The Food and Drug Administration (FDA) has approved escitalopram, an
antidepressant marketed by Forest Laboratories, for the acute and maintenance
treatment of major depressive disorder in adolescents aged 12 to 17.
The March 20 approval came less than a month after the U.S. Attorneys
Office for the Massachusetts district filed a federal civil suit accusing
Forest of having illegally marketed escitalopram and citalopram for off-label
use in children and adolescents from 1998 to 2005 (Psychiatric News,
April 3). The suit also alleges that Forest knowingly suppressed unfavorable
facts about citalopram from the medical community and the public, including
the lack of efficacy in one trial and the increase in suicidality reported by
Citalopram is a racemic mixture of R- and S- isomers of the molecule, while
escitalopram contains only the S- isomer, the active component of the
According to an announcement by Forest, the FDA's decision to approve
escitalopram for treating adolescent depression was based on two randomized,
placebo-controlled trials. In one trial, the greater efficacy of escitalopram
10 mg to 20 mg daily compared with placebo was statistically significant after
eight weeks of treatment in patients aged 12 to 17 with major depressive
disorder. The efficacy endpoint was measured by improvement in the Children's
Depression Rating Scale-Revised (CDRS-R) scores.
The second trial supporting the approval was an earlier trial conducted on
citalopram. In that study patients aged 7 to 17 treated with 20 mg to 40 mg
daily of citalopram improved statistically significantly more than subjects
taking placebo. The improvement was also measured by CDRS-R scores. These
positive efficacy data "largely came from the adolescent
subgroup," according to the company.
However, two other placebo-controlled trials, one of each conducted on
citalopram and escitalopram, had failed to demonstrate significant benefits of
either drug over placebo, the company acknowledged. One trial tested
escitalopram in patients aged 7 to 17; the other tested citalopram in
"Escitalopram is the only active enantiomer of the racemic drug
citalopram, so we considered it reasonable to [deem] the positive citalopram
study along with the positive escitalopram study as sufficient evidence ... to
support the approval," Karen Mahoney, an FDA spokesperson, told
None of these clinical trials studied the long-term efficacy and safety of
citalopram or escitalopram. Nevertheless, the FDA approved escitalopram for
maintenance treatment because the efficacy in adolescents "can be
extrapolated from adult data" and from the drug's pharmacokinetic
parameters, according to Forest's announcement.
In 2002, the FDA turned down the company's application for the use of
citalopram in child and adolescent depression based on the two clinical trials
conducted on the medication, one with positive efficacy results and one with
negative efficacy results. The patent on citalopram expired in 2003.
Before the recent escitalopram approval, fluoxetine was the only SSRI
approved for use in patients younger than age 18. Currently, all
antidepressants carry a black-box warning in their prescribing information
about their propensity for increasing the risk of suicidal thoughts and
behaviors in patients under age 25.
In the federal lawsuit, prosecutors said that Forest aggressively promoted
the positive results of the single successful trial in citalopram and
concealed the negative trial from health care professionals and the public.
They also alleged that the company had used kickbacks, gifts, and other
illegal means to persuade or induce physicians to prescribe both drugs for
child and adolescent patients. Because neither drug was approved for pediatric
use at the time, the manufacturer was prohibited by law to promote off-label
use. Despite the recent FDA action, the lawsuit against Forest remains