Accutane-Psychiatric Accutane-Psychiatric DisordersDisorders

A Pharmacoepidemiological A Pharmacoepidemiological Safety AssessmentSafety Assessment

Robert C. Nelson, PhD Robert C. Nelson, PhD

RCN Associates, Inc. Annapolis, MDRCN Associates, Inc. Annapolis, MD

Presentation OverviewPresentation Overview

ObjectivesObjectives

Literature review and model generationLiterature review and model generation

Spontaneous report reviewsSpontaneous report reviews

EpidemiologyEpidemiology

ConclusionsConclusions

ObjectivesObjectives

To determine the nature and extent of any To determine the nature and extent of any relationship between Accutane therapy and relationship between Accutane therapy and psychiatric morbiditypsychiatric morbidity

1)1) Describe the types of reported psychiatric disordersDescribe the types of reported psychiatric disorders

2)2) Identify all associated risk factorsIdentify all associated risk factors

3)3) Assess the magnitude of the identified risk factorsAssess the magnitude of the identified risk factors

4)4) Evaluate causality within the pharmacoepidemiologic frameworkEvaluate causality within the pharmacoepidemiologic framework

Methodological OverviewMethodological Overview Literature ReviewLiterature Review

– determine scope of work and related disciplinesdetermine scope of work and related disciplines– comprehensively review and evaluate literature (250 citations)comprehensively review and evaluate literature (250 citations)– review etiology and epidemiology of psychiatric conditions review etiology and epidemiology of psychiatric conditions

(including suicidal behavior) (including suicidal behavior) – conceptualize proposed relationshipsconceptualize proposed relationships

Review Spontaneous ReportsReview Spontaneous Reports– evaluate spontaneous reports for category, quality and contentevaluate spontaneous reports for category, quality and content– determine the value of spontaneous reports in explaining determine the value of spontaneous reports in explaining

proposed relationshipsproposed relationships

Review Epidemiology - Conduct Epidemiologic AnalysesReview Epidemiology - Conduct Epidemiologic Analyses– evaluate relative likelihood of all risk factors identifiedevaluate relative likelihood of all risk factors identified– derive relevant conclusionsderive relevant conclusions

Presentation OverviewPresentation Overview

ObjectivesObjectives

Literature review (Dr. Jacobs)Literature review (Dr. Jacobs)

Spontaneous report reviewsSpontaneous report reviews

EpidemiologyEpidemiology

ConclusionsConclusions

Presentation OverviewPresentation Overview

ObjectivesObjectives

Literature review and model generationLiterature review and model generation

Spontaneous report reviewsSpontaneous report reviews

EpidemiologyEpidemiology

ConclusionsConclusions

Spontaneous Report Case RetrievalSpontaneous Report Case Retrieval

WHOART SOC. 500 - All Psychiatric Cases WHOART SOC. 500 - All Psychiatric Cases by “Reporter Term”by “Reporter Term”

8 functional diagnostic categories (DSM-IV)8 functional diagnostic categories (DSM-IV)

Reviewed reports received between 1982 Reviewed reports received between 1982 and April 30, 1999and April 30, 1999

WorldwideWorldwide

Mood disorders

1247

(53.1%)

Anxiety disorders

249

(10.6%)

Psychotic disorders

120

(5.1%)

Cognitive disturbances

174

(7.4%)

Sleep disorders

82

(3.5%)

Personality disorders

41

(1.7%)

Suicidal behavior

168

(7.1%)

Excluded terms

265

(11.3%)

Total:

2346

(100%)

ResultsResultsDistribution of Cases By CategoryDistribution of Cases By Category

Reasons For Suspecting A Possible Relationship Reasons For Suspecting A Possible Relationship Between A Drug And An Adverse EventBetween A Drug And An Adverse Event

Temporal associationTemporal association

Dose-responseDose-response

DechallengeDechallenge

RechallengeRechallenge

MechanismMechanism

Class EffectClass Effect

Absence of alternativesAbsence of alternatives

Methodology For Evaluation of Methodology For Evaluation of Individual Spontaneous ReportsIndividual Spontaneous Reports

Review individual case Review individual case

Assess coded/reported term Assess coded/reported term

Assess data quality Assess data quality

Assess consistency of data, including onset/offsetAssess consistency of data, including onset/offset

Above relative to the 7 reasons on prior slideAbove relative to the 7 reasons on prior slide

Then, review as case seriesThen, review as case series

Interpretation of Spontaneous ReportsInterpretation of Spontaneous Reports

When spontaneous reports are well documented When spontaneous reports are well documented and for rare ADRs that have background rates and for rare ADRs that have background rates that are low, the spontaneous reports yield the that are low, the spontaneous reports yield the most defensible datamost defensible data

Spontaneous reports are of very diminished Spontaneous reports are of very diminished value when the outcome has a common value when the outcome has a common background ratebackground rate

Mood Disorder ResultsMood Disorder Results

Of 1247 mood disorder reports:Of 1247 mood disorder reports:– 367 dechallenge reports 367 dechallenge reports

23 positive dechallenge and rechallenge reports23 positive dechallenge and rechallenge reports 37 reports had mood disorder diagnosis subsequent to exposure37 reports had mood disorder diagnosis subsequent to exposure

33 1414 11 88 00 88 44 3030

Health ProfessionalHealth Professional ConsumerConsumer OtherOther TotalTotal

Dechallenge/Rechallenge Reports (34)Dechallenge/Rechallenge Reports (34)Mood Symptoms or DisordersMood Symptoms or Disorders

DxDx No DxNo Dx DxDx No DxNo Dx DxDx No DxNo Dx DxDx No DxNo Dx

Mood Disorder Results Mood Disorder Results (cont’d)(cont’d)

Even the dechallenge reports had a high level of Even the dechallenge reports had a high level of diversity/inconsistencydiversity/inconsistency

In summary: At the individual case level, a small In summary: At the individual case level, a small number of cases imply a causal association between number of cases imply a causal association between depressive symptoms and/or mood disorders, and depressive symptoms and/or mood disorders, and AccutaneAccutane

Psychotic Disorder ResultsPsychotic Disorder Results

Of 120 psychotic disorder reports:Of 120 psychotic disorder reports:– 20 dechallenge reports 20 dechallenge reports – 5 positive dechallenge and rechallenge reports5 positive dechallenge and rechallenge reports

3 reports had a diagnosis of psychotic disorder 3 reports had a diagnosis of psychotic disorder

– 100 other reports: 100 other reports: 9 additional reports with diagnosis 9 additional reports with diagnosis

No pattern of consistency in the available dataNo pattern of consistency in the available data

In summary: At the individual case level, at least 3 reports In summary: At the individual case level, at least 3 reports imply a causal association between the described imply a causal association between the described psychotic disorder and Accutane administrationpsychotic disorder and Accutane administration

Suicidal Behavior ReportsSuicidal Behavior Reports

Total of 168 reports of suicidal behavior (1982 to April 30, 1999)Total of 168 reports of suicidal behavior (1982 to April 30, 1999)– 104 reported suicide attempts104 reported suicide attempts– 64 reports of completed suicides64 reports of completed suicides

Overall suicide reports were poorly documented; none had Overall suicide reports were poorly documented; none had psychological autopsypsychological autopsy

No apparent dose relationshipNo apparent dose relationship

Ratio of M/F is 5 to 1 for completed suicide reportsRatio of M/F is 5 to 1 for completed suicide reports

In summary: None of the 168 reports implies direct causality In summary: None of the 168 reports implies direct causality between suicidal behavior and Accutane administration, at the between suicidal behavior and Accutane administration, at the individual case levelindividual case level

Presentation OverviewPresentation Overview

ObjectivesObjectives

Literature review and model generationLiterature review and model generation

Spontaneous report reviewsSpontaneous report reviews

Epidemiology & Epidemiological AnalysesEpidemiology & Epidemiological Analyses

ConclusionsConclusions

Demographics of Accutane PatientsDemographics of Accutane Patients

Accutane useAccutane use– 70% in 15-24 age group70% in 15-24 age group

85% of males85% of males 55% of females55% of females

Prevalence of Major Depressive Disorder Prevalence of Major Depressive Disorder (MDD): Age 15-24 (MDD): Age 15-24

30-day: 6.1% (4.3% M::8.2% F)30-day: 6.1% (4.3% M::8.2% F)

12-month: 10.3% (9.5% M::16.3% F)12-month: 10.3% (9.5% M::16.3% F)

Lifetime: 17.1% (11.0% M::20.8% F)Lifetime: 17.1% (11.0% M::20.8% F)

2.5 Million2.5 MillionUS IndividualsUS Individuals

Aged 15-24 Aged 15-24 YearsYears

182,500182,500

30,500 +42,700

30,500 +42,70084,00084,000

25,29025,290

??????

Major DSM IV Depressive DisorderMajor DSM IV Depressive Disorder((With acne estimates not available)With acne estimates not available)

t1 t2

152,500152,500Current Current DiseaseDisease

240,000240,000By History By History

OnlyOnly

2,107,000 2,107,000 No DiseaseNo Disease

No Change or No Change or 80% Abated then80% Abated then

35% Recur35% Recur

35% Recur or35% Recur orNo ChangeNo Change

1. 2% incident 1. 2% incident cases or No cases or No

changechange

?# of Accutane-?# of Accutane-Induced CasesInduced Cases

MDD Morbidity During Any Six Month Exposure Period MDD Morbidity During Any Six Month Exposure Period

Observed vs ExpectedObserved vs Expected

*Major Depressive Disorder

All Other New Total Depressive

Incidence Incidence Symptoms & MDD* MDD Disorders

Observed 102 336 911(102+234)

Expected 25,000 152,000 ~500,000-1,000,000

DoseDose10 - 120mg10 - 120mg

Time to Onset: 0 - 180 daysTime to Onset: 0 - 180 days

Dose & Time to Onset of Dose & Time to Onset of Background OccurrencesBackground Occurrences

Estimated Prevalence of Substance Abuse In Estimated Prevalence of Substance Abuse In Accutane-Treated Cohort (15-24 yrs)Accutane-Treated Cohort (15-24 yrs)

7.2% (180,000) heavy alcohol users7.2% (180,000) heavy alcohol users

Approximately same number of illicit drug Approximately same number of illicit drug abusers abusers

Assuming extensive co-morbidity, combined Assuming extensive co-morbidity, combined alcohol and illicit drug abuse includes alcohol and illicit drug abuse includes approximately 250,000 (10% of exposed) approximately 250,000 (10% of exposed) young Accutane patientsyoung Accutane patients

Alternate Risk FactorsAlternate Risk Factors

Nearly one-quarter million alcohol/substance abusers Nearly one-quarter million alcohol/substance abusers are amongst the 2.5 million of Accutane-exposed are amongst the 2.5 million of Accutane-exposed cohort cohort

Many of these abusers are also comorbid with the Many of these abusers are also comorbid with the 152,000 incident mood disorder cases or with people 152,000 incident mood disorder cases or with people with depressive symptoms or different diseasewith depressive symptoms or different disease

The total numbers in the cohort with some form DSM-The total numbers in the cohort with some form DSM-IV disorder may be up to 16-20% (up to 1/2 million) of IV disorder may be up to 16-20% (up to 1/2 million) of the total cohort the total cohort

Psychotic Disorders - Psychotic Disorders - Alternate Risk FactorsAlternate Risk Factors

Prevalence in ages 15-24 is 1% Prevalence in ages 15-24 is 1% (25,000 expected amongst exposed)(25,000 expected amongst exposed)

Prevalence in ages 25-34 is 2%Prevalence in ages 25-34 is 2% (14,000 expected amongst exposed) (14,000 expected amongst exposed)

Add alcohol and drug abuse covariates Add alcohol and drug abuse covariates (>3,900 expected amongst exposed)(>3,900 expected amongst exposed)

Suicidal BehaviorSuicidal Behavior

WOMEN

Any mood disorder 21.3 9.4-48.3 < 0.0001 79.2 58.3 26.3-129.4 < 0.0001 80.8

Any substance use 2.7 1.0-7.3 > 0.05 22.4 3.8 1.2-11.5 < 0.03 26.2disorder

Any antisocial disorder 2.3 0.9-6.2 > 0.05 21.5 1.2 0.2-9.1 > 0.05 6.3

Any anxiety disorder 1.5 0.5-4.7 > 0.05 7.0 1.3 0.5-3.3 > 0.05 5.0

Any eating disorder 8.6 0.8-91.7 > 0.05 14.8 1.1 0.5-6.5 > 0.05 1.6

95% Population 95% PopulationDSM-III-R Category Odds Confidence Attributable Odds Confidence Attributable By Gender Ratio Interval P Risk Ratio Interval P Risk

Age < 30 Years Age > 30 Years

Risk of a Serious Suicide Attempt Adjusted for Confounding Risk of a Serious Suicide Attempt Adjusted for Confounding Mental Disorders, by Gender and Age, for 302 Persons Who Mental Disorders, by Gender and Age, for 302 Persons Who Made Serious Suicide Attempts and 1,028 Comparison SubjectsMade Serious Suicide Attempts and 1,028 Comparison Subjects

SOURCE: Beautrais, A.L, et al. (1996) Prevalence and Comorbidity of Mental Disorders in Persons Making Serious Suicide Attempts: A Case-Control Study. American Journal of Psychiatry, 153(8): 1012

Observed vs Expected SuicidesObserved vs Expected Suicidesin Accutane-Exposed Cohort in Accutane-Exposed Cohort (United States Data and Estimates)(United States Data and Estimates)

Male (33) Female (5)Under 25 Over 25 Unk Under 25 Over 25 Unk Total

27 4 2 5 0 0 38

Male (319) Female (79)Under 25 Over 25 Under 25 Over 25 Total

262 57 48 31 398

Observed Suicide by Gender & Age

Expected Suicide by Gender & Age

Presentation OverviewPresentation Overview

ObjectivesObjectives

Literature review and model generationLiterature review and model generation

Spontaneous report reviewsSpontaneous report reviews

EpidemiologyEpidemiology

ConclusionsConclusions

ConclusionConclusionMood DisordersMood Disorders There are a small number of reported cases that imply There are a small number of reported cases that imply

causality between depressive symptoms or mood causality between depressive symptoms or mood disorders and Accutane administration, at the individual disorders and Accutane administration, at the individual case level. case level.

However, an assessment in the context of natural However, an assessment in the context of natural history and alternative risk factors provides strong history and alternative risk factors provides strong evidence that the described symptomatology and evidence that the described symptomatology and disorders are much more likely to be associated with disorders are much more likely to be associated with factors other than Accutane. factors other than Accutane.

Unfortunately the analysis of these kinds of data do not Unfortunately the analysis of these kinds of data do not allow any potential risk factor to be completely ruled allow any potential risk factor to be completely ruled out, no matter how unlikely it may appear.out, no matter how unlikely it may appear.

ConclusionConclusionPsychotic DisordersPsychotic Disorders

There are a very small number (3) of reported cases that There are a very small number (3) of reported cases that imply causality between a described psychotic disorder and imply causality between a described psychotic disorder and Accutane administration, at the individual case level.Accutane administration, at the individual case level.

However, an assessment in the context of natural history However, an assessment in the context of natural history and alternative risk factors provides strong evidence that the and alternative risk factors provides strong evidence that the described symptomatology and disorders are much more described symptomatology and disorders are much more likely to be associated with factors other than Accutane. likely to be associated with factors other than Accutane.

Unfortunately the analysis of these kinds of data do not allow Unfortunately the analysis of these kinds of data do not allow any potential risk factor to be completely ruled out, no matter any potential risk factor to be completely ruled out, no matter how unlikely it may appear.how unlikely it may appear.

ConclusionConclusionSuicidal BehaviorSuicidal BehaviorThere are no reports amongst the 168 reviewed There are no reports amongst the 168 reviewed

that imply direct causality between suicidal that imply direct causality between suicidal behavior and Accutane.behavior and Accutane.

An assessment in the context of natural history An assessment in the context of natural history and alternative risk factors provides strong and alternative risk factors provides strong supportingsupporting evidence that the reported cases are evidence that the reported cases are much more likely to be due to factors other than much more likely to be due to factors other than Accutane.Accutane.

Overall ConclusionOverall Conclusion

Given:Given:– no biological plausibilityno biological plausibility– no consistent patterns in the datano consistent patterns in the data– complex environment of background symptomscomplex environment of background symptoms– very high background rates of diseasevery high background rates of disease– very high background rates of alternative risk factorsvery high background rates of alternative risk factors

There is no evidence in these data to support a There is no evidence in these data to support a causal relationship between Accutane administration causal relationship between Accutane administration and psychiatric disordersand psychiatric disorders