Introduction

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.