International Review of Psychiatry

ISSN: 0954-0261 (Print) 1369-1627 (Online) Journal homepage: http://www.tandfonline.com/loi/iirp20

Psychiatric comorbidities in epilepsy

Colin B. Josephson & Nathalie Jetté

To cite this article: Colin B. Josephson & Nathalie Jetté (2017): Psychiatric comorbidities in
epilepsy, International Review of Psychiatry, DOI: 10.1080/09540261.2017.1302412

To link to this article: http://dx.doi.org/10.1080/09540261.2017.1302412

Published online: 06 Jul 2017.

Submit your article to this journal

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=iirp20

Download by: [Cornell University Library] Date: 07 July 2017, At: 11:48
INTERNATIONAL REVIEW OF PSYCHIATRY, 2017
http://dx.doi.org/10.1080/09540261.2017.1302412

REVIEW ARTICLE

Psychiatric comorbidities in epilepsy

Colin B. Josephson
and Nathalie Jette

Department of Clinical Neurosciences, Hotchkiss Brain Institute and O’Brien Institute for Public Health, Cumming School of Medicine,
University of Calgary, Calgary, AB, Canada

ABSTRACT ARTICLE HISTORY

Psychiatric comorbidities, including mood, anxiety, and psychotic disorders, are common in Received 2 January 2017
epilepsy, often occurring at rates 2–3-fold or higher than in the general population without Revised 11 February 2017
epilepsy. This article discusses the epidemiology of psychiatric disorders in epilepsy, hypotheses Accepted 28 February 2017
regarding the pathogenesis of these comorbidities, and treatment implications. More specifically,
it addresses: (1) How common are major depressive disorder, anxiety disorders, and psychotic KEYWORDS
disorders in epilepsy? (2) How does one screen for these psychiatric disorders in persons with Mental health; depression;
epilepsy? (3) Why do psychiatric conditions occur in epilepsy? (4) Is the treatment of psychiatric anxiety; psychosis;
comorbidity in epilepsy associated with seizures? The important topic of suicide and suicidal epidemiology
ideation in epilepsy, risk factors for their occurrence, and how to screen for these co-existent
conditions is also discussed. Finally, gaps in knowledge regarding psychiatric conditions in epi-
lepsy are briefly discussed.

Introduction Psychiatric disorders are common in people with

epilepsy. However, in order to produce a cogent
An epileptic seizure is defined as a transient occur-
understanding of the impact of psychiatric disorders
rence of signs and/or symptoms due to abnormal
excessive or synchronous neuronal activity in the on people with epilepsy, it is first integral to under-
brain (Fisher et al., 2005). Seizures can be focal (origi- stand the concept of what constitutes ‘comorbidity’.
nating in networks limited to one hemisphere of the If stringently defined, one can consider a comorbid-
brain) or generalized (arising within and rapidly ity to be a medical condition that either exists at
engaging networks in both hemispheres) (Berg et al., the time of diagnosis or arises during the course of
2010). Epilepsy is defined as a disorder of the brain the disease process, but does not occur as a conse-
characterized by an enduring predisposition to gener- quence of said disease (Ording & Sorensen, 2013).
ate epileptic seizures, and by the neurobiological, cog- Therefore, from an epidemiological perspective, psy-
nitive, psychological, and social consequences of this chiatric comorbidities in epilepsy should occur con-
condition (Fisher et al., 2005). The International comitantly with the disease at some point during its
League Against Epilepsy’s clinical definition of epi- natural history, but should not develop as a direct
lepsy requires two unprovoked seizures separated by result of the condition. Shared mechanisms may
more than 24 h, one unprovoked seizure with a future contribute to the emergence of both epilepsy and a
10-year risk of recurrence equal to that of someone psychiatric condition in the same patient. Although
with epilepsy (60%; the risk is determined by clinical data are scarce, evidence does exist that those with
history, physical examination, and diagnostic tests), or focal epilepsies from the temporal (60% risk) or
the diagnosis of an epilepsy syndrome (Fisher et al., extratemporal (54% risk) regions may have a
2014). Epilepsy is a common condition effecting higher risk of a psychiatric comorbidity than those
people of all ages, gender, and socioeconomic status. with a generalized epilepsy syndrome (37%)
It is the third most common neurological cause of (Edeh & Toone, 1987), thus suggesting differing
years lived with disability in the world pathophysiology.
(Global Burden of Disease Study 2013 Collaborators, On this background, it is imperative to consistently
2015). apply this definition of comorbidities to epilepsy.

CONTACT Nathalie Jette nathalie.jette@albertahealthservices.ca Department of Clinical Neurosciences, Hotchkiss Brain Institute and O’Brien
Institute for Public Health, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
*CBJ and NJ vest copyright privileges to the Institute of Psychiatry.
ß 2017 Institute of Psychiatry and Johns Hopkins University
2 C. B. JOSEPHSON AND N. JETTE

Psychiatric disorders can occur as discrete, self-limited presenting with suspected epilepsy may be ultimately
entities resulting directly from a seizure (‘periictal’ or misdiagnosed with another condition (Chadwick &
‘postictal’ psychiatric disturbances) or occur independ- Smith, 2002; Scheepers, Clough, & Pickles, 1998;
ently in the context of epilepsy (‘interictal’ psychiatric Smith, Defalla, & Chadwick, 1999). Hence, care must
disorders). It is this latter phenomenon that we will be taken when attempting to recruit people into pro-
consider a comorbidity for the purposes of this paper. spective cohort studies. Administrative and electronic
Admittedly, whilst peri- and postictal psychiatric dis- health record case definitions for epilepsy do exist,
orders are both common and debilitating for people but are never 100% sensitive and specific (Kee,
with epilepsy, especially for those with drug-resistant Gilchrist, Granner, Sarrazin, & Carnahan, 2012;
epilepsy, the emphasis of this article will be on inter- St Germaine-Smith et al., 2012; Tu et al., 2014;
ictal psychiatric conditions that are comorbid with Williamson et al., 2014).
epilepsy. Likewise, cases of psychiatric disease can also be
Specifically, this narrative review addresses the epi- difficult to diagnose. Unlike physical comorbidities,
demiology, clinical manifestations, and treatment con- mental disorders often lack tangible, physical symp-
siderations for common comorbid psychiatric toms. Hence, they may not be as readily identified
conditions that include major depressive disorder, and classified by some practitioners. Furthermore,
anxiety, and psychosis. Other related outcomes, these conditions may occur as acute, paroxysmal,
including suicide and suicidal ideation, will also be self-limited events that may go unnoticed by clini-
briefly addressed. Ultimately, the goal of this paper cians due to the ephemeral nature of the symptoms,
will be to familiarize the reader with the challenges a propensity to downplay the severity of the episode,
associated with performing high-quality research on or due to reluctance of the individual to present to
comorbid conditions in epilepsy and to present these medical attention because of perceived stigma.
issues in a clinically relevant fashion with direct appli- Differential and non-differential misclassification bias
cation to the manifestations and evidence-based treat- can, thus, occur if those with depression are not
ment of these conditions. adequately identified and assigned to the correct
exposure group. Psychiatric conditions in people
What are methodological issues in the study with epilepsy may also display features that are dis-
of psychiatric comorbid conditions in cordant with those typically seen in conventional
epilepsy? forms of the disorder. Thus, these comorbidities are
at risk of being missed in cohort studies if investiga-
Studies into psychiatric comorbidities in epilepsy are
tors unfamiliar with their characteristics are monitor-
frequently limited by selection bias. Much of our
ing individuals during follow-up. Although
understanding of comorbid psychiatric disorders in
administrative and electronic health records are an
epilepsy is derived from tertiary care centres that, by
definition, tend to treat people on the more severe alternative to prospective cohort studies, validated
end of the spectrum. Therefore, bias exists in many of case definitions are lacking for many psychiatric con-
these investigations, since they focus on people with ditions, whilst psychiatric disease itself is frequently
drug-resistant epilepsy. Population-based studies, under-ascertained and often miscoded in these data-
whether accomplished through prospectively accruing sets (Fiest et al., 2014).
individuals or by interrogating administrative and In addition to the aforementioned issues, it is also
electronic health records, are the ideal means of defin- challenging to discern, in those with epilepsy, between
ing the risk of psychiatric disease in a general popula- ictal-related psychiatric phenomenon and interictal dis-
tion of people with epilepsy. However, these studies ease. Seizures themselves, especially those originating
are often hindered by challenges in diagnosing both from a limbic focus, may present with preictal, ictal, or
the source population (epilepsy) and the condition of postictal depression, anxiety, or psychosis. For
interest (psychiatric disease). instance, preictal depression may precede seizures by
Epilepsy can be challenging to diagnose, with many hours to days, whilst ictal depression, albeit rare, can
conditions exhibiting symptoms that can masquerade manifest as paroxysmal, stereotyped episodes of dys-
as seizures. Syncope, cardiac arrhythmias, and psycho- phoric mood that are uncharacteristic and incongruent
genic non-epileptic attacks are among many condi- with the individual’s antecedent emotional state.
tions that commonly involve episodic loss of Postictal depression can occur within 5 days of a seiz-
consciousness, altered awareness, or convulsions ure in up to 50% of people with medication-resistant
(Smith, 2012). Indeed, up to 20–31% of people epilepsy.
 INTERNATIONAL REVIEW OF PSYCHIATRY 3

Those with uncontrolled epilepsy may also suffer and treatment outcomes in people with epilepsy
from depression or anxiety related to the fear of add- (Hamid et al., 2014; Kanner, 2008). However, consid-
itional seizures, from loss of the ability to drive and/or erable heterogeneity exists amongst studies reporting
work, from depressed socioeconomic status, or from depression incidence that is likely in part due to the
the psychotropic effects of antiepileptic drug (AED) types of depressive syndromes (e.g. major depressive
polytherapy. These adverse emotional responses must disorder, dysthymia, bipolar disorder, cyclothymic dis-
be distinguished from an endogenous predisposition order) encountered in the interictal setting.
towards psychiatric disease if one is going to isolate the A recent systematic review and meta-analysis of
biological mechanisms that may underpin both epi- population-based studies examining depression in epi-
lepsy and its comorbid diseases. lepsy yielded 23 articles reporting on 14 distinct pop-
Hence, selection and misclassification bias typically ulations. The estimated overall pooled estimate for the
detract from studies examining the influence of incidence of active depression (current or past-year)
psychiatric comorbid conditions on the overall quality- derived from nine studies reporting on 29 891 people
of-life in people with epilepsy. For instance, depression was 23.1% (95% confidence interval [95%
can be defined using a number of existing CI] ¼ 20.6–28.3%) (Fiest et al., 2013) (Table 1). The
clinical criteria (e.g. DSM-V (American Psychiatric risk of lifetime depression, derived from four studies
Association, 2013)) with which many clinicians may reporting on 5454 people with epilepsy, was estimated
not be intimately familiar, and those with mild depres- at 13% (95% CI ¼5.1–22.1%).
sion may not present or be identified, thus leading to As anticipated, significant statistical inconsistency
selection bias that will systematically inflate the effect and variation in quality was noted between studies
estimates of the influence of the disease on epilepsy (Fiest et al., 2013). Response rates of 70%, compari-
outcomes. sons with non-responders, accepted classification sys-
tems for epilepsy, and controlling for confounders
was inconsistently applied amongst included studies.
Depression and epilepsy
Heterogeneity was primarily related to methodological
Interictal depression approaches and, in particular, mechanisms used to
define and identify depression. Furthermore, as out-
How common is depression in epilepsy?
lined in the prior section, depression represents an
Prior estimates have indicated that depression may be entity that is frequently subject to personal interpret-
3 to 10 times more common in those with epilepsy ation in the clinical setting and exists both as acute,
compared to the general population (Lambert & paroxysmal episodes and in prolonged, chronic forms.
Robertson, 1999). Proper treatment is critical, since Formal definitions also differ, and the disorder is vari-
depression itself appears to exert a major influence on ably identified through validated and unvalidated rat-
the quality-of-life (Kobau, Gilliam, & Thurman, 2006) ing scales or via formal definitions such as those

Table 1. Prevalence of various psychiatric comorbidity in epilepsy and associated factors or pathophysiology.
Pathophysiology (hypotheses) and associated
Psychiatric comorbidity How common in persons with epilepsy? factors
Mood disorders Depression (active prevalence): 23.1%  Bidirectional relationship
Manic symptoms: 12.2%  Lesional epilepsy (especially temporal lobe)
Postictal mania/hypo-mania: 22% persons admitted  Dysfunction of temporal, orbitofrontal and
to seizure unit inferior prefrontal areas
 Stigma
Anxiety disorders Anxiety (lifetime prevalence): 22.8%  Amygdalar atrophy
 GABAergic mechanisms
 Stigma
 Seizure unpredictability
 Lack of education
Psychosis Interictal psychosis: 5.2%  Bidirectional relationship
Interictal psychosis  Abnormalities in post-synaptic dopamine
(temporal lobe epilepsy only): 7% receptor sensitivity
Postictal psychosis: 2%  Increased GABA turnover
 Aberrant synaptic circuits in the dentate-
CA3-CA1 circuit
 Autoimmunity (NMDA and LG1 encephalitis)
Personality disorders Overall epilepsy: 4–38%  Unknown
Suicide attempts and completed suicide 5–14.3% of person with epilepsy  Mood disorder
 Prior suicide attempt
4 C. B. JOSEPHSON AND N. JETTE

provided in the Diagnostic and Statistical Manual of However, although evidence exists supporting a
Mental Disorders V (DSM V) (American Psychiatric common neuroanatomical relationship, those with
Association, 2013). This inevitably introduced add- epilepsy also regularly face psychosocial stressors in
itional heterogeneity into the results. Studies reporting excess of that seen in the general population. Stigma
adjusted estimates also appeared to be more conserva- and socioeconomic stress are thought to be major
tive, suggesting that additional clinical parameters mediators of mental discord and personal dissatisfac-
may confound the relationship between epilepsy and tion in people with epilepsy (Jacoby, Baker, Steen,
depression. Alternatively, adjusting for these variables Potts, & Chadwick, 1996). In particular, the lack of
may have spuriously masked their effect on the causal independence may significantly contribute to acute
pathway between epilepsy and depression (Fiest et al., and chronic depressed mood. Driving and vocational
2013). Therefore, the random-effects pooled result in restrictions, social isolation, and stigma may all con-
the above systematic review is likely the best available tribute to lowered self-esteem. Driving, employment,
estimate to date. and independence, AED adverse effects, safety, seizure
However, this meta-analysis was unable to stratify unpredictability, and seizure aversion were the major
people by seizure frequency or seizure severity, or sources of dissatisfaction leading to impaired quality-
account for use of anti-epileptic drugs with psycho- of-life in one study (Gilliam et al., 1997).
tropic effects. Rates of depression appear to be par-
ticularly prominent in those with drug-resistant How do we identify depression in epilepsy?
epilepsy, with up to 50% experiencing clinically sig-
nificant symptoms during their lifetime, as compared Due to the under-ascertainment of depression in epi-
to 10% in those whose seizures are in remission lepsy, international consensus now exists that screen-
(Gilliam & Kanner, 2002; Hermann, Seidenberg, & ing for depression in epilepsy should occur on an
Bell, 2000). annual basis (Kerr et al., 2011). This is primarily pre-
dicated on the basis that those with epilepsy have
increased risks of suicide, that depression influences
What is the pathophysiology of depression in quality-of-life and seizure control, and that there is an
epilepsy? independent association between depression and
The link between epilepsy and interictal depression is healthcare costs for people with epilepsy (Cramer,
highly complex. Prior studies have reported a bidirec- Blum, Fanning, & Reed, 2004; Kerr et al., 2011). A
tional relationship between the two disorders as the number of depression screening tools now exist to
incidence rate ratios (the ratio of the incidence rate of facilitate the diagnosis of depression in people with
depression [number of new cases of depression div- epilepsy (Gill et al., 2017). Perhaps the most com-
ided by person time for the epoch of interest] for sub- monly used is the Neurological Disorders Depression
jects over the incidence rate of depression for controls Inventory for Epilepsy (NDDI-E) (Gilliam et al.,
for each year in the study period) for depression are 2006). This is a validated six-item questionnaire, with
significantly elevated both before and after an epilepsy 4-points allocated to each question. Increasing scores
diagnosis (Hesdorffer et al., 2012). Furthermore, those indicate more severe depression, with a cut-off of 15
with lesional temporal lobe epilepsy secondary to hip- typically used to identify major depressive disorder.
pocampal sclerosis, a major nexus in the limbic net- A commonly used alternative tool validated in epi-
work, may be at higher risk of depression, whilst lepsy is the Patient Health Questionnaire-9 (PHQ-9)
hypoperfusion of the temporal lobe and bilateral (Fiest et al., 2014; Rathore et al., 2014). The PHQ-9,
frontal regions on single-photon emission computed similarly to the NDDI-E, is publicly available, free to
tomography (SPECT) is associated with higher Beck use, and easy to score. In addition, unlike the NDDI-
Depression Inventory scores (Quiske, Helmstaedter, E, it has been validated in both epilepsy and in the
Lux, & Elger, 2000; Schmitz et al., 1997). Both depres- general population. The Beck Depression Inventory-II,
sion and epilepsy have been linked to abnormal struc- the Hospital Anxiety and Depression scale (HADS),
ture and/or function of the temporal, orbitofrontal, and the Major Depression Inventory (MDI) have also
and inferior prefrontal areas while, at a synaptic level, been used to identify mood disorders in people with
they have been linked to altered expression and action epilepsy amongst other screening tools, but are not
of certain neurotransmitters (Kanner, 2005; Mayberg, available in the public domain (Fiest et al., 2014).
1994). These results have fuelled the debate as to Although seemingly counterintuitive, the DSM cri-
whether epilepsy and depression share similar aetio- teria for major depressive disorder may not be as
logical factors and pathogenic mechanisms. robust for detecting major depression in those with
 INTERNATIONAL REVIEW OF PSYCHIATRY 5

epilepsy. In fact, in one study, only 29% of depressed Hansen, 2015). Hence, caution must be exercised when
people with epilepsy met the DSM-IV criteria for applying these criteria, as inclusion or exclusion of this
major depressive disorder (Kanner, Kozak, & Frey, condition in estimates of the prevalence of depression
2000). Rather, depressed people with epilepsy tend to in epilepsy would lead to diluted or elevated summary
exhibit more dysthymia and comparatively fewer estimates of association, respectively.
neurotic traits (somatization, anxiety, guilty, and Bipolar spectrum disorders were conventionally
hopelessness) than individuals without epilepsy thought to be rare in epilepsy. However, systematic
(Mendez, Cummings, & Benson, 1986). investigations using US survey data have in fact
revealed an association between epilepsy and bipolar
spectrum disorder, as manic symptoms may be pre-
Preictal, ictal, and postictal depression sent in up to 12.2% of patients with epilepsy (7-
times that recorded in a healthy population of people)
It is integral to discern between interictal comorbid
(Ettinger, Reed, Goldberg, & Hirschfeld, 2005).
depression and seizure-related depression. These con-
Unfortunately, robust studies of the specific features
ditions are directly related to seizures and, therefore,
of bipolar spectrum disorder and epilepsy have yet to
should not be considered as equivalents to interictal
be conducted. Smaller studies have suggested that
depression. Rather, preictal depression occurs hours to
manic symptoms tend to manifest as periictal phe-
days before a seizure, and is primarily characterized by
nomena (Mula et al., 2008). By nature, it is difficult to
dysphoria (Blanchet & Frommer, 1986). Affective
study preictal symptomatology, due to the lack of a
symptoms, especially a depressed mood, may also com-
clear onset, but it has been reported that people with
plicate 15% of auras that involve psychiatric symptoms
epilepsy will report a labile mood, euphoria, and irrit-
(Kwon & Park, 2014). Ictal depression itself is quite
ability in the hours leading up to a seizure (Mula
rare and typified by short, self-limited, stereotyped epi-
et al., 2010), whilst postictal mania/hypomania have
sodes of dysphoria, often with intact cognition (focal
been reported in 22% of people with drug-resistant
non-dyscognitive seizures), that are incongruent with
epilepsy admitted to a seizure monitoring unit
the person’s current social situation. Postictal depres-
(Kanner et al., 2004). Additional research further
sion occurs within 5 days of a seizure and persists for a
defining the relationship between bipolar spectrum
median of 24 h (Kanner, Soto, & Gross-Kanner, 2004).
disorder and epilepsy is desirable.
Unfortunately, there are no population-based studies
that have examined the epidemiology of these types of
depression in epilepsy. Hopefully, over time, more will Anxiety and epilepsy
be known about these self-limited but albeit severe
Interictal anxiety
depressive conditions.
How common are anxiety disorders in epilepsy?
Anxiety disorders represent a broad entity of syn-
Additional mood disorders
dromes with varied manifestations. Ranging from
The majority of studies conducted to date that focus conditions such as generalized anxiety disorder to
on affective disorders primarily describe the associ- more specific sources of anxiety found in phobias and
ation between depression and epilepsy. However, obsessive compulsive disorder (now a separate classifi-
other mood disorders, such as dysthymia and cation in the Diagnostic and Statistical Manual-V
bipolar spectrum disorders, are common, often under- (American Psychiatric Association, 2013), these ultim-
recognized, and under-treated (Kanner, 2007). ately represent a unique collection of diseases with a
The rather controversial entity, interictal dysphoric common underlying feature of heightened fear
disorder (IDD), may distort overall estimates of the responses out of proportion to a threat or spontan-
association between bona fide depression and epilepsy. eous stimuli in the absence of tangible danger.
Some consider IDD to be a separate somatoform- Interestingly, compared to depression, there is a
depressive entity that is typical of people with epilepsy. relative paucity of evidence concerning comorbid anx-
It is conventionally characterized by labile depressive, iety in people with epilepsy. This may be secondary to
affective, and euphoric symptoms with intermixed par- the heterogeneous forms of anxiety disorders com-
oxysmal irritability (Blumer, 2000). Although diagnos- pared to depression. Ultimately, estimates of the life-
tic criteria for IDD exist (the Interictal Dysphoric time prevalence of overall anxiety in the epilepsy
Disorder Inventory) (Mula et al., 2010), they may have population may be as high as 22.8% (95% CI
a low reproducibility in specific populations (Amiri & ¼14.8–30.9%) (Tellez-Zenteno, Patten, Jette, Williams,
6 C. B. JOSEPHSON AND N. JETTE

& Wiebe, 2007) according to population-based stud- limbic onset or spread to the limbic region. Focal
ies. This is compared to 5.6% in the general popula- seizures without impairment of awareness of limbic
tion without epilepsy (Gaitatzis, Carroll, Majeed, & origin may present as isolated fear or panic and,
Sander, 2004) (Table 1). Ultimately, there appears to when present, other features of temporal lobe seizures
be a 2.4 (95% CI ¼1.5–3.8) fold elevation in the odds may accompany them (e.g. deja vu, epigastric rising
of reporting an anxiety disorder in those with epilepsy sensation, olfactory hallucinations). Often, if ictal, the
compared to the general population free of the condi- anxiety will occur in a paroxysmal, stereotyped man-
tion (Tellez-Zenteno et al., 2007). ner lasting for seconds to minutes, and may evolve to
Similar to depression, accurate recognition and a focal seizure with impaired awareness.
documentation of anxiety is critical for epidemiological Postictal anxiety can manifest in a number of ways.
studies, and the use of varying tools may explain the It typically occurs within 6–24 h after seizure offset,
mild discrepancy in incidence and prevalence seen and may present as anxiety, panic, agoraphobia, or
between population-based studies. The Hospital compulsions (Kanner, Trimble, & Schmitz, 2010b),
Anxiety and Depression Scale for anxiety (HADS-A) but is often accompanied by other dysphoric symp-
has been evaluated in epilepsy with the conclusion that toms such as depression (Kanner, Stagno, Kotagal, &
it may simply detect distress rather than bona fide anx- Morris, 1996).
iety disorders (Gandy et al., 2015). On the other hand,
the Generalized Anxiety Disorder-7 (GAD-7) scale Psychosis and epilepsy
appears to have utility in people with epilepsy due to
its high sensitivity and specificity at a cut-point of 10 Interictal psychosis
(Seo et al., 2014). How frequent is interictal psychosis?

What is the pathophysiology of anxiety in epilepsy? The connection between psychosis and epilepsy has
historically been of keen interest to epileptologists and
It can be challenging to discern between reactionary psychiatrists alike. A recent systematic review and
anxiety to epilepsy itself and comorbid anxiety occur- meta-analysis was completed, with 58 studies identi-
ring in the setting of epilepsy. Stigma, concern over fied, of which 10% were population-based (Clancy,
the unpredictability of seizures, and a lack of educa- Clarke, Connor, Cannon, & Cotter, 2014). Those
tion regarding epilepsy itself have all been associated with epilepsy had elevated odds of psychosis com-
with risk of anxiety (Jacoby et al., 1996). pared to the general population (OR ¼ 7.8; 95%
Evidence of shared pathophysiological mechanisms CI ¼ 2.81–21.79), although the overall pooled estimate
is mainly predicated on the phenomenon of ictal fear. was imprecise due to a paucity of studies (n ¼ 4) that
The amygdala, in particular, is associated with fear included a control group (Clancy et al., 2014). Few
responses, and is often involved in temporal lobe epi- population-based studies exist reporting the incidence
lepsy (Satishchandra et al., 2003). MRI brain evalua- of psychosis in epilepsy. A Danish study using a
tions have demonstrated concordance between national register of linked data, that included 67 116
amygdala atrophy and the seizure focus in over half people, extracted data from all people with epilepsy
of people with features of ictal fear in their habitual admitted to a general hospital over a 15-year period.
semiology (Cendes et al., 1994; Van Paesschen, King, The reported standardized incidence ratio (an esti-
Duncan, & Connelly, 2001). Additionally, the neuro- mate of the occurrence of psychosis in the population
transmitter c-aminobutyric acid (GABA) may also of interest relative to what is expected in a compara-
play a central role in the interplay between epilepsy tor population designated as ‘normal’; therefore it is
and anxiety as GABAergic medications, such as val- the ratio of the observed number of psychosis cases to
proic acid, barbiturates, and benzodiazepines, the expected number of cases multiplied by 100) of
have both anti-convulsant and anxiolytic properties psychosis, after excluding individuals with learning
(Mohler, 2006). disabilities and substance misuse, was 2.30 (95%
CI ¼ 2.02–2.59) (Bredkjaer, Mortensen, & Parnas,
1998). Similar results were reported for non-affective
Preictal, ictal, and postictal anxiety
psychosis (2.74) and schizophrenia (2.15) (Bredkjaer
Similar to depression, it is critical to separate interictal et al., 1998). The incidence ratio according to a tertiary
anxiety from that related to seizures. Symptoms of care centre study of people with epilepsy was 0.3%
anxiety at seizure onset should be sought in all cases (Onuma, Adachi, Ishida, Katou, & Uesugi, 1995).
of focal epilepsy, since such symptoms may suggest a The pooled prevalence of interictal psychosis from 10
 INTERNATIONAL REVIEW OF PSYCHIATRY 7

studies was 5.2% (95% CI ¼ 3.3–7.2), whilst that spe- general population (Hammer et al., 2014). More
cifically to temporal lobe epilepsy, derived from 17 research in this area, specifically focusing on blood–
studies, was 7.0% (95% CI ¼ 4.9–9.1%) (Clancy et al., brain barrier integrity, is warranted (Hammer et al.,
2014) (Table 1). These estimates must be interpreted 2014).
with caution, however, as there was substantial hetero-
geneity across studies that could not be explained by
What are other types of psychoses associated with
study design, study setting, the instrument used to
epilepsy?
assess psychosis, types of reported epilepsy, year of
study, family history of psychosis, the version of the Ictal psychosis is uncommon in persons with epilepsy,
International League Against Epilepsy classification of and is usually identified through concurrent epilepti-
epilepsy used, exclusion criteria employed by studies, form discharges on electroencephalography (EEG).
and the country of origin. These episodes tend to be brief, stereotyped, out of
Some of the discrepancies reported in the literature character for the person, and often associated with
may be due to clinical heterogeneity between epilepsy- subtle automatisms (Mula, 2014).
related psychosis and that of schizophrenia. Similar to Postictal psychosis is a common enough phenom-
schizophrenia, interictal psychosis tends to be chronic enon that criteria have been devised to facilitate its
but, in comparison, is typically less severe. Retention diagnosis (Logsdail & Toone, 1988). A recent meta-
of insight is not uncommon, and negative symptoms analysis of 13 studies derived an estimated pooled
are less common. Finally, treatment responses may be prevalence 2.0% (95% CI ¼ 1.2–2.8%) for this condi-
better in interictal psychosis as compared to schizo- tion (Clancy et al., 2014). The symptoms tend to
phrenia (Kanner, 2000). occur within 72 h following a seizure (Kanner et al.,
1996) and can persist for 15 h to under 2 months
What is the pathophysiology of psychosis in (Logsdail & Toone, 1988). In many cases, postictal
epilepsy? psychosis can be distinguished from other psychotic
disorders by a lucid interval intervening between seiz-
There is no clear current understanding of the patho- ure cessation and the onset of psychosis. The episodes
physiologic link between psychosis and epilepsy. tend to remit spontaneously or respond to low dose
Some have suggested that shared abnormalities in anti-psychotic agents (Kanner et al., 1996).
post-synaptic dopamine receptor sensitivity, increased Another associated entity is that of ‘forced normal-
GABA turnover, aberrant synaptic circuits in the den- ization’. This typically results from aggressive medical
tate-CA3-CA1 circuit, strategically located cortical dys- or surgical therapy such that a person is rendered
plasia or acquired cerebral insults may lead to seizure-free and the electroencephalogram (EEG) nor-
concurrent psychosis and epilepsy (Roy, Balon, malizes. Rapid medication titration schedules, medica-
Penumetcha, & Levine, 2014). Recent interest, though, tion-resistant epilepsy, and temporal lobe epilepsy
has focused on autoimmune aetiologies. Conditions may be risk factors for this controversial condition
such cerebral lupus, N-methyl-D-aspartate (NMDA)- (Krishnamoorthy & Trimble, 1999; Trimble, Rusch,
encephalitis, and leucine-rich, glioma-inactivated 1 Betts, & Crawford, 2000). As a result, the person is
(LGI-1) encephalitis result in both psychosis and seiz- now seizure-free, but psychiatric symptoms develop,
ures (Pollak, Nicholson, Mellers, Vincent, & David, often psychotic in nature.
2014). Interestingly, these conditions target many of
the basic neuroanatomical structures that have previ-
ously been implicated in psychosis. Of most interest, Personality disorders
impaired function of NMDA receptors and elevated Personality disorders may be relatively common in
extracellular levels of glutamate have been proposed as people with epilepsy, although comprehensive studies
a mechanism of schizophrenia (Liu & Moghaddam, are lacking. Part of the issue are the methods used to
1995; Moghaddam & Javitt, 2012) and drug-related diagnose axis II disorders (i.e. using the DSM-V
psychosis (Rowland et al., 2005), a theory that is con- (American Psychiatric Association, 2013) criteria,
sistent with the putative effect of NMDA antibodies. Minnesota Multiphasic Personality Inventory-2, or
However, a major caveat is the reporting variation other metrics). Taking into account study heterogen-
found in the literature. For instance, one study only eity, personality disorders are estimated to occur in
yielded positive test results for neuronal antibodies in 4–38% of people with epilepsy (Swinkels, Kuyk, van
10% of a large cohort with schizophrenia; a proportion Dyck, & Spinhoven, 2005). Although few direct com-
that does not vary significantly from that found in the parisons exist, the prevalence does appear to be higher
8 C. B. JOSEPHSON AND N. JETTE

than that reported in the general population Suicide and epilepsy

(5.9–13.4%) (Swinkels et al., 2005), and those with
How common are suicides and suicide attempts in
epilepsy have higher rates of axis II disorders when
persons with epilepsy?
compared to a control group of people with other
neurological disorders (Schwartz & Cummings, 1988). Suicide is an important consideration in epilepsy.
Typically, there appears to be a predominance of Suicide attempts and completed suicide occur in
Cluster C personality traits in people with epilepsy, 5.0–14.3% of people with epilepsy; proportions far
although it is unclear as to whether this is an higher than those observed in the general population
endogenous phenotypic pattern, is reflective of the (1.0–4.6%) (Pompili, Girardi, Tatarelli, Angeletti, &
unique psychosocial challenges faced by people with Tatarelli, 2006). The estimated suicide-specific stand-
epilepsy, or is a culmination of both processes ardized mortality ratio determined from 74 articles
(Swinkels et al., 2005). Attempts to disentangle these (76 cohorts of people with epilepsy) is estimated at
competing mechanisms have proven challenging; the 3.3 (95% CI ¼ 2.8–3.7) compared to the general popu-
presence of an aura was the only feature associated lation (Bell, Gaitatzis, Bell, Johnson, & Sander, 2009).
with a personality disorder in one study (Lopez- The standardized mortality ratio appears highest in
Rodriguez et al., 1999), whilst epilepsy specific those who are institutionalized (4.6) and in those with
factors could only modestly explain the variance in temporal lobe epilepsy (6.6), whilst it was elevated,
the presence of cluster C personality disorders in peo- but lower, in those with new onset epilepsy (2.1) and
ple with epilepsy (Swinkels, Duijsens, & Spinhoven, those evaluated in tertiary care clinics (2.3) (Bell et al.,
2003). 2009).
It can be challenging to identify people at elevated
risk of suicide. The most consistent feature independ-
Temporal lobe personality disorders
ently associated with suicide is, unsurprisingly, a his-
A contested disorder remains that of the putative tory of a mood disorder (Altura et al., 2016;
Geschwind personality. Defined by alterations in sex- Hecimovic et al., 2012; Jones et al., 2003). A history
ual behaviour, hyper-religiousness, hypergraphia, bra- of suicide attempts should be elicited in all people
dyphrenia, and a ‘sticky’ thought process (Waxman with epilepsy, since 10–20% of these individuals will
& Geschwind, 1975), this personality construct is successfully complete suicide within 10 years (Monk,
considered to be interictal in nature, and is associ- 1987). Assessment of suicide risk can be achieved
ated with temporal lobe epilepsy. However, no for- through the Mini-International Neuropsychiatric
mal criteria have been developed for this possible Interview (MINI) suicidality module (Sheehan et al.,
condition, and its existence remains controversial 1998); an approach that has been successfully
at best. employed in epilepsy (Andrade-Machado, Ochoa-
Urrea, Garcia-Espinosa, Benjumea-Cuartas, & Santos-
Sub-syndromal and atypical symptoms Santos, 2015). Using the MINI as a reference stand-
ard, item 4 of the NDDI-E has also been validated for
It is not uncommon for people with epilepsy to dis-
the detection of suicidal ideation in epilepsy, and per-
play sub-syndromal symptoms of psychiatric disor-
formed well (area under the curve ¼ 0.906; 95%
ders. In addition, up to one-half of people with
CI ¼ 0.820–0.992) (Mula et al., 2016). One of the
epilepsy fail to meet conventional diagnostic criteria
PHQ-9 items (‘Over the last 2 weeks, how often have
for mood disorders, as duration is either too brief or
the entire complement of requisite symptoms is not you been bothered by the following problem: thought
present (Mendez et al., 1986). Rather, people with epi- that you would be better off dead, or of hurting your-
lepsy are prone to a constellation of symptoms more self in some way?’) has also been validated as a
consistent with an intermittent (often lasting hours to screening measure for suicidal ideation in epilepsy
days), dysthymic disorder rather than major depres- against the Structured Clinical Interview for DSM-IV.
sive disorder (Kanner, 2003). Recognition and treat- The PHQ-9 had good sensitivity, specificity, and nega-
ment of sub-syndromal and atypical depression is far tive predictive value for suicidal ideation in epilepsy
from trivial, as these conditions detract from overall (90% or more) (Altura et al., 2016). According to this
quality-of-life according to a number of epilepsy- analysis, the 2-week prevalence of suicidal ideation in
specific metrics (Kanner, Barry, Gilliam, Hermann, & people with epilepsy may be as high as 12.7% (Altura
Meador, 2010a). et al., 2016).
 INTERNATIONAL REVIEW OF PSYCHIATRY 9

Anti-epileptic drug use and suicidality suicidal behaviour, there was no association between
AED use and suicidal behaviour in a large, general
The putative association between AED use and sui-
practice based cohort of people with epilepsy (Arana,
cidal ideation and completed suicide is significant
Wentworth, Ayuso-Mateos, & Arellano, 2010).
enough to warrant separate discussion. The US Food
Although prospective studies are lacking, and should
and Drug Administration issued a warning linking
be conducted, most feel the current evidence is insuffi-
AED used to suicidality in 2008. Subsequent survival
cient to support the notion of increased suicidal behav-
analyses and case-crossover studies performed on
iour after a prescription for an AED (Mula & Sander,
large, retrospective observational cohorts of people
2015).
with epilepsy, appeared to justify this warning (Olesen
et al., 2010; Patorno et al., 2010). These studies sug-
gested the odds of suicidal behaviour were 1.84-fold How safe are psychotropic drugs in persons
higher (95% CI ¼ 1.36–2.49) (Olesen et al., 2010), with epilepsy?
whilst the hazard ratios ranged from 1.42–2.41
Mood stabilizers
(depending on the specific drug) (Patorno et al.,
2010) following initiation of an AED. As already elaborated in extensive detail, psychiatric
However, despite these data, epileptologists still comorbidities are common in people with epilepsy.
questioned their validity, since basic epidemiological However, despite their prevalence, treatment has
issues, such as confounding by indication, were not remained sub-optimal due to fears about the putative
addressed in the initial studies. Innovative analyses effect of psychiatric medications on the seizure
incorporating temporality ultimately proved useful in threshold.
refuting this erroneous association. Applying an Antidepressants have been particularly controver-
approach successfully used to control for protopathic sial in epilepsy. On careful review, though, it should
bias (when a pharmacologic agent is prescribed in be noted that the initial concerns voiced about con-
response to premonitory symptoms that do not yet ventional antidepressants, such as tricyclic and tetra-
meet bona fide criteria for a particular disorder; the cyclic antidepressants, were primarily predicated on
disorder may then fully manifest later, and the investi- hospital-based series of individuals using high doses
gator is at risk of spuriously suggesting the prescrip- (Jabbari, Bryan, Marsh, & Gunderson, 1985; Preskorn
tion caused the disorder of interest) and confounding & Fast, 1992; Rosenstein, Nelson, & Jacobs, 1993). It
by indication in large population-based data collected is, therefore, important to note that follow-up studies
during routine care (Simon, Savarino, Operskalski, & have, in fact, demonstrated minimal risk when these
Wang, 2006), multiple authors were able to demon- medications are used at therapeutic doses in out-
strate an acute rise in suicidal behaviour just prior to patient populations (Preskorn & Fast, 1992).
first AED prescription (Pugh et al., 2013). Suicide- Despite this, concerns of a ‘proconvulsant’ effect
related behaviour peaked just prior to a code for an persisted, which limited the use of these medications
AED prescription (40 unique people with an ICD-9 to the detriment of people with epilepsy whose
code for suicidal ideation, behaviour, or completed sui- affective disorders were being under-managed,
cide/100 000), and dropped significantly during the thus directly impairing quality-of-life (Kobau et al.,
first month following a code for an AED prescription 2006).
(18 codes/100 000) (Pugh et al., 2013). In fact, there It is integral, therefore, that all practitioners man-
were more codes for suicide-related behaviour prior to aging epilepsy realize that the opposite of this com-
the AED exposure (106 episodes in 92 individuals) mon misperception is true. When analysed as a class
compared to that following AED prescription (84 epi- medication, antidepressants are associated with anti-
sodes in 74 individuals) (Pugh et al., 2013). When convulsant effects. In a major review of the public
using the first 30 days prior to an AED prescription as domain data issued by the US Food and Drug
a reference point, the odds of suicide-related behaviour Administration pertaining to Phase II and III clinical
following an AED code was significantly reduced, trials of psychotropic medications approved between
implying the presence of confounding by indication 1985–2004, contrary to popular conception, antide-
(i.e. presumably mood-stabilizing AEDs were pre- pressants as a class were associated with lower stand-
scribed in reaction to suicidal ideation expressed by the ardized incidence of seizures compared to the placebo
individual) (Pugh et al., 2013). Furthermore, when group (standardized incidence ratio [SIR] ¼ 0.48; 95%
controlling for a myriad of conditions related to CI ¼ 0.36–0.61) (Alper, Schwartz, Kolts, & Khan,
10 C. B. JOSEPHSON AND N. JETTE

2007). Many antidepressants only lower the seizure Epilepsy treatment-related psychiatric adverse
threshold when used in supramaximal doses (Kanner, effects
2016). The only antidepressants clearly associated with
First generation antiepileptic drugs
an increased risk for seizures in epilepsy at thera-
peutic doses are bupropion, clomipramine, amoxa- Antiepileptic drugs have varying effects on mood and
pine, and maprotiline, and even those only tend to be affect. Some improve mood, others are neutral, and
associated with an increased risk when used at higher finally some can be associated with psychiatric adverse
doses (Kanner, 2016). effects. Of the older antiepileptic agents, barbiturates in
particular appear to have a negative impact on mood
when used over long periods (>1 year) (Smith,
Are antipsychotic agents safe or not in epilepsy?
Mattson, Cramer, Collins, Novelly, & Craft, 1987).
Antipsychotic agents, unfortunately, are more chal- This effect appears accentuated in those receiving poly-
lenging to prescribe in epilepsy. Atypical anti- therapy, and in those with a personal or family history
psychotic agents may be particular culprits for of a mood disorder (Robertson, Trimble, & Townsend,
lowering the seizure threshold. There is a clear dose- 1987). Benzodiazepines, such as nitrazapam, clonaze-
related decrease in the seizure threshold related to pam, and clobazam, whilst mostly associated with
clozapine (Devinsky, Honigfeld, & Patin, 1991). fatigue and mental slowness, can induce mood changes
Complicating factors is that clozapine itself can and behavioural alterations (Kwan & Brodie, 2001),
induce slowing and the presence of apparent epilep- including aggression and irritability, primarily in chil-
tiform activity in the form of spike-wave and sharp dren (Bensch et al., 1977). Phenytoin mainly causes
wave discharges, thus complicating interpretation of mental/cognitive slowing, although, in rare cases, it has
the EEG in people presenting with symptoms sug- been associated with depression, anxiety, and aggres-
gestive of, but not definite, for seizures (Centorrino sion (Kwan & Brodie, 2001; Mula & Sander, 2007a).
et al., 2002). Furthermore, olanzapine, molecularly On the other hand, valproic acid is typically con-
similar to clozapine, also induces similar EEG sidered a mood-stabilizer, although it can have
changes (Centorrino et al., 2002), although its associ- adverse effects on cognition at high doses (Kwan &
ation with seizures is less consistent (Alper et al., Brodie, 2001; Prevey, Mattson, & Cramer, 1989).
2007). Interestingly, the same study analysing data Carbamazepine is traditionally considered a mood-sta-
published in the public domain by the US Food and biliser as well, although high-quality studies evaluating
Drug Administration pertaining to Phase II and III its efficacy are lacking (Kwan & Brodie, 2001).
clinical trials of psychotropic medications approved
between 1985–2004 demonstrated an increased seiz- Second generation antiepileptic drugs
ure risk of all antipsychotics (SIR ¼ 2.05; 95%
CI ¼ 1.74–2.40), but only when clozapine and olanza- The newer agents appear to have better psychological
pine were included. Removal of clozapine and olan- and cognitive profiles (Kwan & Brodie, 2001).
zapine from the overall analysis diminished the effect Whilst most are mood-neutral, the following caveats
size (SIR ¼ 1.18; 95% CI ¼ 0.92–1.49) and rendered exist. For instance, whilst generally well tolerated, post-
the result no longer statistically significant, although marketing analyses of levetiracetam indicate that psy-
this could be either due to removing two medica- chiatric adverse effects may be much higher than
tions that are prone to cause seizures or simply due anticipated, with up to 31% of people on levetiracetam
to compromised statistical power (Alper et al., 2007). exhibiting behavioural abnormalities, 29% irritability,
Finally, when examining specific drugs, only cloza- 10% aggression, and 5% hallucinations (Penovich,
pine (SIR ¼ 9.50; 95% CI ¼ 7.27–12.20), olanzapine 2004). Case reports of acute mania (Park, Holmes, &
(SIR ¼ 2.50; 95% CI ¼ 1.58–3.74), and quetiapine Reeder-Hayes, 2014); delirium (Hwang, Siemianowski,
(SIR ¼ 2.05; 95% CI ¼ 1.21–3.23) were associated Sen, & Patel, 2014); psychosis (Bayerlein, Frieling,
with an elevated risk of seizures. Due to the Beyer, Kornhuber, & Bleich, 2004; Youroukos,
increased risk, clozapine should not be considered Lazopoulou, Michelakou, & Karagianni, 2003); aggres-
first-line therapy for psychosis epilepsy, and should sive behaviour (Wieshmann & Baker, 2013); and sui-
only be used when other agents fail (Koch-Stoecker, cidal ideation have been published (Mula & Sander,
2002). Otherwise, antipsychotic agents do appear 2007b). Likewise, post-marketing analyses of topira-
safe, as long as they are carefully administered, mate suggest there is a dose–response correlation
slowly titrated, and used at the lowest therapeutic between drug levels and affective disorders.
dose (Koch-Stoecker, 2002). Specifically, the prevalence of mood lability may be as
 INTERNATIONAL REVIEW OF PSYCHIATRY 11

high as 17% (Mula & Sander, 2007a), whilst that for portend worse seizure outcomes, and may be associ-
depression may be in the region of 10.7% (Mula, ated with medication non-adherence (Brodtkorb &
Trimble, Lhatoo, & Sander, 2003). Preliminary evi- Mula, 2006). Therefore, future studies should focus on
dence also suggests that perampanel is also associated accurate recognition of these conditions, as their mani-
with greater risks of psychiatric adverse effects (pri- festations may differ from those exhibited in people
marily hostility and aggression) compared to placebo without epilepsy. There are excellent screening tools to
(Ettinger et al., 2015). assess for depression in epilepsy (NDDI-E and PHQ-
Similar to carbamazepine and valproic acid, lamo- 9), but there is a dearth of evidence on the best tool(s)
trigine appears to function as a mood stabilizer to screen for anxiety and psychosis in epilepsy. This is
(Herman, 2004). Likewise, oxcarbazepine may also even more critical given that psychiatric comorbidities
have this effect, although the evidence is compara- in epilepsy are prone to being unrecognized and
tively limited (Spina & Perugi, 2004). Preliminary evi- under-treated, thus leading to worse psychosocial and
dence also suggests that lacosamide may function as a potentially seizure-related outcomes. Knowledge of
mood- and anxiety-stabilizer (Moseley, Cole, Iwuora, psychiatric adverse effects from AEDs is important,
Strawn, & Privitera, 2015). since these may affect the aetiology of the person’s
problems. If so, lowering the dose or changing the
Is epilepsy surgery associated with psychiatric out-
AED may alleviate the symptom. However, if the cause
comes, and are psychiatric conditions associated
of the person’s psychiatric distress is unrelated to
with epilepsy surgery outcomes?
medication, then the overwhelming weight of the evi-
The effect of epilepsy surgery on psychiatric outcomes dence to date suggests that, apart from a minority of
remains controversial. Surgery is associated with either medications, psychotropic medications are safe in epi-
no change or potential improvement in depression that lepsy. Prompt recognition and treatment of psychiatric
ultimately appears dependent on seizure outcome comorbidities is paramount, since mood states highly
(Macrodimitris et al., 2011). Only one study in this sys- influence quality-of-life, as judged by validated epi-
tematic review reported worse outcomes following epi- lepsy-specific instruments (Kanner et al., 2010a;
lepsy surgery (Macrodimitris et al., 2011). Subsequent Tracy, Dechant, Sperling, Cho, & Glosser, 2007).
to this, the large Multi-centre Study of Epilepsy Furthermore, comorbid psychiatric conditions are
Surgery trial (n ¼ 256 evaluated for depression) associated with an increased risk of suicide
reported congruent results in which resective surgery (Christensen, Vestergaard, Mortensen, Sidenius, &
was associated with improvements in mood, as long as Agerbo, 2007) and premature death. Hence, there is no
the individual was able to achieve good or excellent reason that these people should not receive optimal
seizure outcomes (Hamid et al., 2011). On the other therapy for their psychiatric comorbidities.
hand, a careful psychiatric history is important before
surgery, as a lifetime history of psychiatric disorder has
been found to be associated with worse seizure out-
comes after temporal lobe surgery, specifically after Acknowledgements
temporal lobectomy (Kanner, Byrne, Chicharro, C. Josephson has nothing to disclose. N. Jette is the holder
Wuu, & Frey, 2009). of a Canada Research Chair in Neurological Health Services
Research.

Conclusions
Psychiatric comorbidities are common in epilepsy.
Disclosure statement
There may be shared pathophysiological mechanisms
that explain the association between epilepsy and the No potential conflict of interest was reported by the
myriad of psychiatric comorbidities with which it is authors.
related. Recognition of these conditions is critical, and
future research should aim to determine whether Funding
neuroanatomical mechanisms governing epilepsy-type
N. Jette holds operating grants as a principal or co-principal
(i.e. generalized vs focal epilepsy; temporal vs extra- investigator from NINDS (NIH U54), the Canadian
temporal) preferentially associate with specific psychi- Institutes for Health Research, the University of Calgary
atric symptoms. Associated psychiatric comorbidities Brain and Mental Health Research Strategy, Alberta Health,
have a deleterious effect on quality-of-life, appear to and the University of Calgary Hotchkiss Brain Institute.
12 C. B. JOSEPHSON AND N. JETTE

References National epidemiologic study. The British Journal of

Psychiatry, 172, 235–238. http://dx.doi.org/10.1192/bjp.
Alper, K., Schwartz, K.A., Kolts, R.L., & Khan, A. (2007). 172.3.235
Seizure incidence in psychopharmacological clinical trials: Brodtkorb, E., & Mula, M. (2006). Optimizing therapy of
An analysis of Food and Drug Administration (FDA) seizures in adult patients with psychiatric comorbidity.
summary basis of approval reports. Biological Neurology, 67, S39–S44. http://dx.doi.org/10.1212/WNL.
Psychiatry, 62, 345–354. http://dx.doi.org/10.1016/j.biop- 67.12_suppl_4.S39
sych.2006.09.023 Cendes, F., Andermann, F., Gloor, P., Gambardella, A.,
Altura, K.C., Patten, S.B., Fiest, K.M., Atta, C., Bulloch, Lopes-Cendes, I., Watson, C., … Olivier, A. (1994).
A.G., & Jette, N. (2016). Suicidal ideation in persons with Relationship between atrophy of the amygdala and ictal
neurological conditions: Prevalence, associations and val- fear in temporal lobe epilepsy. Brain, 117, 739–746.
idation of the PHQ-9 for suicidal ideation. General https://doi.org/10.1093/brain/117.4.739
Hospital Psychiatry, 42, 22–26. doi: 10.1016/j.genhosp- Centorrino, F., Price, B.H., Tuttle, M., Bahk, W.M.,
psych.2016.1006.1006 Hennen, J., Albert, M.J., & Baldessarini, R.J. (2002). EEG
American Psychiatric Association. (2013). Diagnostic and abnormalities during treatment with typical and atypical
Statistical Manual of Mental Disorders. 5th ed. antipsychotics. The American Journal of Psychiatry, 159,
Washington (DC): APA.
109–115. http://dx.doi.org/10.1176/appi.ajp.159.1.109
Amiri, M., & Hansen, C.P. (2015). The interictal dysphoric
Chadwick, D., & Smith, D. (2002). The misdiagnosis of epi-
disorder in patients with epilepsy: A doubtful disorder
lepsy. British Medical Journal, 324, 495–496. http://dx.doi.
lacking diagnostic tools. Seizure, 24, 70–76. doi:10.1016/
org/10.1136/bmj.324.7336.495
j.seizure.2014.1008.1009
Christensen, J., Vestergaard, M., Mortensen, P.B., Sidenius,
Andrade-Machado, R., Ochoa-Urrea, M., Garcia-Espinosa,
P., & Agerbo, E. (2007). Epilepsy and risk of suicide: A
A., Benjumea-Cuartas, V., & Santos-Santos, A. (2015).
population-based case-control study. The Lancet
Suicidal risk, affective dysphoric disorders, and quality-
Neurology, 6, 693–698. http://dx.doi.org/10.1016/S1474-
of-life perception in patients with focal refractory epi-
4422(07)70175-8
lepsy. Epilepsy & Behaviour, 45, 254–260. doi:10.1016/j.
Clancy, M.J., Clarke, M.C., Connor, D.J., Cannon, M., &
yebeh.2015.1001.1005
Cotter, D.R. (2014). The prevalence of psychosis in epi-
Arana, A., Wentworth, C.E., Ayuso-Mateos, J.L., &
lepsy: A systematic review and meta-analysis. BMC
Arellano, F.M. (2010). Suicide-related events in patients
treated with antiepileptic drugs. The New England Psychiatry, 14, 75. doi:10.1186/1471-1244X-1114-1175
Cramer, J.A., Blum, D., Fanning, K., & Reed, M. (2004).
Journal of Medicine, 363, 542–551. doi: 510.1056/
NEJMoa0909801 The impact of comorbid depression on health resource
Bayerlein, K., Frieling, H., Beyer, B., Kornhuber, J., & utilization in a community sample of people with epi-
Bleich, S. (2004). Drug-induced psychosis after long-term lepsy. Epilepsy & Behaviour, 5, 337–342. http://dx.doi.org/
treatment with levetiracetam. The Canadian Journal of 10.1016/j.yebeh.2004.01.010
Psychiatry, 49, 868. Devinsky, O., Honigfeld, G., & Patin, J. (1991). Clozapine-
Bell, G.S., Gaitatzis, A., Bell, C.L., Johnson, A.L., & Sander, related seizures. Neurology, 41, 369–371. http://dx.doi.
J.W. (2009). Suicide in people with epilepsy: How great is org/10.1212/WNL.41.3.369
the risk? Epilepsia, 50, 1933–1942. doi: 1910.1111/j.1528- Edeh, J., & Toone, B. (1987). Relationship between interictal
1167.2009.02106.x psychopathology and the type of epilepsy. Results of a
Bensch, J., Blennow, G., Ferngren, H., Gamstorp, I., survey in general practice. British Journal of Psychiatry,
Herrlin, K.M., Kubista, J., … Dahlstrom, H. (1977). A 151, 95–101. http://dx.doi.org/10.1192/bjp.151.1.95
double-blind study of clonazepam in the treatment of Ettinger, A.B., LoPresti, A., Yang, H., Williams, B., Zhou,
therapy-resistant epilepsy in children. Developmental S., Fain, R., & Laurenza, A. (2015). Psychiatric and
Medicine & Child Neurology, 19, 335–342. doi: 10.1111/ behavioral adverse events in randomized clinical studies
j.1469-8749.1977.tb08369.x of the noncompetitive AMPA receptor antagonist peram-
Berg, A.T., Berkovic, S.F., Brodie, M.J., Buchhalter, J., panel. Epilepsia, 56, 1252–1263. doi: 1210.1111/epi.13054
Cross, J.H., van Emde Boas, W., … Scheffer, I.E. (2010). Ettinger, A.B., Reed, M.L., Goldberg, J.F., & Hirschfeld,
Revised terminology and concepts for organization of R.M. (2005). Prevalence of bipolar symptoms in epilepsy
seizures and epilepsies: Report of the ILAE Commission vs other chronic health disorders. Neurology, 65,
on Classification and Terminology, 2005-2009. Epilepsia, 535–540. http://dx.doi.org/10.1212/01.wnl.0000172917.
51, 676–685. doi: 610.1111/j.1528-1167.2010.02522.x 70752.05
Blanchet, P., & Frommer, G.P. (1986). Mood change pre- Fiest, K.M., Dykeman, J., Patten, S.B., Wiebe, S., Kaplan,
ceding epileptic seizures. The Journal of Nervous and G.G., Maxwell, C.J., … Jette, N. (2013). Depression in
Mental Disease, 174, 471–476. http://dx.doi.org/10.1097/ epilepsy: A systematic review and meta-analysis.
00005053-198608000-00005 Neurology, 80, 590–599. doi: 510.1212/WNL.1210b101
Blumer, D. (2000). Dysphoric disorders and paroxysmal 3e31827b31821ae31820
affects: Recognition and treatment of epilepsy-related Fiest, K.M., Jette, N., Quan, H., St Germaine-Smith, C.,
psychiatric disorders. Harvard Review of Psychiatry, 8, Metcalfe, A., Patten, S.B., & Beck, C.A. (2014). Systematic
8–17. http://dx.doi.org/10.3109/hrp.8.1.8 review and assessment of validated case definitions for
Bredkjaer, S.R., Mortensen, P.B., & Parnas, J. (1998). depression in administrative data. BMC Psychiatry, 14,
Epilepsy and non-organic non-affective psychosis. 289. doi: 10.1186/s12888-12014-10289-12885
 INTERNATIONAL REVIEW OF PSYCHIATRY 13

Fisher, R.S., Acevedo, C., Arzimanoglou, A., Bogacz, A., suicidality in epilepsy. Epilepsy & Behaviour, 24, 426–429.
Cross, J.H., Elger, C.E., … Wiebe, S. (2014). ILAE offi- doi: 410.1016/j.yebeh.2012.1005.1005
cial report: A practical clinical definition of epilepsy. Herman, E. (2004). Lamotrigine: A depression mood
Epilepsia, 55, 475–482. doi: 410.1111/epi.12550 stabiliser. European Neuropsychopharmacology, 14(Suppl
Fisher, R.S., van Emde Boas, W., Blume, W., Elger, C., 2), S89–S93. http://dx.doi.org/10.1016/j.euroneuro.2004.
Genton, P., Lee, P., & Engel, J. Jr. (2005). Epileptic seiz- 03.003
ures and epilepsy: Definitions proposed by the Hermann, B.P., Seidenberg, M., & Bell, B. (2000).
International League Against Epilepsy (ILAE) and the Psychiatric comorbidity in chronic epilepsy:
International Bureau for Epilepsy (IBE). Epilepsia, 46, Identification, consequences, and treatment of major
470–472. http://dx.doi.org/10.1111/j.0013-9580.2005. depression. Epilepsia, 41(Suppl 2), S31–S41. http://dx.doi.
66104.x org/10.1111/j.1528-1157.2000.tb01522.x
Gaitatzis, A., Carroll, K., Majeed, A., & Sander J, W. (2004). Hesdorffer, D.C., Ishihara, L., Mynepalli, L., Webb, D.J.,
The epidemiology of the comorbidity of epilepsy in the Weil, J., & Hauser, W.A. (2012). Epilepsy, suicidality, and
general population. Epilepsia, 45, 1613–1622. http://dx. psychiatric disorders: A bidirectional association. Annals
doi.org/10.1111/j.0013-9580.2004.17504.x of Neurology, 72, 184–191. doi: 110.1002/ana.23601
Gandy, M., Sharpe, L., Perry, K.N., Miller, L., Thayer, Z., Hwang, E.S., Siemianowski, L.A., Sen, S., & Patel, R. (2014).
Boserio, J., & Mohamed, A. (2015). Anxiety in epilepsy: Levetiracetam: An unusual cause of delirium. American
A neglected disorder. Journal of Psychosomatic Research, Journal of Therapeutics, 21, e225–e228. doi: 10.1097/
78, 149–155. doi: 110.1016/j.jpsychores.2014.1012.1002 MJT.0b013e31828fdaed
Gill, S.J., Lukmanji, S., Fiest, K.M., Patten, S.B., Wiebe, S., Jabbari, B., Bryan, G.E., Marsh, E.E., & Gunderson, C.H.
& Jette, N. (2017). Depression screening tools in persons (1985). Incidence of seizures with tricyclic and tetracyclic
with epilepsy: A systematic review of validated tools. antidepressants. Archives of Neurology, 42, 480–481.
Epilepsia, 58, 695–705. doi: 10.1111/epi.13651 http://dx.doi.org/10.1001/archneur.1985.04060050082013
Gilliam, F., & Kanner, A.M. (2002). Treatment of depressive Jacoby, A., Baker, G.A., Steen, N., Potts, P., & Chadwick,
disorders in epilepsy patients. Epilepsy & Behaviour, 3, D.W. (1996). The clinical course of epilepsy and its psy-
2–9. http://dx.doi.org/10.1016/S1525-5069(02)00503-0 chosocial correlates: Findings from a U.K. Community
Gilliam, F., Kuzniecky, R., Faught, E., Black, L., Carpenter, study. Epilepsia, 37, 148–161. http://dx.doi.org/10.1111/j.
G., & Schrodt, R. (1997). Patient-validated content of epi- 1528-1157.1996.tb00006.x
lepsy-specific quality-of-life measurement. Epilepsia, 38, Jones, J.E., Hermann, B.P., Barry, J.J., Gilliam, F.G., Kanner,
233–236. http://dx.doi.org/10.1111/j.1528-1157.1997. A.M., & Meador, K.J. (2003). Rates and risk factors for
tb01102.x suicide, suicidal ideation, and suicide attempts in chronic
Gilliam, F.G., Barry, J.J., Hermann, B.P., Meador, K.J., epilepsy. Epilepsy & Behaviour, 4(Suppl 3), S31–S38.
Vahle, V., & Kanner, A.M. (2006). Rapid detection of http://dx.doi.org/10.1016/j.yebeh.2003.08.019
major depression in epilepsy: A multicentre study. The Kanner, A.M. (2000). Psychosis of epilepsy: A neurologist's
Lancet Neurology, 5, 399–405. http://dx.doi.org/10.1016/ perspective. Epilepsy & Behaviour, 1, 219–227. http://dx.
S1474-4422(06)70415-X doi.org/10.1006/ebeh.2000.0090
Global Burden of Disease Study 2013 Collaborators. (2015). Kanner, A.M. (2003). Depression in epilepsy: A frequently
Global, regional, and national incidence, prevalence, and neglected multifaceted disorder. Epilepsy & Behaviour,
years lived with disability for 301 acute and chronic dis- 4(Suppl 4), 11–19. http://dx.doi.org/10.1016/j.yebeh.2003.
eases and injuries in 188 countries, 1990-2013: A system- 10.004
atic analysis for the Global Burden of Disease Study Kanner, A.M. (2005). Depression in epilepsy: A neurobio-
2013. The Lancet, 386, 743–800. doi: 710.1016/S0140- logic perspective. Epilepsy Currents, 5, 21–27. http://dx.
6736(1015)60692-60694 doi.org/10.1111/j.1535-7597.2005.05106.x
Hamid, H., Blackmon, K., Cong, X., Dziura, J., Atlas, L.Y., Kanner, A.M. (2007). Epilepsy and mood disorders.
Vickrey, B.G., … Devinsky, O. (2014). Mood, anxiety, Epilepsia, 48(Suppl 9), 20–22. http://dx.doi.org/10.1111/j.
and incomplete seizure control affect quality of life after 1528-1167.2007.01395.x
epilepsy surgery. Neurology, 82, 887–894. doi: 810.1212/ Kanner, A.M. (2008). Depression in epilepsy: A complex
WNL.0000000000000183 relation with unexpected consequences. Current Opinion
Hamid, H., Liu, H., Cong, X., Devinsky, O., Berg, A.T., in Neurology, 21, 190–194. doi: 110.1097/WCO.
Vickrey, B.G., … Spencer, S.S. (2011). Long-term associ- 1090b1013e3282f1094e1978
ation between seizure outcome and depression after Kanner, A.M. (2016). Most antidepressant drugs are safe for
resective epilepsy surgery. Neurology, 77, 1972–1976. doi: patients with epilepsy at therapeutic doses: A review of
1910.1212/WNL.1970b1013e31823a31820c31890 the evidence. Epilepsy & Behaviour, 61, 282–286. doi:10.
Hammer, C., Stepniak, B., Schneider, A., Papiol, S., Tantra, 1016/j.yebeh.2016.1003.1022
M., Begemann, M., … Ehrenreich, H. (2014). Kanner, A.M., Barry, J.J., Gilliam, F., Hermann, B., &
Neuropsychiatric disease relevance of circulating anti- Meador, K.J. (2010a). Anxiety disorders, subsyndromic
NMDA receptor autoantibodies depends on blood-brain depressive episodes, and major depressive episodes: Do
barrier integrity. Molecular Psychiatry, 19, 1143–1149. they differ on their impact on the quality of life of
doi: 1110.1038/mp.2013.1110 patients with epilepsy? Epilepsia, 51, 1152–1158. doi:
Hecimovic, H., Santos, J.M., Carter, J., Attarian, H.P., 1110.1111/j.1528-1167.2010.02582.x
Fessler, A.J., Vahle, V., & Gilliam, F. (2012). Depression Kanner, A.M., Byrne, R., Chicharro, A., Wuu, J., & Frey, M.
but not seizure factors or quality of life predicts (2009). A lifetime psychiatric history predicts a
14 C. B. JOSEPHSON AND N. JETTE

worse seizure outcome following temporal lobectomy. Logsdail, S.J., & Toone, B.K. (1988). Post-ictal psychoses. A
Neurology, 72, 793–799. doi: 710.1212/1201.wnl. clinical and phenomenological description. British Journal
0000343850.0000385763.0000343859c of Psychiatry, 152, 246–252. http://dx.doi.org/10.1192/bjp.
Kanner, A.M., Kozak, A.M., & Frey, M. (2000). The use of 152.2.246
sertraline in patients with epilepsy: Is it safe? Epilepsy & Lopez-Rodriguez, F., Altshuler, L., Kay, J., Delarhim, S.,
Behaviour, 1, 100–105. http://dx.doi.org/10.1006/ebeh. Mendez, M., & Engel, J. Jr.(1999). Personality disorders
2000.0050 among medically refractory epileptic patients. The
Kanner, A.M., Soto, A., & Gross-Kanner, H. (2004). Journal of Neuropsychiatry & Clinical Neurosciences, 11,
Prevalence and clinical characteristics of postictal psychi- 464–469. http://dx.doi.org/10.1176/jnp.11.4.464
atric symptoms in partial epilepsy. Neurology, 62, Macrodimitris, S., Sherman, E.M., Forde, S., Tellez-Zenteno,
708–713. http://dx.doi.org/10.1212/01.WNL.0000113763. J.F., Metcalfe, A., Hernandez-Ronquillo, L., … Jette, N.
11862.26 (2011). Psychiatric outcomes of epilepsy surgery: A sys-
Kanner, A.M., Stagno, S., Kotagal, P., & Morris, H.H. tematic review. Epilepsia, 52, 880–890. doi: 810.1111/j.
(1996). Postictal psychiatric events during prolonged 1528-1167.2011.03014.x
video-electroencephalographic monitoring studies. Mayberg, H.S. (1994). Frontal lobe dysfunction in secondary
Archives of Neurology, 53, 258–263. http://dx.doi.org/10. depression. The Journal of Neuropsychiatry & Clinical
1001/archneur.1996.00550030070024 Neurosciences, 6, 428–442. doi: https://doi.org/10.1176/
Kanner, A.M., Trimble, M., & Schmitz, B. (2010b). Postictal jnp.6.4.428
affective episodes. Epilepsy & Behaviour, 19, 156–158. Mendez, M.F., Cummings, J.L., & Benson, D.F. (1986).
doi: 110.1016/j.yebeh.2010.1006.1024 Depression in epilepsy. Significance and phenomenology.
Kee, V.R., Gilchrist, B., Granner, M.A., Sarrazin, N.R., & Archives of Neurology, 43, 766–770. http://dx.doi.org/10.
Carnahan, R.M. (2012). A systematic review of 1001/archneur.1986.00520080014012
validated methods for identifying seizures, convulsions, Moghaddam, B., & Javitt, D. (2012). From revolution to
or epilepsy using administrative and claims data. evolution: The glutamate hypothesis of schizophrenia and
Pharmacoepidemiology and Drug Safety, 21(Suppl 1), its implication for treatment. Neuropsychopharmacology,
183–193. doi: 110.1002/pds.2329 37, 4–15. doi: 10.1038/npp.2011.1181
Kerr, M.P., Mensah, S., Besag, F., de Toffol, B., Ettinger, A., Mohler, H. (2006). GABAA receptors in central nervous
Kanemoto, K., … Wilson, S.J. (2011). International con- system disease: Anxiety, epilepsy, and insomnia. Journal
sensus clinical practice statements for the treatment of of Receptors and Signal Transduction Research, 26,
neuropsychiatric conditions associated with epilepsy. 731–740. http://dx.doi.org/10.1080/10799890600920035
Epilepsia, 52, 2133–2138. doi: 2110.1111/j.1528-1167. Monk, M. (1987). Epidemiology of suicide. Epidemiologic
2011.03276.x Review, 9, 51–69. http://dx.doi.org/10.1093/oxfordjour-
Kobau, R., Gilliam, F., & Thurman, D.J. (2006). Prevalence nals.epirev.a036308
of self-reported epilepsy or seizure disorder and its asso- Moseley, B.D., Cole, D., Iwuora, O., Strawn, J.R., &
ciations with self-reported depression and anxiety: Privitera, M. (2015). The effects of lacosamide on depres-
Results from the 2004 HealthStyles Survey. Epilepsia, 47, sion and anxiety in patients with epilepsy. Epilepsy
1915–1921. http://dx.doi.org/10.1111/j.1528-1167.2006. Research, 110, 115–118. doi: 10.1016/j.eplepsyres.2014.
00612.x 1012.1007
Koch-Stoecker, S. (2002). Antipsychotic drugs and epilepsy: Mula, M. (2014). Epilepsy-induced behavioral changes dur-
Indications and treatment guidelines. Epilepsia, 43(Suppl ing the ictal phase. Epilepsy & Behaviour, 30, 14–16. doi:
2), 19–24. http://dx.doi.org/10.1046/j.1528-1157.2002. 10.1016/j.yebeh.2013.1009.1011
043s2019.x Mula, M., Jauch, R., Cavanna, A., Gaus, V., Kretz, R.,
Krishnamoorthy, E.S., & Trimble, M.R. (1999). Forced nor- Collimedaglia, L., … Schmitz, B. (2010). Interictal dys-
malization: Clinical and therapeutic relevance. Epilepsia, phoric disorder and periictal dysphoric symptoms in
40(Suppl 10), S57–S64. http://dx.doi.org/10.1111/j.1528- patients with epilepsy. Epilepsia, 51, 1139–1145. doi:
1157.1999.tb00886.x 1110.1111/j.1528-1167.2009.02424.x
Kwan, P., & Brodie, M.J. (2001). Neuropsychological effects Mula, M., McGonigal, A., Micoulaud-Franchi, J.A., May,
of epilepsy and antiepileptic drugs. Lancet, 357, 216–222. T.W., Labudda, K., & Brandt, C. (2016). Validation of
http://dx.doi.org/10.1016/S0140-6736(00)03600-X rapid suicidality screening in epilepsy using the NDDIE.
Kwon, O.Y., & Park, S.P. (2014). Depression and anxiety in Epilepsia, 57, 949–955. doi: 910.1111/epi.13373
people with epilepsy. Journal of Clinical Neurology, 10, Mula, M., & Sander, J.W. (2007a). Negative effects of antie-
175–188. doi: 110.3988/jcn.2014.3910.3983.3175 pileptic drugs on mood in patients with epilepsy. Drug
Lambert, M.V., & Robertson, M.M. (1999). Depression in Safety, 30, 555–567. doi: 10.2165/00002018-200730070-
epilepsy: Etiology, phenomenology, and treatment. 00001
Epilepsia, 40(Suppl 10), S21–S47. http://dx.doi.org/10. Mula, M., & Sander, J.W. (2007b). Suicidal ideation in epi-
1111/j.1528-1157.1999.tb00884.x lepsy and levetiracetam therapy. Epilepsy & Behaviour,
Liu, J., & Moghaddam, B. (1995). Regulation of glutamate 11, 130–132. http://dx.doi.org/10.1016/j.yebeh.2007.04.008
efflux by excitatory amino acid receptors: Evidence for Mula, M., & Sander, J.W. (2015). Suicide and epilepsy: Do
tonic inhibitory and phasic excitatory regulation. Journal antiepileptic drugs increase the risk? Expert Opinion on
of Pharmacology and Experimental Therapeutics, 274, Drug Safety, 14, 553–558. doi: 510.1517/14740338.
1209–1215. 14742015.11010506
 INTERNATIONAL REVIEW OF PSYCHIATRY 15

Mula, M., Schmitz, B., Jauch, R., Cavanna, A., Cantello, R., related to mesial temporal sclerosis. Epilepsy Research, 39,
Monaco, F., & Trimble, M.R. (2008). On the 121–125. http://dx.doi.org/10.1016/S0920-1211(99)00117-
prevalence of bipolar disorder in epilepsy. Epilepsy & 5
Behaviour, 13, 658–661. doi: 610.1016/j.yebeh.2008. Rathore, J.S., Jehi, L.E., Fan, Y., Patel, S.I., Foldvary-
1008.1002. Epub 2008 Sep 1019.http://dx.doi.org/10.1016/ Schaefer, N., Ramirez, M.J., … Tesar, G.E. (2014).
j.yebeh.2008.08.002 Validation of the Patient Health Questionnaire-9 (PHQ-
Mula, M., Trimble, M.R., Lhatoo, S.D., & Sander, J.W. 9) for depression screening in adults with epilepsy.
(2003). Topiramate and psychiatric adverse events in Epilepsy & Behaviour, 37, 215–220. doi: 10.1016/
patients with epilepsy. Epilepsia, 44, 659–663. http://dx. j.yebeh.2014.1006.1030. Epub 2014 Jul 1026.
doi.org/10.1046/j.1528-1157.2003.05402.x Robertson, M.M., Trimble, M.R., & Townsend, H.R. (1987).
Olesen, J.B., Hansen, P.R., Erdal, J., Abildstrom, S.Z., Phenomenology of depression in epilepsy. Epilepsia,
Weeke, P., Fosbol, E.L., … Gislason, G.H. (2010). 28, 364–372. http://dx.doi.org/10.1111/j.1528-1157.1987.
Antiepileptic drugs and risk of suicide: A nationwide tb03659.x
study. Pharmacoepidemiology and Drug Safety, 19, Rosenstein, D.L., Nelson, J.C., & Jacobs, S.C. (1993).
518–524. doi: 510.1002/pds.1932 Seizures associated with antidepressants: A review.
Onuma, T., Adachi, N., Ishida, S., Katou, M., & Uesugi, S. Journal of Clinical Psychiatry, 54, 289–299.
(1995). Prevalence and annual incidence of psychosis in Rowland, L.M., Bustillo, J.R., Mullins, P.G., Jung, R.E.,
patients with epilepsy. Psychiatry and Clinical Lenroot, R., Landgraf, E., … Brooks, W.M. (2005).
Neuroscience, 49, S267–S268. http://dx.doi.org/10.1111/j. Effects of ketamine on anterior cingulate glutamate
1440-1819.1995.tb02201.x metabolism in healthy humans: A 4-T proton MRS study.
Ording, A.G., & Sorensen, H.T. (2013). Concepts of comor- The American Journal of Psychiatry, 162, 394–396.
bidities, multiple morbidities, complications, and their Roy, K., Balon, R., Penumetcha, V., & Levine, B.H. (2014).
clinical epidemiologic analogs. Clinical Epidemiology, 5, Psychosis and seizure disorder: Challenges in diagnosis
199–203. doi: 10.2147/CLEP.S45305 and treatment. Current Psychiatry Reports, 16, 509. doi:
Park, E.M., Holmes, J.A., & Reeder-Hayes, K.E. (2014). 510.1007/s11920-11014-10509-11921
Acute mania associated with levetiracetam treatment. Satishchandra, P., Krishnamoorthy, E.S., van Elst, L.T.,
Psychosomatics, 55, 98–100. doi: 110.1016/j.psym.2013. Lemieux, L., Koepp, M., Brown, R.J., & Trimble, M.R.
1006.1008 (2003). Mesial temporal structures and comorbid anxiety
Patorno, E., Bohn, R.L., Wahl, P.M., Avorn, J., Patrick,
in refractory partial epilepsy. The Journal of
A.R., Liu, J., & Schneeweiss, S. (2010). Anticonvulsant
Neuropsychiatry & Clinical Neurosciences, 15, 450–452.
medications and the risk of suicide, attempted suicide, or
http://dx.doi.org/10.1176/jnp.15.4.450
violent death. JAMA, 303, 1401–1409. doi: 1410.1001/
Scheepers, B., Clough, P., & Pickles, C. (1998). The misdiag-
jama.2010.1410
nosis of epilepsy: Findings of a population study.
Penovich, P.E. (2004). Much ado about something or noth-
Seizure, 7, 403–406. http://dx.doi.org/10.1016/S1059-
ing: Behavioral problems with levetiracetam use in epi-
1311(05)80010-X
lepsy patients. Epilepsy Currents, 4, 145–146. http://dx.
Schmitz, E.B., Moriarty, J., Costa, D.C., Ring, H.A., Ell, P.J.,
doi.org/10.1111/j.1535-7597.2004.44009.x
Pollak, T.A., Nicholson, T.R., Mellers, J.D., Vincent, A., & & Trimble, M.R. (1997). Psychiatric profiles and patterns
David, A.S. (2014). Epilepsy-related psychosis: A role for of cerebral blood flow in focal epilepsy: Interactions
autoimmunity? Epilepsy & Behaviour, 36, 33–38. doi: 10. between depression, obsessionality, and perfusion related
1016/j.yebeh.2014.1004.1022 to the laterality of the epilepsy. Journal of Neurology,
Pompili, M., Girardi, P., Tatarelli, G., Angeletti, G., & Neurosurgery, and Psychiatry, 62, 458–463. http://dx.doi.
Tatarelli, R. (2006). Suicide after surgical treatment in org/10.1136/jnnp.62.5.458
patients with epilepsy: A meta-analytic investigation. Schwartz, J., & Cummings, J.L. (1988). Psychopathology
Psychological Reports, 98, 323–338. http://dx.doi.org/10. and epilepsy: An outpatient consultation-liaison experi-
2466/pr0.98.2.323-338 ence. Psychosomatics, 29, 295–300. http://dx.doi.org/10.
Preskorn, S.H., & Fast, G.A. (1992). Tricyclic antidepres- 1016/S0033-3182(88)72366-X
sant-induced seizures and plasma drug concentration. Seo, J.G., Cho, Y.W., Lee, S.J., Lee, J.J., Kim, J.E., Moon,
Journal of Clinical Psychiatry, 53, 160–162. H.J., & Park, S.P. (2014). Validation of the generalized
Prevey, M.L., Mattson, R.H., & Cramer, J.A. (1989). anxiety disorder-7 in people with epilepsy: A MEPSY
Improvement in cognitive functioning and mood state study. Epilepsy & Behaviour, 35, 59–63. doi: 10.1016/j.
after conversion to valproate monotherapy. Neurology, yebeh.2014.1004.1005
39, 1640–1641. http://dx.doi.org/10.1212/WNL.39.12. Sheehan, D.V., Lecrubier, Y., Sheehan, K.H., Amorim, P.,
1640-a Janavs, J., Weiller, E., … Dunbar, G.C. (1998). The
Pugh, M.J., Hesdorffer, D., Wang, C.P., Amuan, M.E., Mini-International Neuropsychiatric Interview (M.I.N.I.):
Tabares, J.V., Finley, E.P., … Bryan, C.J. (2013). The development and validation of a structured diagnos-
Temporal trends in new exposure to antiepileptic tic psychiatric interview for DSM-IV and ICD-10.
drug monotherapy and suicide-related behavior. Journal of Clinical Psychiatry, 59(Suppl 20), 22–33.
Neurology, 81, 1900–1906. doi: 1910.1212/1901.wnl. Simon, G.E., Savarino, J., Operskalski, B., & Wang, P.S.
0000436614.0000451081.0000436612e (2006). Suicide risk during antidepressant treatment. The
Quiske, A., Helmstaedter, C., Lux, S., & Elger, C.E. (2000). American Journal of Psychiatry, 163, 41–47. http://dx.doi.
Depression in patients with temporal lobe epilepsy is org/10.1176/appi.ajp.163.1.41
16 C. B. JOSEPHSON AND N. JETTE

Smith, D., Defalla, B.A., & Chadwick, D.W. (1999). The quality of life ratings in epilepsy. Neurology, 68,
misdiagnosis of epilepsy and the management of refrac- 1101–1107. http://dx.doi.org/10.1212/01.wnl.0000242582.
tory epilepsy in a specialist clinic. QJM, 92, 15–23. http:// 83632.73
dx.doi.org/10.1093/qjmed/92.1.15 Trimble, M.R., Rusch, N., Betts, T., & Crawford, P.M.
Smith, D.B., Mattson, R.H., Cramer, J.A., Collins, J.F., (2000). Psychiatric symptoms after therapy with new
Novelly, R.A., & Craft, B. (1987). Results of a nationwide antiepileptic drugs: psychopathological and seizure
Veterans Administration Cooperative Study comparing related variables. Seizure, 9, 249–254. http://dx.doi.org/10.
the efficacy and toxicity of carbamazepine, phenobarbital, 1053/seiz.2000.0405
phenytoin, and primidone. Epilepsia, 28(Suppl 3), Tu, K., Wang, M., Jaakkimainen, R.L., Butt, D., Ivers,
S50–S58. http://dx.doi.org/10.1111/j.1528-1157.1987. N.M., Young, J., … Jette, N. (2014). Assessing the val-
tb05778.x idity of using administrative data to identify patients
Smith, P.E.M. (2012). Epilepsy: Mimics, borderland and with epilepsy. Epilepsia, 55, 335–343. doi: 310.1111/epi.
chameleons. Practical Neurology, 12, 299–307. doi:10. 12506
1136/practneurol-2012-000304 Van Paesschen, W., King, M.D., Duncan, J.S., & Connelly, A.
Spina, E., & Perugi, G. (2004). Antiepileptic drugs: (2001). The amygdala and temporal lobe simple partial
Indications other than epilepsy. Epileptic Disorders, 6, seizures: A prospective and quantitative MRI study.
57–75.
Epilepsia, 42, 857–862. http://dx.doi.org/10.1046/j.1528-
St Germaine-Smith, C., Metcalfe, A., Pringsheim, T.,
1157.2001.042007857.x
Roberts, J.I., Beck, C.A., Hemmelgarn, B.R., … Jette, N.
Waxman, S.G., & Geschwind, N. (1975). The interictal
(2012). Recommendations for optimal ICD codes to
behavior syndrome of temporal lobe epilepsy. Archives of
study neurologic conditions: A systematic review.
Neurology, 79, 1049–1055. doi: 1010.1212/WNL.1040b General Psychiatry, 32, 1580–1586. http://dx.doi.org/10.
1013e3182684707 1001/archpsyc.1975.01760300118011
Swinkels, W.A., Duijsens, I.J., & Spinhoven, P. (2003). Wieshmann, U.C., & Baker, G.A. (2013). Self-reported feel-
Personality disorder traits in patients with epilepsy. ings of anger and aggression towards others in patients
Seizure, 12, 587–594. http://dx.doi.org/10.1016/S1059- on levetiracetam: Data from the UK antiepileptic drug
1311(03)00098-0 register. BMJ Open, 3, e002564. doi: 002510.001136/
Swinkels, W.A., Kuyk, J., van Dyck, R., & Spinhoven, P. bmjopen-002013-002564
(2005). Psychiatric comorbidity in epilepsy. Epilepsy & Williamson, T., Green, M.E., Birtwhistle, R., Khan, S.,
Behaviour, 7, 37–50. http://dx.doi.org/10.1016/j.yebeh. Garies, S., Wong, S.T., … Drummond, N. (2014).
2005.04.012 Validating the 8 CPCSSN case definitions for chronic
Tellez-Zenteno, J.F., Patten, S.B., Jette, N., Williams, J., & disease surveillance in a primary care database of elec-
Wiebe, S. (2007). Psychiatric comorbidity in epilepsy: A tronic health records. The Annals of Family Medicine, 12,
population-based analysis. Epilepsia, 48, 2336–2344. 367–372. doi: 310.1370/afm.1644
http://dx.doi.org/10.1111/j.1528-1167.2007.01222.x Youroukos, S., Lazopoulou, D., Michelakou, D., &
Tracy, J.I., Dechant, V., Sperling, M.R., Cho, R., & Karagianni, J. (2003). Acute psychosis associated with
Glosser, D. (2007). The association of mood with levetiracetam. Epileptic Disorders, 5, 117–119.