Professor Robin M.
From the archived Special Topic of
Schizophrenia is the medical term for a group of
psychoses characterized by hallucinations, delusions,
and bizarre behavior. It is probably not a disease in
itself, but rather a collection of conditions. The
proportion of the general population who will have a
schizophrenic episode at some point in their life is
less than 1%.
According to our October 2007 Special Topics analysis
of schizophrenia research, Professor Robin Murray ranks
at #3, with 139 papers cited a total of 3,872 times.
Science IndicatorsSM from
Professor Murray's citation record includes 163 papers cited a total of
4,865 times in the field of Psychiatry & Psychology, as well as 52
papers cited a total of 1,427 times in the field of Neuroscience &
Professor Murray is a Professor of Psychiatry in the Institute of
Psychiatry at the Maudsley, King's College, University of London; he is
also a consultant psychiatrist at Maudsley Hospital.
In this interview, he talks with
ScienceWatch.com correspondent Simon Mitton about
the main themes of his group's research on
How did you get into this field?
I started work in the 1970s. At that time some of the biological theories,
or explanations, for schizophrenia were crazier than the condition itself.
We were interested in the theory that people with schizophrenia were
walking hallucinogenic factories, and we studied the hallucinogenic
substance dimethyltryptamine. We found significantly more
dimethyltryptamine in the urine of schizophrenic patients than in other
psychotic patients or in healthy controls. So for a while we seemed to be
However, about this time the dopamine hypothesis became the pre-eminent
neurochemical explanation for schizophrenia. Dysregulation of the dopamine
system was subsequently strongly linked to psychosis and schizophrenia,
with abnormally high striatal dopamine shown to underlie these conditions.
So although the endogenous hallucinogenic theory was never disproved, it
just died of fatigue and disinterest.
Could you tell me about your group?
I am at the Institute of Psychiatry, London, which is by far the largest
psychiatric research center in Europe. We have about 1,000 academics and
researchers, of whom about 150 concentrate on schizophrenia and bipolar
disorder. Within our group there is a range of research mainly looking at
etiological questions. In epidemiology we take advantage of the UK's
National Health Service that has provided us with data across the
population and over a large span of time. Epidemiology is important to us
in part because our US colleagues cannot do it: there is no database of
patient records at the national level in North America.
We work on the precursors of psychosis. For example, we ask questions such
as: what are the children like who later develop schizophrenia, or, what
characterizes children who will later have bipolar disorder? We look at
which groups are particularly prone: city dwellers, migrants, and so forth.
This research is impossible in countries with fragmented health care.
How disabling is it? Can the average person hold down
their job for example?
No, mostly they cannot, and so the condition contrasts with most other
psychiatric disorders. Sadly, the majority of people with schizophrenia
will not recover to their previous level of functioning. Among sufferers,
the luckiest 20% have just one episode, after which they may still have
some problems, but are able to manage without medication. At the other
extreme, the worst 20% will go into a nosedive and deteriorate: they become
very sick and highly dependent. Then in the middle, we have 60% who will
have one or more episodes, from which they recover to a certain extent, but
after each episode they don't quite regain their previous level of
What are environmental risk factors?
"Schizophrenia is not a total
enigma any longer; rather it's like a huge jigsaw
There are a number of risk-increasing factors. One of the most important is
living in a city. There is ample evidence from across the western world
that being born and brought up in a city increases risk. The best evidence
is from Denmark: people brought up in Copenhagen are about 2.5 times more
likely to develop schizophrenia than people in the rural population.
Does this suggest it is stress related?
We do not know. Researchers have pointed their fingers at everything from
lead poisoning and subsequent cognitive impairment through to the idea that
it is easier to become isolated and paranoid in the inner city; another
theory is that illicit drug use is more prevalent in cities. However, none
of these theories have been proven.
Among your most-cited papers are the two, with Alastair
Cardno as the first author, that use twin studies to investigate
genetic relationships (Cardno AG, et al., "Heritability
estimates for psychotic disorders - the Maudsley twin psychosis
series," Arch. Gen. Psychiat. 56: 162-8, February 1999,
and Cardno AG, et al., "A twin study of genetic relationships
between psychotic symptoms," Amer. J. Psychiat. 159:
539-45, April 2002).
Here at the Maudsley Hospital, we are very lucky to have a twin register.
Anybody who presents to our hospital is asked if they are a twin. The
question sometimes perplexes the patients although it is useful for us!
The Cardno study was the first to look at the monozygotic co-twins of
people with schizophrenia to see not only if they also had schizophrenia or
alternatively were well, but also to see if they had suffered from mania.
What was surprising was that when we relaxed the hierarchical system of
classifying psychotic disorders, we found that while 40% of the co-twins
had schizophrenia (which we expected), but also that 8% had had a manic
episode (which was unexpected).
Thus we were able to show that schizophrenia and bipolar disorder are not
totally genetically discrete. We calculated that probably about half the
genetic liability is in common between the two disorders, a liability to
psychosis in general. If an individual additionally suffers
neurodevelopmental impairment (because he has additional genes that
slightly deviate brain development or because he suffers some early hazard
such as hypoxia at birth) this pushes the individual towards the
schizophrenia end of the continuum of psychosis. On the other hand, if the
individual has the predisposition to psychosis but is cognitively very able
as a child then he is more likely to end up with the clinical picture
typical of the bipolar disorder end of the continuum.
Why did the papers make such an impact?
The papers are highly cited because the Cardno study caused a lot of fuss
in the US community. There is a big split between European psychiatry,
where there is considerable skepticism about the validity of the diagnostic
categories that we use, and American psychiatry, which has tended to
believe that the categories in DSM-IV are actual disease entities.
Therefore there was a heated debate about this study. American critics
asked: could we diagnose schizophrenia correctly—was there a
statistical artifact? But basically it was a reluctance of American
psychiatrists to believe that there was a genetic relationship between the
two conditions. Now, several years on, the link is much more widely
accepted, and indeed there are some molecular studies suggesting that some
of the risk genes for schizophrenia are also risk genes for bipolar
The investigations led by Louise Arseneault on cannabis
and schizophrenia have also attracted a huge amount of interest
(Arseneault L, et al., "Causal association between cannabis
and psychosis: examination of the evidence," Brit. J.
Psychiat. 184: 110-7, February 2004).
Beginning in the 1990s it was apparent to clinicians like myself that a lot
of patients with psychosis smoked cannabis. However, initially (being
children of the '60s and '70s) we thought, "Well, poor souls, they have a
lot of problems, they are miserable, they are poverty-stricken, they are
hearing voices – what's wrong with them having a few puffs?"
Then families started saying to me "Could this have been caused by
cannabis? He's been smoking it since he was 13..." Gradually we began to
take this question seriously, and cohort studies were initiated, following
up adolescents who did and did not smoke cannabis to see how many of each
group developed psychosis.
In 2002 the UK government decided to lower the illegality of cannabis,
making its use subject to lighter penalties. Their timing was very
unfortunate because within months there appeared several papers linking
cannabis use by young people with later onset of schizophrenia. The
Arseneault paper was one of the first of these. Of course, the relationship
is nothing like as strong as that connecting smoking with lung cancer.
Nevertheless, the more cannabis you smoke in adolescence the greater the
risk of schizophrenia: for the heaviest users the risk increases about
five-fold. Thus instead of a risk of under 1%, about 5 in every 100
heavy-using teenagers will develop psychosis.
I think the high citation rates are a partly a result of the UK political
parties turning cannabis classification into a political football.
Policymakers opposed to the decriminalization of cannabis used our results
to support their case, while those in favor pointed out that our studies
show that the vast majority of cannabis users come to no harm.
Your group's high-impact papers include striking results
on auditory hallucinations, in which patients complain of "hearing
Patients with schizophrenia believe the voices are external. They are
adamant that the voices are real. If you put patients in an fMRI scanner
and ask them to indicate when they are hearing voices, you see activation
of Broca's area where speech is produced. This confirmed Chris Frith's
theory that the voices are a misinterpretation of inner speech. There does
not seem to be anything wrong with the production of inner speech itself in
sufferers. But, in normal individuals the production of inner speech
somehow turns off the neural system that normally processes external
In contrast, Suhki Shergill used MRI studies to show that when patients are
hallucinating they are activating temporal lobe areas that are normally
involved in the processing of external speech (Shergill SS, et
al., "Mapping auditory hallucinations in schizophrenia using
functional magnetic resonance imaging," Arch. Gen. Psychiat.
57:1033-8, 2000). People with schizophrenia show activation of this
auditory processing system when they are hearing voices; no wonder they are
convinced the voices are real.
The outstanding question is how do we relate these observations to the
neurochemical abnormalities; we do not know that yet. We have the dopamine
hypothesis and we have the explanation for the voices, but how is it that
an excess of striatal dopamine somehow facilitates the misinterpretation of
It's also a striking feature of your list of hot papers
that the group has found that obstetric complications are a risk
factor for the later development of schizophrenia.
There is indeed an increased risk with pre- and perinatal events. The
effect is not large: it's a doubling of risk. My interest goes back to 1978
when I went to Scandinavia for a couple of weeks. In Denmark and Sweden I
discovered that there was a lot of research on the role of obstetric
complications leading to schizophrenia. This was all totally new to me.
The 2002 paper led by Mary Cannon (Cannon M, Jones PB, Murray RM,
"Obstetric complications and schizophrenia: historical and meta-analytic
review," Amer. J. Psychiat. 159: 1080-92, July 2002) reviewed
all the sound epidemiological studies, and confirmed that there is a
risk-increasing effect of pre- and perinatal events: for example, mother
having had a severe viral infection, or the baby being small for its
gestational age (which would indicate nutritional problems), or hypoxia at
birth. The factor that is best established is hypoxia: babies who suffered
oxygen starvation at birth tend to have small hippocampi. This is
postulated to lead to a dopamine system that is vulnerable to becoming
over-activated after puberty.
Are we getting closer to a scientific understanding of
Schizophrenia is not a total enigma any longer; rather it's like a huge
jigsaw puzzle. We have a reasonable idea of the big picture, and we have
some sections where the bits fit together, but we do not know how to match
up all the different parts and fill in the missing areas.
My view is that the final common pathway is dopamine dysregulation in the
striatum. People developing psychosis are releasing excess dopamine. One
pathway to this is neurodevelopmental: you either inherit genes that cause
subtle impairment of cortical development, or you have some brain insult
which results in you having a neural system which is compromised; this
renders you prone to dysregulation of dopamine after you go through
adolescence. A second pathway is abuse of drugs such as amphetamines,
cocaine, and cannabis, which mess up the dopamine system. I believe that a
third pathway is through severe chronic social stress, which also can
impact on the dopamine system. However, this latter notion is not yet
In summary, we know about the effect of genes and several environmental
risk factors. What we do not know is how they interact or what are the
intervening mechanisms that link the etiological risk factors to the final
common pathway of dopamine dysregulation. These are the critical questions
Professor Robin M. Murray, MD DSc FRCP FRCPsych FMedSci
Institute of Psychiatry at the Maudsley Hospital
King's College London
London, United Kingdom
Professor Robin M.
Murray's most-cited paper with 361 cites