The American College of Neuropsychopharmacology (ACNP) has determined that"
SSRIs and other new-generation antidepressant drugs, in aggregate, are
associated with a small increase in the risk of [adverse event] reports (AEs)
of suicidal thinking or suicide attempts in youth." However, ACNP
believes, increased reports of AEs are highly unlikely to accurately reflect
real changes in incidence of actual suicidal events.
Moreover, ACNP said, its analysis of the AE reports upon which the Food and
Drug Administration (FDA) based antidepressant black-box warnings shows the
data are highly variable and inadequate to address the question of an actual
causal association between the drugs and increased risk of suicidal thoughts
While AE reports appear to indicate an increased risk of suicidality with
antidepressants compared with placebo, ACNP pointed out that clinical trials
in which standardized questionnaires have been used to measure suicidal
thoughts and behaviors have found no statistically significant difference in
patients taking an active drug compared with those taking placebo.
More importantly, the report added, "Three other lines of evidence in
youth: epidemiologic studies, autopsy studies, and recent cohort surveys,
[also] do not support the hypothesis that SSRIs induce suicidal acts and
suicide, instead indicating a possible beneficial effect."
The report concluded that the benefits of treating youth who have
depression with one antidepressant medication, in particular, outweigh the
increase in risk of suicidal thoughts and nonfatal suicidal behavior found in
an analysis of an FDA database of AE reports.
ACNP made six recommendations on how to approach the treatment of
depression in youth and determine what association, if any, antidepressant
drugs have with suicidality (see
"This is an excellent and well-referenced report," said Darrel
Regier, M.D., M.P.H., executive director of the American Psychiatric Institute
for Research and Education and director of APA's Division of Research."
It complements the
summaries prepared by APA and the American Academy of Child and Adolescent
Psychiatry earlier this year." Regier is a member of ACNP.
The ACNP report details an exhaustive review by a task force made up of
psychopharmacology specialists who reviewed the evidence both for and against
an association between the drugs and suicidal thoughts and behaviors and, in
particular, analyzed the same data used by the FDA to support requiring
black-box warnings on all antidepressants marketed in the U.S.
The ACNP report appeared in the January Neuropsychopharmacology.
While ACNP, a nonprofit professional society, does receive some of its revenue
from pharmaceutical companies, no pharmaceutical industry funding was used to
support the task force's work or fund the writing and publication of the
The task force first reviewed the clinical trials submitted to regulatory
agencies (including the FDA and the U.K. Medicines and Health Care Products
Regulatory Agency) in applications for marketing approval to determine if
individual antidepressants have shown significant efficacy in treating
depression in youth.
The task force found that only fluoxetine (Prozac) had consistently
demonstrated statistically significant efficacy in treating depression in
children and adolescents in two placebo-controlled clinical trials (the
minimum standard for FDA approval). Both citalopram (Celexa) and nefazodone
(Serzone) have demonstrated significant efficacy in one clinical trial of
youth with depression, but each drug was separately found to be no different
from placebo in a second clinical trial.
Paroxetine (Paxil) and sertraline (Zoloft) each demonstrated significant
efficacy compared with placebo in one trial; however, two other trials of each
drug found no difference between drug and placebo. Venlafaxine (Effexor) and
mirtazapine (Remeron) were no better than placebo in two clinical trials
Across the clinical trials that found some degree of efficacy for
antidepressants in youth with depression, the degree of reported efficacy
varied considerably, the ACNP task force noted. In looking at the individual
positive trials, ACNP calculated the "number needed to treat"
(NNT) and found a wide range from five to 51, with an average of 17.4.
The NNT signifies efficacy by determining that on average, 1 out of every
17.4 young patients treated with antidepressants would respond to the drug.
Efficacy was as good as 1 out of every 5 patients (with fluoxetine) and as
weak as 1 out of every 51 patients (citalopram).
When the task force looked at the AE reports in the FDA's database, it
concluded that the case reports were so variable and questionable that any
specific connection between AEs and a particular drug was negated.
It reviewed several meta-analyses of case reports detailing AEs, each of
which came to differing conclusions. One meta-analysis found "no
evidence of higher rates of suicide or suicide attempts, respectively,"
for any antidepressant in children and adolescents.
Another published meta-analyses found that SSRIs "did not increase
risk of suicide, and a protective effect could not be ruled out." Still
another large meta-analysis, which included more than 700 randomized clinical
trials involving 87,650 patients, found more suicide attempts in the SSRI
group compared with placebo, but no differences compared with other non-SSRI
In addition, the third meta-analysis found no difference in suicide rates
between SSRIs, non-SSRIs, and placebo.
"By including so many trials," the task force concluded,"
the study was limited by an absence of data on past suicidal behavior,
heterogeneity of patient populations, short duration of most studies, and
trials with small sample sizes. Thus, these meta-analyses [on the whole]
provide no clear conclusion or consensus."
Furthermore, the ACNP task force reviewed a large epidemiologic study of
more than 159,000 general practice patients in the U.K. who took
antidepressants between 1993 and 1999. This analysis found no difference in
the incidence of suicidal thoughts and/or behaviors in those receiving an SSRI
compared with a tricyclic antidepressant; however, this particular report did
find that suicidal behavior was more common early in treatment.
Another recent epidemiological study, involving 65,103 patients who had
more than 82,000 prescriptions for an antidepressant, examined risk of
suicidality prior to starting the antidepressant as well as in the six months
after starting medication. This study found the risk to be highest in the 30
days before medication was begun, not immediately after the start of
In parallel with the task force's calculation of NNTs for the individual
drugs, the panel also calculated the number needed to harm
(NNH)—including suicidal thoughts, behaviors, and attempts—in the
clinical trials database. Again the task force found a wide range of NNHs,
from 24 up to 2,000 and an average of 402. This means 402 patients would have
to be given antidepressant medications before one experienced an AE involving
suicidal thoughts or behaviors.
"The NNH on average is 23 times that of the NNT average across the
studies," the task force concluded. "If one were to take an end
point of suicide, since there have been none in these studies, the NNH value
is unknown, but huge, implying a substantial risk-benefit ratio."
Plainly put, ACNP strongly believes that antidepressant therapy,
particularly with fluoxetine, can be highly beneficial while carrying some
As such, ACNP recommends continued use of fluoxetine, while calling for
more studies to establish efficacy of other antidepressants. The task force
also urges complete public disclosure of all data on the benefits and risks of
SSRIs in children and adolescents
Ultimately, ACNP said, the challenge lies with researchers and clinicians
to design better, systematic measures and assessments for evaluating suicidal
behavior within the context of clinical trials. Improved monitoring of
patients and more reliable reporting measures for AEs within clinical trials
and after drugs are on the market are also needed.
The bottom line, the report concluded, is "more effective treatments
are needed urgently." Additional clinical trials must be conducted and
should include high-risk patients, "such as those with a history of
"Fears of unproven risks may lead to more untreated major depression
in children and adolescents and more suicide. Prompt support for more
definitive controlled clinical studies is urged to better guide clinical
Child and adolescent psychiatrist and APA Trustee David Fassler, M.D.,
commented, "As the authors note, there is no evidence that the use of
SSRI antidepressants increases the risk of suicide in children and
adolescents. The report is a useful contribution to the ongoing public and
professional dialogue on this complex and controversial issue."
The "ACNP Task Force Report on SSRIs and Suicidal Behavior in
Youth" is posted at<www.nature.com/npp/journal/vaop/ncurrent/full/1300958a.html>.▪