When clozapine was licensed as an antipsychotic in the US and
UK over 15 years ago, it seemed a revolutionary drug with
improved efficacy over existing agents.1This triggered the
development of a series of new drugs termed ‘atypical’ (or
second-generation) on the basis of an apparently reduced risk of
clozapine’s pharmacology of lower dopamine D2receptor affinity
and higher affinity for other neuroreceptors, in particular 5-HT2A.
This new class of drugs was heralded as the first major advance
in the therapeutics of schizophrenia for 40 years. The second-
generation drugs appeared to have important advantages over
their first-generation (typical or conventional) predecessors, in-
cluding better efficacy for positive, negative and mood symptoms,
and improved tolerability. In addition, it was reported that they
had cognitive-enhancing effects.2It was also claimed that the
higher cost of these drugs would be offset by savings resulting
from decreased use of healthcare services. None the less, the
global antipsychotic drug market has increased 30-fold since
the late 1980s to more than US$15 billion per year.
Despite these claims, meta-analyses and systematic reviews
have provided only limited support for the superiority of
second-generation antipsychotics.3–5Much of the evidence about
their efficacy relative to first-generation drugs comes from short-
term, industry-funded trials where patients are highly selected,
drop-out rates are high and outcomes are based mainly on statis-
tical comparisons of symptom ratings.6As a result, healthcare pol-
icy makers on both sides of the Atlantic faced a dilemma with
respect to the rising costs of mental healthcare and the lack of
demonstrably improved outcomes of patients. In addition, many
questions remained unanswered. Were the second-generation
antipsychotics incontrovertibly superior to the first-generation
drugs and where was the evidence showing that they represented
a major advance in routine mental healthcare settings? Were
some better than others? Was clozapine superior to other
second-generation antipsychotics? To address these questions,
the National Institute of Mental Health in the US and the
NHS Health Technology Assessment R&D Office in the UK
each separately funded a ‘pragmatic’, or practical, clinical trial
in the late 1990s, with no sponsorship from industry. Pragmatic
trials characteristically have broad inclusion criteria and long
follow-up, aiming to mimic routine clinical practice as far as
is consistent with a rigorous randomised design.7Their purpose
is to clarify the effects of an intervention in real-life clinical
practice and patient populations.
The US Clinical Antipsychotic Trials of Intervention Effectiveness
(CATIE)8was a double-blind trial in which 1493 patients
with chronic schizophrenia were randomised to one of the
second-generation antipsychotics olanzapine, quetiapine, risperi-
done, ziprasidone (the last was added into the design after the
study had begun), or the medium-potency first-generation drug
perphenazine. The primary aim of the trial was to compare the
effectiveness of perphenazine with several second-generation anti-
psychotics. The primary outcome for the trial, chosen to reflect
real-world practice, was discontinuation of the drug and switching
to another antipsychotic for any reason, be it lack of efficacy, too
many side-effects or patient choice. This outcome was chosen,
rather than symptom improvement, since it was felt to encapsu-
late all kinds of ‘drug failure’ in a simple categorical variable.
The trial was run over 57 sites between 2001 and 2004 and the
sample size had 76% power to detect 12% differences in disconti-
nuation rates. The participants were in general largely stable out-
patients with a mean illness duration and treatment history of 14
years. Clinicians prescribed medication to participants under
double-blind conditions, with dose titrated against clinical
response, and analyses later showed that drug dosage used was
generally similar to US clinical practice with some variation.
The results showed, first, that all drugs had limitations, in that
74% of patients were discontinued from their randomised treat-
ment over 18 months. Median time to discontinuation overall
was 4.6 months. Olanzapine proved to be the most effective in
terms of having the lowest discontinuation rate (64%), but had
the highest side-effect burden overall. Surprisingly, the remaining
second-generation drugs differed neither from each other, nor
from the first-generation antipsychotic perphenazine, in terms
of effectiveness or extrapyramidal side-effects. There was no
evidence that second-generation drugs were better for negative
symptoms or cognitive deficits.9Individual drugs differed in
specific side-effects. Olanzapine caused most weight gain and dys-
lipidaemia, quetiapine caused most anticholinergic effects, risperi-
done the most hyperprolactinaemia and sexual side-effects.
CATIE and CUtLASS: can we handle
Sho ˆn Lewis and Jeffrey Lieberman
Two large, non-commercial clinical trials comparing first- and
second-generation antipsychotic drugs for people with
chronic schizophrenia in the US and UK have shown
unexpected results. In general, the newer drugs were no
more effective or better tolerated than the older drugs.
Clozapine outperformed other second-generation drugs. The
implications are considered.
Declaration of interest
S.L. is the Chief Investigator of the CUtLASS study and J.L. is
the Chief Investigator of the CATIE study. S.L. has received
honoraria from several pharmaceutical companies. J.L. has
received research funding from several pharmaceutical
The British Journal of Psychiatry (2008)
192, 161–163. doi: 10.1192/bjp.bp.107.037218
Sho ˆn Lewis (pictured) is Head of the Psychiatry Research Group at the
University of Manchester. His research interests focus on risk factors and
interventions in early psychosis. Jeffrey Lieberman is Chairman of Psychiatry
at the Columbia University College of Physicians and Surgeons and Director of
the New York State Psychiatric Institute. His research has centred on the
neurobiology, pharmacology and treatment of schizophrenia and related
Perphenazine had highest rates of discontinuation for extrapyra-
midal side-effects, even though direct measures of these effects
did not differ significantly between drugs.
CATIE included a subsequent trial for those participants who
discontinued the first phase because of a lack of efficacy.10They
were invited to be re-randomised to a comparison of open-label
clozapine v. other second-generation antipsychotics, with time
to all-cause discontinuation again as the primary outcome. In
the 99 participants entering CATIE phase 2, clozapine emerged
as being significantly more effective than the other second-
generation drugs, with a median time to discontinuation of 10
months, twice the length of the next best, olanzapine.
The UK Cost Utility of the Latest Antipsychotic Drugs in
Schizophrenia Study (CUtLASS)11,12comprised a pair of smaller,
open (i.e. not-masked to patients and clinicians) randomised trials
comparing classes of drug as grouped in most clinical guidelines:
first-generation v. second-generation drug other than clozapine
(CUtLASS 1), and other second-generation drug v. clozapine. Pri-
mary outcome was quality of life at 1 year and symptoms were the
main secondary outcome. Outcomes were assessed by assessors
masked to treatment allocation. In CUtLASS 1, 227 people with
schizophrenia, mostly out-patients, who were being assessed by
their clinical team for medication review because of poor response
or adverse effects were randomised to either a first-generation or a
second-generation drug other than clozapine (amisulpride, olan-
zapine, quetiapine or risperidone). The choice of individual drug
within each class was made by the managing clinician in advance
of randomisation. The rate of follow-up interview was 81% at 1
year. The results showed no advantage of second-generation drugs
in terms of quality of life or symptoms over 1 year. In fact, those
participants receiving a first-generation antipsychotic did rather
better. In addition, there were no significant differences in rates
of objectively assessed extrapyramidal side-effects. Participants re-
ported no clear preference for either class of drug. The CUtLASS 2
trial was of similar design and compared clozapine with other
second-generation drugs in 136 patients who had not responded
well to two or more previous drugs. Results showed that there
was a significant advantage for clozapine in symptom improve-
ments over 1 year; moreover, patients significantly preferred it.
How do these two trials compare? The rationale for each trial
was the perceived need for relevant, real-life trial data to inform
policy and routine clinical practice. The trials were designed
wholly separately of each other and conducted in different
healthcare systems. The investigators in both trials predicted that
generation drugs, and that clozapine would be the most effective.
Both trials were government funded and both were designed to
reflect routine clinical practice as much as possible, with broad
inclusion criteria intended to enroll representative patients. The
participants were very similar clinically and demographically in
the two trials. The main results were broadly the same in each trial
and surprised both groups of investigators. In both trials, the
primary hypotheses were not supported and second-generation
antipsychotics were not found to be more effective (with the ex-
ception of olanzapine in CATIE). Moreover, they did not produce
measurably fewer extrapyramidal side-effects overall. In both
trials, clozapine was the most effective for treatment-resistant
Are first-generation as good
as second-generation drugs?
Why did both trials fail to find the expected clinical advantage for
second-generation antipsychotic drugs? Could each have had
design flaws? Sample size was not a problem in CATIE. CUtLASS
had 75% power to find an effect and the results showed a trend for
participants receiving first-generation drugs to do better, suggest-
ing that a larger sample would not have changed the result.
Another possible problem might be that both trials included
mostly patients with long histories of treatment. This may have
limited the scope for any medication to demonstrate improve-
ments. None the less, both trials went on to show that clozapine
had a significant advantage. A related issue is that, if patients were
already taking a second-generation drug at baseline and this pre-
sumably was not fully effective, then this meant that the sample
was biased to non-responders to second-generation anti-
psychotics. However, in CUtLASS 1 80% of patients were being
treated with a first-generation drug when referred into the trial.
Moreover, CATIE patients switched at study entry from a
second-generation antipsychotic to perphenazine did no better
(or worse) than those switched to another second-generation
One possible contributor to the unexpected findings is in
choice of first-generation comparator. In CUtLASS, clinicians
chose sulpiride in 49% of cases and in contrast to most
industry-sponsored trials, haloperidol was chosen in just 8%.
Sulpiride has been viewed anecdotally as having some atypical
properties, but a recent Cochrane review14finds no evidence to
support this. The avoidance by clinicians of high-potency first-
generation drugs and the use of moderate doses in both trials
probably explains the failure to find excess rates of extrapyramidal
effects. A further factor in explaining the results was the way the
data were analysed, using more advanced methods than has been
usual in the past. For example, in dealing with the problem of
missing data, both trials chose to avoid the usual practice of using
‘last observation carried forward’ for patients who drop out
during the trial, where the last available ratings are counted as if
they are real end-point data. There is now evidence that this
produces bias in the final results.
There are caveats. One is that neither trial was powered to look
at the issue of tardive dyskinesia, the be ˆte noir of first-generation
antipsychotics. Although there is emerging evidence that second-
generation drugs may not be as free of risk for tardive dyskinesia
as once thought, this is still a potential limitation of first-
generation antipsychotics.15This needs to be set against the risk of
serious metabolic consequences of some second-generation drugs.
Into the future
In the end, we think that the convergence in the results of these
two trials is compelling. The finding of clinical equivalence
between second- and first-generation antipsychotics derives
further support from a third trial with a similar pragmatic
design,16which found no advantage for olanzapine in comparison
with haloperidol given in lower doses than has been traditional.
One issue is the differences in design between the CATIE/
CUtLASS trials and most previous trials. CATIE and CUtLASS
aspired to go beyond efficacy comparisons (can drug A work
better than drug B under ideal conditions?) and compare the
effectiveness of drug treatments (does drug A work better than
drug B as really used in clinical practice?). We would argue that
such practical trials are more relevant to policy makers, mental
healthcare administrators and practitioners, since the results they
produce are more generalisable to routine clinical practice.
A final aim of both CATIE and CUtLASS was to look at the
economics of prescribing. In CUtLASS, the detailed costs of direct
healthcare over 1 year varied greatly between patients, with a mean
of £18800 for those in the first-generation arm and £20100 in the
Lewis & Lieberman
CATIE and CUtLASS Download full-text
second-generation arm. Of these costs, just 2.1% and 3.8% were
costs of the drugs themselves. For clozapine it was a similarly
low proportion, at 4%. Schizophrenia is an expensive disorder
to manage but not because of the prices of drug treatments. The
cost-effectiveness data from the CATIE trial indicated that per-
phenazine was significantly less costly and not less effective
than the second-generation antipsychotics as a group,17a result
replicated for the first-generation antipsychotics in CUtLASS.18
Where does this leave prescribers? Our conclusion must be
that first-generation drugs, if carefully prescribed, are as good as
most second-generation drugs in many if not most patients with
established schizophrenia. This is good news as it increases the
range of choices of antipsychotic drugs. Careful prescribing of
first-generation antipsychotics means using lower doses than
was often done in the past and avoiding high-potency drugs.
Clozapine clearly remains an important drug where others have
failed. Choosing which drug to switch to may depend on the
reasons for switching in the first place: lack of efficacy might
suggest a switch to olanzapine or clozapine, whereas lack of toler-
ability might suggest another choice. Note that the findings may
not be the same for first-line treatments19,20and that the role of
long-acting medications has yet to be made clear.
It is worth reflecting on how crudely we often use anti-
psychotic drugs. Polypharmacy, the prescribing of two or more
antipsychotics in parallel, is widespread despite the lack of evi-
dence to support it and the knowledge that it doubles costs and
multiplies safety risks. Off-label prescribing is common. It is
perhaps not surprising that, in the context of a severe, chronic ill-
ness, clinicians are tempted to resort to untested measures. It is
the same sense of frustration that allowed us to be ‘beguiled’, as
Peter Jones described it (Washington Post article 3 October
2006/10/02/AR2006100201378.html), by the promise of a new
class of drugs. These trials emphasise again the urgent need for
discovering new, safe, effective medications, as well as knowing
how to best use our existing treatments.
Sho ˆn Lewis, MD, FMedSci, Neuroscience and Psychiatry Unit, University of
Manchester, Manchester, UK; Jeffrey Lieberman, MD, Department of Psychiatry,
College of Physicians and Surgeons, Columbia University and New York State
Psychiatric Institute, and Lieber Center for Schizophrenia Research, and New York
Presbyterian Hospital and Columbia University Medical Center, New York, USA
Correspondence: Professor Sho ˆ n Lewis, University of Manchester University
Place (3rd floor east), Stopford Building, Oxford Road, Manchester M13 9PL, UK.
First received 21 Mar 2007, final revision 22 Jun 2007, accepted 10 Jul 2007
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