F Hieronymus, A Lisinski, S Nilsson and E Eriksson. Efficacy of selective serotonin reuptake
inhibitors in the absence of side effects: a mega-analysis of citalopram and
paroxetine in adult depression.
Molecular Psychiatry. In press.
Abstract
It has been suggested that the superiority of
antidepressants over placebo in controlled trials is merely a consequence of
side effects enhancing the expectation of improvement by making the patient
realize that he/she is not on placebo. We explored this hypothesis in a
patient-level post hoc-analysis including all industry-sponsored, Food and Drug
Administration-registered placebo-controlled trials of citalopram or paroxetine
in adult major depression that used the Hamilton Depression Rating Scale (HDRS)
and included a week 6 symptom assessment (n=15). The primary analyses, which
compared completers on active treatment without early adverse events to
completers on placebo (with or without adverse events) with respect to
reduction in the HDRS depressed mood item showed larger symptom reduction in
patients given active treatment, the effect sizes being 0.48 for citalopram and
0.33 for paroxetine. In actively treated subjects reporting early adverse
events, who also outperformed those given placebo, the severity of the adverse
events did not predict response. Several sensitivity analyses, for example,
including (i) those using change of the sum of all HDRS-17 items as effect
parameter, (ii) those excluding all subjects with adverse events (that is, also
those on placebo) and (iii) those based on the intention-to-treat population,
were all in line with the primary analyses. The finding that both paroxetine
and citalopram are clearly superior to placebo also when not producing adverse
events, as well as the lack of association between adverse event severity and
response, argue against the theory that antidepressants outperform placebo
solely or largely because of their side effects.
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Investigators are hoping a new "mega-analysis"
puts a final cap on the ongoing controversy over whether antidepressants,
particularly selective serotonin reuptake inhibitors (SSRIs), are effective for
depression.
The review of 15 studies, with more than 3300 patients,
showed that compared with those who received placebo, participants without
early adverse events (AEs) who received either of the SSRIs citalopram
(multiple brands) or paroxetine (multiple brands) had significantly greater
reductions in symptoms, as assessed with the Hamilton Depression Rating Scale
(HDRS) depressed mood item.
Previous research suggests antidepressants' superiority is
"merely a psychological consequence of the side effects of the drugs
enhancing the expectation of improvement," the investigators write.
However, the new analysis showed that patients who had early
AEs and who were receiving one of the active drugs also had significantly
greater reductions in symptoms vs their counterparts who were taking placebo.
This suggests that "the severity of the adverse events did not predict
response," the investigators write.
"I think, once and for all, we've answered the SSRI
question. And we have effectively rebutted the side-effects theory,"
principal investigator Elias Eriksson, PhD, professor of pharmacology at the
University of Gothenburg, Sweden, told Medscape Medical News.
In 2010, a study by University of Pennsylvania investigators
that was published in JAMA suggested that although patients with severe
depression may significantly benefit from antidepressant treatment, there would
be little to no benefit for those with mild to moderate depression compared
with receiving placebo.
The arguments boiled over in 2012 when the news program 60
Minutes broadcast an episode with psychologist Irving Kirsch, PhD, associate
director of the Program in Placebo Studies at Harvard Medical School, Boston,
Massachusetts.
The episode featured Dr Kirsch and his book The Emperor's
New Drugs, which claims there are no clinical differences in the effectiveness
of antidepressants vs placebo in depression. This was followed by a terse
statement from the American Psychiatric Association (APA) countering the
claims.
Then incoming President-elect of the APA Jeffrey Lieberman,
MD, Columbia University, New York City, told Medscape Medical News at the time
that that information was "misleading to people and potentially harmful to
those who really suffer from depression."
"There has been considerable [news] in and out of the
United States suggesting that SSRs are not effective. On the one hand, patients
get these drugs from doctors, but on the other hand, they're reading the
newspapers," said Dr Eriksson. "So we wanted to clarify these
matters."…
The analysis included 2759 participants who completed trials
in which paroxetine was compared with placebo. Of these, 938 patients received
placebo; 421 received paroxetine and had no "early" AEs, defined as
AEs that occur within the first 2 weeks of treatment; and 1399 received paroxetine
and did have early AEs.
There were also 585 patients who completed trials comparing
citalopram with placebo. Of these, 132 patients received placebo, 93 received
citalopram and had no early AEs, and 360 received citalopram and did have early
AEs.
Results showed that in the active-treatment groups, with and
without AEs, there were significantly greater reductions in scores on the HDRS
depressed mood measure at 6 weeks compared with the placebo groups.
"The finding that both paroxetine and citalopram are
clearly superior to placebo...when not producing adverse events, as well as the
lack of association between adverse event severity and response, argue against
the theory that antidepressants outperform placebo solely or largely because of
their side effects," write the investigators.
In addition, "our results indirectly support the notion
that the two drugs under study do display genuine antidepressant effects caused
by their pharmacodynamics properties."
The paroxetine-treated patients with early AEs did have a
small yet significantly greater reduction in symptoms than those receiving the
drug who did not have early AEs (effect size, 0.15; P = .008). There were no
significant differences between the citalopram-treated patients with or without
early AEs.
Commenting on the findings for Medscape Medical News, Dr
Kirsch said that even if there is an effect from antidepressants, that effect
is so small as to be clinically insignificant.
Dr Eriksson countered that perhaps Dr Kirsch investigated
doses that are too low to be effective. He also noted that using the
HDRS-17-sum "has been severely criticized. That measure has been shown to
not be reliable," which is why they chose to focus just on the scale's
depressed mood item. "And we did have an impressive, robust difference
between active drug and placebo," he added.
Dr Kirsch went on to note that the new analysis "was
interesting" but questioned the investigators' not using the full HDRS
scale.
"To use just one item is unusual," he said. But
more important was that the difference "of about half a point between placebo
and the active drugs is so tiny as to have no clinical meaning. Doctors
evaluating a patient would see no real change at all."
The question comes down to this: At what extent is a
clinically meaningful difference "really due to the drug or to patients
realizing they're receiving the active drug rather than the placebo, hence the
placebo effect?" said Dr Kirsch. "They found evidence that that may
be partially the case with one of the two drugs assessed," he added.
"However, from their findings, at least part of this
tiny difference between drug and placebo may actually be due to something not
related to side effects. And that may very well be, but we don't have enough
data right now to really know for sure," Dr Kirsch said.
"The bottom line is, what is the cause of this
miniscule, clinically meaningless difference? What one ought to do is look at
side-effect profile and health risks and then use the safest of the alternative
treatments available. And that's certainly not an SSRI."
http://www.medscape.com/viewarticle/884921
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