have some biological characteristics, but these are characteristics that are merely more common in people with schizophrenia; they're not exclusively found in people with schizophrenia. Take, for example, the brain structural abnormalities: You can study 100 people with schizophrenia and show that their brains differ significantly from those controls, but you can't look at the MRI brain scan of an individual and say, oh yes, this person obviously has schizophrenia.

SRF: What do you think of the notion of a spectrum of disorders, where the individual symptoms are each determined by particular genetic abnormalities, and which combination of symptoms a person shows follows from which genes are affected?

RM: That is likely to be the case. The genes are likely to encode proteins which will affect brain physiology and tend to push the individual in the direction of a particular pathophysiology and ultimately a particular cluster of symptoms. Modern genetics is compatible with the heterogeneous picture. I think a large number of genes will play a role in schizophrenia, and depending on the particular hand of genes you get dealt, the particular picture will present. People who have both schizophrenic and affective symptoms probably have genes that are common to the two disorders.

SRF: In that sense, it's less surprising that strong Mendelian, autosomal-dominant genes haven't been found for schizophrenia.

RM: I don't think there are any. We did our first linkage study in 1983. At the time, we were looking for big genes, like a gene for Huntington disease. Sometimes I say like a gene for Spiderman, where a chunk of spider DNA was inserted into one of his genes. Schizophrenia is not like that, but for many years, geneticists were looking for that kind of gene. Now we know there can be no gene that increases the risk of schizophrenia more than two- or threefold. So we're looking for lots of little genes.

SRF: The way schizophrenia genetics is taking shape these days reminds me of what genetics is doing in paleontology, where it is redrawing the classic evolutionary trees. I'm wondering if genetics will do the same thing with the psychiatric classifications.

RM: Genetics will probably persuade even the most recalcitrant American—because it's largely an American view —that DSM categories don't exist. If you have the huntingtin triplet repeat expansions, you get Huntington disease; otherwise, you don't. If there were a big gene for schizophrenia, there would have been a clear-cut distinction between people who are schizophrenic and people who are not.

But if 15 or 20 genes contribute to schizophrenia, then some people will have a whole pack of them and will have severe schizophrenia. If you just have, say, three or four, then you may be schizotypal or somewhere on the spectrum. If you have half a dozen schizophrenia susceptibility genes and some affective susceptibility genes, you'll look schizoaffective.

It's much easier to understand the difficulties we have with classification when we know that the genes are genes of small effect that interact with each other and with environmental factors. So the genes will probably be more compatible with dimensional classifications, and indeed, that's one of the discussions that the DSM-V working groups are going to have.

Your basic point is right, that if we understood the genetics, we would be able to study our patients and see whether particular susceptibility genes and risk alleles tend to be associated with one type of symptom rather than another. We might well end up abolishing the category of schizophrenia altogether and defining patients according to the cluster of genes, or according to some biological phenomena.

SRF: In your mind, what causes schizophrenia? What do you think are the steps leading to this syndrome?

RM: It is often said that schizophrenia is a disease of unknown etiology. That is no longer true. We know there is a big genetic component. At last, research has begun to identify some of the susceptibility genes like neuregulin and dysbindin. Hopefully we'll be able to identify the susceptibility genes. But even if you take identical twins, where one twin has schizophrenia, the second twin will also be schizophrenic in less than 50 percent of cases. It's likely that that is because of exposure to different environmental factors. People don't inherit genes that cause schizophrenia directly but rather genes that make them susceptible to particular environmental factors. Fortunately, now we know quite a bit about the environmental factors.

The best evidence available concerns obstetric events. A range of obstetric hazards, from prematurity to hypoxia at birth, increases the risk of schizophrenia—on average, your risks are about double if you are subject to an obstetric complication (Cannon et al., 2002).

We also know that being born and brought up in a city increases your risk. We don't know why, but that's fairly consistently so, at least in Western societies. We also know that abuse of particular drugs, including amphetamines, cocaine, and cannabis, increases the risk of schizophrenia. Most of the evidence concerning cannabis is quite new. It came out in the last 3 or 4 years. There are now seven studies showing that if you are a heavy cannabis user in your adolescence, you increase your risk two- to threefold of going psychotic later on (Henquet et al., 2005).

In addition to obstetric events, urban living, and drug abuse, the fourth factor is migration. People who migrate from one country to another are at increased risk. Thus, some of the environmental components are biological, but migration and social adversity seem also to contribute to risk, and these are social variables.

So when you ask what is the cause, I say there is no single cause. There are contributory causes or risk factors, just like for heart disease. You may inherit susceptibility genes that affect your cholesterol, your clotting times, your blood pressure, diabetes. Your genes can make you liable to heart disease, but then you may compound the genetic predisposition if you become obese, smoke cigarettes, and don't exercise. My model for the causes of schizophrenia is a similar, multifactorial one.

SRF: A genetic susceptibility with environmental factors impinging on that background.

RM: Yes. That is something we didn't know 10 years ago. Then, researchers were still looking for "the" cause of schizophrenia. A few are still thinking there's going to be one big cause, but it seems very unlikely.

SRF: These environmental risk factors: Are they environmental in the true sense of the word, i.e., a blow coming from outside? Or are they just a different expression of a deeper genetic problem? For example, the obstetric complications: Does an unexpected delivery problem raise the schizophrenia risk in an otherwise normal infant, or do mothers with a genetic predisposition encounter delivery problems more frequently? Can you sort that out?

RM: Yes, to a large extent—though we will never be absolutely sure till we have the genes. Women with schizophrenia don't go to antenatal care and don't look after themselves, and therefore are more likely to have obstetric complications. But now there has been a whole series of big epidemiological studies, which, so far as they are able, show that obstetric events have an independent, though modest, effect of doubling the risk. Of course, obstetric problems are not necessary or sufficient to cause schizophrenia. Lots of people develop schizophrenia having had normal births and pregnancies, and lots of people are born premature but never develop schizophrenia. Again, it's likely to be an interaction between genes and environmental factors.

The difficulty is that we're trying to distinguish the liability to obstetric events from genetic predisposition when we haven't known the identity of the genes, so we've had to use family history as a proxy. We can't exclude it, but I think it's unlikely that the bulk of the obstetric events occur merely because of the strange behavior of the mother.

It is difficult to look at the relationship between environmental and genetic factors, but we have examined that question in relation to cannabis. We now know that there is an interaction between the catechol-O-methyl transferase gene (COMT), which some regard as a susceptibility gene for schizophrenia, and cannabis consumption. People with the Val/Val variant of COMT are much more likely to develop psychosis if they abuse cannabis in their adolescence, but there is no evidence that people with the Val/Val genotype of COMT actually take more cannabis than the rest of the population. So it's not that the cannabis consumption is a manifestation of predisposition to schizophrenia. Rather, cannabis consumption interacts with genetic susceptibility to schizophrenia. The result is that the majority of the population can abuse as much cannabis as they like and don't come to much harm. But a vulnerable minority, about 25 percent of the population, is prone to psychotic reactions if they take regular cannabis (Caspi et al., 2005).

SRF: Is cannabis use a large factor?

RM: Many American psychiatrists still regard cannabis consumption as safe, but it's become a very lively issue in Europe where most psychiatrists regard cannabis consumption as a cause of schizophrenia. However, the evidence is that it accounts for only a minority of schizophrenia. We found that if no one in New Zealand smoked cannabis, then the incidence of schizophrenia would decrease by about 8 percent; the comparable figures for Germany are 10 percent, and for Holland, 13 percent.

SRF: I would think that Americans vilify cannabis consumption more stridently than do Europeans. European governments have legalized or decriminalized its use. In America, that can't even be discussed, and the federal government recently petitioned the Supreme Court to overturn a law in Oregon allowing just its medicinal use, mainly as a painkiller.

RM: You are talking about policy makers and the general public. With psychiatrists, it's different. The reason why European psychiatrists are much more interested in cannabis use is precisely because people smoke more cannabis in Europe, and stronger varieties, than in the U.S.A. That's why we've seen more problems. If you'd asked me 15 years ago if cannabis causes schizophrenia, I would have said: "Of course not." But cannabis consumption in Europe has been escalating fast, whereas in America it has been fairly stable for about 25 years.

SRF: Do European psychiatrists want a tightening of the policies?

RM: There is a big dispute. In Britain, for example, the government didn't legalize cannabis, but made it less criminal. Here it's said that you only get arrested if you blow the smoke in a policeman's face. Our government made that change in 2002. Ironically, that was when the big new epidemiological studies started coming out. Personally, I don't think the legislation is that important. What matters is education. In Britain, now that the risks of cannabis consumption are becoming more widely known, there has been a dip in consumption, even though the legislation is now more liberal. It's probably more useful to educate people that there's a risk, rather than attempting to forbid it legally.

SRF: Is the effect of cannabis on risk strong enough that when you compare incidence rates in the States and Europe, where in the States, consumption of cannabis was stable and in Europe it's gone up, you can detect an increase in the incidence?

RM: I'm not aware of any competent large incidence study ever having been done in the U.S.A.

SRF: Why is the data from the U.S.A missing?

RM: Because you have a fragmented health system.

SRF: In Europe, has schizophrenia incidence gone up due to increased cannabis use?

RM: In Europe, there are good on-off epidemiological studies, but there's only one place that has data collected in the same way over decades. That's in South London, where I work. Here, the incidence of schizophrenia, as assessed by the same criteria from 1964 to 1999, has doubled (Boydell et al., 2003).

The reasons for that are complicated. One is because many more migrants live in London now, and migrants have higher rates of schizophrenia. But even if we look just at the native white population, rates went up, and our evidence is that drug abuse contributes to that. Nobody else has data collected in the same way consistently over decades, so it's difficult to make a broader assessment. We've discussed how difficult it is to define schizophrenia, and because of that you sometimes appear to see differences in incidence that are just due to differences in definition.

SRF: What kinds of changes do these data call for? Do you see social policy as the priority area?

RM: Should we embark on some major preventive policy for schizophrenia? We don't know enough about how to do it yet. It's too early to think that we could actually prevent schizophrenia, except in very small groups. For example, women with schizophrenia who get pregnant tend to get terrible obstetric care because they don't go see an obstetrician in the first place, and when they do they exasperate the doctors. Therefore, the children end up not only with their inherited genetic predisposition for schizophrenia, but also, too frequently, with an additional obstetric hazard. So one area to which we should devote resources is to the absolute optimum care of people with schizophrenia.

SRF: Let's talk about maternal care. That's interesting historically because poor parenting was blamed for schizophrenia in the middle years of the 20th century. Then the realization of a genetic component seemed to throw that out for a while and lifted the guilt off the shoulders of parents. Now, though, work by Michael Meaney and other groups revisits the issue in a different form (see, for example, Meaney and Szyf, 2005).

RM: I don't think he works on schizophrenia.

SRF: No, he studies the regulation of the stress response. But how robustly you can withstand stress, social adversity, and anxiety is part of the risk predisposition to schizophrenia.

RM: Yes. We've always known that people with schizophrenia were more anxious or depressed, and we thought that came later because they're hearing voices, they think they're being persecuted, they've got no money, they've got no friends. But people with schizophrenia have more depression and anxiety at the beginning of their illness; indeed, the anxiety and the depression often come before the psychotic symptoms. We've done cohort studies following children from birth, and they, too, show that children who are going to go on to develop schizophrenia have more depression and anxiety than the general population. So another way of looking at it is that these individuals are vulnerable to anxiety and depression, and that the anxiety and depression may contribute to them developing psychosis. To this extent, social factors that impact on anxiety and depression might contribute.

SRF: Does that say anything new about parental care and risk for schizophrenia?

RM: This is a tricky area. Schizophrenia researchers are deeply ashamed of the era when parents were accused of having contributed to the cause. Remember the era of "refrigerator mothers" and "schizophrenogenic mothers"; the specious argument that the way parents communicated with their children drove them mad. I think particularly biological psychiatrists were so ashamed of that episode that we did not study family factors and at the possibility that they could contribute. We just avoided it.

But when you do begin to look, you find an effect. We've done a number of cohort studies where you take, say, 5,000 children, you examine them throughout childhood, and then you follow them up to see who develops schizophrenia. It's quite clear from that research that children with a poor relationship with their mother do have a higher risk.

That raises the question of whether the child is so odd to begin with that even the best mother in the world can't make a good relationship with him or her. And there's also the possibility that mum may be carrying some susceptibility genes, as well, and may therefore have some minor spectrum characteristics. But I think the evidence is beginning to suggest some effects in those who are genetically vulnerable, whereby the more socially hazardous your upbringing, the more at risk you are. Also, adoption studies have looked at adopted children of schizophrenic mums placed with families versus those placed in orphanages, and the ones placed in orphanages have a higher risk than those with a good adoptive family. This evidence, too, does seem to show that the social environment can compound the genetic predisposition. We also have unpublished work that indicates that children who are separated from parents have a slightly higher risk of schizophrenia, just like they have a higher risk of depression.

SRF: That last bit again fits with work by Michael Meaney, for example. There's quite a bit of similarity in particular aspects.

RM: Yes. And, of course, his work shows that it's not in opposition to the biology; it's the social factors impacting on the biology.

SRF: Precisely. The work is drawing so much attention because it offers a biology underlying the social difference. It traces a path from the difference in maternal care to neurophysiology, and even down to chromatin modification and epigenetic modification of particular genes. I think it serves as an example of a new direction because environmental factors often leave you unsatisfied in the end, because you can't easily move beyond their description and quantification into how they act.

RM: That's a good point. Remember, in schizophrenia we do know some of the risk factors but we have no idea about the pathogenesis. We don't know how neuregulin-1 actually increases risk of schizophrenia. We don't know, really, how hypoxia contributes to somebody going psychotic 20 years later. We don't know what it is about certain social adversities that contributes to people becoming psychotic. If you look at medical disorders, scientists often don't know much more about the risk factors than we do, but they do understand the pathogenic pathways from the genes through to diabetes, or from the genes through to the stroke, whereas we just know so little about pathogenic mechanisms.

SRF: Is establishing a molecular pathogenesis the biggest research priority for the next decade?

RM: It's one of them. I see four areas. The first is understanding what the susceptibility genes do. The second is examining the impact of social factors on dopamine neurotransmission. Dopamine is the final common pathway whereby people develop psychotic symptoms; we know that how psychotic people are correlates with elevated release of dopamine in their striatum. But now we're beginning to realize you can manipulate the dopamine system by social means. There are animal studies where researchers have put animals in isolation and shown that this influences the dopamine system. Again, if a primate is placed into a common cage where he becomes submissive, then this seems to rev up his dopamine systems, whereas if you put him into a communal area where he becomes dominant, then this seems to normalize the dopamine system.

You can see that if people have a genetic tendency to dopamine dysregulation and you put them in a particular social circumstance, then that might make them more or less likely to develop dopamine sensitization and psychosis. This is not ignoring the genetic explanation; rather, it is showing that some of the social explanations can be seen as having an impact on the same system through which the genes work.

SRF: That's interesting. How does one study that?

RM: It probably has to be through animal models. A third area with a lot of promise is brain imaging. Indeed, when you talk to the relatives of people with schizophrenia, the research that impresses them most is the understanding of what is happening in the brain of their sick relative when he or she is hearing voices. Functional imaging has shown us that when people with schizophrenia hear voices, they are producing the words in Broca's area in the same way that we can all produce inner speech (e.g., silently saying a poem to ourselves). However, unlike the rest of us, they then process the words in their auditory cortex in the temporal lobe; somehow, their brain misidentifies these internal words as coming from the outside and therefore activates the auditory cortex and the subcortical areas that normally process external speech. When you show that on a fMRI scan to relatives, they begin to understand that the patient isn't making up the voices but really thinks the voices are voices because they hear them through the same auditory system that you and I hear external speech (Shergill et al., 2000). (Editor's note: For a vivid and utterly disturbing simulation of the voices people with schizophrenia hear, listen to an archived report on National Public Radio.)

SRF: You've published extensively in this area, too. Let me needle you a bit about it. Does the functional imaging merely show us at a different level what we already know, or can it teach us truly new things? For example, will we be able to develop a diagnostic out of it, or treatment monitoring?

RM: At present, the functional imaging shows us correlates of symptoms. It doesn't show us that the abnormal physiology causes the symptoms. It's difficult to make that leap, but I think it will contribute to our understanding of pathogenesis. It builds a bridge between neuroscience and the clinic, which has been a difficult area. For decades, scientists have been doing research into the dopamine hypothesis, but that has meant nothing to clinicians dealing with people who hear voices or who think the neighbors are trying to poison them. When Shitij Kapur developed a theory that linked excessive dopamine release in the striatum with misinterpretations of stimuli and with contriving meaningful connections between unconnected events, clinicians began to understand the continuity between the basic neurochemical research and the phenomena they see in their clinic (Kapur, 2003).

The fourth area we need to study is psychotic symptoms in normal people. If you think of progress in understanding myocardial infarctions or diabetes, it didn't come just from investigating people with coronary artery disease and diabetics. It came through looking at the epidemiology of cholesterol, or the epidemiology of blood pressure, or the epidemiology of glucose metabolism in the whole population. Schizophrenia researchers have concentrated on people with the diagnosis. Now we're realizing that there is a distribution of psychotic symptoms in the population in the same way that hypertension or glucose tolerance abnormalities are distributed through the general population. It's a graded phenomenon, not a categorical one. Many normal people have minor psychotic symptoms; they are paranoid about their neighbors or they feel others are influencing their thoughts by telepathy. (Anyone who watched the way the leaders of our two countries deluded themselves about WMD in Iraq will not be surprised by the idea that normal people are not entirely sane.)

Very interesting findings are coming from studies of minor psychotic symptoms in the general population. For example, we know that people brought up in cities have more schizophrenia. Now Jim Van Os has shown with a whole-population survey in Holland that people living in cities also have more paranoid ideas and more quasi-psychotic symptoms than people in the rural area. There is a parallel between minor isolated psychotic ideas and their distribution in the community, and the distribution of full-blown schizophrenia. Just as there's a distribution between obesity and the general body weight. It isn't just that obesity is more common among Americans than the French, but the mean body weight is higher in Americans than in the French. I shouldn't pick on Americans.

SRF: And I haven't even starting asking yet. Let's get to it. Maybe more than most other diseases, schizophrenia as a disease, or syndrome, of the mind is subject to prevailing cultural attitudes. What are the biggest differences in how prescribing physicians approach schizophrenia in Europe and the U.S. at the clinical level?

RM: It's interesting you say disease of the mind, which I agree with. I think many American psychiatrists see it as just a disease of the brain, like Alzheimer's. I don't agree with that. It's more than a simple brain disease. Take the example of asthma. Asthma is a lung disease, but the lungs process air and the quality of the air has an impact on the incidence of asthma. If you live next to a motorway or in a polluted area, you're more likely to develop asthma, and you're more likely to have a worse outcome. I say the same for schizophrenia. There is brain dysfunction in schizophrenia, but that dysfunction makes you more vulnerable to particular toxic factors in the social environment. What I find interesting about it is that it is a disorder at the interface between the brain and the social environment.

Another big difference between the continents is that the epidemiological context is much better examined in Europe. The greater European interest in epidemiology of schizophrenia comes partly from our socialized or semi-socialized health systems, where you can get good data. In the privatized U.S. system, it's difficult to get sufficient numbers of people with schizophrenia to do epidemiology. American research has excelled in applying neuroscience to schizophrenia, and we don't have enough money to compete effectively with American neuroscience.

In terms of daily practice, the biggest difference is the extent to which the drug companies dominate the thoughts of the practitioners. My own view is that the academic establishment in North America has been unduly influenced by the pharmaceutical industry.

SRF: Leading to overprescription?

RM: Not necessarily overprescription but, for example, leading to a mindless acceptance that atypical antipsychotics are hugely better than typical antipsychotics. To my knowledge, around 90 percent of the antipsychotics prescribed in the United States are now atypicals, as compared to 50 percent in Britain. American psychiatrists have been convinced for a long time that the atypicals were superior. Many European psychiatrists agree that clozapine is superior, but are less convinced that the novel atypicals are superior. In fact, a big American study called the CATIE study just demonstrated that there isn't much difference in efficacy. I look forward to many American academics eating their words.

SRF: Schizophrenia Research Forum is planning a live journal club with Jeffrey Lieberman and other authors of the CATIE study, and inviting other scientists in the area to come and ask their questions (Lieberman et al., 2005).

RM: We have similar data here. We did a randomized study called the Cutlass study—cutlass as in pirates—and basically showed that after 1 year, people on atypicals did no better than people on typicals, with the exception of clozapine. This study is published as a report to the U.K. government; the paper is submitted.

SRF: In a study last year, you argue for treating the cognitive deficits in people with schizophrenia because the antipsychotics don't do that well. You wrote that verbal memory dysfunction, for example, should be a target for therapy (Toulopoulou and Murray, 2004). How would you treat that? With existing drugs such as cholinesterase inhibitors?

RM: We must find ways of improving cognition in schizophrenia. Unfortunately, antipsychotics, typical or atypical, have only marginal effects, and so far cholinesterase inhibitors have been disappointing, also. Perhaps we have to wait till we understand the neurochemistry of memory better. In the meantime, psychologists have been attempting to improve cognition via cognitive remediation therapies using techniques borrowed from rehabilitating those with brain injury. Sadly, although such means can teach people with schizophrenia to do neuropsychological tests better, the effects don't generalize much to everyday life.

One area where British psychologists have contributed a lot has been the application of cognitive behavior therapy. This is not to remedy cognitive deficits, but rather to target anxiety, depression, abnormal experiences, and delusions. There are now 5 randomized controlled trials in the U.K. that show that cognitive behavior therapy is useful as an adjunct to antipsychotics, so this type of treatment is much more common in the U.K. than in the States.

SRF: That's a talk therapy?

RM: Yes, but not an analytically-based talk therapy, rather a science-based talk therapy. It started in schizophrenia by being aimed at diminishing the neurotic and depressive symptoms that many psychotic patients suffer. But now it has developed to help patients do cognitive work to reassess whether they were interpreting their world in a paranoid way, and consider that perhaps they might have been mistaken. It's silly to argue with deluded people, but you can, by cognitive means, examine the evidence that drove them to the delusional explanation. There is quite good evidence that this can work. I was skeptical of this approach, but our local psychologists did a study that included my patients, and its effectiveness surprised me.

Of course, we need to determine to what extent it's specific, or just a result of somebody taking care and interest in the patient. Too often, a schizophrenic patient comes to see the doctor, and the conversation consists of:
"Are you still hearing the voices?"
"Are you taking your medication?"
"Well, here's a prescription for a bigger dose and I'll see you again in a month."
Some psychiatrists seem to practice a kind of veterinary medicine without listening to their patients. Cognitive therapy teaches us to pay attention to what the patient says.

SRF: It does seem counterintuitive when the problem is delusions and paranoia�

RM: I was taught that it is unimportant what the voice a person hears is saying. That's the traditional psychiatric belief. But as we discussed earlier, voices are actually a misinterpretation of inner speech. Inner speech is what we're thinking, so the voices can be concerned with things that are of great moment to the patient. Here's a particular patient of mine. A woman with chronic schizophrenia heard voices telling her, "Your husband's having an affair," and also, "They're going to take your children away." But this woman was getting an antipsychotic which decreased her sexual interest. Not surprisingly, she begins to think that if she can't have a sexual relationship with her husband, maybe he'll look somewhere else. Plus, she's in and out of hospital often, and we all know what happens to the children of people like that; the social workers take them away. So you see that these voices were worries of hers. You and I would merely worry, whereas she misinterprets her internal worries as voices.

One of the things cognitive therapy can do is to help the average psychiatrist take seriously the experiences people with schizophrenia endure. Instead of saying, "This is a lunatic idea and we need to pour antipsychotics into this person until it goes away," it's important to say, "How did this person develop this delusion? Is there a way of getting him or her to re-look at that belief?" or "Now that we have normalized the dopamine dysfunction with antipsychotics, is this patient able to look at his/her delusional explanation and begin to realize that he/she came to this conclusion on too little evidence?"

SRF: That gets back to your argument for more sophisticated care for schizophrenia patients.

RM: Sure. People with schizophrenia have the greatest difficulty dealing with the social environment. Even when we get them better, their social adjustment is precarious. And how do we treat them? We put them in terrible hostels, or we kick them out into the street and force them to live in circumstances that you and I couldn't cope with. I couldn't exist in a hostel full of dropouts and alcoholics; I couldn't live on the streets. Yet, the very people who are least able to cope with these stressful social situations are put in exactly that position. It's a mad world where those of us who would be better able to cope with such social adversity protect ourselves from it by living in suburbs and away from the stressful day-to-day events that our poor patients are subject to because they have to live in the worst part of town.

SRF: Do you put faith in better drug treatments?

RM: Of course. The treatment of schizophrenia was transformed when the antipsychotics first came out, and I am very hopeful that we will develop better drug treatments. I'm an enthusiast for clozapine. It's an excellent drug, though unfortunately with many side effects. I do not remember getting presents from my patients before 1989, but after clozapine was introduced, patients starting giving me presents when they recovered. Before that, the patients didn't recover and they didn't like the drugs we gave. My experience has been that people on clozapine are much more likely to recover and be grateful for the help they received.

SRF: If we hope for a new generation of drugs, with a new mechanism of action, how do we square that with animosity against drug companies?

RM: I don't blame the companies. Their business is to produce new drugs and get the evidence to sell their products. They just behave like big capitalist companies are supposed to. My argument is with a minority of academic psychiatrists, who, I think, are na�ve, or occasionally corrupt. Sadly, a few academic psychiatrists will support one drug on a Tuesday and another drug on a Wednesday; if they're paid to speak in support of a particular drug, then they'll do it. Health economists are worse, in that their studies always say that the new drug (produced by the company funding the study) will be cheaper in the long run; their subject has become just a branch of drug company advertising.

SRF: Have you had financial arrangements with Novartis, the maker of clozapine?

RM: No. In recent years I have spoken at many satellite symposia organized by drug companies, but not at any organized by Novartis. I won't claim I was purer than pure but at least I don't usually speak about drug treatment and never about the merits of a particular drug. I generally put the honorarium offered, or its equivalent, into our research funds.

SRF: Is the financial support of practicing psychiatrists different in England than in the States?

RM: The National Health Service, an arm of government and almost a monopoly system, pays most psychiatrists in the U.K.

SRF: In the States, psychiatrists do not draw their salaries from the drug companies, either, but many have consulting and other arrangements for additional income. That is part of how the industry exerts influence. Are you saying this is not the case in England and Europe, generally?

RM: It's similar in the U.K. and Europe. And it is reasonable for academics to accept money from pharmaceutical companies when it's open, and everybody understands the basis of the transaction, as in consulting. What I object to are academics who speak at symposia, who do not present their own data, but who arrive at the conference the day before and the drug company gives them the slides. The drug company explains the slides to the speaker, and then the speaker parrots them in a presentation to those attending the meeting. The psychiatrists attending the meeting don't know that this academic is simply being used as a hired gun to present the company's data. Nor do they realize that sometimes when a famous psychiatrist is the first author on a paper examining the effectiveness of a new drug, he or she may have had little to do with the study.

SRF: �but was made an author to lend academic credibility and a false perception of independence. Does that account for the prescribing difference you mentioned between the U.S. and Europe?

RM: No. That goes back more to our having more socialized systems. Our countries' governments required more evidence that the more expensive atypicals were indeed superior drugs before they were willing to spend the country's money on them. And because there is a national policy on this, the decision on what to prescribe is not so much up to individual payers, practitioners, or patient families.

I'm not saying atypical antipsychotics have no advantages. We now have a much wider range of antipsychotics so we can pick the side effects to suit the patient. Many people get terrible extrapyramidal symptoms from typicals, and we can prevent this by using an atypical antipsychotic. But some atypicals can cause obesity and in such circumstances it might be better to use a very small dose of a typical.

SRF: A related issue is heating up in Alzheimer disease. In the U.K., driven by the National Health Service, studies are underway to assess whether the cholinesterase inhibitors are cost-effective enough to continue to be prescribed. The problem is not side effects so much as the smallness of the therapeutic effect. That issue is muted here in the U.S. Here, again, you have a national health service looking hard at costs and exerting a level of power that a privatized system doesn't, because it's too fragmented.

RM: Yes. That can be good or bad. Sometimes patients in Britain are prevented from receiving necessary care in time. The U.S. spends about 13 percent of their GNP on health care. Under the Thatcher government, the U.K. spent 5 and, under the current government, 9 percent. We just can't afford as much, and part of the constraints on the sale of atypicals was purely the government trying to save money. This could have been very detrimental if the atypicals had turned out be better by an order of 2 or 3 in terms of their effectiveness. They've turned out to be only marginally better, and therefore, by accident, our present mix of typicals and atypicals is perhaps more sensible than the North American one.

SRF: So much for drugs. What are the differences in schizophrenia research between Europe and America?

RM: The best of American research is better.

SRF: What makes you think so?

RM: There's no way British or European psychiatric research can stand up to the might of American neuroscience because your funding is so much greater. We cannot do the innovative neuroscience studies or neuroimaging studies at the sheer volume that they're done in the U.S.

SRF: You're making it sound like quantity is everything. British research is known for making clever use of limited funds.

RM: Lord Rutherford, who was involved in splitting the atom, said, "We have no money; therefore, we have to think."

SRF: Can you expand on the differences in the research?

RM: A lot of modern research requires big resources. The U.S. has a population of 280 million (Britain's is 60 million), and furthermore, spends proportionally more per head of population on health care and research. Therefore, the NIMH can concentrate huge amounts of resources and technology in one center. Europe has about the same population, spends less on research, and it's all split into little tin-pot countries, each of which is running its separate research policies. Fortunately, with the European Union, there now are more Europe-wide research projects.

SRF: That was my next question. Are there policy initiatives or big science programs that might bear on schizophrenia research?

RM: These are beginning to develop, but from a lower base. Yesterday, I wrote a grant with European colleagues. The approach is to try and get outstanding researchers from centers across Europe to collaborate. It's a good trend and means that we can do bigger studies.

I personally am very fortunate. The Institute I work in is the biggest center in Europe, with 1,000 psychiatric researchers, so I can't complain. That's as big as any of the American centers outside the NIH.

SRF: You have published books and hundreds of papers. What do you consider your best contribution to schizophrenia research?

RM: I consider our work in contributing to the neurodevelopmental hypothesis of schizophrenia as the most important, the idea that schizophrenia is in part a developmental condition rather than a condition which comes on out of the blue at age 18 or 25 (Murray et al., 1987).

The neurodevelopmental hypothesis arose out of neuropathological studies in the mid-1980s, which were subsequently found to be artifacts. Our work on obstetric complications and on the antecedents of psychosis sustained the hypothesis.

SRF: That's the work on subtle signs in children?

RM: Yes. Genes or environmental factors operate from early in life and cause the children to be more deviant. Then a cascade of increasing deviance ensues, which culminates in the psychosis (Jones et al., 1994).

The neurodevelopmental hypothesis is now so widely accepted that people are beginning to react against it. One of the reasons is that some researchers claim that schizophrenia is just a neurodevelopmental disease. That's obviously an exaggeration; neurodevelopmental deviance is one component.

Another area in which we have made a contribution is in the shift towards looking at schizophrenia in the wider epidemiological context: What is the combination of risk factors that contribute to the illness? Out of that follows a multifactorial approach to understanding schizophrenia, and a multifactorial approach to treatment. That's why I think the treatment should not be only drugs, because schizophrenia isn't only a disorder of abnormal synapses.

SRF: Do you believe U.S. scientists are too enamored of genetics? There is now much excitement in the U.S. about postgenomic initiatives to look at microRNA, to look at "junk" DNA, to look at gene expression differences. People are trying to move past sequence information per se to get at new mechanisms of regulation, and I'm wondering if you think that's a good thing or that it happens to the exclusion of everything else?

RM: It's a good thing. I ran a genetics unit for many years and am enthusiastic about the new evidence about susceptibility genes that is coming out. We'll learn a lot from these genes. We just have to balance them up with other areas of research.

SRF: What, to you, is the single most vexing question in schizophrenia research that is still totally open after all these years?

RM: Personally, I would like to understand the interactions between individual genes and individual environmental factors. We have a first example of that in the interaction between COMT and cannabis, those with the Val/Val genotype being especially vulnerable to psychosis if they abuse cannabis. I suspect some schizophrenic people carry particular susceptibility genes that make them vulnerable to particular environmental phenomena, while other people with schizophrenia do not carry these genes and, therefore, can withstand these particular environmental factors, but are vulnerable to others. That greatly interests me, and I think we're going to be able to identify other such gene-environmental interactions in the next few years.

SRF: Linking a known environmental risk factor to a genetic predisposition�?

RM: �to precisely what it is about a particular risk allele that makes a person with that allele prone to develop psychosis after an obstetric complication, when living in a city, or to cannabis, or to some specific environmental factor that doesn't make you or me psychotic. These gene/environment interactions are most exciting at present.

SRF: Then epigenetics should be a research priority in psychiatry research?

RM: Yes. Gene-environmental interactions and also gene-gene interactions. On their own, susceptibility genes like neuregulin or dysbindin seem to have only a small effect, roughly doubling the risk of schizophrenia, but what if one carries both risk haplotypes? We will need big studies to look at the interactions between 2 or 3 or more susceptibility genes.

SRF: As a journalist who has observed many disease fields, it seems to me that the bar is low in psychiatry. We have some drugs, we've had them for a long time, and it seems that the field is content to accept that the drugs help a fraction of the patients with a fraction of the symptoms. But the field is not aiming aggressively to cure schizophrenia or to treat it so effectively that people can work and function fully as parents and spouses. Compared to other arms of medicine, expectations somehow seem low. Do you agree?

RM: That's true. But, the fact that the bar is low in psychiatry is not just the fault of the doctors and nurses who care for the mentally ill. In my view, by and large, they do their best. It is because psychiatry has been starved of resources. The fault may lie partly with us because we haven't shouted loud enough about the neglect of the mentally ill, but it mainly lies with the rest of society who don't care about people with schizophrenia. Treating the mentally ill has not had the priority it deserves. For example, the leaders of both our countries prefer to spend money on waging war on those with whom they disagree, rather than to direct the resources towards the mentally ill.

But you are correct that it is also partly because of the acceptance of the Kraepelinian view that schizophrenia is a deteriorating illness. If you believe schizophrenia is a disease like Alzheimer's that is going to progress, then what you're trying to do is minimize the progression. This view has been responsible for a lot of pessimism. But I don't believe it's a deteriorating disease, and I don't see this inevitable progression that people talk about. If you treat patients enthusiastically and appropriately at onset, then some of them will make a good recovery. In the U.K., a government initiative has established a unit specializing in the treatment of first-onset psychosis in every region, so this is very hopeful. Of course, many who recover will still have to keep taking medication. For example, I have been looking after a woman for nearly 20 years who still takes antipsychotics to tame her voices. But she is a successful, married physician, and none of her colleagues or patients have any idea that she has schizophrenia.

One reason why some psychiatrists believe that schizophrenia is a progressive disease is that we only see those patients who keep having symptoms. Those who recover just get on with their lives and usually one doesn't hear from them. However, now and again one meets them in ordinary social life. Recently I met, by accident, a woman in her 30s with a very well-paid job, two children, and what seemed a happy marriage. Then I realized that I knew her, for when she was 18, she had gone psychotic and had been admitted to hospital twice and undoubtedly met criteria for schizophrenia. I had become involved in her treatment at the point where it was going badly wrong, but she made a good recovery, and after about 9 months, we phased out her medication. She completed her degree and hasn't seen a psychiatrist or taken an antipsychotic in the last 15 years. That's not most people's picture of what happens to somebody with schizophrenia.

SRF: Will we be able to cure schizophrenia?

RM: I don't think we'll be able to cure it with a single drug. Possibly, a combination of specific pharmacological and psychological interventions tailored differently for different patients may return most people to normal function. Even more excitingly, we may be able to prevent the development of the psychosis. We already have some weakly predictive childhood markers—being more clumsy, having more cognitive difficulties, having more social anxiety, and so on—but we will have more powerful predictors. Will it then be possible to screen such children and carry out neurophysiological or imaging or genetic tests, and identify the children who are especially likely to develop schizophrenia? Will we then be able to intervene before overt symptoms show up?

At present, the only attempt at preventive intervention is by treating those people who are on the brink of developing psychosis—the so-called "at risk mental state." This is far too late and is aimed at symptoms, not their precursors. But in the same way that people at risk for heart disease can take statins or hypotensives, I am hopeful we'll have ways of intervening that will stop the progression of the pathogenic processes underlying schizophrenia before the clinical symptoms manifest themselves.

This is the most promising time I can remember in schizophrenia. You may think research is going slowly, but it's going a lot faster than it did for the first 20 years that I studied schizophrenia.

SRF: Let's follow up in a few years to see what has happened in the interim. Thank you for this conversation.

RM: It was my pleasure.