From the archived Special Topic of
In October 2007, Special Topics ranked Dr. Jeffrey
#2 on its list of the most-cited
schizophrenia researchers over the past decade, with
117 papers cited a total of 4,435 times. When the
analysis was originally performed, in July 2001, Dr.
Lieberman was ranked at #4. According to
Essential Science IndicatorsSMfrom
Dr. Lieberman’s record includes 111 papers cited
a total of 3,848 times to date in the field of
Psychiatry & Psychology, as well as 71 papers cited
a total of 2,156 times to date in the field of
Neuroscience & Behavior.
His most-cited paper, "Effectiveness of antipsychotic drugs in patients
with chronic schizophrenia," (Lieberman JA, et al., N. Engl. J.
Med. 353: 1209-23, 22 September 2005), is a Highly Cited Paper in
the field of Clinical Medicine, with 463 cites to date. In addition, this
paper is the most-cited paper on schizophrenia published in the past two
At present, Dr. Lieberman is the Lawrence E. Kolb Chairman of Psychiatry at
the Columbia University College of Physicians and Surgeons and Director of
the New York State Psychiatric Institute. He also holds the Lieber Chair
and Directs the Lieber Center for Schizophrenia Research in the Department
of Psychiatry at Columbia.
correspondent Gary Taubes talks with Dr. Lieberman
about his most-cited paper and its
Your 2005 New England Journal of Medicine
article continues to be cited at a remarkable rate. What prompted that
study? Why test so many antipsychotic drugs so relatively late in the
To understand why the study was necessary, you have to understand the
history and development of antipsychotic drugs. These drugs were invented
in the 1950s and were then known as neuroleptic drugs. The term was derived
from the ability of these drugs to cause a kind of psychomotor paralysis, a
characteristic slowness or rigidity of the animals or people who took them.
But at the same time these drugs produced a near-miraculous quelling of
psychosis, for which there had never been an effective treatment. After the
prototype of this kind of drug was developed, a series of similar drugs,
essentially analogues, were introduced. They all had the same therapeutic
property but varied in terms of the potency and the therapeutic dose at
which they had to be administered. Through this process of essentially
imitating the prototype with relatively specific or minor refinements in
potency and side effects, a whole cohort of antipsychotic drugs were
developed, which eventually came to be known as first-generation or typical
For close to 40 years these drugs were used, and they worked, albeit with
limitations of which the medical field and the patients who took them
became increasingly aware. This period witnessed no real progress, no real
innovation, in terms of improving the effectiveness of treatment and
improving upon the pharmacology of these antipsychotic medications.
When did this change and what did it?
In 1989 clozapine was introduced, and this was really a different kettle of
fish. It was the first antipsychotic medication that had therapeutic
efficacy, but did not produce this characteristic psychomotor paralysis. It
was called an atypical neuroleptic or antipsychotic. In addition, clozapine
had a greater capacity to alleviate psychotic symptoms. This was
demonstrated by testing it in patients who were not responsive to existing
medications and finding that these patients improved substantially with
clozapine. So clozapine proved to be a huge sensation. It was touted as a
breakthrough drug and was even the subject of a cover story of
Time magazine in 1990.
"If you looked at the data, at
the clinical trials that were done comparing first- and
second-generation drugs, it wasn’t obvious that
the second-generation drugs were actually
But like all good things, there was a catch. In this case, there was a very
serious potentially deadly side effect called
agranulocytosis—toxicity against white blood cells. This side effect
occurs in about one in 150 people who take the drug. If it isn’t
detected in time, it renders people susceptible to infection and possible
death by sepsis. As a result the drug was approved by the FDA only to be
used in people who did not respond to other antipsychotic medications and
with the requirement that they have their blood tested on a weekly basis
for as long as they took the medication.
Did the pharmaceutical industry come up with other drugs
that had the same efficacy of clozapine but not this potentially fatal
Yes, clozapine motivated the pharmaceutical industry—you could say
galvanized it—to develop a clozapine-like drug that did not have
agranulocytosis as a side effect. So other drugs were developed, tested,
approved, and introduced, beginning in 1994 with a drug called risperadone;
then 1996, olanzapine; 1997 was quetiapine; and in 2001, ziprasidone. These
drugs were ostensibly clozapine-like, meaning they had better therapeutic
efficacy and less or no potential for the neurologic side effects that the
first-generation drugs had.
These drugs began to be used preferentially over the older drugs, to the
point that by the end of the decade—the end of the
century—upwards of 90% of all prescriptions for antipsychotic
medications were for the newer medicines. One result was a tremendous
increase in the cost of antipsychotic medications. In the U.S., the cost of
these medications, pre-clozapine, was on the order of $300 million per
year. By 1999, it was about $7 billion.
How much better were these second-generation
If you looked at the data, at the clinical trials that were done comparing
first- and second-generation drugs, it wasn’t obvious that the
second-generation drugs were actually better. It was by no means absolutely
conclusive. And if they were better, they didn’t appear to be all
that much better.
So the National Institute of Mental Health (NIMH), as one of its
initiatives to stimulate large practical clinical trials in mental illness,
awarded us a contact to do a study evaluating the effectiveness of
antipsychotic medications. What they said is, "We would like to know how
the first-generation and second-generation drugs compare. And if the
second-generation drugs are better, how do these compare to each other and
which are the best?"
Then your study was prompted by the NIMH?
Yes. They issued an RFA, a request for applications, to submit a proposal
for a study that would provide evidence and hopefully answer this question
of the comparative effectiveness of the various antipsychotic medications.
How many drugs did you test and on how many
We initially framed the question of wanting to test first-generation drugs
against second-generation drugs, and then, secondly, comparing
second-generation drugs to each other. So the design involved all the
existing second-generation antipsychotic drugs approved by the FDA. Then it
compared them to one first-generation drug, which we used as a proxy for
all of them, since none were considered to be any better or worse than any
of the others. We selected as our proxy a drug that was of intermediate
potency and less widely used than some of the others.
Seems like an odd choice. What was your
The prevailing clinical practice was to use the high-potency
first-generation drugs—these were the ones that produced the greatest
amounts of neurologic side effects. We reasoned that if we’re going
to retest these drugs, we should use one that is not obviously going to
produce noxious side effects. We wanted to use a drug that would at least
have a reasonable chance of being tolerated, but still worked by the same
mechanism as all the other first-generation drugs. We selected a drug
How many subjects did you have in the study?
Well, we carried out the study at sites in 57 locations in the U.S. and
enrolled 1,500 patients. The study called for every patient to be in for a
year and half. What’s important to understand is that the patients
included in the study were representative of people with chronic
We allowed for people to be in the study who had other psychiatric or
medical co-morbidities and might require other adjunctive medications, in
addition to their experimentally assigned anti-psychotic medication. This
meant we could generalize the study sample and results to patients in the
Is that what you meant when you said the NIMH funded you
to run a "practical" randomized controlled trial?
Yes, exactly. This is somewhat of a different type of study design that is
kind of intermediary between what are called classical randomized,
controlled trials and observational or naturalistic studies.
Did you find what you expected to find?
When we began this study we fully believed and hypothesized that the
second-generation drugs would be far superior and would be shown to be both
more effective and safer than perphenazine. What we found, much to our
surprise, was that the drug that did the best overall was olanzapine, but
it was only by a small amount and there was absolutely no difference
between the first-generation drug perphenazine and the other
There was a high switch rate from all the medications, indicating that over
that year-and-a-half period, the majority of the people voted with their
feet to try and find a medication that worked better than the one to which
they were originally allocated. That said that, yes, these treatments work,
but not ideally, and that neither the patients nor their physicians are
wholly satisfied with them.
Was olanzapine better at controlling side effects or
symptoms or both?
It was better at controlling symptoms but it produced substantial side
effects—principally weight gain. And when we looked at perphenazine,
it did not produce any significant degree of neurologic side effects, so it
was as effective as the other medications and as comparatively safe.
How did the pharmaceutical companies respond to your
Did they try to dispute the results?
Yes. Each company has had their own take on the study and its results.
Has anyone else replicated your results?
As it turned out, at the same time we were doing our study, colleagues in
England, unbeknownst to us, were doing a very similar study. This was the
CUtLASS study, and it had been commissioned by the National Health Service
in the U.K., also to compare first-and second-generation drugs. CUtLASS had
a slightly different design, but it was asking the same questions—it
was also a practical clinical trial, and it basically came up with the
Even down to the slight superiority of
Yes, it did show some superiority for olanzapine within the patients who
received second-generation drugs, but not enough people were treated with
olanzapine to give the statistical power to show a significant difference
from the others. But on the question of first generation vs. second
generation, CUtLASS found no difference between the two classes.
How do you make sense of your results, considering the
belief that these second-generation drugs were "breakthroughs" in
I think there were two main reasons for this disconnect between the
exuberant claims and the disappointing performance of these
second-generation drugs in the two trials. The first reason is what I call
the efficacy-effectiveness gap. This is something well known to researchers
as the explanation or as the basis for why treatments often don’t
work as well in clinical practice as they appear to do in the clinical
trials on which the FDA approvals are based.
Is this because the clinical trials are set up to show
the maximum possible benefits?
Right. Phase two and phase three trials, the ones submitted to the FDA for
review, are short term; they’re conducted at least partially in
hospital settings; they involve a selected sub-sample of patients for whom
the drug will eventually be used; and they exclude patients who have
different types of co-morbid conditions and so are more complicated to
In addition, the measures they use to assess effectiveness are usually
ratings of symptoms, whereas in clinical practice, you’re measuring
how well the patients are functioning, how they feel subjectively, as well
as what the severity of their symptoms are.
The second reason for the disparity between the results and our
expectations is simply that the claims for the superiority of
second-generation antipsychotics were greatly exaggerated, and this may
have been encouraged by an overly expectant community of clinicians and
patients who were eager to believe in the power of new medications. They
were hoping for something new and better, they were told here it is, and
they bought into it.
At the same time, these newer drugs were very aggressively marketed by the
pharmaceutical industry. Although marketing is supposed to be based on
evidence, that evidence was largely coming from the clinical trials. It was
not representative of how the drugs would necessarily perform in the real
world, in the broader population of patients.
One of my colleagues in England was interviewed on this subject and he said
that it wasn’t that clinicians were misled or deceived. Rather they
were sort of "beguiled" into thinking that these new drugs were better.
It’s like you go into a supermarket or an automobile showroom and
somebody shows you a generic version of a product and you compare it to one
that has very fancy and attractive packaging. There was a sort of slick
presentation to these drugs that gave the perception they were not only
newer but better.
Your NEJM paper has obviously been very highly
cited. Do you think the results of your study have actually influenced
I think one big effect the paper has had is to change the debate in the
field. So rather than thinking it’s a foregone conclusion that these
drugs are better and that it is substandard care or possibly even
malpractice to be using the older drugs, this is no longer the case.
At the same time, if you look at prescription rates and marketing data,
there hasn’t been a rush back to the older medications. The question
is, what are the incentives and what are the motivational forces?
The main motivational force, apart from knowledge, is financial. But when
doctors decide what medications to use, they don’t think about how
much it costs; they think about how effective it might be and what are the
side effects. Now we have an entire generation of doctors who have been
trained only on the new medications. They’ve never even used the
Do you think this will change?
It could. One reason is that the government, insurance companies, the
pharmaceutical-benefits companies, the Veterans Administration, and the
state Medicaid offices are all deciding how to use data from our study and
from CUtLASS, and whether the formularies and the reimbursement policies
should encourage consideration, if not use, of first-generation drugs. If
these drugs work as well, more or less, and cost a fraction of what the
newer medications cost—the ones that are still under
patent—then from a public health standpoint we should be trying to be
more efficient and economical. So changes in policy may affect practice
patterns in response to these results.
However, there are also significant political considerations. Patients, the
American people, and the doctors don’t like to be told what to do and
they don’t like to be deprived of choice. People want to have a right
to have what they want, and ostensibly the very best treatment, even if it
costs a heck of a lot more. And this is true, of course, particularly when
they’re not paying for it.
What people forget is that ultimately we are paying for it, either
from our tax dollars or higher insurance premiums. I’m just a
scientist and physician, but as a result of this study, I and my colleagues
have been drawn into a policy debate and it’s ongoing.
If a patient comes into your office tomorrow and you
diagnose him with schizophrenia, what drug do you give him?
For first-episode patients, that’s still an open question. For
chronic patients, I would review what treatments had been already used,
what’s worked, and what side effects have appeared. At the end of the
day, if there are no such special considerations emerging from the
treatment history, then there is no reason not to prescribe perphenazine or
another intermediate potency first-generation drug, because I know
it’s as good as any other drug and particularly if cost is an issue.
For treatment-resistant patients who haven’t gotten better on
anything else, then clozapine is the drug to be used.
For first-episode patients, we don’t know. Those patients are
relatively rare. They weren’t a part of our study or the British
study. But the beginning of the illness is the point when the patient is
most responsive to treatment. So it’s possible that a slight
difference in effectiveness may have exaggerated benefits in this group.
There is a study looking at first-episode patients that’s just been
completed in Europe. We’re waiting for the results, which will be the
next important piece of evidence or chapter in this story.
How have you personally followed up on this
We’re doing a couple of studies, trying to determine how to manage
the weight-gain side effect of these second-generation drugs. Is it better
to switch to a drug that doesn’t cause weight gain or to manage the
We’re also doing a study comparing long-acting injectable first- and
second-generation antipsychotic drugs. Here the same cost differential
applies. We’re also spending a lot of time and effort looking for new
and novel drugs. It’s clear even if the new drugs are a little bit
better, they’re still far from being panaceas. We desperately need
mechanistically novel, new medications. So we’re now very involved in
a program of experimental therapeutics.
Jeffrey A. Lieberman, M.D.
New York, NY, USA
Lieberman's most-cited paper with 463 cites