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Depression and suicide attempt as risk factors for incident unprovoked seizures.

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Depression and Suicide Attempt as Risk
Factors for Incident Unprovoked Seizures
Dale C. Hesdorffer, PhD,1,2 W. Allen Hauser, MD,1–3 Elias Olafsson, MD,1,4 Petur Ludvigsson, MD,5 and
Olafur Kjartansson, MD6
Major depression has been shown to increase the risk for development of epilepsy, but prior studies have not evaluated
whether this is due to specific symptoms of depression. We conducted a population-based case–control study of all newly
diagnosed unprovoked seizures among Icelandic children and adults aged 10 years and older to test the hypothesis that
major depression is a risk factor for developing unprovoked seizure and epilepsy, and to address whether specific symptoms of depression account for this increased risk. Cases were matched to the next two same sex births from the
population registry. Using standardized interviews, we ascertained symptoms of major depression to make a Diagnostic
and Statistical Manual, Fourth Edition (DSM-IV) diagnosis. A history of major depression was 1.7-fold more common
among cases than among controls (95% confidence interval, 1.1–2.7). A history of attempted suicide was 5.1-fold more
common among cases than among controls (95% confidence interval, 2.2–11.5). Attempted suicide increased seizure risk
even after adjusting for age, sex, cumulative alcohol intake, and major depression or number of symptoms of depression.
Major depression and attempted suicide independently increase the risk for unprovoked seizure. These data suggest that
depression and suicide attempt may be due to different underlying neurochemical pathways, each of which is important
in the development of epilepsy.
Ann Neurol 2006;59:35– 41
Several studies suggest that depression occurs more
often than expected among patients with a diagnosis
of epilepsy1–10; however, most of these studies are
cross sectional and cannot evaluate the temporal sequence. Only two studies, both conducted in
adults,7,10 address the time order of the association.
One population-based study of 83 cases with incident
unprovoked seizure and 130 control subjects found
that a history of depression increased the risk for development of unprovoked seizure 7-fold.7 Another
population-based, incident case–control study 10
found that prior depression according to the Diagnostic and Statistical Manual, Third Edition, Revised
(DSM-III-R) was 4-fold more common in 145 cases
with incident unprovoked seizure than in 290 controls. The increased risk was greater among cases with
partial-onset seizures, although the difference was not
statistically significant.7,10 Similar population-based
studies in children have not been published.
Prior studies of depression preceding a first unprovoked seizure have not evaluated whether the increased risk is due to specific symptoms of depression.
In this light, some studies of causes of death among
patients with epilepsy suggest that completed suicide
may occur more often than expected in the general
population.11–15 When studies with at least 100
deaths are examined, standardized mortality ratios for
suicide in patients with epilepsy range from 3.512 to
5.0,13 and the proportionate mortality ratio ranges
from 0.716 to 20%.15 These observations suggest that
suicidal ideation and suicide attempt may also be risk
factors for unprovoked seizure.
We conducted a population-based case–control
study of incident unprovoked seizure and newly diagnosed epilepsy among Icelandic children and adults to
address whether major depression is associated with an
increased risk for development of unprovoked seizures
and whether specific symptoms of major depression account for this risk.
From the 1Gertrude H. Sergievsky Center, Columbia University;
Department of Epidemiology, Mailman School of Public Health;
Department of Neurology, Columbia University, New York, NY;
and Departments of 4Neurology, 5Pediatrics, and 6Radiology, Landspitalinn University Hospital, Reykjavik, Iceland.
Published online Oct 10, 2005, in Wiley InterScience
( DOI: 10.1002/ana.20685
Received Apr 19, 2005, and in revised form Jul 12 and Aug 16.
Accepted for publication Aug 19, 2005.
Subjects and Methods
A nationwide surveillance system was established that included all hospitals, emergency departments, regional
health care centers, nursing homes, and other health care
facilities throughout Iceland. Each facility was contacted on
a regular basis to identify potential new cases of seizure
Address correspondence to Dr Hesdorffer, Gertrude H. Sergievsky
Center, 630 West 168th Street, P & S Unit 16, New York, NY
10032. E-mail:
© 2005 American Neurological Association
Published by Wiley-Liss, Inc., through Wiley Subscription Services
disorders. In addition, all four radiology laboratories in the
country with magnetic resonance/computed tomography facilities and the two electroencephalogram (EEG) laboratories in the country were screened to identify referrals for
episodic symptoms potentially of epileptic origin.
Our cases were drawn from this active seizure surveillance system. Once a study nurse identified a potential
case, medical records were reviewed to verify the occurrence
of an incident seizure disorder. Unprovoked seizure was defined as a seizure without an identified proximate precipitant, for example, fever, head trauma, central nervous system infection.17 Seizures in association with toxic doses of
antidepressants were excluded. Epilepsy was defined as at
least two unprovoked seizures regardless of seizure type.
Multiple seizures occurring in a 24-hour interval were considered a single event.
Cases in this analysis were all Icelandic children and adults
aged 10 years and older with unprovoked seizures or epilepsy
first diagnosed between December 1, 1995, and February 28,
1999. The participation rate was 81.2%.
CONTROLS. Age-matched controls were selected from the
Icelandic population registry as the next two same sex births
who were alive, resided in Iceland at the time of the index
seizure, and did not have a history of unprovoked seizure on
the date of the case’s incident seizure. The participation rate
was 79.6%.
symptoms occurred or until the index date for individuals
reporting no symptoms of depression.
Three study neurologists
(W.A.H., P.L., E.O.) reviewed all information, including
results of neuroimaging and EEG, to classify cases by seizure type and etiology, based on criteria of the International League Against Epilepsy Commission on Epidemiology.17
Seizure type was classified based on the description in the medical chart, interview, and EEG where
possible and categorized as generalized from onset and partial
from onset.17
Generalized seizures included generalized tonic, clonic,
tonic-clonic, atonic, absence, or myoclonic seizures. Partial
seizures included simple or complex partial seizures (including partial seizures with secondary generalization). If the clinical characteristics of the seizure were unclear, seizures were
characterized as “unknown” seizure type.
Seizures were categorized as symptomatic or
idiopathic/cryptogenic.20 Seizures were considered symptomatic in the presence of a history of a static or nonstatic
central nervous system insult associated with an increased
risk for epilepsy (eg, stroke, head trauma, mental retardation, cerebral palsy, meningitis, degenerative neurological
diseases).20 Seizures were considered idiopathic/cryptogenic
in the absence of an acute precipitating factor or a history
of prior neurological insult.
Measures and Assessments
ASSESSMENT. After obtaining informed
consent, a structured telephone interview was administered
to make a DSM-IV18 diagnosis of major depression. We
interviewed parents of children about symptoms of major
depression before the date of the cases’ incident unprovoked
seizure or epilepsy, using an Icelandic translation of the
lifetime module of the Diagnostic Interview Schedule for
Children (DISC).19 Among adults, we used an Icelandic
translation of a standardized interview based on the Structured Clinical Interview for DSM-IV Axis I disorders
(SCID)20 to ascertain symptoms of major depression before
the index date and make a DSM-IV diagnosis of major
Past diagnosis of bipolar disorder was ascertained to exclude these individuals from the diagnosis of major depression. The number of symptoms of depression was considered
as a continuous variable. Cases and control subjects were
coded as not having depression or bipolar disorder if their
age in years at onset of symptoms was the same as their age
at first unprovoked seizure for cases (n ⫽ 4) or their age at
the index date for controls (n ⫽ 7).
Alcohol intake, a known correlate of
completed suicide,21,22 is a potential confounder of the relation between suicide attempt and seizures. Frequency and
amount of alcohol intake, collected by decade of life beginning in the teenage years, was used to calculate cumulative
alcohol intake up until the decade in which any depressive
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CASES. Once the treating physician received permission for
us to contact parents, guardians, adults, or their representatives for study purposes, an introductory letter explaining the
purpose of the study was sent, followed by a phone contact
at which time verbal agreement to participate in the study
was obtained and a time was scheduled to administer the
structured interviews.
CONTROLS. A letter explaining our study was sent to potential control subjects or their parents. This was followed
by a telephone contact to determine willingness to participate. If permission was not granted, the next eligible potential controls was identified and the same procedure was
followed until two controls agreed to participate. Potential
controls were excluded if they had a history of unprovoked
seizure or were a sibling of the case.
This study was reviewed and approved by the Icelandic Data Protection
Commission (Tolvunefnd rikisins), the Ethics Committee
of the Chief Medical Officer of Iceland, the Medical Ethics
Board of the National University Hospital of Iceland
(Landspitalinn), the Institutional Review Board of the College of Physicians and Surgeons of Columbia University,
and the Review Board of the National Institutes of Health
(Office of Protection from Research Risks).
Table 1. Characteristics of Case and Controls
Cases (N ⫽ 324)
Controls (N ⫽ 647)
Single unprovoked seizure
Median age in years (IQR)
Family history of afebrile seizure
Past febrile seizures
Seizure type
Partial onset
Generalized onset
Remote/progressive symptomatic
EEG abnormality
Focal epileptiform
Generalized epileptiform
Focal slowing
Nonspecific abnormality
EEG not done
MRI or CT abnormality
Arteriovenous malformation
Mesial temporal sclerosis
Migrational abnormality
Congenital abnormality
Focal decreased volume
Focal hyperintensities
Postoperative changes
Posttraumatic changes
Other abnormality
More than one abnormality
Imaging not done
137 (42.3%)
187 (57.7%)
34.0 (19.9–62.5)
33.5 (19.9–62.2)
160 (49.4%)
164 (50.6%)
319 (49.3%)
328 (50.7%)
34 (10.5%)
290 (89.5%)
38 (5.9%)
609 (94.1%)
5 (1.5%)
319 (98.5%)
11 (1.7%)
636 (98.3%)
118 (36.4%)
203 (62.7%)
3 (0.9%)
218 (67.3%)
106 (32.7%)
141 (43.6%)
14 (4.3%)
31 (9.6%)
40 (12.4%)
56 (17.3%)
132 (40.7%)
51 (15.7%)
135 (41.7%)
17 (5.3%)
1 (0.3%)
2 (0.6%)
8 (2.5%)
7 (2.2%)
1 (0.3%)
2 (0.6%)
4 (1.2%)
14 (4.3%)
5 (1.5%)
6 (1.9%)
18 (5.6%)
2 (0.6%)
48 (14.8%)
156 (48.2%)
33 (10.2%)
EEG ⫽ electroencephalogram; MRI ⫽ magnetic resonance imaging; CT ⫽ computed tomography; N/A ⫽ not applicable; IQR ⫽ interquartile
Statistical Analysis
We used Student’s t test to compare continuous variables
and the ␹2 statistic to compare categorical variables. Data
were analyzed with SAS (SAS Institute, Cary, NC) using
conditional logistic regression for matched sets as formulated by Breslow and Day.23 Models were constructed for
the whole study population and separately by seizure type,
cause, and sex. Univariate models were constructed for
symptoms of depression, major depression, and bipolar disorder. Final models were adjusted for the matching variables of age and sex and for cumulative alcohol intake.
Three hundred twenty-four cases and 647 control
subjects were 10 years of age or older. The median
age was 34.0 years for cases and 33.5 years for controls (Table 1). Most cases were identified due to a
first epilepsy diagnosis (57.7%) and most were male.
Partial-onset seizures occurred in 36.4% of cases, and
most cases were idiopathic/cryptogenic. Seizure type
at diagnosis was unknown in three cases. Imaging abnormalities on computed tomography or magnetic
Hesdorffer et al: Depression, Suicide and Epilepsy
Table 2. Symptoms of Depression as Risk Factors for Incident Unprovoked Seizure in Icelandic Children and Adults
Symptoms of Depression
Depressed mood
Loss of interest
Weight change
Psychomotor agitation or retardation
Worthlessness or guilt
Difficulty concentrating
Suicidal ideation
Suicide attempt
Cases N
Controls N
95% CI
95% CI
64 (19.8%)
55 (17.0%)
4 (1.2%)
44 (13.6%)
64 (19.6%)
67 (20.7%)
62 (19.1%)
54 (16.7%)
37 (11.4%)
21 (6.5%)
51 (15.7%)
59 (9.1%)
57 (8.8%)
2 (0.31%)
45 (7.0%)
73 (11.3%)
63 (9.7%)
52 (8.0%)
50 (7.7%)
35 (5.4%)
9 (1.4%)
59 (9.1%)
Univariate odds ratio from a conditional logistic regression adjusting for age and sex.
Model contains all symptoms that were statistically significant on the univariate analysis and adjusts for age and sex and cumulative alcohol
intake before onset of symptoms of depression.
OR ⫽ odds ratio; CI ⫽ confidence interval.
resonance imaging were present in 41.7% of cases,
and 43.6% showed an abnormality on EEG (see Table 1).
Risk for Unprovoked Seizures by Symptoms
of Depression
Among cases, the four most common symptoms of depression were fatigue, depressed mood, psychomotor
agitation/retardation, and worthlessness or guilt. These
were almost the same as in controls, except that in controls, loss of interest replaced worthlessness or guilt in
the four most common symptoms. The four least common symptoms (irritability, suicide attempt, suicidal
ideation, and weight change) were identical in cases
and controls. Although the same symptoms were common in cases and controls, the frequency of each symptom was greater in cases.
Ten symptoms of depression were statistically significantly associated with development of unprovoked seizures (Table 2). In a model adjusting for age, sex, and
cumulative alcohol intake up until the onset of depressive symptoms, only suicide attempt was significantly
associated with an increased risk for development of
unprovoked seizure (odds ratio [OR], 3.9; 95% confidence interval [CI], 1.4 –11.5). The increased risk observed for suicide attempt remained statistically significant after adjusting for age, sex, cumulative alcohol
intake, major depression, and bipolar disorder (OR,
3.5; 95% CI, 1.5– 8.6; Table 3). This pattern was observed for all subgroups examined and was significant
for most.
We evaluated whether the increased risk observed for
suicide attempt differed according to the presence or
absence of depression. For this analysis, individuals
were categorized as depressed if they met DSM-IV criteria for major depression or for bipolar disorder.
Compared with individuals without depression or past
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suicide attempt (see Table 3), there was a 13.3-fold
increased risk for unprovoked seizure associated with
attempted suicide in the absence of depression, a 4.2fold increase associated with attempted suicide in the
presence of depression, and a 1.5-fold increased risk
associated with major depression in the absence of attempted suicide. The association remained after adjusting for cumulative alcohol intake up to the time of the
suicide attempt or episode of major depression.
Among cases and controls who had attempted suicide, 37.5% were treated with antidepressant drugs and
70.0% reported seeing a health professional. Among
cases and controls who had never attempted suicide,
4.1% were treated with antidepressant drugs for their
depressive symptoms ( p ⬍ 0.0001) and 7.9% reported
seeing a health professional ( p ⬍ 0.0001). Antidepressant use was associated with more severe depression
(mean number of symptoms was 6.9 without antidepressants vs 7.5 with antidepressants; p ⫽ 0.04).
Risk for Unprovoked Seizures after Major Depression
Major depression was associated with an increased risk
for development of incident unprovoked seizure (OR,
1.7; 95% CI, 1.1–2.7; see Table 3). This pattern was
observed for almost all subgroups, and it was statistically significant for the group as a whole, for idiopathic/cryptogenic etiology, for generalized seizures, for single unprovoked seizure, for females, and for adults 25
years and older (data not shown). Bipolar disorder also
increased the risk for development of incident unprovoked seizure, but this was not statistically significant.
In adjusted models, the association between major depression and incident unprovoked seizure was no
longer statistically significant (see Table 3).
Compared with controls, cases had a greater mean
number of symptoms of depression (1.5 vs 0.8; p ⬍
0.0001), regardless of DSM-IV diagnoses of this disor-
Table 3. Depression, Bipolar Disorder and Suicide Attempt as Risk Factors for Incident Unprovoked Seizure in Icelandic Adults
and Children
95% CI
95% CI
39 (12.0%)
4 (1.2%)
21 (6.5%)
48 (7.4%)
1 (0.1%)
9 (1.4%)
29 (9.0%)
7 (2.2%)
14 (4.3%)
274 (84.6%)
42 (6.5%)
2 (0.3%)
7 (1.1%)
596 (92.1%)
Whole group (324 cases and 647 controls)
Model 1
Major depression
Suicide attempt
Whole group (324 cases and 647 controls)
Model 2
Depression only
Attempted suicide only
Adjusted OR and 95% CI. Adjusts for age, sex, alcohol intake before depression, and each of the other psychiatric conditions.
OR ⫽ odds ratio; CI ⫽ confidence interval.
der. The OR for unprovoked seizure for each unit increase in the number of symptoms of depression was
1.09 (95% CI, 1.038 –1.16). Adjustment for age, sex,
attempted suicide, and alcohol intake did not alter this
association (OR, 1.09; 95% CI, 1.02–1.16).
Among cases and controls with symptoms of depression, 32.2% were treated with antidepressants and
62.1% reported seeing a health professional for their
depressive symptoms. Among cases and controls without symptoms of depression, 2.3% were treated with
antidepressants ( p ⬍ 0.0001) and 4.5% reported seeing a health professional ( p ⬍ 0.0001).
Reporting Bias
We evaluated whether reporting bias might explain our
results. Reporting bias was possible because some cases
and controls reported major depression or suicide attempt more than 20 years before their seizures.24 Six
cases and 7 controls reported major depression or attempted suicide 20 or more years before the seizure
index date. Among the remaining cases and controls
meeting criteria for major depression, episodes occurred within 5 years of the index date for 65.6% of
cases and 53.7% of control subjects. Among the remaining cases and controls reporting suicide attempt,
attempts occurred within 5 years of the index date in
60% of cases and 55.6% of controls. When we reclassified cases reporting suicide attempt or major depression more than 20 years before the index date as unexposed, the results were essentially unchanged (OR for
any attempted suicide, 3.6; 95% CI, 1.5– 8.5; OR for
any major depression, 1.69; 95% CI, 1.04 –2.74). In
addition, the four most frequent symptoms of major
depression and the four least frequent symptoms of
major depression were nearly identical for cases and
controls. This suggests that reporting bias is unlikely in
our data, and that if it does exist, the misclassification
of depressive symptoms is the same for cases and con-
trols. Such nondifferential misclassification would lead
to an underestimation of the reported associations. Reporting bias is therefore an unlikely explanation for our
Children and adults with incident unprovoked seizure
were 1.7-fold more likely to have a history of major
depression, meeting DSM-IV criteria before seizure onset. Similar to an earlier study,10 we also found an association between number of depressive symptoms and
incident unprovoked seizure, regardless of a DSM-IV
diagnosis of major depression. We did not find a
greater association for depression in partial seizures
compared with generalized seizures, as reported previously.7,10 In addition, the association between major
depression and incident unprovoked seizure was no
longer statistically significant after adjustment for bipolar disorder, attempted suicide, and cumulative alcohol
intake, which are adjustments that have not been made
in prior studies. The prevalence of major depression
ranges from 3 to 10%,25 translating to between 8.5
and 29 million affected individuals in the United
States. The lifetime prevalence is as high as 35%26 and
suggests that as many as 100 million people in the
United State have had an episode of major depression
in their lifetime. If 10% of people who develop unprovoked seizures have such a lifetime history, then the
public health burden of this comorbidity is significant.
In our study, attempted suicide was independently
associated with an increased risk for incident unprovoked seizure, after adjusting for major depression, bipolar disorder, and cumulative alcohol intake. Completed suicide occurs more often in patients with
epilepsy than expected in the general population.11–15
The assumption has been that having epilepsy increases
the risk for depression and, in a subgroup, completed
suicide. In a study of deaths in an Icelandic incident
Hesdorffer et al: Depression, Suicide and Epilepsy
cohort of 224 patients with epilepsy13 first diagnosed between 1960 and 1964 (different from the subjects in this
study), the standardized mortality ratio for suicide was
5.0 (95% CI, 1.3–11.1, calculated from data in the article). This study did not address suicide attempt and
major depression before the diagnosis of epilepsy. Other
studies show that suicide attempt increases the risk for
later completed suicide.27,28 This shared underlying susceptibility to suicidal behavior and unprovoked seizure
may explain the observed increased risk for completed
suicide among patients with epilepsy.12,13
Some subjects in our study who had attempted suicide previously never met criteria for major depression
according to DSM-IV (42.9% in cases and 22.2% in
control subjects). In a study examining the rates and
risk factors for suicidal ideation and suicide attempts
among 139 patients with prevalent epilepsy,11 a lifetime history of a major depressive episode or of a
manic episode increased the risk for suicide attempt,
but, similar to our study, not all patients who had attempted suicide had such a history. Other studies confirm that major depression is only one of many diagnoses associated with suicide.21,22 These data suggest
that different mechanisms may influence depression
and suicidal behavior, and that both mechanisms may
be important in the development of epilepsy.
An association between antidepressants and seizures
has been reported,29 –31 with risks of about 1% in a
review of clinical trials, case series, and postmarketing
surveillance.31 For most of these studies, the presence
of a prior seizure disorder or other pre-existing condition was not assessed. In a previous article,10 we demonstrated that the association between antidepressants
and seizures could be explained almost entirely by major depression (OR for tricyclic antidepressants, 2.2,
95% CI, 1.1– 4.5 before adjustment; OR, 1.6, 95%
CI, 0.8 –3.5 after adjustment for major depression and
other medical therapies). The widespread use of antidepressants,32 which has been increasing over time, has
not been associated with a parallel increase in the incidence of unprovoked seizures,33 arguing against a
meaningful seizure-inducing effect of these drugs. In
this study, use of antidepressant medications was assessed in connection with a history of symptoms of depression before the first unprovoked seizure, but we did
not ask about dose, duration of use, or use up to the
date of the incident seizure. It is possible that antidepressant use contributed to the development of unprovoked seizure in people who met criteria for major depression sometime before their first unprovoked
seizure, assuming treatment to our seizure index date.
We cannot assess this possibility with our data. Further
work is needed to address this question.
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Possible Mechanisms
The involvement of serotonin and noradrenalin in depression is underscored by the efficacy of drug therapies targeting these amines.34,35 In addition, reduced
serotonergic activity is associated with suicidal behavior.36 Although serotonin is not generally implicated in
epilepsy, the genetically epilepsy-prone rat has deficits
in the noradrenergic system, including reduced noradrenaline content in several brain regions.37 Antidepressants acting on serotonin or noradrenaline are anticonvulsant in these animals.38 Paradoxically, the
literature also suggests that antidepressants lower seizure threshold, although the risk for seizures in antidepressant users is estimated at less than 1%31 and is influenced by previous seizure history.
We confirm that major depression is a risk factor for
unprovoked seizure. However, the relation between depression and unprovoked seizure is more complex than
previously appreciated: Major depression and attempted suicide are independent risk factors for the development of unprovoked seizure. These data and recent evaluations of selective serotonin reuptake
inhibitors in depressed adolescents suggest that different neurotransmitters may influence depression and
suicidal behavior. Further study is needed to elucidate
the underlying mechanisms explaining this increased
risk and to describe possible contributions of family
history of depression or suicide attempt. Clearly, patients presenting with a new onset unprovoked seizure
should be evaluated for a history of suicide attempt
and major depression. This history may be useful in
directing choice of treatment and efforts to prevent
later completed suicide.
This work was supported by the NIH, (National Institute of Neurological Disorders and Stroke, 5R01 NS 32663, W.A.H.)
We thank I. Olafsdottir, O. Gunnarsdottir, and I. Einarsdottir for
their assistance with this study. We also thank Dr M. Gould and T.
Greenberg for their valuable comments.
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factors, incident, seizure, suicide, attempts, unprovoked, risk, depression
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