Antidepressant Medications in Children

PERSPECTIVE

Antidepressant Medications in Children

Benedetto Vitiello, M.D., and Susan Swedo, M.D.

In June 2003, the Medicine and Healthcare Products Regulatory Agency of the British Department
of Health warned physicians to avoid the off-label
use of paroxetine, a selective serotonin-reuptake
inhibitor (SSRI) antidepressant, for the treatment of
depression in children (18 years of age or younger).
This action was taken in response to concern about
a possible association between SSRIs and suicidal
behavior, which includes a broad range of symptoms ranging from fleeting thoughts of self-harm
to attempted suicide. Proprietary data examined by
the United Kingdom regulatory agency showed a
slight increase in suicidal behavior among patients
who were randomly assigned to SSRI treatment, as
compared with subjects who received placebo (3.7
percent vs. 2.5 percent). The U.S. Food and Drug
Administration (FDA) issued a similar warning,
with a note of caution that paroxetine treatment
should not be discontinued suddenly, so that withdrawal reactions can be avoided.
The issue now is whether SSRIs increase the risk
of suicidal behavior in depressed children. The FDA
has initiated its own examination of this question.
At a joint meeting on February 2, 2004, of the Psychopharmacologic Drugs Advisory Committee and
the Pediatric Subcommittee of the Anti-Infective
Drugs Advisory Committee, the FDAs review revealed several problems in the interpretation of the
available data and outlined plans for the ongoing
evaluation of the results.1 On March 22, the FDA
took the additional step of requesting that labels
on SSRIs and related antidepressants include a
warning that all patients should be monitored
closely for worsening depression or the emergence
of suicidality. (Further information is available at
www.fda.gov.)
Does this mean that SSRIs are simply unsafe? As
with any treatment, the safety of these drugs is a relative concept to be examined in the light of the severity of the disorder being treated and the anticipated benefits and risks of treatment.
First introduced in the late 1980s, the SSRIs are
considered to represent an improvement over older
antidepressants because they are better tolerated
and are safer in overdose an important feature

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for drugs that are prescribed to patients who are at

increased risk for suicide. Over the years, the use of
SSRIs in children has increased substantially. Fluvoxamine, sertraline, and fluoxetine are approved
by the FDA for the treatment of obsessivecompulsive disorder in children, and fluoxetine is also approved for the treatment of major depressive disorder in patients eight years of age or older. In addition, other antidepressants, such as paroxetine,
citalopram, and venlafaxine (a drug that is closely
related to the SSRIs), are prescribed to children for
off-label use.
Both obsessivecompulsive disorder and major
depressive disorder can be severe illnesses, often
having a chronic or recurrent course and causing
substantial functional impairment. Although most
children with depression have symptoms similar
to those seen in adults, such as sad mood, apathy,
lack of energy, and vegetative signs, in some children the disorder is manifested only by irritability
or social isolation and may not be brought to clinical attention. Prevalence estimates suggest that up
to 6 percent of adolescents currently meet the criteria for major depressive disorder, and up to 25 percent have been affected by this disorder by their late
teens.2 Depression is a major risk factor for suicide,
which ranks third as a cause of death among teenagers in the United States. The increased use of antidepressants among children 10 to 19 years of age
has been accompanied by a significant decrease in
the suicide rate in this age group.3 For each 1 percent increase in the use of SSRIs among adolescents,
there was a decrease of 0.23 suicide per 100,000
adolescents per year.
However, these findings represent an epidemiologic association, rather than evidence of causality.
To demonstrate a causal link, either positive or negative, between antidepressant treatment and suicide
is an extremely difficult task. Suicide is a relatively
rare event, and controlled clinical trials with thousands of subjects would be required in order to detect a possible treatment effect. In fact, no suicide
has ever been reported among the more than 4100
subjects enrolled in pediatric clinical trials of SSRIs.
Nonlethal suicidal attempts and suicidal ideation

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PERSPECTIVE
are more common, but establishing an association
would still require systematic, controlled studies involving hundreds of subjects. Controlled trials typically exclude patients who are considered to be at
high risk for suicide, such as those with a history of
suicide attempts or current suicidal ideation. (However, suicidal ideation is not an accurate predictor of
suicide, since most persons with such ideation do
not attempt or die by suicide.) Data bases of spontaneously reported adverse events among community-treated patients, such as MedWatch, are also of
limited usefulness in addressing this issue, because
suicidal behavior can be a symptom of depression
rather than a distinct toxic effect like agranulocytopenia or liver failure. Keeping these methodologic limitations in mind, what can we say about the
riskbenefit balance of SSRI use in children?
For the treatment of obsessivecompulsive disorder, the balance appears to be favorable: fluvoxamine, sertraline, and fluoxetine have been shown
to be effective, and although they have been associated with an increased rate of adverse behavioral
events such as nervousness and agitation, their benefits seem to outweigh the associated risks. For the
treatment of depression, the picture is more equivocal. The efficacy of an antidepressant is considered
to be proved if two separate, independently conducted, controlled clinical trials have found a statistically and clinically significant improvement with
the use of the medication as compared with the use
of placebo. According to this definition, efficacy has
been proved only for fluoxetine.
The response rate was 56 percent with fluoxetine treatment and 33 percent with placebo in the
first study, which was funded by the National Institute of Mental Health (NIMH), and 65 percent with
fluoxetine treatment and 53 percent with placebo in
the second study, which was funded by Eli Lilly.4,5
These data, which are not substantially different
from those obtained in studies involving adults, indicate that fluoxetine is moderately effective in children, that there is a high rate of response to placebo
(between one third and one half of patients), and
that the medication has no benefit for about one
third of patients. The rate of suicidal behavior was
the same with fluoxetine treatment as with placebo
in these two controlled trials. Agitation and manic
symptoms were more common with fluoxetine
treatment, affecting about 1 in 10 children, which
is similar to the rates reported with other SSRIs. All
adverse events resolved completely after the discon-

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Antidepressant Medications in Children

tinuation of treatment. The other SSRIs and venlafaxine have not been proved to have a favorable
riskbenefit ratio, since there have not been replicative trials confirming the superiority of these
medications over placebo. The high rate of response
to placebo appears to be the primary factor contributing to the lack of statistically significant differences between groups, as had been previously found
in trials of antidepressant medications in adults.
It is noteworthy that adverse behavioral events
such as agitation, hyperkinesia, mania, and hypomania tended to be more frequent among patients
treated with SSRIs (including fluoxetine) than
among those receiving placebo (1 to 6 percent vs.
0 to 4 percent).1 Although a causal link between
SSRI use and suicidal behavior has not been proved
by current data, it is theoretically possible that the
agitation and nervousness that occur in some children treated with SSRIs might have the potential to
increase the risk of self-injurious acts; clinicians
must therefore monitor patients carefully for such
adverse effects.
Nonpharmacologic interventions, such as cognitivebehavioral therapy and other psychotherapies, have been found to be beneficial in children
with depression. One means of improving the risk
benefit balance associated with SSRIs may be to reserve medications for those children who have persistent or recurrent forms of depression that are
deemed, on the basis of data from studies in adults,
to be unlikely to respond to psychotherapy, behavioral or environmental change, or general emotional
support. In many cases, nonpharmacologic interventions accompanied by an early follow-up appointment may be helpful in establishing the persistence of a depressive syndrome before any
decision is made regarding the introduction of antidepressant medication. An NIMH-funded, multisite, controlled clinical trial, the Treatment for Adolescents with Depression Study, with more than
400 enrollees, is currently comparing the relative
efficacy of fluoxetine, cognitivebehavioral therapy,
and their combination; results are expected later
this year.
While we search for answers to the questions
raised about the safety of SSRIs, we must not ignore the documented link between depression and
suicide. The sad reality is that depressed children
and adolescents are at increased risk for attempting
and committing suicide. The recognition and appropriate treatment of children with depressive dis-

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Antidepressant Medications in Children

PERSPECTIVE
orders remain vitally important; unfortunately, in
caring for such a patient today, when the safety of
SSRIs is still under review, physicians may sometimes be forced to choose a treatment that has
proven efficacy in adults with depression but has
not yet been tested in children.
The views expressed in this article are those of the authors and do
not necessarily reflect the views of the National Institute of Mental
Health, the National Institutes of Health, or the Department of
Health and Human Services.
From the National Institute of Mental Health, Bethesda, Md.
1. Psychopharmacologic Drugs Advisory Committee and the Anti-

Infective Drugs Advisory Committee. Briefing information. Rock-

ville, Md.: Food and Drug Administration, February 2, 2004. (Accessed March 18, 2004, at: http://www.fda.gov/ohrms/dockets/ac/
04/briefing/4006b1.htm.)
2. Kessler RC, Avenevoli S, Merikangas KR. Mood disorders in
children and adolescents: an epidemiologic perspective. Biol
Psychiatry 2001;49:1002-14.
3. Olfson M, Gameroff MJ, Marcus SC, Waslick BD. Outpatient
treatment of child and adolescent depression in the United
States. Arch Gen Psychiatry 2003;60:1236-42.
4. Emslie GJ, Rush AJ, Weiberg WA, et al. A double-blind, randomized, placebo-controlled trial of fluoxetine in children and
adolescents with depression. Arch Gen Psychiatry 1997;54:10317.
5. Emslie GJ, Heiligenstein JH, Wagner KD, et al. Fluoxetine for
acute treatment of depression in children and adolescents: a placebo-controlled randomized clinical trial. J Am Acad Child Adolesc Psychiatry 2002;41:1205-15.

Increasing HDL Cholesterol Levels

H. Bryan Brewer, Jr., M.D.

In the past decade, high-density lipoproteins (HDL)

have emerged as a new potential therapeutic target
for the treatment of cardiovascular disease. The key
role of HDL as a carrier of excess cellular cholesterol
in the reverse cholesterol transport pathway is believed to provide protection against atherosclerosis.
In reverse cholesterol transport, peripheral tissues
(e.g., vessel-wall macrophages) remove their excess cholesterol through the ATP-binding cassette
transporter 1 (ABCA1) to poorly lipidated apolipoprotein A-I, forming pre-b-HDL. Lecithincholesterol acyltransferase then esterifies free cholesterol
to cholesteryl esters, converting pre-b-HDL to mature spherical a-HDL (see Figure).
HDL cholesterol is transported to the liver by two
pathways: through the first pathway, it is delivered
directly to the liver through interaction with the
scavenger receptor, class B, type I (SR-BI); through
the second pathway, cholesteryl esters in HDL are
transferred by the cholesteryl ester transfer protein
(CETP) to very-low-density lipoproteins (VLDL) and
low-density lipoproteins (LDL) and are then returned to the liver through the LDL receptor. HDL
cholesterol that is taken up by the liver is then excreted in the form of bile acids and cholesterol, completing the process of reverse cholesterol transport.1
HDL also decreases atherosclerosis by protecting

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LDL from oxidation.2 Oxidized or modified LDL,

unlike normal LDL, is readily taken up by the macrophage scavenger receptor SR-A or CD36, resulting
in the formation of foam cells. HDL may also slow
the progression of lesions by selectively decreasing
the production of endothelial celladhesion molecules that facilitate the uptake of cells into the vessel wall.3
Several lines of evidence support the concept that
increasing the HDL level may provide protection
against the development of atherosclerosis. Epidemiologic studies have shown an inverse correlation
between HDL cholesterol levels and the risk of cardiovascular disease.1 Increasing the HDL cholesterol level by 1 mg may reduce the risk of cardiovascular disease by 2 to 3 percent. Overexpressing the
apolipoprotein A-I gene in transgenic mice and
rabbits and infusing complexes consisting of apolipoprotein A-I and phospholipids into hyperlipidemic rabbits increase HDL cholesterol levels and
decrease the development of atherosclerosis.1 In
humans, infusing either of these complexes or
proapolipoprotein A-I results in short-term increases in HDL cholesterol, biliary cholesterol, and fecal
sterol loss, reinforcing the concept that elevating the
HDL cholesterol level decreases the risk of cardiovascular disease.1

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