Quelle:
Medline Abstract
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
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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over placebo treatment, and when unpublished trial data are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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