Epilepsy & Behavior 10 (2007) 397401

Oxcarbazepine improves mood in patients with epilepsy

Abstract

This study prospectively examined whether continued add-on treatment with

oxcarbazepine (OXC) is associated with quantitative improvement in mood and
anxiety symptoms in adult patients with partial epilepsy. Depressive symptoms
and anxiety were assessed by clinical interview using the Hamilton Depression
Rating Scale (HDRS), the Cornell Dysthymia Rating Scale (CDRS), the Beck
Depression Inventory (BDI), and the Hamilton Anxiety Rating Scale (HARS). Forty
controls (patients with epilepsy treated with anti-epileptic drugs other than OXC)
and 40 OXC-treated patients were enrolled and completed the study. In our
study, a significant improvement in affect, as measured by the CDRS, was
demonstrated during the course of OXC treatment for 3 months. HDRS and BDI
scores also declined in the OXC-treated group, but these decreases did not reach
statistical significance. In addition, 28 of 40
OXC-treated subjects who were dysthymic by CDRS criteria on study entry (score
P20) demonstrated affective improvement consistent with a treatment-related
antidepressant effect (score <20). Although our results do not provide conclusive
evidence supporting the specific use of OXC as an antidepressant, the significant
decline in dysthymic symptoms in OXC-treated subjects compared with controls
lends support to the hypothesis that OXC improves mood.

1. Introduction
Oxcarbazepine (OXC) is a keto-analog of carbamazepine and was developed to
provide a compound chemically similar enough to carbamazepine to mimic its
efficacy while improving its side effect profile. The effect of OXC is probably due
to the blockade of voltage-sensitive sodium and calcium channels. OXC has been
demonstrated to be effective in the treatment of partial seizures and painful
neuropathies. The main active metabolite of OXC is the monohydroxy derivative
(MHD). In contrast to carbamazepine and its active epoxide metabolite, OXC and
its MHD have fewer side effects and negative drug interactions, so OXC has been
further studied as a possible mood stabilizer, with the added advantage that
fewer serious side effects are expected than with carbamazepine [1].

OXC has been approved as an anticonvulsant in Europe since the early 1980s; it
was approved in the United States in 2000 for use as monotherapy in partial
seizures in adults, and as an adjunctive therapy for partial and secondarily
generalized seizures in children aged 416 [2].

There are few data on the teratogenicity of OXC, but it passes through the
placenta and is eliminated in the maternal milk. Compared with carbamazepine,
OXC is a much weaker inducer of cytochrome P450 3A4/5, and it inhibits only the
2C19 enzyme [3]. For this reason, there are few clinically significant drug
interactions, although the plasma levels of the estrogen and progesterone
components of oral contraceptives tend to be reduced. High-dose
contraceptives, or alternative means of contraception, should be used to
counteract this effect.

The most common side effects are headache, somnolence, dizziness, fatigue,
and nausea. Other less common side effects are skin eruption, vomiting,
parkinsonism, and leukopenia.

Hyponatremia, which is defined as a serum sodium level <125 mmol/L, has been
reported in 2550% of patients receiving OXC [4]. In addition, OXC may induce
P450C1 and P450C24, the enzymes responsible for the metabolism of 25hydroxyvitamin D [5]. Elevations in biomarkers that are consistent with increased
bone turnover may well predispose patients to bone loss over time. It is possible
that OXC has adverse effects on bone metabolism at higher doses, but not at
lower doses, and surely more studies are needed to verify these findings.
Anyway, it may be prudent for patients taking OXC to be prescribed 25hydroxyvitamin D replacement.

2. Oxcarbazepine, epilepsy, and mood disorders

Some studies indicate that OXC as monotherapy may be a favorable treatment
option for patients with partial seizures or poor tolerability for their existing
monotherapy regimen [6,7]. OXC can be an effective component in the initial
treatment of newly diagnosed partial andgeneralized tonicclonic seizures, and
also as an adjunct for medically intractable partial seizures in both adults and
children [2,3,8,9].

Investigations from university-based epilepsy centers indicate that depression is

the most common interictal psychiatric disorder, with a lifetime-to-date rate of
Diagnostic and Statistical Manual of Mental Disorders (DSM)-defined major
depression approximating 30% across published studies, which is significantly
elevated compared with the population lifetime-to-date estimate of 16%. In
addition, surveys of the concerns ofpersons with epilepsy reveal that
approximating 30% spontaneously report depressed mood as a significant
problem in living and dealing with epilepsy [10,11]. Blumer et al. [12] described

an atypical mooddisorder in one-third of patients with epilepsy admitted for

neurodiagnostic monitoring. This mood disorder was characterized by depressed
mood, anergia, irritability, episodic euphoria, atypical pain, insomnia, and
phobias. Interictal mood disorder was suggested as a new diagnostic category
of mood disorder to recognize the probable organic basis for epilepsy-related
aberrant mood symptoms.
Kanner and Palac [13] suggest that a significant proportion of patients with
epilepsy suffering from interictal depression present with a dysthymic-like
disorder characterized by depression following a chronic course but periodically
interrupted by symptom-free periods.

Because of the higher incidence of depression in patients with epilepsy, it is

possible that the epileptic process predisposes to occurrence of depression, but
this correlation has not been proven [14]. Emotional states of high intensity
evoke change in neurotransmission, and inversely, changes in neurotransmission
evoked by seizures, localized in specific brain regions, predispose to
intensification of emotional disturbances. A role for kindling, the well-known
epileptogenic phenomenon, in the occurrence of depression in patients with
epilepsy has notyet been proven [15]. The notably increased predisposition for
depression is also suggestedby the frequent occurrence of severe depressive
syndromes requiring hospitalization and the elevated risk for suicide in patients
with epilepsy. Both significantly exceed the risks observed in other somatic and
neurological diseases [1618].

Anecdotal reports from our patients suggested that OXC as part of an

antiepileptic drug (AED) regimen is associated with feeling better. Therefore,
we prospectively examined whether the addition of OXC to an AED regimen is
associated with quantitative improvement in mood and anxiety symptoms in a
consecutive series of adult patients with partial epilepsy.

3. Methods
This investigation was an open-label study in which OXC was added to patients
current AED regimens. Consecutive adult patients in whom OXC was judged to be
clinically indicated for seizure control were enrolled. Subjects were adult patients
recruited from the Epilepsy Center at the Department of Neurosciences of the
Catholic University of Sacred Heart in Rome. Those patients unable to
comprehend the test battery because of cognitive limitations were excluded from
the study.

The control group consisted of adult patients with epilepsy who continued to
have seizures but were unwilling to change their AED regimens and, therefore,
were on a stable AED regimen. No placebo medication was used.

Informed consent was obtained from all patients. The study was limited to
patients with partial epilepsy. Patients with a progressive structural neurological
illness, such as a brain tumor, were excluded. Patients with a psychiatric history
who were taking a stable dose of antidepressant medication were not excluded.
These patients were not excluded specifically so that any possible effect of OXC
on improving mood could be detected.

3.1. Mood and anxiety evaluations

Patients underwent baseline testing of mood and anxiety. Depressive symptoms
were assessed by clinical interview using the Hamilton Depression Rating Scale
(HDRS) [19]. The Cornell Dysthymia Rating Scale (CDRS), composed of 20
clinician-rated questions with five degrees of severity per question, was similarly
used [20]. Scores >40 on the CDRS correlate with clinical dysthymia, and scores
from 20 to 40 correlate with mild to moderate dysthymic symptoms. Additionally,
scores <20 after treatment correlate with an antidepressant treatment response.
To obtain the patients perspectives on their symptoms, the self-reported Beck
Depression Inventory (BDI) [21] was administered. Anxiety was assessed by
clinical interview using the Hamilton Anxiety Rating Scale (HARS) [22].

In the OXC-treated group, the battery of mood and anxiety scales was
administered at Time 1, which was P2 weeks after a stable dose of OXC, which
was required for seizure control, was achieved. For the control subjects, the
battery of mood and anxiety scales was repeated at Time 2, which was
predetermined to be approximately 3 months after Time 1.
The 3-month separation between Time1and Time2 was based on the estimated
time required to stabilize doses of OXC in the treated group and was therefore
maintained for the control group. Concomitant AED doses and other background
medications remained unchanged between the two evaluations. Seizure
frequency and medication side effects were monitored for all subjects throughout
the study.
The interviewer was not specifically blinded as to whether subjects were in the
OXC-added group or control group, but the interviewer did not review the
subjects medicines or Time1 results when testing at Time 2.

3.2. Statistical analysis

Statistical analysis was performed using a two-factor repeated-measures analysis

of variance (ANOVA) to assess differences between the OXC-treated group and
control group in terms of seizure frequency and mood and anxiety test scores.
The significance level was set at the 95% confidence limit. Linear regression
analysis was used for analysis of the correlation of OXC dose with test scores.

4. Results
Forty controls and 40 OXC-treated patients were enrolled and completed the
study. Sex ratio and age characteristics are listed in Table 1. Three patients in the
OXC-treated group had diagnoses of mood disorders before their entrance into
the study and were taking stable doses of selective serotonin reuptake inhibitors
(SSRIs) during the study period.

Mean monthly seizure frequency at Time 1 and Time 2 for the OXC-treated and
control groups is outlined in Table 1. All patients reported having partial-onset
seizures during the study period, which included complex partial seizures,
secondarily generalized tonicclonic seizures, or both.

Among the OXC-treated group, 31 patients reported a reduction in seizure

frequency, 4 reported an increase, and 4 reported no change. One patient was
unable to provide an accurate assessment of seizure count at Time 2. In the
control group,8 reportedadecreasein seizure frequency, 6 reported an increase,
and 26 reported no change.
However, no significant difference in seizure frequency between Time 1 and Time
2 for each group, or between the OXC-treated and the control group, was found
(P = 0.31). No correlation was found between changes in mood scales and
seizure frequency over time.

AED baseline regimens for the controlandOXC-treated groups are givenin

Table2.OXC wasadministered asaddon AED for all 40 patients.

In the OXC-treated group, the final OXC dose ranged from 600 to 1800 mg/day,
with a mean dose of 1215 (470)mg. Time between evaluations ranged from 1
to 6 months, with a mean of 2.8 (1.5) months. For the control group, time
between evaluations ranged from 1 to 6 months, with a mean of 3.6 (1.5)
months.
5. Discussion

These findings support anedoctal reports of an association between OXC use and
improved sense of well-being in patients with epilepsy, and further suggest that
the mechanism of this effect may be a reduction in depressive symptoms.
While our results do not provide strong evidence that OXC treatment is
associated with improved mood in our patients, our ability to compare directly
OXC-treated patients with control subjects matched for age, sex, epilepsy type,
seizure frequency, and baseline mood and anxiety test scores allowed us to
demonstrate quantitatively measurable mood improvement attributable to OXC
in a non-dose-dependent manner over time.
Seizure reduction alone cannot fully account for affective improvement in OXCtreated subjects compared with controls: whereas a trend toward fewer seizures
was noted in the OXC-treated group relative to controls, this was not statistically
significant. The occurrence of possible competing causes and confounding
factors (e.g., favorable life events, improved compliance) is possible though not
probable, because of the accuracy of patients monitoring.

Our study presents some limits. First, this study was not blinded and is thereby
susceptible to investigator bias.
Second, this study was not placebo controlled. Quantitative assay of subjects
affective state was performed using the HDRS, BDI, and CDRS. The HDRS and
BDI are widely used affect assessment instruments most useful in assaying
treatment response when subjects meet generally accepted criteria for major
depression following DSM-IV. Because patients with epilepsy are known to have
frequent depressive complaints, it may be that conventional depression
assessment instruments are not sufficiently sensitive to detect the subsyndromic
depressive symptoms more commonly associated with chronic epilepsy.
Thus, the CDRS may be particularly elucidating in the epilepsy population [23].

The CDRS has been demonstrated to correlate with the HDRS and BDIwhen used
to assess treatment response of depressed subjects.Areductionin CDRS <20,
identified as the optimal cutoff score, has shown a highly sensitive and specific
correlation with effective antidepressant treatment [24]. The CDRS appears to be
more sensitive than the HDRS or BDI in detecting dysthymic disorder, a form of
chronic depression [23]. In particular, some authors [25] have demonstrated that
the CDRS has greater severity range scores than the HDRS and has better
content validity than the HDRS when it comes to the dysthymic population.

In our study, significant improvement in affect, as measured by the CDRS, was

demonstrated in OXC-treated subjects relative to controls. HDRS and BDI scores
also declined in the OXC-treated group, but these decreases did not reach

statistical significance. Thus, the CDRS may be a tool that is more sensitive in
assessing changes over a wide range of depressive phenomena in the epilepsy
outpatient population. An explanation for this greater sensitivity may be that the
CDRS is weighted more toward assaying subtle dynamic and interpersonal
depressive symptoms (e.g., low self-esteem) and less toward assessing
neurovegetative symptoms of depression [20].

Although our results do not provide conclusive evidence supportingthe specific

useofOXC asanantidepressant,28 of 40 OXC-treated subjects who were dysthymic
by CDRS criteria on study entry (score P20) demonstrated affective improvement
consistent with a treatment-related antidepressant effect (score <20).

In the control group, CDRS, HDRS, and HARS scores declined, but these
decreases did not reach statistical significance.

Thus, a significant decline in dysthymic symptoms in OXC-treated subjects

compared with controls in this study population of patients with epilepsy
(nonselected for depression) lends support to the hypothesis that OXC improves
mood.

6. Conclusions
The past decade has seen an explosion in the number of anticonvulsant drugs
used in both psychiatry and neurology. As a class, anticonvulsants are unique in
their widespread usage and efficacy for seemingly divergent brain-based clinical
conditions. Several anticonvulsants are broad-spectrum primary and adjunctive
mood stabilizers used for bipolar and unipolar mood disorders, yet
are also effectively used for localization-related and primary generalized epilepsy
[26]. In particular, the potential dual role of mood stabilizers/anticonvulsants
has been pondered in the literature, as these drugs are broadly used as first-line
agents for both epilepsy and psychiatric mood disorders [27]. Especially
intriguing is that anticonvulsant medicine may function by targeting underlying
central nervous system pathophysiology that may be at the root of both epilepsy
and mood disorders.
The etiology of depression in epilepsy has not been determined, but is likely to
involve a complex, patient-specific interplay of origins including the brain
pathology giving rise to and arising from the epilepsy, the negative psychosocial
impact of epilepsy, and side effects of antiepileptic drugs. Because antiepileptic
drugs can either exacerbate or mitigate depression, careful choice among the
therapeutic options is paramount in managing patients with epilepsy.