REVIEWS

Management of psychiatric and

neurological comorbidities in epilepsy
Andres M. Kanner
Abstract | The treatment of epileptic seizure disorders is not restricted to the achievement of
seizure-freedom, but must also include the management of comorbid medical, neurological,
psychiatric and cognitive comorbidities. Psychiatric and neurological comorbidities are relatively
common and often co-exist in people with epilepsy (PWE). For example, depression and anxiety
disorders are the most common psychiatric comorbidities in PWE, and they are particularly
common in PWE who also have a neurological comorbidity, such as migraine, stroke, traumatic
brain injury or dementia. Moreover, psychiatric and neurological comorbodities often have a
more severe impact on the quality of life in patients with treatment-resistant focal epilepsy than
do the actual seizures. Epilepsy and psychiatric and neurological comorbidities have a complex
relationship, which has a direct bearing on the management of both seizures and the
comorbidities: the comorbidities have to be factored into the selection of antiepileptic drugs,
and the susceptibility to seizures has to be considered when choosing the drugs to treat
comorbidities. The aim of this Review is to highlight the complex relationship between epilepsy
and common psychiatric and neurological comorbidities, and provide an overview of how
treatment strategies for epilepsy can positively and negatively affect these comorbidities
and vice versa.

Department of Neurology,
University of Miami,
Miller School of Medicine,
14th Street, 1120 NW, Miami,
33136 Florida, USA.
Correspondence to
a.kanner@med.miami.edu
doi:10.1038/nrneurol.2015.243
Published online 18 Jan 2016
Psychiatric and neurological comorbidities are rela-
tively common in people with epilepsy (PWE), affect-
ing, on average, 30–50% of patients1. Population-based
studies have identified a 35% lifetime prevalence of
psychiatric comorbidities, most commonly mood and
anxiety disorders, in these patients2; among neurolog-
ical comorbidities, migraines are the most common,
with a reported prevalence of 20–40%3.
The relationship between epilepsy and psychi­
atric and neurological comorbidities is complex, and
needs to be considered when planning the manage­
ment of any seizure disorder. Some of the psychi-
atric comorbidities (such as mood and anxiety
disorders) often co-occur with some of the common
neurological comorbidities associated with epilepsy
(such as migraine, stroke, dementia, traumatic brain
injury (TBI) and autistic spectrum disorder (ASD)).
Moreover, not only are PWE at increased risk of devel-
oping neurological and psychiatric comorbidities, but
patients with certain primary psychiatric disorders
(attention deficit–hyperactivity disorder (ADHD) and
mood, anxiety and psychotic disorders) are at increased
risk of developing epilepsy4,5 and neurological comor-
bidities (including migraine and stroke)6,7. These find-
ings imply a bidirectional relationship between epilepsy
and some of the neurological and psychiatric comor-
bidities, and a bidirectional relationship has also been
reported between some of these neurological (stroke,
migraine, dementia, TBI) and psychiatric (depression
and anxiety disorders) comorbidities (TABLE 1).
In any PWE, a comprehensive treatment plan is not
restricted to aiming for a seizure-free state, but also
requires careful investigation and treatment of psychi-
atric and neurological comorbidities. Unfortunately,
more often than not, several obstacles prevent such
comprehensive management: psychiatric comorbidities
often go unrecognized and untreated; the management
of neurological comorbidities is often not factored into
the therapeutic plan for the seizure disorder; the treat-
ment of psychiatric comorbidities is empirical, as data
that are based on methodologically sound research do
not exist; several misconceptions about ‘reported pro-
convulsant effects’ of psychotropic drugs have become
an obstacle in the treatment of psychiatric comorbid-
ities in PWE; and the pharmacological and surgical
treatments of seizure disorders can negatively affect
psychiatric and neurological comorbidities.
The purpose of this article is to review prac-
tical principles that should be considered in the
management of the most common psychiatric and

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Key points
• Psychiatric and neurological comorbidities are relatively common in epilepsy, affecting
up to half of the patients
• Psychiatric and neurological comorbidities have a complex relationship with epilepsy:
comorbidities can exacerbate epilepsy or each other, and vice versa
• Treatment of psychiatric and neurological comorbidities needs to be incorporated into
the overall management of patients with epilepsy
• Both pharmacological and surgical management of the seizure disorder can have
either a negative or a positive impact on psychiatric and neurological comorbidities
• Neurologists should be able to treat some of the more common psychiatric
comorbidities in patients with epilepsy and identify patients at risk of adverse events
from psychotropic medications, because psychiatric care is not available to all patients
• This Review provides practical principles and considerations for the management of
the most common psychiatric and neurological comorbidities in patients with epilepsy
neurological comorbidities in PWE, based on the
complex relationship that exists between epilepsy and
these comorbidities. Moreover, considerations for
neurologists treating PWE with these comorbidities
are outlined.
A common problem
Psychiatric comorbidities
Mood and anxiety disorders are the most frequent
psychiatric comorbidities in adult and paediatric
patients with epilepsy, with lifetime prevalence rates
of up to 30–35%1,2, whereas ADHD is typically iden-
tified in paediatric populations with prevalence rates
of 13–50%8,9. The prevalence of ADHD in adults with
epilepsy is yet to be established, but if one estimates
that 50–75% of children with primary ADHD remain
symptomatic in adulthood10, prevalence in adults with
epilepsy is expected to be relatively high. Psychotic
disorders are less common than ADHD, but their
prevalence rates are higher in PWE (7–10%) than in
the general population (0.4–1%)1. Of note, all of these
psychiatric comorbidities tend to recur throughout the
life of the PWE.
Neurological comorbidities
Any insult to the CNS has the potential to cause sei-
zures or epilepsy. The most frequent of these insults
include cerebrovascular incidents, cerebral palsy (with
or without mental retardation), arteriovenous malfor-
mations, brain tumours, cortical malformations, CNS
infections, TBI, dementia and autoimmune disorders11.
Some neurological disorders, including migraine,
stroke, dementia, brain tumours, and autoimmune
disorders, require long-term follow‑up and ongoing
thera­peutic interventions to achieve remission or pre-
vent their recurrence. Others — for example cerebral
palsy, ASD and TBI — require symptomatic treatment
of neurological, cognitive and psychiatric complica-
tions. In some neurological comorbidities, such as
dementia, migraine, stroke and autoimmune dis­
orders, both of these intervention types are necessary.
The pharmacological treatment of the seizure disorder
can have either negative or positive impact on these
neurological comorbidities.
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A complex relationship
Psychiatric comorbidity and epilepsy
As indicated in the Introduction, several population-­
based studies have suggested the existence of a
bi­directional relationship between epilepsy, ADHD,
and primary mood, anxiety, and psychotic disorders.
Not only are PWE at higher risk of developing one
of these psychiatric disorders, but patients with one of
these primary psychiatric disorders are at greater risk
of developing epilepsy4–7. This phenomenon is of great
importance in the management of these psychiatric
comorbidities, as the occurrence of a seizure or epi-
lepsy in patients treated with a psychotropic drug is
not necessarily the expression of an iatrogenic effect
(as it is typically diagnosed), but rather could reflect the
natural course of the underlying psychiatric disorder.
Failure to treat psychiatric comorbidity in PWE,
in turn, has important negative implications at sev-
eral levels. For example, comorbid mood and anxiety
dis­orders have been identified as the strongest inde-
pendent variables that predict an increased risk of
suicide11, pre­mature death12 and poor quality of life13.
In addition, these disorders have been associated with
a reduced tolerance to AEDs 14, which in turn can
interfere with compliance and thereby increase the
risk of seizure recurrence. Furthermore, two studies
have already identified a relationship between a his-
tory of depression preceding the onset of epilepsy and
an increased risk of treatment-­resistant epilepsy15,16.
Although poor AED compliance cannot be excluded
as a cause of refractory epilepsy, endogenous neuro­
biological aspects of mood and anxiety disorders have
been suggested as pathogenic mechanisms of treatment
resistance17. In children with epilepsy and ADHD, fail-
ure to treat ADHD is likely to have dire consequences
on their academic performance and social interactions;
untreated ADHD in adults with epilepsy is likely to
have a compounding effect on cognitive disturbances
associated with several epilepsy syndromes, interfere
in their professional achievements and worsen their
quality of life.
Psychiatric and neurological comorbidities
Mood and anxiety disorders have been identified as
independent predictors of a worse quality of life that
occur alongside other common neurological comor-
bidities associated with epilepsy, including migraine18,
stroke19, TBI20 and dementia21; an increased risk of sui-
cide was found to be associated with TBI23 and migraine
with aura22. Moreover, patients with TBI who experi-
enced depression that persisted for at least 6 months
after the injury had worse psychosocial outcomes then
TBI patients without depression; short-term depression
(<3 months) did not affect recovery24.
In addition, failure to treat psychiatric comorbidity
associated with neurological comorbidity can have a
direct negative impact on the course of the neurolog-
ical comorbidity. For example, in patients with stroke
(the most frequent cause of epilepsy in elderly PWE),
poststroke depression impairs recovery from cognitive
deficits and the ability to perform activities of daily
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Table 1 | Common psychiatric comorbidities that occur with neurological comorbidities in people with epilepsy
Neurological comorbidity
Stroke
Migraine/headaches
Dementia
Traumatic brain injury
Cerebral palsy (with
or without intellectual
disability)
Autistic spectrum disorder
Multiple sclerosis
ADHD, attention deficit–hyperactivity syndrome.
Common co‑occurring psychiatric Bidirectional relationship between
comorbidities epilepsy and neurological comorbidity?
• Depressive disorders Yes
• Anxiety disorders
• Psychotic disorders
• Depressive disorders Yes
• Anxiety disorders
• Depressive disorders Yes
• Anxiety disorders
• Psychotic disorders
• Depressive disorders No
• Anxiety disorders
• Behavioral disorders
• ADHD No
• Behavioural disorders
• Depressive disorders
• Anxiety disorders
• Psychotic disorders
• ADHD Yes
• Behavioural disorders
• Anxiety disorders
• Depressive disorders
• Psychotic disorders
• Depressive disorders No
• Anxiety disorders

living (ADL), and increases mortality19,25. In the case
of migraines, psychiatric comorbidity has been linked
with more severe headaches and a poorer response
to treatment26. Likewise, a history of depression can
be associated with a worse course of dementia27, both
in patients with mild cognitive impairment — who
develop symptoms of dementia at a much earlier age
than those without a prior history of a depressive
disorder — and in patients with Alzheimer disease, in
whom comorbid depression is associated with faster
cognitive deterioration, including worse deterioration
in the ability to perform ADL, and earlier placement in
a nursing facility21,28,29. Depression associated with TBI
impairs patients’ motivation and engagement in rehab­
ilitation programmes and social activities; the ability
of these patients to recover from cognitive deficits and
impaired ADL is reduced even after remission of the
depressive disorder.
Psychiatric comorbidities in PWE
Recognizing the type of psychiatric symptom in PWE is
essential for planning appropriate therapy. Psychiatric
symptoms in epilepsy can be the expression of spontane-
ous interictal psychiatric disorders, peri-ictal symptoma-
tology (including preictal, ictal and postictal), para-ictal
episodes (forced normalization phenomenon), or iatro­
genic psychiatric episodes triggered by pharmacological
or surgical treatment of the seizure disorder. All of these
possibilities must be investigated before initiating any
treatment regimen.
Clinicians tend to assume that any reported psychi-
atric phenomena are interictal; rarely do they investi-
gate the possibility of peri-ictal symptoms. Furthermore,
screening of psychiatric symptoms often fails to discrim-
inate between interictal and peri-ictal symptoms. Yet, as
shown below, the course of the disease and response to
treatment in these two contexts vary widely.
Peri-ictal episodes
Peri-ictal episodes include signs and symptoms that are
temporally related to seizures; their existence has been
acknowledged since the ninteenth century, but more
often than not, they have gone unrecognized.
Preictal symptoms and episodes. Preictal symptoms typi-
cally present as a dysphoric mood preceding a seizure by
a period of between several hours and up to 3 days. The
severity worsens during the 24 hours before the seizure
and remits postictally, though occasionally, the symptoms
can persist for a few days after the seizure30.
Postictal psychiatric symptoms or episodes. Typically,
postictal psychiatric symptoms are observed after
a symptom-free period of between several hours
and up to 7 days after a seizure. Postictal psychi­atric
symptoms are relatively frequent in patients with
treatment-­resistant focal epilepsy. For example, one
study of 100 consecutive patients with treatment-­
resistant focal epilepsy identified recurrent postictal
symptoms after >50% of seizures durin the 3 month
study period: depression in 43% of patients, anxiety in
45% and suicidal tendencies in 13%31. Postictal psychi­
atric symptoms can also occur in PWE with interictal
psychiatric disorders that are in remission (or con-
trolled with psychotropic medication), or can present
as psychiatric symptoms with postictal exacerbation of

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interictal symptoms. To date, only postictal psychotic
symptoms or episodes have been found to respond to
pharmacological interventions, whereas symptoms of
depression, anxiety, irritability, suicidality and impul-
sive behaviour failed to do so31. Clearly, remission of
postictal psychiatric symptoms can only be achieved
with full remission of the seizure disorder. Of note, the
symptom-free period between the seizure and the onset
of psychiatric symptoms can often lead to misdiagnosis
as interictal phenomena.
Ictal psychiatric symptoms. Seizure activity can mani-
fest as ictal psychiatric symptoms. Ictal fear or panic is
the most common type, comprising 60% of ictal psy­
chiatric episodes; ictal symptoms of depression are the
second-most common type32. Failure to recognize ictal
fear has often resulted in misdiagnosis of ictal fear as
an interictal panic disorder.
Paraictal episodes
Paraictal psychiatric episodes are rare psychiatric
disorders in PWE, and can result from either forced
normalization 33 or certain psychiatric and cogni-
tive disorders, including hypothalamic hamartomas
and epileptic aphasia of childhood34,35 — the onset,
improvement and/or remission of these disorders is
closely associated with the onset and remission of the
seizure disorder.
Forced normalization. Forced normalization, also
known as alternative psychopathology, refers to the
development of psychotic or severe affective symptom-
atology following seizure remission in patients with a
treatment-resistant seizure disorder. Forced normaliza-
tion has been associated with the use of certain AEDs,
including vigabatrin, clobazam and ethosuximide 33.
The psychopathological symptoms remit upon the
recurrence of epileptic seizures, though symptomatic
treatment can be attempted with psychotropic drugs.
The presentation of forced normalization as a psychotic
episode is rare and has been estimated to occur in
approximately 1% of patients with treatment-resistant
epilepsy, but its presentation as a depressive episode is
thought to be more common and often unrecognized33.
Hypothalamic hamartomas. Hypothalamic hamar-
tomas have been associated with the occurrence of
cognitive and severe behavioural disturbances, includ-
ing psychotic symptomatology, that are difficult to
control with psychotropic drugs. Complete resection
or ablation of the hamartoma and the subsequent sei-
zure remission result in remarkable improvement or
remission of psychiatric disturbances35. Of note, par-
tial resections do not yield the same improvement in
seizure frequency and psychiatric disturbances.
Iatrogenic psychiatric phenomena
Iatrogenic psychiatric symptomatology can be caused
by AEDs or epilepsy surgery. The pathogenic mech-
anisms of these adverse events are complex and
multifactorial, and are discussed in greater detail below.
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Impact of epilepsy treatments on comorbidites
Any comprehensive treatment plan of a seizure dis­order
has to factor in the existence of any neurological and
psychiatric comorbidities and any concomitant medi-
cations prescribed for their management. Certain AEDs
can have a therapeutic effect for several neurological
and psychiatric comorbidities, whereas others can result
in iatrogenic symptoms or affect the course of these
comorbidities, primarily through pharmaco­dynamical
mechanisms or pharmacokinetic interactions with
concomitant medications.
Impact of AEDs on psychiatric comorbidities
Therapeutic effects. In the past three decades, manu­
facturers have tested AEDs for mood-stabilizing, anti­
depressant, antimanic and anxiolytic effects, as well as
for analgesic effects in neuropathic pain and headaches
(TABLE 2). Accordingly, AEDs with mood-stabilizing,
antidepressant (valproic acid, carbamazepine, oxcarba-
zepine and lamotrigine) or anxiolytic properties (pre-
gabalin, gabapentin) can be considered even in patients
with a current or prior history of a mood or anxiety dis­
order. Certain exceptions have been reported, including
behavioural disturbances in children treated with val-
proic acid at high doses36. This effect is dose-dependent
and remits at lower doses36. Likewise, lamotrigine and
gabapentin can cause behavioural disturbances (irrita-
bility, poor frustration tolerance, agitation) in patients
with cognitive impairment37.
Iatrogenic psychopathology. AED-related iatrogenic
psychiatric symptoms can occur in PWE after expo-
sure to any AED, particularly when the drug used at
high doses. Such symptoms include depression, anxiety,
psychosis and ADHD, and can mimic one of these psy­
chiatric conditions. However, psychiatric adverse events
are more likely to occur in several specific groups of
patients: those who are considered to be at risk of psy­
chiatric disorders in any case (that is, patients with a
personal or family (particularly first-degree relatives)
history of psychiatric disorders (TABLE 2))38; patients
who are started on AEDs with known negative psycho­
tropic properties (including GABAergic drugs (such as
the barbiturates phenobarbital and primidone, benzo­
diazepines, vigabatrin and tiagabine), topiramate,
zonisamide, levetiracetam, ezogabin and perampanel);
patients who discontinue AEDs with anxiolytic or
mood stabilizing properties (which might have kept an
underlying anxiety or mood disorder under control);
and patients who are on psychotropic drugs to man-
age a mood, anxiety or psychotic disorder and who are
started on an AEDs with enzyme-inducing properties
(carbamazepine, phenytoin, barbiturates, rufinamide,
high dose of topiramate and oxcarbazepine) that can
accelerate the clearance of some of these psychotropic
drugs and limit their efficacy (see below).
In 2008, the FDA issued a warning that suggested
that “all” AEDs had the potential to cause suicidal
ideation and behaviour and led to the inclusion of a
warning of suicidality in the package information for
all AEDs39. The validity of the data that resulted in
REVIEWS

Table 2 | Antiepileptic drugs with positive and negative psychotropic properties

Drug Psychiatric benefits Psychiatric iatrogenic symptoms Analgaesic value
Barbiturates Anxiolytic • Depression No
• Behavior disturbance and/or
ADHD
Benzodiazepines Anxiolytic • Depression No
• Behavioral disturbance and/or
ADHD
Carbamazepine • Mood stabilizing Not reported Neuralgic pain
• Anti-manic
Oxcarbazepine • Mood stabilizing Not reported Neuralgic pain
• Anti-manic
Ethosuximide No • Behavioural disturbance No
• Psychotic symptoms
Tiagabine Anxiolytic Depression No
Levetiracetam No • Depression No
• Anxiety
• Behavioural disturbance
Topiramate No • Depression • Headaches and
• Behavioural disturbance migraines
• Anxiety • Neuralgic pain
Zonisamide No Depression No
Felbamate No Depression No
Vigabatrin No • Depression No
• Behaviour disturbance and/or
ADHD
• Psychosis
Perampanel No • Behavioural disturbance No
• Psychosis
• Depression
Lamotrigine • Mood stabilizing • Anxiogenic No
• Antidepressant • Behavioural disturbance in
cognitively impaired patients
Valproic acid • Mood stabilizing Behavioural disturbance at high Headaches and migraines
• Anti-manic doses in children
• Anti-panic
Gabapentin Anxiolytic (social phobia) Not reported • Headaches
• Neuralgic pain
Pregabalin Anxiolytic (generalized anxiety Not reported • Fibromyalgia
disorder) • Neuralgic pain
ADHD, attention deficit–hyperactivity disorder.

this warning has been questioned because of several
method­ological problems40,41. Furthermore, attempts to
replicate these findings in large studies have resulted in
discrepant data42–45. In the opinion of this author, some
AEDs can cause iatrogenic symptoms of depression,
which can facilitate the development of suicidal idea-
tion and behaviour in vulnerable patients. Yet, the FDA
data have to be considered in the context of a higher
risk of suicidality associated with epilepsy alone, which
is further enhanced in the presence of mood, anxiety
and psychotic disorders12. Clearly, identification of PWE
with a current, past and/or family psychiatric history is
the first step in minimizing the occurrence of iatrogenic
psychiatric symptomatology.
Comorbidities caused by epilepsy surgery. In adults with
treatment-resistant focal epilepsy, the prevalence of
psychiatric comorbidity can be as high as 40–60%46–49;
in children, prevalence rates can be even higher46. Epilepsy
surgery can have various effects on psychi­atric comor-
bidity: it can improve pre­surgical psychiatric comorbid-
ity or cause its remission, it can cause a recurrence or
worsening of a presurgical comorbidity, or it can cause
the development of a de novo psychiatric comorbidity47.
Episodes of depression and anxiety are relatively com-
mon post­surgical psychiatric complications: they are
observed after 20–40% of anterotemporal lobectomies
and occur within 3–6 months of surgery46–48. Often, these
complications are an exacerbation or recurrence of pre-
surgical dis­orders, though de novo episodes of depression
or anxiety have been reported in 10–15% of patients46,47.
Although mood and anxiety disorders tend to remit
in the majority of patients by the end of the first year
after surgery, they persist in approximately 10–15% of
patients47. De novo postsurgical psychotic episodes are
less common, observed in 3–10% of patients47.

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Although postsurgical episodes of mood and anxiety
disorders should be anticipated in patients with a psychi-
atric history, these data are rarely obtained in presurgical
evaluations. The use of psychotropic medication is nec-
essary and often sufficient to achieve symptom remission
(see below), though in patients with more severe forms of
mood disorder, electroconvulsive therapy has sometimes
been required.
Therapeutic effects of epilepsy surgery. In 30–50% of
patients with presurgical mood and anxiety disorders,
particularly in patients that become seizure-free, antero­
temporal resections can yield a marked improvement
or remission of affective symptoms47–49. Remission of
obsessive–compulsive disorders has also been reported50,51.
Impact of psychotropic drugs
Do psychotropic drugs cause seizures? A long-held belief
that psychotropic drugs have proconvulsant properties
has become the biggest obstacle in the management
of psychiatric comorbidities in PWE, but do the data
support these concerns? This question was carefully
investigated in a study published in 2007 by Alper and
colleagues — before their investigation, much of the
data on psychotropic drugs and seizures were based on
anecdotal reports and small case series52. Alper et al.
compared the incidence of seizures among patients ran-
domly assigned to a psychotropic drug and patients who
received a placebo in phase II and III, multicentre, ran-
domized placebo-controlled trials that were submitted
to the FDA for regulatory purposes between 1985 and
2004. A total of 75,873 patients with primary psychiatric
disorders were included. In addition, the investigators
compared the incidence of seizures during the rand-
omized placebo-controlled trials with the published
rates of unprovoked seizures among the general popu-
lation. Trials of antidepressants included several tricyclic
anti­depressants, selective serotonin reuptake inhibitors
(SSRIs), the serotonin-noradrenaline reuptake inhibi-
tor (SNRI) venlafaxine, the α2‑antagonist mirtazapine,
and the noradrenaline–dopamine reuptake inhibitor
bupropion. The incidence of seizures was substantially
lower among patients who received antidepressants than
among those given a placebo (standardized incidence
ratio = 0.48; 95% CI 0.36–0.61), whereas in patients
randomly assigned to receive a placebo, seizure occur-
rence was 19‑fold higher than in the general population.
Of note, the incidence of seizures in patients assigned
to either antidepressants or placebo was greater than
the published incidence of unprovoked seizures in the
general population52. These data support the notion that
depression is a risk factor for the development of unpro-
voked seizures and epilepsy, and raises the question of
whether SSRIs and SNRIs could protect from seizures.
Data from animal models of epilepsy seem to support
this hypothesis53,54, but no controlled studies have yet
been conducted in humans. It should be noted, however,
that Alper et al. also found that the incidence of seizures
was higher among patients who received bupropion or
clomipramine than in those who received a placebo52.
According to a general consensus, antidepressants
can cause seizures at toxic doses; indeed, most reported
seizures associated with antidepressants have occurred
after overdoses. One other antidepressant, maprotiline,
has been reported to increase the risk of seizures in
patients without epilepsy (incidence rate of 15.6%) in a
dose-dependent manner55.
Alper et al. also reported that patients randomly allo-
cated to receive the second-generation antipsychotic
drugs clozapine, olanzapine or quetiapine had a higher
incidence of seizures than those who received the pla-
cebo52. The first-generation antipsychotic drugs with the
lowest proconvulsant properties include haloperidol,
perfenazine, fluphenazine and molindone56.
The data on suspected proconvulsant properties of
CNS stimulants is anecdotal at best. Yet, there is a con-
sensus among recognized experts in pharma­cotherapy
of ADHD in epilepsy57, supported by five small studies of
human patients58–62, that these drugs and the noradren-
ergic drug atomoxetine are safe, and that treatment, if
clinically indicated, should not be withheld57.
There is almost no evidence-based data on the effi-
cacy of psychotropic drugs for the treatment of psy­
chiatric comorbidities in PWE. Thus, clinicians have
followed the treatment strategies used in primary
psychiatric disorders for the treatment of psychiatric

Table 3 | Efficacy of SSRIs and SNRIs in primary depression and anxiety disorders
Antidepressant Depression Panic Generalized Starting dose Maximum dose
drug disorder anxiety (mg daily) (mg daily)
Paroxetine* ++ ++ ++ 10 60
Sertraline* ++ ++ + 25 200
Fluoxetine* ++ ++ – 10 80
Citalopram* ++ + ++ 10 60
Escitalopram* ++ + + 5 30
Fluvoxamine + + + 50 300
Venlafaxine‡ ++ + + 37.5 300
Duloxetine ‡
++ + + 20 120
+ indicates that the drug is used for the treatment of this condition; ++ indicates that the drug has an FDA approval for this
condition; – indicates that the drug is not used to treat this condition. SNRI, selective noradrenaline reuptake inhibitor; SSRI;
selective serotonin reuptake inhibitor. *SSRI; ‡SNRI.

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Table 4 | Adverse effects linked to SSRIs and SNRIs
Adverse effect Prevalence
Nausea 35%
Insomnia 25%
Diarrhoea 19%
Headache 15%
Dry mouth 13%
Impaired sexual function 9–20%
Only most common adverse effects are included. SSRI,
selective serotonin reuptake inhibitor; SNRI, selective
noradrenaline reuptake inhibitor.
comorbidities in PWE. Although many antidepressant
drugs are considered to be safe for the management of
depressive and anxiety disorders (TABLE 3), these drugs
have common adverse events even in indivi­duals without
epilepsy (TABLE 4); the same goes for neuro­leptic drugs
(TABLE 5). A number of CNS stimulants and noradrener-
gic agents are commonly prescribed for the treatment of
ADHD and are considered acceptable in PWE, though
these drugs are also associated with common adverse
events (TABLE 6).
Pharmacokinetic interactions
Interaction between psychotropic drugs and AEDs. As
indicated above, certain (but not all) enzyme-­inducing
AEDs can increase the clearance of psycho­tropic drugs
metabolized in the liver, including tricyclic antidepres-
sants, SSRIs and mirtazapine, trazadone, first-­generation
antipsychotics (including chlorpromazine, fluphenazine
and haloperidol) and atypical antipsycho­tics (including
clozapine, olanzapine, ris­peridone (with the exception
of phenytoin which inhibits ris­peridone clearance),
quetiapine, aripiprazole and ziprazidone)63,64.
By contrast, valproic acid has been reported to
decrease the clearance of certain tricyclic antidepres-
sants (amitriptyline, nortriptyline) and antipsychotic
drugs (clozapine, olanzapine, quetiapine). Given that the
second-generation and third-generation AEDs are gen-
erally less reliant upon the cytochrome P450 isoenzyme
system for their disposal, they are likely to have fewer
opportunities for pharmacokinetic inter­actions with
other AEDs, psychotropic drugs and other concomitant
medications63,64.
Conversely, several psychotropic drugs can inhibit the
clearance of some enzyme-inducing AEDs, in particular
phenytoin and carbamazepine. These psycho­tropic drugs
include the SSRI antidepressants fluoxetine, fluvoxamine
and paroxetine, some of the first-generation (haloperi-
dol and loxapine) and second-­generation (risperidone,
quetiapine) anti­psychotic drugs and the CNS stimulant
methylphenidate, which has been reported to increase
the serum levels of pheno­barbital, phenytoin, primidone,
SSRIs and tricyclic antidepressants65. Citalopram and
escitalopram do not inhibit other drugs, and the inhibi-
tory effect of sertraline is minimal. Although definitive
studies are lacking, it has also been suggested that ven-
lafaxine and duloxetine are unlikely to cause significant
interactions with currently available AEDs.
AEDs and drugs used in neurological comorbidities.
Enzyme-inducing AEDs can increase the clearance of,
and thereby render less effective, various calcium chan-
nel blockers, as well as beta-blockers, antihypertensive
agents (such as losartan), oral anticoagulants (dicouma-
rol and warfarin), statins (atorvastatin and simvastatin),
acetylcholinesterase inhibitors (donepezil) and steroids
(dexamethasone, methylprednisolone and prednisolone).
Valproic acid can increase the risk of bleeding when
interacting with oral anticoagulants65.

Table 5 | Adverse effects of antipsychotic drugs

Antipsychotic Seizure Impact on EEG recordings Extrapyramidal Metabolic Anticholinergic Hyper QTc
threshold symptoms syndrome effects prolactinemia prolongation
Slowing of Interictal
lowering
background epileptiform
activity activity
Low potency FGAs ++ ++ – + ++ +++ ++ +
(chlorpromazine,
tioridazine,
perphenazin*)
High potency + + – +++ + +/− +++ ++
FGAs (haloperidol,
trifluoperazin,
fluphenazine)
Aripiprazole – + – + −/+ – – +
Clozapine +++ +++ +++ – +++ +++ – +
Olanzapine + ++ + + +++ + −/+ +
Quetiapine + ++ – – ++ + – +
Risperidone −/+ + – ++ + −/+ +++ +
Ziprasidone – + – + −/+ + ++
– indicates a rare adverse effect; + indicates low risk; ++ indicates medium risk; +++ indicates high risk. The mood–stabilizing property of FGAs is notably worse than
that of second-generation antipsychotics; FGAs are included in this table for comparison purposes. Symptoms of metabolic syndrome include weight gain,
increased risk of diabetes mellitus type II and hypertriglyceridaemia. FGA, first generation antipsychotic. *Low to medium potency.

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© 2016 Macmillan Publishers Limited. All rights reserved


Table 6 | Commonly used drugs for the treatment of ADHD
Drug Mechanism of action Initial Range of daily Adverse effects
daily dose dose
Methylphenidate DA and NA reuptake 5 mg 20–30 mg
inhibitor (0.3 mg/kg)
d,l‑amphetamine • DA and NA reuptake 5 mg 20–40 mg
inhibitor
• Pseudosubstrate
for NA and DA
transporters
Atomoxetine • NA‑reuptake inhibition 0.5 mg/kg 1–1.8 mg/kg
• Increases DA indirectly
ADHD, attention deficit–hyperactivity disorder; DA, dopamine; NA, noradrenaline.
Calcium channel blockers can inhibit the metab-
olism of carbamazepine, phenytoin and topiramate,
whereas propranolol and sumatriptan can inhibit the
clearance of topiramate. Likewise, the anti­platelet
ticlopidine and the anticoagulant dicoumarol can
inhibit phenytoin clearance.
Pharmacodynamic effect of AEDs on comorbidities
AEDs might improve psychiatric comorbidities. Several
AEDs have positive psychotropic properties (TABLE 2),
which should always be considered in the selection of
an AED. For example, in a patient with focal epilepsy
and a generalized anxiety disorder, the use of pregabalin
can improve both conditions66, and gabapentin can be
a potential drug of choice in patients with social pho-
bia37. Although there is no evidence that AEDs with
anti­depressant properties, such as lamotrigine, preclude
the use of an antidepressant to treat a major depressive
episode (MDE) in PWE. Once the patient reaches a
euthymic state, AEDs with mood stabilizing properties
might maintain remission of the depressive disorder if
the antidepressant drug is discontinued. Discontinuing
this type of AED in PWE who have a prior history of
mood disorder can result in recurrence of a depressive
episode67. Clearly, the choice to use one of these AEDs
has to be weighed against its tolerability and its toxicity
and pharmacokinetic profiles.
AEDs might improve neurological comorbidities.
Most AEDs that enter the market today are tested for
their prophylactic and analgaesic effects in different
types of migraine and neuropathic pain. For example,
topiramate, gabapentin and valproic acid are commonly
in use as prophylactic agents for the treatment of head-
aches68, and gabapentin, pregabalin, carbamazepine and
topiramate can improve neuropathic pain69.
Yet, in PWE, neurological comorbidities are often
accompanied by psychiatric comorbidities. The treat-
ment of comorbid headaches, in particular migraines,
illustrates the potential benefits and limitations of AEDs
in the setting of comorbid psychiatric symptoms. In
NATURE REVIEWS | NEUROLOGY VOLUME 12 | FEBRUARY 2016 | 113
© 2016 Macmillan Publishers Limited. All rights reserved
REVIEWS
Potential for Safety in people
drug abuse with epilepsy
• Appetite suppression Moderate Safe at therapeutic
• Emotional lability doses
• Sadness
• Anxiety
• Insomnia
• Psychotic symptoms
• Appetite suppression Moderate Safe at therapeutic
• Emotional lability doses
• Sadness
• Anxiety
• Insomnia
• Psychotic symptoms
• Sedation Low Safe at therapeutic
• Loss of appetite doses
• Nausea
• Drowsiness
PWE, migraines and other types of headaches can occur
inter­ictally or can be temporally related to seizures,
either preceding them (known as migralepsy, present
in 3% of PWE) or — more commonly — following
the seizure (postictal headaches, present in 20–40% of
PWE)2. Theoretically, topiramate and valproic acid can
have a prophylactic effect against migraines and focal
and generalized epilepsy. Yet, certain caveats need to
be considered before these AEDs can be prescribed.
Topiramate — particularly if started at a high dose or
titrated rapidly — can increase the risk of depression
in PWE who have a previous personal or a family his-
tory of mood disorder70. Valproic acid would seem to
be the ideal AED, given its broad spectrum efficacy
in epilepsy, its prophylactic effect on migraines and
headaches, and its mood-stabilizing and anxiolytic
properties37,68. Yet, its potentially serious and relatively
frequent teratogenic effects and iatrogenic effects on
women’s reproductive functions limit its use in women
of childbearing age71.
In addition, headaches are a common adverse effect
of high-dose AEDs in the early stages of therapy after
a rapid dose titration. Furthermore, headaches can be
an adverse effect of certain AEDs (such as lamotrigine)
even at low doses. It should also be kept in mind that
enzyme-­inducing AEDs can interfere with the thera-
peutic effects of certain migraine prevention medica-
tions, including calcium channel blockers, by increasing
their clearance and thereby substantially lowering their
serum concentration.
AEDs can worsen neurological comorbidities. AEDs
with enzyme-inducing properties have displayed athero­
genic effects through their effect on the cytochrome
P450 system. Indeed, in one study, discontinuation of
either pheny­toin or carbamazepine, or switching to
AEDs with no enzyme-inducing properties (for exam-
ple lamotrigine or levetiracetam), resulted in a notable
reduction of several atherogenic chemicals including
total cholesterol, LDL cholesterol, triglycerides and
C‑reactive protein72. In addition, lipoprotein (a) levels
REVIEWS
Box 1 | Considerations for drug selection
The following factors should be considered when
choosing antiepileptic and psychotropic drugs in
patients with epilepsy.
Demographic data
• Gender
• Age
• Education
• Occupation
• Marital status
Epilepsy data
• Seizure types
• Epileptic syndrome
Is this medication likely to
• Worsen or improve a comorbid medical disorder?
• Worsen or improve a comorbid neurologic disorder?
• Worsen or improve a comorbid psychiatric disorder?
• Worsen comorbid cognitive disturbances?
• Interact with concomitant antiepileptic drugs or other
medications?
• Affect reproductive functions?
• Affect bone health?
• Affect the blood lipid profile?
Additional information to aid selection of a
psychotropic drug
• Psychiatric comorbidity
• Depressive or anxiety disorder
• Attention deficit–hyperactivity disorder
• Psychotic disorder
Is this medication likely to
• Worsen or improve a comorbid medical disorder?
• Worsen or improve a comorbid neurologic disorder?
• Worsen the seizure disorder?
• Interact with concomitant antiepileptic drugs or other
medications?
• Affect reproductive functions?
• Affect bone health?
• Affect lipid profile?
dropped in PWE who discontinued carbamazepine,
whereas those who discontinued phenytoin had a
decrease in blood levels of homocysteine72. The authors
of the study concluded that enzyme-inducing AEDs
increase the risk of cardio­vascular and cerebrovascu-
lar disease by facilitating the synthesis of atherogenic
chemicals. Other investi­gators have demonstrated that
the weak enzyme inducers oxcarbazepine (>900 mg
daily) and topiramate (200 mg daily) are associ­ated
with hyperhomocysteinaemia, which suggests that the
atherogenic effect might not be exclusive to AEDs with
strong enzyme-inducing properties73. A later prospec-
tive study of AEDs without enzyme-inducing properties
also demonstrated an association of these drugs with
an increase in several atherogenic chemicals74. Of note,
a population based-study in the UK demonstrated
that a history of epilepsy increased the risk of stroke75;
114 | FEBRUARY 2016 | VOLUME 12 www.nature.com/nrneurol
© 2016 Macmillan Publishers Limited. All rights reserved
whether these pharmacological effects of AEDs account
for some of this increased risk is yet to be established.
Cognitive disturbances are often associated with sev-
eral neurological comorbidities, including stroke, TBI,
ASD, MS and dementia. Most — if not all — AEDs,
when taken at high doses, are linked with cognitive dis-
turbances in PWE of all ages; elderly patients are also
more susceptible to cognitive adverse events at relatively
low doses because the drug clearance is lower in this
age group76.
AEDs such as topiramate77 and zonisamide78 are
known to impair verbal functions; specifically, they
can cause word-finding difficulties, spelling errors
and memory disturbances. These iatrogenic effects
are magnified when either AED is combined with
valproic acid77,78.
Of note, comorbid mood disorders are also com-
monly linked to poor concentration and memory
disturbances79. Thus, screening for mood disorder is
essential in the assessment of any iatrogenic cognitive
adverse event attributed to an AED or epilepsy surgery.
Other pharmacodynamic effects. From a pharmaco­
dynamic standpoint, the following properties of psycho-
tropic drugs must be kept in mind in the treatment of
PWE with and without neurological comorbidity. First,
all antipsychotic drugs have the potential to increase the
QT interval; among the first-generation antipsychotic
drugs, haloperidol, fluphenazine and trifluoperazine
carry the highest risk, whereas among the second-­
generation antipsychotic drugs, ziprasidone carries the
greatest risk. Given that PWE are at increased risk of
sudden death, and prolonged QT has been suggested as
one of the possible pathogenic mechanisms80, patients
treated with these AEDs should have an ECG before the
treatment is started and once the target dose is reached.
Repeated EKG is even more important in those patients
who have a neurological comorbidity associated with
a cardiovascular disease, such as dementia or history
of stroke. Second, SSRIs and SNRIs can increase the
risk of bleeding, warranting cautious use in PWE on
anticoagulants or NSAIDs81. Third, SSRIs and SNRIs
can facilitate the development of hyponatraemia by
promoting excessive antidiuretic hormone secretion82;
serum electrolytes must be monitored in patients taking
these drugs, in particular if they are on diuretic agents
simultaneously with carbamazepine, oxcarbazepine,
or eslicarbazepine. Fourth, SSRIs have been linked
to osteopenia and osteo­porosis in population-based
studies83,84; in addition to the supplementation of vita-
min D3 and calcium, bone mineral density should
be monitored, particularly in PWE who are taking
enzyme-inducing AEDs.
Who should treat these comorbidities?
In an ideal world, any PWE with a psychiatric comor-
bidity would be referred to a mental health professional
who would decide on the best course of treatment.
Unfortunately, access to psychiatric care is usually lim-
ited in both industrialized and developing countries,
and in both universal and private health care systems.
 REVIEWS

Managing the psychiatric comorbidities in PWE with
and without neurological comorbidities cannot wait
until this serious and very complex problem is solved.
One potential solution is for neurologists to begin
pharmacological therapy for uncomplicated and non-
refractory mood and anxiety disorders and ADHD in
patients who are not comorbid with an increased risk
of suicide, a personality disorder, drug or alcohol abuse,
a bipolar disorder or a psychotic disorder. Mood dis­
orders that do not remit after two treatment courses
with two different antidepressant drugs at optimal
doses must be considered as treatment-resistant. A
bipolar disorder can be suspected in PWE who experi-
enced hypomanic or manic symptoms after exposure
to antidepressant drugs, or who have a family history
of bipolar illness85. In addition, PWE who had an initial
MDE before the age of 15 have a 50% chance of having
a bipolar disorder.
To conclude, the psychiatric comorbidities for
which neurologists could offer pharmacological treat-
ment include: mood disorders presenting as a MDE,
dysthymic disorder and subsyndromic depressive epi-
sode, defined as the presence of symptoms of depres-
sion but which do not meet criteria of the other two
conditions; anxiety disorders presenting as general-
ized anxiety disorder (GAD) and panic disorders; and
attention deficit disorders of hyperactive, inattentive
and mixed type, as well as adult-type ADHD.
MDE and GAD in PWE can be easily identified
with two self-reporting screening instruments that
patients can complete at every visit. These screening
instruments can be completed in less than 5 min-
utes, and are available in multiple languages. One of
these instruments, Neurologic Depressive Disorder
Inventory in Epilepsy (NDDI‑E) 86, was developed
specifically for PWE. NDDI‑E is a six-item screening
tool in which each item is scored on the Lickert scale
(1–4). A score of >15 is suggestive of a MDE86. To iden-
tify GAD in PWE, the Patient Health Questionnaire-
Generalized Anxiety Disorder‑7 has been widely used
in general practice87. It consists of seven items scored
on a Lickert scale (0–3), where a score >10 is suggestive
of GAD. Neurologists can follow the response to treat-
ment over time by having the patient complete these
instruments at each visit.
Conclusions
The studies reviewed in this article clearly demonstrate
that PWE are at increased risk of psychiatric and neuro­
logical comorbidities, which can precede or follow the
onset of the seizure disorder. Thus, early recognition
of these comorbidities and their risk factors, such as
family history of psychiatric symptoms, at the time of
the initial evaluation is crucial for formulating a com-
prehensive treatment plan. Accordingly, treatment
of the seizure disorder must be based on the AED’s
efficacy for the seizure type and epileptic syndrome,
its adverse event profile, and its pharmacokinetic and
pharmaco­dynamic properties that can have therapeutic
or iatrogenic effects on comorbid medical, psychiatric
and neurological comorbidities. Likewise, the pharma­
cological regimen for treatment of psychiatric and neu-
rological comorbidities must be selected not only on
the basis of the potential therapeutic effect, but also
on potential iatro­genic effects on the seizure disorder.
Going through a simple list of considerations (BOX 1)
will ensure that every aspect of the patient’s history has
been considered in the formulation of a comprehensive
treatment plan. Just as seizure freedom is the goal of
any pharmacological or surgical intervention in PWE,
the treatment of psychi­atric comorbidities must aim
to reach complete remission of all psychiatric symp-
toms. With certain exceptions, the use of most psycho-
tropic drugs at therapeutic doses is safe in PWE, and
the occurrence of seizures does not need to result in
discontinuation of such drugs.
Whether neurological comorbidities increase the
risk of developing psychiatric comorbidities (and vice
versa) remains to be investigated. Yet, an effective
treatment of psychiatric comorbidities in PWE with a
neurological comorbidity is of the essence to minimize
worsening of the neurological comorbidity.

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Competing interests statement
The author declares no competing interests.