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Reexamining the Link Between Antidepressants and Suicidality in Children and Adolescents

Reexamining the Link Between Antidepressants and Suicidality in Children and Adolescents

In October 2004, the FDA mandated
that a black box warning be added
for all antidepressants used in
children and adolescentsa move that
sparked widespread concern about the
use of these drugs.1 The FDA's decision
followed similar action by the
British Medicine and Healthcare
Products Regulatory Agency.

The FDA based its decision on a
review of pooled analyses of 9 antidepressants
(selective serotonin reuptake
inhibitors [SSRIs] and other novel
antidepressants) used in 24 short-term
(4 weeks to 16 weeks), randomized, placebo-placebo-
controlled trials, both published
and unpublished.2 The trials involved
4587 children and adolescents with major
depression, obsessive-compulsive disorder,
and other disorders. The initial metaanalysis
revealed an average risk of
broadly defined suicidal behavior of 4%
as determined by adverse event reporting,
which is twice the placebo rate.

The FDA also concluded that
although there had been trials supporting
the efficacy of citalopram, sertraline,
and paroxetine, only fluoxetine had
met the efficacy standard of showing
a benefit in at least 2 randomized
controlled trials. They noted that a third,
multi-site, randomized controlled trial,
the Treatment for Adolescents with
Depression Study (TADS), confirmed
that fluoxetine, alone or in conjunction
with cognitive-behavioral therapy, was an effective treatment for depression.3
In the TADS, 61% of the participants
responded to fluoxetine alone, and 71%
responded to fluoxetine plus therapy,
which was twice the response rate of
35% for participants who received
placebo. Weighing the efficacy data
against the risks of suicidal behavior and
ideation, the FDA concluded that only
fluoxetine showed significant advantage
over placebo and, therefore, the
benefit of this drug exceeded the risk.

Hammad and colleagues4 reported on
a more detailed reanalysis of all the
randomized placebo-controlled studies,
including the TADS data. In this study,
the investigators analyzed the suicidal behavior data separately from other
adverse events; they also separated the
data on major depressive disorder
(MDD) trials from data from other disorders.
The overall risk ratio of suicidal
ideation or nonfatal self-injurious events
compared with placebo was found to be
1.95 (95% confidence interval [CI], 1.28
to 2.98%) for all disorders and 1.66 (95%
CI, 1.02 to 2.68) for MDD.

Table 1 shows the risk ratios for
suicide attempts and suicide behavior
for each drug within MDD trials as
compared with all other trials. Although
there were some differences in the
degree of risk among the 9 antidepressants
evaluated, the FDA did not
exempt any antidepressant from the
black box warning because of differential
risk rates. The FDA has not
contraindicated any of the medications for use in pediatric populations but encourages
physicians to balance the risk
with clinical indications.

Reactions to the FDA warning

The FDA's actions and related studies
have caused public consternation and
sparked an ongoing debate in the medical
community. The profusion of commercially
sponsored trials that were
not required to be reported for analysis
created the perception of a reporting
bias.5 The FDA quickly moved to
start requiring the reporting of all data
positive and negative.

Psychotropic medication use in children
and adolescents has come under even more scrutiny with concerns about
direct-to-consumer marketing and the
increase in medication prescriptions for
children. These concerns were illustrated
by the recent recommendation
of an FDA advisory committee to add
a black box warning and further investigate
possible cardiovascular risks
of medications used to treat attentiondeficit/
hyperactivity disorder. However,
another FDA panel then reversed the
recommendation to add a black box
warning.

Since the FDA's first public health
advisory on antidepressants, reports
suggest that there has been a 20%
drop in the number of antidepressant
prescriptions dispensed for minors.6
The public health consequences of
this are unclear. In June 2005, a report
issued by the AMA Council on Scientific Affairs stated that SSRIs
should continue to be available as a
component of depression treatment for
children and adolescents.7 The AMA
requested an independent review of the
current data and asked the FDA to evaluate
the impact of its regulatory actions
on treatment patterns, compliance, and
access to care.

Significance of the findings

The significance of these data is far
from clear, because there are a variety
of alternative explanations as well as
methodologic limitations that make the
findings concerning suicide risk and
clinical efficacy difficult to interpret.
For instance, the trials were carried
out in a pediatric population, in which
actual suicide is rare, so the events reported
were very small in number. The
relationship of suicidal ideation and
suicidal behavior to completed suicide
in this age group is also unclear. Suicidal
ideation is common among adolescents,
occurring in approximately 19%.

The studies analyzed by the FDA
involved spontaneously reported adverse
events rather than explicitly
assessed behaviors. They also lacked
uniformity in how suicidal behaviors
were defined and lacked adequately
explicit measurements of suicidal behaviors
or ideation, including measures of
severity of intent. It is important to
emphasize that there were no suicides
among the nearly 5000 cases reviewed
by the FDA and that behaviors considered
by external consultants as probable
suicide attempts were rare. Thus, the
pooled data include behaviors that may
not pose a significant risk of suicide.
Finally, adherence to assigned treatment
was not measured, and investigators did
not account for the possibility that
discontinuation symptoms contributed
to adverse events.8

With respect to efficacy, the duration
of the trials (less than 16 weeks) was,
in general, too short to allow identification
of the long-term beneficial effects
of antidepressant medications. Simon
and colleagues9 recently published a
report on attempted and completed
suicide in a large HMO sample for
whom antidepressants were prescribed.
They found that the highest risk of
suicide attempts and completion was in
the month before antidepressant use, and
the risk went down steadily during the
course of treatment over 6 months, even
for patients younger than 18.

The large number of multi-site trials
included in the FDA meta-analysis presented additional problems for efficacy
measurement. These include high variance
because of multiple sites with few
patients in each site, probable variations
in methodologic and recruiting strategies,
and variable placebo response rates.8

Mann and colleagues10 noted other
problems with these trial results. They
found that the trials did not document
past suicide attempts nor did they include,
in general, patients with current suicidality.
As a result, these authors recommended
that future trials be designed with
high-risk patients, using stratification to
avoid confounding effects.

Various alternative explanations for
the trial results have been advanced.
Among these is the possibility that the
patients receiving medications were
more able to report suicidal behavior
(either because they elicited attention
for other reasons or they were more
communicative).4 It has also been
posited that some of the adverse effects
of antidepressant treatmentsuch as
insomnia, agitation, restlessness, and
irritabilityoccurred in patients at risk
for bipolar disorder who may not have
been adequately monitored or treated.11

Epidemiologic data also fail to support
the conclusions of the FDA meta-analysis,
since the recent increase in SSRI
prescriptions has been correlated with a
decrease in the youth suicide rate.12 Adult
data also show a decrease in the suicide
rate corresponding to the period of increased
SSRI prescriptions (with the
exception of the elderly population).

In addition, autopsy studies have
failed to find antidepressant use in most
suicide victims, which is also inconsistent
with the FDA's findings.4 A Swedish
toxicology study compared suicides with
natural deaths and reported that no SSRIs
were detected in 52 suicides in persons
younger than 15 years. In the 15– to 19–
year-old age group, persons with
detectable concentrations of SSRIs had
a lower relative risk of suicide over
a period of 9 years than those with
detectable levels of other antidepressants.
13 Data on regional trends in
prescribing antidepressants correlated
with suicide statistics suggest that antidepressant
treatment is inversely related
to suicide for older adolescents and for
males in general, who are at highest risk
for suicide.14

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