Guía de Epilepsia y Trastornos Afectivos

ARTICLE IN PRESS
Epilepsy & Behavior xxx (2008) xxxxxx
Contents lists available at ScienceDirect
Epilepsy & Behavior

journal homepage: www.elsevier.com/locate/yebeh
Consensus statement: The evaluation and treatment of people with epilepsy

and affective disorders
John J. Barry a,*,1, Alan B. Ettinger b,1, Peggy Friel c,1, Frank G. Gilliam d,1, Cynthia L. Harden e,1,
Bruce Hermann f,1, Andres M. Kanner g,1, Rochelle Caplan h,2, Sigita Plioplys i,2, Jay Salpekar j,2,
David Dunn k,l,2, Joan Austin k,l,2, Jana Jones m,2
a
Department of Psychiatry and Behavioral Sciences, Stanford University Medical Center, Stanford, CA, USA
Department of Neurology, Long Island Jewish Medical Center, New Hyde Park, NY, USA
Swedish Neuroscience Institute, Seattle WA, USA
d
Columbia University, New York, NY, USA
e
Weil Medical College of Cornell University, New York, NY, USA
f
University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
g
Department of Neurological Sciences and Department of Psychiatry, Rush Medical College, Rush Epilepsy Center, Rush University Medical Center, Chicago, IL, USA
h
Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, CA, USA
i
Department of Child and Adolescent Psychiatry, Childrens Memorial Hospital, Chicago, IL, USA
j
Center for Neuroscience and Behavioral Medicine, Childrens National Medical Center, George Washington University School of Medicine, Washington, DC, USA
k
Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA
l
Indiana University School of Nursing, Indianapolis, IN, USA
m
Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
b
c
a r t i c l e
i n f o
Article history:
Received 7 April 2008
Accepted 9 April 2008
Available online xxxx
Keywords:
Depression
Anxiety
Bipolar disorder
Postictal depression
Ictal depression
Interictal depression
Suicidality
Intractable epilepsy
Temporal lobe epilepsy
Antidepressants
a b s t r a c t
Affective disorders in people with epilepsy (PWE) have become increasingly recognized as a primary factor in the morbidity and mortality of epilepsy. To improve the recognition and treatment of affective disorders in PWE, an expert panel comprising members from the Epilepsy Foundations Mood Disorders
Initiative have composed a Consensus Statement. This document focuses on depressive disorders in particular and reviews the appearance and treatment of the disorder in children, adolescents, and adults. Idiosyncratic aspects of the appearance of depression in this population, along with physiological and
cognitive issues and barriers to treatment, are reviewed. Finally, a suggested approach to the diagnosis
of affective disorders in PWE is presented in detail. This includes the use of psychometric tools for diagnosis and a stepwise algorithmic approach to treatment. Recommendations are based on the general
depression literature as well as epilepsy-specic studies. It is hoped that this document will improve
the overall detection and subsequent treatment of affective illnesses in PWE.
2008 Elsevier Inc. All rights reserved.
1. Introduction
Depression has become increasingly recognized as a pivotal factor in determining the quality of life of people with medical diseases. Morbidity and mortality and overall prognosis of many
medical illnesses are adversely affected by the presence of depression. This is true for cardiovascular disease, cancer, HIV/AIDS, and
* Corresponding author. Fax: +1 650 724 9900.

E-mail addresses: jbarry@leland.stanford.edu, lschreiber@efa.org (J.J. Barry).
1
For adults. Consultants on treatment issues: Charles DeBattista, M.D., Terrance
Ketter, M.D., Department of Psychiatry and Behavioral Sciences, Stanford University
Medical Center, Stanford, CA, USA.
2
For children and adolescents.
neurological diseases like stroke, Parkinsons disease, multiple

sclerosis, Alzheimers disease, and epilepsy [1]. It has been estimated that by 2020, the second leading cause of disability, after
cardiovascular disease, will be the presence of depression [2].
The presence of depression as a comorbidity in medical diseases
increases the costs of the disorder by 50% [3]. Another fascinating
observation is that depression and medical illnesses appear to have
a bidirectional relationship. This has been noted for cardiovascular
disease, cancer, HIV/AIDS, and the neurological illnesses stroke,
dementia, Parkinsons disease, and epilepsy.
Despite the growing recognition of the importance of depressive illness, many reports document that there is a lack of appropriate screening and treatment. There may be a myriad of
1525-5050/$ - see front matter 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.yebeh.2008.04.005
Please cite this article in press as: Barry JJ et al., Consensus statement: The evaluation and treatment of people with epilepsy ..., Epilepsy
Behav (2008), doi:10.1016/j.yebeh.2008.04.005
ARTICLE IN PRESS
2
J.J. Barry et al. / Epilepsy & Behavior xxx (2008) xxxxxx
reasons for physician neglect, but fear can be a signicant factor. If

you ask, you are responsible to treat. In PWE, there are a panoply of
road blocks in the treatment of depressive disorders. The goal of
this article is to resolve some of these obstacles by providing the
physician with an understanding of the phenomenological spectrum of depressive disorders in PWE. In addition, this document attempts to provide a review of the barriers to treatment which
range from iatrogenically induced depression, to drug interactions,
to antidepressant-induced decrease in the seizure threshold. Finally, a stepwise recommendation of treatment options for children,
adolescents, and adults with affective illness is presented.
This guide is a resource tool for professionals who treat patients
with epilepsy. It is designed to be a compendium of current knowledge about the denition, recognition, and treatment of childhood,
adolescent, and adult affective disorders, but with a particular
emphasis on depressive illness.
2. Composition of the expert panel

The authors of this Consensus Statement represent members
from a panel of neurologists, psychiatrists, psychologists, and social workers who have been part of the Mood Disorders Initiative
sponsored by the Epilepsy Foundation. The group originally met
in 2003 for the Epilepsy Foundations Mood Disorders Expert Meeting in Alexandria, VA, USA. Prior to that meeting, the Foundation
had sponsored a survey of concerns for PWE that highlighted the
need for the development of a group to spearhead an initiative to
improve the recognition and treatment of mood disorders in
PWE. One of the target goals, the development of a screening tool
to detect depression in PWE in the clinic, resulted in the Neurological Disorders Depression Inventory for Epilepsy, which is discussed in the Statement. Another important goal was the
development of a Consensus Statement for practitioners.
The panel represents a group of experts who have been working in the eld of epileptology and have focused their interests in
depression as a comorbidity of epilepsy. The group has authored
extensively in the eld. The Consensus Statement was designed
to be a compendium of the published data in the eld and to provide a concise stepwise method to treat PWE and depression in a
clinical setting. It attempts to answer how to recognize the disorder, barriers to treatment and how to overcome them, treatment
recommendations, and, for the neurologist, when to refer to psychiatry and what to expect from their psychiatry colleagues.
3. How to recognize depression in people with epilepsy
3.1. What is the problem?
Depression is the most common comorbid psychiatric disorder
in PWE [4]. For example, Tellez-Zenteno et al. used the Canadian
Community Health Survey (CCHS 1.2) to investigate the prevalence
of psychiatric comorbidity in PWE in the community compared
with those without epilepsy [5]. The CCHS included the administration of the World Mental Health Composite International Diagnostic Interview to a sample of 36,984 subjects. A prevalence of
epilepsy of 0.6% was identied in this cohort. A 17.4% lifetime prevalence of major depressive disorders was found in patients with
epilepsy (95% CI: 10.024.9) versus 10.7% (95% CI: 10.211.2) in
the general population. Furthermore, patients with epilepsy had
a 24.4% (95% CI: 16.032.8) lifetime prevalence for any type of
mood disorder versus 13.2% (95% CI: 12.713.7) among the general
population. Its prevalence is signicantly higher than in healthy
controls, as well as in people with other chronic medical disorders
[47]. Despite relatively higher prevalence rates, depression remains underrecognized and undertreated. For example, in a study
of 97 consecutive patients with epilepsy and a depressive disorder

severe enough to warrant pharmacotherapy, Kanner et al. found
that referral for psychiatric treatment was suggested after more
than 1 year from the onset of symptoms in 63% of patients with
a spontaneous mood disorder and in 54% with an iatrogenic
depressive episode [8]. Wiegartz et al found that 43% of PWE had
a current major depressive disorder and 68% a minor depression;
38% of patients with lifetime histories of major depressive disorder
had never been referred for treatment [9]. Furthermore, this problem is highly prevalent in other cultures and affects all age groups.
For example, De-Marinis et al. identied a major depressive disorder with the Structured Clinical Interview for Axis I DSM-IV Disorders (SCID-I) in 44 of 200 consecutive patients with epilepsy in
Chile [presented as a poster at the 2006 Annual meeting of the
American Epilepsy Society, San Diego, CA, USA]. In only 25% had
this disorder been identied prior to their participation in the
study. This problem is not restricted to adults with epilepsy. Ettinger et al. found symptoms of depression in 26% of 44 children, none
of whom had been previously diagnosed or treated [10].
Prevalence rates of depression range from 20 to 55% in patients
with refractory epilepsy, with the highest rates seen in epilepsyspecic clinics, and from 3 to 9% in patients with well-controlled
epilepsy [11]. Although female gender predominance is seen for
depression in the general population, this has been an inconsistent
nding in surveillance of depression in patients with epilepsy. Two
recent reports, however, have found that female gender is associated with depression in epilepsy [12,13]. In an evaluation of
depressive symptoms in 201 patients with epilepsy, using the Beck
Depression Index-21, high seizure frequency and symptomatic focal epilepsy were independent determinants of depression, and female gender showed a strong trend toward this association
(P = 0.054) [12]. In a mailed survey for depression using the Center
for Epidemiology Studies Depression Scale [CES-D]), comparing
775 persons with epilepsy, 395 with asthma, and 362 healthy subjects, depression was signicantly associated with female gender,
young age, lower income, worse quality-of-life scores, more disability, more social concerns, more adverse drug events, less
past-month employment, and fewer working days [13].
Failure to identify comorbid mood disorders in epilepsy is not
surprising given that physicians fail to inquire about this condition.
For example, in a survey of neurologists, Gilliam found that 80% do
not routinely screen patients with epilepsy for depression [14].
There are several reasons for this phenomenon: (1) There is the
common misconception by patients, relatives, and (not infrequently) clinicians of depression being a normal reaction to facing a life with seizures and the expected obstacles in social,
academic, professional, and economic domains. Accordingly,
depressive episodes are not reported to the treating physician,
even if symptoms persist for a protracted period, and physicians
fail to inquire about them. (2) Frequently, depressive disorders
have an atypical clinical expression in patients with epilepsy (see
below). (3) Patients become accustomed to living in a chronic depressed state to the point where they end up forgetting what it
was like to live in a euthymic mood. Thus, it is not rare for patients
to deny feeling depressed, and it is only a spouse, parent, or close
friend who reports mood changes in the patient. In fact, inquiring
about specic symptoms (i.e., Are you unable to nd pleasure in
your daily activities? or Do you have to push yourself to go out?)
may allow the patient to recognize the existence of a pathologic
mood state. (4) Patients and their relatives misperceive that the
depressive symptomatology is part of the epilepsy and hence
does not require special treatment. (5) The dont ask, dont tell
phenomenon refers to a deliberate decision by nonpsychiatrists
not to inquire about symptoms of depression because they do
not know how to manage depression or where to refer. Indeed, this
has become probably one of the more frequent obstacles in the
Behav (2008), doi:10.1016/j.yebeh.2008.04.005
ARTICLE IN PRESS
diagnosis and treatment of comorbid psychiatric disorders in patients with medical and neurological disorders. This problem is addressed in great detail in the section on treatment of mood
disorders [14].
It is typically assumed that mood disorders are a consequence
of the seizure disorder. Yet, recent evidence suggests that a significant number of patients with new-onset epilepsy were already
suffering from mood and anxiety disorders before they ever had
a rst seizure [1518]. In fact, three population-based studies suggest that patients with depression have a four- to seven-fold higher
risk of developing epilepsy than controls [1618]. In a recently
published study of children and adolescents with new-onset epilepsy, 19% were found to have a mood disorder and 24% an anxiety
disorder at the time of diagnosis [15]; 45% had experienced the
psychiatric disorders before the onset of the seizure disorder.
Depression has a signicant negative impact on the quality of
life of PWE [19]. In addition, recent studies have demonstrated that
the presence of untreated depression is associated with greater
medical costs, independent of the cost of psychiatric treatment
[20]. Depressed patients are also more likely to experience adverse
events from their antiepileptic drugs (AEDs) [21,22]. Furthermore,
a history of depression appears to be predictive of a worse response to pharmacological and surgical treatment of the seizure
disorder. Indeed, in a study of 780 consecutive patients with
new-onset epilepsy who were followed for a 20-year period, Hitiris
et al. found that patients with comorbid psychiatric disease at the
time of diagnosis of epilepsy were almost three times less likely to
achieve seizure freedom with AEDs [23]. Most of the variance
was accounted for by a history of depression. By the same token,
in a study of 100 consecutive patients with temporal lobe epilepsy
(TLE), Kanner et al. found that a lifetime history of depression is a
predictor of failure to reach freedom from auras and disabling seizures following anterotemporal lobectomy (ATL) [24]. Clearly,
mood disorders affect patients with epilepsy at multiple levels
and their recognition and timely treatment are of the essence.
3.2. Mood disorders in epilepsy: Far from a homogeneous disorder
The fourth edition (text revised) of the Diagnostic and Statistical
Manual of Mental Disorders (DSM-IV-TR) classies mood disorders
into Major Depressive Disorder (MDD), Dysthymic Disorder, Minor
Depression, Bipolar Disorder, Cyclothymia, and Depressive Disorder Not Otherwise Specied [25,26]. This last category includes
all forms of depression that do not meet full DSM-IV criteria for
the suggested categories. The difference between Major Depressive
Disorder and Dysthymic Disorder is based largely on severity, persistence, and chronicity. According to DSM-IV criteria, symptoms
in both disorders may include combinations of depressed mood,
anhedonia, worthlessness and guilt, decreased concentration ability, and recurrent thoughts of death and neurovegetative symptoms (i.e., weight loss or gain, insomnia or hypersomnia,
psychomotor agitation or retardation, fatigue). A diagnosis of
MDD is considered in patients with recurrent major depressive
episodes, in which at least 2 weeks of either depressed mood or
anhedonia must accompany four of the symptoms listed above.
In contrast, dysthymic disorder is a more chronic but less intense
process with symptoms persistent for more days than not for at
least 2 years. Minor Depression is a category that is similar to a major depressive episode in duration but encompasses at least two
but fewer than ve of the depressive symptoms noted above.
There are two types of Bipolar Disorder, depending on the
occurrence of manic (type I) or hypomanic (type II) episodes in
addition to major depressive episodes. The DSM-IV diagnosis for
manic episodes includes the requirement of a distinct period of
abnormally and persistently elevated mood lasting at least 1 week,
of sufcient severity to cause marked impairment in social func-
tioning. The diagnosis for a hypomanic episode includes the

requirement of a distinct period of persistently elevated mood lasting throughout at least 4 days and observable as a disturbance by
others. The diagnosis of Cyclothymia requires the presence of
numerous hypomanic and minor depressive episodes for at least
2 years.
Recent studies in patients with primary mood disorders indicate that the DSM classication may not be sufcient to include
all forms of depression. Indeed, patients with a history of major
depressive disorder may not achieve complete symptom remission
and present with subsyndromic forms of depression. Recognition
of these less severe presentations is of the essence, as these patients are at increased risk of experiencing a recurrence of major
depressive episodes. In patients with epilepsy, the presence of subsyndromic forms of depression is associated with a worse quality
of life. Indeed, in a study of 193 consecutive outpatients from ve
epilepsy centers, Kanner et al. identied psychiatric comorbidity
with two structured interviews (SCID and Mini International Neuropsychiatric Interview [MINI]) [22]. Patients were also asked to
complete self-rating screening instruments of symptoms of
depression, such as the Beck Depression Inventory II (BDI-II) and
the Center for Epidemiologic Studies Depression Scale (CES-D). A
diagnosis of subsyndromic depression was made in patients who
failed to meet any axis I diagnosis according to DSM-IV-TR criteria
with the SCID and MINI, but whose scores on the BDI-II and/or CESD were greater than 12 and 16, respectively. Among the 193 patients, 103 were totally asymptomatic, 22 met our diagnostic criterion of subsyndromic depressive episode, 10 met a DSM-IV
criterion of major depressive disorder, 30 of an anxiety disorder,
24 of a mixed major depressive and anxiety disorder, and 4 of dysthymia. The Quality of Life in Epilepsy Inventory 89 (QOLIE-89)
was used to assess patients perception of their quality of life. Patients with subsyndromic depressive episodes perceived their
quality of life as being signicantly worse (QOLIE-89 total
score = 59 11.5) than that of asymptomatic patients (80 10,
P < 0.0001). Furthermore, having only a major depressive disorder
or a mixed major depressive and anxiety disorder had a differential
impact on patients quality of life, as the latter perceived it to be
worse than the former and than those with only anxiety.
The comorbid occurrence of anxiety and mood disorders is relatively frequent and contributes to the heterogeneous characteristics of mood disorders. Indeed, in the study cited above, 24 of the
34 patients with major depressive disorders met DSM-IV-TR criteria for an anxiety disorder. Conversely, the 30 patients who met
criteria for an anxiety disorder only on the MINI had a score on
the BDI-II suggestive of symptoms of depression of mild severity
(mean score = 13.3 10.6) and signicantly higher than that of
asymptomatic patients (3.4 3.3, P < 0.0001).
Patients with epilepsy have a signicantly higher suicidal risk
than the general population [2730]. For example, in the Canadian
population-based study cited above, the lifetime prevalence of suicidal ideation was twice as high in patients with epilepsy (25%, 95%
CI = 17.432.5) as in the general population (13.3%, 95% CI = 12.8
13.8) [4]. This gure was replicated in a population-based study
specically designed to compare suicidal risk among patients with
epilepsy in Denmark [30]. Suicidal cases were identied in the
Cause of Death Register from 1981 to 1997. Up to 20 controls,
matched by sex, birth year, and calendar date, were assigned to
each suicide case. The study included 21,169 suicidal cases and
423,128 controls. Patients with epilepsy were found to have a three
times higher risk of committing suicide than controls, as 492
(2.32%) individuals who committed suicide had epilepsy compared
with 3140 (0.74%) controls (risk ratio = 3.17, 95% CI = 2.883.50)
The risk ratio remained signicantly higher after excluding individuals with a history of psychiatric disease and adjusting for socioeconomic factors (1.99, 95% CI = 1.712.32). The highest risk of
Behav (2008), doi:10.1016/j.yebeh.2008.04.005
ARTICLE IN PRESS
4
suicide was identied in patients with epilepsy and comorbid psychiatric disease, even after adjusting for socioeconomic factors
(13.7, 95% CI = 11.816.0). The nding that the highest risk of suicide among patients with epilepsy occurred during the rst half
year after diagnosis (5.35, 95% CI: 3.438.33) was of great importance. This risk was particularly high in individuals with a history
of comorbid psychiatric disease (29.2, 95% CI = 16.451.9). Indeed,
such risk is higher among depressed patients who also suffer from
a comorbid anxiety disorder.
Suicidal ideation can occur as part of an interictal mood/anxiety
disorder or as postictal symptomatology (see below) [31]. For
example, in a study of 100 consecutive patients with pharmacoresistant partial epilepsy, habitual postictal suicidal ideation was reported by 13 patients. The median duration of this symptom was
24 hours. In summary, it is critically important that the evaluation
of mood disorders always encompasses an investigation of symptoms of anxiety disorders, during both the interictal and postictal
periods. Furthermore, it is important to recognize the bidirectional
relationship existing between suicidality and epilepsy. That is, not
only do patients with epilepsy have a greater risk of experiencing
suicidal ideation and behavior, but patients with a history of suicidality have a 5.1 greater risk of developing epilepsy [18].
cidal ideation. More typically, however, ictal symptoms of depression are followed by alteration of consciousness as the ictus
evolves from a simple into a complex partial seizure.
3.3.2. Preictal depressive episodes

There are very few studies in the literature of this form of
depressive episodes, which typically present as a dysphoric mood
preceding a seizure by several hours to days. Blanchet and Frommer investigated mood changes over the course of 56 days in 27
PWE who were asked to rate their mood on a daily basis. Mood ratings pointed to a dysphoric state 3 days prior to a seizure in 22 patients [32]. This change in mood was more accentuated during the
24 hours preceding the seizure. In our experience, preictal symptoms of depression manifest as irritability, poor frustration tolerance, motor hyperactivity, and aggressive behavior in children
with epilepsy.
3.3.4. Postictal symptoms of depression

Postictal symptoms of depression (PSD) have been recognized
for a very long time, but have been poorly studied in a systematic
manner. Their prevalence in large populations of PWE has recently
been investigated in a study that assessed the presence of PSD in
100 consecutive patients with poorly controlled partial seizure disorders [34]. Only symptoms that occurred following more than 50%
of seizures for the previous 3-month period were included in the
study. In this study, the postictal period was dened as the 72
hours that followed a seizure. The investigating also identied
those symptoms that occurred during both interictal and postictal
periods and compared their severity during these periods. Neurovegetative symptoms and fatigue, which are common postictal
symptoms, as well as symptoms of depression, were analyzed separately, so as not to falsely inate the prevalence of PSD.
Among the 100 patients, 43 experienced a mean of 4.8 2.4 PSD
(range = 29, median = 5). The median duration of two-thirds of
symptoms was 24 hours. Thirteen of these patients experienced
a minimum of seven PSD lasting 24 hours or longer. As stated
above, postictal suicidal ideation was identied in 13 patients.
Eight patients experienced passive and active suicidal thoughts,
whereas ve reported only passive suicidal ideation. Ten of these
13 patients (77%) had a past history of either major depression
or bipolar disorder, and this association was highly signicant. Furthermore, the presence of postictal suicidal ideation was also signicantly associated with a history of psychiatric hospitalization.
Clearly, the presence of postictal suicidal ideation should alert
the clinician to the existence of a current or past serious history
of depression.
Postictal symptoms of depression did not occur in an isolated
manner, but more often than not were accompanied by postictal
symptoms of anxiety and postictal neurovegetative symptoms.
By the same token, 7 of the 100 patients reported habitual postictal
psychotic symptoms. Every one of these patients also experienced
symptoms of depression and anxiety.
Thirty-seven patients had reported interictal symptoms of
depression. These interictal symptoms worsened in severity during
the postictal period in 30 patients (who, in addition, experienced
de novo PSD). These data indicate that PSD are an integral part of
the psychiatric symptoms frequently reported by patients with
refractory partial seizure disorders. Yet, in none of the studies carried out to identify the prevalence of depression in epilepsy did the
investigators discriminate between an interictal, preictal, or postictal occurrence. The impact that PSD may have in shaping the psychiatric clinical phenomena of depression in PWE is yet to be
established. Yet, it is likely that preictal and postictal symptoms
of depression may account for the frequent atypical characteristic of depressive disorders.
3.3.3. Ictal symptoms of depression

Ictal symptoms of depression are the clinical expression of a
simple partial seizure in which these symptoms constitute its predominant phenomenology. It has been estimated that psychiatric
symptoms occur in 25% of auras; 15% of these involve affect or
mood changes [33]. For example, ictal symptoms of depression
ranked second after symptoms of anxiety/fear which were the
most common type of ictal affect in one study. At times, mood
changes represent the only expression of simple partial seizures,
and consequently, it may be difcult to recognize them as epileptic
phenomena. They typically are brief, are stereotypical, occur out of
context, and are associated with other ictal phenomena. The most
frequent symptoms include feelings of anhedonia, guilt, and sui-
3.3.5. Atypical interictal expressions of depression in epilepsy

It is not unusual for patients with epilepsy to experience
depressive episodes that fail to meet any DSM criteria. Kraepelin
[35] and then Bleuler [36] were the rst authors to describe a pleomorphic pattern of symptoms that included affective symptoms
consisting of prominent irritability intermixed with euphoric
mood, fear, and symptoms of anxiety, as well as anergia, pain,
and insomnia. Gastaut conrmed Kraepelins and Bleulers observations [37], and nally, Blumer coined the term interictal dysphoric disorder (IDD) to refer to this type of depression in
epilepsy [38] and estimated that it occurred in two-thirds of depressed patients with epilepsy. Blumer described the chronic
course of this disorder with recurrent symptom-free periods that
3.3. Unique clinical expressions of mood disorders in epilepsy

3.3.1. Peri-ictal symptoms of depression
Patients with epilepsy may experience symptoms of depression
and anxiety temporally related to the occurrence of seizures, either
before a seizure (preictally), as a clinical expression of the seizure
(ictal), or following a seizure (postictally). It is not unusual for preictal symptoms to persist into the postictal period. Furthermore,
we have found that interictal symptoms can worsen in severity
during the postictal period (see below). These forms of depressive
episodes are the least studied in a systematic manner and usually
are not investigated by clinicians in routine evaluations of seizure
disorders. Furthermore, their occurrence has never been factored
in any study of the prevalence of depressive disorders in epilepsy
and would not be detected with the standard diagnostic instruments used to generate DSM-based diagnoses.
Behav (2008), doi:10.1016/j.yebeh.2008.04.005
ARTICLE IN PRESS
responded well to low doses of antidepressant medication. In a

more recent study, Kanner et al. conrmed Blumers description
of the pleomorphic characteristics of mood disorders [39].
Using DSM-III-R criteria, Mendez et al. had to classify almost
50% of depressive disorders as Atypical Depression [40]. Wiegartz
et al. found that the depressive episodes of 25% of PWE were also
classied as Atypical Depression Not Otherwise Specied [9]. Other
investigators have been impressed as well by the atypical and
pleomorphic presentation of depressive disorders in epilepsy. For
example, among 97 consecutive patients with refractory epilepsy
and depressive episodes severe enough to merit pharmacotherapy,
Kanner et al. found that 28 (29%) met DSM-IV criteria for major
depressive disorder [8]. The remaining 69 patients (71%) failed to
meet criteria for any of the DSM-IV categories and presented with
a clinical picture consisting of anhedonia (with or without hopelessness), fatigue, anxiety, irritability, poor frustration tolerance,
and mood lability with bouts of crying. Some patients also reported
changes in appetite and sleep patterns and problems with concentration. Most symptoms had a waxing and waning course, with repeated interspersed symptom-free periods of one to several days
duration. The semiology most resembled a dysthymic disorder,
but the recurrence of symptom-free periods intermittently precluded DSM criteria for this condition. Kanner referred to this form
of depression as Dysthymic-Like Disorder of Epilepsy (DLDE).
3.4. Why should nonpsychiatrists care?
Clearly, no one expects neurologists or other nonpsychiatrists to
remember the DSM-IV-TR classication and diagnostic criteria of
mood disorders described above. Yet, it is important that they recognize the following expressions of these disorders: (1) major
depressive episodes, as these represent their more common debilitating type; (2) postictal depressive symptoms or episodes, given
their relatively high prevalence in patients with refractory epilepsy
and the fact that they may persist even with the use of antidepressant medication given for interictal mood disorders; (3) suicidal
ideation and behavior; (4) the comorbid occurrence of anxiety
symptoms and disorders in depressed patients, as these are the
ones at greater risk of suicidal ideation and attempts; (5) bipolar
disorders or patients at risk for this form of mood disorder, as antidepressant medication must be used with great caution in these
patients to avert a switch to manic or hypomanic episodes or,
worse, a rapid cycling bipolar disorder, which is more refractory
to treatment. In patients with a major depressive episode, the suspicion of bipolar disease must be considered in the following circumstances: (1) history of manic or hypomanic symptoms after
exposure to an antidepressant drug; (2) family history of bipolar
disease; and (3) a rst major depressive episode before the age
of 15, as these patients have a 40 to 60% probability of developing
bipolar illness.
3.5. Recognition of iatrogenically caused depressive episodes
Depressive episodes can be triggered by changes in AEDs in
three ways: (1) after introduction of an AED with negative psychotropic properties; (2) after discontinuation of an AED with moodstabilizing properties in individuals with a mood disorder that
had been in remission because of the therapeutic effect of the disease; and (3) after introduction of an AED with enzyme-inducing
properties in patients taking psychotropic drugs (e.g., antidepressants) for the treatment of an underlying mood disorder. These
AEDs cause a signicant increase in the clearance of the psychotropic drugs, limiting their efcacy and often leading to recurrence of
the depressive episode. It is important to keep in mind that AEDinduced depressive episodes are more likely to occur in patients
with a prior history and/or a family history of mood or anxiety dis-
orders or of alcoholism. Clearly, to avert the development of iatrogenically induced depressive episodes, clinicians must always
inquire about such past personal or family psychiatric histories.
Every AED, including those with positive psychotropic properties, can trigger psychiatric symptoms in epileptic patients, some
with a greater severity than others [40,41]. Phenobarbital can result in depression that may occasionally be related to the presence
of suicidal ideation and behavior. Other AEDs reported to often
trigger symptoms of depression include primidone, tiagabine, vigabatrin, felbamate, topiramate, levetiracetam, and zonisamide [41
48]. Furthermore, identifying any current or prior depressive disorder may have an important effect on the threat of developing adverse cognitive events when exposed to topiramate. In fact,
cognitive adverse events were reported by 41% of 592 patients in
a study of topiramate polytherapy [48]; a history of a depressive
disorder was a signicant predictor of these cognitive adverse
events.
3.6. Recognition of depressive disorders in the neurology clinic
Ideally, every patient suspected of having a mood disorder
should undergo a psychiatric evaluation to identify the type of
mood disorder and comorbid psychiatric conditions. Unfortunately, this is very often an unlikely option, given the lack of availability of psychiatrists and lack of reimbursement of psychiatric
services by third-party payers. Thus, it often falls on the neurologist to treat the comorbid mood disorder.
How is a neurologist (or any clinician without special training in
psychiatric aspects of epilepsy for this matter) expected to identify
the existence of a depressive disorder in her or his patients with
epilepsy in the midst of a busy clinic with already limited time
allotted to address the epilepsy-related issues?
An initial and very simple step is to inquire about the existence
of the symptom of anhedonia, that is, the inability to nd pleasure
in most activities. In fact, identication of anhedonia is a very good
predictor of the presence of depression and, often, unaffected by
physical complaints secondary to drugs or underlying illness ; it
is a barometer of the intensity of the depression in the medically
ill.
Second, having patients complete one of the self-rating screening instruments used to identify symptomatic patients can be
very useful. In fact, a six-item screening instrument, the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E), was recently validated to identify major depressive episodes specically
in PWF [49]. This instrument has the advantage that it was constructed to minimize the potential for confounding by adverse
events related to AEDs or cognitive problems associated with epilepsy that plague other instruments. Completion of this instrument
takes less than 3 minutes. A score above 15 is suggestive of the
possibility of a major depressive episode and serves as a red ag
to carry out a more in-depth evaluation [50].
Other self-rating screening instruments developed to identify
symptoms of depression in the general population, the BDI-II and
the CES-D, have recently been found to be valid instruments to
screen symptoms of depression in PWE [51]. Total scores >11
and 14, respectively, are suggestive of depressive disorders of at
least mild to moderate severity. Also, the Mood Disorders Questionnaire (MDQ) has been used in PWE as a screen for the presence
of symptoms consistent with a bipolar disorder [52]. Finally, the
Hospital Anxiety and Depression Scale (HADS) is a useful screening
instrument to identify symptoms of anxiety and depression, but it
has yet to be validated in PWE.
It should be emphasized that these instruments are not diagnostic by themselves of major depressive or other mood disorders, and
when the score is suggestive of a mood disorder, patients should
undergo a more in-depth evaluation. Once the diagnosis of a mood
Behav (2008), doi:10.1016/j.yebeh.2008.04.005
ARTICLE IN PRESS
6
disorder has been established by psychiatric evaluation, these

instruments can be given at every visit to measure changes in
symptom severity or to document symptom remission.
On the other hand, it is very useful to generate a list of symptoms for each patient that serves as target for pharmacological
and /or psychotherapeutic interventions. Indeed, the aim of any
of the selected therapies must be their total remission, lest an increased risk of recurrence of the depressive disorder exists. This
is a proposed list of the most common symptoms of anxiety and
depression that any nonpsychiatrist can use as a model [52]:
3.6.0.1. Symptoms of Depression
1. Are you having difculty nding pleasure in activities you
used to enjoy?
2. Do you have to push yourself now to do things that you used
to enjoy in the past?
3. Do people get on your nerves for things that never used to
bother you before?
4. Do you have little tolerance for people?
5. Do you notice that your mood changes without any apparent
reason? For example, one day you are happy, and without
any reason you get moody, cranky, and cannot enjoy anything the next day?
6. Do you feel so bad that you feel completely hopeless?
7. Do you feel that there is nothing you can do to feel better
about yourself?
8. Do you sometimes wish you were dead?
9. Do you think about ways of harming yourself?
10. Do you nd yourself crying for things that never made you
cry before?
11. Do you have difculty falling asleep?
12. Do you wake up in the middle of the night and have difculty falling asleep again?
13. Has your appetite changed? If so, how?
14. Have you lost or gained weight as a consequence of a change
in your appetite?
3.6.0.2. Symptoms of Anxiety

1. Do you worry about things you never worried about before?
2. Do you fear that something bad will happen to your loved ones,
even though you know there is nothing to worry about?
3. Does your heart start beating fast, out of the blue, and you feel
like you cannot catch your breath and that something terrible is
going to happen to you, like having a heart attack, a stroke, etc.?
4. Do you get frightened of being left alone or leaving the house by
yourself?
5. Do you nd yourself pacing constantly and unable to relax?
3.7. The identication of mood disorders in research

One of the most frequent methodological errors that occur
repeatedly in research studies of depression in epilepsy is the sole
reliance on screening instruments in the diagnosis of a depressive
disorder. The argument to limit the psychiatric evaluation to the
use of these instruments is that they have been validated to identify conditions such as major depressive episodes, some with
acceptable levels of sensitivity and specicity, and the severity of
the depressive episodes. Thus, the common argument suggests:
If a patient has a score >30 on the BDI-II, what else can the patient
have but a major depressive episode? Although this statement is
probably correct, a major depressive episode can be the expression of more than one type of mood disorder, each with a different
prognosis and treatment strategies. For example, a major depressive episode: (1) can be the rst major depressive episode ever,
which implies a 50% risk of experiencing additional episodes; (2)
can be one of multiple episodes indicating a diagnosis of major
depressive disorders with an almost 100% probability of recurrent
episodes, lest the patient remains on prophylactic treatment; (3)
can occur as part of bipolar disorder, which implies a worse prognosis for symptom remission and suicidal risk than major depressive disorders and calls for a different treatment strategy (i.e., very
cautious use of antidepressant medication); (4) can occur as part of
a double depression, which consists of recurrent major depressive
episodes in the midst of a dysthymic disorder.
Clearly, the use of screening instruments in psychiatric research
in patients with epilepsy must be followed by structured psychiatric interviews designed to establish distinct Axis I diagnoses. With
such diagnoses in hand, the use of screening instruments on a repeated basis can yield meaningful data with respect to change in
severity of symptomatology after the start of treatment.
3.8. Comments
Mood disorders are relatively frequent in patients with epilepsy
and their early identication is essential to minimize suicidal risks,
the negative impact on quality of life, and costs. Neurologists
should be trained in the recognition of mood and anxiety disorders
and the treatment of major depressive and dysthymic disorders.
However, psychiatrists should be involved in the management of
patients with bipolar disorders, suicidal ideation, or psychotic
depressive episodes, or any patient whose depressive episodes
have failed to respond to pharmacotherapy in the past.
4. Psychological and physiological factors associated with

depression in epilepsy
Similar to depression occurring in the absence of neurological
disorders, depression in PWE is probably caused by multiple factors. Depression symptoms in different samples of patients with
epilepsy have been associated with specic psychological proles,
structural brain abnormalities, and metabolic dysfunction. However, the causal relationships of these ndings have not been determined, and no imaging test or psychological prole has been
demonstrated to have diagnostic value.
Very few studies have evaluated psychological correlates of persons with depression and epilepsy, especially regarding potential
predictive or causal relationships [53]. Hermann et al. [54] used
the BDI and the CES-D to examine the association of depression
with a key component of the revised theory of learned helplessness
(i.e., attributional style) dened by the Optimism/Pessimism Scale.
The study sample consisted of 143 patients with unilateral TLE. The
severity of depression symptoms was signicantly associated with
attributional style, even after controlling for potential confounding
variables such as age, sex, age at onset of epilepsy, and laterality of
epilepsy. The authors concluded that the results indicate that the
concept of learned helplessness in general, and attributional style
in particular, is related to the genesis of depression in epilepsy
[54].
Several investigative groups have evaluated the association of
structural MRI changes with depression in epilepsy. Quiske et al.
[55] compared BDI scores in 60 patients with TLE. Mean depression
scores were signicantly higher in subjects with mesial temporal
sclerosis (MTS), independent of lateralization of the MTS. The
investigators concluded that depression is a good indicator of
MTS, but not vice versa [55]. Mula et al. found that hippocampal
volumes were associated with the occurrence of depression after
initiation of topiramate [56], but not levetiracetam [57]. Briell-
Behav (2008), doi:10.1016/j.yebeh.2008.04.005
ARTICLE IN PRESS
mann et al [58] did not nd a difference in volumes or T2 relaxation times in hippocampi of patients with TLE with and without
a history of depression, but rather demonstrated that depression
was associated with more normal T2 relaxation times in the amygdala contralateral to the lobe of seizure onset. Richardson et al. [59]
reported that both left and right amygdala volumes correlated with
BDI scores in 18 subjects with TLE, but hippocampal volumes did
not.
Bromeld et al [60] were among the rst to use [18F]uorodeoxyglucose positron emission tomography (FDG-PET) to evaluate
metabolic correlates of depression in epilepsy. They studied
metabolism in nine brain regions in 23 patients; 18 had TLE and
5 had poorly localized EEG abnormalities. Inferior frontal cortex
was the only region that had an association, showing decreased
metabolism in subjects with increased symptoms of depression.
Salzberg and colleagues [61] reported similar ndings after comparing resting FDG-PET scans of 9 patients who had a prior history
of depression with those of 14 patients who did not have the prior
history of depression. Using statistical parametric mapping to evaluate metabolic patterns, they found that subjects with prior
depression had areas of hypometabolism in the ipsilateral inferior
frontal lobe, compared with subjects with no prior history of
depression. This nding suggests that dysfunction in extratemporal regions contributes to depression in patients with TLE. Some
prior studies in subjects with nonepileptic depression also identied regions of hypometabolism, whereas others have found increased metabolism in specic mesial frontal areas. An earlier
analysis limited to temporal lobe interictal FDG-PET hypometabolism found that patients with left temporal hypometabolism had
higher rates of major depressive episodes compared with those
with only right temporal abnormalities [62]. However, depression
was also strongly associated with bilateral hypometabolism, and
severity of depression was associated with increased severity of
hypometabolism on the right. The association between the presence of temporal lobe hypometabolism and higher BDI scores
was also reported in another study [63]. Although few studies have
compared MR spectroscopy ndings with measures of depression
in epilepsy, a recent investigation found that the extent of voxels
with abnormal N-acetyl aspartate/creatine ratios in hippocampi
correlated with severity of depression symptoms in 31 subjects
with TLE [64].
As the serotonin model of depression may also be relevant in
epilepsy, several investigators have evaluated PET ligands that bind
to 5HT1A receptors in TLE. Recent studies using trans-4-[18F]uoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl-N-(2-pyridyl)cyclohexanecarboxamide (18F-FCWAY) have noted decreased
binding with higher BDI scores [65,66] and the presence of major
depression [67]. However, a study using carbonyl-11C WAY found
an inverse correlation between decreased binding in the cingulate
gyrus and increased Montgomerysberg Depression Rating Scale
scores in subjects with TLE [68].
4.1. Comments
Specic psychological characteristics, as well as structural and
functional brain abnormalities, have been demonstrated to be
associated with increased symptoms of depression in relatively
small samples of patients. A pessimistic attributional style appears
to be a signicant risk factor. The hippocampus and amygdala are
the most frequently involved anatomical regions, but other limbic
areas are also implicated by the results of some studies. TLE has
been more frequently studied than other syndromes, so few conclusions can be drawn regarding idiopathic or extratemporal forms
of epilepsy.
5. Depression and cognitive function

An important aspect of the problem of depression in PWE is the
degree to which depression may add to the cognitive burden of the
disorder. The ways in which epilepsy and its treatment may affect
neuropsychological status in epilepsy have been the subject of
excellent reviews [69,70], but comparatively less is known about
the added neuropsychological morbidity attributable to depression
in epilepsy. Several investigations [7174,55], but not all [75], have
reported that comorbid depression is associated with additional
cognitive pathology in persons with epilepsy. This is not surprising
given the literature characterizing the cognitive status of patients
without epilepsy with unipolar depression or bipolar disorder in
whom impairments in memory and executive function have been
reported [7678].
Given the magnitude of the problem of psychiatric comorbidity
in epilepsy in general, and depression in particular, the degree to
which these psychiatric complications are associated with additional cognitive burden is important to determine, as is the degree
of relief provided by effective depression treatment.
There are several important issues to address in this literature
and a few areas requiring investigation in the future are listed
below.
5.1. Denition of depression
Much of the previous research has examined the association of
cognitive impairment with scores derived from self-report depression symptom inventories (e.g., BDI, CES-D). Many times, arbitrary
cut scores (e.g., >10) are used to derive depressed and nondepressed groups. Although not uncommon in this literature, such
procedures are of little diagnostic signicance and are certainly
not equivalent to formal psychiatric diagnoses. Epilepsy research
is increasingly moving to DSM-IV- and ICD-10-dened diagnoses,
and cognitive studies of depression in epilepsy should reect this
move as well.
5.2. Progression of depression
It has now been established that in some epilepsies (e.g.,
chronic TLE), there may be progression of DSM-IV Axis I disorders,
including mood and anxiety disorders [79]. The degree to which
progressive cognitive changes may be associated with the progression of depression versus progression of the underlying neurobiology of the disorder needs to be determined.
5.3. The contribution of anxiety
Anxiety is often comorbid with depression in epilepsy [79,80]
and has been shown to be associated with its own neuropsychological morbidity in the general population. The degree to which
depression only versus mixed mood disorders affect cognitive status in chronic epilepsy remains to be determined.
5.4. Relationship to epilepsy variables
There is longstanding interest and debate regarding the relationship between depression and features of the epilepsies including seizure type, laterality of seizure onset, underlying
neuropathology (e.g., hippocampal sclerosis), and other factors
[81]. Some [7173] but not all [75] groups have shown that depression in left TLE is associated with signicant cognitive morbidity,
thus representing an interaction between mood disorder and specic seizure features on cognition. Complex relationships between
Behav (2008), doi:10.1016/j.yebeh.2008.04.005
ARTICLE IN PRESS
8
clinical seizure features and depression and their effects on mood

remain to be fully characterized.
seling. Concern about the stigma of depression is also a factor for

predicting adherence to antidepressant medication [89].
5.5. Cognitive domains
6.2. Barriers to depression treatment in people with epilepsy: Patient

factors
Memory, attention, higher executive functions, and cognitive

and psychomotor processing speed have been shown to be affected
by depression in the general population [7678]. The relative degree to which these abilities are affected in depressed persons with
epilepsy remains to be determined. Further, some consensus on
the best tests with which to assess these cognitive domains would
prove helpful so various investigative groups around the world
might share some common instrumentation.
5.6. Subjective memory complaints
It is now well appreciated that subjective memory complaints
are strongly associated with the degree of self-reported depressive
symptoms on inventories such as the BDI and CES-D [8285]. This
represents another avenue through which to explore the effects of
depression on real and perceived cognitive status.
5.7. Postictal depression and its interictal cognitive signature
Postictal depression is a unique and serious psychiatric complication oftentimes independent of interictal depression [32]. The
degree to which postictal psychiatric complications, including
postictal depression in particular, may exhibit interictal cognitive
markers would be of interest and importance.
6. Barriers to the detection and treatment of depression
6.1. Barriers to depression treatment in the general population: Patient
factors
Despite the high prevalence and signicant personal and societal burden of mood disorders and the availability of effective treatments, the vast majority of people with mood disorders do not
receive care. An even smaller subset receive evidence-based treatment [86]. Although the literature on the epilepsy population is
limited, extrapolation from research on general barriers to mental
health treatment can be helpful.
The rst steps in the help-seeking process for persons with
mood disorders are awareness of symptoms and perception of
the need for care. The most important predictors of the perception
of need for care are severity of the psychopathology and life limitations imposed by the condition. With psychopathology controlled for, the following variables are associated with perceived
need for care: marital loss, female gender, physical conditions,
younger age (1524 years), maternal psychopathology, insurance,
and positive inclination toward mental health treatment [87].
In persons who perceive a need for care, it is somewhat counterintuitive that the severity of psychopathology does not affect
the decision to seek help. At this stage, the main determinants
are attitudinal and sociodemographic. Being older (4554 years),
having a physical condition, and having a positive attitude toward
mental health seeking were associated with seeking professional
help [87].
Misperceptions about antidepressant medication also contribute to an unwillingness to undergo further psychiatric evaluation.
Many people believe that antidepressants are addictive, and prefer
psychological treatment approaches or no treatment at all [88]. In
one study in which 211 depressed patients were surveyed for
treatment preference prior to initiating treatment, 53% were receptive to antidepressant medication, and 69% were receptive to coun-
A recent study evaluated the reasons why adult patients with

epilepsy who endorsed signicant depressive symptoms refused
further evaluation and treatment for a possible mood disorder
[90]. In this study, 113 consecutive adult patients were evaluated
for depressive symptoms using the Quick Inventory of Depressive
Symptomatology Self-Report (QIDS-SR) [91]. The results of the
scale were immediately discussed with the patient by a clinical social worker, and the decision to refer for further psychiatric intervention was based on the scale score and follow-up interview.
Of 113 patients, 67 patients (59%) did not need referrals as indicated by the above assessment. Of the 46 who were determined to
need referral (including all patients with at least moderate depression), 17 (15%) were already under the care of a mental health professional. Twenty-nine patients (26%) were referred for further
treatment for possible depression. Of these, 17 (56% of 29) refused
to accept information about mental health referral. The most frequently stated reasons for declining referral were:
1. Patients felt that they did not need treatment for depression
and seemed not to recognize that they may be depressed.
2. Patients thought that their current mood problems were related
to an acute, temporary situation.
3. Patients stated they did want to consider taking another
medicine.
4. Patients who scored in the severe and very severe ranges who
refused therapy stated that it had not been helpful in the past.
These specic reasons (that clearly were barriers to treatment)
are very similar to those revealed in the general population, starting with the challenge of the self-awareness of symptoms and the
perception of the need for mental health care. However, the ndings also suggest that patients with epilepsy seem reluctant to
acknowledge the possibility of being depressed. The reasons for
this are unclear, but are likely complex and may include the stigma
of depression, and reluctance to accept the burden of additional
diagnoses and the possibility of further medication treatment. Patients also frequently stated that any current mood problems were
due to an acute situation that may resolve in the foreseeable future, such as undergoing treatment for a brain tumor, recent pregnancy, and family and employment stressors. Because of the
increased risk of depression and suicide in patients with epilepsy,
these ndings indicate that the epilepsy population would benet
from ongoing surveillance and discussion of mood problems and
monitoring of depressive symptoms.
6.3. Barriers to depression treatment in people with epilepsy: Physician
factors
6.3.1. Access to care
There are many economic factors that represent barriers to the
access to mental health services for patients with epilepsy and
depression. These factors include potential lack of health insurance, possible lack of acceptance of insurance by mental health
care practitioners (many of whom understandably are unable to
practice with potentially onerous restrictions imposed by managed
care plans), and a paucity of psychiatrists in various regions of the
country. Some psychiatrists are uncomfortable caring for patients
with concomitant serious neurological disorders like epilepsy; specic, sometimes unfounded fears of managing epilepsy are described below.
Behav (2008), doi:10.1016/j.yebeh.2008.04.005
ARTICLE IN PRESS
9
6.3.2. Fear of lowering the seizure threshold

A common assumption is that all antidepressants (ADs) lower
the seizure threshold. Yet many lines of evidence belie this commonly held dogma. Assessment of the epileptogenic risk of ADs
is confounded by the paucity of controlled AD trials in epilepsy
and the possibility (reminiscent of observations with AEDs) that
lower doses may have more anticonvulsant effects while higher
doses may be proconvulsant (perhaps via antimuscarinic or antihistaminic effects) [92,93]. Furthermore, a seizure that occurs during AD administration, and therefore is presumed to be caused by
the AD, needs to be interpreted with a caveat of recalling spontaneous seizure point incidence rates (often cited as slightly less than
0.1%) [94]. These spontaneous rates are often no different than
the rates associated with some specic ADs. On the other hand,
lack of differences in the mean rates of two populations may belie
individual cases of seizures that appear to be associated with an
AD.
Another confounder is the insufcient quantity of reliable AD
exposure data from either premarketing trials or postmarketing
experience to generate accurate statistics on seizure rates (particularly for such a low-frequency event). Premarketing trials with
their notorious rigid inclusion and exclusion criteria may not be
representative of a more general population. In postmarketing
data, there is immense variability in the nature of the patients,
associated independent comorbid conditions that could give rise
to seizures, lengths of observation, and drug combinations. Many
fears about AD-induced seizures are based on seizures associated
with AD overdoses, which may have little predictive value with respect to the risk of seizures with routine AD dosing [9597]. Other
factors to consider include the nature of possible prior seizures, effects of concomitant agents (both directly on seizure threshold and
through pharmacokinetic effects on the AD), variability in rates of
escalation or nal dose, effects of concomitant conditions, and possible occult illicit substance abuse [93].
Effects on seizure threshold vary among the different ADs, yet
some limited case series describe possible antiepileptic effects of
some ADs such as uoxetine [98] and citalopram [99], although
these studies need to be further replicated. Monoamine oxidase
inhibitors (MAOIs), which are uncommonly used because of the
risk of other adverse effects, are also believed to have antiepileptic
action [100]. The possibility of AD antiepileptic effects is also supported by commonalities in neurochemical effects between ADs
and antiepileptic drugs (AEDs). For example, selective serotonin
reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake
inhibitors (SNRIs) and MAOIs, as well as some antiepileptic treatments (e.g., lamotrigine and vagal nerve stimulation), may work
in part by enhancing norepinephrine concentrations [101]. Similarly, serotonin levels may be increased by the SSRIs as well as
by some AEDs including carbamazepine, lamotrigine, zonisamide,
and valproic acid [102104]. In animal studies, these commonalities are demonstrated in the deciency of norepinephrine in the
highly seizure-prone GEPR-3 rat [105] and the knowledge that
AD therapies are often believed to work through enhancement of
noradrenergic transmission [106108].
Although a detailed review of the estimated seizure risk associated with each of the ADs is beyond the scope of this consensus
statement, a number of general recommendations can be provided.
ADs best avoided in epilepsy include amoxapine [109,110], clomipramine [111113], bupropion [114117], and maprotiline [118
122]. Overall, the SSRIs and SNRIs are associated with low rates
of seizures (usually approximating the rate of spontaneous seizures in the general population) and are considered to be more
optimal than tricyclic antidepressants (TCAs). However, even before the advent of the newer ADs, TCAs were reasonably tolerated
in PWE, particularly when administered in low doses and advanced
very slowly (a principle that should also apply to use of any AD).
6.3.3. Antidepressantantiepileptic drug interactions

Many clinicians are understandably intimidated by the complex
potential drug interactions between ADs and AEDs, possibly leading to a disinclination to treat depression. Although these interactions are complicated, several general principles can help the
clinician manage the pharmacokinetic issues.
One salient principle is the fact that many AEDs and ADs are
metabolized in the liver. This means that either class of drugs is
vulnerable to possible effects of the CYP-450 hepatic enzyme system. Agents in either class may be metabolized by specic isoenzymes, in which case a second agent that induces or inhibits that
isoenzyme can result in reduced (and potential loss of efcacy)
or increased (and possible toxicity) levels of the rst agent. For
example, older-generation enzyme-inducing AEDs (EIAEDs: phenytoin, phenobarbital, primidone, carbamazepine) can lead to reduced levels of some TCAs. Conversely, also, discontinuing an
EIAED previously used in combination with a TCA can increase
TCA levels and even induce toxicity. Alternatively, valproate, an enzyme inhibitor, may inhibit the metabolism of some psychotropic
agents. The effects on specic isoenzymes are summarized in
Table 1. Agents that do not induce or inhibit the CYP isoenzyme
system include levetiracetam, lamotrigine, gabapentin, pregabalin,
tiagabine, and zonisamide. AEDs may also be a substrate for induction or inhibition by psychotropic medications. For example, uoxetine inhibits many isoenzymes and may result in increased
phenytoin and carbamazepine levels. Fluvoxamine inhibits the
CYP1A2, 3A4, 2C9, and 2C19 isoenzymes; it may raise phenytoin
levels. For these reasons, as well as the aforementioned issues related to lowering seizure threshold, many clinicians favor the use
of the specic SSRIs or SNRIs that have little effect on the CYP system, such as citalopram and escitalopram. Pharmacokinetics is also
an important factor in the selection of antiepileptic agents in patients with comorbid depression. In general, many neurologists
are moving toward the use of the newer-generation AEDs, many
of which have a more favorable side effect prole and fewer tendencies toward drug interactions. Additionally, AED psychotropic
properties (extensively discussed in a recent review [123]) should
Table 1
Antiepileptic drug (AED) effects on antidepressants (ADs)
Isoenzyme
CYP1A2
CYP2C19
CYP3A4
CYP2D6
AD
Amitriptyline
Imipramine
Clomipramine
Fluvoxamine
Amitriptyline
Imipramine
Clomipramine
Citalopram
Moclobemide
Amitriptyline
Imipramine
Nortriptyline
Desipramine
Clomipramine
Sertraline
AED Inducer
Phenytoin
Carbamazepine
Phenobarbital
Primidone
Phenytoin
Carbamazepine
Phenobarbital
Primidone
AED inhibitor
None
Felbamate
Topiramate
Oxcarbazepine
Phenytoin
Carbamazepine
Phenobarbital
Primidone
Mildly with
oxcarbazepine
or topiramate
None
Paroxetine
Fluoxetine
Venlafaxine
Mianserin
Nefazodone
Amitriptyline
Clomipramine
Nortriptyline
Imipramine
Desipramine
Trazodone
Maprotiline
None
None
Source. Adapted from Table 4.2 in Kanner AM, Gidal BE. The use of psychotropic
drugs in epilepsy: A review of pharmacokinetic, pharmacodynamic, and safety
issues. In: Ettinger AB, Kanner AM, editors. Psychiatric issues in epilepsy: a practical
guide to diagnosis and treatment. 2nd ed. Philadelphia: Lippincott Williams &
Wilkins; 2007. p. 5166.
Behav (2008), doi:10.1016/j.yebeh.2008.04.005
ARTICLE IN PRESS
10
be strongly considered in selecting an agent given the high rates of

comorbid depression, anxiety, and mood instability in epilepsy. For
example, lamotrigine [124] and vagal nerve stimulation [125] not
only are antiepileptic but may also have favorable effects on mood.
Gabapentin [126] and pregabalin [127] may have anxiolytic effects.
Conversely, agents like phenobarbital [128] and topiramate [129]
may have adverse effects on mood. Levetiracetam [130], although
usually very well tolerated, may exacerbate underlying depression
and anxiety symptoms.
Beyond pharmacokinetic effects, adverse synergistic pharmacodynamic effects (i.e., effects of these agents on the body) should
also be noted. Examples include increased weight gain associated
with the AEDs gabapentin, valproic acid, carbamazepine, and pregabalin and the ADs sertraline and paroxetine. Sexual dysfunction
noted commonly in epilepsy may be exacerbated by EIAEDs (theoretically as a result of induction of metabolism of testosterone) and
most ADs. Serotonin syndrome (described below) has been reported with the combination of carbamazepine and uoxetine
[131], whereas myoclonus has been noted with the mixture of lamotrigine and escitalopram [132].
6.3.4. Antidepressant side effects
Although the neurologist may be inclined to relegate prescribing of ADs to mental health care specialists, in fact, many nonpsychiatric clinicians such as primary care physicians and neurologists
do prescribe antidepressants.
Overall, newer ADs such as the SSRIs are felt to have a much
more favorable safety prole compared with TCAs, especially with
respect to cardiac complications. However, the clinician needs to
be on guard for a number of notable side effects with the SSRIs
[114,133136]. These include the rare serotonin syndrome characterized by transient symptoms of hyperthermia, muscle rigidity,
myoclonus, and altered mental status. Risks for this potentially
fatal syndrome include the combination of SSRIs with a MAOI,
making this combination contraindicated. This kind of interaction
resulting from combination of an SSRI and a TCA is much less common. Concepts of drug interactions discussed earlier also apply
here in which SSRIs (e.g., paroxetine, uoxetine, and, to a lower extent, sertraline) may increase TCA levels (see Section 6).
Other side effects include activation of manic symptoms; therefore, examination for evidence of bipolar symptoms is indicated
before prescribing an AD. Questionnaires such as the Mood Disorder Questionnaire, which efciently screens for bipolar symptoms,
may be useful. Suicidal ideation has been described especially in
youth receiving ADs such as SSRIs [137] (see Section 5). This implies that proper treatment must include a careful system of regular and frequent follow-up with the patient (see Section 6). Other
symptoms described include gastrointestinal upset, insomnia,
and akithesia. Sexual dysfunction in epilepsy, which runs the gamut of decreased libido, difculty attaining orgasm, and disturbances in arousal and ejaculatory function, are well established.
The EIAEDs may exacerbate these symptoms and SSRIs may increase these symptoms further [138]. Although physician and patient alike are often reluctant to raise the issue of sexual
dysfunction, this is another important area that needs to be
followed.
Although the TCAs are less frequently used today in epilepsy, it
is worthwhile reviewing side effects with this class of drugs as well
[134,139141]. Potential adverse effects include sedation or
insomnia, nausea, sexual dysfunction, weight gain, anticholinergic
symptoms (e.g., blurry vision, urinary hesitancy, constipation, and
confusion), cardiac arrhythmias and orthostatic hypotension, tremor and agitation, and potential induction of mania as described
earlier. Especially, in combination with MAOIs, TCAs may induce
sympathomimetic effects.
6.4. Comments
The seriousness of depression and suicide in persons with epilepsy merits ongoing surveillance for mood destabilization, especially in the months after the initial diagnosis and when seizures
are pharmacoresistant. The physician treating the patients epilepsy has a pivotal role in assessing mood disorders and helping
the patient to accept the diagnosis and obtain treatment. Ideally
a nurse or social worker can assist the patient in formulating a plan
of action, solving problems, and accessing community resources.
Addressing a treatment approach for depression in persons with
epilepsy requires recognition of some important general concepts
regarding the patients points of view. Attention to patients
knowledge of mental health conditions and their attitudes toward
treatment is essential in guiding an initial course of treatment.
Many people with mood disorders, including people with epilepsy,
may not be aware that their feelings constitute depression. They do
not attribute their symptoms to a mental health problem, want to
deal with the problems by themselves, or think that the symptoms
will go away. Further, they may not believe that treatment will
help. Younger people with mood disorders express concerns about
embarrassment from using mental health services and fear of
involuntary hospitalization [142].
Patients are more likely to become engaged in their treatment if
they are assisted in formulating a plan of action with specic steps
of where to go and how to access treatment. This assistance should
include such nuts and bolts problem solving to overcome objective barriers as transportation, obtaining funding for treatment,
and nding time for treatment [143].
The risks of using ADs in persons with epilepsy should be
demystied. As discussed, the risk of inducing seizures appears
to be low with the use of the newer-generation ADs. AD and AED
pharmacokinetic interactions are conned primarily to mild to
moderate interactions between the rst-generation SSRIs, TCAs,
and the standard older AEDs. These interactions are less problematic with most of the newer AEDs and more recently marketed ADs
(see Table 1) [144].
Depression in PWE causes signicant misery and risk of suicide.
On the other hand, the treatment of such is relatively low risk and
often effective. Because of the frequent presence of this serious and
eminently treatable condition, neurologists treating persons with
epilepsy should develop a comfort level for assessing the presence
of depression and for initiating AD treatment in depressed patients
with epilepsy, with a plan for follow-up and referral when
appropriate.
7. Mood and anxiety disorder in pediatric epilepsy: Diagnosis
and treatment
This section provides a consensus with guidelines for clinicians
on how to diagnose and treat mood and anxiety disorders in children and adolescents with epilepsy. Described here are the problems involved in making these diagnoses in children, clinical
approaches to address these diagnostic difculties, criteria for psychiatric and psychological referrals of these children, commonly
used diagnostic and screening instruments, and the ndings obtained with these instruments in pediatric epilepsy. After brief review of the multimodal treatments for these disorders in youth
with epilepsy, the psychopharmacological treatment of depression,
anxiety disorders, and bipolar disorder in children with epilepsy is
described. The group consensus underscores that the treatment of
these disorders in children requires the expertise of mental health
professionals, a child psychiatrist for psychopharmacological intervention, and a child psychiatrist, psychologist, or social worker for
the nonpharmacological treatments.
Behav (2008), doi:10.1016/j.yebeh.2008.04.005
ARTICLE IN PRESS
As described in adults with epilepsy, this section of the Consensus Statement focuses on pediatric epilepsy. It provides a consensus on the diagnosis and treatment of mood and anxiety
disorders in children and adolescents with epilepsy. However, unlike adults with epilepsy, only few studies have been conducted on
mood and anxiety disorders in children with epilepsy [145
148,10,149151]. Some of these studies have focused on establishing a DSM-IV diagnosis [145,147,149], whereas others have identied mood and anxiety symptoms in children with epilepsy
[146,148,10,150,151].
Similarly, there have been no double-blind studies on the psychopharmacological treatment of mood and anxiety disorders in
youth with epilepsy. In terms of other treatment modalities, to
date only one open treatment study examined use of cognitivebehavioral therapy (CBT) to prevent development of depression
in adolescents with epilepsy [152]. Therefore, the consensus presented in this section integrates the ndings of diagnostic and
treatment studies of mood and anxiety disorders in children and
adolescents without epilepsy, studies of youth with epilepsy, and
the clinical experience of the authors of this section.
In the rst subsection, diagnostic issues, particularly problems
involved in making a diagnosis of mood and anxiety disorders in
children with epilepsy, how clinicians should approach diagnosis
of these disorders in children, and available diagnostic and screening instruments, are discussed. The subsection concludes with a
schematic presentation (Fig. 1) of guidelines for clinicians on clinically relevant information from parents and children that help
rule in or rule out the diagnoses of mood and anxiety disorder.
In the second subsection, treatment modalities (e.g., psychoeducation, cognitive-behavioral therapy, supportive therapy, family
therapy, psychopharmacological treatment) used to treat mood
and anxiety disorders in children without epilepsy and their application to comorbid affective and anxiety disorders in pediatric epilepsy are discussed. Although clinicians are provided with a
decision tree and guidelines for the psychopharmacological treatment of these disorders in children with epilepsy, the group con-
11
sensus stipulates that treatment of these disorders requires the

expertise of a child psychiatrist. However, input from epileptologists or pediatric neurologists on possible epilepsy-related effects
on the treatment response is essential for optimal care of youth
with these disorders.
7.1. Diagnosis
7.1.1. Diagnostic difculties
Depression and anxiety are common comorbid conditions identied in 1226% of children with epilepsy [147,10,151,153]. More
worrisome are the high suicide [145] and suicidal ideation
[147,10] rates associated with epilepsy and mood disorders in children and adolescents. Unfortunately, mood and anxiety disorders,
like other forms of psychiatric illness, remain underdiagnosed and
undertreated in pediatric epilepsy [154].
Furthermore, the DSM-IV-TR criteria for mood and anxiety disorders are often inadequate to effectively diagnose children with
these disorders [155]. For example, the distinction between episodic depression and a chronic course of dysthymia is less relevant
in the pediatric population. Children also more commonly have a
chronic course of illness, whereas adults may have a more episodic
course.
Additionally, although children infrequently experience true
dysphoria, a key component of major depressive disorder, they suffer from irritability signicantly more often than adults. Recent efforts to describe behaviors, such as explosive mood and outerdirected irritability have led to wider consideration that aggressive and disruptive behavior may represent underlying depression
or bipolar disorder in a pediatric population [156158], as well as
anxiety disorders [159]. The appreciation of irritability as sufcient
mood disruption for meeting requirements for categorization with
major depressive disorder or even bipolar spectrum disorder has
improved our understanding of mood disorder phenomenology
in children [160]. Children with undiagnosed anxiety also can present with irritability and aggressive behavior [159].
Fig. 1. History and examination to rule in/out diagnosis of mood and anxiety disorders in pediatric epsilepsy.
Behav (2008), doi:10.1016/j.yebeh.2008.04.005
ARTICLE IN PRESS
12
In addition to these age-related diagnostic difculties, lack of

knowledge of comorbid mood and anxiety disorders among parents [161] and providers [162,163], together with their focus on
childrens seizure control, contribute to the unmet mental health
needs of these children. Thus, parents might refrain from talking
about their childrens behavior problems with their childs physician (e.g., pediatrician, epileptologist, neurologist) because they regard their childrens emotional or behavioral outbursts as
manifestations of undiagnosed seizures, antiepileptic drug side effects, or the normal frustration of dealing with epilepsy
[164,165].
Despite the many challenges in identifying mood disorder in
children with epilepsy, a cogent, sophisticated, and practical approach helps make these diagnoses in children. The rst step is
to recognize that although depression and anxiety may be common
in youth with epilepsy, they rarely present with the classic
symptoms of these disorders, such as sadness, insomnia, anhedonia, psychomotor retardation, and decreased appetite in depression and overt worrying in generalized anxiety disorder or
overanxious disorder (see Fig. 1). The next step is to determine
whether behaviors consistent with depression or anxiety and their
chronology are related to epilepsy characteristics; psychosocial
stressors involving the family, academics, or social environment;
or normal age-related changes.
7.1.4. Related learning disorders

Learning disorders and academic challenges may complicate
cognitive development [178,179]. The presence of linguistic decits and their relationship to both cognition and social competence
are additional burdens these children face [180,181]. Learning difculties are associated with mood and anxiety disorders in children without epilepsy [182]. In addition, inattentiveness,
distractability, forgetfulness, and suboptimal cognitive performance found in mood and anxiety disorders further limit childrens
academic performance [183185]. As these behaviors might be
misinterpreted as seizures, related changes in AEDs might further
compromise cognition.
Summary. The overall severity of epilepsy and psychosocial
stress, as well as associated learning, linguistic, and social difculties, appears to play a role in the depression and anxiety of children
with epilepsy. Given the complex factors related to mood and anxiety disorders in pediatric epilepsy, to make or rule out these diagnoses, clinicians should take a detailed history and chronology of
changes in the childs behavior and how these might relate to epilepsy-related changes including type, number, and dose of antiepileptic drugs (AEDs); subclinical or unnoticed seizures; parent
coping with the childs epilepsy; parenting; family functioning;
and the childs school performance and social skills (see Fig. 1).
7.2. Diagnostic and screening instruments
7.1.2. Association with epilepsy features

With respect to illness effects, there is a greater understanding
in neuropsychiatry that epilepsy characteristics themselves may
increase the index of suspicion for mood and anxiety disorder
[166]. Thus, the presence of seizure foci in the temporal lobe
may represent a higher risk for the development of depression
and anxiety [167]. However, high rates of anxiety disorders have
been identied in both children with absence seizures [168] and
those with cryptogenic epilepsy with complex partial seizures
and focal temporal or temperofrontal epileptic activity [147].
Although seizure frequency may play a role in the increased behavior problems of children with epilepsy [169], ndings are inconsistent regarding the relationship of mood and anxiety disorders to
seizure variables [147,150,164,170,171].
7.1.3. Role of psychosocial stress
The impact of psychosocial stress on the development of mood
and anxiety disorders in the general population of children [172]
and in pediatric epilepsy cannot be understated [see review in
173]. Within the family, both the child and parents might experience anticipatory anxiety with fear related to having a seizure
and associated loss of consciousness. The unpredictability of seizures may have a wide impact affecting the entire family in terms
of reorganization of interaction styles to accommodate the child
with epilepsy [174]. The child might regress and become more
dependent in response to parental overprotection [see review in
173]. Other family members, particularly mothers [175], may develop depression, have difculties with coping and stress management, and unwittingly convey their anxieties to others in the
family [151].
How parents deal with the unpredictability of seizures can
impact the childs self esteem, coping, and problem solving, factors associated with depression in youth with epilepsy [see review in 176]. Social development is further complicated for
teenagers seeking independence or struggling with medication
adherence issues. Furthermore, stigma remains a challenge for
many patients and their families. More specically, children
and their families may feel isolated, and depressive symptoms
may occur in children who do not feel empowered in their environments [177].
7.2.1. Challenges
In the pediatric neurology ofce setting, the evaluation of mood
and anxiety disorders may be challenging and time consuming,
particularly when engaging children and adolescents in questions
regarding depression or suicidality. However, asking these questions with only the child present and gradually approaching these
sensitive topics constitute an effective strategy. Referral to a child
psychiatrist is recommended if the parent(s) or child describes
behaviors that are signicantly disruptive or self-destructive or involve substance abuse.
7.2.2. Symptoms
To identify irritability, physicians can ask: (1) Do you have a bad
temper? (2) Do you sometimes get mad for no reason? (3) If a little
thing goes wrong, are you bothered by it for a long time?
Sample questions for depressed mood include the following: (1)
Are you as happy as others around you? (2) Do you think that you
have a bright future? (3) Have you ever thought that life was not
worth living?
When probing for anxiety, clinicians can query the patient as
follows: (1) Are you the type of person who worries? (2) What
do you worry about? (3) Is it sometimes so bad that you feel like
you cant sit still? (4) What things are you scared of and do you feel
unsafe? (5) Do you worry and forget what you are worrying about?
7.2.3. Informants
Screening for mood and anxiety disorders involves different
informants (e.g., child, parents, teachers) and instruments (structured psychiatric interviews, self-report instruments, parent or
teacher questionnaires) and identies either DSM-IV mood and
anxiety disorder diagnoses or clinically relevant symptoms of these
mood states or disorders in children [186,187]. In terms of the
informant and type of information, children and adolescents frequently do not share internalizing symptoms, such as depression, anxiety, fears, suicidal ideation, hopelessness, helplessness,
hallucinations, and delusions, with their parents. Alternatively,
parents are a better source when measuring acting out, irritable,
and aggressive behavior with poor judgment in the child or
adolescent.
Behav (2008), doi:10.1016/j.yebeh.2008.04.005
ARTICLE IN PRESS
The informants emotional state, age, and gender also can affect
the type of information provided. For example, parents with a past
history of depression tend to overdiagnose depression in their children [186]. Although anxious parents are more sensitive to the
childs emotions and fears, they might also worry about behaviors
in their children that would otherwise be considered normal. Adolescents are more likely to report depression than children, particularly if they are females [188].
7.2.4. Instruments
As for informants, instruments differ in the type of information
they provide. Thus, structured psychiatric interviews, such as the
Diagnostic Interview Schedule for Children (SCID) [189] and the
Schedule for Affective Disorders and Schizophrenia for SchoolAge ChildrenPresent and Lifetime Version K-SADS-PL [190],
determine a psychiatric diagnosis through information obtained
separately from the child and parent. Other than the Child/Adolescent Inventory [191,192], most self-report, parent, and teacher
instruments [see reviews in 187,193] identify symptoms, such as
depression and anxiety, and provide quantitative scores that are
highly correlated with the presence of the relevant psychiatric
diagnoses. In terms of instrument limitations, structured psychiatric interviews take a long time to administer and require interviewer training, compared with self-report and parent-completed
instruments. Self-report instruments cannot be used with children
under age 8 and/or with a reading age below third grade (e.g., dyslexia, developmental disabilities).
7.2.5. Screening instrument ndings in pediatric epilepsy
Community studies using the self-report Childrens Depression
Inventory [194] found depression in 25% of adolescents with epilepsy [164], 26% of 7- to 18-year-old epilepsy youth [10], youth
with epilepsy with mild mental retardation [146] scores, as well
as more depression in 12- to 18-year-olds than in 9- to 11-yearolds with epilepsy [150]. Structured psychiatric interviews identify
depression and anxiety disorder diagnoses in 33% and suicidal ideation in 20% of children with epilepsy [147]. Epidemiological studies using structured psychiatric interviews and parent
questionnaires describe increased risk for depression and suicide
in patients with new-onset seizures aged 10 and older [195], as
well as increased emotional problems (akin to depression and anxiety disorders) in youth with epilepsy compared with youth with
chronic illness and normal children [196]. Similar to the general
population of youth with depression and anxiety disorders
[188,197], there is more depression in adolescent girls with epilepsy [164] and anxiety disorders in young children with epilepsy
[147,150].
According to a recent sensitivity and specicity study of two
self-report instruments, the Childrens Depression Inventory
(CDI) [194] and the Multidimensional Anxiety Scale for Children
(MASC) [198] scores as well as the anxiety/depression factor score
of the parent Child Behavior Checklist (CBCL) [199], together correctly identied 87.5% of children with epilepsy who had structured interview-based depression and/or anxiety disorder
diagnoses [200]. They also correctly classied 91.7% of those without these diagnoses. These ndings in a large sample of 87 children
with epilepsy and 40 normal children suggest that these instruments could be used to screen for these diagnoses in children with
epilepsy. To date, there have been no studies evaluating instruments to screen for bipolar disorder in youth with epilepsy.
13
disorders, including substance use [201203]. Treatment should,

therefore, be started as soon as these disorders are recognized,
and continued until clinical symptoms fully resolve. However,
there are no evidence-based data on treatment efcacy and safety
in children with epilepsy with comorbid mood and anxiety disorders, as these children are typically excluded from all double-blind,
placebo-controlled pharmacological and psychotherapy treatment
studies. Therefore, the treatment described in this section integrates principles contained in the American Academy of Child
and Adolescent Psychiatry (AACAP) practice parameters (PP): The
Assessment and Treatment of Children and Adolescents with Anxiety, Depression, and Bipolar Disorders with specic features of
epilepsy and AED treatment, http://www.aacap.org/galleries/PracticeParameters/JAACAP_Anxiety_2007. pdf, P-Dep: http://www.aacap.org/galleries/PracticeParameters/InPress_2007_DepressiveDisorders.pdf, and [204]). The PP for the assessment and treatment of
depression recommends acute, continuation, and maintenance
treatment phases. Each treatment phase must incorporate psychoeducational, supportive, family, and school interventions (see
Fig. 2).
7.3.2. Psychoeducation
This intervention for pediatric epilepsy should increase parental
knowledge about pediatric mood disorders, as well as about epilepsy, AEDs, associated learning difculties, and stigma. Increased
knowledge can enhance parental awareness and recognition of
mood disorders in their children, and decrease parental anxiety.
It also improves childrens behaviors, competence, coping skills,
independence, sense of mastery, and perceived quality of life
[205208].
In addition, open discussion of how children perceive the stigma associated with epilepsy may improve their adjustment to
the illness by preventing the negative impact on their self-esteem,
avoidance of age-appropriate normal activities, and social isolation
[148,209,210]. Furthermore, such discussion may decrease parental fear of stigma, improve the associated lower parental expectations from their children, and decrease the limitations they set
on their childrens normal developmental activities [211].
7.3.3. Supportive therapy
This type of intervention helps children adjust to both their epilepsy and mood disorder, improve their problem-solving and coping skills, and ensure treatment compliance. To achieve these
goals, supportive treatment should address illness-related negative
feelings [212], secretive feelings about epilepsy, and feelings of
shame related to epilepsy, all of which are more common in
pediatric epilepsy than in other pediatric chronic illnesses
[164,213].
7.3. Treatment
7.3.4. Cognitive-behavioral therapy and interpersonal psychotherapy

Cognitive-behavioral therapy (CBT) and interpersonal psychotherapy (ITP) are equally effective as supportive therapy in children with mild depression, but superior to this treatment
modality when patients have more severe depression with hopelessness and suicidality [214]. Based on the PP, both psychotherapy
(e.g., CBT or ITP) and pharmacological treatment are required for
moderate to severe depression and anxiety. There is evidence that
in comparison to supportive therapy, CBT signicantly reduces
symptoms of depression in adolescents with epilepsy [152]. Children with epilepsy and depression or anxiety disorders who require psychotherapy should be referred to child and adolescent
psychiatrists, psychologists, or social workers.
7.3.1. Overview
Pediatric mood disorders have high relapse rates, continue into
adulthood, and are often comorbid with other psychiatric
7.3.5. Family therapy

Increased problems in the families of children with epilepsy
compared with children with chronic illnesses [177,215] include
Behav (2008), doi:10.1016/j.yebeh.2008.04.005
ARTICLE IN PRESS
14
Fig. 2. Treatment of mood and anxiety disorders in pediatric epsilepsy: decision tree.
poor organization of the family environment and family adaptation

to illness, overcontrolling parenting style, reduced parental support of the child, and maternal depression [see review in 173].
Though there are no data on family therapy for children with epilepsy, family involvement should be an essential treatment component, particularly in those children with mood disorders.
Behav (2008), doi:10.1016/j.yebeh.2008.04.005
ARTICLE IN PRESS
7.3.6. School interventions

Accommodations in the school are important given the high
rate of subtle to more severe learning difculties in children with
epilepsy [see review in 173]. Although children with epilepsy can
receive special education services under the Other Health Impaired
disability category, those with mood disorders may receive additional services through the Emotional Disturbance disability category [216].
7.3.7. Pharmacological treatment (Fig. 2)
7.3.7.1. Depression and anxiety disorders. Prior to initiating psychopharmacological treatment for mood disorders in children with
epilepsy, it is important to obtain a detailed history to determine
if the childs mood symptoms reect AED withdrawal (e.g., lamotrigine, valproic acid, carbamazepine), high doses of AED polytherapy, or use of AEDs with known behavioral side effects in
patients with a history of mood or anxiety disorders. Changing
the AED, adjusting AED doses, or crossing over to an AED with
mood-stabilizing properties is recommended in these cases.
Clinicians should also establish if the child has a past history of
a psychiatric diagnosis and treatment and the response to
treatment.
Selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs). SSRIs are rst-line drugs in
the treatment of depression and anxiety in children and include
uoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), uvoxamine (Luvox), citalopram (Celexa), and escitalopram (Lexapro).
Second-line ADs, mixed receptor agents, or SSNRIs, such as venlafaxine hydrochloride (Effexor), mirtazapine (Remeron), and duloxetine hydrochloride (Cymbalta), are not recommended for the
initiation of treatment of mood disorders in children because of
the lack of randomized, controlled pediatric studies. However,
these drugs may be helpful in older adolescents and those with
resistant depression.
Although both SSRIs and SNRIs are metabolized in liver via
CYP450 enzymes, about 5 to 10% of children are slow metabolizers. In these children a single medication dose may lead to 10- to
15- time higher plasma concentrations and drugdrug interactions
with AEDs even after discontinuing medications, such as uoxetine, because the active metabolites have a longer half-life than
the parent compound [217].
Tricyclic antidepressants and bupropion (Wellbutrin). These medications are not recommended for use in children with epilepsy because of the potential increased seizure risk. Additionally, these
drugs have anticholinergic side effects, a high risk for a lethal overdose, and a lack of clinical efcacy compared with placebo [218].
Dosing, drugdrug interactions, side effects, and FDA approval. For
detailed information on dosing, drugdrug interactions, and side
effects of the previously described medications used for depression
and anxiety disorders, please refer to the Physicians Desk Reference,
http://www.pdr.net (accessed November 2007). The following
antidepressants have FDA approval for use in the treatment of
pediatric mood disorders (http://www.fda.gov/medwatch/index.html): uoxetine in major depressive disorder in children
above age 8 and in obsessivecompulsive disorder (OCD) in those
over age 7; sertraline in children with OCD older than 6; and uvoxamine in patients older than 8 with this diagnosis [219]. Evidence-based data and clinical experience in adults guide the use
of other ADs in children.
In 2004, the FDA issued a Black Box warning regarding a twofold increased risk of suicidal thinking and behaviors in children
during the rst months of AD treatment together with AD monitoring guidelines [220,221]. These guidelines mandate weekly faceto-face visits during the rst month of treatment, with documentation of the patients mood, sleep, activation, suicidality, side effects,
and treatment response. Once the patient is stable, the frequency
15
of subsequent visits can be decreased to every 2 weeks for the following 2 months. An FDA-approved medication guide must be distributed to families when an AD is prescribed for children. Patients
with a family history of bipolar disorder should be monitored for
mania or mixed mood state (P-Dep). Medication guidelines
are available at www.fda.gov/cder/Ofces/ODS/medication_
guides.htm-03-04-2008.
A recent meta-analysis of 27 randomized, placebo-controlled
antidepressant trials [222] revealed increased risk of spontaneously reported suicidal thinking and attempts for drugs versus placebo (0.7%; 95% CI; 0.1% to 1.3%) but no statistically signicant
pooled risk differences within each indication. The authors conclude that second-generation AD treatment provides greater benet than the risks from suicidality. The single efcacy and safety
study of SSRIs conducted to date in pediatric epilepsy found that,
other than gastrointestinal symptoms and rash, uoxetine and sertraline are both safe and effective treatments for depression in
these children [223].
7.3.7.2. Bipolar disorder. The AACAP practice parameters for bipolar
disorder list as a minimal standard three recommendations for
treatment [204]. Children and adolescents with mania require
pharmacotherapy; patients on medication must have monitoring
of vital signs, glucose, and lipids; and psychotherapy is an essential
component of therapy.
See Section 6 for guidelines on treatment of bipolar disorder in
adults with epilepsy. As there are currently no double-blind, placebo-controlled trials of psychotropic medications for bipolar disorder in children with epilepsy, decisions on medication should
be based on efcacy in children and adolescents without epilepsy,
with modications made because of the presence of seizures. Risperidone has been approved for adolescents with bipolar disorder,
and double-blind trials have demonstrated the effectiveness of
lithium, divalproex, and quetiapine for adolescents with bipolar
disorder [224,225]. Studies in adults have resulted in approval of
the atypical antipsychotics olanzapine, ziprasidone, and aripiprazole, as well as the mood stabilizer lamotrigine, for the treatment of
bipolar disorder.
A retrospective review found that lamotrigine, divalproex,
carbamazepine, and oxcarbazepine improved symptoms of
bipolar disorder and reduced seizure frequency in pediatric patients [226]. Two case series found that risperidone could be
safely used in pediatric patients with epilepsy [227,228]. Clozapine and chlorpromazine should be avoided because of their
known potential to precipitate seizures. Lithium may increase
seizure frequency and should not be considered a rst-line
agent in children or adolescents with epilepsy and bipolar
disorder.
8. Treatment of mood disorders in adults with epilepsy

The Consensus Group has agreed on the recommendations presented in this section. As in the reviews presented so far, unipolar
depression is the focus, with a short segment on bipolar affective
disorder, its recognition, and its treatment.
This section covers the following:
1. A brief review of the expected course of an idiopathic depressive disorder and its usual response to treatment.
2. A review of current data on the response of depressive disorders
in PWE to AD intervention. Data are sparse on the phenomenology, longitudinal course, and treatment response of PWE and a
comorbid depressive disorder. Thus, information obtained from
the psychiatric literature referring to patients with an idiopathic depression is relied on.
Behav (2008), doi:10.1016/j.yebeh.2008.04.005
ARTICLE IN PRESS
16
3. Review of sequential treatment algorithms in patients with an

idiopathic depressive disorder with the hope that information
from these studies can be used as a guide to intervention in
PWE and a mood disorder.
4. Recommended steps for the identication of a mood disorder,
initial treatment, longitudinal evaluation, and response to intervention and treatment resistance in PWE. The goals of therapy
are symptom recognition, remission, and return to complete
psychosocial functioning with prevention of relapse [229].
Pharmacotherapeutic interventions are recommended on the
basis of evidence of utility, safety, and tolerance.
5. Special circumstances.
8.1. What is the natural history of idiopathic depressive disorders and

their response to antidepressants?
Mood disorders are relapsing and remitting and episodic in
nature. In up to 50 to 80%, a rst episode of depression will be
followed by another [230]. In the epilepsy population, longitudinal data are not available, but in other central nervous system
diseases like strokes, multiple sclerosis, Parkinsons disease, and
Huntingtons disease, a long-term course is anticipated [231
234].
In patents with an idiopathic depressive disorder, the initial response to an AD intervention is in the range of 50 to 65% [235
237]. However, in most successful AD trials, a cutoff score of
P50% improvement in depressive symptoms on a validated psychometric instrument is used as a dependent variable. Residual
symptoms may therefore exist, and these can have important
consequences.
Relapse in major depressive disorder (MDD) symptoms was
evaluated by Judd et al. [238] as a function of the presence of residual symptoms. Of the 96 patients investigated, those with residual
symptoms (N = 26) relapsed almost ve times earlier than the
asymptomatic group. Similar studies completed by Paykel [239]
and Miller [240] and their colleagues conrmed these observations
(see Fig. 3). Judd et al. [238] analyzed several studies performed
over 15 years and concluded, it is only when patients with MDD
are completely symptom free that psychosocial function returns
to good or very good levels. . .. There is strong evidence during
the long-term course of illness that major, minor, dysthymic, and
subsyndromal symptoms wax and wane within the same patient. . .. MDD is dimensional, not categorical, in nature. And nally, abatement of subsyndromal symptoms is of fundamental
Proportion of Patients Relapsing After Remission

With residual symptoms
Without residual symptoms
Proportion Relapsed
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
1
10
11
12
13
14
15
Months
Paykel ES, et al. Psychol Med. 1995;25:1171-1180. Reprinted with the permission of
Cambridge University Press.
Fig. 3. Proportion of patients relapsing after remission. From Paykel ES, et al. Psychol Med 1995;25:117180. Reprinted with the permission of Cambridge University Press.
importance (p. 696) and at least 8 weeks or more of symptom

freedom is necessary to conclude that a patient has achieved full
remission.
8.2. Nonpharmacological and combination interventions
There exist evidence-based data substantiating the clinical efcacy of CBT and interpersonal psychotherapeutic approaches in patients with idiopathic depressive disorders [241]. The response
rates of different forms of psychotherapy have been reviewed by
Hollen et al. [242].
In an NIMH Collaborative Research Program for Depression,
these interventions were compared with pharmacotherapy, with
all techniques showing equal efcacy [241]. Medication interventions had greater utility for people demonstrating more severe
depressive symptoms. In addition, the use of combinations has included the use of pharmacotherapy and psychotherapy. In a study
by Keller et al. [243], nefazodone was evaluated alone and in conjunction with the cognitive-behavioral analysis system of psychotherapy (CBAS) in people with a chronic depressive disorder. The
response rate was 55% with medication, 52% with psychotherapy,
and 85% with a combination. In addition, Fava et al. used CBT as
an add-on for residual symptoms after the use of an AD and found
fewer relapses; the effect was noted for up to 4 years of observation [244].
8.3. Nonpharmacological interventions in people with epilepsy
In PWE and depression, CBT has been used successfully in a controlled study by Davis et al. [245] and also for PWE and social phobia [246]. Two studies are currently underway evaluating CBT in
the treatment of PWE and depression. The rst compares CBT
and sertraline, and the second, group CBT therapy versus a wait-list
control. Results of both studies are pending. Finally, couples and
family therapy may be of use to help ameliorate communication
difculties and relationship issues in the families of PWE [246].
8.4. Pharmacological interventions in people with epilepsy
Given the frequency and severity of depression in this population, it is surprising that there is such a lack of information on
the effectiveness of ADs in PWE and an MDD. Available studies in
this population are reviewed here with a focus on depression
amelioration.
Robertson and Trimble [247] completed the only double-blind
trial in PWE and an MDD. In this study, amitriptyline and nomifensine were compared with placebo in a 6-week study. Notably, subtherapeutic dosages of amitriptyline (75 mg/day) were used. In the
rst 6 weeks of the study, no differences were noted between
groups; however, all patients improved. In the second 6 weeks,
the placebo group was dropped and medication nonresponders
had their drug dosage doubled. Amitriptyline serum levels were
in the low therapeutic range. Six of thirteen patients were
responders, but with Hamilton Depression Rating Scale (HAMD)
item scores decreased only slightly from 20 to 17 and BDI scores
similarly marginally decreased from 24 to 20. Again, depressive
symptoms persisted. The nomifensine arm faired better, with a decrease in scores by the end of the study to a HAMD of 10 and a
mean BDI of 15. However, nomifensine is no longer approved by
the FDA because of a high incidence of hemolytic anemia [248].
Ojemann et al. completed two studies [249,250] that appeared
to show that ADs can reduce depressive symptoms and may also
result in improved seizure control. The rst study evaluated the
effectiveness of the TCA doxepine in dosages ranging from 10 to
500 mg/day (mean = 161 mg/day) to treat 19 depressed patients
evaluated via DSM criteria (15 patients had chronic depression
Behav (2008), doi:10.1016/j.yebeh.2008.04.005
ARTICLE IN PRESS
and it is unclear whether they met criteria for an MDD). In 83%,

depressive symptoms improved and there appeared to be a possible causal link between seizure improvement (seen in 72%, with
greater than 50% improvement witnessed in half the patients)
and a decline in depressive symptoms, but this effect was not statistically signicant. No psychometric tools were used to determine clinical response.
In the second study, the records of 59 patients were evaluated,
40 of whom had an MDD. Again, seizure improvement (53%) was
found in conjunction with an 86% improvement in psychiatric
symptoms. Data on 59 patients were presented, but no psychiatric
descriptions were provided. A mild to excellent response in 51 participants was reported.
Two studies have evaluated the effectiveness of citalopram in
the treatment of MDD in PWE. In the rst, Havorka et al. [251] entered 43 patients into their study if they had a Hamilton HAMD
score P15. Subjects were given 20 mg/day. Mean scores were
21.5 2.9 (range = 1729) at baseline, 14.4 2.9 (range = 1019)
after 4 weeks, and 9.9 3.1 (range = 419) after 8 weeks
(P < 0.001). There was a >50% decline in the HAMD score in 65.1%
[251]. How many patients continued to have scores in the depressed range is unclear from the study data, and it is important
to note that the therapeutic range for citalopram is usually 20
60 mg/day. There was no change in seizure frequency in comparisons made for the 2 months before the treatment started.
In a second investigation, Specchio et al. [252] treated 39 patients with 20 mg/day citalopram. The authors used the The Montgomerysberg Depression Rating Scale (MADRS), and a score P20
was required to enter the study. It should be noted that with the
MADRS, a score P25 is considered indicative of at least a moderate
depression, a score of 15 is consistent with a mild depression,
and a score of 7 is considered to indicate remission. Patients began
with a mean score of 26 4.9 and nished with a mean score of
15.3 7.1 at the conclusion of the study. As noted previously,
although it appears that a clinical effect was observed here, patients were still generally mildly depressed and would be expected
to more quickly relapse compared with those more aggressively
treated for a longer period. Generally, seizure frequency improved
in the study patients.
Khn et al. [253] prospectively evaluated 123 inpatients with
TLE and a diagnosis of an MDD meeting DSM-IV criteria in a post
hoc analysis. To be included in the study, patients had to have a
HAMD score >15. They received either mirtazepine (N = 27) with
a mean endpoint dosage of 32.2 mg/day (SD = 6.8) or citalopram
(N = 33) 24.2 mg/day (SD = 8.3) or reboxetine (N = 15) 6.9 mg/day.
Again, dosages used were low in comparison with those for the
treatment of patients with an idiopathic depression, for which mirtazepine dosages ranged from 15 to 45 mg/day, and reboxetine,
from 8 to 10 mg/day. Response was dened as P50% reduction
in HAMD scores. In the mirtazepine group, 51.9 responded; in
the citalopram group, 36.9%; and in the reboxetine group, 53.9%.
Remission rates were noted in this study and were dened as a
HAMD score 610. With use of this criterion, remission rates were
14.8% for the mirtazepine, 21.8% for the citalopram, and 20.0% for
the reboxetine group [253]. As is discussed later, these rates are
low compared with those for sequentially investigated treatment
paradigms like the Sequenced Treatment Alternatives to Relieve
Depression (STAR*D) investigation.
In another evaluation by Kanner et al. [8], 97 patients with a
depressive disorder were evaluated. According to DSM-IV criteria,
26 had an MDD but the other 69 had varying symptoms of a
depressive illness. They were all treated with sertraline, and 54%
experienced a complete response. As the study was designed to
investigate the safety of the drug, no further data involving treatment response were available. Six patients experienced an increase
17
in seizure frequency, but for only one patient was there a denite
causal relationship to sertraline as dened by the authors.
The investigations reviewed so far have dealt with depressive
disorders dened in the context of a DSM criterion. Blumer et al.
[254] have conceptualized depression in PWE in a different fashion, considering it a mixture of affective and somatoform symptoms. Their case studies have revealed a high response rate to
the TCA imipramine, often in low doses. Resistance was found in
15%, and double antidepressants; the combination of a TCA and
SSRI (paroxetine or uoxetine) was used or an atypical neuroleptic
was added on [250,255]. Drug interactions with these combinations need to be recognized [256]. These data contrast with the
1030% nonresponse rates seen in patients with idiopathic MDD,
for whom much more intensive intervention regimens, such as
those reviewed later, are used.
8.5. Data from patients with an idiopathic depressive disorder: A
review of sequential steps of interventions and algorithms
There is clearly a paucity of information to guide the practitioner in the appropriate treatment of PWE and an mood disorder.
Most studies are nonrandomized and without control group comparisons. The response of PWE to AD treatment appears to be similar to that of patients with an idiopathic depression. Levels of
treatment resistance and longitudinal response rates can be made
on only a speculative basis, however. If there is a biological commonality between the depression seen in PWE and idiopathic
depressive disorders as noted by several authors [231
233,108,257260] and possibly conrmed by the similar rates of
rst response to AD, then extrapolating information from the psychiatric literature would seem to be valid. There have been two
large-scale reviews of these issues in psychiatric populations. The
rst, the Texas Medication Algorithm Project (TMAP) [261,262],
was followed by the Sequenced Treatment Alternatives to Relieve
Depression (STAR*D) investigation.
The development of these algorithms has been based on the
observation that treatment as usual (TAU) does not produce as
good an outcome as a guidelines approach [263267]. There is a
gap between what is considered best practice and the actual delivery of care [268], with patients often underdosed (only two-fths
receive an adequate dose ), one-third stopping medication in the
rst month, and many patients receiving inadequate follow-up.
In past studies, Katon et al. found that using a treatment algorithm
improved response (74% vs 44%) [263] and overall patient satisfaction [269].
The goal of the TMAP study was to determine if algorithmguided treatment (ALGO) for patients provided with clinician
support and patient education resulted in better clinical and economic outcomes than TAU. In this study there were few patient
exclusions in an attempt to imitate the usual clinical situations
[261,267,270]. Not only was there a signicant difference in
the paradigms in the rst quarter of treatment, but the differences continued over time. From the TMAP study, algorithmbased treatment appears to offer a substantial improvement over
TAU. Although all patients improved in the study, the ALGO
group had signicantly greater improvements in the primary
outcome measure, the Inventory of Depressive Symptomatology
Clinician-Rated Scale (ICS-C30), and the secondary measure, the
30-item Inventory of Depressive Symptomatology Self-Report.
In addition, the 12-item Short Form Health Survey (SF-12) revealed signicantly more improvement in the ALGO group than
the TAU group [269]. More than 60% of the group had concurrent medical illnesses [271]. The next question is what treatment
should be used, and that question was addressed in the STAR*D
investigation.
Behav (2008), doi:10.1016/j.yebeh.2008.04.005
ARTICLE IN PRESS
18
There are three basic strategies in the treatment of treatmentresistant depression (TRD): (1) optimizing the dose when there is
a partial response, (2) augmenting or combining therapies, (3)
switching ADs [272]. Augmentation strategies that have some support in the literature include switching from one SSRI to an SNRI
with a resultant response rate of between 30 and 60%; however,
when patients switched from one SSRI to another SSRI, the response was 4050%. Switching one TCA to another TCA led to a
poorer response [273,274]. The initial use of certain agents, that
is, use of a dual-acting agent like venlafaxine instead of an SSRI
[275], addition of mirtazepine to an SSRI regimen [276], or the
use of mirtazepine alone [277], has been associated with a better
response. The use of specic agents for targeted symptoms, for
example, mirtazepine [278] or benzodiazepines for sleep [279]
and anxiety [280], duloxetine for associated pain [281], and venlafaxine [282] for somatic symptoms [283], has also been demonstrated to be of some use.
Combination therapy may be synergistically effective. This may
be the result of genetic idiosyncrasies in individual patients, with
dual-acting agents having perhaps a greater probability of positive
interactions in differing serotonin receptor sites [283]. For example, the serotonin 2A receptor is encoded by HTR2A, which is
downregulated by citalopram. In the genetic predictors of response
in the STAR*D investigation, it was found that those patients
homozygous for the A allele had a greater likelihood of response
than those patients homozygous for the allele [267,284]. Adverse
effects may also be associated with the serotonin transporter gene
[285], with treatment-emergent suicidal ideation also related to
common polymorphisms [286].
STAR*D (refer to Fig. 4) [267] was designed to study the utility
of a variety of prospectively evaluated interventions to treat nonpsychotic MDD after a failed rst attempt with an SSRI, in this case,
citalopram. The drug was used for a 14 weeks of therapy at a maximum dose of 60 mg/day (level 1) [287]. With intolerance of the
medication or a lack of efcacy, patients were eligible for randomization to any of four options. Patients were allowed to choose
from differing option strategies, but not for specic medication
interventions. Cognitive therapy was included as an option. Each
higher step in the algorithm included medication frequently used
for treatment resistant depression (TRD) but with the trade-off of
possibly greater side effects. Exclusion criteria were few, and each
level lasted 12 weeks. STAR*D tried to imitate the types of issues
facing clinicians in the real world, as generalizable as possible to
what happens in the clinicians ofce. Responders at any level
would enter a 12-month follow-up period.
The STAR*D investigation involved 3671 patients with an
MDD. Of this group, two-thirds had a recurrent depression and
Fig. 4. Sequenced Treatment Alternatives to Relieve Depression (STAR*D) algorithm. Reprinted with permission from Rush and co-workers [287].
nearly as many had a family history of depression, with onefourth of the group having symptoms for more than 2 years.
The age at the rst episode of depression was low at a mean of
25.5 years, and a third of the patient population had at least
one comorbid psychiatric condition. Anxiety disorders were seen
in 44.6% of the group. These depressive features would be harbingers of a poor response rate.
The remission rate was 36.8% at step 1, 30.6% at step 2, 13.7% at
step 3, and 13.0% at step 4, with intolerable side effects increasing
in each step from 16.3% to 19.5, 25.6, and 30.1%, respectively [271].
The theoretical overall remission rate would therefore be 67%
assuming no dropouts. Importantly, however, when pooled rates
of patients followed over time were evaluated, only 43% sustained
a remission [288]. The times to remission were 5.4 to 7.4 weeks in
all groups, emphasizing the fact that more time may be required
before we deem a treatment ineffective. As each group was not
randomized, and there were signicant differences between the
augmentation and switch groups, these different interventions
cannot be compared validly [271].
Because the rst two steps in the STAR*D protocol involve medications for which we have evidence of utility in PWE, these steps
are evaluated further. Step 1 involves 2876 patients, 80% of whom
had a chronic or recurrent MDD with a high degree of psychiatric
and medical comorbidity (with nearly two-thirds having a concurrent medical illness). The mean citalopram dosage was 48.3 mg/
day (note the contrast with the aforementioned studies involving
PWE with 21.4 mg/day as an average dose). The mean time to
remission was 6.7 weeks, and 56% of the patients responded only
at or after 8 weeks. Patients were followed closely and were seen
at 2,4, 6, 9, and 12 weeks [289].
Results from step 2 indicate that bupropion-SR (not recommended in PWE), sertraline, and venlafaxine-XR, when used in patients who did not respond favorably to citalopram therapy,
elicited similar rates of response, with about one-fourth achieving
remission. Augmentation of citalopram with bupropion-SR or
buspirone resulted in remission in approximately one-third of patients [290]. Comparing cognitive therapy with pharmacotherapy
was difcult because less than a third of patients allowed randomization to CBT therapy. However, comparison of the data revealed
that CBT and pharmacotherapy elicited similar rates of response,
with medication having a more rapid effect than interventions
using CBT, but the latter having fewer side effects [291]. Augmentation with either lithium or thyroid showed an overall remission
rate of 20.5%, with lithium effective in only 14.5% vs. thyroid in
25.7% with less side-effects in the latter group [292]. A comparison
of mirtazepine or nortriptyline following the failure of two monotherapy trials resulted in a poor remission rate of 12.3% versus
19.8% for QIDS-SR16 [293]. Responses to tranylcypromine versus
venlafaxine-XR plus mirtazepine were low and not signicantly
different at 6.9 and 13.7%, respectively, and a relapse rate of nearly
50% was noted in this group [294].
Caveats from this study include not stopping a vigorously dosed
intervention after 6 weeks. If a modest improvement is noted:
maximize the dose and wait for up to 10 to 12 weeks. Patients preferred to augment if they had minimal intolerance and some response in prior steps. However, with a marginal response and/or
intolerance, a switch in ADs was more popular. From the STAR*D
protocol, the evaluation of initial augmentation as a rst step could
not be ascertained; however, it does have some theoretical benets
from a genetic standpoint as discussed previously.
CBT elicited a response rate equal to that of pharmacotherapy
but was chosen by few. The issue of convenience may be operative
here and may be particularly important in a population like PWE,
who often have transportation issues. The tolerability and mild
efcacy of mirtazepine and venlafaxine-XR as an option for the
refractory group need to be noted as well. The attrition rate was
Behav (2008), doi:10.1016/j.yebeh.2008.04.005
ARTICLE IN PRESS
substantial regardless of the fact that free care was being offered
[271].
8.6. Recommendations
Given these results, what can be recommended for PWE and a
unipolar depressive disorder?
8.6.1. Step 1: Identication of a mood disorder
8.6.1.1. Depression. As discussed by Kanner, ALL PWE should be
screened for an MDD. The Neurological Disorders Depression
Inventory for Epilepsy (NDDI-E) can be used to screen for depression. Patients with an NDDI-E score >15 should proceed to step 2
[295]. In addition, asking the patient about anhedonia is a superb
marker for the presence of a depressive disorder and is often
impervious to the negative psychotropic effects of drugs and the
illnesses they treat. It can also give the practitioner a barometer
of the intensity of the mood disorder as well [296]. In addition, asking the patient about suicidal ideation or intent at this and at any
of the steps noted below is critically important given the frequency
of suicide in PWE. At that point, psychiatric referral may be
indicated.
8.6.1.2. Bipolar disorder. The Mood Disorders Questionnaire (MDQ)
is a reasonable screening tool for bipolar affective disorder (BAD).
On the MDQ, a score of P7 mood elevation items, with symptoms
being concurrent and causing at least moderate problems, is suggestive of a bipolar mood disorder. The MDQ had a specicity of
0.90 and a sensitivity of 0.73 when used in the psychiatric clinic
setting by Hirschfeld et al. in the diagnosis of bipolar spectrum disorders. Thus a score of P7 mood elevation items might indicate the
need for evaluation by a psychiatrist consultant for recommendations of treatment [297]. As an alternative to evaluation via the
MDQ, symptoms of BAD can be assessed by separately reviewing
the items noted in the review by Kanner and colleagues [295]. In
addition, asking patients whether they or any family members
(1) have been diagnosed with bipolar disorder or manic depression
and (2) have had unexpected reactions to ADs (worsening of
depression or transition into mood elevation) is also worthwhile
and may point to the need for a psychiatric consultation.
The following comments refer to PWE and a unipolar depressive
disorder.
8.6.2. Step 2: Further evaluation
8.6.2.1. Beck Depression Inventory II. At this point, a conrmatory
psychometric tool like the BDI-II can be used. It was validated
for use in PWE in a study by Jones et al. and can be employed
to follow the longitudinal response of patients to psychiatric
intervention [298]. A score >11 had a sensitivity of 0.957 and
a specicity of 0.783 for the presence of an MDD. Generally, a
score of 1117 on the BDI-II is considered to be associated with
a mild depression; however, in PWE, it may trigger concern over
a dysthymic-like disorder of epilepsy, which in itself can be
associated with a decline in quality of life and may warrant
treatment. Some authors have recommended that scores on the
BDI-II greater than 18 indicate the presence of a DSM-III-R mood
disorder [299]. At this point, the symptoms noted by Kanner and
co-workers [295] should be reviewed and the presence or absence of an MDD determined.
8.6.2.2. Adverse Events Prole. AED side effects should be evaluated
using the Adverse Events Prole as discussed by Gilliam et al.
[300].
8.6.2.3. Further evaluation: Postictal, iatrogenic factors. If the BDI-II is
elevated (P18) and an MDD is present, further evaluation is re-
19
quired. Remember that the BDI does not provide a diagnosis of

MDD only an indication of the degree of depression. A word of caution: Although psychometric tools are useful it is important to
evaluate the patient individually. A patient who feels his or her
quality of life is compromised by depression may warrant treatment even though the BDI-II is below the cutoff noted above. In
addition, several items on the BDI-II refer to changes in the
way the person may feel, for example, I do not enjoy things as
much as I used to and I am much more irritable than I used to
be. In several studies by one of the authors (J.J.B.), PWE answer
negatively to these items because they are irritable all the time
and there has been no signicant change in their complaints.
As in any area of medicine, careful observation and attention to
the patient are of more importance than a psychometric tool.
As discussed by Kanner and Balabanov, depressive symptoms
should be assessed in their relation to an ictal event and the postictal period. In addition, association of the advent of depression
with the recent introduction of a new medication should be assessed [231]. Iatrogenic depressive symptoms associated with an
AED may respond to a medication change. If it is not advisable to
change the offending AED, then the introduction of an AD can be
considered. In the study by Kanner et al. [8], 28 of the 97 patients
evaluated experienced iatrogenic depression, and in 46.7% of these
patients, a positive response to the introduction of sertraline was
noted. When depression is associated with the introduction of an
effective AED when other medication choices are not available or
advisable, the use of an AD is reasonable in the authors opinion.
However, few data are available to guide the practitioner.
8.6.2.4. Mild depression and/or dysthymic symptoms. If depressive
symptoms are mild, that is, they do not meet criteria for an
MDD, and a switch in AED is contemplated, then use of an AED
with positive psychotropic properties, like lamotrigine, can be considered. The effects of lamotrigine in PWE and depression have
been discussed elsewhere [301,302].
8.6.3. Step 3: Psychosocial evaluation and psychotherapy options
8.6.3.1. Psychosocial issues. Psychosocial issues may be a primary
instigator of a comorbid mood disorder [303306]. These should
be evaluated, and if salient, an intervention targeted to ameliorating these issues needs to be considered.
8.6.3.2. Psychotherapy options. At this point, the utility of psychotherapeutic intervention needs to be assessed. Several forms of
psychotherapy can be used including family, couples, group, and
individual work therapy [307]. As noted in the STAR*D study, patient preferences may be an important issue here and alternatives
need to be discussed [291].
8.6.4. Step 4: Psychoeducation
8.6.4.1. Further history and review of target symptoms. The treatment options available should be discussed. If medications are considered, target symptoms, medication options, past history of
personal and family AD use and response, potential medication
interventions and side effects, and cost should be discussed. Answers to these questions may color the choice of AD. For example,
an AD that worked in the past, given the genetic issues discussed
previously, should probably be chosen again, except if there were
tolerance issues. Assessment of personal history should also involve a family history of depressive disorders, previous personal
episodes of depression, including onset and longitudinal course,
history of child abuse and neglect, and external locus of control
[304,305,308]. These are all harbingers of a poorer response to
treatment. Additionally, given the genetic issues discussed previously, an AD that was successful for a family member may be
useful.
Behav (2008), doi:10.1016/j.yebeh.2008.04.005
ARTICLE IN PRESS
Involvement of family, if possible, is recommended, especially

to evaluate postictal states and mood vacillations. How long medications will be used for acute response and for relapse protection
should be discussed, as should follow up and emergency appointments and depression exacerbation potential and response. If medications are considered, then we proceed to the next step.
8.6.5. Step 5: Pharmacotherapeutic intervention
8.6.5.1. An SSRI. As noted in [256], rapid dose escalation may be
associated with an increased seizure risk. Therefore, starting with
the lowest dose formulation is recommended, and available formulations can even be split. A gradual dose increase at 2-week intervals is appropriate, except in the case of more severe symptoms. If
a more rapid dose increase is considered, closer observation is recommended and may take place in an inpatient setting.
As noted previously, factors involved in the choice of AD should
include drug interactions, past history of response or lack thereof
to a particular AD, as well as family history of AD usage. Although
ADs are often considered equal in efcacy, subtypes of depression
probably respond differently to AD usage but specic head-to-head
information is lacking. Those ADs with complex neurotransmitter
activity may elicit more complete responses than SSRIs (as noted
below), but are perhaps more complex to use. Additionally, there
is evidence for targeting symptoms like pain (use an SNRI), atypical
features (MAOI or SSRI), gender (women are more responsive to
SSRIs), other psychiatric comorbidity (kill two birds with one
stone), and melancholic features (TCA, SNRI, or mirtazepine)
[309]. In addition, cost is a factor: SSRIs, especially generics (citalopram, uoxetine, paroxetine, sertraline: $58$84 per month for the
lowest daily dosage), are less costly than SNRIs (duloxetine/venlafaxine: $108$104 per month for comparable dosage); a month
supply of mirtazapine costs $62 [310].
In light of all these factors, in usual outpatient settings, initiating treatment with a 5-mg dosage of escitalopram and increasing
to 10 mg in 1 week is recommended. A response of at least 20%
should be observed in the rst week or two after a full therapeutic
dosage is reached (as noted in STAR*D, this may be up to 60 mg/
day citalopram). Kennedy noted that this is a good harbinger of a
full clinical response in 6 to 12 weeks [237]. As found in STAR*D,
an aggressive dose intervention should be implemented with a
trial of up to 10 weeks as a goal of treatment before determining
that there has been a lack of response. Alternatively, with steady
improvement, waiting until a plateau is reached with subsequent
follow-up is reasonable. If an optimal response is not obtained,
then a dosage increase should ensue. The diagnosis and its treatment should be reappraised if there is no or only a partial response.
If subsyndromal symptoms of depression persist, more aggressive
action is warranted [238,256].
8.6.5.3. Tricyclic antidepressants. As noted by Blumer and colleagues

previously [254,255,314], TCAs can also be used, but serum levels
of the drug, as well as potential drug interactions, must be assessed
[256]. Mirtazapine, a monotherapy alternative, can be used, and its
effectiveness in this population was reported by Khn et al. [253].
8.6.5.4. Phases of treatment: Acute, continuation, and maintenance. As noted in Fig. 5, the acute phase of depression treatment
lasts from the establishment of an effective dosage of the AD to the
6 to 12 weeks subsequent to it, when full clinical response is expected. The patient should be watched carefully during this period
for increasing depression and suicidal ideation. Contact is recommended with the patient at 2, 4, 6, 8, and 12 weeks, as employed
in the STAR*D protocol. The frequency of contact encourages continuation of treatment and allows a quick response to side effects
including increased suicidal ideation and tolerance issues. It is
preferable that these contacts are in person with the physician or
a health care professional working with the epilepsy service. From
a practical standpoint, patients may be contacted by a nurse practitioner by phone if necessary.
The acute phase of treatment usually lasts from 6 to 12 weeks,
and it is during this time that full clinical response is expected with
the aim of the remission of symptoms. Subsequent to this is a continuation period, lasting from 4 to 9 months during which time
treatment is required to prevent relapse. Maintenance therapy
may be required for many patients given the probability of relapse
of up to 85%. Long-term treatment is recommended for patients
with three or more depressive events, a particularly severe episode, continued residual symptoms, suicidality, or psychosis [230].
The dosage of medication should be kept the same depending
on tolerability issues. If a medication is being discontinued and another started, an overlap and taper [229] strategy should be used.
There needs to be ongoing evaluation of psychosocial issues.
Drug withdrawal syndrome. A drug withdrawal syndrome may
result from abrupt discontinuation of a short-acting SSRI or SNRI
with the acute onset of dizziness, nausea, fatigue, sweating,
insomnia, vivid dreams, and psychological symptoms like agitation, impulsivity, depersonalization, and neurological complaints
(i.e., paresthesias, dyskinesias). Symptoms usually occur 17 days
after stopping the drug and last 7 to 14 days, but may last for up
to 3 weeks or months. SSRIs with a short half-life, for example, paroxetine (21 hours), in contrast to uoxetine (72144 hours), are
Phases of Treatment for Depression

Remission
Recovery
Relapse
Normalcy
Response
ssi
der
on
r
iso
gre
D
To
Syndromes
Recurrence
Relapse
Pro
8.6.5.2. An alternative: SNRI. An alternative to the SSRI citalopram

or escitalopram is the SNRI venlafaxine. The more complex neurotransmitter activity of the drug may be responsible for the higher
remission rates than obtained with SSRIs [256,311]. Venlafaxine
may take effect faster than uoxetine as well [311] and may have
a wider spectrum of activity than SSRIs, for example, somatic
depressive symptoms [312]. However, venlafaxine requires more
dosing changes, which may be difcult for cognitively impaired
PWE. It also has signicant withdrawal symptoms [313]. The XR
preparation of venlafaxine should be used and can be ingested
once a day. It can be started at 37.5 mg/day and increased to
75 mg/day if no response is noted in 1 to 2 weeks. The dose can
be increased in 37.5 mg/day increments to 150 mg/day and, if no
response is elicited, escalated to a maximum of 375 mg/day if necessary [256]. There have been anecdotal reports of the safety and
efcacy of venlafaxine in dosages from 75 to 225 mg/day without
an increase in seizure frequency [231]. Lethargy, irritability, and
the induction of hypertension are the side effects observed [313].

Blood pressure elevations associated with the drug are usually
seen at higher dosages, that is, 3% at <100 mg/day and 13% at
>300 mg/day [313]. The SNRI duloxetine can also be used.
Severity of symptoms
20
Syndrome
Treatment Phases
Acute
(6-12 wks)
Continuation
(4-9 mos)
Maintenance
(1 or more yrs)
Time
Adapted from Kupfer DJ. J Clin Psychiatry. 1991;52(suppl 5):28-34.
Fig. 5. Phases of treatment for depression. Adapted from Kupfer DJ. J Clin Psychiatry
1991;52(Suppl. 5):2834. (see Ref. [315]).
Behav (2008), doi:10.1016/j.yebeh.2008.04.005
ARTICLE IN PRESS
more often associated with withdrawal syndrome. Treatment consists of reintroduction of the SSRI or SNRI with a more gradual taper, usually 25% per week [256,313].
Drug tolerance. Tolerance may develop during the course of
treatment [316]. Tolerance is often called tachyphylaxis or breakthrough depression, and may be seen in 9 to 33% of patients. Neurotransmitter accommodation or increased disease severity may be
causative. In the sertraline study by Kanner et al. [8] discussed earlier, of the 97 PWE treated, 14 developed tolerance, with 5 of the
patients responding to a medication change to paroxetine at a dosage of 20 mg/day [256].
Inadequate response. Inadequate patient response to an initial
AD should cause the neurologist to consider psychiatric consultation. The diagnosis and any complicating concomitant pharmacological side effects (especially of AEDs), comorbid medical
conditions, and substance abuse issues may need to be evaluated.
Also, side effects of the AD need to be reviewed and compliance assessed [237,308,317]. Medication changes should be based on lack
of efcacy, poor tolerability, and safety of the drug.
8.6.6. Step 6: Resistance to antidepressants
Patients who do not respond to an initial treatment regimen pose
a particular problem. At this point, the neurologist can institute a
second intervention. Alternatively, a referral to a psychiatrist can
be made, especially one associated with an epilepsy clinic. According to STAR*D, a switch to another SSRI or a dual-acting agent like
venlafaxine or mirtazepine may be implemented in the event of
treatment resistance. The decision may be inuenced by secondary
symptoms: if sleep or weight loss is a salient issue, mirtazepine may
be considered, whereas if pain or somatic symptoms are considerable, venlafaxine may be a good choice. CBT is also an alternative,
alone or in conjunction with an AD. Blumer has noted the utility of
double antidepressants in patients resistant to medication [255].
If treatment resistance continues, then several options are available. Extrapolation from STAR*D would seem to advocate the augmentation of an SNRI with thyroid, mirtazepine, and/or cognitive
therapy. Augmentation strategies have also been discussed
[256,308]. An MAOI like tranylcypromine could be used after 2
weeks of AD washout, but it appears that the yield may be low.
8.6.7. Step 7: Electroconvulsive therapy
Continued treatment resistance and/or an increased level of
acuity and suicidality, especially when associated with psychotic
symptoms, should prompt consideration of electroconvulsive therapy (ECT) [318]. ECT can be used safely in PWE and depression and
raises the seizure threshold considerably over the course of treatment [319]. The utility of ECT in PWE and refractory depressive
disorders and with status epilepticus has been documented elsewhere [320322]. In a recent review, 43 PWE were treated with
ECT. The procedure was found to be safe, and adequate seizure
induction was obtained. Eventual AED dosage reduction was
needed in some cases. There was a moderate to marked improvement in psychiatric symptoms [323]. In another review, there
was no evidence of kindling as manifest in the de novo occurrence
of epilepsy in 166 ECT-treated patients [324].
Unilateral ECT may be initiated without a change in AEDs [319].
Bilateral treatments may be used for lack of response or excessive
elevation of seizure threshold precluding the effectiveness of unilateral treatments. AED dosage may need to be reduced and the
lowest therapeutic serum levels followed as treatments continue
[325]. AEDs should be withheld the morning of therapy except if
there is a high risk of status epilepticus [319].
8.6.8. Step 8: Other considerations
8.6.8.1. Other augmentation strategies. So far, the discussion of augmentation interventions has focused on data gleaned from the
21
STAR*D protocol. However, there are ample data on the utility of

several other augmentation strategies.
Atypical antipsychotics are 5HT1a and partial dopamine agonists
as well as 5HT2 receptor antagonists. They have been used for mood
disorders in people with bipolar affective disorder (BAD) and also
those with unipolar depression. In fact, aripiprazole is the rst agent
in this category to receive FDA approval for adjunctive intervention
for unipolar depression. Olanzepine and quetiapine are also being
evaluated for the same purpose ([326]. Use of these medications in
PWE has been reviewed elsewhere [327].
Psychostimulants like amphetamines, methylphenidate, and
pramipexole have also been used as augmenters for depression
treatment, as has modanil. Studies conrming their utility have
been reviewed by DeBattista [328]. Use of stimulants in PWE has
been reviewed elsewhere [327].
Additionally, the use of gonadal and adrenal steroids as augmentation factors for the treatment of iatrogenic depressive disorder has been reviewed elsewhere [329]. Estrogen has been used as
monotherapy or as an adjunct, especially in perimenopausal women, and testosterone has been used in hypogonadal men, but
the results have been inconsistent and more data are needed given
the side effect proles. Dehydroepiandrosterone (DHEA) has also
been studied for use in the treatment of depression by Wolkowitz
et al. [330] with positive results. These issues have been discussed
for PWE by Herzog [331333] and Morrell et al. [138].
Finally, repetitive transcranial magnetic stimulation (rTMS) has
also been evaluated as an adjunctive therapy in the treatment of
resistant depression. Results have been mixed to date [334,335],
with two recent randomized, controlled trials showing negative results [336,337].
The presence of continued depressive symptoms may warrant
other treatment considerations. Vagal nerve stimulators have
been implanted in more than 40,000 patients with refractory seizures. Seizure reduction may be seen in 40% of patients and
P75% reduction of seizure activity in 20% of patients with refractory epilepsy [338]. Rush et al. evaluated the device for the treatment of refractory MDD or bipolar I disorder (depressive phase)
and reported a 40% response rate, that is, a P50% reduction from
baseline in scores on the 28-item Hamilton Depression Rating
Scale and the Clinical Global Impressions-Improvement Index
and a 50% reduction in MontgomeryAsberg Depression Rating
Scale scores [256,339,340]. One hundred thirty-ve patients with
refractory depression who had failed at least two but not more
than six adequate treatment trials were entered and a sham control was used. After 10 weeks, HRSD-24 scores indicated a nonstatistically signicant response. Note that responses on a secondary measure, the Inventory of Depressive Symptomatology SelfReport (IDS-SR 30), were 17.0% for the active group and 7.3%
for the sham group (P = 0.032, LOCF) [341]. When the vagal nerve
stimulation (VNS) groups long-term outcome was compared with
that of a TAU group in another study, after 1 year, the VNS and
TAU groups had response rates of 27 and 13%, respectively
(P < 0.011) [342]. On this basis, VNS was approved for the
adjunctive long-term treatment of chronic or recurrent depression in patients 18 years of age or older who are experiencing a
major depressive episode and have not had an adequate response
to four or more adequate antidepressant treatments (FDA
Announcement, 2006).
The aforementioned stepwise algorithm is summarized in Fig. 6.
8.7. Special situations
8.7.1. Treatment of depression associated with bipolar affective
disorder
The depressive phase of a bipolar disorder is treated differently
than unipolar depression. The treatment of the depressive phase of
Behav (2008), doi:10.1016/j.yebeh.2008.04.005
ARTICLE IN PRESS
22
Proposed Algorithm: Stages of Medical Therapy
Stage 1: MonotherapySSRI (eg, citalopram, escitalopram), venlafaxine, or mirtazapine and/or CBT
Partial response or nonresponse
possible augmentation agents
Stage 2: Monotherapyswitch to another SSRI, TCA, venlafaxine, or mirtazapine
Stage 3: MonotherapySSRI, TCA, venlafaxine, mirtazapine, or MAOIfrom a class

other than that used in stage 1 or 2; or combined antidepressantsTCA + SSRI, TCA +
venlafaxine or mirtazapine, venlafaxine and mirtazepine
Stage 4: Combined antidepressantsTCA + SSRI, TCA + venlafaxine or mirtazapine or venlafaxine

and mirtazepine
Stage 5: ECT
TCA = tricyclic antidepressant; MAOI = monoamine oxidase inhibitor;

SSRI = selective serotonin reuptake inhibitors.
Adapted from Crismon ML, et al. J Clin Psychiatry. 1999;60(suppl 3):16-20.
Fig. 6. Proposed algorithm: stages of medical therapy. CBT, cognitive-behavioral therapy; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; MAOI,
monoamine oxidase inhibitor; ECT, electroconvulsive therapy. Adapted from Crismon ML, et al. J Clin Psychiatry 1999;60(Suppl. 3):1620.
BAD with an AD without a mood-stabilizing agent runs the risk of

pushing the patient into the manic phase of the illness and changing the appearance of the disorder, that is, cycle acceleration [343].
First-line therapies include FDA-approved agents (quetiapine or
the combination of olanzapine and uoxetine). However, in view
of tolerability limitations (e.g., sedation and weight gain), an
important alternative is lamotrigine, which is approved for bipolar
maintenance, particularly for preventing depressive episodes, and
there are some controlled data suggesting its utility in acute bipolar depression. Aside from the risk of serious rash, it is generally
very well tolerated. In view of lamotrigines lack of acute antimanic
and only limited mania prevention effects, this agent is commonly
administered with another drug with more robust antimanic effects, such as lithium or divalproex, although the latter doubles
lamotrigine blood concentrations, requiring downward adjustment
of the lamotrigine dose. A commonly used older approach, which,
unfortunately, has only limited supporting systematic data, is rst
to administer a mood stabilizer alone and then to add an antidepressant if necessary. The management of bipolar depression is
sufciently complex that algorithms can be of substantial utility.
An algorithm for the treatment of acute depressive illness in BAD
and for maintenance therapy has recently been presented as part
of an update of the Texas Implementation of Medication Algorithm
(TIMA) [229].
For an acute depressive exacerbation of BAD with a history of

a severe or recent manic episode, an antimanic agent plus lamotrigine is recommended in TIMA. Otherwise, lamotrigine can be
used alone. In the event of a lack of response, quetiapine or an
olanzapine plus uoxetine combination can be used. Subsequently, an antimanic agent combined with an AD like an SSRI,
venlafaxine, bupropion (not in PWE), or eventually ECT can also
be used. Lamotrigine (LTG) appears to be adequate for maintenance therapy in patients without a recent or history of severe
mania; otherwise it is combined with an antimanic agent. Further information on overall recommendations can be obtained
elsewhere [229].
Lithium has a signicant wealth of literature supporting its
utility as an antimanic agent, but is less effective for symptoms
of dysphoria or mixed states or rapid cycling [229,344,345]. Lithium has been associated with encephalopathy, especially when
used in combination with carbamazepine [346,347]. Lithium
has been considered to be proconvulsant, but has, however, been
used safely in studies by Shukla et al. [348] and Lyketsos
et al.[349].
The AEDs divalproex, carbamazepine, and, to a much lesser
extent, oxcarbazepine have proven efcacy for manic symptoms. The atypical antipsychotics (olanzapine, quetiapine, risperidone, aripiprazole, ziprasidone) are also considered
Behav (2008), doi:10.1016/j.yebeh.2008.04.005
ARTICLE IN PRESS
effective antimanic drugs with less potential, compared with

older antipsychotics, to cause tardive dyskinesia and extrapyramidal reactions [350]. Olanzapine, quetiapine, and risperidone
have been associated with weight gain and metabolic syndrome, including diabetes, hyperlipidemia, and hypercholesterolemia, whereas aripiprazole and ziprasidone can cause
akathisia [229]. Like all dopamine blockers, these agents may
lower seizure threshold. This issue has been reviewed elsewhere [351].
8.7.2. Psychosis
In the physicians initial assessment of depression, the presence
of a psychotic component to an interictal depression must be recognized. The presence of psychotic features may increase the
lethality of the depression as a harbinger of eventual suicide
[352]. Delusional depression may be unique neurobiologically
from an uncomplicated affective disorder and respond differently
to ADs as well. Generally, an AD should be combined with an antipsychotic agent, usually an atypical agent [317]. As noted previously, ECT remains the treatment of choice for this presentation
of an affective disorder, especially in the event of severe symptoms
and suicidality. Tardive diskinesia needs to be assessed in this population with the use of typical and atypical neuroleptics, as it appears to occur more frequently in patients with mood disorders
than in schizophrenic patients being treated with antipsychotics
[317].
8.7.3. Geriatric population
As a result of comorbid medical conditions like cerebrovascular
disease, degenerative disease, and trauma, epilepsy has become
one of the most common neurological disorders in the geriatric
population [353]. In addition, depressive disorders have become
increasingly prevalent in this population, being seen in nearly
6.5% and accounting for 18% of the suicides in the U.S. population
[307,354]. Age-related metabolic changes can alter AD pharmacokinetics and pharmacodynamics. These include an increase in fat
storage, which increases the half-life of lipophilic ADs; an up to
50% decrease in glomerular ltation rate by age 70 [355]; hepatic
changes; and decreased gastrointestinal absorption. Polypharmacy
and drugdrug interactions and overall neurotransmitter and neuronal loss may also impinge on the response to pharmacotherapy
[356].
Comorbid conditions need to be evaluated; medications like
TCAs should be avoided in patients with cardiac conduction defects
and Alzheimers disease because of anticholinergic effects. Generally, the SSRIs and the SNRI venlafaxine, noted previously, can be
used at one-half the usual starting dose and maintained for 2 years
or longer with a frequent or severe episode. Please refer to [357] for
more information.
8.8. Conclusion
This section has focused on treatment options in PWE and a
mood disorder, with a focus on unipolar depression. Data available for the treatment of mood disorders in PWE have been reviewed but unfortunately are sparse. As a result, information
from psychiatric studies on people with idiopathic depressive
disorders has been used as a template for the recommendation
of a stepwise approach to treatment of PWE and a mood disorder. Special circumstances have also been reviewed including
those involving bipolar affective disorder, psychotic depression,
and mood disorders in the geriatric population. It is hoped that
this Consensus Statement will be an easy-to-use reference that
will help in the recognition and treatment of mood disorders
in PWE.
23
9. Future research: Unanswered questions

This review has presented current concepts in the recognition
and treatment of affective disorders in PWE. Unfortunately there
are a myriad of unanswered questions that require future research.
For example, is the depressive disorder in PWE different phenomenologically from that observed in people with an idiopathic
depression? Certainly, some features are the same and, when severe, meet criteria for a mood disorder. However, the presence of
an irritative central nervous system focus responsible for a localization-related epilepsy may be responsible for features of depression that are discrepant from what is seen in psychiatric patients.
The most salient example of this is the postictal phenomenon discussed previously. Pathophysiologically, deciencies in norepinephrine and serotonin may be similar in both disorders, along
with structural changes in hippocampus and amygdala and regions
of hypometabolism discussed previously, but further investigation
is needed. In the area of cognition, the comorbidity of depression
and epilepsy pose many questions. What is the association between depression and cognition in PWE? Is it remediable with
treatment? What are the underlying pathological factors? What
is the role of cortisol, brain-derived neurotropic factor, etc.? Finally, what is the longitudinal appearance of depression in PWE? Is it
the same as observed in people with an idiopathic depressive disorder? What are the risk factors, including age, gender, family history, seizure focus, epilepsy syndrome, post-anterior temporal lobe
resection, and overall response to treatment? Many questions remain, but the presence of some uncertainty about treatment does
not excuse the lack of detection and treatment that exists today. It
is hoped that this Consensus Statement will help to dene current
knowledge of these issues and catalyze further investigation to
help answer many of these important questions.
Acknowledgments
The Consensus Statement was developed by the Mood Disorder
Advisory Group of the Epilepsy Foundation as part of its Mood Disorder Initiative. The Foundation expresses its deep appreciation to
all advisory group members and experts who further contributed
to the Consensus Statement. The Epilepsy Foundation also gratefully acknowledges the support of Cyberonics, Inc. for the Mood
Disorder Initiative.
References
[1] Evans DL, Charney DS. Mood disorders and medical illness: a major public
health problem [editorial]. Biol Psychiatry 2003;54:17780.
[2] Michaud CM, Murray CJ, Bloom BR. Burden of disease: implications for future
research. JAMA 2001;285:5359.
[3] Katon WJ. Clinical and health services relationships between major
depression, depressive symptoms, and general medical illness. Biol
Psychiatry 2003;54:21626.
[4] Tellez-Zenteno JF, Patten SB, Jett N, Williams J, Wiebe S. Psychiatric
comorbidity in epilepsy: A population-based analysis. Epilepsia
2007;48(12):233644.
[5] Jacoby A, Baker GA, Steen N, et al. The clinical course of epilepsy and its
psychosocial correlates: ndings from a U.K. Community study. Epilepsia
1996;37:14861.
[6] ODonoghue MF, Goodridge DM, Redhead K, et al. Assessing the psychosocial
consequences of epilepsy: a community-based study. Br J Gen Pract
1999;49:2114.
[7] Edeh J, Toone B. Relationship between interictal psychopathology and the
type of epilepsy: results of a survey in general practice. Br J Psychiatry
1987;151:95101.
[8] Kanner AM, Kozak AM, Frey M. The use of sertraline in patients with epilepsy:
is it safe? Epilepsy Behav 2000;1:1005.
[9] Wiegartz P, Seidenberg M, Woodard A, et al. Co-morbid psychiatric disorder
in chronic epilepsy: recognition and etiology of depression. Neurology
1999;53(Suppl. 2):S38.
[10] Ettinger AB, Weisbrot DM, Nolan EE, et al. Symptoms of depression and
anxiety in pediatric epilepsy patients. Epilepsia 1998;39:5959.
Behav (2008), doi:10.1016/j.yebeh.2008.04.005
ARTICLE IN PRESS
24
[11] Gilliam FG, Santos J, Vahle V, Carter J, Brown K, Hecimovic H. Depression in

epilepsy: ignoring clinical expression of neuronal network dysfunction?
Epilepsia 2004;45(Suppl. 2):2833.
[12] Kimiskidis VK, Triantafyllou NI, Kararizou E, et al. Depression and anxiety in
epilepsy: the association with demographic and seizure-related variables.
Ann Gen Psychiatry 2007;6:28.
[13] Ettinger AB, Reed M, Cramer J, for the Epilepsy Impact Project Group.
Depression and co-morbidity in community-based patients with epilepsy or
asthma. Neurology 2004;63:100814.
[14] Gilliam F, Kanner AM. The treatment of depression in epilepsy. Epilepsy
Behav 2002;3:6.
[15] Jones JE, Watson R, Sheth J, Caplan R, Koehn M, Seidenberg M, Hermann B.
Psychiatric comorbidity in patients with epilepsy. Dev Med Child Neurol
2007;49:4937.
[16] Forsgren L, Nystrom L. An incident case referent study of epileptic seizures in
adults. Epilepsy Res 1990;6:6681.
[17] Hesdorffer DC, Hauser WA, Annegers JF, et al. Major depression is a risk factor
for seizures in older adults. Ann Neurol 2000;47:2469.
[18] Hesdorffer DC, Hauser WA, Olafsson E, Ludvigsson P, Kjartansson O.
Depression and suicidal attempt as risk factor for incidental unprovoked
seizures. Ann Neurol 2006;59:3541.
[19] Gilliam F, Kuzniecky R, Faught E, et al. Patient-validated content of epilepsyspecic quality-of-life measurement. Epilepsia 1997;38:2336.
[20] Cramer JA, Blum D, Fanning K, Reed M, for the Epilepsy Impact Project Group.
The impact of comorbid depression on health resource utilization in a
community sample of people with epilepsy. Epilepsy Behav 2004;5:33742.
[21] Cramer JA, Blum D, Reed M, et al. The inuence of comorbid depression on
quality of life for people with epilepsy. Epilepsy Behav 2003;4(3):51521.
[22] Kanner AM, Gilliam FG, Barry J, Hermann B, Meador KJ. Differential impact of
mood and anxiety disorders on the quality of life and perception of adverse
events to antiepileptic drugs in patients with epilepsy. In: Abstracts from the
2007 Annual Meeting of the American Epilepsy Society. Epilepsia
2007;48(s6).
[23] Program 1.283, Abstract Viewer. Philadelphia: American Epilepsy Society;
2007.
[24] Hitiris N, Mohanraj R, Norrie J, Sills GJ, Brodie MJ. Predictors of
pharmacoresistant epilepsy. Epilepsy Res 2007;75:1926.
[25] Kanner AM, Byrne R, Smith MC, Balabanov A, Frey M. Does a lifetime history
of depression predict a worse postsurgical seizure outcome following a
temporal lobectomy [abstract]? Ann Neurol 2006;60(S10):19.
[26] Diagnostic and Statistical Manual of Mental DisordersFourth Edition. Text
Revised. Washington, DC: American Psychiatric Press; 2000.
[27] Barraclough B. Suicide and epilepsy. In: Reynolds EH, Trimble MR, editors.
Epilepsy and psychiatry. Edinburgh: Churchill Livingstone; 1981. p. 726.
[28] Robertson MM. Suicide, parasuicide, and epilepsy. In: Engel J, Pedley TA,
editors. Epilepsy: a comprehensive textbook. Philadelphia: LippincottRaven;
1997. p. 214151.
[29] Rafnsson V, Olafsson E, Hauser WA, et al. Cause-specic mortality in adults
with unprovoked seizures: a population-based incidence cohort study.
Neuroepidemiology 2001;20:2326.
[30] Nilsson L, Tomson T, Farahmand BY, et al. Cause-specic mortality in
epilepsy: a cohort study of more than 9,000 patients once hospitalized for
epilepsy. Epilepsia 1997;38:10628.
[31] Christensen J, Vestergaard M, Mortensen PB, Sidenius P, Agerbo E. Epilepsy
and risk of suicide: a population-based casecontrol study. Lancet Neurol
2007;6:6667.
[32] Kanner AM, Soto A, Gross-Kanner H. Prevalence and clinical characteristics of
postictal
psychiatric
symptoms
in
partial
epilepsy.
Neurology
2004;62:70813.
[33] Blanchet P, Frommer GP. Mood change preceding epileptic seizures. J Nerv
Ment Dis 1986;174:4716.
[34] Daly D. Ictal affect. Am J Psychol 1958;115:97108.
[35] Kraepelin E. Psychiatrie, vol. 3. Leipzig: Johann Ambrosius Barth; 1923.
[36] Bleuler E. Lehrbuch der Psychiatrie. 8th ed. Berlin: Springer; 1949.
[37] Gastaut H, Roger J, Lesvre N. Diffrenciation psychologique des pileptiques
en fonction des formes lectrocliniques de leur maladie. Rev Psychol Appl
1953;3:23749.
[38] Blumer D, Altshuler LL. Affective disorders. In: Engel J, Pedley TA, editors.
Epilepsy: a comprehensive textbook, vol. II. Philadelphia: LippincottRaven;
1998. p. 208399.
[39] Kanner AM, Wuu J, Barry J, Hermann B, Meador KJ, Gilliam F. Atypical
depressive episodes in epilepsy: a study of their clinical characteristics and
impact on quality of life. Neurology 2004;62(Suppl. 5):A249.
[40] Mendez MF, Cummings J, Benson D, et al. Depression in epilepsy: signicance
and phenomenology. Arch Neurol 1986;43:76670.
[41] Collaborative Group for Epidemiology of Epilepsy. Reactions to
antiepileptic drugs: a multicenter survey of clinical practice. Epilepsia
1986;27:32330.
[42] McConnell H, Duncan D. Treatment of psychiatric comorbidity in epilepsy. In:
McConnell
H,
Snyder
P,
editors.
Psychiatric
comorbidity
in
epilepsy. Washington, DC: American Psychiatric Press; 1998. p. 245.
[43] Brent D, Crumrine P, Varma R. Phenobarbital treatment and major depressive
disorder in children with epilepsy. Pediatrics 1987;80:90917.
[44] Ferrari N, Barabas G, Matthews W. Psychological and behavioral disturbance
among epileptic children treated with barbiturate anticonvulsants. Am J
Psychol 1983;140:1123.
[45] Smith D, Collins J. Behavioral effects of carbamazepine, phenobarbital,

phenytoin and primidone. Epilepsia 1987;28:598.
[46] Barabas G, Matthews W. Barbiturate anticonvulsants as a cause of severe
depression. Pediatrics 1988;82:2845.
[47] Ring H, Reynolds E. Vigabatrin and behavior disturbance. Lancet
1990;335:970.
[48] McConnell H, Synder PJ, Duffy JD, et al. Neuropsychiatric side effects related
to treatment with felbamate. J Neuropsychiatry Clin Neurosci
1996;8(3):3416.
[49] Kanner AM, Faught E, French J, et al. Psychiatric adverse events caused by
topiramate and lamotrigine: a postmarketing prevalence and risk factor
study. Epilepsia 2000;41(Suppl. 7):169.
[50] Gilliam FG, Barry JJ, Meador KJ, Hermann BP, Vahle V, Kanner AM. Rapid
detection of major depression in epilepsy: a multicenter study. Lancet Neurol
2006;5:399405.
[51] Jones JE, Hermann BP, Woodard JL, et al. Screening for major depression in
epilepsy with common self-report depression inventories. Epilepsia
2005;46:7315.
[52] Ettinger AB, Reed ML, Goldberg JF, Hirschfeld RM. Prevalence of bipolar
symptoms in epilepsy vs other chronic health disorders. Neurology
2005;65:53540.
[53] Kanner AM, Weisbrot D. Psychiatric assessment of the epileptic patient: a
non-psychiatrist perspective. In: Ettinger A, Kanner AM, editors. Psychiatric
issues
in
epilepsy:
a
practical
guide
to
diagnosis
and
treatment. Philadelphia: Lippincott Williams & Wilkins; 2007. p. 11932.
[54] Hermann BP, Trenerry MR, Colligan RC. Learned helplessness, attributional
style, and depression in epilepsy. Bozeman Epilepsy Surgery Consortium.
Epilepsia 1996;37:6806.
[55] Quiske A, Helmstaedter C, Lux S, Elger CE. Depression in patients with
temporal lobe epilepsy is related to mesial temporal sclerosis. Epilepsy Res
2000;39:1215.
[56] Mula M, Trimble MR, Sander JWAS. The role of hippocampal sclerosis in
topiramate-related depression and cognitive decits in people with epilepsy.
Epilepsia 2003;44:15737.
[57] Mula M, Sander JW, Trimble MR. The role of hippocampal sclerosis in
antiepileptic drug-related depression in patients with epilepsy: a study on
levetiracetam. Seizure 2006;15:4058.
[58] Briellmann RS, Hopwood MJ, Jackson GD. Major depression in temporal lobe
epilepsy with hippocampal sclerosis: clinical and imaging correlates. J Neurol
Neurosurg Psychiatry 2007;78:122630.
[59] Richardson EJ, Grifth HR, Martin RC, et al. Structural and functional
neuroimaging correlates of depression in temporal lobe epilepsy. Epilepsy
Behav 2007;10:2429.
[60] Bromeld EB, Altshuler L, Leiderman DB, et al. Cerebral metabolism
and depression in patients with complex partial seizures [published
erratum appears in Arch Neurol 1992;49:976]. Arch Neurol
1992;49:61723.
[61] Salzberg M, Taher T, Davie M, et al. Depression in temporal lobe epilepsy
surgery patients: an FDG-PET study. Epilepsia 2006;47:212530.
[62] Victoroff JI, Benson F, Grafton ST, Engel Jr J, Mazziotta JC. Depression in
complex partial seizures. electroencephalography and cerebral metabolic
correlates. Arch Neurol 1994;51:15563.
[63] Gilliam FG, Santos J, Vahle V, Carter J, Brown K, Hecimovic H. Depression in
epilepsy: ignoring clinical expression of neuronal network dysfunction?
Epilepsia 2004;45(s2):2833.
[64] Gilliam FG, Maton BM, Martin RC, et al. Hippocampal 1H-MRSI correlates
with severity of depression symptoms in temporal lobe epilepsy. Neurology
2007;68:3648.
[65] Giovacchini G, Toczek MT, Bonwetsch R, et al. 5-HT1A receptors are reduced
in temporal lobe epilepsy after partial-volume correction. J Nucl Med
2005;46:112835.
[66] Theodore WH, Hasler G, Giovacchini G, et al. Reduced hippocampal 5HT1A
PET receptor binding and depression in temporal lobe epilepsy. Epilepsia
2007;48:152630.
[67] Hasler G, Bonwetsch R, Giovacchini G, et al. 5-HT1A receptor binding in
temporal lobe epilepsy patients with and without major depression. Biol
Psychiatry 2007;62:125864.
[68] Savic I, Lindstrom P, Gulyas B, Halldin C, Andree B, Farde L. Limbic reductions
of 5-HT1A receptor binding in human temporal lobe epilepsy. Neurology
2004;62:134351.
[69] Elger CE, Helmstaedter C, Kurthen M. Chronic epilepsy and cognition. Lancet
Neurol 2004;3:66372.
[70] Loring DW, Marino S, Meador KJ. Neuropsychological and behavioral effects
of antiepilepsy drugs. Neuropsychol Rev 2007;17:41325.
[71] Dulay MF, Schefft BK, Fargo JD, Privitera MD, Yeh H. Severity of depressive
symptoms, hippocampal sclerosis, auditory memory, and side of seizure
focus in temporal lobe epilepsy. Epilepsy Behav 2004;5:52231.
[72] Helmstaedter C, Sonntag-Dillender M, Hoppe C, Elger CE. Depressed mood
and memory impairment in temporal lobe epilepsy as a function of focus
lateralization and localization. Epilepsy Behav 2004;5:696701.
[73] Paradiso S, Hermann BP, Blumer D, Davies K, Robinson RG. Impact of
depressed mood on neuropsychological status in temporal lobe epilepsy. J
Neurol Neurosurg Psychiatry 2001;70:1805.
[74] Pulliainen V, Kuikka P, Kalska H. Are negative mood states associated with
cognitive function in newly diagnosed patients with epilepsy? Epilepsia
2000;41:4215.
Behav (2008), doi:10.1016/j.yebeh.2008.04.005
ARTICLE IN PRESS
[75] Tracy JI, Lippincott C, Mahmood T, et al. Are depression and cognitive
performance related in temporal lobe epilepsy? Epilepsia 2007;48:232735.
[76] Stoddart SD, Craddock NJ, Jones LA. Differentiation of executive and attention
impairments in affective illness. Psychol Med 2007;37:161323.
[77] Burt DB, Zembar M, Niederehe G. Depression and memory impairment: a
meta-analysis of the association, its pattern, and specicity. Psychol Bull
1995;117:285305.
[78] Taylor JV, Clark L, Cannon DM, Erickson K, Drevets WC, Sahakian BJ. Distinct
proles of neurocognitive function in unmedicated unipolar depression and
bipolar II depression. Biol Psychiatry 2007;62:91724.
[79] Jones JE, Hermann BP, Barry JJ, Gilliam F, Kanner AM, Meador KJ. Clinical
assessment of Axis I psychiatric morbidity in chronic epilepsy: a multicenter
investigation. J Neuropsychiatry Clin Neurosci 2005;17:1729.
[80] Johnson EK, Jones JE, Seidenberg M, Hermann BP. The relative impact of
anxiety, depression, and clinical seizure features on health-related quality of
life in epilepsy. Epilepsia 2005;45:54450.
[81] Kanner AM, Nieto J. Depressive disorders in epilepsy. Neurology 1999;53(5,
Suppl. 2):S2632.
[82] Corcoran R, Thompson P. Epilepsy and poor memory: who complains and
what do they mean? Br J Clin Psychol 1993;32:199208.
[83] Hendriks MP, Aldenkamp AP, van der Vlugt H, Alpherts WC, Vermeulen J.
Memory complaints in medically refractory epilepsy: relationship to
epilepsy-related factors. Epilepsy Behav 2002;3:16572.
[84] Piazzini A, Canevini MP, Maggiori G, Canger R. The perception of memory
failures in patients with epilepsy. Eur J Neurol 2001;8:61320.
[85] Vermeulen J, Aldenkamp AP, Alpherts WC. Memory complaints in epilepsy:
correlations with cognitive performance and neuroticism. Epilepsy Res
1993;15:15770.
[86] Collins KA, Westra HA, Dozois DJA, Burns DD. Gaps in accessing treatment for
anxiety and depression: challenges for the delivery of care. Clin Psychol Rev
2004;24:583616.
[87] Mojtabai R, Olfson M, Mechanic D. Perceived need and help-seeking in adults
with mood, anxiety, or substance use disorders. Arch Gen Psychiatry
2002;59:7784.
[88] Althaus D, Stefanek J, Hasford J, Hegerl U. [Knowledge and attitude of the
general public regarding symptoms, etiology and possible treatments of
depressive illnesses]. Nervenarzt 2002;73:65964.
[89] Sirey JA, Bruce ML, Alexopoulos GS, Perlick DA, Friedman SJ, Meyers BS.
Stigma as a barrier to recovery: perceived stigma and patient-rated severity
of illness as predictors of antidepressant drug adherence. Psychiatr Serv
2001;52:161520.
[90] Quinn H, Nikolov B, Jovine L, et al. How do persons with epilepsy react when
they are referred for symptoms of depression? Epilepsia 2006;47:12.
[91] Rush AJ, Trivedi MH, Ibrahim HM, et al. The 16-Item Quick Inventory of
Depressive Symptomatology (QIDS), clinician rating (QIDS-C), and self-report
(QIDS-SR): a psychometric evaluation in patients with chronic major
depression. Biol Psychiatry 2003;54:57383.
[92] Pisani F, Spina E, Oteri G. Antidepressant drugs and seizure susceptibility:
from in vitro data to clinical practice. Epilepsia 1999;40(Suppl. 10):S4856.
[93] Montgomery SA. Antidepressants and seizures: emphasis on newer agents
and clinical implications. Int J Clin Pract 2005;59:143540.
[94] Rosenstein DL, Nelson JC, Jacobs SC. Seizures associated with antidepressants:
a review. J Clin Psychiatry 1993;54:28999.
[95] Cuenca PJ, Holt KR, Hoee JD. Seizure secondary to citalopram overdose. J
Emerg Med 2004;26:17781.
[96] Balit CR, Lynch CN, Isbister GK. Bupropion poisoning: a case series. Med J Aust
2003;178:613.
[97] Mainie I, McGurk C, McClintock G, Robinson J. Seizures after buproprion
overdose. Lancet 2001;357:1624.
[98] Favale E, Rubino V, Mainardi P, Lunardi G, Albano C. Anticonvulsant effect of
uoxetine in humans. Neurology 1995;45:19267.
[99] Favale E, Audenino D, Cocito L, Albano C. The anticonvulsant effect of
citalopram as an indirect evidence of serotonergic impairment in human
epileptogenesis. Seizure 2003;12:3168.
McConnell
H,
Snyder
P,
editors.
Psychiatric
comorbidity
in
epilepsy. Washington, DC: American Psychiatric Press; 1998. p. 245361.
[101] Naritoku DK, Terry WJ, Helfert RH. Regional induction of fos
immunoreactivity in the brain by anticonvulsant stimulation of the vagus
nerve. Epilepsy Res 1995;22:5362.
[102] Yan QS, Mishra PK, Burger RL, Bettendorf AF, Jobe PC, Dailey JW.
Evidence that carbamazepine and antiepilepsirine may produce a
component of their anticonvulsant effects by activating serotonergic
neurons in genetically epilepsy-prone rats. J Pharmacol Exp Ther
1992;261:6529.
[103] Yan QS, Jobe PC, Dailey JW. Evidence that a serotonergic mechanism is
involved in the anticonvulsant effect of uoxetine in genetically epilepsyprone rats. Eur J Pharmacol 1993;252:10512.
[104] Nadkarni S, Devinsky O. Psychotropic effects of antiepileptic drugs. Epilepsy
Curr 2005;5:17681.
[105] Jobe PC, Mishra PK, Adams-Curtis LE, et al. The genetically epilepsy-prone rat
(GEPR). Ital J Neurol Sci 1995;16:919.
[106] Clough RW, Peterson BR, Steenbergen JL, et al. Neurite extension of
developing noradrenergic neurons is impaired in genetically epilepsy-prone
rats (GEPR-3s): an in vitro study on locus coeruleus. Epilepsy Res
1998;29:13546.
25
[107] Ryu JR, Jobe PC, Milbrandt JC, et al. Morphological decits in noradrenergic
neurons in GEPR-9s stem from abnormalities in both the locus coeruleus and
its target tissues. Exp Neurol 1999;156:8491.
[108] Jobe PC, Dailey JW, Wernicke JF. A noradrenergic and serotonergic hypothesis
of the linkage between epilepsy and affective disorders. Crit Rev Neurobiol
1999;13:31756.
[109] Koval G, VanNuis C, Davis TD. Seizures associated with amoxapine. Am J
[110] Giannini AJ, Price WA. Amoxapine-induced seizures: case reports. J Clin
[111] Cardoni AA. Clomipramine. Englewood, CO: Micromedics Electronic Version;
1999.
[112] Terao T, Ohmori O, Shinkai T. A puzzling case of seizures and visual
hallucinations during clomipramine treatment with a high dose but causing a
low serum concentration. Acta Psychiatr Scand 1999;99:38890. discussion
3902.
[113] DeToledo JC, Haddad H, Ramsay RE. Status epilepticus associated with the
combination of valproic acid and clomipramine. Ther Drug Monit
1997;19:713.
[114] Perroud N, Lazignac C, Baleydier B, Cicotti A, Maris S, Damsa C. Restless legs
syndrome induced by citalopram: a psychiatric emergency? Gen Hosp
[115] Ickowicz A. Bupropionmethylphenidate combination and grand mal
seizures. Can J Psychiatry 2002;47:7901.
[116] Pesola GR, Avasarala J. Bupropion seizure proportion among new-onset
generalized seizures and drug-related seizures presenting to an emergency
department. J Emerg Med 2002;22:2359.
[117] Davidson J. Seizures and bupropion: a review. J Clin Psychiatry
1989;50:25661.
[118] Hoffman BF, Wachsmuth R. Maprotiline and seizures. J Clin Psychiatry
1982;43:1178.
[119] Ramirez AL. Seizures associated with maprotiline. Am J Psychiatry
1983;140:50910.
[120] Molnar G. Seizures associated with high maprotiline serum concentrations.
Can J Psychiatry 1983;28:5556.
[121] Atri PB, Julius DA. Maprotiline hydrochloride associated with a clinical state
of catatonic stupor and epileptic encephalogram. J Clin Psychopharmacol
1984;4:2079.
[122] Bernard PG, Levine MS. Maprotiline-induced seizures. South Med J
1986;79:117980.
[123] Ettinger AB. Psychotropic effects of antiepileptic drugs. Neurology
2006;67:191625.
[124] Ettinger AB, Kustra RP, Hammer AE, Messenheimer JA. Effects of lamotrigine
on mood in adult patients with generalized tonicclonic seizures. Epilepsia
2005;46(Suppl. 8):174.
[125] Harden CL, Pulver MC, Ravdin LD, Blagovest N, Halper JP, Labar DR. A pilot
study of mood in epilepsy patients treated with vagus nerve stimulation.
Epilepsy Behav 2000;1:939.
[126] Pande AC, Pollack MH, Crockatt J, et al. Placebo-controlled study of
gabapentin treatment of panic disorder. J Clin Psychopharmacol
2000;20:46771.
[127] Pande AC, Crockatt JG, Feltner DE, et al. Pregabalin in generalized
anxiety disorder: a placebo-controlled trial. Am J Psychiatry
2003;160:53340.
[128] Brent DA, Crumrine PK, Varma R, Brown RV, Allan MJ. Phenobarbital
treatment and major depressive disorder in children with epilepsy.
Pediatrics 1987;80:90917.
[129] Kanner AM, Wuu J, Faught E, Tatum WO, Fix A, French JA. A past psychiatric
history may be a risk factor for topiramate-related psychiatric and cognitive
adverse events. Epilepsy Behav 2003;4:54852.
[130] Mula M, Trimble MR, Lhatoo SD, Sander JW. Topiramate and psychiatric
adverse events in patients with epilepsy. Epilepsia 2003;44:65963.
[131] Dursun SM, Mathew VM, Reveley MA. Toxic serotonin syndrome after
uoxetine plus carbamazepine. Lancet 1993;342:4423.
[132] Rosenhagen MC, Schmidt U, Weber F, Steiger A. Combination therapy of
lamotrigine and escitalopram may cause myoclonus. J Clin Psychopharmacol
2006;26:3467.
[133] Paul MA, Gray GW, Love RJ, Lange M. SSRI effects on psychomotor
performance: assessment of citalopram and escitalopram on normal
subjects. Aviat Space Environ Med 2007;78:6937.
[134] Wilson K, Mottram P. A comparison of side effects of selective serotonin
reuptake inhibitors and tricyclic antidepressants in older depressed patients:
a meta-analysis. Int J Geriatr Psychiatry 2004;19:75462.
[135] Mendhekar DN, Gupta D, Girotra V. Sertraline-induced hypomania: a genuine
side-effect. Acta Psychiatr Scand 2003;108:704.
[136] Dording CM, Mischoulon D, Petersen TJ, et al. The pharmacologic
management of SSRI-induced side effects: a survey of psychiatrists. Ann
Clin Psychiatry 2002;14:1437.
[137] Bridge JA, Barbe RP, Birmaher B, Kolko DJ, Brent DA. Emergent suicidality in a
clinical psychotherapy trial for adolescent depression. Am J Psychiatry
2005;162:21735.
[138] Morrell MJ, Flynn KL, Done S, Flaster E, Kalayjian L, Pack AM. Sexual
dysfunction, sex steroid hormone abnormalities, and depression in women
with epilepsy treated with antiepileptic drugs. Epilepsy Behav 2005;6:3605.
[139] Papakostas GI. Limitations of contemporary antidepressants: tolerability. J
Clin Psychiatry 2007;68(Suppl. 10):117.
Behav (2008), doi:10.1016/j.yebeh.2008.04.005
ARTICLE IN PRESS
26
[140] Schatzberg AF. Safety and tolerability of antidepressants: weighing the

impact on treatment decisions. J Clin Psychiatry 2007;68(Suppl. 8):2634.
[141] Segraves RT. Sexual dysfunction associated with antidepressant therapy. Urol
Clin North Am 2007;34:5759.
[142] Sareen J, Jagdeo A, Cox BJ, et al. Perceived barriers to mental health service
utilization in the United States, Ontario, and The Netherlands. Psychiatr Serv
2007;58:35764.
[143] Mechanic D. Removing barriers to care among persons with psychiatric
symptoms. Health Aff (Millwood) 2002;21:13747.
[144] Kanner AM, Gidal BE. The use of psychotropic drugs in epilepsy: a review of
pharmacokinetic, pharmacodynamic, and safety issues. In: Ettinger AB,
Kanner AM, editors. Psychiatric issues in epilepsy: a practical guide to
diagnosis and treatment. Philadelphia: Lippincott Williams & Wilkins; 2007.
p. 5166.
[145] Brent D, Crumrine P, Varma R, Allan M, Allman C. Phenobarbital treatment
and major depressive disorder in children with epilepsy. Pediatrics
1987;80:90917.
[146] Buelow J, Austin J, Perkins S, Shen J, Dunn D, Fastenau P. Behavior and mental
health problems in children with epilepsy and low IQ. Dev Med Child Neurol
2003;45:68392.
[147] Caplan R, Siddarth P, Gurbani S, Hanson R, Sankar R, Shields WD. Depression
and anxiety disorders in pediatric epilepsy. Epilepsia 2005;46:72030.
[148] Dunn D, Austin J, Huster G. Symptoms of depression in adolescents with
epilepsy. J Am Acad Child Adolesc Psychiatry 1999;38:11328.
[149] Jones J, Watson R, Sheth R, et al. Psychiatric comorbidity in children with new
onset epilepsy. Dev Med Child Neurol 2007;49:4937.
[150] Oguz A, Kurul S, Dirik E. Relationship of epilepsy-related factors to anxiety
and depression scores in epileptic children. J Child Neurol 2002;17:3740.
[151] Williams J, Steel C, Sharp GB, et al. Anxiety in children with epilepsy. Epilepsy
Behav 2003;4:72932.
[152] Martinovic Z, Simonovic PRD. Preventing depression in adolescents with
epilepsy. Epilepsy Behav 2006;9:61924.
[153] Plioplys S. Depression in children and adolescents with epilepsy. Epilepsy
Behav 2003;4(Suppl. 3):S3945.
[154] Ott D, Siddarth P, Gurbani S, et al. Behavioral disorders in pediatric epilepsy:
unmet psychiatric need. Epilepsia 2003;44:5917.
[155] Kanner AM, Dunn DW. Diagnosis and management of depression and
psychosis in children and adolescents with epilepsy. J Child Neurol
2004;19(Suppl. 1):S6572.
[156] Barzman DH, McConville BJ, Masterson B, et al. Impulsive aggression with
irritability and responsive to divalproex: a pediatric bipolar spectrum
disorder phenotype? J Affect Disord 2005;88:27985.
[157] Donovan SJ, Nunes EV, Stewart JW, et al. Outer-directed irritability: a
distinct mood syndrome in explosive youth with a disruptive behavior
disorder? J Clin Psychiatry 2003;64:698701.
[158] Wozniak J, Biederman J, Kiely K, et al. Mania-like symptoms suggestive of
childhood-onset bipolar disorder in clinically referred children. J Am Acad
Child Adolesc Psychiatry 1995;34:86776.
[159] Boylan K, Vaillancourt T, Boyle M, Szatmari P. Comorbidity of internalizing
disorders in children with oppositional deant disorder. Eur Child Adolesc
Psychiatry 2007.
[160] Leibenluft E, Blair RJ, Charney DS, Pine DS. Irritability in pediatric mania and
other childhood psychopathology. Ann NY Acad Sci 2003;1008:20118.
[161] Vona P, Siddarth P, Lanphier K, et al. Informing parents about the
comorbidities of pediatric epilepsy, accepted for publication.
[162] Smith K, Siddarth P, Zima B, et al. Unmet mental health needs in pediatric
epilepsy: Insights from providers. Epilepsy Behav 2007;11:4018.
[163] Wu K, Lieber E, Siddarth P, Smith K, Ankar R. Pediatric epilepsy: parents speak
up, accepted for publication.
[164] Dunn D, Austin J. Behavior issues in pediatric epilepsy. Neurology
1999;53:S96S100.
[165] Oostrom K, Schouten A, Kruitwagen CL, Peters AC, Jennekens-Schinkel A, for
the Dutch Study Group of Epilepsy in Childhood (DuSECH). Epilepsy-related
ambiguity in rating the child behavior checklist and the teachers report
form. Epileptic Disord 2001;3:3945.
[166] Kanner AM, Palac S. Neuropsychiatric complications of epilepsy. Curr Neurol
Neurosci Rep 2002;2:36572.
[167] Thome-Souza S, Kuczynski E, Assumpcao Jr F, et al. Which factors may play a
pivotal role on determining the type of psychiatric disorder in children and
adolescents with epilepsy? Epilepsy Behav 2004;5:98894.
[168] Caplan R, Siddarth P, Stahl L, et al. Childhood absence epilepsy: risk factors for
behavioral, cognitive, and linguistic comorbidities, accepted for publication.
[169] Dunn DW, Austin JK. Differential diagnosis and treatment of psychiatric
disorders in children and adolescents with epilepsy. Epilepsy Behav
2004;5(Suppl. 3):S107.
[170] Brent D, Crumrine P, Varma R, Brown R, Allan M. Phenobarbital treatment
and major depressive disorder in children with epilepsy: a naturalistic follow
up. Pediatrics 1990;85:108691.
[171] Williams J, Phillips T, Geiebel M, et al. Factors associated with achievement in
children with controlled epilepsy. Epilepsy Behav 2001;2:21733.
[172] Hammen C. Stress and depression. Annu Rev Clin Psychol 2005;1:293319.
[173] Austin J, Caplan R. Behavioral and psychiatric comorbidities in pediatric
epilepsy: toward an integrative model. Epilepsia 2007;48:163951.
[174] Rodenburg R, Stams GJ, Meijer AM, Aldenkamp AP, Dekovic M.
Psychopathology in children with epilepsy: a meta-analysis. J Pediatr
Psychol 2005;30:45368.
[175] Shore CP, Austin JK, Huster GA, Dunn DW. Identifying risk factors for
maternal depression in families of adolescents with epilepsy. J Spec Pediatr
Nurs 2002;7:7180.
[176] Caplan R, Gillberg C, Dunn D, Spence SJ. Child psychiatric disorders. In: Engel
J, Pedley T, editors. Epilepsy: a comprehensive textbook. New York: Raven
Press; 2007. p. 217994.
[177] Austin JK, Dunn DW, Johnson CS, Perkins SM. Behavioral issues involving
children and adolescents with epilepsy and the impact of their families:
recent research data. Epilepsy Behav 2004;5(Suppl. 3):S3341.
[178] Austin JK, Huberty TJ, Huster GA, Dunn DW. Academic achievement in
children with epilepsy
or asthma. Dev Med Child Neurol
1998;40:24855.
[179] Fastenau PS, Shen J, Dunn DW, Perkins SM, Hermann BP, Austin JK.
Neuropsychological predictors of academic underachievement in pediatric
epilepsy: moderating roles of demographic, seizure, and psychosocial
variables. Epilepsia 2004;45:126172.
[180] Caplan R, Sagun J, Siddarth P, Gurbani S, Koh S, Gowrinathan R, et al. Social
competence in pediatric epilepsy: insights into underlying mechanisms.
[181] Caplan R, Siddarth P, Bailey CE, et al. Thought disorder: a developmental
disability in pediatric epilepsy. Epilepsy Behav 2006;8:72635.
[182] Goldston D, Walsh A, Mayeld Arnold E, et al. Reading problems, psychiatric
disorders, and functional impairment from mid- to late adolescence. J Am
Acad Child Adolesc Psychiatry 2007;46:2532.
[183] Lepist T, Soininen M, Ceponiene R, Almqvist F, Ntnen R, Aronen ET.
Auditory event-related potential indices of increased distractibility in
children with major depression. Clin Neurophysiol 2004;115:6207.
[184] Maughan B, Rowe R, Loeber R, Stouthamer-Loeber M. Reading problems and
depressed mood. J Abnorm Child Psychol 2003;31:21929.
[185] Toren P, Sadeh M, Wolmer L, et al. Neurocognitive correlates of anxiety
disorders in children: a preliminary report. J Anxiety Disord 2000;14:23947.
[186] Grills A, Ollendick T. Issues in parentchild agreement: the case of structured
diagnostic interviews. Clin Child Fam Psychol Rev 2002;5:5783.
[187] Myers K, Winters N. Ten-year review of rating scales: II. Scales for
internalizing disorders. J Am Acad Child Adolesc Psychiatry 2002;41:63459.
[188] Angold A, Costello E, Worthman C. Puberty and depression: the roles of age,
pubertal status and pubertal timing. Psychol Med 1988;28:5161.
[189] Shaffer D, Fisher P, Lucas CP, Dulcan MK, Schwab-Stone ME. NIMH Diagnostic
Interview Schedule for Children Version IV (NIMH DISC-IV): description,
differences from previous versions, and reliability of some common
diagnoses. J Am Acad Child Adolesc Psychiatry 2000;39:2838.
[190] Kaufman J, Birmaher B, Brent D, et al. Schedule for Affective Disorders and
Schizophrenia for School-Age ChildrenPresent and Lifetime Version (KSADS-PL): initial reliability and validity data. J Am Acad Child Adolesc
[191] Gadow K, Sprafkin J, Carlson GA, et al. A DSM-IV-referenced, adolescent selfreport rating scale. J Am Acad Child Adolesc Psychiatry 2002;41:6719.
[192] Sprafkin J, Gadow KD, Salisbury H, Schneider J, Loney J. Further evidence of
reliability and validity of the Child Symptom Inventory-4: parent checklist in
clinically referred boys. J Clin Child Adolesc Psychol 2002;31:51324.
[193] Brooks S, Kutcher S. Diagnosis and measurement of anxiety disorder in
adolescents: a review of commonly used instruments. J Child Adolesc
Psychopharmacol 2003;13:351400.
[194] Kovacs M. The Childrens Depression Inventory (CDI). Psychopharmacol Bull
1985;21:9958.
[195] Hesdorffer DC, Hauser WA, Olafsson E, Udvigsson P, Kjartansson O.
Depression and suicide attempt as risk factors for incident unprovoked
seizures. Ann Neurol 2006;59:3541.
[196] Davies S, Heyman I, Goodman R. A population survey of mental health
problems in children with epilepsy. Dev Med Child Neurol 2003;45:2925.
[197] Flemming J, Offord D. Epidemiology of childhood depressive disorders: a
critical review. J Am Acad Child Adolesc Psychiatry 1990;29:57180.
[198] March J, Parker D, Sullivan K, Stallings P, Conners C. The Multidimensional
Anxiety Scale for Children (MASC): factor structure, reliability, and validity. J
Am Acad Child Adolesc Psychiatry 1997;36:55465.
[199] Achenbach T. Manual for the Child Behavior Checklist and Revised Child
Behavior Prole. Burlington: Department of Psychiatry, University of
Vermont; 1991.
[200] Caplan R, Siddarth P, Bailey C, et al. Depression and anxiety in children with
epilepsy. In: Annual Meeting of International League Against Epilepsy;
Singapore; 2007.
[201] Birmaher B, Arbelaez C, Brent D. Course and outcome of child and adolescent
major depressive disorder. Child Adolesc Psychiatr Clin N Am
2002;11:61937.
[202] Costello E, Pine DS, Hammen C, et al. Development and natural history of
mood disorders. Biol Psychiatry 2002;52:52942.
[203] Lewinsohn P, Rohde P, Seeley JR, Hops H. Comorbidity of unipolar depression:
I. Major depression with dysthymia. J Abnorm Psychol 1991;100:20513.
[204] American Academy of Child and Adolescent Psychiatry. Practice parameter
for the assessment and treatment of children and adolescents with bipolar
disorder. J Am Acad Child Adolesc Psychiatry 2007;46:10725.
[205] Austin J, McNelis AM, Shore CP, Dunn DW, Musick B. A feasibility study of a
family seizure management program: Be Seizure Smart. J Neurosci Nurs
2002;34:307.
[206] Lewis M, Salas I, de la Sota A, et al. Randomized trial of a program to enhance
competencies of children with epilepsy. Epilepsia 1990;31:1019.
Behav (2008), doi:10.1016/j.yebeh.2008.04.005
ARTICLE IN PRESS
[207] Tieffenberg J, Wood EI, Alonso A, Tossutti MF. A randomized eld trial of
ACINDES: a child-centered training model for children with chronic illnesses
(asthma and epilepsy). J Urban Health 2000;77:28997.
[208] Snead K, Ackerson J, Bailey K, Schmitt MM, Madan-Swain A, Martin RC.
Taking charge of epilepsy: the development of a structured
psychoeducational group intervention for adolescents with epilepsy and
their parents. Epilepsy Behav 2004;5:54756.
[209] Austin J, Shafer P, Deering J. Epilepsy familiarity, knowledge, and perceptions
of stigma: report from a survey of adolescents in the general population.
[210] McLeod J, Austin JK. Stigma in the lives of adolescents with epilepsy. Epilepsy
Behav 2003;4:1127.
[211] Bishop MEMB. Teachers knowledge about epilepsy and attitudes toward
students with epilepsy: results of a national survey. Epilepsy Behav
2006;8:397405.
[212] Oostrom K, Schouten A, Olthof T, Peters AC, Jennekens-Schinkel A. Negative
emotions in children with newly diagnosed epilepsy. Epilepsia
2000;41:32631.
[213] Houston E, Cunningham CC, Metcalfe E, et al. The information needs and
understanding of 510-year old children with epilepsy, asthma or diabetes.
Seizure 2000;9:3404.
[214] Treatment for Adolescents with Depression Study (TADS) Team. Fluoxetine,
cognitive-behavioral therapy, and their combination for adolescents with
depression: Treatment for Adolescents with Depression Study (TADS)
randomized controlled trial. JAMA 2004;292:80720.
[215] Rodenburg R, Marie Meijer A, Dekovic M, Aldenkamp AP. Family predictors of
psychopathology in children with epilepsy. Epilepsia 2006;47:60114.
[216] American Academy of Child and Adolescent Psychiatry. Practice Parameter
for psychiatric consultation to schools. J Am Acad Child Adolesc Psychiatry
2005;44:106883.
[217] Chiu S, Leonard H. Antidepressants: I Selective serotonin reuptake
inhibitors. New York: Oxford Univ. Press; 2003. p. 27483.
[218] Hazell P, OConnell D, Heathcote D, et al. Tricyclic drugs for depression in
children and adolescents. Cochrane Database Syst Rev 2002;2:CD002317.
[219] Wagner K, Ambrosini PJ. Childhood depression: pharmacological therapy/
treatment. J Clin Child Psychol 2001;30:8897.
[220] Hammad T, Laughren T, Racoosin J. Suicidality in pediatric patients treated
with antidepressant drugs. Arch Gen Psychiatry 2006;63:3329.
[221] Food and Drug Administration. Relationship between psychotropic drugs and
pediatric suicidality: review and evaluation of clinical data. 2007 [cited;
Available from: .
[222] Bridge J, Iyengar S, Salary CB, et al. Clinical response and risk for reported
suicidal ideation and suicidal attempts in pediatric antidepressant
treatment: a meta-analysis of randomized controlled trials. JAMA
2007;297:168396.
[223] Thom-Souza M, Kuczynski E, Valente KD. Sertraline and uoxetine: safe
treatments for children and adolescents with epilepsy and depression.
[224] Delbello M, Kowatch RA, Adler CM, et al. A double-blind randomized pilot
study comparing quetiapine and divalproex for adolescent mania. J Am Acad
Child Adolesc Psychiatry 2006;45:30513.
[225] Findling R, McNamara NK, Youngstrom EA, et al. Double-blind 18-month trial
of lithium versus divalproex maintenance treatment in pediatric bipolar
disorder. m. J Am Acad Child Adolesc Psychiatry 2005;44:40917.
[226] Salpekar J, Conry JA, Doss W, et al. Clinical experience with anticonvulsant
medication in pediatric epilepsy and comorbid bipolar spectrum disorder.
[227] Gonzalez-Heydrich J, Pandina GJ, Fleisher CA, et al. No seizure exacerbation
from risperidone in youth with comorbid epilepsy and psychiatric disorders:
a case series. J Child Adolesc Psychopharmacol 2004;14:295310.
[228] Holzhausen S, Guerreiro MM, Baccin CEMAM. Use of risperidone in children
with epilepsy. Epilepsy Behav 2007;10:4126.
[229] Suppes T, Dennehy EB, Hirschfeld RM, et al. The Texas Implementation of
Medication Algorithms: update to the algorithms for treatment of bipolar I
disorder. J Clin Psychiatry 2005;66:87086.
[230] Charney DS, Berman RM, Miller HL. Treatment of depression. In: Schatzberg
AF, Nemeroff CB, editors. Textbook of psychopharmacology. Washington,
DC: American Psychiatric Press; 1998. p. 70531.
[231] Kanner AM, Balabanov A. Depression and epilepsy: how closely related are
they? Neurology 2002;58(8, Suppl 5):S2739.
[232] Kanner AM, Barry JJ. Is the psychopathology of epilepsy different from that of
nonepileptic patients? Epilepsy Behav 2001;2:17086.
[233] Kanner AM. Depression and the risk of neurological disorders. Lancet
2005;366:11478.
[234] Evans DL, Charney D. Mood disorders and medical illness: a major public
health problem. Biol Psychiatry 2003;3:17780.
[235] Greden JF. Unmet need: what justies the search for a new antidepressant? J
Clin Psychiatry 2002;63(Suppl. 2):37.
[236] Nierenberg AA, Peterson TJ, Alpert JE. Prevention of relapse and recurrence in
depression: the role of long-term pharmacotherapy and psychotherapy. J Clin
Psychiatry 2003;64(Suppl. 15):137.
[237] Kennedy SH, Lam RW, Nutt DJ, Thase ME. Treating depression
effectively. New York: Martin Dunitz; 2004.
[238] Judd LL, Akiskal HS, Maser JD, et al. Major depressive disorder: prospective
study of residual subthreshold depressive symptoms as predictor of rapid
relapse. J Affect Disord 1998;50:97108.
27
[239] Paykel ES, Ramana R, Cooper Z, Hayhurst H, Kerr J, Barkocka A. Residual

symptoms after partial remission: an important outcome in depression.
Psychol Med 1995;25:117180.
[240] Miller IW, Keitner GI, Schatzberg AF, et al. The treatment of chronic
depression: Partt 3: Psychological functioning before and after treatment
with sertraline or imipramine. J Clin Psychiatry 1998;59:60819.
[241] Agras WS. Behavioral therapy. In: Sadock BJ, editor. Comprehensive textbook
of psychiatry/VI. Baltimore: Williams & Wilkins; 1995. p. 1788807.
[242] Hollon SD, Jarrett RB, Nierenberg AA, Thase ME, Trivedi M, Rush AJ.
Psychotherapy and medication in the treatment of adult and geriatric
depression: which monotherapy or combined treatment? J Clin Psychiatry
2005;66:45568.
[243] Keller MB, McCullough Jr JP, Klein DN, et al. A comparison of nefazodone, the
cognitive behavioral-analysis system of psychotherapy, and their
combination for the treatment of chronic depression. N Engl J Med
2000;342:146270.
[244] Fava GA, Rafanelli C, Grandi S, et al. Six-year outcome for cognitive behavioral
treatment of residual symptoms in major depression. Am J Psychiatry
1998;155:146270.
[245] Davis GR, Armstrong Jr HE, Donovan DM, Temkin NR. Cognitive-behavioral
treatment of depressed affect among epileptics: preliminary ndings. J Clin
Psychol 1984;40:9305.
[246] Newsom-Davis I, Goldstein HL, Fitzpatrick D. Fear of seizures: an
investigation and treatment. Seizure 1998;7:1016.
[247] Robertson MM, Trimble MR. The treatment of depression in patients with
epilepsy: a double-blind trial. J Affect Disord 1985;9:12736.
[248] Obach RS, Dalvie DK. Metabolism of nomifensine to a dihydroisoquinolinium
ion metabolite by human myeloperoxidase, hemoglobin, monoamine oxidase
A, and cytochrome P450 enzymes. Drug Metab Dispos 2006;34:13106.
[249] Ojemann LM, Friel PN, Trejo WJ, et al. Effect of doxepin on seizure frequency
in depressed epileptic patients. Neurology 1982;33:6468.
[250] Ojemann LM, Baugh-Bookman C, Dudley DL. Effect of psychotropic
medications on seizure control in patients with epilepsy. Neurology
1987;37:15257.
[251] Havorka J, Herman E. Nemcova, Treatment of interictal depression with
citalopram in patients with epilepsy. Epilepsy Behav 2000;1:4447.
[252] Specchio LM, Iudice A, Specchio N, et al. Citalopram as treatment of
depression in patients with epilepsy. Clin Neuropharmacol 2004;27:1336.
[253] Kuhn KU, Quednow BB, Thiel M, Falkai P, Maier W, Elger CE. Antidepressive
treatment in patients with temporal lobe epilepsy and major depression: a
prospective study with three different antidepressants. Epilepsy Behav
2003;4:6749.
[254] Blumer D, Zielenski JJ. Pharmacologic treatment of psychiatric disorders
associated with epilepsy. J Epilepsy 1988;1:13550.
[255] Blumer D. Antidepressant and double antidepressant treatment for the
affective disorder of epilepsy. J Clin Psychiatry 1997;58:311.
[256] Barry J, Lembke A, Gisbert PA, Gilliam F. Affective disorders in epilepsy. In:
Ettinger AB, Kanner AM, editors. Psychiatric issues in epilepsy: a practical
guide to diagnosis and treatment. Philadelphia: Lippincott Williams &
Williams; 2007. p. 20347.
[257] Jobe PC. Common pathogenic mechanisms between depression and epilepsy:
an experimental perspective. Epilepsy Behav 2003;4:S1424.
[258] Jobe PC. Current and future therapeutic opportunities in the comorbidity
between the epilepsies and affective disorders. Clin EEG Neurosci
2004;35:13.
[259] Kanner AM. Depression in epilepsy: prevalence, clinical semiology,
pathogenic mechanisms, and treatment. Biol Psychiatry 2003;54:38898.
[260] Gilliam FG. Diagnosis and treatment of mood disorders in persons with
epilepsy. Curr Opin Neurol 2005;18:12933.
[261] Trivedi MH, Rush AJ, Crismon ML, et al. Clinical results for patients with
major depressive disorder in the Texas Medication Algorithm Project. Arch
Gen Psychiatry 2004;61:66980.
[262] Trivedi MH. Remission of depression and the Texas Medication Algorithm
Project. Manag Care Interface 2003;Suppl. B:913.
[263] Katon W, Von Korff M, Lin E, et al. Collaborative management to achieve
treatment guidelines: impact on depression in primary care. JAMA
1995;273:102631.
[264] Katon W, Von Korff M, Lin E, et al. Stepped collaborative care for primary care
patients with persistent symptoms of depression: a randomized trial. Arch
Gen Psychaitry 1999;56:110915.
[265] Katon W, Von Korff M, Lin E, et al. The pathways study: a randomized trial of
collaborative care in patients with diabetes and depression. Arch Gen
Psychaitry 2004;61:10429.
[266] Trivedi MH. Using treatment algorithms to bring patients to remission. J Clin
[267] Trivedi MH, Fava M, Marangell LB, Osser DN, Shelton RC. Use of treatment
algorithms for depression. Prim Care Companion J Clin Psychiatry
2006;8:2918.
[268] Trivedi MH, Rush AJ, Gaynes BN, et al. Maximizing the adequacy of
medication treatment in controlled trials and clinical practice:
STAR(*)D
measurement-based
care.
Neuropsychopharmacology
2007;32:247989.
[269] Trivedi M. Use of decision support tools for treatment algorithms. CNS Spectr
2007;12:916.
[270] Trivedi MM. The link between depression and physical symptoms. Prim Care
Companion J Clin Psychiatry 2004;6(Suppl. 1):126.
Behav (2008), doi:10.1016/j.yebeh.2008.04.005
ARTICLE IN PRESS
28
[271] Sackeim H, Kupfer DJ, Luther J, et al. Acute and longer-term outcomes in
depressed outpatients requiring one or several treatment steps: a STAR*D
report. Am J Psychiatry 2006;163:190517.
[272] Souery D, Papakostas GI, Trivedi M. Treatment-resistant depression. J Clin
[273] Nierenberg AA, White K. What next? A review of pharmacologic strategies for
treatment resistant depression. Psychopharmacol Bull 1990;26:42960.
[274] Shelton RC. Treatment options for refractory depression. J Clin Psychiatry
1999;60(Suppl. 4):5761.
[275] Poirier M, Boyer P. Venlafaxine and paroxetine in treatment-resistant
depression: double-blind, randomized comparison. Br J Psychiatry
1999;175:126.
[276] De la Gandara J, Aguera L, Rojo J, et al. Use of antidepressant combinations:
which, when and why? Results of a Spanish survey. Acta Psychiatr Scand
2005;428(Suppl.):326.
[277] Nelson J. Managing treatment-resistant major depression. J Clin Psychiatry
64;2003(Suppl. 1):512.
[278] Fava M. Daytime sleepiness and insomnia as correlates of depression. J Clin
[279] Erman M. Therapeutic options in the treatment of insomnia. J Clin Psychiatry
2005;66(Suppl. 9):1821.
[280] Pollack MH. Comorbid anxiety and depression. J Clin Psychiatry
2005;66(Suppl. 8):229.
[281] Westanmo A, Gayken J, Haight R. Duloxetine: a balanced and selective
norepinephrine and serotonin-reuptake inhibitor. Am J Health Syst Phar
2005;62(Suppl. 9):1823.
[282] Meoni P, Hacket D, Lader M. Pooled analysis of venlafaxine XR efcacy on
somatic and psychic symptoms of anxiety in patients with generalized
anxiety disorder. Depress Anxiety 2004;19:12732.
[283] Souery D, Papakostas GI, Trivedi MH. Treatment-resistant depression. J Clin
[284] McMahon FJ, Buervenich S, Charney D, et al. Variation in the gene encoding
the serotonin 2A receptor is associated with outcome of antidepressant
treatment. Am J Hum Genet 2006;78:80414.
[285] Hu XZ, Rush AJ, Charney D, et al. Association between a functional
serotonin transporter promoter polymorphism and citalopram treatment
in adult outpatients with major depression. Arch Gen Psychiatry
2007;64:78392.
[286] Perlis RH, Purcell S, Fava M, et al. Association between treatment-emergent
suicidal ideation with citalopram and polymorphisms near cyclic adenosine
monophosphate response element binding protein in the STAR*D study. Arch
Gen Psychiatry 2007;64:68997.
[287] Fava M, Rush AJ, Trivedi MH, et al. Background and rationale for the
sequenced treatment alternatives to relieve depression (STAR*D) study.
Psychiatr Clin North Am 2003;26:45794.
[288] Fava M, Tomba E, Grandi S. The road to recovery from depression: dont drive
today with yesterdays map. Psychother Psychosom 2007;76:2605.
[289] Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with
citalopram for depression using measurement-based care in STAR*D:
implications for clinical practice. Am J Psychiatry 2006;163:2840.
[290] Rush AJ, Trivedi MH, Wisniewski SR, et al. Bupropion-SR, sertraline, or
venlafaxine-XR after failure of SSRIs for depression. N Engl J Med
2006;354:123142.
[291] Thase ME, Friedman ES, Biggs MM, et al. Cognitive therapy versus medication
in augmentation and switch strategies as second-step treatments: a STAR*D
report. Am J Psychiatry 2007;164:73952.
[292] Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T(3)
augmentation following two failed medication treatments for depression: a
STAR*D report. Am J Psychiatry 2006;163:151930. quiz 1665.
[293] Fava M, Rush AJ, Wisniewski SR, et al. A comparison of mirtazapine and
nortriptyline following two consecutive failed medication treatments for
depressed outpatients: a STAR*D report. Am J Psychiatry 2006;163:116172.
[294] McGrath PJ, Stewart JW, Fava M, et al. Tranylcypromine versus venlafaxine
plus mirtazapine following three failed antidepressant medication trials for
depression: a STAR*D report. Am J Psychiatry 2006;163:153141.
[295] Gilliam F, Barry JJ, Hermann BP, Meador KJ, Vahle V, Kanner AM. Rapid
detection of major depression in epilepsy: a multicentre study. Lancet Neurol
2006;5:399405.
[296] Cassem EH. Depression secondary to medical illness. In: Frances AJ, Hales RE,
editors. Review of psychiatry. Washington, DC: American Psychiatric Press;
1988. p. 25673.
[297] Hirschfeld RMA, Williams JBW, Spitzer RL, et al. Development and validation
of a screening instrument for bipolar spectrum disorder: the Mood Disorder
Questionnaire. Am J Psychiatry 2000;157:18735.
[298] Jones JE, Hermann BP, Woodard JL, et al. Screening for major depression in
epilepsy with common self-report depression inventories. Epilepsia
2005;46:7315.
[299] Beck A, Steer R. Beck Depression Inventory. In: Force T, editor. Handbook of
psychiatric measures. Washington, DC: American Psychiatric Press; 2000. p.
51923.
[300] Gilliam FG, Fessler AJ, Baker G, Vahle V, Carter J, Attarian H. Systematic
screening allows reduction of adverse antiepileptic drug effects: a
randomized trial. Neurology 2004;62:237.
[301] Fakhoury TA, Barry J, Miller MJ, Hammer AE, Vuong A. Lamotrigine in patients
with epilepsy and comorbid depressive symptoms. Epilepsy Behav
2007;10:15562.
[302] Ettinger AB, Kustra RP, Hammer AE. Effect of lamotrigine on depressive
symptoms in adult patients with epilepsy. Epilepsy Behav 2007;10:14854.
[303] Hermann BP, Whitman S. Neurobiological, psychosocial, and pharmacological
factors underlying interictal psychopathology in epilepsy. In: Smith DB,
Treiman DM, Trimble MR, editors. Advances in neurology. New York: Raven
Press; 1991. p. 43952.
[304] Hermann BP, Wyler AR. Depression, locus of control, and the effects of
epilepsy surgery. Epilepsia 1989;30:3328.
[305] Hermann BP, Trenerry MR, Colligan RC. Learned helplessness, attributional
style, and depression in epilepsy. Bozeman Epilepsy Surgery Consortium.
Epilepsia 1996;37:6806.
[306] Hermann BP. Psychopathology in epilepsy and learned helplessness. Med
Hypoth 1979;5:7239.
[307] Thompson PJ, Upton D. The impact of chronic epilepsy on the family. Seizure
1992;1:438.
[308] Boland RJ, Keller MB. Treatment of depression. In: Schatzberg AF, Nemeroff
DB, editors. Textbook of psychopharmacology. Washington, DC: American
Psychiatric Press; 1998. p. 54765.
[309] Schatzberg AF, Cole JO, DeBattista C. Manual of clinical psychopharmacology.
4th ed. Washington, DC: American Psychiatric Press; 2003.
[310] Abramowicz M. Drugs for psychiatric disorders. Treat Guide Med Lett
2006;4(46):3546.
[311] Thase ME, Entsuah AR, Rudolph RL. Remission rates during treatment with
venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry
2001;178:23441.
[312] Silverstone PH, Ravindran A. Once-daily venlafaxine extended release (XR)
compared with uoxetine in outpatients with depression and anxiety. J Clin
[313] Bezchlibnyk-Butler KZ, Jeffries JJ, Virani A, editors. Clinical handbook of
psychotropic drugs. Cambridge, MA: Hogrefe & Huber; 2007.
[314] Blumer D. Psychiatric aspects of intractable epilepsy. Adv Exp Med Biol
2002;497:13347.
[315] Kupfer DJ. Long-term treatment of depression. J Clin Psychiatry
1991;52(suppl. 5):2834.
[316] Sharma V. Loss of response to antidepressants and subsequent refractoriness:
diagnotic issues in a retrospective case series. J Affect Disord
2001;64:99106.
[317] Schatzberg AF, Cole JO, DeBattista C. Augmentation strategies for treatmentresistant disorders. In: Manual of clinical psychopharmacology. Washington,
DC: American Psychiatric Press; 2003. p. 43780.
[318] Figiel GS, McDonald WM, McCall WV, et al. Electroconvulsive therapy. In:
Schatzberg
AF,
Nemeroff
CB,
editors.
Textbook
of
psychopharmacology. Washington, DC: American Psychiatric Press; 1998.
p. 52345.
McConnell H, Snyder PJ, editors. Psychiatric comorbidity in epilepsy: basic
mechanisms, diagnosis, and treatment. Washington, DC: American
Psychiatric Press; 1998. p. 245362.
[320] Regenold WT, Weintraub D, Taller A. Electroconvulsive therapy for epilepsy
and major depression. Am J Geriatr Psychiatry 1998;6:1803.
[321] Kaufman KR, Saucedo C, Schaeffer J, Levesque M, Scannell T, Glouberman M.
Electroconvulsive therapy (ECT) for intractable depression following epilepsy
neurosurgery. Seizure 1996;5:30712.
[322] Fink M, Kellner CH, Sacheim HA. Intractable seizures, status epilepticus, and
ECT. J ECT Lett 1999;15:2824.
[323] Lunde ME, Lee EK, Rasmussen KG. Electroconvulsive therapy in patients with
epilepsy. Epilepsy Behav 2006;9:3559.
[324] Blackwood DH, Cull RE, Freeman CP, Evans JL, Mawdsley CA. A study of
epilepsy following ECT. J Neurol Neurosurg Psychiatry 1980;43:1098102.
[325] The practice of electroconvulsive therapy: recommendations for
treatment, training and privileging. A Task Force Report of the American
Psychiatric Association. Washington, DC: American Psychiatric Press;
2001. p. 3158.
[326] Rutherford B, Sneed J, Marissa M, et al. An open trial of aripiprazole
augmentation for SSRI non-remitters with late-life depression. Int J Geriatr
[327] Barry J, Huynh N. Psychotropic properties of antiepileptic drugs in patients
with developmental disabilities. In: Devinsky O, Westbrook LE, editors.
Epilepsy and developmental disabilities. Boston: Butterworth Heinemann;
2002. p. 20518.
[328] DeBattista C. Augmentation and combination strategies for depression. J
Psychopharmacol 2006;20:118.
[329] DeBattista C, Hawkins J, Buckley T. Gonadal and adrenal steroids in the
treatment of major depression. Depression Mind Body 2006;2:948.
[330] Wolkowitz OM, Reus VI, Keebler A, et al. Double-blind treatment of major
depression with dehydroepiandrosterone. Am J Psychiatry 1999;156:6469.
[331] Herzog AG. Psychoneuroendocrine aspects of temporolimbic epilepsy.
Psychosomatics 1999;40:95101.
[332] Herzog AG. Psychoneuroendocrine aspects of temporolimbic epilepsy: Part II.
Epilepsy and reproductive steroids. Psychosomatics 1999;40:1028.
[333] Herzog AG. Psychoneuroendocrine aspects of temporolimbic epilepsy: Part
III. Case reports. Psychosomatics 1999;40:10916.
[334] Thase ME. Pharmacological strategies for treatment-resistant depression: an
update on the state of the evidence. Psychiatr Ann 2005;35:9708.
[335] Gross M, Nakamura L, Pascual-Leone A, Fregni F. Has repetitive transcranial
magnetic stimulation (rTMS) treatment for depression improved? A
Behav (2008), doi:10.1016/j.yebeh.2008.04.005
ARTICLE IN PRESS
[336]
[337]
[338]
[339]
[340]
[341]
[342]
[343]
[344]
[345]
[346]
systematic review and meta-analysis comparing the recent vs. the earlier
rTMS studies. Acta Psychiatr Scand 2007;116:16573.
Mogg A, Pluck P, Eranti SV, et al. A randomized controlled trial with 4-month
follow-up of adjunctive repetitive transcranial magnetic stimulation of the
left prefrontal cortex for depression. Psychol Med 2007:111.
Herwig U, Fallgatter AJ, Hoppner J, et al. Antidepressant effects of
augmentative transcranial magnetic stimulation. Br J Psychiatry
2007;191:4418.
Schachter SC. Vagus nerve stmulation therapy summary: ve years after FDA
approval. Neurology 2002;59:S4855.
Rush JA, George MS, Sackeim HA, et al. Vagus nerve stimulation for
treatment-resistant depression: a multicenter study. Biol Psychiatry
2000;47:27686.
Nahas Z, Marangell LB, Husain MM, et al. Two-year outcome of vagus nerve
stimulation (VNS) for treatment of major depressive episodes. J Clin
Psychiatry 2005;66:1097104.
Rush AJ, Marangell LB, Sackeim H, et al. Vagus nerve stimulation for
treatment-resistant depression: a randomized, controlled acute phase trial.
Biol Psychiatry 2005;58:34754.
George MS, Rush AJ, Marangell LB, et al. A one-year comparison of vagus
nerve stimulation with treatment as usual for treatment-resistant
depression. Biol Psychiatry 2005;58:36473.
Manji HK, Drevets WC, Charney DS. The cellular neurobiology of depression.
Nat Med 2001;7:5417.
Barry JJ. Psychiatric uses for anticonvulsants. Merritt-Putnam Lectures. CME
monograph. West Hartford, CT: American Epilepsy Society; 1999. p. 89105.
Barry JJ, Lembke A, Bullock KD. Current status of the utilization of
antiepileptic treatments in mood, anxiety and aggression: drugs and
devices. Clin EEG Neurosci 2004;35:413.
Shukla S, Godwin CD, Long LE, Miller MG. Lithiumcarbamazepine
neurotoxicity and risk factors. Am J Psychiatry 1984;141:16046.
29
[347] Schatzberg AF, Cole JO, DeBattista C, editors. Manual of clinical

psychopharmacology, 3rd ed., vol. 70. Washington, DC: American
Psychiatric Press; 1997.
[348] Shukla S, Mukherjee S, Decina P. Lithium in the treatment of bipolar disorders
associated with epilepsy: an open study. J Clin Psychopharmacol
1988;8:2014.
[349] Lyketsos CG, Stoline AM, Longstreet P, et al. Mania in temporal lobe epilepsy.
Neuropsychiatry Neuropsychol Behav Neurol 1993;6:1925.
[350] Suppes T, Dennehy EB, Hirscheld RMA, et al. The Texas Implementation of
Medication Algorithms: update to the algorithms for treatment of bipolar 1
disorders. J Clin Psychiatry 2005;66:87086.
[351] Barry JJ, Huynh N. Psychotropic drug use in patients with epilepsy and
developmentl disabilities. In: Devinsky O, Westbrook LE, editors. Epilepsy
and developmental disabilities. Boston: Butterworth/Heinemann; 2002. p.
20518.
[352] Barry JJ. The recognition and management of mood disorders as a
comorbidity of epilepsy. Epilepsia 2003;44(Suppl. 4):3040.
[353] Leppik IE, Birnbaum AK. Epilepsy in the elderly. In: Wyllie E, Gupta A,
Lachhwani DK, editors. The treatment of epilepsy. New York: Lippincott
Williams & Wilkins; 2006. p. 593621.
[354] Crystal S, Sambamoorthi U, Walkup JT, Akincigil A. Diagnosis and treatment
of depression in the elderly medicare population: predictors, disparities, and
trends. J Am Geriatr Soc 2003;51:171828.
[355] Jenike MA. Metabolic changes with aging. In: Jenike MA, editor. Geriatric
psychiatry and psychopharmacology: a clinical approach. Chicago: Year Book
Medical; 1989. p. 2532.
[356] Sommer BR, Fenn H, Pompei P, et al. Safety of antidepressants in the elderly.
Expert Opin Drug Saf 2003;2:36783.
[357] Jacobson SA, Pies RW, Greenblatt DJ. Antidepressants. In: Handbook of
geriatric psychopharmacology. Washington, DC: American Psychiatric Press;
2002. p. 10186.
Behav (2008), doi:10.1016/j.yebeh.2008.04.005

Guía de Epilepsia y Trastornos Afectivos

Загружено:

Сведения о документе

Авторское право

Доступные форматы

Поделиться этим документом

Поделиться или встроить документ

Параметры публикации

Этот документ был вам полезен?

Это неприемлемый материал?

Авторское право:

Доступные форматы

Guía de Epilepsia y Trastornos Afectivos

Загружено:

Авторское право:

Доступные форматы

ARTICLE IN PRESS

Epilepsy & Behavior xxx (2008) xxxxxx

Contents lists available at ScienceDirect

Epilepsy & Behavior

Consensus statement: The evaluation and treatment of people with epilepsy

* Corresponding author. Fax: +1 650 724 9900.

neurological diseases like stroke, Parkinsons disease, multiple

J.J. Barry et al. / Epilepsy & Behavior xxx (2008) xxxxxx

reasons for physician neglect, but fear can be a signicant factor. If

2. Composition of the expert panel

of 97 consecutive patients with epilepsy and a depressive disorder

tioning. The diagnosis for a hypomanic episode includes the

J.J. Barry et al. / Epilepsy & Behavior xxx (2008) xxxxxx

3.3.2. Preictal depressive episodes

3.3.4. Postictal symptoms of depression

3.3.3. Ictal symptoms of depression

3.3.5. Atypical interictal expressions of depression in epilepsy

3.3. Unique clinical expressions of mood disorders in epilepsy

responded well to low doses of antidepressant medication. In a

J.J. Barry et al. / Epilepsy & Behavior xxx (2008) xxxxxx

disorder has been established by psychiatric evaluation, these

3.6.0.2. Symptoms of Anxiety

3.7. The identication of mood disorders in research

4. Psychological and physiological factors associated with

5. Depression and cognitive function

J.J. Barry et al. / Epilepsy & Behavior xxx (2008) xxxxxx

clinical seizure features and depression and their effects on mood

seling. Concern about the stigma of depression is also a factor for

5.5. Cognitive domains

6.2. Barriers to depression treatment in people with epilepsy: Patient

Memory, attention, higher executive functions, and cognitive

A recent study evaluated the reasons why adult patients with

J.J. Barry et al. / Epilepsy & Behavior xxx (2008) xxxxxx

6.3.2. Fear of lowering the seizure threshold

6.3.3. Antidepressantantiepileptic drug interactions

J.J. Barry et al. / Epilepsy & Behavior xxx (2008) xxxxxx

be strongly considered in selecting an agent given the high rates of

sensus stipulates that treatment of these disorders requires the

J.J. Barry et al. / Epilepsy & Behavior xxx (2008) xxxxxx

In addition to these age-related diagnostic difculties, lack of

7.1.4. Related learning disorders

7.1.2. Association with epilepsy features

disorders, including substance use [201203]. Treatment should,

7.3.4. Cognitive-behavioral therapy and interpersonal psychotherapy

7.3.5. Family therapy

J.J. Barry et al. / Epilepsy & Behavior xxx (2008) xxxxxx

poor organization of the family environment and family adaptation

7.3.6. School interventions

8. Treatment of mood disorders in adults with epilepsy

J.J. Barry et al. / Epilepsy & Behavior xxx (2008) xxxxxx

3. Review of sequential treatment algorithms in patients with an

8.1. What is the natural history of idiopathic depressive disorders and

Proportion of Patients Relapsing After Remission

Without residual symptoms

importance (p. 696) and at least 8 weeks or more of symptom

and it is unclear whether they met criteria for an MDD). In 83%,

J.J. Barry et al. / Epilepsy & Behavior xxx (2008) xxxxxx

quired. Remember that the BDI does not provide a diagnosis of

Involvement of family, if possible, is recommended, especially

8.6.5.3. Tricyclic antidepressants. As noted by Blumer and colleagues

Phases of Treatment for Depression

8.6.5.2. An alternative: SNRI. An alternative to the SSRI citalopram

the induction of hypertension are the side effects observed [313].

STAR*D protocol. However, there are ample data on the utility of