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.

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

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

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 15-24 age group representing 20% of suicides (approximately 6,000)

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

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 15-24 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

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 15-24 age population: 100/1 (parasuicide) Serious suicide attempts indicative of severe psychiatric illness

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

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

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

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

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

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

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)

Suicide Rates for All Persons and Persons Aged 15 to 24, U. S Ages 15-24 1950 = 4 1980 = 12.3 13.35 Suicide Rate (per 100,000) 11.9 1950 1980 Year Adapted from: Rosenberg et al, 1987. 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

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

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

Clinical Analysis of Spontaneous Reports Dr. Jacobs

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?

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

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

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

“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

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

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 12 cases off Accutane

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

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

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

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

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