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Antidepressants and Placebos: Secrets, Revelations, and Unanswered Questions

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We are very heartened by the thoughtful responses to our article. Unlike some of the responses to a previous meta-analysis of antidepressant drug effects (Kirsch & Sapirstein, 1998), there is now unanimous agreement among commentators that the mean difference between response to antidepressant drugs and response to inert placebo is very small. It is so small that, despite sample sizes involving hundreds of participants, 57% of the trials funded by the pharmaceutical industry failed to show a significant difference between drug and placebo. Most of these negative data were not published (see Thase, 2002) and were accessible only by gaining access to U.S. Food and Drug Administration (FDA) documents. The small difference between the drug response and the placebo response has been a "dirty little secret" (Hollon, DeRubeis, Shelton, & Weiss, 2002), known to researchers who conduct clinical trials, FDA reviewers, and a small group of critics who analyzed the published data and reached conclusions similar to ours (e.g., Greenberg & Fisher, 1989). It was not known to the general public, depressed patients, or even their physicians. 1 We are pleased that our effort facilitates dissemination of this information. The pharmaceutical company data that we have analyzed reveal a mean drug/placebo difference of less than 2 points on the Hamilton depression scale (HAM-D), a difference that is not clinically significant (see Jacobson, Roberts, Berns, & Mcglinchey, 1999). Another way of describing this difference is in terms of response rates. Thase (2002), for example, notes that 35% -50% of patients respond to medication compared with 25% -30% who respond to placebo (see also Brown, 2002; Hollon et al., 2002). This is interpreted as indicating that 10% -20% of depressed clinical trial patients show a true drug effect, in which case it follows that 80% -90% of these patients do not.
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Prevention & Treatment © 2002 by the American Psychological Association
July 15, 2002 Vol. 5, Article 33 For personal use only--not for distribution.
Antidepressants and Placebos: Secrets, Revelations, and Unanswered Questions
Irving Kirsch
University of Connecticut
Alan Scoboria
University of Connecticut
Thomas J. Moore
George Washington University
We are very heartened by the thoughtful responses to our article. Unlike some of the responses to a
previous meta-analysis of antidepressant drug effects ( Kirsch & Sapirstein, 1998), there is now unanimous
agreement among commentators that the mean difference between response to antidepressant drugs and
response to inert placebo is very small. It is so small that, despite sample sizes involving hundreds of
participants, 57% of the trials funded by the pharmaceutical industry failed to show a significant difference
between drug and placebo. Most of these negative data were not published (see Thase, 2002) and were
accessible only by gaining access to U.S. Food and Drug Administration (FDA) documents.
The small difference between the drug response and the placebo response has been a "dirty little
secret" ( Hollon, DeRubeis, Shelton, & Weiss, 2002), known to researchers who conduct clinical trials, FDA
reviewers, and a small group of critics who analyzed the published data and reached conclusions similar to
ours (e.g., Greenberg & Fisher, 1989). It was not known to the general public, depressed patients, or even
their physicians. 1 We are pleased that our effort facilitates dissemination of this information.
The pharmaceutical company data that we have analyzed reveal a mean drug/placebo difference of
less than 2 points on the Hamilton depression scale (HAM-D), a difference that is not clinically significant
(see Jacobson, Roberts, Berns, & Mcglinchey, 1999). Another way of describing this difference is in terms
of response rates. Thase (2002), for example, notes that 35% - 50% of patients respond to medication
compared with 25% - 30% who respond to placebo (see also Brown, 2002; Hollon et al., 2002). This is
interpreted as indicating that 10% - 20% of depressed clinical trial patients show a true drug effect, in which
case it follows that 80% - 90% of these patients do not.
Response rate increments of 10% - 20% seem clinically important to some commentators (e.g., Thase,
2002) who have interpreted them as indicating the percentage of patients who show a strong response to
antidepressants but would not be helped by placebo. This interpretation is mistaken ( Moncrieff, 2002). To
classify patients as responders or nonresponders, one must establish a cutoff point (e.g., a 50% decrease
in depressive symptoms; Mulrow et al., 1999). Consider two patients with baseline HAM-D scores of 20.
One is randomized to the drug condition and shows a 10-point improvement on the HAM-D. The other is
assigned to the placebo group and shows a 9-point improvement. The first would be classified as a
responder and the second as a nonresponder, but in fact, the difference in response (1 point) is negligible.
What makes this example particularly important is that these two patients are typical, rather than
exceptions. A 50% drug response is the median in published clinical trials ( Mulrow et al., 1999), and a
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10-point decrease was the mean drug response in the FDA data set. Thus, the 10%-20% difference
between drug and placebo response rates could be due entirely to those patients showing a moderately
strong response (just above criterion) to drug and those showing almost as strong a response (just below
criterion) to placebo. It would be obtained if there were not even one patient with a strong true drug effect. 2
Of course, it could also be obtained if there were some patients with a larger true drug effect and others on
which the drug had a negative effect or no effect at all. This would be true if there were a hidden moderator
variable, a possibility raised by some reviewers and discussed by us below.
We have suggested two possible explanations for the small differences between the drug response and
the placebo response: Either drug and placebo effects are not additive (in which case, conventional clinical
trials are an inappropriate means of evaluating drug effects because they could lead to the rejection of truly
effective medications, the benefits of which are largely masked by placebo), or the drug effect is very small.
The commentators have raised three additional possibilities. They suggest that (a) there may be flaws in
the ways in which trials sponsored by the pharmaceutical companies are conducted, (b) the small mean
differences between drug and placebo obscure strong drug effects produced by some antidepressants in a
subset of depressed patients, and (c) the effects of medication may be more stable than those of placebo.
In the present reply to the commentaries, we consider each of these possibilities. We also consider the
suggestion that the use of antidepressants is justified, no matter how small the effect, as long as it is
statistically significant ( Brown, 2002; Moerman, 2002; Salamone, 2002; Thase, 2002).
The Adequacy of the Clinical Trials
The medications evaluated in the clinical trials that comprise the FDA data set were sponsored by the
companies that manufacture them and therefore stand to benefit financially from a positive outcome. So, if
there were any biases in these trials, one would expect them to favor the investigated drug ( Antonuccio,
Burns, & Danton, 2002). Indeed, a quantitative review of the factors affecting response to antidepressants
in clinical trials indicated that sponsorship of a trial by a drug company tended to produce effects favoring
the sponsor's product ( Freemantle, Anderson, & Young, 2000). Some of the commentators on our analysis
of the FDA data set have suggested that the opposite may be the case. Brown (2002) suggests that
zealous researchers inflate baseline scores so that mildly depressed potential participants are not screened
out (see also Thase, 2002). Hollon et al. (2002) maintain that low doses may be used to minimize side
effects.
Brown's (2002) suggestion is particularly troubling; it is tantamount to charging that clinical researchers
have been fudging the data. Even more troubling is the news that this charge has been confirmed by a
spokesperson for the FDA ( Elias, 2002). Inflating baseline scores also inflates the apparent benefit
produced by treatment. Thus, both the drug response and the placebo response might be overestimated.
These data were the basis on which the medications were approved by the FDA. If they are suspect, then
perhaps the decision to approve the medications should be reconsidered.
Hollon et al. (2002) suggest that the manufacturers of fluoxetine may have used low doses in their
clinical trials, so as to be able to claim low levels of side effects when marketing their product. As a result,
the therapeutic effect might also have been underestimated. This possibility is contradicted by the data.
Fluoxetine is prescribed in dosages ranging from 20 to 60 mg daily. The two dose-response studies
submitted by Eli Lilly to the FDA evaluated fluoxetine doses of 20, 40, and 60 mg. In one of these trials
(conducted on mildly depressed patients), no significant differences were found between doses or between
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any dose and placebo. In the other study (conducted on moderately to severely depressed patients), the
two lower doses were significantly more effective than the high dose, which was not significantly more
effective than placebo. According to the package label for fluoxetine, a particularly high dose (80 mg) was
used in other clinical trials submitted to the FDA.
Moderator Variables
It has been suggested that some patients may be more responsive than others to medication or that
some antidepressants are more effective than others ( Brown, 2002; Hollon et al., 2002; Thase, 2002). If
this is the case, then drug/placebo differences, collapsed across patients and drugs, might underestimate
the effect that some medications have on some patients.
Our analysis included six different antidepressant medications. Among those medications for which
complete data were reported, the range of drug/placebo differences was between 1 and 3 points on the
HAM-D. Even for those medications for which data on trials with negative results were withheld, the highest
mean difference was 3.21 points. Thus, if there are any mean differences between these medications, they
must be very small.
Hollon et al. (2002) express the concern that excluding estimates for the three medications for which
scores for unsuccessful trials were not reported might result in the inadvertent omission of "several of the
more powerful current medications" (¶ 10). They make specific reference to venlafaxine as a medication
that might "produce the most robust effects" (¶ 10) because it works on multiple neurostransmitter systems.
This concern is not well founded. First, venlafaxine was not one of the medications that were excluded in
estimating effects across medication. Second, a meta-analysis of 105 clinical trials ( Freemantle et al.,
2000) indicates that drugs that work on multiple neurotransmitter systems are not more effective than purely
serotonergic medications. Third, the weighted mean drug/placebo difference for the three excluded
medications was 2.31 HAM-D points. Because this is an overestimate, in which one third of the trials (those
showing particularly poor results for the active drug) were excluded, the real drug/placebo difference for the
excluded medications cannot be significantly more than that of the medications for which full data were
reported.
If the medications do not produce significantly different responses, perhaps there are patient differences
that mask more potent pharmacological effects. In support of this contention, Hollon et al. (2002) presented
data from an unpublished study of paroxetine, in which patients were matched (post hoc) on rank order of
change scores (i.e., the patient showing the least improvement in the active drug condition was matched
with the patient showing the least improvement in the placebo condition, etc.). Drug/placebo differences
between change scores of matched patients varied as a function of change score rank, but even among
those pairs of participants showing the most change, the mean difference was only 3.39 points on the
HAM-D.
Hollon et al. (2002) also report percentages of pairs of patients showing differences of 4 points or
greater and differences of 6 points or greater. They interpret the existence of these differences as indicating
that some patients show a greater drug effect than do others. However, measurement error always
produces a distribution around a mean, and Hollon et al.'s data provide no reason to suspect any other
explanation. Even if the true drug/placebo differences were always between 2 and 3 points, some of the
observed differences would be greater and some would be smaller. Further, there is an exceptionally high
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degree of error in the scores assessed by Hollon et al. Change scores are notoriously unreliable, even
when pre- and posttest scores are highly reliable ( Campbell & Kenny, 1999). Differences between change
scores are doubly unreliable. This unreliability is evident in the study described by Hollon et al., in which the
pattern of differences between drug and placebo change scores varied substantially between the two sites
at which the study was conducted.
One method of coping with unreliability is to examine mean scores from large groups of participants
rather than individual participants or (as in the case of Hollon et al.'s [2002] data) pairs of participants. Even
with relatively large samples, differences in sample size produce differences in the reliability of the data.
Figure 1 displays drug/placebo differences in the FDA data set as a function of sample size.
These differences vary widely in small samples, but they are substantially more reliable in large
samples. In addition, there is a tendency for large samples to show smaller drug/placebo differences. As
seen in Figure 1, a mean difference of about 2 points on the HAM-D characterizes drug/placebo differences
in the larger (and therefore, more reliable) studies.
The most frequently proposed hypothetical moderator is baseline severity. The hypothesis is that more
severely depressed patients show a greater response to medication and a smaller response to placebo. In
the FDA data set, there was only one trial conducted on mildly depressed patients. Three trials were
conducted on severely depressed, hospitalized inpatients, but the data from two of these trials were not
reported because significant drug/placebo differences were not found. The vast bulk of the trials was
conducted on patients judged to be moderately to severely depressed, and it is with these patients that the
drug/placebo difference was approximately 2 points on the HAM-D. Thus, the drug/placebo difference
appears to be negligible for most of the patients to whom antidepressants are prescribed.
Figure 2 displays the relation between baseline scores and improvement in the larger ( N= 200 or
greater), and therefore more reliable, clinical trials described in the FDA data set.
More severely depressed patients showed greater improvement, but this is true of patients treated with
placebo as well as those treated with medication. This is due to regression toward the mean ( Campbell &
Kenny, 1999), which almost always produces a correlation between baseline scores and change scores. 3
3
The slope of the regression line appears steeper for drug than for placebo, suggesting a greater
drug/placebo difference among more severely depressed patients, but a regression analysis indicates that
this difference is not statistically significant ( p> .20). Nevertheless, because tests of differences in slope
have very low power, a greater drug/placebo difference among more severely depressed patients cannot
be ruled out. Therefore, we calculated the drug/placebo differences observed in the six large studies with
the lowest baseline depressions scores (range = 17.21 - 24.25) and compared them to the differences
observed in the six large studies with the highest baseline depression scores (range = 25.15 - 27.85). Mean
drug/placebo differences were 1.46 points in studies with lower baseline scores and 2.56 in studies with
higher baseline scores. Further, this is likely to be an overestimate of the drug/placebo difference for the
more severely depressed patients because it does not include the unreported data from two trials
conducted on severely depressed, hospitalized inpatients, neither of which showed a significant difference
between drug and placebo. The bottom line is that even in studies with more severely depressed patients,
there is a strong placebo response and a relatively small difference between drug and placebo.
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Finally, it is possible that different patients respond to different medications ( Hollon et al., 2002).
Although there are scant experimental data in support of this hypothesis, clinicians report that patients who
do not respond to a particular antidepressant sometimes respond when given a different medication. The
results of an early study on the prevention of nausea are pertinent to this issue ( Wolf, Doering, Clark, &
Hagans, 1957). Patients were successively given seven different treatments for nausea, following which
ipecac was administered?. Response was defined as blocking the emetic effects of ipecac. There was
substantial variability in response rates. Some participants responded to all treatments; some to none. Most
responded to some treatments but not to others. Thus, the pattern of responding was similar to that
observed clinically, following the administration of antidepressants: Patients who did not respond to a given
medication often responded to another. In the Wolf et al. (1957) study, however, all seven treatments were
known to be ineffective for the condition being treated. They were placebos. These data demonstrate that
the response to placebo is inconsistent. Thus, finding that patients sometimes respond after switching to a
different antidepressant is exactly what one would expect if antidepressants were nothing more than active
placebos.
The most extensive study of the hypothesis that different patients respond to different medications is the
Freemantle et al. (2000) meta-analysis. They reviewed 105 clinical trials in which serotonin uptake inhibitors
(SSRIs) were compared with other types of antidepressant and used regression analysis to find predictors
of differential outcome. Hypothesized predictors included pharmacological action (noradrenaline reuptake
inhibition, serotonin reuptake inhibition, and 5-HT2 receptor antagonism, dual action, and triple action),
treatment setting (inpatient vs. outpatient), dose of the comparator drug, method of analysis (LOCF vs.
completer data), age of the patient, measurement scale (HAM-D vs. any other), and sponsor of the trial.
Only one of these factors bordered on significance: There was "a trend towards increased efficacy of the
sponsor's drug" ( Freemantle et al., 2000, p. 294).
Freemantle et al. (2000) did not use some of the factors that the commentators cited as potential
predictors of differential outcome, and one can never rule out the possibility of undetected moderator
variables. But if there are hidden moderators, the overall mean difference between drug and placebo (2
points on the HAM-D) constrains the conclusions that can be drawn from them. If the mean drug/placebo
difference is greater than 2 points for a subset of medications or patients, then it must be less than 2 points
for the others. For example, if the mean difference between drug and placebo is 4 points for half of the
patients (which is still a rather small drug effect), then the mean effect of antidepressants on the other
patients must be 0, and if it is more than 4 points for half the patients, then the medications must be causing
harm to at least some others who would fare better on placebo.
Is the Drug Response More Stable Than the Placebo Response?
Our analysis was limited to the acute efficacy studies submitted to the FDA. It is possible that short-term
drug/placebo differences are negligible but that drug effects may be more stable than placebo effects,
resulting in lower relapse rates ( Brown, 2002; Hollon et al., 2002; Thase, 2002), just as psychotherapy
effects appear be more stable than medication effects ( Hollon, Shelton, & Loosen, 1991). Before looking at
the data, however, it is necessary to consider two issues: the way in which the outcome is described and
the design of long-term studies.
There are two ways in which long-term outcome can be described. One is in terms of relapse following
initial improvement; the other is in terms of continued response to treatment. Thase (1999), for example,
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reported 12-month relapse rates of 20% with venlafaxine and 34% with placebo in a pooled analysis of four
clinical trials. Thus, there were 1.5 times more relapses with placebo than with medication. Described in
terms of continued efficacy, however, these same data indicate that, after 12 months, 80% of the patients
receiving medication remained in remission, compared with 66% of patients on placebo. Thus, 83% of the
effect of medication was duplicated by placebo. 4 That this effect is similar to that seen in the short-term
trials rules out the possibility that antidepressant drug effects might be substantially greater over a longer
period of treatment.
A second issue that must be considered in understanding the results of long-term studies is the design
of the study. There are two experimental designs that have been used. The more common design is the
relapse prevention trial, in which patients who have responded to medication are then randomized to either
continue on medication or be switched to placebo. A less common method of assessing long-term response
is with continuation or extension trials, in which patients who have responded to either drug or placebo
during an acute efficacy trial are continued on the treatment to which they were originally assigned.
The relapse prevention design is particularly biased against finding placebo effects. First, the clinical
trials from which the patients are drawn typically begin with placebo washout periods, in which all patients
who respond to placebo are eliminated from the study. Thus, participation in the relapse prevention trial is
limited to patients who have not only responded to the active medication but have also failed to respond to
placebo. Second, this design may exacerbate the problem of breaking blind on the basis of perceived side
effects. It seems likely that a person who has been on an active medication and is then switched to placebo
will be likely to detect the change.
Despite this bias, relapse prevention trials often show large placebo responses. For example, one of the
two 24-week relapse prevention trials reported to the FDA by the manufacturer of citalopram showed 2-year
response rates of 69% for placebo and 90% for citalopram. The other showed response rates of 76% for
placebo and 86% for citalopram. Thus, in these studies, the long-term placebo response among patients
who had been successfully treated with an active antidpressant was between 77% and 88% of the
medication response. Similar results were reported by Walach and Maidhof (1999) in a meta-analysis of
relapse prevention trials published between 1973 and 1990. In these trials, 71% of the drug response was
duplicated by placebo. Walach and Maidhof also examined response to treatment as a function of the
duration of the trial. Their data indicate that responses to both drug and placebo decrease over time.
Contrary to conventional wisdom, however, the correlation between duration of the trial and response to
treatment was higher for active medication ( r= -.84) than for placebo ( r= -.62), suggesting a steeper
decline in effectiveness for active drugs than for placebo.
Continuation trials are relatively rare, but the data confirm the relative stability of the placebo response
over time. As Antonuccio et al. (2002) note, the 18-month followup of the NIMH Collaborative Depression
Study ( Shea et al., 1992) reported equivalent long-term outcomes for both drug and placebo, with a lower
relapse rate among remitted patients in the placebo group. A more recent study compared hypericum,
sertraline, and placebo ( Hypericum Depression Trial Study Group, 2002) and reported 26-week
continuation data for patients who had responded to treatment during the 8-week clinical trial. Of the 79
patients who entered the continuation phase, none of the placebo patients relapsed, none of the setraline
patients relapsed, and only one taking hypericum relapsed.
What Do We Do Now?
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As many of the commentators have noted, the basic findings of our analysis are clear and undisputed.
The mean difference between response to antidepressant medication and response to placebo is very
small. This raises the question of what should be done in clinical practice. The response to both drug and
placebo is substantial. How is this therapeutic benefit to be elicited if these medications, which may be little
more than active placebos, are abandoned? Some commentators have argued that they should be given to
depressed patients, even if their pharmacological effect is negligible. If nothing else, they can be the vehicle
by means of which the placebo response is elicited ( Hollon et al., 2002; Moerman, 2002).
This argument rests on the assumption that a genuine pharmacological effect has been proven. The
emperor's new clothes may not be the elegant suit his subjects were led to expect, but at least they are
made with real fabric ( Thase, 2002). We have not denied that antidepressant medication might have
genuine pharmacological effects. In fact, we raised the possibility that its effects could be much larger and
reliable than the data suggest. The problem is that the effects of antidepressant medication are unknown.
They may be very large, vanishingly small, or completely nonexistent. The emperor may be wearing an
elegant invisible suit, a fig leaf, or nothing at all.
It is true that, on average, there is a significantly greater response to medication than to placebo. What
is not yet known is the reason for this difference in response. It may be a drug effect, but it may also be an
enhanced placebo effect associated with the perception of side effects and the breaking of blind (
Greenberg, 2002; Greenberg & Fisher, 1989). 5 It is known that antidepressants produce significantly more
side effects than do those observed in inert placebo control groups ( Mulrow et al., 1999), patients assigned
to conventional antidepressants are able to break blind to a significant degree ( Rabkin et al., 1986), and a
drug effect has not been convincingly demonstrated in studies using active placebos ( Moncrieff, Wessely,
& Hardy, 2001), despite the fact that the medications used as active placebos may not prevent patients
from breaking blind ( Hollon et al., 2002). These data do not prove that the drug/placebo difference is due to
the breaking of blind, but they do suggest this as a reasonable possibility, one that needs to be ruled out
before the claim of even minimal drug effectiveness can be considered to have been substantiated (
Greenberg, 2002).
In addition, the additivity assumption needs to be tested directly. The indirect data are mixed. As Brown
(2002) notes, data showing different brain changes in placebo responders and drug responders ( Leuchter,
Cook, Witte, Morgan, & Abrams, 2002) suggest that the effects may not be additive. Conversely, data
showing similar brain changes in placebo responders and drug responders ( Mayberg et al., 1999) suggest
a common mechanism, which is consistent with the additivity hypothesis. Additivity is also suggested by the
parallel increases in response rates for SSRIs and placebos over the years ( Walsh, Seidman, Sysko, &
Gould, 2002). Since the composition of the medication has not changed, the change must be due to other
factors. We suspect that it is due to the dissemination of information (or misinformation) about the
marvelous success of the newer antidepressants.
We have raised the possibility of using the balanced placebo design, perhaps with active placebos as
an aid in preserving the manipulation, as the most straightforward test of the additivity hypothesis. Hollon et
al. (2002) have raised some useful concerns about the success of using active placebos for this purpose.
Salamone (2002) has provided suggestions that might address some of those concerns, and Antonuccio et
al. (2002) have suggested an alternative (assessing the degree to which blind is broken) that should be
implemented routinely in pharmacological research but that does not obviate the need for direct tests of the
additivity assumption.
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There also are other questions that need to be answered. We need to know more about the placebo
effect and its underlying mechanisms. Rehm (2002) has provided many insightful research suggestions
aimed at addressing this issue, and we hope that clinical researchers will implement them. We also think
that Salamone's (2002) suggestions for new studies of the dose-response relationship are worthwhile. The
data sent to the FDA by the pharmaceutical companies included studies in which up to four different doses
were evaluated, and except for the finding that lower doses of fluoxetine were more effective than a high
dose, they failed to find reliable linear or quadratic differences between doses. It is possible, as Salamone
(2002) suggests, that studies involving six or seven different doses would reveal some more complex
relationships. In addition, there is a need for additional tests of possible moderator variables (chronicity,
cortisol secretion, etc.).
In the meantime, what are the alternatives for treating patients? Imagine having a choice between four
treatments. Treatment A produces a large therapeutic response but also a large number of adverse effects,
including diarrhea, nausea, anorexia, sweating, forgetfulness, bleeding, seizures, anxiety, mania, sleep
disruption, and sexual dysfunction. Treatments B and C produce therapeutic responses that are almost as
great as those produced by treatment A, but without the adverse effects. In fact, the side effects produced
by Treatment B are beneficial (e.g., better general physical health). However, the therapeutic effects of
Treatments B and C have been evaluated in relatively few studies. Treatment D has been assessed in
many comparative studies, in which it has been found to be as effective as Treatment A in the short term
and more effective in the long term. It does not produce adverse effects. Given a choice between these
alternatives, which would you choose?
Of course, these alternatives are not merely hypothetical. Treatment A corresponds to SSRIs, and the
list of side effects is drawn from those that have been shown to be produced by these medications (
Antonuccio, Danton, DeNelsky, Greenberg, & Gordon, 1999; Mulrow et al., 1999). Treatment B is physical
exercise, which has been reported to have lasting therapeutic benefits in the treatment of major depression
( Babyak et al., 2000). It may be nothing more than a placebo, but if so, it is one with desirable rather than
adverse side effects. Treatment C is bibliotherapy (e.g., Burns, 1999), another low-cost treatment with
demonstrated effectiveness ( Jamison & Scogin, 1995; Smith, Floyd, Jamison, & Scogin, 1997) and little
danger of side effects. Treatment D is psychotherapy. As noted by Antonuccio et al. (2002), "psychotherapy
(particularly cognitive therapy, behavioral activation, and interpersonal therapy) compares favorably with
medications in the short term, even when the depression is severe (e.g., DeRubeis, Gelfand, Tang, &
Simons, 1999), and appears superior to medications in long-term comparative studies (Antonuccio et al.
1995; Hollon, Shelton, & Loosen, 1991)" (http://journals.apa.org/prevention/volume5/pre525c.html#p24
24). Given these data, antidepressant medication might best be considered a last resort, restricted to
patients who refuse or fail to respond to other treatments.
It may well be that the effects of psychotherapy are due to expectancy, conditioning, and other
psychological factors that have been hypothesized to be the basis of placebo effect ( Kirsch, 1997). Indeed,
changing maladaptive expectations is an essential cornerstone of cognitive therapy. But this does not
negate its effectiveness. The contention (e.g., Salamone, 2002; Thase, 2002) that the logic of
placebo-controlled evaluation should be extended to psychotherapy is mistaken ( Kirsch, 1978). In drug
research, placebos are used to distinguish the pharmacologically produced effects of substance
administration from its psychologically produced effects. However, there are no pharmacologically produced
effects of psychotherapy. The effects of a psychological intervention can only be due to psychological
factors. Control conditions consisting of alternative psychological treatments (including those erroneously
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called placebos) are useful in establishing which psychological factors are important in producing the
effects of a particular therapy but not in evaluating the efficacy of that treatment. Like placebos, effective
psychotherapies may accomplish their effects by changing expectations ( Kirsch, 1985, 1990, 1999), but
unlike placebos, they do so without deception.
References
Antonuccio, D. O., Burns, D. D., & Danton, W. G. (2002). Antidepressants: A triumph of marketing over
science? Prevention & Treatment, 5, Article 25. Available on the World Wide Web:
http://www.journals.apa.org/prevention/volume5/pre525c.html.
Antonuccio, D. O., Danton, W. G., DeNelsky, G. Y., Greenberg, R. P., & Gordon, J. S. (1999). Raising
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1An internal memorandum by the Director of the Division of Neuropharmacological Drug Products indicates FDA
awareness of this situation:
The Clinical Efficacy Trials subsection within the Clinical Pharmacology section not only describes the clinical
trials providing evidence of citalopram's antidepressant effects, but make mention of adequate and well
controlled clinical studies that failed to do so. I am mindful, based on prior discussions of the issue, that the
Office Director is inclined toward the view that the provision of such information is of no practical value to
either the patient or prescriber. I disagree. I believe it is useful for the prescriber, patient, and 3rd-party payer
to know, without having to gain access to official FDA review documents, that citalopram's antidepressants
(sic) effects were not detected in every controlled clinical trial intended to demonstrate those effects. I am
aware that clinical studies often fail to document the efficacy of effective drugs, but I doubt that the public, or
even the majority of the medical community, is aware of this fact. I am persuaded that they not only have a
right to know but that they should know. Moreover, I believe that labeling that selectively describes positive
studies and excludes mention of negative ones can be viewed as potentially "false and misleading" (Leber,
1998, p. 11).
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We agree that the public and the medical community should be informed of these data.
2The drug effect is conventionally interpreted as the difference between the response to the drug and the response to
placebo. It is that part of the drug response that is due to the pharmacological action of the drug. In contrast, the drug
response includes the effect of the drug, the placebo effect, spontaneous remission, regression to the mean, and any
other factors that might contribute to changes observed following the administration of medication. Similarly, the placebo
effect is that portion of the placebo response that is actually due to the administration of a placebo.
3Regression artifacts also affect the correlation between drug response and placebo response. Moerman reviewed prior
meta-analyses showing that these correlations range between .43 and .90. Similarly, if the analysis is limited to the more
reliable clinical trials in the FDA data set?those with samples of 200 or greater?the correlation between drug response
and placebo response in the FDA data set is .72. However, because baseline scores are necessarily correlated with
change scores (Campbell & Kenny, 1999), when the baseline scores of two groups are correlated (as they are in
meta-analyses of drug and placebo responses), the change scores will also be correlated. For example, when normally
distributed baseline scores in two samples are perfectly correlated with each other, and normally distributed posttest
scores in these samples are uncorrelated either with each other or with baseline scores, the correlation between the two
sets of change scores will be .50.
4The way in which this method of describing the data can be misleading can be illustrated by applying it to the Khan,
Warner, and Brown (2000) analysis of the data submitted to the FDA. These data indicate that there were twice as many
suicide attempts among patients given active medication than among those given placebo. This might be interpreted as
indicating that medication doubled the risk of suicide attempts, but this method of describing the data is misleading. The
actual rates were 0.8% with antidepressant medication and 0.4% with placebo. Thus, suicide attempts were absent in
99.2% of patients treated with drugs and 99.6% of patients treated with placebo, and as noted by Khan et al. (2000), the
difference was not statistically significant.
5Contrary to the implication in Muñoz's (2002) commentary, this hypothesis does not suggest duplicity on the part of
patients or researchers.
Correspondence concerning this article should be addressed to Irving Kirsch, Department of Psychology,
University of Connecticut 406 Babbidge Road, U-20, Storrs, CT 06269-1020
E-mail: irving.kirsch@uconn.edu
Figure 1. Drug/placebo differences as a function of sample size.
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Figure 2. Regression toward the mean in response to drug and placebo.
... For instance, while authors have found antidepressant medications are significantly better than placebo [36][37][38][39][40] and are deemed clinically effective especially in severe depression [41,42], others have queried these findings. For example, a large proportion of depressed patients (sometimes up to 80%) fail to respond to antidepressant therapy in clinical trials [43][44][45][46], and the reported superiority of antidepressants over placebos does not reach a clinically acceptable significant level [43][44][45][46]. While these findings have been heavily criticized by other authors [41,42,47], the Position Statement of the European Psychiatric Association on the value of antidepressants in the treatment of unipolar depression provided some clarification on this ambiguity, proposing that the risk/benefit relationship of antidepressant treatment is favourable in clinical settings, and that better results are achieved by co-medication/augmentation therapy approaches [42]. ...
... For instance, while authors have found antidepressant medications are significantly better than placebo [36][37][38][39][40] and are deemed clinically effective especially in severe depression [41,42], others have queried these findings. For example, a large proportion of depressed patients (sometimes up to 80%) fail to respond to antidepressant therapy in clinical trials [43][44][45][46], and the reported superiority of antidepressants over placebos does not reach a clinically acceptable significant level [43][44][45][46]. While these findings have been heavily criticized by other authors [41,42,47], the Position Statement of the European Psychiatric Association on the value of antidepressants in the treatment of unipolar depression provided some clarification on this ambiguity, proposing that the risk/benefit relationship of antidepressant treatment is favourable in clinical settings, and that better results are achieved by co-medication/augmentation therapy approaches [42]. ...
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Posted July 15, 2002. Comments on the article by I. Kirsch, T. J. Moore, A. Scoboria, and S. S. Nicholls (see record 2002-14079-003) which presents findings that represent an extension of Kirsch's already-well-known search into better knowledge about antidepressants. Rather than doubting the honesty of patients and researchers, Kirsch et al should accept the call by F. M. Quitkin, J. G. Rabkin, J. Gerald, J. M. Davis, and D. F. Klein (2000) to conduct "mega-trials" with investigators of varied theoretical orientations. Participation of psychopharmacologists and psychotherapists should produce findings that can be replicated in many centers.
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Posted July 15, 2002. The work of I. Kirsch, T. J. Moore, A. Scoboria, & S. S. Nicholls (2002) has focused attention on the relatively small effect size of antidepressant drug treatment and has stimulated additional debate about the therapeutic utility and scientific importance of these drugs. Nevertheless, it is important not to exaggerate the claims of minimal effect size, and it is vital not to ignore that some people may be helped substantially by antidepressants. Moreover, it is extremely weak to claim that psychotherapy cannot be studied relative to control conditions that are comparable to placebos. In the present commentary, depression is discussed in terms of neurochemical systems that promote interaction with the environment, and this view allows for recognition of the importance of environmental stimulation, placebo effects, and drug actions.
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Posted July 15, 2002. In a meta-analysis of the Food and Drug Administration (FDA) database of controlled trials used in the initial approval for the most popular antidepressants, I. Kirsch, T. J. Moore, A. Scoboria, and S. S. Nicholls (2002) found that antidepressants demonstrated a clinically negligible advantage over inert placebo. These results are surprising, because they come from studies underwritten by the drug manufacturers. This analysis probably overestimates the antidepressant effect because placebo washout strategies, penetration of the blind, reliance on clinician ratings, use of sedative medication, and replacement of nonresponders may penalize the placebo condition or boost the drug condition. These findings do not appear to justify the popularity of antidepressants, which may have been fueled in part by publication bias and outstanding marketing. Psychotherapy may offer an effective alternative with fewer medical risks.
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Posted July 15, 2002. The article by I. Kirsch, T. J. Moore, A. Scoboria, and S. S. Nicholls (2002) is a significant contribution to the debate about the true benefits of antidepressant drugs when compared with placebo treatments. The present commentary is aimed at examining their findings in the light of past studies that have looked at antidepressant effectiveness. Discussion focuses on the consistency of results across several studies, research design limitations, the importance of psychosocial factors in medication treatments, and the degree to which the obtained modest drug effects might mirror real-world outcomes.
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Posted July 15, 2002. In a review of efficacy data submitted to the U. S. Food and Drug Administration (FDA), I. Kirsch, T. J. Moore, A. Scoboria, & S. S. Nicholls (2002) found that mean posttreatment differences in symptom levels between drug and placebo were modest at best. This led the authors to suggest that either medication effects are trivial or that new designs are needed that do not assume additive effects. We suggest that not all patients necessarily respond to a given medication and that effect sizes based on the "average" patient may underestimate drug-placebo differences for those who do. Data submitted to the FDA can also underestimate how a drug will perform in clinic practice, as studies sometimes are designed as much for marketing purposes as they are to estimate the magnitude of a medication's effects. Finally, even when drug-placebo differences are small, antidepressant medication remains a potent treatment that typically matches or exceeds the efficacy of alternative interventions.
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Posted July 15, 2002. In the fairy tale "The Emperor's New Clothes," a vainglorious ruler is duped into wearing an imaginary garment; his subjects are similarly bluffed for a time (to not point out his foolishness) because of a collective wish not to look stupid. I. Kirsch, T. J. Moore, A. Scoboria, & S. S. Nicholls (2002) draw upon this tale in their study, the results of which demonstrate yet again that antidepressants have modest effects in a meta-analysis of placebo-controlled randomized clinical trials. The present commentary does not dispute these main findings but does call into question the authors' choice of metaphor and their contention that such modest effects are negligible in clinical practice. Moreover, it is asserted that part of the problem is the result of the research methods used by the pharmaceutical industry in pursuit of regulatory approval, not just that the treatments are weak. Last, it is argued that studies of alternate treatments of depression, including various time-limited psychotherapies, are subject to the same biases and criticisms as those evaluating antidepressant medications. It is concluded that the emperor's "suit" is indeed relatively small but that it is made of real and valuable fabric.
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Posted July 15, 2002. I. Kirsch, T. J. Moore, A. Scoboria, & S. S. Nicholls (2002), like the others who have looked at antidepressant clinical trials, find a vanishingly small difference between drug and placebo. Clearly, antidepressant medication is not as effective as sundry stakeholders, particularly the pharmaceutical industry, would have us believe. However, these drugs may have more inherent effectiveness than they appear to in clinical trials. The clinical trials process, which offers participants an unusual amount of attention and can evoke high expectations for improvement, and the sorts of depressed patients that enter clinical trials, enhance the likelihood of a placebo response. And it is the placebo response that determines an antidepressant's apparent efficacy. A lower placebo response rate and greater drug/placebo differences occur in selected populations of depressed patients, including those with excessive cortisol secretion, the chronically ill, and the severely ill. Antidepressants look as ineffective as they do in part because they are given to the wrong patients.
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Posted July 15, 2002. Comments on the article by I. Kirsch, T. J. Moore, A. Scoboria, and S. S. Nicholls (see record 2002-14079-003) which presents findings that represent an extension of Kirsch's already-well-known search into better knowledge about antidepressants. Rather than doubting the honesty of patients and researchers, Kirsch et al should accept the call by F. M. Quitkin, J. G. Rabkin, J. Gerald, J. M. Davis, and D. F. Klein (2000) to conduct "mega-trials" with investigators of varied theoretical orientations. Participation of psychopharmacologists and psychotherapists should produce findings that can be replicated in many centers.