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

2. Outline Overview of Studies Escitalopram Pediatric Study Analysis of SREs  Columbia classification  Lundbeck EU Study 94404 Activating Adverse Events Responder Analyses

3. Overview 3 completed placebo-controlled studies in pediatric MDD 2 citalopram (Celexa®) studies US Study: CIT-MD-18 (7-17 years) EU Study: 94404 (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

4. SCT-MD-15: Escitalopram Ped Depression Study 8-week, double-blind, flexible dose  Placebo (N=133)  Escitalopram 10-20 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

5. 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)

6. Risk Number Treated Number w/ SRE Study SREs (Columbia Classification) CIT-MD-18 Treatment Placebo2850.024 Citalopram1890.011 SCT-MD-15* Placebo21330.015 Escitalopram11310.008 94404 Placebo51120.045 121 Citalopram90.074 All Studies Placebo93300.027 ESC/CIT 113410.032 * not classified by Columbia

7. Relative Risk of SREs: Drug vs. Placebo 0.48 1.67 1.18 0.51 CIT-MD-18 94404 Overall Relative Risk SCT-MD-15.010.11.010100

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

9. 93 Risk Number Treated Number with SRE Study SREs – Excluding Patients with History of Hospitalization or Inpatients CIT-MD-18 Treatment Pbo 2 850.024 Cit 1 89 0.011 SCT-MD-15 * Pbo Esc 2 1 133 131 0.015 0.008 94404 Pbo Cit 3 3 93 0.032 All Studies Pbo Esc/Cit 7 5 311 313 0.023 0.016 * Not classified by Columbia

10. Relative Risk of SREs: Drug vs. Placebo Exc Patients with Hx of Hospitalization or Inpatients 0.48 0.51 0.71 1.00 CIT-MD-18 94404 Overall Relative Risk SCT-MD-15.010.11.010100

11. 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

12. Risk Number Treated Number w/ AAE Study Activation Adverse Events (AAEs) CIT-MD-18 Treatment Placebo8850.09 Citalopram11890.12 SCT-MD-15* Placebo91330.07 Escitalopram131310.10 94404 Placebo361120.32 121 Citalopram370.31 All Studies Placebo533300.16 ESC/CIT 613410.18 * Not classified by Columbia

13. Relative Risk of AAEs: Drug vs. Placebo 1.31 1.11 0.95 1.47 CIT-MD-18 94404 Overall Relative Risk SCT-MD-15.010.11.010100

14. 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)

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

16. 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

17. 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