Psychiatric News July 1, 2005
Volume 40 Number 13
© 2005 American Psychiatric Association
p. 1
Experts Square Off Across Antipsychotic Generation Gap
Mark Moran
Four annual meeting debaters arrive at a consensus on two points:
second-generation antipsychotics are not a homogenous class, and the best
treatment is tailored to each patient's unique needs.
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Debating the relative merits of first-generation and second-generation
antipsychotics at APA's 2005 annual meeting in Atlanta are (from left) William
Carpenter, M.D., Rajiv Tandon, M.D., Richard D'Alli, M.D., and John Davis,
M.D. Ira Glick, M.D. (not shown), was the other debater. David Hathcox
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Are second-generation antipsychotics (SGAs) uniformly superior in efficacy
and safety to first-generation antipsychotics (FGAs)?
Four leading lights in schizophrenia research sought to answer that
question in a spirited debate at APA's 2005 annual meeting in May in
Atlanta.
Answering in the affirmative were John Davis, M.D., a professor of
psychiatry at the University of Illinois, Chicago, and Ira Glick, M.D., a
professor of psychiatry and behavioral science at Stanford University School
of Medicine.
They emphasized the findings of a meta-analysis of 124 randomized,
controlled trials comparing efficacy data on first- and second-generation
agents and 18 comparison studies of SGAs published in the June 2003
Archives of General Psychiatry. The results showed that while SGAs do
not constitute a completely homogenous group, clozapine, amisulpride,
risperidone, and olanzapine each showed greater efficacy than FGAs
(Psychiatric News, July 4, 2003).
Davis and Glick, co-authors of the article, argued also that studies
strongly suggest that the SGAs have a superior effect on negative symptoms, as
well as on cognition. The result is better overall functioning in the long
term, they said.
Defending the FGAs were Rajiv Tandon, M.D., director of the schizophrenia
division in the Department of Psychiatry at the University of Michigan, and
William Carpenter, M.D., director of the Maryland Psychiatric Research Center.
They criticized much of the existing clinical-trials data comparing SGAs and
FGAs for methodological problems and biases. Among them was improper dosing
with FGAs. Carpenter and Tandon said putative benefits of SGAs disappeared
when they were compared with haloperidol given in lower doses in combination
with anticholinergic drugs.
Carpenter said that many of the industry studies looked at quality of life
but did not include those data in their reports. That omission suggests that
the SGAs are not making a good showing in the truly important category of
functional improvement.
"None of the studies shows that we are changing functional outcome
with any of these drugs," Carpenter said. "Industry has created
blockbuster markets without creating important therapeutic
advantages."
Presenting data from the June 2003 Archives report, Davis told the
standing-room-only audience that much of the greater efficacy found for at
least some of the SGAs (olanzapine, clozapine, amisulpride, and risperidone)
was due to their greater effect on negative symptoms.
"I feel the four more effective antipsychotics have a broader
spectrum of action," Davis said. "They are doing more, and most of
why they are doing better is that they are doing more for symptoms that are
not helped by the conventional antipsychotics."
Davis added that though the evidence is limited, SGAs may have a better
effect on cognition. Especially intriguing, he said, is evidence from a
comparison of olanzapine and haloperidol in first-episode schizophrenia
suggesting the SGA was associated with less deterioration of gray matter
(Psychiatric News, May 5).
Glick underscored the importance of advances against negative symptoms.
"Long-term maintenance is where the action is," he said.
"Overall, as we manage patients over many decades, the SGAs clearly have
a major advantage.... The focus is no longer on positive symptoms; it's on
long-term quality of life, negative symptoms, and cognition."
"I will go for every bit of benefit I can get," Davis said.
"You have more flexibility with the SGAs, and ultimately you will come
out with a better result. Weight gain is [a major] side effect, but the way to
minimize it is to start working on it in the first episode and manage all the
risk factors. If the patient is doing better [overall], you will be able to do
a better job [managing weight gain]."
In response, Tandon emphasized what the Davis-Glick meta-analysis showed as
well—that the SGAs are not a homogenous group and that there was
significant variability in between-group differences. For that reason alone,
he said, it was not possible to agree with the assertion that SGAs are
"uniformly" superior in efficacy, safety, and tolerability.
Tandon went on to say, however, that while some SGAs, particularly
clozapine, may have superior efficacy with refractory patients, the evidence
is much less clear with first-episode patients. "The differences in
efficacy are very soft," he said.
He also criticized as problematic the use of "last observation
carried forward" (LOCF) analysis in many studies. LOCF is sometimes used
in longitudinal studies to make up for treatment drop-out and attrition and to
preserve sample size, but its use may result in faulty estimation of treatment
effects. "Our patients are not the last observation carried
forward," Tandon said.
Carpenter echoed this criticism, saying that unless attrition is random
from both arms of the comparison, LOCF is not a valid tool for analysis.
Patients who do not respond in a short period to haloperidol, for instance,
may drop out or switch to the comparator drug; the last observed value for
their performance is carried forward as the value that will be used in the
results.
"If you agree that eight weeks of Haldol beats two weeks of Haldol,
then you have to accept that how long you are on treatment really
matters," Carpenter said. "So the last observation carried forward
is very problematic."
Carpenter cited a host of other methodological problems with comparison
studies between FGAs and SGAs. Principal among these is the fact that all of
the studies recruited patients who had failed on FGAs, ensuring a bias in the
results toward efficacy with SGAs.
He also cited very high doses of FGAs in many studies and the failure to
pre-treat those receiving FGAs with anti-Parkinsonian drugs. When lower doses
and anti-Parkinsonian drugs are used, SGAs' advantages in efficacy disappear,
Carpenter said.
Because of the large sample sizes, studies may result in fairly small
effect sizes that, while statistically significant, are clinically all but
negligible.
Carpenter was also highly critical of the claim that SGAs improved
cognition. "It is preposterous to think of these as pro-cognition drugs
when the advantages are in comparison to drugs that we know interfere with
cognition," he said.
Finally, Carpenter and Tandon stressed that weight gain associated with
SGAs is a serious, potentially life-shortening side effect that cannot be
minimized. Tandon noted, for instance, that the greatest cause of increased
mortality among patients with schizophrenia was cardiovascular disease.
There was agreement among the debaters that SGAs are not homogenous and
that the best treatment is one tailored to each patient.
"You must individualize treatment for each patient," Glick
said. "Do the maximum that you can for the patient and the family over
the long run and don't overtreat. I consistently emphasize monotherapy and a
minimum of concomitant therapy because of the side-effect issues."
Carpenter said, "There is a wide range of drugs that vary mostly in
their side-effect profiles. We ought to be matching up an individual patient
with the side-effect profile that would be most advantageous for that
particular patient." 
Related Article:
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APAPAC Helps Spread Psychiatry's Message on Capitol Hill
- James H. Scully, Jr.
Psychiatr News 2005 40: 4.
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