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Antidepressants Black-Box Warning 10 Years Later

cate physicians, to help them understand that although they cannot ignore that small risk, they
can safely manage it by carefully
monitoring their patients, particularly children and adolescents,
during pharmacotherapy.
What should the FDA do in
light of these observational data?
Given that the agencys 2007
modification of the black-box
warning has not been sufficient
to prevent what seems to be a
chilling effect on depression
treatment perhaps the mere
presence of a warning speaks
louder than any clarification it
may contain I believe its unlikely that further modification
would be helpful. I would there-

fore argue that the FDA should

consider removing the warning
entirely. At the very least, the
medical profession should have a
discussion about this possibility.
I believe we cannot ignore the
weight of these epidemiologic
data or the very real possibility
that the FDA advisory has un
intentionally discouraged depressed patients from seeking
treatment and doctors from prescribing antidepressants.
Disclosure forms provided by the author
are available with the full text of this article
at NEJM.org.
From the Department of Psychiatry and the
Psychopharmacology Clinic, Weill Medical
College of Cornell University, New York.
1. Hamad T. Relationship between psychotropic drugs and pediatric suicidality: review

and evaluation of clinical data. Silver Spring,

MD: Food and Drug Administration (http://
www.fda.gov/ohrms/dockets/ac/04/briefing/
2004-4065b1-10-TAB08-Hammads-Review
.pdf).
2. Lu CY, Zhang F, Lakoma MD et al. Changes
in antidepressant use by young people and
suicidal behavior after FDA warnings and
media coverage: quasi-experimental study.
BMJ 2014;348:g3596.
3. Valuck RJ, Libby AM, Orton HD, Morrato
EH, Allen R, Baldessarini RJ. Spillover effects
on treatment of adult depression in primary
care after FDA advisory on risk of pediatric
suicidality with SSRIs. Am J Psychiatry 2007;
164:1198-205.
4. Libby AM, Orton HD, Valuck RJ. Persisting decline in depression treatment after
FDA warnings. Arch Gen Psychiatry 2009;66:
633-9.
5. Suicide among adults aged 3564 years
United States, 19992010. MMWR Morb
Mortal Wkly Rep 2013;62:321-5.
DOI: 10.1056/NEJMp1408480
Copyright 2014 Massachusetts Medical Society.

The FDA Warning on Antidepressants and Suicidality

Why the Controversy?
Marc B. Stone, M.D.

he controversy over the decision by the Food and Drug

Administration (FDA) in late 2004
to require a boxed warning on
antidepressants regarding the risk
of suicidality in children and
adolescents reached a crescendo
in 2007 with the publication of
a study that presented two time
series in separate graphs.1 One
showed a steady increase in antidepressant prescribing to U.S.
adolescents, with a notable downtick in the last year of the series;
the other showed a steady decrease in suicide rates among
U.S. adolescents, with a notable
uptick at the end. It seemed obvious to many observers that the
two were related. Apparently,
none of the authors, reviewers,
or editors had noticed that the

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prescription downtick occurred

in 2005, whereas the suicide uptick had occurred in 2004. It
seemed that people who feared
adverse consequences from the
boxed warning were poised to
believe any allegation that supported their concerns. In fact,
adolescent suicide rates actually
decreased for several years beginning in 2005 (see graph). Despite the admitted error, the report was never retracted and is
still widely cited.
Over the years, other researchers have made similar claims
about adverse consequences from
the boxed warning. Most commonly, their studies have involved the identification of trends
or changes in what could well be
random fluctuations,1,2 framing

of before and after periods

that absorb changes or trends
that may have begun either well
before3 or well after4 the issuing
of the boxed warning (or some
other dividing point), or use of
inferior data sources when better
sources were available.4
There has also been a general
failure to distinguish the possible effect of the boxed warning
from the effect of general public
awareness of the suicidality issue. When investigators found adverse outcomes beginning in 2005,
they blamed the late-2004 decision to issue a boxed warning.2
When the same authors addressed
adverse outcomes that had preceded the warning by at least a year,
with rates that did not worsen
when the warning was issued,3

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PE R S PE C T IV E

FDA Warning on Antidepressants and Suicidality

A Completed Suicides

Rate per 100,000

3.5

3.0

2.5

2.0
0.0

2001

2002

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2003

2004

2005

2006

2007

2008

2009

2010

2011

2012

2010

2011

2012

B Suicide Attempts
300

Rate per 100,000

250
200
150
100
0

2001

2002

C Nonfatal Poisonings
160

Rate per 100,000

140

Accidental

120
100
80
Intentional
60
0

2001

2002

2003

2004

2005

2006

2007

2008

2009

Rates of Completed Suicides, Suicide Attempts, and Nonfatal Poisonings among Children
and Adolescents 10 to 17 Years of Age in the United States, 20012012.
AUTHOR:
Stone
Data are from the Centers for Disease Control and Prevention.
FIGURE:

1 of 1

ARTIST:

ts

they blamed more equivocal advi- not mean that the two phenomAUTHOR, PLEASE NOTE:
sories issued Figure
a year
earlier
rather ena were connected. Critics have
has been redrawn and type has been reset.
Please check
than the public controversy
thatcarefully.
suggested a connection by prehad prompted
those
senting
time series that show a
Issue
date: advisories.
10-30-14
OLF:
Even if suicide or some other steady rate of increase in anti
adverse outcome had worsened depressant-prescription rates and
in 2005, coincident with a decline a steady decrease in suicide rates
in antidepressant use, it would through 2003, and they propose,

through extrapolation, that trends

would have continued in the absence of the boxed warning. The
idea that, in general, changes in
the incidence of suicide (or suicide
attempts) should show a consistent inverse relationship with
changes in the prevalence of antidepressant use may be intuitively
appealing, but I would argue that
its logically unsound.
Even if antidepressants reduce
the risk of suicide, a steady increase in the prevalence of antidepressant use should not result
in steadily decreasing suicide
rates. Antidepressants can reduce
risk only for patients who are at
risk for suicide to begin with.
People are not given antidepressant prescriptions at random;
when antidepressant use is low,
use is skewed toward the highestrisk portion of the population.
When use increases, its because
treatment indications have broadened and treatment thresholds
have been lowered to include
lower-risk patients. Most of any
reduction in suicide rates should
occur when antidepressants are
first introduced into a population; there will be much less reduction as use spreads.
Ecological studies that examine geographic variability in antidepressant use often show an
inverse relationship with suicide
rates, but I believe that these results can best be explained by
confounding. The same socioeconomic factors that promote
greater availability and use of
many prescription drugs (including antidepressants) also lower
suicide rates among even the substantial majority of the population that does not take antidepressants. For example, one study
associated the introduction of
leukotriene-modifying agents for

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PERS PE C T IV E

FDA Warning on Antidepressants and Suicidality

asthma and allergic rhinitis with

a 3% decrease in suicides5 in the
entire population (even though
the drugs are used by only 1% of
the population).
A different logical problem
affects critics interpretation of
other time series that show increasing antidepressant prescribing rates accompanied by a plateau in suicide rates, followed by
an increase in suicide rates when
antidepressant use plateaued. If
theres a causal relationship between antidepressant use and suicide attempts, then the substantial annual increase in the
proportion of the population taking antidepressants was necessary to maintain the initial plateau in the suicide rate. In other
words, the population-wide prevalence of potentially suicidal depression was increasing throughout the time series an otherwise
unrecognized but worsening epidemic and was held back only
by aggressive diagnosis and prescription of antidepressants. The
initial stability in suicide rates
would then imply that, until the
boxed warning, the health care
system was exceedingly successful in recognizing and treating
depression. But antidepressants
are not 100% effective in preventing suicide attempts, so the suicide rate before the boxed warning should have been increasing
even if everyone at risk was being
diagnosed and treated. Thus, the
premise that the prevalence of
potentially suicidal depression was
steadily increasing (and increased
antidepressant use was preventing an increase in suicides) must
be incorrect.
Indeed, it cannot even be assumed that 2005 decreases in
antidepressant-prescription rates

1670

were a reaction to the controversy.

The number of U.S. antidepressant prescriptions decreased from
2004 to 2005 in every age subgroup through 54 years of age
but increased in every older subgroup. If the controversy discouraged antidepressant prescribing
not just for adolescents but for
everyone through the age of 54,
why were prescribing trends unaffected among adults 55 or older? The period was one of transition in the antidepressant market:
popular brands went off patent,
generics market share sharply

increased, and promotional expenditures for antidepressants decreased by 35% from 2004 through
2006. It is possible that the modest reduction in antidepressant
prescribing reflected drug makers reduced marketing of brandname antidepressants to everyone except patients who would
soon be eligible for the new Medicare prescription-drug benefit.
Finally, critics have been undeterred when their favored findings cannot be replicated when
better information sources are
used. For example, Lu et al.4
compared the aggregate number
of antidepressant prescriptions
with the aggregate number of
psychotropic-drug overdoses without being able to establish
whether the overdoses were intentional. They used poisoning
by psychotropic agents (without
regard to intent) as a proxy measure for suicide attempts, citing a
study that they claim validates its
use for this purpose, even though
that study did not investigate
whether the relationship between
the proxy and attempted suicide
remains stable over time. Superior data are available from the
Centers for Disease Control and

Prevention, which prospectively

collects data on poisonings and
trauma from a statistically valid
sample of the entire United
States, with on-site determination
of the presence of suicidal intent.
Like completed suicides, incidents
of nonfatal, intentional self-harm
(attempted suicide), both from
poisonings and from all causes,
peaked in 2003 or 2004 and then
decreased. The rate of accidental
drug poisoning (such as overdoses of drugs of abuse) increased significantly in 2005 and
2006 (see graph). Other data
sources that provide more direct
and valid measures of suicidal
behavior among young people
(including the Youth Risk Behavior Survey) also show no increase
in suicide attempts in this population subsequent to the issuing
of the boxed warning.4
These data should be sufficient to dispel any serious concerns, but nearly 10 years after
the labeling changes, the idea
that the boxed warning had adverse consequences persists in the
minds of many health professionals, in the media, and among
the general public. Because thousands of data sources, geographic areas, time frames, and outcome measures can be examined,
continued pursuit of this question will probably provide additional examples that achieve little
beyond reinforcing concerns about
something that did not happen.
The views expressed in this article are
those of the author and are not intended to
reflect the position of the U.S. Food and
Drug Administration.
Disclosure forms provided by the author
are available with the full text of this article
at NEJM.org.
From the Food and Drug Administration,
Silver Spring, MD.

n engl j med 371;18nejm.orgoctober 30, 2014

PE R S PE C T IV E

FDA Warning on Antidepressants and Suicidality

1. Gibbons RD, Brown CH, Hur K, et al. Early

evidence on the effects of regulators suicidality warnings on SSRI prescriptions and suicide in children and adolescents. Am J Psychiatry 2007;164:1356-63.
2. Valuck RJ, Libby AM, Orton HD, Morrato
EH, Allen R, Baldessarini RJ. Spillover effects
on treatment of adult depression in primary
care after FDA advisory on risk of pediatric
suicidality with SSRIs. Am J Psychiatry 2007;
164:1198-205.

3. Libby AM, Orton HD, Valuck RJ. Persisting decline in depression treatment after
FDA warnings. Arch Gen Psychiatry 2009;
66:633-9.
4. Lu CY, Zhang F, Lakoma MD, et al. Changes in antidepressant use by young people
and suicidal behavior after FDA warnings and
media coverage: quasi-experimental study.
BMJ 2014;348:g3596.
5. Schumock GT, Gibbons RD, Lee TA, Joo
MJ, Valuck RJ, Stayner LT. Relationship be-

tween leukotriene-modifying agent prescriptions dispensed and rate of suicide deaths by

county in the US. Drug Healthc Patient Saf
2011;3:47-52.
DOI: 10.1056/NEJMp1411138
Copyright 2014 Massachusetts Medical Society.

perspec tive roundtable

Innovation in Health Care Leadership

A video
is available
at NEJM.org

A growing demand for transparency has brought innovation in many

areas of health care. In a video roundtable, three expert panels, led by
Amy Compton-Phillips, David Blumenthal, and Thomas Lee, discuss the
benefits and challenges of these innovations, examining transparency in
provider-driven quality data, in pricing, and in medical records.

n engl j med 371;18nejm.orgoctober 30, 2014

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Reproduced with permission of the copyright owner. Further reproduction prohibited without
permission.