US concerns surfaced in the early 1990s that treatment with antidepressants (ATDs) in the selective serotonin reuptake inhibitor (SSRI) subclass might increase the risk of suicidal ideation or behavior in depressed adults and youth diagnosed with obsessive compulsive disorder.
INTRODUCTION
US
concerns surfaced in the early 1990s that treatment with antidepressants
(ATDs) in the selective serotonin reuptake inhibitor (SSRI) subclass might
increase the risk of suicidal ideation or behavior in depressed adults
(Teicher, Glod and Cole, 1990) and youth diagnosed with obsessive compulsive
disorder (OCD) (King et al., 1991).
The reports were based on a case series and a small clinical trial. This news led
to a Food and Drug Administration (FDA) hearing, but responses faded by the
mid-1990s. In 2000, a systematic analysis from adult regis-tration trial data
concluded that suicides were not more
frequent for those treated with SSRIs than for those treated with placebo
(Khan, Warner and Brown, 2000). However, in June 2003, the suicidality issue
began to draw renewed media attention following the publication from the United
Kingdom (UK) drug regu-latory agency (MHRA) of a preliminary report on
paroxetine clinical trial data which revealed that chil-dren receiving this
SSRI experienced more suicidality than randomly assigned children receiving
placebo (3.7% vs. 2.5%, respectively) (Medicines and Health-care products
Regulatory Agency, 2004). FDA hear-ings on this subject in February 2004 and
September 2004 reviewed 25 US pediatric trials of ATDs with respect to the risk
of suicidality (defined as suicidal ideation or attempts). These
industry-conducted regis-tration trials were submitted to FDA, many in response
to the FDA Pediatric Rule, which extended patent exclusivity for 6 months
regardless of trial outcome. The intense media coverage of the public hearings
reflected the sharply differing public comments, either supporting or
dismissing the clinical importance of the elevated risk of treatment-emergent
suicidality (defined as ideation, attempts or completed suicides) based on
depression trial data for youth exposed to SSRIs relative to placebo.
Recommendations from MHRA in the United Kingdom and the European agency
(European Medicines Agency, 2005) contrast with US drug regulators (FDA, 2004)
and have led to confusion and limited, often misleading interpreta-tions of the
pertinent scientific information. Although no completed suicides occurred in
the trials, the FDA pediatric panel of reviewers recommended caution, and in
October 2004, the FDA announced that a black box warning would be added to the
official label for all ATDs, stressing the risk of treatment-emergent
suicidality. In contrast to UK announcements restrict-ing the use to
fluoxetine, no contraindication for SSRI use to treat depression in children
and adoles-cents was recommended except to discourage use of paroxetine. Also
in 2004, the European drug safety agency (EMEA) issued similar warnings for
SSRIs and like the United Kingdom also prohibited prescrip-tion of SSRIs to
treat depression in youths (European Medicines Agency, 2005). In summary,
throughout the period from June 2003 through October 2004, there was intense
press coverage and debate in both the lay media and in the professional
literature regard-ing the safety (and to a minor extent on the efficacy) of
SSRIs for the treatment of depression in children and adolescents in the United
States. A review of the efficacy studies from clinical trials in youth is a
critical starting point to contrast the European and US regulatory actions.
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