Jeffrey Jonas, MD Vice President CNS - Forest Research Institute Citalopram and Escitalopram Pediatric Safety Data

Outline Overview of Studies Escitalopram Pediatric Study Analysis of SREs  Columbia classification  Lundbeck EU Study Activating Adverse Events Responder Analyses

Overview 3 completed placebo-controlled studies in pediatric MDD 2 citalopram (Celexa®) studies US Study: CIT-MD-18 (7-17 years) EU Study: (13-18 years) 1 escitalopram (Lexapro®) study US Study: SCT-MD-15 (6-17 years) –Submitted to FDA (May 19, 2004); SREs not classified by Columbia

SCT-MD-15: Escitalopram Ped Depression Study 8-week, double-blind, flexible dose  Placebo (N=133)  Escitalopram mg/day (N=131) DSM-IV defined major depressive disorder Children and adolescents 6-17 years, outpatients only CDRS-R  40 at baseline Patients at high risk for suicide excluded Mean Age: 12.3 yrs Study Design

Efficacy Overview StudyPrimary MeasureOutcome CIT-MD-18CDRS-RPositive SCT-MD-15 * CDRS-RNegative 94404K-SADS-PNegative *US escitalopram study showed clear trends in adolescent subpopulation (12-17 years)

Risk Number Treated Number w/ SRE Study SREs (Columbia Classification) CIT-MD-18 Treatment Placebo Citalopram SCT-MD-15* Placebo Escitalopram Placebo Citalopram All Studies Placebo ESC/CIT * not classified by Columbia

Relative Risk of SREs: Drug vs. Placebo CIT-MD Overall Relative Risk SCT-MD

Inclusion Criteria: US vs EU Studies Inpatient Recent psychiatric hospitalization History of suicide attempt US Studies EU Study NO YES

93 Risk Number Treated Number with SRE Study SREs – Excluding Patients with History of Hospitalization or Inpatients CIT-MD-18 Treatment Pbo Cit SCT-MD-15 * Pbo Esc Pbo Cit All Studies Pbo Esc/Cit * Not classified by Columbia

Relative Risk of SREs: Drug vs. Placebo Exc Patients with Hx of Hospitalization or Inpatients CIT-MD Overall Relative Risk SCT-MD

Activation Adverse Events (AAEs) “Activating” AEs are  Associated with initiation of treatment with antidepressant drugs  Precursors to SREs AAEs examined include  Agitation, akathisia, anxiety, anxiety attack, depression, depression aggravated, emotional lability, hyperkinesia, hypomania, impulsive behavior, insomnia, irritability, manic reaction, nervousness, personality disorder, suicidal tendency, suicide attempt

Risk Number Treated Number w/ AAE Study Activation Adverse Events (AAEs) CIT-MD-18 Treatment Placebo Citalopram SCT-MD-15* Placebo Escitalopram Placebo Citalopram All Studies Placebo ESC/CIT * Not classified by Columbia

Relative Risk of AAEs: Drug vs. Placebo CIT-MD Overall Relative Risk SCT-MD

Responder Analyses Hypothesis: Suicide related events (SREs) are associated with course of depression rather than antidepressant treatment Analyses: Compared course of response in patients with and without SREs using change from baseline in primary efficacy measure (K-SADS or CDRS-R)

Study 94404: Response in Patients w/wo SRE * similar effect seen with responder rates K-SADS (LOCF)*

Summary and Conclusions Numerical rate of SREs in the 2 US studies lower in active drug groups vs. placebo EU study enrolled patients with baseline imbalances in suicide-related risk factors. Removing this subset eliminates the SRE signal for this study

Summary and Conclusions No evidence of overall increased rate of AAEs in the active drug group relative to placebo Patients with SREs were typically poor responders whether receiving placebo or active drug