How to assess the suicidal risk
of patients with epilepsy
undergoing AED trials?
Andres M Kanner, MD
Professor of Neurological Sciences and Psychiatry,
Rush Medical College
Director, Laboratory of EEG and VideoVideo-EEGEEG-Telemetry,
Associate Director, Rush Epilepsy Center,
Rush University Medical Center, Chicago, IL.
• In January 2008, the FDA issued an alert that
all AEDs are associated with a 1.8-fold
increased risk of suicidality (suicidal ideation
and behavior)
– Based on a meta-analysis of data from 199
randomized trials of 11 AEDs involving nearly
44,000 patients treated for epilepsy, psychiatric
disorders, and other disorders
Package Insert Label in all AEDs
5 WARNINGS AND PRECAUTIONS
5.1 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including XAED, increase the risk of suicidal
thoughts or behavior in patients taking these drugs for any indication.
indication.
Patients treated with any AED for any indication should be monitored for the
emergence or worsening of depression, suicidal thoughts or behavior,
and/or any unusual changes in mood or behavior.
The FDA Alert on Suicidality and AEDs:
Fire or False Alarm?
• Major limitations and caveats
– Analysis based on spontaneous adverse event reports
– The analysis grouped together all 11 drugs as one class
despite major differences in MOA
– Only topiramate and lamotrigine were associated with a
statistically significant increased risk of suicidality
– The analysis is likely confounded by multiple factors
including diagnosis and history of suicidality
Hesdorffer DC Kanner AM. Epilepsia. 2009;50:978-986.
AEDs and Risk of Suicidality
Study
Database
Events
considered
Gibbons
cohort study
(bipolar)
PharMetrics
medical claims
Attempted
suicide
No drug
Yes
↑ risk: TPM & CBZ
↓ risk: GBP, VPA,
LTG, OXC
Olesen
cohort study
Danish
populationbased recordslinkage
Completed
suicide
CBZ
No
↑ risk vs CBZ:
VPA, LTG, PB, LEV
Patorno
cohort study
Insurance
claims
Completed
suicide
TPM
CBZ
Yes
↑ risk vs TPM:
GBP, LTG, OXC, TGB,
VPA
Vancott
matched
case control
study
VA & Medicare
Ideation and
attempted
suicide
GPB
Yes
↑ risk vs GPB:
VPA, LTG, LEV
↓ risk vs GPB:
PHT, PB, CBZ
Hesdorffer DC et al. Epilepsy Curr. 2010;10:137-145.
Referent
standard
Controlled
for prior SB
Result
(relative risk)
AEDs and Risk of Suicidality:
v The results are inconsistent and contradictory both
across studies and within studies
v No clear or convincing evidence that all AEDs are
associated with an increased risk of suicidality
v The potential for bias is great
v Indication for prescription of AEDs is an important
confounding factor
Ø Only prospective, randomized, controlled trials in a
single indication that systematically collects and
controls for all relevant variables can answer this
question
Hesdorffer DC et al. Epilepsy Currents. 2010;10:137-145.
Family
Psychiatric history
Axis I Diagnosis
Mood Disorders
Anxiety Disorders
Personality
Disorders
Psychotic Disorders
Postictal
Psychiatric
Episodes
Suicidality
Type of seizure
disorder
AEDs
Suicide and Epilepsy
11.5%
Jones JE et al. Epilepsy Behav 4 (Suppl 3):S31-8, 2003
Suicide in RCT in Epilepsy
Ryvlin et al., AED mtg.
•N = 21,490 patients
•Deaths, n = 33
•Suicides, n = 2 (6% of deaths)
Epilepsy, Psychiatric Disorders and Suicide
Rate Ratio
No Epilepsy
Epilepsy
P value
1
2.4 (2.0
(2.0--2.8)
Epilepsy +
<0.0001
<0.0001
Affective Disorder
32.0 (20.8
(20.8--49.4)
<0.0001
Anxiety Disorder
11.4 (4.16(4.16-31.4)
<0.0001
Schizophrenia
12.5 (8.05
(8.05--22.7)
<0.0001
Christensen et al. Lancet Neurology 6: 693–98, 2007
Lifetime Prevalence
Tellez-Zenteno, JF et al., Epilepsia, 2007; 48:2336-2344
Psychiatric
Disorder
Controls (%)
Epilepsy (%)
Major Depressive
Disorder
10.7 (10.2–
(10.2–11.2)
17.4 (10.0–
(10.0–24.9)
Anxiety Disorder
11.2 (10.8–
(10.8–11.7)
22.8 (14.8–
(14.8–30.9)
Mood/Anxiety
Disorders
19.6 (19.0–
(19.0–20.2)
34.2 (25.0–
(25.0–43.3)
Suicidal Ideation
13.3 (12.8–
(12.8–13.8)
25.0 (17.4
(17.4–
–32.5)
Any Psychiatric
Disorder
20.7 (19.5–
(19.5–20.7)
35.5 (25.9
(25.9–
–44.0)
Screening instruments…
Item 9 BDI-II Suicidal Ideation
In the last two weeks:
0. I don’
t have any thoughts of killing myself
1. I have thoughts of Killing myself, but I
would not carry them out.
2. I would like to kill myself
3. I would kill myself if I had the chance.
Suicidality Module M.I.N.I.
1.
Did you ever make a suicide attempt? YES
NO
In the past month did you:
2.
3.
4.
5.
6.
Think you would be better off dead or
wish you were dead?
YES
Want to harm yourself?
YES
Think about suicide?
YES
Have a suicide plan?
YES
Attempt suicide?
YES
YES in 1, or 2, or 3 = LOW RISK
YES in 4 or 1 + 3 = MODERATE RISK
YES in 5 or 6 or 1+4 = HIGH RISK
NO
NO
NO
NO
NO
Columbia--Suicide Severity Rating Scale (C
Columbia
(C--SSRS)
Posner, Brent, Lucas, Gould, Stanley, Brown, Fisher, Zelazny, Burke, Oquendo, & Mann.
Columbia--Suicide Severity Rating Scale (C
Columbia
(C--SSRS)
Posner, Brent, Lucas, Gould, Stanley, Brown, Fisher, Zelazny, Burke, Oquendo, & Mann.
Neurological Disorders Depression Inventory
in Epilepsy (NDDI-E)
For the statements below, please circle the number that best describes
you over the last two weeks including today.
Always or
Often
Sometimes
Rarely
Never
Everything is a struggle
4
3
2
1
Frustrated
4
3
2
1
Nothing I do is right
4
3
2
1
Feel guilty
4
3
2
1
Difficulty finding pleasure
4
3
2
1
I’d be better off dead
4
3
2
1
A total score >15 is suggestive of a diagnosis of major depressive episode
Patient Health Questionnaire
Questionnaire--Generalized
Anxiety Disorder
Disorder--7 PHQPHQ-GADGAD-7
Please circle the number that best describes you over the last 2 weeks, including today
Nearly every
day
More than
half the days
Several
days
Not at all
A total score >10 is suggestive of a diagnosis of generalized anxiety disorder
Feeling nervous, anxious or on edge
3
2
1
0
Not being able to stop or control worrying
3
2
1
0
Worrying too much about different things
3
2
1
0
Trouble relaxing
3
2
1
0
Being so restless that it is hard to sit still
3
2
1
0
Being easily annoyed or irritable
3
2
1
0
Feeling afraid as if something awful might
happen
3
2
1
0
Some data…
Quick screen of suicidal risk: Item 9 from BDI-II
N = 187
0. I don’t have any thoughts of killing myself: n = 163
(87.3%)
1.
I have thoughts of killing myself, but I would not
carry them out: n = 22 (7.2%)
2.
I would like to kill myself: n = 1 (0.5%).
3.
I would kill myself if I had the chance: n = 1 (0.5%).
Relation between suicidal ideation and psychiatric diagnosis: Item 9 of
BDI-II and Suicidality Module of the MINI
Crosstab
Count
corrected.compressed.09.29.08
Anxiety
subsyndromic
MDE
disorders
none
BDI Suicidal
Thoughts
or Wishes
I don't have any thoughts
of killing myself.
I have thoughts of killing
myself, but I would not
carry
I would like to kill myself.
I would kill myself if I had
the chance.
Total
Mixed
MDE+AD
Total
99
23
6
24
11
163
3
3
4
3
9
22
0
0
0
0
1
1
0
0
0
1
0
1
102
26
10
28
21
187
Crosstab
Count
none
MINI - Suicidality
Total
No
Yes
97
6
103
corrected.compressed.09.29.08
Anxiety
subsyndromic
MDE
disorders
24
4
23
2
6
5
26
10
28
Mixed
MDE+AD
12
9
21
Total
160
28
188
Screening for Depression, Generalized Anxiety
Disorder and Suicidality at the Rush Epilepsy Center
vN = 655 consecutive English-speaking
adults.
vAge: > 18 year-old
vGender: 54.5% women
ØNDDI-E >15: 17.9%
ØGAD-7 10: 20.4%
ØBoth: 10.9%
Feasibility: Easy
Required time to complete instruments: 4 minutes
Required time for discussion with patient: Depends on findings!
Class I or II evidence: no
Suicidality Module M.I.N.I*.
n = 655
1.
Did you ever make a suicide attempt? YES
NO
7.3%
NO
NO
NO
NO
NO
6.2%
3%
5.4%
1.5%
0.5%
In the past month did you:
2. Think you would be better off dead or
wish you were dead?
3. Want to harm yourself?
4. Think about suicide?
5. Have a suicide plan?
6. Attempt suicide?
YES
YES
YES
YES
YES
Total suicidal Ideation: 15.2%
Kanner et al, Epilepsia 2009. Poster 2.152
Suicidal Risk based on MINI in an outpatient
population of patients with epilepsy
YES in 1, or 2, or 3 = LOW RISK
YES in 4 or 1 + 3 = MODERATE RISK
YES in 5 or 6 or 1+4 = HIGH RISK
ØLow risk: 9.2%
ØModerate risk: 3.6%
ØHigh risk: 2.4%
Kanner et al, Epilepsia 2009. Poster 2.152
Association between severity of suicidal risk and the
presence of suspected diagnosis of MDE, GAD and
MDE+GAD
Association* between severity of suicidal risk and:
v NDDI-E > 15:
Ø x2 = 75.6, df = 3, p<0.0001
v GAD-7 > 10
Ø X2 = 77, df = 3, p<0.0001
v NDDI-E > 15 + GAD-7 > 10
Ø X2 = 69.3, df = 3, p<0.0001
*Kruskal Wallis Test
Kanner et al, Epilepsia 2009. Poster 2.152
Change in Suicidality symptoms according to
the M.I.N.I. between two consecutive visits
n total = 115, symptomatic at visit 1, n = 25 (22%)
Question:
No Change Improved Worsened
(Symptomatic)
(De novo)
2. Think you would be better off
dead or wish you were dead?
5
4
5
3. Want to harm yourself?
1
5
3
4. Think about suicide?
1
6
1
5. Have a suicide plan?
1
0
1
6. Attempt suicide?
0
2
0
17
10
Total
8
Study in progress…
Aims of the Study (1)
1)
To determine the proportion of individuals with epilepsy who
endorse active suicidal thoughts within the last 6 months or
suicidal behavior within the 2 years prior to enrollment.
2)
To examine: the feasibility of assessing suicidal risks using
various scales including:
- the C-SSRS
- the suicidality module of the MINI
3)
To assess the capability of epilepsy centers to appropriately
manage the information collected.
4)
To determine how different rating scales for depression and
generalized anxiety correlate with suicidal ideation and behavior
as identified with the C-SSRS.
Aims of the study (2
(2)
v
To assess the prevalence of depression, anxiety and suicidal
thoughts and the feasibility of using the proposed psychiatric
rating scales in future epilepsy clinical trials.
v
To provide an estimate of the proportion of patients with epilepsy
who may be ineligible for future trials.
v
To determine how these two instruments correlate with screening
instruments of depression and anxiety disorders:
BDI-II
NDDI-E
PHQ-9
PHQ-GAD-7
Ø
Ø
Ø
Ø
Methods
v Cross-sectional study enrolling 200 outpatients with treatment
resistant partial epilepsy, receiving 1-3 AEDS from 8 epilepsy
centers.
v One visit or a visit and a telephone call, lasting 1-2 hours, during
which the following tests will be administered:
Ø The MINI International Neuropsychiatric Interview, a structured
interview developed to identify current Axis I psychiatric diagnoses.
Ø Columbia Suicide Severity Rating Scale (C-SSRS).
Ø Suicidality module of the MINI (MINI 5.5.0).
Ø Beck depression Inventory (BDI-II).
Ø Neurologic Depression Disorders Inventory –Epilepsy (NDDIE).
Ø Patient Health Questionnaire- Depression (PHQ-9).
Ø The Patient Health Questionnaire –Generalized Anxiety Disorder-7
(PHQ-GAD7).
Ø Adverse Event Profile (AEP).
Methods (2)
v Inclusion criteria:
• Partial epilepsy, confirmed with EEG studies
• Aged 18 to 70 years-old
• Proficient in English
• Having a minimum of a 4th grade reading level
• Having been on stable doses and type of AEDs for the
previous two months.
• At least 1 seizure/month for the past 6 months.
v Exclusion criteria:
• Non-epileptic seizures with or without comorbid epileptic
seizures
Conclusions
v The screening of suicidal risk must include
an instrument to identify:
Ø Past suicidal attempts.
Ø Current suicidal ideation.
Ø Current depressive episodes.
Ø Current anxiety disorder.
v The ideal instrument to screen for suicidal
risk in patients with epilepsy has yet to be
identified.