The use of sertraline in patients with epilepsy: is it safe?
The Use of Sertraline in Patients with Epilepsy:
Is It Safe?
Division of Epilepsy and Clinical Neurophysiology, Department of Neurological Sciences,
Rush Medical College, Chicago, Illinois; and Rush Epilepsy Center, Rush–Presbyterian
Saint Luke’s Medical Center, Chicago, Illinois 60612
Received January 14, 2000; revised March 17, 2000; accepted for publication March 20, 2000
Purpose. The purpose of this study was to assess the impact of the selective serotonin-reuptake
inhibitor (SSRI) sertraline (SRT) on the severity and frequency of seizures of patients with epilepsy.
Methods. We prospectively assessed the seizure frequency of 100 consecutive patients with partial
(n = 95) and primary (n = 5) generalized epilepsy during a trial with SRT for the treatment of a
depressive (n = 97) or obsessive–compulsive (n = 3) disorder. We compared the monthly seizure
frequency recorded while on SRT with those logged during the 3 and 12 months preceding the start
of SRT. A definite causality between seizure worsening and SRT was considered in the following
circumstances: (1) occurrence of de novo generalized tonic–clonic seizure (GTC); (2) recurrence of a
GTC following a period of at least 1 year without this seizure type; and (3) an increase in the monthly
seizure frequency beyond the maximal recorded monthly frequency during both 3- and 12-month
periods preceding SRT. A probable causality between SRT and seizure worsening was considered in
the case of an increase in monthly seizures beyond the maximal frequency recorded during the
3-month, but not the 12-month, period preceding SRT.
Results. Six patients (6%) experienced an increase in seizure frequency after starting SRT. One and
five patients met criteria for definite and probable causality between SRT and seizure worsening,
respectively. Adjustment of antiepileptic drug doses resulted in a return to baseline seizure frequency
in the latter five patients; four patients were kept on SRT at the same doses. The SRT dose of these
six patients was significantly lower (57.1 ± 23.8 mg/day vs 111.8 ± 56.8 mg/day; F = 6.35, P = 0.01)
than that of the other 94 patients.
Conclusion. SRT can be safely used in the vast majority of patients with epilepsy. © 2000 Academic Press
Key Words: sertraline; selective serotonin-reuptake inhibitors; epilepsy; depression; dysthymic
Depressive disorders represent the most frequent
psychiatric complication of patients with epilepsy (1).
In fact, the incidence of depression and suicide has
been found to be higher among these patients than in
the general population (2). While there is a wide body
1 To whom all correspondence should be addressed at Department
of Neurological Sciences, Rush–Presbyterian Saint Luke's
Medical Center, 1653 West Congress Parkway, Chicago, IL 60612.
Fax: (312) 942-2238. E-mail: email@example.com.
of research on the risk factors and clinical characteristics
of depression in epilepsy, the efficacy of antidepressant
drugs (ADs) has yet to be tested in controlled
studies in these patients. For example, there has only
been one double-blind, placebo-controlled study published
to date on the efficacy of ADs in patients with
epilepsy and a major depressive disorder (MDD) (3).
In short, depression remains an undertreated complication
of epilepsy (4). This phenomenon probably reflects
the temerity of many clinicians of using psychotropic
drugs in these patients because of their potential
to cause seizures. Indeed, all non-monoamine
Copyright © 2000 by Academic Press
All rights of reproduction in any form reserved.
oxidise inhibitor (non-MAOI) ADs, including the
newer selective serotonin-reuptake inhibitors (SSRIs),
have been associated with the occurrence of seizures
(5–7). SSRIs, however, have been thought to be safer
than other classes of ADs. Yet, some authors have
warned against becoming too complacent, given the
conflicting nature of the data on the epileptogenic
potential of SSRIs (8).
Because of their overall safety profile, SSRIs are
currently the ADs of first choice in the treatment of
MDD, dysthymic disorder (DD), and obsessive–compulsive
disorder (OCD) (9). Seizure occurrence has
been estimated to range from 0.1 to 0.2% among nonepileptic
patients treated with SSRI; sertraline (SRT)
had the lowest reported seizure occurrence (10). The
risk of seizure worsening with SRT among patients
with epilepsy is yet to be established, however.
The purpose of this study was to assess the impact
of SRT on the severity and frequency of seizures in 100
consecutive patients with epilepsy and depression or
OCD. We chose SRT among the different SSRIs because
of its insignificant pharmacokinetic interaction
with antiepileptic drugs (AEDs), as well as for the
reported "apparent" paucity of epileptic seizures in
nonepileptic patients (10).
We prospectively monitored the seizure frequency
of 100 consecutive patients with epilepsy after being
started on SRT for the treatment of a depressive (n 5
97) or obsessive–compulsive (n 5 3) disorder. Children
and adults were started on SRT at daily doses of
25 and 50 mg, respectively. The dose was increased by
the same amount at 3-week intervals until patients
became symptom-free, reached a maximal daily dose
of 200 mg, or developed adverse events (AEs). During
SRT titration, AED doses were kept stable, unless an
increase in seizure frequency was reported. Patients
who initially responded to SRT, but then developed
tolerance, underwent additional 50-mg dose increments
until they became again symptom-free, reached
a daily dose of 200 mg, or developed AEs. If symptoms
had not remitted at that dose, patients were
switched to the SSRI paroxetine at a dose of 20 mg/
Assessment of Seizure Frequency
During titration of SRT, patients were followed in
the outpatient clinic every 4 to 8 weeks. Once patients
reached their final dose, they were followed every 12
weeks. All patients kept a record of their seizures in a
seizure calendar, which was checked at every visit and
transcribed to their medical chart. Seizure frequency
for the 12 months preceding the start of SRT was also
available in the medical records of all patients who
had been seen at approximately 3-month intervals. We
calculated each patient’s monthly mean and maximal
seizure frequencies for the 3 and 12 months preceding
the start of SRT, which we used for comparison with
the monthly mean and maximal seizure frequencies
recorded during the SRT trial. A comparison with the
seizure frequencies of the preceding 12 months was
necessary to minimize false-positive conclusions of
seizure worsening, given the natural fluctuation of
seizure frequency in patients with uncontrolled seizures.
For patients whose seizures usually occurred in
clusters (defined as more than one seizure in a 24-hour
period), we calculated the mean and maximal monthly
number of clusters for the same time periods.
Seizure Worsening Criteria
We developed two sets of criteria to establish
whether causality between seizure worsening and
SRT was "probable" or "definite." A definite causality
was considered in the following circumstances: (1)
occurrence of de novo primary or secondarily generalized
tonic– clonic seizure (GTC) in patients with only
absence seizures or simple and complex partial seizures,
respectively; (2) recurrence of a GTC following
a period of at least 1 year without this seizure type;
and (3) an increase in the seizure frequency beyond
the maximal recorded frequency during both the 3-
and 12-month periods preceding the start of SRT. A
probable causality between seizure worsening and
SRT was considered in the case of an increase in
seizure frequency beyond the maximal frequency recorded
during the 3 month, but not the 12-month,
period preceding the start of SRT. All analyses were
done on an intent-to-treat basis.
Every patient underwent a psychiatric evaluation
by one of the authors (A.K.), who is board certified in
neurology and psychiatry. Each patient received a
DSM-IV diagnosis (11) that was based on a semistructured
interview derived from the SCID-I (12). Since a
significant number of patients with epilepsy experience
depressive disorders that fail to meet any DSM
criteria (13), we identified the DSM-IV diagnostic category
with which the clinical phenomenon had the
closest similarities. In addition, we determinedK
||Kanner, Kozak, and Frey
whether the depressive disorder was spontaneous or
iatrogenic. The latter was considered when symptoms
followed the introduction or dose increase of an AED.
At the end of each psychiatric evaluation, we generated
a list of symptoms of depression identified as a
target for SRT therapy. At all follow-up visits each
symptom was rated as follows: (i) present, unchanged;
(ii) present, partially improved; (iii) completely resolved.
Seizure Disorder Profile
Among the 100 patients, 49 were women and 51
men. Their mean age was 29.9 ± 13.5 years (range,
6–62). The mean duration of their seizure disorder
was 16.2 ± 8.5 years (range, 8–40). Ninety-five patients
suffered from partial epilepsy and five from
primary generalized epilepsy. Sixty-two patients had
intractable epilepsy and 38 were seizure-free at the
start of SRT. The latter group included the five patients
with primary generalized epilepsy. Forty-two
patients were on one AED, 51 on two, 5 on three, and
1 on four. One patient was off all AEDs. In 28 patients,
the psychiatric disorder was considered to be iatrogenic,
and was attributed to the introduction of vigabatrin
(VGB) in 14 patients, primidone (PRM) in 12,
and phenobarbital (PB) and topiramate (TPM) in 1
SRT Dose and Impact on Seizure Frequency
The mean dose of SRT taken by the 100 patients was
108 ± 56.9 mg/day (range, 25–200). The mean duration
of treatment was 10.3 ± 10.1 months, and the
median duration, 6 months (range, 0.2–38 months). Six
patients (6%) experienced an increase in seizure frequency
during their SRT trial. A definite causality
between seizure worsening and SRT could be established
in only one patient, however. This patient experienced
a flurry of secondary GTCs while taking
SRT at a daily dose of 50 mg. At that time he was on
a regimen of carbamazepine at daily doses of 800 mg
with a serum concentration of 10.8 mg/liter. This patient
had a single seizure during the year preceding
the start of SRT on the same AED regimen. He was
taken off SRT and no further seizures recurred. In the
other five patients (5%) we established a probable
causality between seizure increase and SRT, as their
monthly seizure frequency was higher than the maximal
monthly frequency recorded during the 3 months
but not the 12 months preceding the start of SRT. All
five patients required an adjustment of their AED
dose. Four patients were kept on SRT at the same
doses without further seizure exacerbation, while one
patient opted to be taken off SRT. Seizure worsening
occurred during the first 2 months of treatment at SRT
doses significantly lower than those reached by the
other 94 patients (57.1 ± 23.8 mg/day vs 111.8 ± 56.8
mg/day; F = 6.35, P = 0.01). The six patients who
experienced seizure worsening failed to differ from
the 94 other patients with respect to the following
variables: type of seizure disorder (F = 0.4, P = 0.5),
baseline seizure frequency (F = 0, P = 0.98), number
of AEDs (F = 0.1, P = 0.8), and whether the psychiatric
event was iatrogenic or spontaneous (F = 0.01,
P = 0.97). For the entire group of 100 patients, the
mean monthly seizure frequency during the 3 months
preceding the start of SRT failed to differ from that
recorded while on the drug (3.7 ± 9.1 vs 3.3 ± 9.0, t =
1.6, P = 0.2).
Among the 100 patients, three met DSM-IV criteria
for OCD. One of these patients developed an OCD as
part of Tourette’s syndrome triggered by lamotrigine.
The other 97 patients had a depressive disorder: 28
met DSM-IV criteria for MDD. The depressive symptoms
of the remaining 69 patients did not meet criteria
of any of the DSM-IV recognized categories of affective
disorders (i.e., MDD, DD, cyclothymia, or bipolar
disorder); therefore, they were classified under the category
of Depressive Disorder Not Otherwise Specified.
These 69 patients presented a pleomorphic clinical
picture consisting of anhedonia, with or without hopelessness,
fatigue, anxiety, irritability and poor frustration
tolerance, and mood liability with bouts of crying.
Changes in appetite and sleep patterns and problems
with concentration were also reported by some patients.
In 33 of these 69 patients (34%), the predominant
and most disabling symptom was anhedonia,
while in the remaining 36 patients, irritability and
poor frustration tolerance were the most disabling
symptoms. Most symptoms presented with a waxing
and waning course, with repeated interspersed symptom-
free periods of one to several days’ duration.
Nevertheless, symptomatology was severe enough in
all patients to disrupt their activities, interpersonal
relations, and overall quality of life and to make them
These clinical phenomena had the strongest similarity
with DD; accordingly, we referred to these symptom
clusters as "dysthymic-like disorder of epilepsy"
Comparison of Patients with Iatrogenic and Spontaneous Depressive Disorders
||Spontaneous depressive disorder
||Iatrogenic depressive disorder
||41 (57%) M
||11 (39%) M
||31 (43%) W
||17 (61%) W
||PGE, n = 5 (7%)
||PGE, n = 0
||PE, n = 67 (93%)
||PE, n = 28
|Duration >1 year
|Previous history of MDD
|Complete symptom remission
|Final dose SRT
||109.2 ± 58.2 mg/day
||105.4 ± 54.2 mg/day
|Duration of SRT trial
||11.2 ± 10.7 months
||8.0 ± 7.9 months
|Discontinuation of SRT
Abbreviations: MDD, major depressive disorder; DLDE, dysthymic-like disorder of epilepsy; OCD, obsessive–compulsive disorder; SRT,
sertraline; AED, antiepileptic drugs.
(DLDE). It was subclassified into two categories,
DLDE-A and DLDE-I, to reflect whether anhedonia or
irritability was the predominant symptom. Patients
with DLDE-A and DLDE-I differed in two additional
ways: A prior history of MDD was elicited with a
significantly greater frequency among patients with
DLDE-A (45.5% vs 19.5%, x2 = 5.3, P = 0.02, Kruskal–
Wallis test). On the other hand, patients with DLDE-I
were more likely to suffer from a iatrogenic depressive
disorder than patients with DLDE-A and MDD (47%
vs 12% vs 21%, x2 = 11.3, P = 0.01, Kruskal–Wallis
The differences between spontaneous and iatrogenic
depressive disorders are summarized in Table 1.
Compared with patients with spontaneous depressive
disorders, patients with iatrogenic episodes suffered
more frequently from intractable epilepsy (F = 8.6,
P = 0.004), were more likely to present with a DLDE-I
and less likely to have experienced a MDD (F = 14.0,
P < 0.001), and were on more AEDs (F = 8.4, P =
Sixty patients had a psychiatric disorder of more
than 1-year duration, while in the remaining 40, it had
been present for less than 4 months. Despite the long
duration of their depressive disorder, only 21 (35%) of
the 60 patients had requested or had been offered
treatment within 6 months of the onset of their symptoms.
Failure to identify the need for therapy did not
significantly differ among patients with chronic MDD
and chronic DLDE (P = 0.46, Fisher exact test). In
addition, MDD, DLDE-A, DLDE-I, and OCD did not
differ with respect to their chronicity (F = 0.91, P =
Response to SRT
Among the 100 patients, 18 experienced adverse
events that resulted in its discontinuation, early in the
course of therapy (1.8 ± 1.7 months), while patients
were still on a relatively low dose of SRT (57.5 ± 37.3
mg/day). Ten of these eighteen patients had been on
SRT during a period too short to allow for a meaningful
evaluation of response to treatment. Nevertheless,
assessment of treatment response was based on an
intent to treat, and these 10 patients were included in
Fifty-four patients (54%) experienced complete resolution
of their identified target psychiatric symptoms.
This included 41 of 72 (57%) patients with a
spontaneous event and 13 of 28 (46.5%) patients with
an iatrogenic event. Among the latter group of patients,
complete symptom remission was observed
with equal frequency in iatrogenic episodes triggered
by PRM and VGB (x2 = 0.6, P = 0.5).
One of the reported advantages of using SRT is its
efficacy in the treatment of irritability and poor frus-
||Kanner, Kozak, and Frey
tration tolerance (9). Complete resolution of these
symptoms was reported by 59 (59%) of our patients.
Improvement was noted to occur within the first 2
weeks of therapy and preceded the response to therapy
of other symptoms of depression.
Fourteen patients developed tolerance to the effect
of SRT. Five responded to further dose increments,
while nine patients had to be switched to another
SSRI, paroxetine, resulting in complete symptom resolution
in all patients at a dose of 20 mg/day. No
seizure worsening was observed in these nine patients
during their trial with paroxetine.
Response to SRT was significantly more frequent
among patients with a past history of MDD (F = 4.81,
P = 0.03) and among patients on one AED only (F =
5.8, P = 0.018). It was significantly less likely among
patients with prior psychopharmacologic treatment of
any psychiatric disorder [not necessarily depression
(F = 7.3, P = 0.008)]. On the other hand, response to
SRT was not associated with dose (109.5 6 53.9 mg/
day vs 106.5 ± 60.7 mg/day, F = 0.06, P = 0.8),
baseline seizure frequency (F = 1.4, P = 0.25), type
of psychiatric disorder (F = 0.5, P = 0.47), or
whether the event was spontaneous or iatrogenic
(F = 0.89, P = 0.35).
Sedation was the most frequent AE (n = 9), followed
by hypomanic symptoms (n = 7). One patient
experienced rheumatic pain in her wrists and another
patient had myoclonus. AEs disappeared following
discontinuation of SRT in all patients. Hypomania
occurred in four patients who were taking VGB, one
patient on LTG, and two on carbamazepine. A family
history of depression was identified in six of the seven
patients who experienced a hypomanic episode.
This is the first study, to the best of our knowledge,
to examine the impact of SRT in a large group of
patients with epilepsy and depression or OCD. The
findings of this study suggest that SRT carries a minimal
risk of worsening seizures among these patients.
We were able to establish a definite causality between
the worsening of seizures and SRT in only one patient.
In five other patients, the change in seizure frequency
met our criteria for a probable causality. Yet, in all five
patients this seizure increment was easily controlled
with an adjustment of the AED dose. Accordingly,
discontinuation of SRT can be averted and should not
be automatically advocated if the patient is deriving a
therapeutic benefit. We also have to recognize our
inability to exclude the possibility that the increase in
seizures in these five patients resulted from the natural
fluctuation of their seizure frequency, as this is a
very common phenomenon in patients with intractable
Complete resolution of depressive symptoms was
achieved in 54% of our patients without having to
proceed to high doses of SRT. This percentage would
have increased to 60% had we excluded the 10 patients
who discontinued the drug very early in the course of
therapy because of AEs. These percentages are identical
to those reported in most double-blind, placebocontrolled
studies of most ADs in nonepileptic depressed
patients (14). The SRT dose did not have an
impact on seizure worsening, as the 6 patients who
experienced this problem were on significantly lower
doses than those with unchanged seizure frequency.
The opposite relationship has been reported with tricyclic
antidepressants (TCAs), which can increase the
risk of seizure occurrence at high doses in nonepileptic
patients (15). Nevertheless, we must view these results
with caution, given the small number of patients in
our study who experienced an increase in seizure
The use of SRT in depressive disorders of epileptic
patients has several advantages over other families of
ADs. First, SRT has been found to be effective in the
treatment of DD (9) and hence should yield a therapeutic
effect in DLDE. Our preliminary treatment response
data appear to support this hypothesis. Yet, the
efficacy of SRT in DLDE can only be demonstrated in
a double-blind placebo-controlled study. Second, its
therapeutic effect on irritability and poor frustration
tolerance is an additional advantage (9), as these are
two prominent symptoms of spontaneous and iatrogenic
DLDE. In our trial, complete remission of irritability
with SRT was observed in two-thirds of patients
and occurred early in the course of therapy, preceding
the remission of other symptoms of depression, such
as anhedonia and feelings of hopelessness and helplessness.
We recognize that we can derive only limited
information from the treatment response to SRT, since
this was an open trial, and placebo effect is relatively
high in psychopharmacologic therapies. Accordingly,
we consider the treatment response data as preliminary
or pilot data. On the other hand, knowledge of
the treatment response was necessary to place in a
proper perspective the doses of SRT reached by patients.
Double-blind placebo-controlled studies are
necessary to confirm these observations as well. Finally,
the safer AE profile of SSRIs compared with that
of TCAs and MAOIs has placed this class of ADs as
the drugs of first choice for the treatment of depressive
disorders in epileptic and nonepileptic patients (9).
Our data clearly show that the majority of patients
with symptoms of depression did not meet criteria of
MDD. Instead, they presented with a pleomorphic
cluster of symptoms that resemble DD, which we
referred to as DLDE. Others have reported similar
observations. For example, among the depressive episodes
identified in a study by Mendez et al., 50% had
to be classified as Atypical Depression, according to
DSM-III criteria (16). Kraepelin described this form of
depression in 1923 (17), and in recent years, Blumer
coined the term interictal dysphoric disorder (IDD) in
referring to this disorder (18, 19). Blumer considers
that almost one-third to one-half of patients with epilepsy
seeking medical care suffer from IDD of sufficient
severity to require pharmacologic treatment (19).
Only one-third of our patients with a depressive
disorder of more than 1-year duration were treated
within 6 months of the onset of their symptoms. Delay
in the start of pharmacotherapy was not related to the
severity of the depressive disorder, as the same proportions
of patients with chronic MDD and DLDE
went without ADs for more than 1 year. Underrecognition
of depressive disorders has been described by
One-third of our patients were treated for an iatrogenic
depressive disorder caused by an AED. In general,
we advocate treating such iatrogenic processes by
lowering the dose or discontinuing the culprit AED.
However, in some patients with refractory epilepsy,
this AED may be the only drug that improves seizure
control. Such was the case in 25 of the 28 patients we
included in the trial with SRT. In 13 of these 25 patients,
all symptoms remitted with SRT, and we were
not forced to discontinue the one AED that had provided
them with the best seizure control.
In conclusion, the risk of worsening seizures with
SRT is minimal in patients with epilepsy. Further, in
this open-label study, symptoms of depression responded
favorably with SRT. Accordingly, treatment
with SRT should not be delayed in depressed patients
with epilepsy requiring AD treatment.
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