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Depressionen:
Moderne Antidepressiva sind möglicherweise nicht
wirksamer als die in klinischen Studien parallel
geprüften Scheinmedikamente (Placebos). Zu
diesem unerwarteten Schluss kommt die hier
vorgestellte Meta-Studie. Die Autoren kommen
daher zu dem Schluss, dass moderne
Antidepressiva selbst bei schwer depressiven
Patienten nur dann verordnet werden sollten,
wenn alle anderen Therapieversuche gescheitert
sind.
Statistisch überzeugende Unterschiede zwischen
den eingesetzten Antidepressiva und den
Scheinmedikamenten konnten nur bei den Patienten
nachgewiesen werden, die unter schwersten
Depressionen litten. Doch dies führen die
Autoren der Studie nicht auf die
pharmakologische Wirkung der Antidepressiva
zurück, sondern darauf, dass die
Scheinmedikamente bei diesen schwerkranken
Patienten kaum noch wirken. Dies führt zu dem
erkennbaren Unterschied in der registrierten
Wirkung.
ausführlicher Artikel zum Thema Deutsches
Ärzteblatt
hier
Die Deutsche Gesellschaft für Psychiatrie, Psychotherapie und
Nervenheilkunde (DGPPN) setzt sich in einer aktuellen Stellungnahme
mit Medienberichten auseinander, die die Wirksamkeit der
antidepressiven Pharmakotherapie anzweifeln.
hier
Die vollständige englischsprachige
Kurzversion dieser Studie (sog. MEDLINE
Abstract) finden Sie
hier
RESEARCH ARTICLE
Open Access
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publish is freely available online
throughout the world, for you to read,
download, copy, distribute, and use (with
attribution) any way you wish. No
permission required. Read a
detailed definition of open access.
Initial Severity
and Antidepressant Benefits: A Meta-Analysis of
Data Submitted to the Food and Drug
Administration
Irving Kirsch1*,
Brett J. Deacon2,
Tania B. Huedo-Medina3,
Alan Scoboria4,
Thomas J. Moore5,
Blair T. Johnson3
1
Department of Psychology, University of Hull,
Hull, United Kingdom,
2
University of Wyoming, Laramie, Wyoming, United
States of America,
3 Center
for Health, Intervention, and Prevention,
University of Connecticut, Storrs, Connecticut,
United States of America,
4
Department of Psychology, University of Windsor,
Windsor, Ontario, Canada,
5
Institute for Safe Medication Practices,
Huntingdon Valley, Pennsylvania, United States
of America
Background
Meta-analyses of
antidepressant medications have reported
only modest benefits over placebo treatment,
and when unpublished trial data are included,
the benefit falls below accepted criteria
for clinical significance. Yet, the efficacy
of the antidepressants may also depend on
the severity of initial depression scores.
The purpose of this analysis is to establish
the relation of baseline severity and
antidepressant efficacy using a relevant
dataset of published and unpublished
clinical trials.
Methods and
Findings
We obtained data on all
clinical trials submitted to the US Food and
Drug Administration (FDA) for the licensing
of the four new-generation antidepressants
for which full datasets were available. We
then used meta-analytic techniques to assess
linear and quadratic effects of initial
severity on improvement scores for drug and
placebo groups and on drug–placebo
difference scores. Drug–placebo differences
increased as a function of initial severity,
rising from virtually no difference at
moderate levels of initial depression to a
relatively small difference for patients
with very severe depression, reaching
conventional criteria for clinical
significance only for patients at the upper
end of the very severely depressed category.
Meta-regression analyses indicated that the
relation of baseline severity and
improvement was curvilinear in drug groups
and showed a strong, negative linear
component in placebo groups.
Conclusions
Drug–placebo
differences in antidepressant efficacy
increase as a function of baseline severity,
but are relatively small even for severely
depressed patients. The relationship between
initial severity and antidepressant efficacy
is attributable to decreased responsiveness
to placebo among very severely depressed
patients, rather than to increased
responsiveness to medication.
Funding:
The authors received no specific funding for
this study..
Competing
Interests: IK has received consulting
fees from Squibb and Pfizer. BJD, TBH, AS, TJM,
and BTJ have no competing interests.
Academic Editor:
Phillipa Hay, University of Western Sydney,
Australia
Citation:
Kirsch I, Deacon BJ, Huedo-Medina TB, Scoboria
A, Moore TJ, et al. (2008) Initial Severity and
Antidepressant Benefits: A Meta-Analysis of Data
Submitted to the Food and Drug Administration.
PLoS Med 5(2): e45
doi:10.1371/journal.pmed.0050045
Received:
January 23, 2007; Accepted:
January 4, 2008; Published:
February 26, 2008
Copyright:
© 2008 Kirsch et al. This is an open-access
article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the
original author and source are credited.
Abbreviations:
d, standardized mean difference; FDA,
US Food and Drug Administration; HRSD, Hamilton
Rating Scale of Depression; LOCF, last
observation carried forward; NICE, National
Institute for Clinical Excellence; SDc,
standard deviation of the change score
* To whom correspondence
should be addressed. E-mail:
i.kirsch@hull.ac.uk
Editors'
Summary
Background.
Everyone feels
miserable occasionally. But for some
people—those with depression—these sad
feelings last for months or years and
interfere with daily life. Depression is a
serious medical illness caused by imbalances
in the brain chemicals that regulate mood.
It affects one in six people at some time
during their life, making them feel
hopeless, worthless, unmotivated, even
suicidal. Doctors measure the severity of
depression using the “Hamilton Rating Scale
of Depression” (HRSD), a 17–21 item
questionnaire. The answers to each question
are given a score and a total score for the
questionnaire of more than 18 indicates
severe depression. Mild depression is often
treated with psychotherapy or talk therapy
(for example, cognitive–behavioral therapy
helps people to change negative ways of
thinking and behaving). For more severe
depression, current treatment is usually a
combination of psychotherapy and an
antidepressant drug, which is hypothesized
to normalize the brain chemicals that affect
mood. Antidepressants include “tricyclics,”
“monoamine oxidases,” and “selective
serotonin reuptake inhibitors” (SSRIs).
SSRIs are the newest antidepressants and
include fluoxetine, venlafaxine, nefazodone,
and paroxetine.
Why Was This Study Done?
Although the US Food
and Drug Administration (FDA), the UK
National Institute for Health and Clinical
Excellence (NICE), and other licensing
authorities have approved SSRIs for the
treatment of depression, some doubts remain
about their clinical efficacy. Before an
antidepressant is approved for use in
patients, it must undergo clinical trials
that compare its ability to improve the HRSD
scores of patients with that of a placebo, a
dummy tablet that contains no drug. Each
individual trial provides some information
about the new drug's effectiveness but
additional information can be gained by
combining the results of all the trials in a
“meta-analysis,” a statistical method for
combining the results of many studies. A
previously published meta-analysis of the
published and unpublished trials on SSRIs
submitted to the FDA during licensing has
indicated that these drugs have only a
marginal clinical benefit. On average, the
SSRIs improved the HRSD score of patients by
1.8 points more than the placebo, whereas
NICE has defined a significant clinical
benefit for antidepressants as a drug–placebo
difference in the improvement of the HRSD
score of 3 points. However, average
improvement scores may obscure beneficial
effects between different groups of patient,
so in the meta-analysis in this paper, the
researchers investigated whether the
baseline severity of depression affects
antidepressant efficacy.
What Did the
Researchers Do and Find?
The researchers
obtained data on all the clinical trials
submitted to the FDA for the licensing of
fluoxetine, venlafaxine, nefazodone, and
paroxetine. They then used meta-analytic
techniques to investigate whether the
initial severity of depression affected the
HRSD improvement scores for the drug and
placebo groups in these trials. They
confirmed first that the overall effect of
these new generation of antidepressants was
below the recommended criteria for clinical
significance. Then they showed that there
was virtually no difference in the
improvement scores for drug and placebo in
patients with moderate depression and only a
small and clinically insignificant
difference among patients with very severe
depression. The difference in improvement
between the antidepressant and placebo
reached clinical significance, however, in
patients with initial HRSD scores of more
than 28—that is, in the most severely
depressed patients. Additional analyses
indicated that the apparent clinical
effectiveness of the antidepressants among
these most severely depressed patients
reflected a decreased responsiveness to
placebo rather than an increased
responsiveness to antidepressants.
What Do These Findings
Mean?
These findings suggest
that, compared with placebo, the
new-generation antidepressants do not
produce clinically significant improvements
in depression in patients who initially have
moderate or even very severe depression, but
show significant effects only in the most
severely depressed patients.
The
findings also show that the effect for these
patients seems to
be due to decreased responsiveness to
placebo, rather than increased
responsiveness to medication.
Given these results,
the researchers conclude
that there is little
reason to prescribe new-generation
antidepressant medications to any but the
most severely depressed patients unless
alternative treatments have been ineffective.
In addition, the finding that
extremely depressed patients are less
responsive to placebo than less severely
depressed patients but have similar
responses to antidepressants is a
potentially important insight into how
patients with depression respond to
antidepressants and placebos that should be
investigated further.
Additional Information.
Please access these Web
sites via the online version of this summary
at
http://dx.doi.org/10.1371/journal.pmed.0050045.
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