1. Overview of Psychiatric Disorders
Douglas Jacobs, MD Associate Clinical Professor of Psychiatry
Harvard Medical School
Introduction
- Psychiatrist and Suicidologist
- studied the problem of suicide for over 25 years
- I developed National Depression screening day, the first National program screening for depression
- has reviewed the records of over 300 suicides applying principles of psychological autopsy
- has edited 3 textbooks on suicide
- still actively treat depressed and suicidal patients
I will present a clinical context for understanding the psychiatric conditions described in the spontaneous reports, specifically suicide and depression first in the general population, then in the major Accutane population (Ages 15-24). This context will focus on the question of Accutane’s relationship to and or impact on these conditions and will examine the dual use of the term depression as an illness vs depression as a symptom, particularly as it relates to medications
Dr. Nelson will then provide an epidemiologic analysis - and then I will close with a clinical analysis of the suicide reports.
In order to address the questions about the relationship of Accutane to the suicide reports, one must understand the factors underlying any suicide.

2. Overview of Clinical Context of Spontaneous Reports
Suicide
clinical and demographic correlates
clinical features
Suicidal Behavior
definitional issues as they relate to spontaneous reports
Depression
definitions - illness vs symptoms
relationship to medications
relationship to suicide
Depression and Suicide in Ages 15-24
diagnostic issues
epidemiology and risk factors

3. Suicide: A Multi-Factorial Event - Adult
No apparent psychopathology
Psychiatric Illness Co-morbidity
Neurobiology
Substance Use/Abuse
Impulsiveness
Severe Medical
Illness
Suicidal
Behavior
SUICIDE
Personality Disorder/Traits
Life Stressors
Access To Weapons
Family History
Hopelessness

4. Incidence of Suicide 30,000 suicides per year in the US
0.01% annual incidence rate (11.4/100,000)
80% suicides are in males (4:1 m/f ratio)
Third leading cause of death in the age group representing 20% of suicides (approximately 6,000)

5. Suicide: Clinical Features
Associated with severe depression
Majority not in mental health treatment
75% have seen a physician in previous six months
No one factor predictive of suicide
60% suicide on first attempt
No medication has ever been proven to cause suicide

6. Profile of the Suicides in the Accutane Medwatch Reports
30,000 suicides per year in the US
0.01% annual incidence rate (11.4/100,000)
80% suicides are in males (4:1 m/f ratio)
Third leading cause of death in the age group representing 20% of suicides
Associated with severe depression
Majority not in mental health treatment
75% have seen a physician in previous six months
No one factor predictive of suicide
60% suicide on first attempt
No medication has ever been proven to cause suicide

7. Definitional Issues - Suicidal Behavior
Suicidal Ideation:
A) nonspecific -- thoughts of death
B) specific -- the thought of death includes an intent to die with a plan of action
Prevalence of suicidal ideation = 2.6%
Thoughts of death = 28.2%
Suicidal ideation (definition B) is associated with a psychiatric disorder, primarily depression
Suicide Attempts:
A) (U.S.) Potential or actual self-injurious behavior accompanied by intent to die
B) (Europe) Parasuicide -- a self-harmful act with nonfatal outcome -- intent not included in definition
(U.S.) Current prevalence estimates: 0.3 to 0.8%
Male/Female ratio 1:3 (inverse of suicides)
Attempts/completion 18/1
Higher incidence of attempts in age population: 100/1 (parasuicide)
Serious suicide attempts indicative of severe psychiatric illness

8. Overview of Suicidal Behavior
Thoughts of death (28%)
Suicide Ideators (2.6%)
Suicide Attempters
Ideators: 5,000,000*
Attempters: 600,000*
Completers: 31,284 (1995)
Completers
Self Destructive Behavior
*estimate

9. Depression: Epidemiology
Prevalent disorder 12% annually - 20 million people
Undertreated and Underdiagnosed - Only 20% with recent episodes in treatment; 40% lifetime.
20% appear in general medical practices; 50% undiagnosed
Decreased age of onset since WW II
Male/Female ratio 1:2

10. Depression: The Illness Versus Depressive Symptoms - (The Blues)
Depression The Blues
Essential distinction: An illness A normal reaction to life situations
Prevalence: 12% 25%
Symptoms: Multiple: mood, Single: mood thoughts, bodily functions
Duration: Persists, episodic Temporary
Suicide Potential: Can result in Rarely produces suicide suicidal thoughts
Treatment: Requires specific Requires a good medical/psychiatric listener and/or treatment time to heal

11. The Issue of Medications and “Depression”
Are medications that are reported to cause depression (approximately 100) associated with diagnosed depressive disorders or depressive symptoms?
Case reports vs empirical evidence
Majority of evidence suggests association with depressive symptoms and not depressive disorders
Clinical significance of depressive symptoms is minimal

12. Adolescent Depression - Clinical Features
Increased moodiness, irritability, argumentativeness
Poor concentration
Sleep and appetite changes
Increased self-criticism
Despair, sadness, emptiness
Loss of energy
Lack of interest in usual activities and friends
Increased talk of death and dying
Threats of suicide

13. Why Adolescent Depression Is Undiagnosed
Normal adolescents often moody, frequently argue
Symptoms of depression overlap with traits of normal adolescence
Parents, teachers and other adults label it “troubled teenage behavior”
Adolescents conceal symptoms from parents and care givers

14. Adolescent Depression - Relationship to Stressful Events
Depression can occur after a stressful event or in teenagers who have not experienced a stressful event (50-50)

15. Suicide Rates for All Persons and Persons Aged 15 to 24, U. S
Ages = = 12.3
13.35
Suicide Rate (per 100,000)
11.9
1950
1980
Year
Adapted from: Rosenberg et al, The Emergence of Youth Suicide: An Epidemiologic Analysis and Public Health Perspective. Annual Review of Public Health, 8:417-44
Updated from National Center for Health Statistics Center
PSY 110, (1063), 7/18/00

16. Suicide: A Multi-Factorial Event - Adolescent
No apparent psychopathology
Psychiatric Illness Co-morbidity
Neurobiology
Substance Use/Abuse
Impulsiveness
Exposure to Suicide
Suicidal
Behavior
SUICIDE
Conduct Disorder
Severe Acne
Age Specific
Stressors
Access To Weapons
Family History
Self-esteem/image
Academic Problems
Disciplinary Crisis/ Humiliation
Hopelessness

17. No Apparent Psychopathology
Psychological autopsy studies reveal risk factors:
subsyndromal psychopathology
past suicidality
familial psychiatric disorder
legal/disciplinary problems
presence of firearm (or other lethal method)
Note: Cases 15, 29, 1, 61, 14, 8 (patient had 2 courses of Accutane, argues against impulsive rx to Accutane

18. Clinical Analysis of Spontaneous Reports
Dr. Jacobs

19. Questions Addressed
Is there any pattern to suicide reports in relationship to Accutane?
e.g., gender distribution and on/off Accutane
What is the significance of the temporal association with “depression”?
Does Accutane exacerbate underlying psychopathology and lead to suicide?
Does Accutane cause impulsive suicides?

20. Categories of Suicides in Medwatch Reports
Relationship to Accutane Use
Concealment of symptoms
Confounding factors e.g. pre-existing psychiatric history
No apparent psychopathology
Miscellaneous

21. Suicide: On/Off Accutane
30 cases were on Accutane, including 4 that were on over 6 months
24 cases were off Accutane
10 unknown
No evidence of predominance of on/off factor
Gender -- total males = 53, total females = 11
total suicides consistent with known demographics
on/off ratio the same, regardless of gender

22. Case Example: Relationship to Accutane
On Accutane < 1 Month
Off Accutane 9 Months
22 year-old male
Firearm
No relevant findings
19 year-old male
Firearm
History of psychosis
School stressors
Duration 6 months
Analysis: No consistent relationship to Accutane

23. “Depression” Occurring While On Accutane
17 out of 64 reports
10 cases committed suicide on Accutane
7 cases committed suicide off Accutane
Only one case had psychiatric treatment

24. Case Example – Concealment of Symptoms
Case Description
Case Analysis
14 year-old male
Committed suicide 2 months on Accutane
Psychiatric History -- none reported
No depression or suicidal ideation noted while on Accutane
Pre existing depression and suicidal ideation -- revealed by diary found after suicide
Depression with suicidal ideation requires psychiatric treatment
Analysis: Depression and suicidal ideation concealed from family and physician

25. Prior Psychiatric History Related to On/Off Accutane
Question: What is the impact of Accutane on this at-risk group for exacerbation of underlying illness leading to suicide?
Results: 9 cases on Accutane cases off Accutane

26. Reports With Prior Psychiatric History That Represent “Controls”
Duration
Time Off
None of these reports developed symptoms of underlying illness while on Accutane
Accutane did not precipitate symptoms in persons at-risk
Suicide unrelated to Accutane
Analysis: Suicide related to underlying psychiatric disorder
8 mo
6 mo
4 mo
3 mo
18 mo
1 yr
> 6 mo
9 mo
18 mo
6 yrs
8 yrs
~ 10 yrs
10 yrs

27. Case Example – No Apparent Psychopathology
Case Description
Case Analysis
18 year-old male
On Accutane < 1 month
No history of depression, mood swings or stressors
Suicide by inhaling pellets placed in a canister, attached to tubing and a face mask
Engaged in risky behavior
Method suggestive of “getting high”
Analysis: Suicide intent not established, possible accidental death

28. Case of Murder-Suicide
Case Description
Case Analysis
Duration = 8 months
Off Accutane 4 months
Method = killed self and child by drowning (child not exposed to Accutane)
Prior history = post-partum depression
Accutane stopped because of “delirium”
Hospitalization offered but refused
Infanticide consistent with psychotic depression
Post-partum depression occurs in manic-depressive illness
“Delirium” most likely was psychotic episode
Analysis: Events related to severe underlying psychiatric disorder

29. Case Example – Substance Abuse/Impulsive Behavior
Case Description
Case Analysis
21 year-old male
Psychiatric history
Patient had been in and out of substance abuse rehabilitation treatment
On Accutane, 6 months
No report of depressive symptoms nor of drug relapse
Committed suicide 1 year off Accutane
Substance abusers are at-risk for mood disorders and impulsive behavior
Accutane did not cause relapse, mood symptoms, or impulsive actions
Analysis: Suicide was related to pre-existing psychiatric conditions and happened a considerable amount of time after discontinuation of Accutane

30. Summary of Clinical Analysis
No alteration of gender distribution
No impact of on/off Accutane
No significant relationship to concurrent “depression”
No exacerbation of underlying psychiatric disorders
Lack of warning signs consistent with youth suicide
No evidence of impulsive factor