| Columbia’s Jeffrey A. Lieberman: A Mind to Prevent Schizophrenia |
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 Schizophrenia
is the prototypic mental illness of our time. The condition affects
one percent of the population, yet its cause is still unknown and
the diagnosis is still based on symptoms—the hallucinations and
delusions known as "positive" symptoms, and the "negative" symptoms
that include apathy, social withdraw, and flattened affect—rather
than the presence of any identifiable molecular abnormality, or a
diagnostic test. The progression of the disorder was thought to be
inexorable—a downward spiral into a hopeless state of chronic
psychosis and disability.
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"If we can potentially
identify people before even the onset of
schizophrenia, before it’s fully diagnosable, we might even
be able to prevent the onset,” says Jeffrey A. Lieberman of
the Columbia University College of Physicians and Surgeons.
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This dire prognosis, however, has been revised radically in the
past decade, thanks in large part to the work of the Columbia
University psychiatrist Jeffrey A. Lieberman. In the current update
to Thomson Scientific’s
Essential Science
Indicators
database, based on papers published and cited over the last ten
years, Lieberman currently ranks among the top 20 most-cited authors
in psychiatry/psychology. Seven years ago, he was featured among the
authors in this publication’s survey of high-impact psychiatry
research (Science Watch, 11[3]: 1-2,
May/June 2000).
More recently, his 2005 New England Journal of Medicine
article, "The effectiveness of antipsychotic drugs in patients with
chronic schizophrenia," has occupied the Medicine Top Ten since
early this year and is currently at #2, with more than 300 citations
recorded in less than two years since publication (see
table below). Moreover, in a recent Hot Papers
bimonthly file, Lieberman and colleagues fielded seven highly cited
reports published over the last two years. Within the last decade,
he’s published 18 papers with over 100 citations each.
Lieberman, now 59, earned his bachelor’s of science degree from
Miami University (Ohio) in 1970 and his medical degree from George
Washington University five years later. He did four years of
postdoctoral training at St. Vincent’s Hospital and Medical Center
in New York and another year as a research fellow at the Bronx
Psychiatric Center. Between 1980 and 1996, Lieberman’s professional
experience included lengthy stints at the Mt. Sinai School of
Medicine and the Long Island Jewish Medical Center of the Albert
Einstein College of Medicine. In 1996, Lieberman became director of
the Mental Health and Neuroscience Clinical Research Center at the
University of North Carolina School of Medicine. Since 2005, he has
been director of the New York State Psychiatric Institute and a
professor and chairman of the Psychiatry Department at Columbia
University College of Physicians and Surgeons.
Lieberman spoke to Science Watch from
his office at Columbia.
Your early research included a seminal longitudinal study of people
diagnosed with their first episode of schizophrenia. What did you
learn from that and how did that shape your research?
Three very interesting findings came out of that study.
First, contrary to what had been the prevailing opinion
previously, when patients with their first episode of
schizophrenia were treated promptly, they had a very good
outcome—a very high rate of response in terms of symptomatic
remission. Second, when we looked at factors that predicted the
rapidity and degree of remission, one of the strongest
predictors was how long patients had been actively psychotic
before that initial treatment intervention. The longer people
were actively sick—actively psychotic prior to that first,
initial treatment—the slower and lower the rate of recovery. The
shorter the duration of illness, the faster and better the rate
of recovery. So the earlier you treated people, the better the
outcome.
Did that observation prompt a change in the way we treat and
diagnose schizophrenics?
It spurred several major initiatives, both in research and in
mental-health-care services and intervention strategies. First,
it accelerated the search for the pathophysiology of the
progressive nature of the illness and its degenerative basis. In
addition, intervention strategies and clinical services were
developed to try to reduce the duration of untreated psychosis,
and even to try and identify people before they are obviously
ill, before they develop the full-blown manifestations of the
illness. The idea is that if we can identify people earlier, we
can intervene and reduce the cumulative morbidity. And if we can
potentially identify people before even the onset of the
illness, before it’s fully diagnosable, we might even be able to
prevent the onset. This is now probably one of the hottest areas
of research currently ongoing in psychotic disorders.
What was the third thing that came out of your prospective study?
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Highly
Cited Papers by Jeffrey A. Lieberman,
Published Since 1996
(Ranked by total citations)
|
Rank |
Paper |
Citations |
| 1 |
J.A. Lieberman, et al.,
"Effectiveness of antipsychotic drugs in patients with
chronic schizophrenia," New Engl. J. Med.,
353(12): 1209-23, 2005. |
345 |
| 2 |
C.M. Beasley, et al.,
"Olanzapine versus placebo: Results of a double-blind,
fixed-dose olanzapine trial," Psychopharmacology,
124(1-2): 159-67, 1996. |
268 |
| 3 |
R.S.E. Keefe, et al.,
"The effects of atypical antipsychotic drugs on
neurocognitive impairment in schizophrenia: A review and
meta-analysis," Schizophrenia Bull., 25(2):
201-22, 1999. |
257 |
| 4 |
D. Robinson, et al.,
"Predictors of relapse following response from a first
episode of schizophrenia or schizoaffective disorder,"
Arch. Gen. Psychiatry, 56(3): 241-7, 1999. |
204 |
|
5 |
B.J. Kinon, J.A. Lieberman,
"Mechanisms of action of atypical antipsychotic drugs: A
critical analysis," Pyschopharmacology, 124(1-2):
2-34, 1996. |
202 |
|
6 |
R.M. Bilder, et al.,
"Neuropsychology of first-episode schizophrenia: Initial
characterization and clinical correlates," Am. J.
Psychiat., 157(4): 549-59, 2000. |
200 |
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As part of the study, our patients would receive annual MRI
assessments to quantify brain morphology. We found that, as had
been reported previously by numerous imaging studies, people
with schizophrenia have some structural differences compared to
healthy controls. These differences are usually in the form of
smaller volumes of grey-matter structures, such as the
hippocampus or superior temporal gyrus, and enlargement of the
fluid-containing regions of the brain, like the lateral
ventricles and the subarachnoid space, which is the space
between the skull and the outer surface of the brain. Over time,
there is further progression of these morphologic
abnormalities—additional loss of grey matter, dilation of the
ventricles, etc., suggesting further progression of the illness.
Are these morphological abnormalities something that can be
prevented?
We think so. In 2005, we published a paper in Archives of
General Psychiatry reporting that we could prevent this loss
of grey matter in the brain by effective early treatment.
Is that what you consider the most important observation to come out
of your research?
More important, I think, is that it changed the notion that
the progression of the illness, this downward spiral, was
inexorable; that people who are genetically at risk for
schizophrenia are "doomed from the womb." We now believe that
with our current pharmacologic agents, by administering them
early in the course of the illness and reducing the period of
psychosis, we can prevent recurrences, and we can prevent this
deterioration in the brain. This has led to a huge effort to
develop early detection and intervention programs. It’s going on
all over the world, although the U.S. is lagging behind to some
degree.
Do different antipsychotic drugs have differing degrees of efficacy
in slowing down or stopping this shrinking of grey matter in the
brain?
That is a key question. The original conception was that
treatments might be able to suppress symptoms but not forestall
the eventual deterioration and disability. Now the question is
whether treating symptoms and stopping the progression of the
disease are the same thing, and whether or not different
antipsychotics are better at one or the other. The ideal study
to answer that would be a randomized trial in first-episode
patients, one in which we assign one group to receive active
antipsychotic medication and another to receive a placebo. Since
that would be unethical, what we did and published in 2005 was
the next best thing: We used two medications, one of which is a
newer, potentially superior treatment that is more tolerable.
The other is a standard older treatment. That study showed a
difference in grey-matter-volume decline between the two drugs.
Had there been a placebo group in that study, our expectation is
that there would have been a greater decline in grey-matter
volume in that group. The implication is that any treatment is
better than no treatment, but some treatments are better than
others at preventing this progression, either through better
tolerability and improved compliance or superior efficacy.
Do you know what causes the deterioration in grey matter?
We believe it’s a combination of two things. We know that
symptoms of the illness are expressed due to dysregulation of
neurotransmission by two neurotransmitters: dopamine and
glutamate. The excess release of these neurotransmitters can
cause over-stimulation or excitatory toxicity of cells, which
could lead to the loss of synaptic connections. The second thing
is that these patients seem to have a deficit in plasticity. In
other words, there is a lack or a reduction in the resilience of
cells to withstand physiological insults or exposure to
toxicity. They’re not able to regenerate cell processes as
rapidly or as effectively. This combination of excess
neurotransmitter release coupled with decreased resiliency
results in a pruning or shrinkage of the whole dendritic arbor
in the affected regions, and this is what is detected on MRI as
a reduction in grey-matter volume.
How would you rate the efficacy of the current generation of drugs
in dealing with the full spectrum of schizophrenic symptoms?
To be perfectly blunt, all the drugs we currently use affect
the psychotic symptoms principally, and they work reasonably
well. But there are no proven effective treatments of negative
symptoms or cognitive symptoms. Studies have suggested efficacy
for those symptom dimensions, but no treatments have been proven
effective, and no drug has an FDA indication for treatment of
those negative and cognitive symptom dimensions.
What makes these negative and cognitive symptoms so much harder to
treat than the positive symptoms?
The causes are probably different. Schizophrenia is likely a
multi-system disease; it has pathologic dimensions that are
mediated by distinct neural and neural-chemical systems. So, for
example, what is known indisputably is that psychosis is caused
by excessive stimulation by dopamine of d2 receptors in the
mesolimbic pathway. Every antipsychotic drug has some affinity
for the d2 receptor and is believed to block dopamine at that
receptor. However, when it comes to negative and cognitive
symptoms, d2 antagonism doesn’t really have an effect.
Are there hypotheses to explain these negative symptoms, and do
these give you any idea of how to go about treating them?
Probably the most straightforward hypothesis is that these
negative symptoms, in part, relate to reduced d1 signaling in
the cortex, particularly in the frontal cortex. That would
suggest that a d1 agonist would be therapeutic. The agonists
developed so far all risk stimulating both the d1 receptors and
the d2 receptors, including in the mesolimbic pathway, and so
they risk exacerbating psychosis. That’s not a viable approach.
One would like a selective d1 agonist, and we don’t have one
yet.
One of your hot papers reports on an increased risk of coronary
heart disease in schizophrenic patients. What’s going on there?
I’m not sure who coined the phrase "no free lunch," but when
it comes to psychotropic drugs, that proves to be the case. All
the drugs we use have serious and significant side effects. The
first general antipsychotic medications had high rates of
neurologic side effects: they produced symptoms resembling
Parkinson’s disease. The newer medications have been found
to produce much fewer neurologic side effects, but they produce
a greater degree of weight gain and disturbances in glucose and
lipid metabolism. So we see in our society in general an
increase in metabolic syndrome related to our lifestyle and
culture. Patients with schizophrenia are subject to the same
influences that have driven up these rates in the general
population, and then they are on medications that can further
contribute to this tendency. The result is that patients with
schizophrenia undergoing treatment invariably have abnormally
high rates of metabolic syndrome and consequent cardiovascular
disease.
Is it the treatment or the schizophrenia that’s mostly responsible?
There are certainly lifestyle-related factors and possibly
some small disease-related contribution to the syndrome. But
there is no question that there’s an added effect from
treatment. Not all treatments are comparably liable to cause
these effects. And there is a cruel irony in the fact that the
most effective treatments therapeutically are also ones that
cause the greatest degree of these side effects.
How would you describe the state of schizophrenia therapy circa
2007, and what needs to be done in the next five years to improve
it?
I think what this group of studies we’ve been talking about
has demonstrated is that, for psychotic disorders, we clearly we
have a class of effective treatments that are huge advances over
what existed in the past. But there are significant limitations
to these treatments. They help patients, but only to a limited
degree. They treat psychosis, but not cognitive or negative
symptoms. They can’t restore people who have already suffered
the clinical deterioration that’s experienced with the illness,
and they cause side effects of one form or another in a
substantial proportion of patients. Also, we have been guilty,
as a field, of using these treatments at all stages of the
illness, as if their effectiveness should be the same at all
stages. And clearly the stage of the illness and the clinical
characteristics of the patient are going to determine how
effective the medications are likely to be. "One approach fits
all" is not optimal for a disease that expresses itself in late
adolescence and from which patients don’t die directly and can
live to ripe old ages. What we have to do now is pursue the
development of mechanistically novel treatments—novel
medications that either maintain or improve efficacy and have
less or no side effects and are also able to target the other
symptom dimensions of the illness, those symptoms not treated by
the current class. We need something new.
Science
Watch®, September/October 2007, Vol. 18, No. 5
Citing URL:
http://www.sciencewatch.com/sept-oct2007/sw_sept-oct2007_page3.htm |
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