October 15, 2004, quickly became known by some as "black
Friday"—the day on which the Food and Drug Administration (FDA)
ordered drug companies to label all antidepressant medications distributed in
the United States with strongly worded warnings that the medications"
increase the risk of suicidal thinking and behavior (suicidality) in
children and adolescents with major depressive disorder (MDD) or other
The FDA's language within the new black-box warning and the additional
information that drug makers will have to add to the"
WARNINGS—Clinical Worsening and Suicide Risk" section of
the drugs' labels is indeed strong, leaving no doubt that the agency believes
there is a direct causal link between the 32 antidepressant medications
currently marketed (see list on
page 48) and increased
suicidal thoughts and behaviors (see text of black-box warning on
The black box urges families and care-givers, as well as clinicians, to
observe patients closely for "clinical worsening, suicidality, or
unusual changes in behavior" associated with the initiation of
antidepressant therapy. Within the expanded "warnings" section,
the label explains "unusual changes in behavior" further, adding"
anxiety, agitation, panic attacks, insomnia, irritability, hostility
(aggressiveness), impulsivity, akathisia (psychomotor restlessness),
hypomania, and mania have been reported in adult and pediatric patients being
treated with antidepressants for major depressive disorder as well as for
other indications, both psychiatric and nonpsychiatric."
The labeling then states that "although a causal link between the
emergence of such symptoms and either the worsening of depression and/or the
emergence of suicidal impulses has not been established, there is concern that
such symptoms may represent precursors to emerging suicidality."
Although the FDA acknowledges no causal link in the above statement, the
agency nonetheless says at the beginning of the new "Warnings"
section, "A causal role for antidepressants in inducing suicidality has
been established in pediatric patients." The labeling does not explain
this seemingly contradictory language.
The new labeling dictates that patients being treated with the drugs"
for any indication" should be closely watched."
Ideally," the new labeling states, "such observation would
include at least weekly face-to-face contact with patients or their family
members or caregivers during the first 4 weeks of treatment, then biweekly
visits for the next 4 weeks, then at 12 weeks, and as clinically indicated
beyond 12 weeks. Additional contact by telephone may be appropriate between
While the new warning language is specific to pediatric patients (those
under 18), it also notes, "Adults with MDD or comorbid depression in the
setting of other psychiatric illness being treated with anti-depressants
should be observed similarly for clinical worsening and suicidality,
especially during the initial few months of a course of drug therapy, or at
times of dose changes, either increases or decreases."
The new labeling is part of a four-pronged plan that also includes FDA's
issuance of a new Public Health Advisory on the issue, a requirement that all
antide-pressant prescriptions—including new prescriptions and
refills—must be dispensed with a patient medication guide, and finally,
a requirement that antidepressant medications be available only in "unit
of use packaging, sealed and labeled for one course of treatment."
The labeling changes, announced by FDA Acting Commissioner Lester Crawford,
D.V.M., at a press briefing on October 15, were effective immediately.
Sandra Kweder, M.D., acting director of FDA's Office of New Drugs in the
Center for Drug Evaluation and Research, noted that clinicians should receive
their "Dear Healthcare Practitioner" letters sometime early this
month and see the new labeling in new stocks of the medications distributed to
pharmacies around the first of the month.
The patient medication guide had not been finalized at the time of the
press briefing; however, Kweder said it should be completed "within the
next few weeks," and patients should see it in the first half of
December. The required "unit of use" packaging, however, may not
appear for several months.
Kweder noted that manufacturers will be allowed to distribute all of their
existing stock. In addition, she said, it will take some time to"
retool" the packaging process at individual drug-production
facilities across the country.
While some believe that the FDA abandoned the scientific evidence base and
perhaps bowed to political pressure, FDA Acting Commissioner Crawford assured
the public during the October 15 press briefing that "these conclusions
are based on the latest and best science and reflect what we have heard from
our advisory committees in the last month." Yet the advisory committees'
support of a black-box warning and language directly linking the medications
to suicidal thoughts and behaviors was not unanimous, and considerable
discussion occurred during the advisory committee meetings regarding the
strengths and weaknesses of the data upon which the warnings should be based
(Psychiatric News, October 15).
In a joint statement, APA President Michelle Riba M.D., M.S., and
President-elect Steven Sharfstein M.D., said, "The American Psychiatric
Association believes antidepressants save lives.... We restate our continued
deep concern that a `black-box' warning on antidepressants may have a chilling
effect on appropriate prescribing for patients. This would put seriously ill
patients at grave risk."
Riba and Sharfstein said that APA is "working to help mitigate such
an impact by collaborating with nonpsychiatric physicians—including
pediatricians and general practitioners—to help them better understand
their patients' needs and properly diagnose, treat, and monitor
In addition, they noted, "we hope the FDA will set in place a system
to track the impact of the black-box warning on prescribing patterns."
Such a system, they said, should track any change in actions by patients to
harm themselves as a result of reduced access to medically necessary treatment
The American Academy of Child and Adolescent Psychiatry (AACAP) announced
prior to October 15 that it did not support issuance of black-box warnings,
stating that the data did not justify such a strong warning. In a press
release following the FDA's announcement, AACAP said that it "applauds
the careful consideration the FDA has shown in issuing the new warning with
accompanying directives for more physician and patient information about side
effects and monitoring."
AACAP also noted that in partnership with APA it has begun the process of
providing "updated practice guidelines" and "a practice
advisory" on the issue.
Psychiatric News will provide more in-depth information on the
reaction of APA and other groups and researchers to the black-box warning in a
The FDA posted information regarding antidepressant use at<www.fda.gov/cder/drug/antidepressants/default.htm>.
It includes links to the new warnings, information on the advisory committee
meetings, and the medications' data on suicidal thoughts and