E-DRUG: antidepressants in children
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[copied as fair use; WB]
Dear e-druggers,
I hope some of you will find the following editorial from this week's
New England Journal of Medicine both interesting and balanced.
Valeria
Dr Valeria Frighi
Oxford Centre for Diabetes, Endocrinology and Metabolism
Churchill Hospital
Oxford OX3 7LJ
UK
Tel # 44 1865 857300
Fax # 44 1865 857636
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NEJM 2004; 350:1489-1491 (8th April)
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 FDA's 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 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
obsessive�compulsive 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 obsessive�compulsive 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 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 risk�benefit
balance of SSRI use in children?
For the treatment of obsessive�compulsive 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 discontinuation of treatment.
The other SSRIs and venlafaxine have not been proved to have a
favorable risk�benefit 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 cognitive�behavioral
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, cognitive�behavioral 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 disorders 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.
Source Information
From the National Institute of Mental Health, Bethesda, Md.
References
1. Psychopharmacologic Drugs Advisory Committee and the
Anti-Infective Drugs Advisory Committee. Briefing information.
Rockville, 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;49:1002-1014.[CrossRef][ISI][Medline]
3. Olfson M, Gameroff MJ, Marcus SC, Waslick BD. Outpatient
treatment of child and adolescent depression in the United States.
Arch Gen Psychiatry 2003;60:1236-1242.[Abstract/Full Text]
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;54:1031-1037.[Abstract]
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;41:1205-1215.[ISI][Medline]
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