Radvilė Stankevičiūtė1, Karolina Kazlauskaitė1, Gintarė Aukselytė2
1Faculty of Medicine, Lithuanian University of Health Sciences, Kaunas, Lithuania
2 Faculty of Medicine, Vilnius University, Vilnius, Lithuania
ABSTRACT
Background: Depression is one of the most common comorbidities in epilepsy patients. It contributes to lower quality of life, higher suicide and drug overdose risks. In spite of its importance for optimum management of people with epilepsy, major depression often goes underdiagnosed. One of the reasons may be the lack of an established clinical standard for depression screening. In regard to treatment, it is difficult to find a suitable antidepressant for patients who not only use antiepileptic drugs, but are also more prone to experience seizures as a side-effect than the general population. However, non-pharmacological treatment options for major depression can also be offered in such circumstances.
Aim: To select and analyse the newest data available on epilepsy with comorbid depression.
Method: The literature review was conducted using “PubMed‘‘ database, selecting publications on the subject of epidemiology, quality of life, diagnostics and treatment of epilepsy comorbid with depression.
Conclusions: Epilepsy and depression have a bilateral relationship making it a substantial comorbidity to diagnose and to treat. Early screening can be conducted with sufficient accuracy using Neurological Disorders Depression Inventory for Epilepsy (NDDI-E), Patient Health Questionnaire (PHQ-9) or Emotional Thermometer (ET7). In epileptic patients major depression can be safely and effectively treated with SSRI’s and SNRI’s. Moreover, cognitive behavioural therapy (CBT) should also be considered as a mean to improve the quality of life, which is significantly reduced in more than a half of people with epilepsy.
Keywords: depression, epilepsy, major depressive disorder, screening tools, antidepressants.
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72
Medical Sciences 2020 Vol. 8 (16), p. 72-86
Detection and treatment of comorbid depression in people with
epilepsy
Radvilė Stankevičiūtė
1
, Karolina Kazlauskaitė
1
, Gintarė Aukselytė
2
1
Faculty of Medicine, Lithuanian University of Health Sciences, Kaunas, Lithuania
2
Faculty of Medicine, Vilnius University, Vilnius, Lithuania
ABSTRACT
Background: Depression is one of the most common comorbidities in epilepsy patients. It contributes to lower quality
of life, higher suicide and drug overdose risks. In spite of its importance for optimum management of people with
epilepsy, major depression often goes underdiagnosed. One of the reasons may be the lack of an established clinical
standard for depression screening. In regard to treatment, it is difficult to find a suitable antidepressant for patients
who not only use antiepileptic drugs, but are also more prone to experience seizures as a side-effect than the general
population. However, non-pharmacological treatment options for major depression can also be offered in such
circumstances.
Aim: To select and analyse the newest data available on epilepsy with comorbid depression.
Method: The literature review was conducted using “PubMed‘‘ database, selecting publications on the subject of
epidemiology, quality of life, diagnostics and treatment of epilepsy comorbid with depression.
Conclusions: Epilepsy and depression have a bilateral relationship making it a substantial comorbidity to diagnose
and to treat. Early screening can be conducted with sufficient accuracy using Neurological Disorders Depression
Inventory for Epilepsy (NDDI-E), Patient Health Questionnaire (PHQ-9) or Emotional Thermometer (ET7). In
epileptic patients major depression can be safely and effectively treated with SSRI’s and SNRI’s. Moreover, cognitive
behavioural therapy (CBT) should also be considered as a mean to improve the quality of life, which is significantly
reduced in more than a half of people with epilepsy.
Keywords: depression, epilepsy, major depressive disorder, screening tools, antidepressants.
Journal of Medical Sciences. May 18, 2020 - Volume 8 | Issue 16. Electronic-ISSN: 2345-0592
73
Introduction
Epilepsy is one of the most common
diseases affecting more than 70 million people
worldwide (1). Predominately a chronic illness, it
puts a heavy burden on healthcare systems, not to
mention the uncertainty, mental and physical
problems an individual has to deal with. Patients
have to endure both the side-effects of treatment
and impaired functioning. The effect this illness
has on their daily lives includes difficulties at
school, troubles finding work and enormous social
stigma (2, 3). Correspondingly, patients suffering
from epilepsy report significantly worse
psychological health, greater cognitive
impairment, difficulty participating in activities,
reduced quality of health compared to adults
without epilepsy diagnosis (4).
Major depressive disorder (MDD) is a
debilitating mental illness affecting more than 264
million people worldwide (5). It causes functional
impairment and can lead to suicide, the latter being
the second leading cause of death in people aged
from 15 to 29 worldwide (6). Psychiatric disorders
are a common comorbidity in people suffering
from epilepsy, ranging from anxiety to depression
and bipolar disorder (7).
The link between depression and epilepsy
Major depression is observed to be one of
the most frequent comorbidities of epilepsy, and its
importance cannot be underestimated. People with
epilepsy (PWE) tend to be diagnosed with MDD 3
to 10 times more often compared to the general
population (7), making it a substantial issue.
Regarding this problem, females are affected more
than males (8) In PWE, psychiatric disorders, such
as depression, may appear as a self-limiting disease
resulting from seizure directly (periictal or postictal
psychiatric disturbances), or occur independently
in the context of epilepsy itself (interictal
psychiatric disorders) (7). However, the
relationship between depression and epilepsy is
known to be bidirectional (9), meaning that people
with depression have a greater risk to develop
epilepsy as well (10). The number of seizures can
be augmented by depression or vice versa and
depressive symptoms can manifest before and after
epilepsy diagnosis (11).
There are several theories about the risk
factors of depression in epilepsy, but only a couple
of them well-established. First is the psychosocial:
unemployment, financial stresses, life uncertainty,
poor seizure control, increasing burden of disease,
stigmatisation and deteriorating psychological
health. Second theory is based on neurobiology,
such as similar substrates and findings in
neuroimaging (10). Concerns about the
medication, its perceived adverse effects and
seizure-related worries seem to be some of the most
important predictors of depression in PWE (12).
Moreover, it is important to note that some
medications that are used to treat epilepsy may
have side effects which may add to development of
depression and suicidal thoughts (9).
Major depression often goes
underdiagnosed and undertreated in patients with
epilepsy (13), sometimes it may even be
underestimated (8). It greatly affects any treatment
provided and has a major impact on the life quality
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74
in PWE (12). Managing depression can improve
seizure control and quality of life (3), therefore we
would like to emphasize the importance of early
diagnosis and treatment.
Diagnosing depression in people with
epilepsy
Epilepsy and depression have been
observed to have a bidirectional relationship,
warranting the need to screen for depressive
symptoms in PWE as early as possible (14, 15).
While there are several validated screening tools,
no clinical standard has been definitively
established and their diagnostic accuracy is subject
to debate (16). Most widely used tools are the
following: The Neurological Disorders Depression
Inventory for Epilepsy, Beck Depression
Inventory, Hamilton Rating Scale for Depression,
Hospital Anxiety and Depression Scale, Patient
Health Questionnaire, and various Emotional
Thermometers (16).
The Neurological Disorders Depression
Inventory for Epilepsy (NDDI-E) is a 6-item
questionnaire, validated to screen for depression in
PWE in over 13 languages, such as French,
German, and Polish (17, 18, 19 ,20). As of early
2020, there is still a need for a translation and
adaptation to Lithuanian language. NDDI-E has a
median sensitivity (Se) of 81% and specificity (Sp)
of 84%, positive predictive value (PPV) of 59%,
and negative predictive value (NPV) of 96% (16,
23). It should be noted that although the original
recommendation of the optimal cut-off score for
the detection of major depressive disorder is > 15,
more recent (2018) meta-analysis suggests
lowering it to > 13, with estimated Se of 87% and
Sp of 80% (17, 23). Overall, NDDI-E is simple to
use and takes only a few minutes to complete,
making it a relatively reliable and easily applicable
assessment tool even in a busy clinical setting (21,
22).
Beck Depression Inventory (BDI) is a 21-
question multiple-choice self-report inventory
designed as a screening tool to measure the severity
of depression (24, 25). The original version has
been translated into more than a dozen languages,
including Lithuanian (26, 27). For non-psychiatric
patients, the mean correlation coefficient between
the clinical ratings and the BDI is 0.60 (28, 29).
Although the BDI cut point for general medical
population is ≥ 13, in PWE it is recommended to
use > 16 (Se, 94%; Sp, 90%; PPV, 79%; NPV,
98%). (16, 33) Studies on the concurrent validity
with other self-rating scales report moderate to
high correlation coefficients with mean
coefficients ranging from 0.58 to 0.79 (29).
Although sufficiently reliable, the BDI takes up to
10 minutes for the patient to complete and some
more time to assess the result, making it a less
convenient screening option when time is scarce
(28). Another disadvantage of the BDI is that it is
copyrighted; a fee must be paid for each copy used
(26).
Hamilton Rating Scale for Depression
(HAM-D) is a multiple item questionnaire that, in
spite of its flaws, is still widely considered to be the
golden standard for assessment of depression in
various settings (22, 30). It has been translated to
most European and a lot of non-European
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75
languages, including Lithuanian (31, 32). When
used to detect depression, performance of the
HAM-D appears to be generally consistent even at
different cut-off points – it has a mean Se of 76%,
mean Sp of 91%, mean PPV of 77% and mean NPV
of 92% (30). Although when it comes to screening
patients with epilepsy specifically, the
recommended cut point for the HAM-D is > 16 (Se,
95%; Sp, 76%; PPV, 59%; NPV, 98%) (16, 33).
The HAM-D can be used as an adequately reliable
screening tool in PWE, however, it takes around 20
minutes for the physician to complete the
assessment, making its use problematic in
ambulatory care (31). In addition to that, it is
important to note that Hamilton himself stated that
the HAM-D has been designed specifically to
measure the severity of depression in patients
already diagnosed with MDD, not as a diagnostic
or screening tool (31, 34).
Hospital Anxiety and Depression Scale
(HADS) is a 14-item self-assessment scale
comprising of seven questions for anxiety and
seven questions for depression, tailored to measure
anxiety and depression in general medical
population (35). It is available in 115 languages,
including Lithuanian (38). Optimal balance
between sensitivity and specificity for HADS as a
screening instrument is achieved at a cut-off score
of > 8, with (means: Se, 77%; Sp, 85%; PPV, 58%;
NPV, 95%) (16, 37, 41). However, for PWE the
recommended cut point for the HADS can be
lowered to 7 (means: Se, 81%; Sp, 86%; PPV,
49%; NPV, 96%) (16, 41). When compared to
other commonly used questionnaires for
depression, the mean correlation coefficients to
HADS were between 0.60 and 0.80, which should
be characterized as moderate to high correlation
(37). Screening for depression with HADS takes up
to 5 minutes, making it a quick and reliable tool,
well-suited for a time-poor clinical setting. (35, 46,
37). The main downside is that, although freely
available in the past, currently the scale is
copyrighted, thus it must be purchased for
administration (35, 46).
Patient Health Questionnaire (PHQ-9) is a
9-item self-administered questionnaire to screen
for depression based on DSM-IV diagnostic
criteria (38). There is also a short version (PHQ-2),
which uses only the first two questions of PHQ-9:
diminished interest or pleasure and depressed
mood (39). It has been translated to over 50
languages, including Lithuanian (40). PHQ-9 has a
pooled Se of 92% and Sp of 80% in various
medical populations, the most optimal trade-off
between sensitivity and specificity at a cut-off
score of 11 (Se, 89%; Sp, 89%; PPV and NPV not
provided; diagnostic odds ratio, 75.03) (38, 39 ,40).
However, in PWE specifically, the best overall
balance is noted at a cut-off score of 9 (Se, 83%;
Sp, 82%; PPV, 42%; NPV, 97%), although a more
recent systematic review suggests to stick with ≥
10 (16, 43). PHQ-2 is not recommended to use in
PWE due to inadequate sensitivity to detect cases,
albeit it is still better than nothing (16, 39, 43, 46).
Studies on the concurrent validity of both PHQ-2
and PHQ-9 demonstrate moderate to high
correlation with other self-assessment measures for
MDD (26, 33, 34).Taking only a few minutes to
complete and available in public domain in
numerous languages, PHQ-9 is convenient and
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adequately reliable screening tool in PWE even for
a busy clinical practice (16, 26, 33, 34).
Emotional Thermometer (ET) is a visual-
analogue self-rating tool, composed of seven
pictorial thermometers (each for one of the four
predictor domains: distress, anxiety, depression,
anger, and three outcome domains: duration of
illness, burden, and need for help) (46, 47). The
ET7 has been professionally translated into over 15
languages, albeit not yet to Lithuanian (46, 47). As
it has been designed as a distress measuring tool
among cancer patients, literature on ET7 as a
screening tool for depression in general and/or
medical populations is practically non-existent (46-
52). A few studies have been specific to PWE and
demonstrated that the optimal cut-off score for ET7
as a screening tool is ≥ 29 (Se, 85.4; Sp, 79.2; PPV,
48%; NPV, 96%) (16, 50). In 2012, due to it being
optimal on its own, DepT has been launched as a
stand-alone single-item tool for screening for
depression with a cut-off score of ≥ 4 (Se, 80%; Sp,
79%), and it also seems to perform just as well in
PWE (47, 48, 50, 51). When compared to other
assessment measures, ET7 has also demonstrated
moderate to high correlation (46-50). Depression
screening with the ET7 takes only a couple of
minutes, is sufficiently reliable and it being a
visual-analogue tool makes ET7 the most
applicable option for patients with low reading
levels (16, 50).
An ideal tool to screen for depression in
PWE should not only be of optimal sensitivity and
specificity, but also convenient to use, brief,
validated, easily accessible in various languages
and cheap (17, 52). To conclude on the discussion
above, we would recommend the Neurological
Disorders Depression Inventory for Epilepsy
(NDDI-E) as the clinician-conducted method of
choice and the Patient Health Questionnaire (PHQ-
9) for a self-administered assessment (16, 17, 43,
53). PHQ-9 can be considered slightly more
specific than NDDI-E, but it requires more of the
physician’s time (16, 45). Owing to it being the
only validated visual screening option, Emotional
Thermometer (ET7) can be used to supplement
either of the aforementioned tools or as a
standalone measure (50, 53). In fact, Drinovac et
al. (2015) recommends using enhanced depression
screening in epilepsy tool (EDET) that contains
both verbal and visual analog scales, which they
created by combining NDDI-E and ET (Se, 89%;
Sp, 88%; PPV, 61%; NPV, 97%) (54). However,
further studies on EDET are needed.
The quality of life
The majority of studies that were
performed on people suffering with epilepsy and
depression conducted that these two comorbidities
significantly decrease life quality of these patients.
A study performed in 2019 by Greek scientists has
shown that people with epilepsy were not only
more susceptible to being diagnosed with
depression, but also have a lower quality of life
considering their physical health, psychological
and social relationships. Being diagnosed with
depression and adverse effects of antiepileptic
drugs were the factors mainly associated with their
low quality of life (55). Moreover, a study that
compared cohorts of people, who were diagnosed
with epilepsy and depression, and healthy
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77
individuals found that people with these two
illnesses are more likely to make a suicide attempt
and have a drug overdose related with their suicidal
ideation. The results between healthy people and
the ones that have been diagnosed only with
epilepsy differed only by a small amount. The
population of people suffering from epilepsy had a
significantly higher incidence rate with such
psychiatric conditions as schizophrenia, insomnia,
anxiety and alcohol related disorders (56).
Concerning that 57,1% of epilepsy patients have a
significant reduction in their life quality (57) it is a
must to apply certain screening tools to identify it.
It was shown that applying such scales as NDDI-E
for major depressive disorder, GAD-7 for anxiety,
and AEP for antiepileptic drug effects allows
having a rapid and reliable screening of life quality
in epilepsy patients (58). Therefore, an adequate
treatment can be administered.
Pharmacological treatment
Choosing a safe antidepressant
medication relies on having a therapeutic effect
without provoking any seizures in epileptic
patients. Since it was shown that tricyclic
antidepressants can induce seizures even in patients
without epilepsy (59) this would not be the first line
choice in PWE. However, it has been tested that
administering SSRI‘s or SNRI‘s in therapeutic
doses does not induce seizures in epilepsy patients
and may reduce seizure frequency for those who
experience it more than 1 time a month. An
improvement of psychiatric symptoms was
experienced by 73% of participants, although a
decrease in seizure frequency was not associated
with it (60). Another study that was performed
specifically with citalopram, mirtazapine and
reboxetine also supports this idea (61). Even
though antidepressants seem to be effective,
studies have shown that such antiepileptic drugs as
carbamazepine increase clearance of
antidepressant medication and this often leads to
the recurrence of depressive episodes. On the other
hand, the clearance of antiepileptic drugs can be
inhibited by some of the antidepressants (62). This
suggests the idea that it would be ideal to have one
medication to treat both epilepsy and depressive
symptoms. A prospective multicentered study was
performed in order to find if lacosamide would
prove to be helpful. Testing scores in both
depression and life quality have significantly
improved in both 3 month and 6 month measuring
periods. People who suffered from moderate
depression seemed to benefit the most from this
medication. Moreover, a significant decrease of the
seizure frequency was observed and it was shown
that the improvements on psychiatric symptoms
were not associated with a better seizure control
(57). Antipsychotic drugs are an area that could be
investigated more since there are several case
reports of olanzapine 2,5 mg/d being a valuable
medication treating both seizures and depression in
patients with difficult to treat epilepsy (63).
However, larger studies are needed to establish its
effectiveness.
Psychotherapy
The study that was performed on people
with both refractory mesial temporal lobe epilepsy
and comorbid psychogenic nonepileptic seizures
proved that cognitive behavioural therapy based
psychotherapeutic intervention can be an efficient
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78
way to manage these problems. The duration of
treatment was 8 weeks and several measurements
took place before and after it. There were
significant improvements in quality of life,
depressive symptoms and seizure frequency
compared to the control group (64). Also the Home
Based Self-management and Cognitive Training
Changes lives (HOBSCOTCH) program was
shown to be effective at improving quality of life
in epilepsy patients. It is composed of subjects such
as psychoeducation, self-awareness training,
compensatory strategies and applying those
strategies in daily life. According to the study, the
life quality significantly increased, but depression
scores did not seem to be significantly different
between the intervention and control groups (65).
The reason to that might be that selected patients
were not diagnosed with depression before
applying the intervention. There is only one pilot
study conducted that compares treatment with
SSRI‘s and psychotherapy. People who were
diagnosed both with major depressive disorder and
temporal lobe epilepsy were compared after
receiving a 12 week long treatment. Both
symptoms of depression and quality of life
improved after applying either one or another
method but no significant differences were found
(66). It suggests that more double blind controlled
studies with a bigger sample size could be done in
order to prove the efficacy of the psychotherapy.
Other treatments
Vagus nerve stimulation has proven to be
an effective way of managing both depressive
symptoms and seizure frequency in patients with
difficult to treat epilepsy. It has been observed that
more than 50% of patients who underwent this type
of treatment experienced an improvement in their
life quality, moreover their scores in depression
measuring scales have improved and two thirds of
patients experienced at least 50% of seizure
frequency reduction (67). Another treatment that is
established to be effective at improving depression
and life quality of these patients is epileptic
surgery. The Hispanic population was followed
before and 1 year post surgery while a full
neuropsychological evaluation was performed. The
number of patients with moderate or severe levels
of depression declined from 37,0% to 15,2%, the
life quality was shown to be improved in moderate
or large amounts (68). Moreover, since it has been
demonstrated that electroconvulsive therapy can be
used to control seizures in a refractory status
epilepticus (69) and is an even more effective
antidepressant treatment than pharmacological
(60) it can be suggested that it is a valuable option
for those who have already tried managing their
illnesses with pharmacological and other kinds of
therapies.
Conclusion
Depression is one of the most common psychiatric
comorbidities in adults with epilepsy (7). Women
are affected more than men (8). Epilepsy and
depression have a bilateral connection meaning
that those who are diagnosed with epilepsy are
much more likely to be diagnosed with depression
and otherwise (9). We would recommend the
Neurological Disorders Depression Inventory for
Epilepsy (NDDI-E) as the clinician-conducted
method of choice and the Patient Health
Questionnaire (PHQ-9) for a self-administered
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79
assessment. (16, 17, 43, 54). PHQ-9 can be
considered slightly more specific than NDDI-E,
but it requires more of the physician’s time (16,
45). Owing to it being the only validated visual
screening option, Emotional Thermometer (ET7)
can be used to supplement either of the
aforementioned tools or as a standalone measure
(50, 54). More than a half of epilepsy patients have
a significant reduction in their quality of life (55,
56, 57) and the factors most associated with it are
being diagnosed with depression and experiencing
adverse effects from their antiepileptic medication
(55). There are many treatment options that can be
considered optimal and effective. SSRI’s and
SNRI’s seem to help 73% of the patients with
depressive symptoms while not putting them at an
increased risk of a seizure (60, 61). Cognitive
behavioural psychotherapy sessions seem to be
helpful with providing a better life quality for these
patients (64, 65). Moreover, there are many other
treatment possibilities to consider if these do not
help.
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