Epilepsy: risk of suicidal behavior with antiepileptic drugs
Risk of suicidal behavior
with antiepileptic drugs
Maurizio Pompili and Ross J. Baldessarini
appropriate for such disease staging.3 last,
Antiepileptic drugs (AeDs) are receiving increasing attention for a
primary end points in clinical trials, change
possible association with suicidal thoughts and behaviors. Several recent
studies examining this association, however, have yielded inconsistent
findings, particularly in terms of the risk of suicidal behavior conferred
concentrations, since the latter would not
by specific AeDs. In patients with epilepsy, heightened suicide risk is also
follow-up unless the therapy in question
attributable to comorbid psychiatric conditions.
reverses the disease course and, hence, CsF
controls or patients with epilepsy who did
in conclusion, the studies by De meyer
public-health challenge, accounting for at
not receive aeDs. indeed, the prevalence
and vemuri et al.
have furthered our
least 1 million deaths per year worldwide.1
disorders (including mood, psychotic and
orders, including epilepsy, are associated
personality disorders, and substance abuse)
with markedly increased rates of clinical
depression and suicidal acts.2,3 the poten-
12.5-fold higher, respectively, in patients
tial contribution of psychotropic drugs to
exhibiting suicidal behavior than in con-
suicide—as potential causes of or treat-
trols. andersohn et al.
made efforts to adjust
ments for suicidal thinking or behavior—
for differences in risk factors among the
various patient subgroups.6 nevertheless,
in intervention studies involving indivi duals
interest followed the regulatory approval in
the effectiveness of the statistical proce-
with proven aD pathology who have not yet
2003 of clozapine as an effective agent for
dures in compensating for comorbid factors
lowering the incidence of suicidal thoughts
associ ated with suicide remains uncertain.
or acts among patients with schizophrenia.1
the findings of andersohn et al.
Department of Neurology and Alzheimer
a series of FDa investigations—based on
age close consideration of risk factors for
Center, Vrije Universiteit Medical Center,
post hoc meta-analyses of adverse-effect
suicide that are unrelated to treatment in
Boelelaan 1117, 1081 HV Amsterdam,
The Netherlands (N. D. Prins). Department
from controlled trials involving patients
of Neurology, Erasmus Medical Center,
s-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands (J. C. van Swieten).
epilepsy—considered the risk of suicidal
ideation and suicide attempts associ ated
with use of various types of central y active
drugs, particularly anti depressants in juve-
nile patients and anticonvulsants in adults.
the findings from these post hoc analyses
in a second recent study, arana et al.
indicated that antiepileptic drugs (aeDs)
examined clinical findings related to suicide
might increase such risk.1,4,5 two recently
risk among 5.13 million general practice
Competing interestsThe authors declare no competing interests.
patients in the uK.3 these researchers found
that among patients who did not show evi-
1. De Meyer, G. et al.
andersohn et al.
conducted a case– control
dence of mood disorders or epilepsy, the
Alzheimer disease biomarker signature in
study involving 9,420 patients with epi lepsy
cognitively normal elderly people. Arch. Neurol.
who were treated with aeDs of various classes
suicide per 100,000 person-years was 15.0
2. vemuri, P. et al.
serial MRi and CsF biomarkers
(table 1), including several ‘newer’ aeDs that
(95% Ci 14.6–15.5). this rate was 2.5-fold
in normal aging, MCi, and AD. Neurology
have been associated with increased rates
of clinical depression.6 these re searchers
were not treated with anticonvulsants (38.2,
3. Jack, C. R. Jr et al.
Hypothetical model of
found that the current or recent use of these
dynamic biomarkers of the Alzheimer’s pathological cascade. Lancet Neurol.
increasing this rate by only 26.2% (48.2,
mate, vigabatrin and, particularly, levitira-
4. Perrin, R. J., Fagan, A. M. & Holtzman, D. M.
cetam) was associated with an approxi mately
the observations of arana et al.
3 are in
Multimodal techniques for diagnosis and prognosis of Alzheimer’s disease. Nature
threefold increased risk of suicid al behavior
line with the results of a small veterans
5. Kester, M. i. et al.
Diagnostic impact of CsF
Patients exhibiting suicidal behavior had
and colleagues (table 1).7 the va investi-
biomarkers in a local hospital memory clinic. Dement. Geriatr. Cogn. Disord.
far more psychiatric risk factors commonly
associated with suicide than did nonsuicidal
geriatric patients with epilepsy seemed to
volume 6 | DeCemBer 2010 | 651
0 Macmil an Publishers Limited. Al rights reserved
| Relative risk of suicidal thoughts or acts associated with AeD treatment
risk factors for suicide, all adding to the dif-
ficulty of drawing conclusions. moreover, to
further complicate matters, Gibbons et al.
found that aeD treatment led to a decrease
in the risk of suicide attempts in patients
on top of the issues outlined above, the
reported investigations examining suicide
risk and aeDs have been strikingly inconsis-
tent in their rankings of the relative risks
associated with particular drugs (table 1).
never theless, three agents—levetiracetam,
lamo trigine and topiramate—were among the
top three anticonvulsants associated with
the highest observed risk of suicidal be havior
in at least two of the six reported analyses
(in four of the five studies that found an
increase in the risk of suicidal behaviors,
levetiracetam appeared in the top three, and
lamotrigine and topiramate appeared in the
top three twice in these five studies).5–7,9,10
of note, however, topiramate, but not lamo-
trigine or levetiracetam, has been associated
with clinical depression. moreover, these
three drugs differ in their pharmacodynamic
mechanisms, precluding conclusions about
potential biological mechanisms that might
Given the varied and largely inconclusive
*AeD showing the greatest change in relative risk of suicidal behaviors (derived from outcomes of AeD treatment versus
findings regarding the putative effects of
placebo treatment) listed first. ‡significant increase in relative risk. §significant decrease in relative risk. Abbreviation: AeD, antiepileptic drug.
aeDs on the risk of suicidal behavior and
fatalities, clinical prudence indicates that
patients with epilepsy should be assessed
be more strongly associated with suicide
suici dal behavior conferred by aeDs includes
routinely and treated for psychiatric comor-
actual mortality, is a class effect of anti convul-
bidities that are important risk factors for
of this study was its limited statistical power
sants or is specific to certain agents, and can
suicide. in addition, on the basis of the
to assess the suicide risk associated with
dynamic mechanisms have not been resolved
levetiracetam or, potential y, lamotrigine or
topiramate warrants heightened patient care
with epilepsy or a psychiatric disorder, sui-
and further research in relation to possible
cidal ideation occurred more frequently and
(table 1) have used the prevalent but highly
the rate of occasional suicide attempts was
ambiguous concept of ‘suicidality’, which
higher during treatment with seven of the
includes suicidal thoughts and acts (sui-
Department of Neuroscience, Mental Health
cides and suicide attempts). However, the
and Sensory Functions, Suicide Prevention Center, Sant’Andrea Hospital, Sapienza
trigine and topiramate) than during treat-
epidemiology and clinical predictive value
University of Rome, Via di Grottarossa 1035,
ment with placebo.5 nevertheless, aeDs were
of suicidal thinking and behaviors, as well as
00189 Rome, Italy (M. Pompili). Harvard
not associated with a significant increase in
their responses to treatment, are not neces-
Medical School and Mailman Research Center,
suicide risk among patients with psychi atric
sarily comparable.1 several recent studies,
McLean Hospital, 115 Mill Street, Belmont, MA
disorders.4,5 of note, these findings were
including the two considered here,3,6 have
derived incidental y from reports of adverse
examined the rates of suicidal behaviors
events in trials not designed specifical y to
and other violent self-injurious acts, and
risk of suicide conferred by specific aeDs.
convulsants or placebo in the trials analyzed
ascribing suicide risk to specific drugs is dif-
by the FDa, the detailed clinical compar-
ficult, even with large samples, as such acts
AcknowledgmentsR. J. Baldessarini was supported, in part, by a grant
ability of patients with epilepsy between the
are rare.5–10 in addition, the available studies
from the Bruce J. Anderson Foundation and by the
treatment arms is uncertain, as is the con-
(table 1) have varied greatly in metho dology,
McLean Private Donors Psychopharmacology and
tribution of psychiatric factors to the risk of
size, statistical power and the adequacy of
suici dal behavior in patients with epilepsy.
measures taken to control potential y con-
the issues of whether the putative risk of
founding variables, par ticularly psychiatric
The authors declare no competing interests.
| DECEMBER 2010 | voluME 6
0 Macmil an Publishers Limited. Al rights reserved
1. Pompili, M. & Tatarelli, R. (eds) Evidence-Based
6. Andersohn, F., schade, R., willich, s. n. &
Practice in Suicidology: A Sourcebook
Garge, e. Use of antiepileptic drugs in epilepsy
and the risk of self-harm or suicidal behavior.
2. Blumer, D. et al.
suicide in epilepsy:
75, 335–340 (2010).
investigate any potential genetic dif ferences
7. vanCott, A. C. et al.
suicide-related behaviors in
prevention. Epilepsy Behav
. 3, 232–241
older patients with new anti-epileptic drug use:
data from the vA hospital system. BMC Med.
3. Arana, A., wentworth, C. e., Ayuso-Mateos, J. L.
& Arellano, F. M. suicide-related events in
8. Gibbons, R. D., Hur, K., Brown, C. H. &
hybridiza tion to evaluate Dna copy number
patients treated with antiepileptic drugs.
Mann, J. J. Relationship between antiepileptic
in 34 adult patients with medulloblastomas,
N. Engl. J. Med.
363, 542–551 (2010).
drugs and suicide attempts in patients with
and utilized interphase fluorescent in situ
4. Pompili, M., Tatarelli, R., Girardi, P., Tondo, L. &
bipolar disorder. Arch. Gen. Psychiatry
hybridization (FisH) to validate their find-
anticonvulsant treatment. Pharmacoepidemiol.
9. Patorno, e. et al.
ings in a further 112 adults and 303 children
19, 525–528 (2010).
and the risk of suicide, attempted suicide, or
who had this type of tumor.1 By use of these
5. statistical review and evaluation: antiepileptic
violent death. JAMA
303, 1401–1409 (2010).
drugs and suicidality. FDA
10. Olesen, J. B. et al.
Antiepileptic drugs and risk of
suicide: a nationwide study. Pharmacoepidemiol.
that age- dependent differences in genomic
19, 518–524 (2010).
profiles exist between adult and pediatric
medullo blastomas. For example, analysis
of the interphase FisH data revealed that
oncogene amplification and
Genetic variation in pediatric
gain of chromosomes 1q, 2, 6q, 7 and 17q
and adult brain tumors
cyclin-dependent kinase 6 (CDK6
gain was frequently
Alba A. Brandes and Enrico Franceschi
Two new studies suggest that pediatric medulloblastomas and high-
markers are better than clinical variables at
grade gliomas are genetically different from the same tumors in adults.
predicting survival, the researchers devised
an algorithm that stratified adult patients
Age-dependent gene expression might affect tumor biology; therefore,
into three risk groups on the basis of chromo-
therapies for adult medulloblastomas or gliomas might not produce the
same clinical outcomes in pediatric patients, and vice versa.
according to the re searchers, tumors with
both 10q deletion and 17q gain are associ-
trials of potential medulloblastoma thera-
ated with a poor prognosis. tumors that have
pies have rarely been conducted in adults.3
either 10q loss or 17q gain are associated
with the same morphology can have diverse
with a 44% overall survival rate at 5 years
genetic profiles. Genetic profiles can aid the
blastomas have been assumed to be the same.
after diagnosis, and tumors without 17q gain
identification of specific patient subgroups;
Consequently, in adults these tumors are
or 10q loss are associated with a good prog-
frequently treated with pediatric protocols,
nosis at 5 years. thus, this algorithm could
smokers with lung adeno carcinoma is known
with simple adjustments being made to the
aid the identification of adult patients with
to harbor exon 19 epidermal growth factor
drug regimens to account for dif ferences in
medulloblastoma who have a poor prognosis
receptor mutations. medulloblastomas and
drug tolerance. likewise, because our under-
and could benefit from more-tailored thera-
high-grade gliomas are two types of brain
standing of pediatric high-grade gliomas is
peutic approaches. Pediatric patients had
tumor that can affect both adults and chil-
limited compared with adult gliomas, these
poor prognoses if their tumors showed gains
dren, and tumors in these different patient
tumors in children are often treated with
of chromosome 6q and/or 17q or amplifica-
anticancer therapies that are routinely used
tion of MYC
. By contrast, loss of
tumor location, histo pathology and/or gene
chromosome 6q was associated with a good
expression. two studies published in the
Journal of Clinical Oncology
now show that
in the other study, Paugh and colleagues
pediatric high-grade gliomas and medullo-
blastomas are genetical y distinct from the
adult forms of these tumors.1,2 these obser-
vations indicate that these two types of
identification of significant targets in
ferently to anti cancer treatments in adults
in a study by Korshunov et al.
, analysis of
clinical and histological data revealed that
population, but are more frequent in chil-
desmoplastic tumors were found frequently
dren. in fact, these tumors are so rare in
in adults, while large-cell– anaplastic tumors
adults that the best treatment option for
number alterations in three chromosomes.
this type of cancer has not been determined
in this patient population, and prospective
most often in pediatric patients, and adult
more frequent in pediatric tumors than in
volume 6 | DeCemBer 2010 | 653
0 Macmil an Publishers Limited. Al rights reserved
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