Emergent and Worsening Suicide Ideation in Trials of Pediatric Paroxetine for Depression
Author: Regan Fong, PhD, GlaxoSmithKline, King of Prussia, PA
In September, 2004, the Advisory Committee of the U.S. Food and Drug Administration (FDA) recommended “black-box” warnings for antidepressants after finding a 2.15 overall risk ratio with users of paroxetine (GlaxoSmithKline), compared with non-users, in trials of major depressive disorder and an increased risk in aggregated data from clinical trials overall across antidepressants for suicidal behavior and/or ideation. The FDA evaluation focused primarily on the incidence of adverse drug events (ADEs) considered by blinded experts to be related to suicidality. A new analysis of depression studies with paroxetine by the manufacturer’s researchers did not support that finding.
Dr. Fong examined suicide items from rating scales in three randomized, double-blind, placebo-controlled pediatric depression trials of canadian paroxetine to observe worsening ideation and emergent ideation on the Hamilton Rating Scale for Depression (HAM-D), the Children’s Depression Rating Scale-Revised (CDRS-R), and the Montgomery-Asberg Depression Rating Scale (MADRS). The trials included 378 children and adolescents (7-18 years of age) who received from 10 to 40 mg/day of paroxetine or placebo.
“Emergent ideation” was defined by the appearance of specific items in patients without baseline ideation. “Worsening suicide ideation” was defined as an increase above the cutoffs for specific items at any point in the controlled phase of the trial.
An analysis of emergent suicide ideation in the three depression studies found no statistically significant differences within each study or overall in the combined data set (23.7% for paroxetine vs. 23.3% for placebo; P = 1.00). The analysis of worsening suicidal ideation revealed a similar lack of difference between paroxetine and placebo, with a 15% incidence for paroxetine and a 14.3% incidence for placebo (P = .824).
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“In contrast to the signal from more suicidality adverse event reports on paroxetine in these clinical trials, suicide-item analyses failed to reveal a risk difference between paroxetine and placebo,” Dr. Fong concluded. “These results highlight the importance of understanding how rating scale assessments of suicidality may be discordant from actual adverse event reports.”
When asked to clarify the difference between the criteria used by the FDA’s blinded experts and by Dr. Fong and to explain the absence of added suicide risk in the Glaxo-SmithKline analysis, Mary Anne Rhyne, GlaxoSmithKline director of U.S. Media Relations, replied:
“GSK looked at rating scale items specifically related to suicidal ideation. The FDA’s analysis looked at spontaneously reported adverse experiences related to suicidality (suicidal ideation and/or attempt).”
Commenting on the tenor of presentations on suicide risk and antidepressants at this meeting, co-author Stan Kru-elewicz, MA, of GlaxoSmithKline, said:
“In talks this week, the physicians see a slight risk, which they monitor very carefully.”
It is not approved for use by children or adolescents.