1. 1 SUICIDALITY CLASSIFICATION PROJECT Kelly Posner, Ph.D. Maria Oquendo, M.D. Barbara Stanley, Ph.D. Madelyn Gould, Ph.D, M.P.H Statistical Consultant: Mark Davies, M.P.H.

2. 2 Rationale for Reclassification The Problem: The Problem: –Field challenged by lack of conceptual clarity about suicidal behavior and corresponding lack of well-defined terminology –Lack of systematic or standardized language used to define suicidal behavior in the 25 industry antidepressant trials –Difficulty in interpreting the meaning of reported adverse events that occurred in these trials

3. 3 The Problem… AEs that should have been called suicidal may have been missed AEs that should have been called suicidal may have been missed AEs may have been inappropriately classified as suicidal AEs may have been inappropriately classified as suicidal

4. 4 Examples of Difficulties in Adverse Event Labeling Original Label Narratives Personality Disorder Age 10: The patient exhibited symptoms of personality disorder, assessed as moderate in severity, and was discontinued from the study due to this event. One day later (date), the patient attempted to hang himself with a rope after a dispute with his father. The investigator did not consider this event to be a suicide attempt, but rather to be part of the personality disorder, which was still ongoing. Suicide Event this patient is reported to have engaged in an episode of ‘automutilation’ where she slapped herself in the face. Medication Error Age 14: The patient took 11 tablets impulsively and then went to school…the patient denied that it was a suicide attempt. Hostility Age 10: Before his mother’s call to the site and again after arguing with his stepfather, he wrapped a cord from the miniblinds around his neck, threatening to kill himself.

5. 5 How to Address this Problem? a common set of guidelines needed to be applied a common set of guidelines needed to be applied Data needed to be examined consistently across trials Data needed to be examined consistently across trials Used research-supported definitions/concepts with reliability and validity Used research-supported definitions/concepts with reliability and validity

6. 6 Broaden Range of Adverse Events: To avoid bias in ratings (would not want raters to only have what sponsors had identified as possibly suicidal) To avoid bias in ratings (would not want raters to only have what sponsors had identified as possibly suicidal) To identify suicidal events that may have been missed To identify suicidal events that may have been missed

7. 7 What Was Included to Broaden Range: Events originally identified by sponsors as possibly suicide related Events originally identified by sponsors as possibly suicide related Accidental Injuries (including accidental overdoses) Accidental Injuries (including accidental overdoses) Serious Adverse Events (this includes life-threatening events and all hospitalizations) Serious Adverse Events (this includes life-threatening events and all hospitalizations)

8. 8 Why Were Experts in Suicide Needed? Limited information provided in narratives, particularly frequent lack of stated suicidal intent Limited information provided in narratives, particularly frequent lack of stated suicidal intent Allowed for inference based on details of behaviors and related clinical information Allowed for inference based on details of behaviors and related clinical information

9. 9 Expert Rater Panel Annette Beautrais, Ph.D David Brent, M.D. Greg Brown, Ph.D. Kees van Heeringen, M.D., Ph.D. Cheryl King, Ph.D., ABPP Peter Marzuk, M.D. Patrick O'Carroll, M.D., M.P.H David Rudd, Ph.D., ABPP Anthony Spirito, Ph.D., ABPP Alternate: Alec Miller, PsyD.

10. 10 Columbia Suicidality Classification Rating Scale Behavior Towards Self Injury Suicidal Thoughts: Intent or Wish to Die Event category Rating +++ Suicide Attempt __ Check if intent is inferred ___ Check if “Suicide Attempt” is only information provided ++ Preparatory Actions Towards Imminent Suicidal Behavior ++? Self-Injurious Behavior, Intent Unknown ++_ Self-Injurious Behavior, No Suicidal Intent, (To Affect Internal State /Circumstance) _+ Suicidal Ideation __ passive __ active__ active w/ plan __type unknown __ Other: No indication of deliberate self-injury or suicidal behavior or ideation Accident________ Medical*________ Psychiatric*________ ?? Not Enough Information *Please specify Comments:

11. 11 Definitions Definitions for the Columbia Suicidality Classification Scale Suicide Attempt Self- injurious behavior associated with some intent to die. Intent can be stated or inferred by rater. No injury needed. Preparatory Acts Towards Imminent Suicidal Behavior Person takes steps to injure self but is stopped by self or other. Intent to die is either stated or inferred. Self-Injurious Behavior, Intent Unknown Self- injurious behavior where associated intent to die is unknown and cannot be inferred. Self-Injurious Behavior, No Intent, Primarily to Affect Circumstance Self- injurious behavior associated with no intent to die – behavior is intended to effect change in others or the environment. Self-Injurious Behavior, No Intent, Primarily to Affect Internal State Self- injurious behavior associated with no intent to die intended to relieve distress. Typical examples are superficial cuts or scratches, hitting/banging, or burns. Suicidal Ideation Passive thoughts about wanting to be dead or active thoughts about killing oneself, not accompanied by preparatory behavior. Other: Accident Passive thoughts about wanting to be dead or active thoughts about killing oneself, not accompanied by preparatory behavior. Other: Psychiatric*_____________ Psychiatric symptoms only (when no evidence of any type of suicidality) Other: Medical*______________ Medical symptoms or procedure only Not Enough Information Insufficient information to classify the event * Infer intent if the behavior is clinically impressive or there is more than one piece of evidence suggesting suicidal intent

12. 12 What is the Classification Scheme? SuicidalNon Suicidal Suicide Attempt Code= 1 N= 36 Suicidal Ideation Code=6 N=62 Self-Injurious Behavior Without Suicidal Intent Codes=4,5,,11 N=17 Other: -Accidental -Psychiatric -Medical Codes=7,8,9,1 2 N= 260 Indeterminate Non- Consensus N = 0 Not Enough Information: Unable to Classify Whether Deliberate Self- Injury or “other” Code = 10 N = 9 Preparatory Actions Towards Imminent Suicidal Behavior Code =2 N = 8 Self-Injurious Behavior With Unknown Intent Code=3 N=35 ? Suicidal

13. 13 What Was Done?: Classification Methodology Chose expert panel Chose expert panel –Expertise in adolescent suicide and suicide assessment –Based on reputation and publications –No involvement in industry youth depression trials in question –No expert rater was employee of Columbia University Training teleconference to review classification parameters Training teleconference to review classification parameters Training reliability exercises (to ensure appropriate application of classification) Training reliability exercises (to ensure appropriate application of classification)

14. 14 Design continued…… All case narratives blinded to any potentially biasing information All case narratives blinded to any potentially biasing information Random distribution of 427 events to 9 experts Random distribution of 427 events to 9 experts –PI blind to randomization procedures –Each case independently rated by 3 raters –Each rater received approx. 125 events to rate –Any group of 3 raters shared only 5 cases Review of all ratings for QA and identification of non- agreement cases Review of all ratings for QA and identification of non- agreement cases Consensus teleconferences for any disagreement cases Consensus teleconferences for any disagreement cases Double data entry for quality assurance Double data entry for quality assurance

15. 15 Consensus Process If ratings did not have unanimous agreement, consensus discussion held If ratings did not have unanimous agreement, consensus discussion held Each case discussed by 3 raters involved Each case discussed by 3 raters involved Discussion of each case led by an expert other than those originally assigned the case Discussion of each case led by an expert other than those originally assigned the case Goal of discussion was to reach 100% agreement Goal of discussion was to reach 100% agreement If 100% agreement could not be reached, case became indeterminant If 100% agreement could not be reached, case became indeterminant Original majority opinion did not always end up as the final consensed classification Original majority opinion did not always end up as the final consensed classification

16. 16 What Was Rated? Blinding of Event Narratives to Avoid Bias Received from FDA blind to all potential drug identifying information: Received from FDA blind to all potential drug identifying information: –Drug name –Company/sponsor name –Patient identification numbers –Active or placebo arm –Any and all medication names and types (e.g. tx with other meds may be associated with a particular antidepressant side effect profile and thus could potentially bias) –Primary Diagnosis Additional Blinding of potentially biasing information: Additional Blinding of potentially biasing information: –Original label of event given by investigator or sponsor –“serious” or “non-serious” labels

17. 17 Rating Guidelines: How Was Classification Scheme Applied? Applied concepts using their clinical expertise and judgment Applied concepts using their clinical expertise and judgment Used experience to integrate clinical information and infer when appropriate Used experience to integrate clinical information and infer when appropriate “Reasonable” certainty in order to commit to a rating “Reasonable” certainty in order to commit to a rating Rating based on what was probable or likely, not what was “possible” Rating based on what was probable or likely, not what was “possible”

18. 18 Guidelines for Intent Inference Infer if “clinically impressive” or Infer if “clinically impressive” or Using 2 smaller pieces of clinical information Using 2 smaller pieces of clinical information Clinical information that could inform inference of intent included: Clinical information that could inform inference of intent included: –Clinical circumstances (method used, number of pills) –Past history of suicide attempt –Past history of self-injurious behavior/self- mutilation –Family history of suicide/suicide attempts

19. 19 Case Example of Inferred Intent: “Clinically Impressive” Circumstances Clinical impressiveness overrules stated intent Clinical impressiveness overrules stated intent “The subject attempted suicide by immolation. Her siblings doused the flames immediately. She was left with minor burns on her abdomen and one on her left shoulder that were treated. The subject admitted that she was angry with her parents for going away and leaving her alone at home, because she was fearful. The subject admitted that she had acted impulsively and had not intended to kill herself.”

20. 20 Another Examples of Clinically Impressive Circumstance: Suicide Attempt CASE 1: The patient, age 16, claimed to have ingested 100 tablets of the taper study medication after a fight with her mother. CASE 1: The patient, age 16, claimed to have ingested 100 tablets of the taper study medication after a fight with her mother. The patient informed her mother, who then brought the patient to an emergency room. The patient reportedly felt “shaky” The patient informed her mother, who then brought the patient to an emergency room. The patient reportedly felt “shaky” The emergency room physician stated that the patient “looked okay,” but was “slightly tachycardic” with a pulse of 100 The emergency room physician stated that the patient “looked okay,” but was “slightly tachycardic” with a pulse of 100 Tox screen negative Tox screen negative The patient remained in the emergency room for several hours until she was completely asymptomatic The patient remained in the emergency room for several hours until she was completely asymptomatic The patient was later admitted to psych unit The patient was later admitted to psych unit

21. 21 Examples of Suicide Attempt, cont. CASE 2: After a conflict with her father, the patient, age 17, took an overdose of 20 (several) tablets. In her father’s opinion, the overdose was 5 tablets. The patient did not have any symptoms of an overdose, “not even nausea”. CASE 2: After a conflict with her father, the patient, age 17, took an overdose of 20 (several) tablets. In her father’s opinion, the overdose was 5 tablets. The patient did not have any symptoms of an overdose, “not even nausea”.

22. 22 Examples of Suicide Attempt, cont. CASE 3: Following a disagreement with her mother, the patient, age 15, intentionally overdosed. She consumed 12 tablets of study meds, 23 __, 12 __, 23 ___, 29 ___, 4 ___ and 10 __ tablets. Consumed 113 tablets. CASE 3: Following a disagreement with her mother, the patient, age 15, intentionally overdosed. She consumed 12 tablets of study meds, 23 __, 12 __, 23 ___, 29 ___, 4 ___ and 10 __ tablets. Consumed 113 tablets. CASE 4: The patient, age 15, impulsively slit her wrists following an altercation with her mother. The wounds were superficial and were not stitched. CASE 4: The patient, age 15, impulsively slit her wrists following an altercation with her mother. The wounds were superficial and were not stitched. CASE 5: Age 17, she attempted suicide by taking 8 tablets of ____ after a fight with her father, whom she considered harsh and rejecting. CASE 5: Age 17, she attempted suicide by taking 8 tablets of ____ after a fight with her father, whom she considered harsh and rejecting.

23. 23 Examples of Self-Injurious Behavior, Intent Unknown CASE 1: The patient, age 10, had superficial scratches, left arm, scratched self with scissors CASE 1: The patient, age 10, had superficial scratches, left arm, scratched self with scissors CASE 2: The patient, age 14, ingested or simulated ingestion of 2-3 cigarettes. The patient was reported as feeling tired and playing a theatrical role CASE 2: The patient, age 14, ingested or simulated ingestion of 2-3 cigarettes. The patient was reported as feeling tired and playing a theatrical role CASE 3: Subject, age 9, reported he had ingested four of his brother’s tablets “on a dare” CASE 3: Subject, age 9, reported he had ingested four of his brother’s tablets “on a dare” CASE 4: The patient, age 10, swallowed a small amount of aftershave lotion while angry CASE 4: The patient, age 10, swallowed a small amount of aftershave lotion while angry

24. 24 Examples of Preparatory Actions CASE 1: Age 16: on day 63, she tried to hang herself and was prevented from doing so by her family. CASE 1: Age 16: on day 63, she tried to hang herself and was prevented from doing so by her family. CASE 2: The voice commanded the patient, age 18, to jump from the roof. Although the patient went to the roof, he did not jump. CASE 2: The voice commanded the patient, age 18, to jump from the roof. Although the patient went to the roof, he did not jump. CASE 3: The patient, age 10, experienced suicidal ideation with plan. Reportedly, the subject held a kitchen knife to her neck while alone but did not cut herself and the event was not witnessed. At her next scheduled visit, the subject reported the suicidal ideation described above. CASE 3: The patient, age 10, experienced suicidal ideation with plan. Reportedly, the subject held a kitchen knife to her neck while alone but did not cut herself and the event was not witnessed. At her next scheduled visit, the subject reported the suicidal ideation described above. CASE 4: The patient, age 18, was noted to be hostile, hopeless, and helpless and had written suicide notes. CASE 4: The patient, age 18, was noted to be hostile, hopeless, and helpless and had written suicide notes.

25. 25 Examples of Self-Injurious Behavior, No Intent CASE 1: The patient stated that there is increased family tension over the past six days and that she made superficial cuts on her wrist with an Exacto Knife. The patient and mother reported that the cuts weren’t deep and that they looked like a “cat scratched her.” The patient adamantly denied any suicidal gestures or intent. The patient stated that she only wanted “a release” and that cutting and hitting her legs offers a “release.” CASE 1: The patient stated that there is increased family tension over the past six days and that she made superficial cuts on her wrist with an Exacto Knife. The patient and mother reported that the cuts weren’t deep and that they looked like a “cat scratched her.” The patient adamantly denied any suicidal gestures or intent. The patient stated that she only wanted “a release” and that cutting and hitting her legs offers a “release.” CASE 2: Denies suicidal thoughts. The first time she cut herself was at age 16 and stated that she did it for attention. Today her cutting was more spontaneous. She reported that cutting gives her “a good weird feeling.” CASE 2: Denies suicidal thoughts. The first time she cut herself was at age 16 and stated that she did it for attention. Today her cutting was more spontaneous. She reported that cutting gives her “a good weird feeling.”

26. 26 Results: Number of Events and Cases 427 Events FDA Severity Hierarchy 378 Cases Suicide Attempt Preparatory Actions Suicidal Ideation SIB, intent unknown Not enough Information

27. 27 Results: Expert Rater Consensus Only 2/427 cases had no agreement among the 3 raters Only 2/427 cases had no agreement among the 3 raters 59 cases had agreement among 2 of 3 raters, had to go to teleconference 59 cases had agreement among 2 of 3 raters, had to go to teleconference No cases in which consensus not able to be reached during teleconference No cases in which consensus not able to be reached during teleconference

28. 28 Discordant Cases Between Sponsor and Columbia Classifications 40/427 cases in which sponsor and Columbia classification differed 40/427 cases in which sponsor and Columbia classification differed –26 new cases identified that had not been identified by sponsors as possibly suicide-related –2 new cases of self-injurious behavior without suicidal intent that had been labeled something other than deliberate self-harm -12 cases originally called possibly suicidal changed to something other than possibly suicidal

29. 29 Discordant Cases: Newly Identified 26 new possibly suicide-related cases identified among expanded body of events 26 new possibly suicide-related cases identified among expanded body of events –26 possibly suicide-related 1 Suicide Attempt 1 Suicide Attempt 1 Preparatory Act 1 Preparatory Act 13 Suicide Ideation Events 13 Suicide Ideation Events 4 Self-Injurious Behavior Intent Unknown 4 Self-Injurious Behavior Intent Unknown 7 Not Enough Information to say whether deliberate self-harm 7 Not Enough Information to say whether deliberate self-harm

30. 30 Example of Newly Identified Suicidal Event: Preparatory Act The patient, age 11, held a knife to his wrist and threatened to harm himself. The patient was hospitalized with an acute exacerbation of major depressive disorder. The patient was treated with __ and discharged in stable condition. The patient, age 11, held a knife to his wrist and threatened to harm himself. The patient was hospitalized with an acute exacerbation of major depressive disorder. The patient was treated with __ and discharged in stable condition. Original Adverse Event Label: Exacerbation of Major Depressive Disorder

31. 31 Discordant Cases: Events Changed from Suicidal to Something “Other” 12 Events 12 Events –2 changed to psychiatric –1 changed to accident –9 changed to self-injurious behavior no suicidal intent Example Event: “this patient is reported to have engaged in an episode of ‘automutilation’ where she slapped herself in the face. The event resolved the same day without any intervention.”

32. 32 Results: Agreement with Sponsor (I): Possibly Suicidal (1,2,6,3,10) 23726 12102 Columbia Classification- Possibly Suicide Related: Yes No Yes 263 114 128249 Sponsor Classification- Possibly Suicide Related: Kappa=.77

33. 33 Results: Agreement with Sponsor (II) Definitely Suicidal (1,2,6) 24815 3282 Columbia Classification- Definitely Suicide Related: Yes No Yes 263 114 97280 Sponsor Classification- Definitely Suicide Related: Kappa=.69

34. 34 Results: Reliability of Columbia University Classification Primary Outcome :ICC Suicide Attempt.81 Preparatory Actions.89 Suicidal Ideation.97 Sensitivity Outcome : SIB, Intent Unknown.67 Not Enough Info.47 Median ICC.86

35. 35 Future Directions Improve adverse event reporting for suicide-related events by: Improve adverse event reporting for suicide-related events by: Developing a consistent terminology Developing a consistent terminology Developing guidelines for classification of suicidality (so adequate info provided by clinician) Developing guidelines for classification of suicidality (so adequate info provided by clinician) Utilization of research assessment tools (what questions to ask, how to ask, and what measures aid this) Utilization of research assessment tools (what questions to ask, how to ask, and what measures aid this) Improved, More Valid Identification and Documentation Of Suicidality Also describes 12