1. 1 Antidepressants and Suicidality in Adults: Data Overview M. Lisa Jones MD, MPH Medical Reviewer Division of Psychiatry Products Psychopharmacologic Drugs Advisory Committee December 13, 2006

2. 2 Antidepressants Studied SSRIs 1. Citalopram (Celexa®) 2. Escitalopram (Lexapro®) 3. Fluoxetine (Prozac®) 4. Fluvoxamine (Luvox®) 5. Paroxetine (Paxil®) 6. Sertraline (Zoloft®) Non-SSRIs 7. Bupropion (Wellbutrin®) 8. Duloxetine (Cymbalta®) 9. Mirtazapine (Remeron®) 10. Nefazodone (Serzone®) 11. Venlafaxine (Effexor®)

3. 3 FDA Data Request Letters FDA analysis based on randomized, controlled trial datasets provided by the sponsors of the antidepressant drugs: FDA analysis based on randomized, controlled trial datasets provided by the sponsors of the antidepressant drugs: FDA sent four data request letters to sponsors from Dec. 2004 to Aug. 2005 FDA sent four data request letters to sponsors from Dec. 2004 to Aug. 2005 Resulting sponsor datasets received by the FDA from Sept. 2005 to Sept. 2006 Resulting sponsor datasets received by the FDA from Sept. 2005 to Sept. 2006

4. 4 Selecting Trials for the Dataset FDA letter provided the following guidance to sponsors on the studies to include in the dataset: FDA letter provided the following guidance to sponsors on the studies to include in the dataset: Randomized, placebo-controlled trials only Randomized, placebo-controlled trials only Trials for any indication Trials for any indication Trials of any length Trials of any length Trials with at least 20 subjects per treatment arm Trials with at least 20 subjects per treatment arm Sponsors submitted a listing of the trials they intended to include/exclude, and the FDA provided feedback on the trials to be included in the final datasets Sponsors submitted a listing of the trials they intended to include/exclude, and the FDA provided feedback on the trials to be included in the final datasets

5. 5 Study Indication Groups 1. Major depressive disorder (MDD) 2. Other depressive disorders 3. Other psychiatric disorders 4. Behavioral disorders 5. Other disorders Trials categorized by reviewer consensus Trials categorized by reviewer consensus MDD and Non-MDD datasets submitted separately MDD and Non-MDD datasets submitted separately Non-MDD Indications

6. 6 Other Depressive Disorders MDD or Bipolar Disorder MDD or Bipolar Disorder Premenstrual Dysphoric Disorder Premenstrual Dysphoric Disorder Post Natal Depression Post Natal Depression Seasonal Affective Disorder Seasonal Affective Disorder Atypical Depression Atypical Depression Bipolar Disorder Bipolar Disorder Depression (Unspecified) Depression (Unspecified) Depression (Non-MDD) Depression (Non-MDD) Dysthymia Dysthymia Dysthymia or Major Depression Dysthymia or Major Depression

7. 7 Other Psychiatric Disorders Neurasthenia Neurasthenia Non-Depressed OCD Non-Depressed OCD Obsessive Compulsive Disorder Obsessive Compulsive Disorder Pain Disorder Pain Disorder Panic Disorder Panic Disorder Post-traumatic Stress Disorder Post-traumatic Stress Disorder Social Anxiety Disorder Social Anxiety Disorder ADHD ADHD Adjustment Disorder Adjustment Disorder Anxiety Disorders Anxiety Disorders Alzheimer’s Disease Alzheimer’s Disease Bulimia Bulimia Generalized Anxiety Disorder Generalized Anxiety Disorder Generalized Social Phobia Generalized Social Phobia Negative Symptoms Of Schizophrenia Negative Symptoms Of Schizophrenia

8. 8 Other Behavioral Disorders Obesity / Diabetes or Glucose Intolerance Obesity / Diabetes or Glucose Intolerance Smoking Cessation Smoking Cessation Weight Loss Weight Loss Weight Maintenance Weight Maintenance Alcoholism Alcoholism Insomnia Insomnia Insomnia and Anxiety Preceding Surgery Insomnia and Anxiety Preceding Surgery Obesity Obesity Obesity and Hypertension Obesity and Hypertension Obesity, Hypertension and Diabetes Obesity, Hypertension and Diabetes

9. 9 Other Disorders Stress Urinary Incontinence Stress Urinary Incontinence Sexual Dysfunction Sexual Dysfunction Sleep in Healthy Volunteers Sleep in Healthy Volunteers Urge Urinary Incontinence Urge Urinary Incontinence Diabetic Neuropathy Diabetic Neuropathy Fibromyalgia Fibromyalgia Mixed Urinary Incontinence Mixed Urinary Incontinence Migraine Prophylaxis Migraine Prophylaxis Neuropathic Pain Neuropathic Pain Non-Ulcer Dyspepsia Non-Ulcer Dyspepsia Premature Ejaculation Premature Ejaculation

10. 10 Trial Disposition Disposition Number of Trials Included372 Excluded Exclusion Reason 26 Fewer than 20 subjects per arm in test-drug or placebo arms 23 Data not available for most subjects 3 Duplicate trials 6 Total 404

11. 11 Event Identification To identify potentially suicide-related adverse events (PSRAEs), sponsors were asked to search the trial preferred terms, verbatim terms and comments for suicide-related text strings (e.g. “accident-,” “attempt,” “burn,” “cut,” “gun”) To identify potentially suicide-related adverse events (PSRAEs), sponsors were asked to search the trial preferred terms, verbatim terms and comments for suicide-related text strings (e.g. “accident-,” “attempt,” “burn,” “cut,” “gun”) Search strictly limited to the double-blind period Search strictly limited to the double-blind period Subjects with events pre-dating baseline were not excluded. Events were counted if they recurred during the trial. Subjects with events pre-dating baseline were not excluded. Events were counted if they recurred during the trial.

12. 12 Event Adjudication Adjudication of PSRAEs as per the Columbia Classification Algorithm of Suicide Assessment (C-CASA) Adjudication of PSRAEs as per the Columbia Classification Algorithm of Suicide Assessment (C-CASA) Due to the large number of subjects in the adult suicidality analysis, adjudications were performed by the sponsors and were not overseen by the FDA Due to the large number of subjects in the adult suicidality analysis, adjudications were performed by the sponsors and were not overseen by the FDA “False positive” events identified by the text string search (e.g. gas/epigastric pain) were excluded “False positive” events identified by the text string search (e.g. gas/epigastric pain) were excluded

13. 13 C-CASA Event Classification The numbering above represents a ranking of event severity, and only the most severe event per patient was submitted in the datasets Events Completed suicide Suicide attempt Preparatory acts Suicidal ideation Self-injurious behavior, intent unknown Not enough information (Fatal) Not enough information (Non-Fatal) Coding1234569

14. 14 Dataset Variables Trial identifiers Trial and subject identifiers, trial indication Trial-related Setting (Inpt. or Outpt.), Location (North America or not), Premature Discontinuations Subjectdemographics Age, Gender, Race Treatment- related Treatment group, information on the active control drug (if any)

15. 15 Dataset Variables Disease-related Prior Attempt, Prior Ideation, Symptom Scale (Scale name, Baseline and Final Scores), Response Outcome- related Suicidality Event, Time to Event or Time on Study Drug Subject Deaths Death by any cause occurring within 90 days after the intended treatment