Depression in Temporal Lobe Epilepsy

Depression in Temporal Lobe Epilepsy: A Review of Prevalence, Clinical Features,
and ana!ement Considerations

C" #" $arcia
Department of Psyc%iatry, #c%ulic% #c%ool of edicine, &niversity of 'estern
(ntario, London, (), Canada )*A +C,
Received - .uly /0,,1 Accepted ,0 #eptember /0,,
Academic Editor: 'arren T" 2lume
Copyri!%t 3 /0,/ C" #" $arcia" T%is is an open access article distributed under
t%e Creative Commons Attribution License, w%ic% permits unrestricted use,
distribution, and reproduction in any medium, provided t%e ori!inal wor4 is
properly cited"
Abstract
Depression in temporal lobe epilepsy %as been establis%ed as a fre5uent
occurrence, and various possible mec%anisms for t%is si!ni6cant comorbidity
%ave been posited" 7owever, t%ere is still little to !uide a clinician in t%e
reco!nition and mana!ement of depression in patients wit% temporal lobe
epilepsy" T%is is in part due to t%e lac4 of consistent 6ndin!s in earlier studies,
w%ic% was li4ely partly due to variabilities in met%odolo!y, samplin!, and
dia!nosis of bot% temporal lobe epilepsy and depression" 7owever, in recent
years, si!ni6cant e8ort %as been made to address t%ese issues and provide a
framewor4 for dia!nosis and mana!ement of depression in t%is population" T%e
followin! is a review of t%e literature, wit% special emp%asis on clinical
p%enomenolo!y of depressive symptoms, described bidirectional ris4 between
depression and temporal lobe epilepsy, and treatment strate!ies in t%e conte9t
of potential dru! interactions wit% antiepileptic dru!s"
," :ntroduction
Temporal lobe epilepsy ;TLE< is t%e most fre5uent of t%e epileptic disorders"
:nterictal depressive symptoms, and interictal ma=or depressive episodes, are
5uite common in epilepsy in !eneral but appear to be particularly lin4ed to TLE
>,?" T%is lin4 between t%ese two disorders %as been a source of !reat interest to
bot% neurolo!ists and psyc%iatrists for many years and %as !enerated an
e9pansion of 4nowled!e in bot% 6elds t%at %as been used to better understand
not only t%ese two disorders, but t%e relations%ip of mood, co!nition, and
temporolimbic function in ot%er related conditions as well >,?"
Despite t%is, a review of t%e literature reveals t%at t%ere is limited co%esive
!uidance re!ardin! t%e prevalence of depression in TLE patients and t%e clinical
features by w%ic% dia!nosis can be made, nor are t%ere universally accepted
!uidelines for t%e mana!ement of depression in t%is population" Di@culties in
study desi!n, variable sample populations, and t%e c%allen!es of con6rmin!
temporal lobe focus in some patient populations are all possible contributors to
t%is !ap" 7owever, many establis%ed aut%orities in t%is 6eld %ave been ma4in!
si!ni6cant e8orts to overcome t%ese issues and move towards a co%esive
approac% to dia!nosis and mana!ement of depression in t%e TLE population"
/" Prevalence of Depression in Temporal Lobe Epilepsy
Alt%ou!% t%ere %ave been many studies e9aminin! t%e fre5uency of depression
in temporal lobe epilepsy patients, it %as been di@cult to establis% a clear
pattern wit% respect to prevalence, particularly in comparison to ot%er types of
epilepsy >/?" 7istorically, depressive symptoms %ave been considered to be more
fre5uent in epilepsy wit% a temporal lobe focus t%an in e9traATLE or !eneraliBed
epilepsy >CDE?" 7owever, several ot%er studies %ave not been able to document
any suc% di8erences >/, FD,G?"
#everal e9planations for t%is %ave been proposed" Firstly, concomitant or
additive mec%anisms may play a role in t%e development of depressive
symptoms in su8erers of TLE" Rodin et al" >G? noted t%at many patients wit% TLE
%ave more t%an one seiBure type, and t%at t%e number of seiBures rat%er t%an
t%e location of t%e focus may be more relevant" Two later studies con6rmed t%at
fre5uency of seiBures were more si!ni6cant in predictin! depressive symptoms
t%an focus location >,E, ,F?" (t%er ris4 factors %ave also been identi6ed, suc% as
a!e of onset and laterality of temporal lobe focus t%at may also place patients at
%i!%er or lower ris4 t%an location of focus alone >/0, /,?" #imilarly, frontal lobe
dysfunction in addition to temporal lobe dysfunction may be an important ris4
factor in developin! depression in TLE patients >/?" Additionally, #win4els et al"
>/? described si!ni6cant met%odolo!ical di8erences amon! t%e various studies
e9aminin! prevalence rates of depression in epilepsy, includin! small sample
siBe, lac4 of control !roups, variable and often nonstandardiBed dia!nostic
instruments, and variability in t%e study population ;inpatients, outpatients,
sur!ical patients, etc"<" Finally, Adams et al" >,+? observed t%at many studies
assessin! psyc%iatric symptoms in epilepsy predate t%e advent of tec%nolo!y
suc% as video electroencep%alo!ram monitorin! and ma!netic resonance
ima!in!, w%ic% may ma4e c%aracteriBation of t%e underlyin! lesion more
unreliable" All of t%e above may be contributin! to t%e fact t%at alt%ou!% t%ere is
a plet%ora of studies dedicated to t%e assessment of prevalence of depression in
temporal lobe epilepsy, consensus %as yet to be ac%ieved"
)evert%eless, a %andful of recent studies %ave attempted to rectify some of t%e
above issues and %ave provided some interestin! data" #anc%eBA$istau et al"
>,*? studied C0E patients t%at were carefully classi6ed as %avin! epileptiform
foci t%at was temporal or e9tratemporal in localiBation" T%ese patients were t%en
administered t%e #tructured :nterview for D#A:H A9is : Psyc%iatric Disorders
;#C:DA:<, and results were compared usin! a multivariate analysis" (f t%e TLE
!roup, //I %ad a lifetime prevalence of a=or Depressive Disorder, and ,-"*I
%ad previous oneAyear prevalence of t%is disorder" E9traATLE su8erers %ad a
lifetime prevalence of ,-"*I and a previous oneAyear prevalence of *"+I" (f all
t%e psyc%iatric disorders assessed ;mood disorders, psyc%otic disorders,
somatoform disorders, substance abuse disorders, and an9iety disorders<, only
previousAyear prevalence of ma=or depressive disorder was si!ni6cantly di8erent
between t%e two !roups, wit% TLE su8erers %avin! a %i!%er rate of ma=or
depression" Adams et al" >,+? followed C,F individuals wit% focal epilepsy over an
,,Ayear period" T%e epileptic site, laterality, and type of t%e lesion were
con6rmed wit% video electroencep%alo!ram monitorin! and R: scans" T%e
patients were assessed by t%e study neuropsyc%iatrist usin! D# :H dia!nostic
criteria prior to t%eir epilepsy dia!nosis bein! made and were reviewed by a
second neuropsyc%iatrist to con6rm dia!nostic concordance" T%e overall
prevalence of depression in t%e study participants was C/"*I" )o si!ni6cant
di8erences were found in t%e prevalence of depression between TLE patients
;C,"/I< and e9traATLE patients ;CG"FI<, nor between left or ri!%tAsided lesions"
(f note, patients wit% nonlesion focal epilepsy e9%ibited a %i!%er rate of
depression ;-,"*I< compared to t%ose wit% a lesion on R:, re!ardless of
temporal or e9tratemporal focus" #win4els et al" >,G? assessed *G TLE patients
and *- e9tratemporal lobe focus patients for depression usin! t%e 2ec4
Depression :nventory and t%e Composite :nternational Dia!nostic :nterview" )o
si!ni6cant di8erences were noted between t%e two localiBation !roups, but rates
of psyc%iatric symptoms were %i!%er in patients wit% more fre5uent and
prolon!ed seiBures"
:n summary, t%e 5uestion of w%et%er a temporal lobe focus of epilepsy assi!ns a
%i!%er prevalence of depression to patients is not yet fully answered" Earlier
studies were divided on t%is issue, but variability in met%odolo!y, patient
samples, accuracy of identi6cation of epileptic focus, and in dia!nostic tools used
for assessment of depression all made comparison of t%e data di@cult"
Additionally, t%is variability in results may also represent multiple factors at play
in t%e development of depression beyond simply localiBation of epileptic focus,
suc% as fre5uency and len!t% of seiBures, a!e, and comorbid dysfunction across
multiple areas"
C" Clinical C%aracteristics of Depression in Temporal Lobe Epilepsy
Alt%ou!% t%is survey of t%e available literature did not uncover studies of t%e
natural %istory of depressive symptoms in TLE patients speci6cally, most studies
e9aminin! t%e relations%ip between depressive symptoms and a!e of onset of
epilepsy or duration of epilepsy do not identify clear association wit% ris4 of
depression >E, //, /C?" (ne study did 6nd a potential lin4 between depression
and development of seiBures in later life >/-?"
(ne of t%e 5uestions t%at %as been raised %istorically is w%et%er depressive
symptoms in t%e epilepsy and TLE population represent a comorbid mood
disorder, wit% dia!nostic c%aracteristics and a natural %istory similar to ma=or
depressive disorder as seen in t%e !eneral population, or w%et%er t%ese
symptoms instead represent a collection of emotional and co!nitive disabilities
similar but not e5ual to a ma=or depressive disorder >/+D/G?"
T%e concept of interictal dysp%oric disorder was proposed to describe t%e latter
in response to studies su!!estin! t%at a si!ni6cant portion of epilepsy patients
wit% depressive symptoms would not %ave met criteria for a=or Depressive
Disorder as typically described in dia!nostic sc%edules >/E, /F?" For e9ample,
Janner et al" >C0? e9amined patients wit% refractory seiBures and depressive
symptoms and found only /FI met D# :H criteria for a=or Depressive
Disorder" :nitially proposed by Jraepelin, t%en later 2leuler, t%is concept
ori!inally described a pattern of symptoms consistin! of prominent irritability,
eup%oria, an9iety, aner!ia, insomnia, and pain" T%ese symptoms are described to
%ave a c%ronic, relapsin! and remittin! course, but to respond well to
antidepressants >C,?" A more speci6c ran!e of symptoms %ad been described by
2lumer et al" in t%eir )eurobiolo!ical :nventory for Epilepsy, w%ic% was a
reformulation of earlier inventories t%at were meant to de6ne t%e TLE personality
c%aracteristics >/+, /F?" Two cate!ories of symptoms %ave been described:
depressiveAsomatoform symptoms ;depressed mood, aner!ia, pain, and
insomnia< and a8ective symptoms ;irritability, eup%oric mood, fear, and an9iety<
>/F?" An%edonia %as also been proposed as a better mar4er for depression in
patients wit% epilepsy, in part secondary to its independence from p%ysical
symptoms associated wit% medications and c%ronic illness >C/?"
7owever, t%ere %ave also been many proponents of t%e belief t%at t%ere is not
su@cient evidence to support a model of psyc%opat%olo!y uni5ue to temporal
lobe epilepsy" Janner and )ieto >CC? proposed t%at t%e symptoms described in
t%ese TLEA or epilepsyAspeci6c psyc%opat%olo!y inventories are 5uite similar to a
stable mood disorder wit% mar4ed depressive and an9iety features rat%er t%an a
de novo condition" Lis%man >C-? also concurred t%at t%e depressive symptoms
described as speci6c to t%e TLE population were an artifact of samplin! and
selective reportin! by patients in institutional settin!s"
E8orts %ave been made to test t%e validity of dia!nosin! depression in t%is
population" Reilly et al" >/+? reasoned t%at t%e latent variable factors observed to
be impacted in depressive disorders ;ne!ative attitude, performance di@culty,
and somatic elements< could be measured in TLE patients to compare t%e level
of dysfunction across t%ese domains to 4nown 5uantities in ma=or depression"
TLE patients manifested di@culties across t%ese domains t%at were very similar
to t%at seen in ma=or depressive disorder, su!!estin! t%at t%ese symptoms
represented a ma=or depressive disorder, rat%er t%an a condition uni5ue to TLE"
.ones et al" documented t%e validity of t%e #C:D and :): ;ini :nternational
)europsyc%iatric :nterview< by comparin! to patient selfAreport of symptoms of
a=or Depressive Disorder, and 6ndin! very %i!% concordance >C+?"
:n summary, t%ere %as been some su!!estion %istorically t%at depressive
symptoms in t%e TLE population may represent not depression but rat%er a
condition uni5ue to t%ese patients" T%is concept %as been described as interictal
dysp%oric disorder" 7owever, t%ere now also %ave been studies t%at appear to
con6rm t%at t%e D# :H criteria for ma=or depression are valid in t%e TLE
population, and t%at t%e depressive symptoms t%ey e9perience can be
understood as a stable mood disorder"
-" )euroanatomical Findin!s of Depression in Temporal Lobe Epilepsy
T%e various structures of t%e limbic system %ave been a focus of interest in
understandin! bot% depression and TLE for 5uite some time" Re!ions of
particular interest for bot% t%ese disorders include t%e temporal lobes
;particularly t%e %ippocampus, amy!dala, entor%inal, and neocortical corte9<, t%e
frontal lobes, and important limbic subcortical structures suc% as t%e basal
!an!lia and t%alamus, as well as t%e circuits connectin! all t%ese structures >,,
CGD-0?" Alt%ou!% t%e %ippocampus and amy!dala %ave been t%e ma=or focus of
attention, all of t%e above structures %ave been found to s%are association
across t%ese two disorders >,?"
:n bot% depression and TLE, %ippocampal volumes %ave been found to be
abnormal >,?" :n depressed patients wit% and wit%out TLE, %ippocampal volumes
are reduced, usually bilaterally or occasionally left sided only >CG, -,D-+?" :n TLE
patients, volumes are usually reduced on t%e side of t%e epileptic focus >-0, -/,
-+?" :n depressed TLE patients, %ippocampal volumes are usually reduced
bilaterally" :nterestin!ly, in patients wit% a leftAsided TLE focus, co!nitive
problems wit% memory and learnin! are more mar4ed >-*?" (t%er studies %ave
con6rmed t%is, lin4in! depression and verbal learnin! impairments in TLE
patients >-G?" T%e suspected cause be%ind t%is is dysfunction wit%in t%e lar!er
lan!ua!e representation in t%e left %emisp%ere >-*, -G?"
T%e amy!dala %as also been a source of intense study in t%e combined 6eld of
depression and TLE, !iven its 4ey role in fear and associated emotions >-E?" T%is
structure appears to c%an!e as an acute depressive episode becomes c%ronic,
initially becomin! enlar!ed bilaterally, t%en s%rin4in! bilaterally as t%e mood
disorder becomes c%ronic >,?" Two studies %ave found a relations%ip between
escalatin! amy!dala volume and severity of symptoms of depression in t%e TLE
population >-F, +0?" LeftAsided volume increases of t%e amy!dala and severity of
depression symptoms in TLE patients seemed particularly associated wit% eac%
ot%er >+0?" T%e suspected mec%anism for t%is is %yperactivity of t%e amy!dala in
t%e acute p%ase of depression in TLE and nonATLE patients, resultin! in an
increase in volume secondary to increased re!ional blood Kow >,, -F, +0?"
T%e two commonest lesions for t%e development of temporal lobe epilepsy are
mesial sclerosis and t%e more rare neocortical temporal lesions >,?" Patients wit%
mesial temporal sclerosis %ave si!ni6cantly %i!%er rates of depression t%an t%ose
wit% neocortical temporal lesions, re!ardless of lateraliBation >+,?" Additionally,
patients wit% mesial temporal sclerosis %ave a !reater fre5uency of co!nitive
side e8ects and mood problems wit% antiepileptic dru!s >+/?" :nterestin!ly,
#al!ado et al" >+C? found si!ni6cantly more widespread !rey matter volume loss
in TLE patients wit% depression as compared to t%eir nondepressed fellow
patients" T%is leads to t%e su!!estion t%at t%ere is a bidirectional relations%ip
between t%ese two disorders >+C?"
:n summary, various important structures of t%e limbic system %ave been found
to be si!ni6cantly di8erent in depressed TLE patients in comparison wit%
nondepressed fellow patients" T%ere may be a bidirectional relations%ip between
depression and TLE inKuencin! t%ese structures"
+" Depression after )eurosur!ery in Temporal Lobe Epilepsy
#ur!ery for intractable epilepsy %as become increasin!ly available for patients,
resultin! in more individuals becomin! seiBureAfree, often t%us dramatically
improvin! 5uality of life >C+, +-?" 7owever, t%ere is an emer!in! reco!nition t%at
psyc%iatric complications can occur in t%e postoperative period, includin! de
novo symptoms of depression >+-?"
T%e stron!est ris4 factor for depression in t%e postoperative course is, per%aps
not surprisin!ly, preoperative depression >++D+G? and %as been reported in
appro9imately /0DC0I of patients under!oin! sur!ery >+ED*0?" Rates of de novo
depression in TLE patients in t%e postoperative period ran!e from + to /+I >+-?"
(t%er ris4 factors identi6ed include older patients at time of sur!ery >*,, */?,
male !ender >++?, stron! family %istory of psyc%iatric illness, and poor seiBure
outcome postoperatively >*,?" T%e %i!%est ris4 period appears to be in t%e 6rst C
mont%s followin! sur!ery, wit% slow improvement at t%e ,/A or /-Amont% mar4
>+-, *C?"
LateraliBation %as been t%e focus of many studies, but no clear, co%esive pattern
appears to %ave emer!ed yet" #everal studies su!!est t%at ri!%t temporal lobe
resections represent a !reater ris4 of postoperative depression >+G, *-?, w%ile
several more support left temporal lobe resection as %i!%er ris4 for t%is
complication >+*, +G?, and yet ot%ers report no evidence of laterality at all >*C?"
T%ese ambivalent results are ec%oed in t%e literature e9aminin! rates of
depression followin! tumor resections >*+, **?"
7owever, some studies %ave documented w%at appears to be a bidirectional ris4
in t%e relations%ip between postoperative seiBure control and depressive
symptoms" etternic% et al" >*G? documented si!ni6cantly lower 2ec4
Depression :nventory scores in patients t%at were seiBureAfree postoperatively"
Reuber et al" >+E? observed t%at postoperative TLE patients improved
si!ni6cantly wit% respect to depressive symptoms in comparison to medically
mana!ed TLE patients, but only if seiBure control was si!ni6cantly improved" T%is
led t%em to suppose t%at depressive symptoms were associated wit% epileptic
activity rat%er t%an structural c%an!es"
Finally, 'renc% et al" >*E? recruited *0 patients under!oin! two types of sur!ery
;mesial temporal lobe resection and nonmesial temporal lobe resection< and
followed t%em lon!itudinally" Preoperatively, -CI of t%ese patients %ad a lifetime
prevalence of depression, wit% no di8erence between t%e sur!ical !roups"
Predictive factors for preoperative depression included family %istory of mental
illness and 6nancial dependency" 7owever, in t%e postoperative p%ase, t%e
mesial temporal resection !roup e9perienced a si!ni6cantly %i!%er rate of
depression, bot% recurrence and de novo >*E?, su!!estin! t%at per%aps
disruption of t%ese structures carries a %i!%er ris4 of depression as a
complication postoperatively"
:n summary, recurrence and de novo development of depression is a ris4 in TLE
patients under!oin! sur!ery, particularly in t%e 6rst C mont%s postoperatively"
Alt%ou!% no clear pattern is emer!in! re!ardin! t%e relevance of laterality, t%ere
is si!ni6cant evidence to support a bidirectional relations%ip between depression
and postoperative seiBure control, w%ere t%e presence of one can e9acerbate t%e
ot%er" T%is ec%oes t%e 6ndin!s previously described earlier in t%is c%apter, in
w%ic% eac% condition may operate as a si!ni6cant ris4 factor for t%e ot%er"
*" Antiepileptic Dru!s and Depression
Antiepileptic dru!s ;AEDLs< %ave been 4nown to %ave positive psyc%otropic
e8ects beyond t%eir antiseiBure e8ect for 5uite some time >*F?" :ndeed, many
AEDLs %ave separate indications for t%e treatment of psyc%iatric disorders,
includin! roles as mood stabiliBers >G0?, an9iolytics >G,?, and in t%e mana!ement
of wit%drawal syndromes >G/?" :t is also e5ually true t%at many AEDLs %ave
ne!ative psyc%otropic e8ects t%at can complicate t%e mana!ement of bot%
epilepsy and depression in patients >*F?"
T%e AEDLs associated wit% t%e %i!%est ris4 of occurrence of depressive symptoms
in patients wit% epilepsy are t%ose w%ic% act at t%e benBodiaBepineA$A2A
receptor comple9 >*F?" T%ese include barbiturates, topiramate, and vi!abatrin"
Levetiracetam and felbamate appear to represent an intermediate ris4 of
depressive symptoms, leavin! t%e ot%er AEDLs as eit%er low ris4 or un4nown >*F?
;Table ,<" &nfortunately, a clear understandin! of w%ic% populations may be at
particular ris4 of developin! depressive symptoms w%ile on AEDLs %as yet to be
developed >*F?, and t%is review of t%e literature did not produce any studies t%at
endeavored to identify t%is in t%e TLE population" 7owever, ula and #c%mitB
>*F? su!!ests a !eneral approac% of monot%erapy if possible, wit% introduction of
any new AEDLs wit% slow, careful titration, and careful %istories of premorbid and
family psyc%iatric disorders bein! collected re!ularly in t%is patient population
>*F?"
tab,
Table ,: Positive and ne!ative e8ects of AEDLs >C*?"
G" Conse5uences of Depression in Temporal Lobe Epilepsy
G"," Depression as a Ris4 Factor for #eiBures
Depression %as been ac4nowled!ed by t%e 'orld 7ealt% (r!aniBation as one of
t%e most si!ni6cant sources of burden of disease and su8erin! !lobally >GC?" T%e
impact of t%is disorder on mortality, morbidity, 5uality of life, social function, and
occupational function %ave been well described" #imilarly, t%e additive burden of
depression in c%ronically medically ill people %as also been well described, bot%
for epilepsy as well as ot%er medical conditions as diverse as C(PD, E#RD,
cancer, and diabetes" T%us, it is e9pected t%at t%ere would be a conse5uence to
be borne by t%ose TLE patients t%at carry t%e comorbidity of t%ese two disorders"
7owever, as previously noted in t%is c%apter, t%ere is stron! support for a
bidirectional ris4 e9istin! between t%ese two disorders" :n ot%er words, t%e
presence of depression may %ave a direct impact on TLE symptom severity,
control, and possibly even onset"
For e9ample, Fors!ren and )ystrom >G-? found t%at t%ere was a sevenAfold
increase in rates of depression bein! dia!nosed prior to t%e onset of t%e seiBure
disorder in patients wit% newly dia!nosed epilepsy w%en compared to a!eA and
se9Amatc%ed controls" T%is remar4able 6ndin! was furt%er raised to a ,GAfold
increase w%en patients wit% a localiBed onset were studied" Anot%er study found
a C"GAfold increase in fre5uency of dia!nosis of depression precedin! t%e 6rst
seiBure in older adults wit% new onset epilepsy >/-?" A study of :celandic c%ildren
and adults wit% new onset epilepsy found a similar increase in rates of
depression precedin! seiBure onset ;,"G fold<, as well as a +",Afold increase in a
premorbid %istory of attempted suicide >G+?" :n a study of c%ildren wit% new
onset seiBures, psyc%opat%olo!ical symptoms ;includin! an9iety, depression,
attention disorders, t%ou!%t disorders, and somatic disorders< were present at
%i!%er rates t%an controls for C/I of t%e newly epileptic c%ildren >G*?" Finally,
recent studies %ave also su!!ested t%at psyc%opat%olo!y could be a si!ni6cant
ris4 factor for infants developin! nonfebrile seiBures or epilepsy in c%ild%ood
>GG?"
Per%aps t%e most interestin! 6ndin! of t%e pattern of mood symptoms predatin!
epilepsy is Alper et alLs" >GE? study of epileptic patients enrolled in ##R:, #)R:,
and mirtaBepine treatment trials" Patients on t%e medications %ad si!ni6cantly
lower rates of seiBures w%en compared to t%eir matc%ed fellow patients receivin!
placebo" T%is last study in particular is su!!estive of t%e potentially e9acerbatin!
role t%at untreated depressive symptoms may %ave on seiBure control"
G"/" #uicidality in TLE Patients
Completed suicide is one of t%e most tra!ic and feared outcomes of a depressive
episode and is always a concern to clinicians w%en wor4in! wit% patients wit%
si!ni6cant psyc%iatric comorbidity" Fortunately, it is a relatively rare event in t%e
!eneral population" &nfortunately, in epilepsy, t%e rate of suicide is
appro9imately two to 6ve times t%at of t%e !eneral population, and t%is is furt%er
elevated to a /+Afold increase amon! patients wit% TLE >GF, E0?" )ot surprisin!ly,
t%e rate of completed suicide is furt%er elevated up to C/Afold by t%e presence of
a comorbid depressive disorder >GF?"
T%is s%oc4in! increase %as been considered to be primarily inKuenced by t%e
psyc%osocial conse5uences of livin! wit% c%ronic epilepsy >E,?" 7owever, recent
data would su!!est t%at t%e situation is more comple9 t%an psyc%osocial
conse5uences of c%ronic illness alone, and t%at a part of understandin!
completed suicide ris4 in epilepsy may lie in t%e e9amination of suicide attempts"
A study comparin! suicide attempts amon! patients wit% epilepsy to comparably
%andicapped controls wit% ot%er c%ronic disabilities found t%at C0I of patients
wit% epilepsy %ad attempted suicide as compared to GI of controls >E0, E,?" T%is
is relevant !iven t%e fact t%at suicide attempts are comple9 be%aviors involvin!
many factors, includin! impulsivity and e9ecutive dysfunction, w%ic% can be
associated wit% temporolimbic function >E/DE*?" .ones et al" >EG? found a lifetime
prevalence of suicide attempts of /0"EI amon! ,CF outpatients followed at
epilepsy centers in t%e &nited #tates" :n t%is sample, t%e %i!%est rates of
attempts were amon! patients wit% a lifetime %istory of a ma=or depressive
episode or manic episode, and %i!%er rates of suicidal ideation were also
associated wit% a lifetime %istory of mood or an9iety disorders" a=or depressive
disorder was t%e most fre5uent psyc%iatric disorder identi6ed amon! patients
wit% a %istory of suicide attempt ;+,"GI<, w%ile an9iety disorders were more
stron!ly associated wit% suicidal ideation ;+E"EI< in t%is sample >EG?"
T%is su!!ests t%at t%ere are c%aracteristics speci6c to epilepsy, in particular TLE,
w%ic% may place patients at elevated ris4 of completed suicide and suicide
attempts, particularly in t%e conte9t of comorbid depression" Espinosa et al" >EE?
studied -/ patients wit% newly dia!nosed TLE over a ,Ayear period and assessed
suicide ris4 via t%e Plutc%i4 Ris4 of #uicide scale" T%ey found t%at +G",I of t%eir
sample scored MG on t%is scale, w%ic% is t%e %i!%est ris4 cate!ory for suicide,
/E"*I %ad a past %istory of suicide attempts, and -+"/I %ad e9perienced
suicidal t%ou!%ts" T%e study aut%ors also assessed for multiple associated
factors includin! psyc%iatric comorbidity, past medical and psyc%iatric %istory,
and neuropsyc%olo!ical de6cits" T%ey discovered a si!ni6cant relations%ip
between %i!%er suicide ris4 and a %i!%er rate of suicide attempts in patients wit%
a family %istory of psyc%iatric diseases, leftAsided TLE, current ma=or depressive
episode, and %i!%er perseverative responses on neuropsyc%olo!ical testin! via
'isconsin Card #ortin! Test ;'C#T<" T%ey also found a stron! correlation
between poor 'C#T performance and severity of depressive symptoms, implyin!
t%at t%e presence of depression li4ely e9acerbates e9ecutive dysfunction in a
population t%at already %as documented di@culty in t%is area" (nce a!ain, t%is
su!!ests a bidirectional relations%ip between depression and epilepsy in t%e
manifestation of suicide ris4"
T%ere is an added layer of comple9ity in understandin! suicidality in TLE
patients" (n December ,*, /00E, t%e &# Food and Dru! Administration issued a
warnin! about an increased ris4 of suicidal ideation and be%avior amon! people
ta4in! AEDLs >EF?" T%e a!ency %ad performed a review of ,,F clinical trials of ,,
AEDLs and noted a ,"EAfold increase in suicidal be%avior or ideation in patients
ta4in! AEDLs in comparison to t%ose ta4in! placebo" Alt%ou!% many
met%odolo!ical issues %ave been identi6ed wit% t%is study, it raised concernin!
5uestions re!ardin! t%e used of t%ese dru!s in a population 4nown to su8er
si!ni6cant psyc%iatric comorbidity" As described previously in t%is c%apter, AEDLs
%ave been documented to produce bot% positive and ne!ative psyc%otropic
e8ects, and t%e FDALs announcement produced a Kurry of epidemiolo!ic wor4 to
attempt to con6rm t%is increased ris4 of suicidality and %opefully su!!est
mec%anisms >F0?" T%ese 5uestions are still bein! answered, and t%e studiesL
6ndin!s %ave been 5uite mi9ed, but results t%us far su!!est t%at if t%ere is an
elevated ris4 of suicidality wit% AEDLs, it appears to be very low >*F?, and t%at no
clear pattern is emer!in! re!ardin! ris4 strati6cation across t%e various AEDLs
>*F, F0?" Additionally, none of t%ese studies %ave focused on TLE in particular,
but rat%er %ave included samples t%at tend to be 5uite broad bot% in type of
epilepsy and comorbidity of psyc%iatric illness >F0?, w%ic% in part may e9plain
t%e variability of 6ndin!s" 'en et al" >F0? noted an interestin! trend in t%eir
retrospective analysis of patients in t%e Compre%ensive Epilepsy Researc%
Pro!ram ;CERP< database over a C/Amont% period" 2rieKy, t%ey noted t%at t%e
stron!est predictors for t%e development of suicidality over time were t%e
presence of depressive symptoms or suicidality prior to AED treatment, and t%at
t%ose patients started on new or multiple AEDLs %ad less improvement of
suicidality over time in comparison wit% t%ose w%o %ad no c%an!es made to t%eir
AED re!imen" Additionally, t%ey found no si!ni6cant di8erence in suicidality
between t%e AEDLs t%emselves" T%is led t%e aut%ors to su!!est t%at per%aps t%e
6ndin!s of t%e ori!inal FDA study were !enerated by t%e artifact of patients on
AEDLs improvin! less t%an placebo controls wit% respect to t%eir suicidality
symptoms over time"
G"C" Nuality of Life Conse5uences for Patients wit% Comorbid Depression and TLE
ultiple studies in epilepsy in !eneral and TLE speci6cally %ave made e8orts to
e9amine t%e relations%ip between various factors associated wit% livin! wit%
epilepsy and t%e impact on 5uality of life >F,DFE?" Janner >FF? reviewed + studies
in particular t%at consistently demonstrated t%at depression was t%e most
powerful predictor of %ealt%Arelated 5uality of life across multiple domains, even
w%en controllin! for factors suc% as seiBure fre5uency, severity, and ot%er
psyc%osocial variables" eldolesi et al" >FE? studied ,0* patients wit% dru!A
resistant unilateral temporal lobe epilepsy, administerin! various standardiBed
5uality of life instruments as well as t%e 2ec4 Depression :nventory and an
an9iety scale" T%ey also found depression to be consistently t%e stron!est
predictor of lower scores on all N(L domains e9cept seiBure worry" T%is e8ect
was independent of socioeconomic status, !ender, lateraliBation of seiBure focus,
seiBure fre5uency and severity, and an9iety"
Additionally, comorbid depression appears to be associated wit% a !reater
li4eli%ood of adverse events associated wit% antiepileptic dru!s, more fre5uent
visits to p%ysicians, and %i!%er cost of medical care related to t%e seiBure
disorder, rat%er t%an any cost associated wit% t%e psyc%iatric disorder and its
treatment >FGDFF?" T%is is an interestin! 6ndin! in li!%t of t%e recurrin! t%eme
woven t%rou!% t%e literature of t%e bidirectionality of depressive symptoms and
epilepsy symptoms" A!ain, t%e presence of one appears to ma4e t%e
mana!ement of t%e ot%er more of a c%allen!e"
E" ana!ement #trate!ies for Depression in Temporal Lobe Epilepsy
:n !eneral, evidence for treatment strate!ies of mood disorders in epilepsy are
lac4in!, and development of mana!ement approac%es tend to rely on clinical
e9perience rat%er t%an evidenceAbased trials favorin! one treatment over
anot%er >*F?" T%e paucity of data is even more pronounced w%en e9aminin! t%e
literature for TLEAspeci6c depression treatment studies" )ot surprisin!ly t%en,
t%ere are no widely accepted !uidelines for t%e treatment of depression in TLE
patients"
7owever, clinicians can turn to a body of literature t%at, w%ile lac4in! in lar!e,
doubleAblinded, and placeboAcontrolled RTCLs, still includes several smaller open
label trials, case series reports, and a %andful of comparative studies" T%e bul4 of
t%is data does not limit itself to TLE alt%ou!% a recently publis%ed comparative
study in TLE patients in particular is included in t%e followin! discussion"
E"," Antidepressants
T%ere are t%ree main considerations w%en initiatin! an antidepressant trial in a
patient wit% epilepsy: e9acerbation of seiBure control, potential for interaction
wit% AEDLs, and e@cacy of t%e antidepressant in depression symptom resolution"
T%ere appears to be variability between and also wit%in t%e various
antidepressant dru! classes alt%ou!% some !eneraliBations can be made from
t%e available literature"
E","," Antidepressants and #eiBure Ris4
T%e potential for antidepressants to provo4e seiBures %as been a source of
concern and possibly a barrier to treatment of depression in patients wit%
epilepsy >,00?" T%e data documentin! seiBures secondary to antidepressants is
derived lar!ely from psyc%iatric populations, in vitro or animal model studies, or
from samples w%ic% were not speci6cally patients wit% epilepsy >C*, ,00?" (ften,
seiBures associated wit% antidepressants are described in cases of to9icity, suc%
as accidental or intentional overdose >C*, ,00?" T%is ma4es it di@cult, if not
impossible, to !eneraliBe 6ndin!s to epilepsy patients" T%e situation is furt%er
complicated by t%e fact t%at animal and %uman studies su!!est t%at some
antidepressants may %ave an anticonvulsant e8ect, w%ile some may %ave a
proconvulsant e8ect, and yet ot%ers may %ave a bip%asic e8ect, in w%ic% t%ey
are anticonvulsant at lower doses and proconvulsant at %i!%er doses >C*?"
ec%anisms proposed for t%e proconvulsant e8ect include t%e antic%oliner!ic
e8ect of many antidepressants ;particularly at %i!%er doses<, as well as t%e
elevation of serotonin and noradrenalin neurotransmission >C*?" Anticonvulsant
e8ect may be mediated by t%e interaction of t%e antidepressant wit% ot%er
factors, includin! AEDLs" For e9ample, Kuo9etine %as been noted to en%ance t%e
anticonvulsant e8ect of p%enytoin and carbamaBepine via selective in%ibition of
serotonin upta4e >C*?"
Tricyclic antidepressants ;TCALs< %ave a wide variety of neurotransmitter related
e8ects, many of w%ic% are dose dependent as well" (verall, t%ey are considered
proconvulsant, in lar!e part secondary to t%eir si!ni6cant antic%oliner!ic e8ect,
w%ic% is 4nown to lower seiBure t%res%old >C*?" As stated previously, some
selective serotonin reupta4e in%ibitors ;##R:Ls< may actually %ave an
anticonvulsant e8ect >,0,D,0C?" :n !eneral, clinical and researc% e9perience
su!!ests t%at t%e ris4 of seiBures wit% ##R:Ls is very low and per%aps not
di8erent from placebo, and certainly lower t%an wit% TCALs >,0,?" A special
consideration wit% ##R:Ls is t%e fact t%at t%ey can promote %yponatremia, w%ic%
can represent a ris4 in t%e precipitation of seiBures >C*?" (t%er antidepressants
w%ic% are considered to be O%i!% ris4P for seiBures in t%e !eneral population or in
to9icity studies ;e"!", bupropion< %ave been found overall to %ave an acceptably
low ris4 w%en prescribed correctly >C*?"
(verall, t%e incidence of seiBures wit% antidepressants is less t%an 0"+I,
particularly w%en used wit%in t%e recommended t%erapeutic ran!e and w%en
ot%er ris4 factors are e9cluded >C*? ;Table /<" $iven t%e si!ni6cant conse5uences
described earlier in t%is c%apter associated wit% depression in TLE, it would
t%erefore seem t%at concerns about e9acerbatin! seiBure control s%ould not be
enou!% to rule out antidepressants in most TLE patients"
tab/
Table /: #eiBure prevalence in psyc%iatric samples durin! treatment wit%
antidepressant dru!s >C*?"
E","/" :nteractions between Antidepressants and AEDLs
TCALs %ave, by nature of t%eir lon!evity, per%aps t%e most collective clinical
e9perience in many medical conditions, epilepsy included" Amitriptyline,
clomipramine, and imipramine are e9tensively metaboliBed by CQP ,A/, /D*,
and CA- ;Table C<" )ortriptyline and desipramine, t%e metabolites of amitriptyline
and imipramine respectively, are metaboliBed mainly by CQP /D*" All AEDLs wit%
enBymeAinducin! properties ;barbiturates, carbamaBepine, and p%enytoin< all
induce t%e metabolism of TCALs" 7owever, carbamaBepine also reduces protein
bindin! of imipramine and desipramine, resultin! in increased free fraction of
t%ese dru!s, and t%us resultin! in little need to alter dosin! of t%ese two TCALs
w%en coadministered wit% carbamaBepine" Halproate can in%ibit t%e metabolism
of TCALs resultin! in increased plasma levels at comparable dosa!e" (verall,
coadministration of TCALs and AEDLs can be done safely and e8ectively as lon!
as dosin! is done slowly and carefully and is accompanied by re!ular monitorin!
of blood levels of bot% dru!s >C*?"
tabC
Table C: CQP-+0 enBymes in%ibition and induction by antidepressants and
antiepileptic dru!s >C*?"
##R:Ls are !enerally more tolerable and safe t%an TCALs, due in part to t%eir
reduced antic%oliner!ic e8ect and inability to bloc4 sodium c%annels, even in
overdose >,0-?" As a result, t%ese dru!s are widely prescribed" Fluo9etine and
paro9etine are metaboliBed by CQP /D*, sertraline by CQP CA-, Kuvo9amine by
CQP ,A/, and 6nally citalopram by CQP /C >,0-?" Paro9etine is an in%ibitor of CQP
/D*, Kuvo9amine in%ibits CQP ,A/, and Kuo9etine moderately in%ibits CQP /D*
and CA-" #ertraline and citalopram do not seem to %ave si!ni6cant
inductionRin%ibition properties >,0+?"
Fluo9etine %as a %i!% ris4 of interaction wit% p%enytoin, but less clearly wit%
carbamaBepine >C*, ,0*, ,0G?" Paro9etine and sertraline seem to %ave low ris4 of
interaction wit% p%enytoin >C*, ,0*?" 7owever, carbamaBepine seems to induce
citalopramLs metabolism si!ni6cantly, t%us reducin! plasma concentrations and
possibly e@cacy of t%is dru! >C*?" Paro9etine appears to %ave little interaction
wit% carbamaBepine, valproate, or p%enytoin >C*?" Fluvo9amine appears to %ave
no e8ect on carbamaBepine levels >C*?" 7owever, t%ere is a paucity of evidence
on t%e safety of Kuvo9amine coadministration wit% valproate or p%enytoin >C*?"
#ertraline was found to increase t%e levels of lamotri!ine in two documented
cases >C*?" Finally, sertraline was found to %ave no si!ni6cant e8ect on
carbamaBepine levels in a doubleAblind randomiBed, placeboAcontrolled trial of ,-
%ealt%y volunteers >C*?" #ertraline and clonaBepam were also found to be safe in
coadministration >C*?"
#)R:Ls ;venlafa9ine and dulo9etine< are primarily metaboliBed by CQP /D* >,0-?,
but interactions wit% AEDLs %ave yet to be studied >C*?"
irtaBepine is a noradrener!ic and speci6c serotoner!ic reupta4e in%ibitor
;)a##A< and is primarily metaboliBed by CQP /D*" #tudies are lac4in! in t%is
population on interactions wit% AEDLs, but t%is medication %as been noted to
bind %istaminic receptors, resultin! in sedation, increased appetite, and wei!%t
!ain" $iven t%at t%ese are side e8ects of many AEDLs, t%e potential for an
additive e8ect is present >C*?"
2upropion is a noradrener!ic and dopaminer!ic reupta4e in%ibitor ;)DR:<"
CarbamaBepine is a potent inducer of t%e metabolism of bupropion, si!ni6cantly
reducin! plasma levels >,0-?" 2upropion in turn %as mar4ed in%ibitory properties,
increasin! levels of valproate and p%enytoin >C*?"
E","C" E@cacy of Antidepressants in TLE
A!ain, t%ere is a deart% of evidenceAbased, controlled trials t%at attempt to study
e@cacy of antidepressants in epilepsy in !eneral, and t%e number of trials
speci6c to TLE found in t%is review of t%e literature was a sin!le one"
T%e earliest controlled trial in patients wit% epilepsy involved amitriptyline and
an antidepressant t%at no lon!er e9ists ;nomifensine<" At * wee4s, improvement
of depressive symptoms was documented in bot% dru!s, but at ,/ wee4s,
nomifensine was superior to amitriptyline" (verall, data about TCALs e@cacy in
t%e treatment of depression in epilepsy is lar!ely uncontrolled or anecdotal but
appears to support e@cacy and tolerability >C*?"
##R:Ls %ave become t%e 6rst line of p%armacot%erapy in most depressive
disorders due to t%eir proven e@cacy and beni!n sideAe8ect pro6les" 7owever,
e@cacy in epilepsy speci6cally %as not been well studied yet" A series of open
label studies support some e@cacy and tolerability for sertraline, citalopram,
mirtaBepine, and Kuo9etine" :n !eneral, ##R:Ls seem to be e8ective and well
tolerated, but t%e response rates %ave been 5uite mi9ed across studies, li4ely
due to !reat variability in sample populations, limited control of comorbid
psyc%iatric disorders, and t%e occasional presence of co!nitive disorders or brain
dama!e in t%e samples >C*?"
7owever, JS%n et al" >,0E? produced a prospective study of safety and e@cacy of
citalopram, mirtaBepine, and rebo9etine ;not available in )ort% America< in TLE
patients" T%ey performed a post %oc analysis of G+ TLE patients wit% depression
w%o received standard treatment wit% one of t%e above dru!s" :n !eneral, t%ey
found t%at all t%e antidepressants were e8ective in treatin! t%e symptoms of
depression, and t%at t%ere were no serious adverse events or dru! interactions"
7owever, t%e dropout rate was si!ni6cantly %i!%er for mirtaBepine t%at t%e ot%er
two a!ents, per%aps a!ain because of t%e tendency of t%is dru! to cause
sedation, increased appetite, and wei!%t !ain in a population already often prone
to t%ese complications secondary to AEDLs"
E"/" Lit%ium
Alt%ou!% most 4nown for its e@cacy in bipolar disorders, lit%ium is also used as
an au!mentation strate!y for treatment resistant unipolar depression"
&nfortunately, even less %as been publis%ed on t%e safety and e@cacy of lit%ium
in epilepsy t%an for antidepressants >C*?"
Coadministration of lit%ium carbonate and carbamaBepine may %ave a bene6t in
terms of mood stabiliBation but appears to be associated wit% multiple
interactions, includin! %ematolo!ic, t%yroid, and electrolyte disre!ulation"
7owever, lit%ium appears to be relatively tolerable w%en administered wit%
valproate, but once a!ain t%e additive aspects of sedation, wei!%t !ain, and
tremor were noted" Lamotri!ine and lit%ium appeared to be well tolerated
to!et%er, t%ou!% topiramate and lit%ium was associated wit% to9icity in at least
one case >C*?"
Lit%ium also is 4nown to be proconvulsive at %i!%er doses, but t%is does not
seem to be a si!ni6cant concern at lower doses in epilepsy patients on AEDLs"
7owever, as lit%ium is usually administered as an au!mentation a!ent in
unipolar depression, t%e additive ris4 of serotonin syndrome and lowered seiBure
t%res%old of bot% an antidepressant and lit%ium bein! administered to an
epilepsy patient must be considered >C*?"
E"C" Psyc%ot%erapy
(nce a!ain, very little data %as been collected on psyc%olo!ical t%erapies in t%e
epilepsy population, let alone TLE" 7owever, t%e few studies t%at e9ist seem to
support t%e e@cacy of co!nitive be%avioral t%erapies as useful in t%e treatment
of depression in epilepsy >*F?"
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Depresi pada epilepsi lobus temporal sering terjadi, dan berbagai mekanisme telah
dikemukakan untuk komorbiditas yang signifikan ini. menggambarkan risiko dua arah antara
depresi dan epilepsi lobus temporal, dan strategi pengobatan dalam konteks interaksi obat
potensial dengan obat antiepilepsi.
1 Pendahuluan
Epilepsi lobus temporal (TLE) adalah yang paling sering dari gangguan epilepsi. Gejala
depresi interiktal, dan interiktal episode depresi mayor, cukup umum pada epilepsi pada
umumnya, terutama terkait dengan TLE !".
2 Prevalensi Depresi di Temporal Lobe Epilepsy
#ertama, mekanisme bersamaan atau aditif memainkan peran dalam pengembangan gejala
depresi pada penderita TLE. $odin et al. %" mencatat bah&a banyak pasien dengan TLE
memiliki lebih dari satu jenis kejang. Dua penelitian kemudian menegaskan bah&a frekuensi
kejang yang lebih signifikan dalam memprediksi gejala depresi daripada fokus lokasi !',
!(". )aktor risiko lain juga telah diidentifikasi, seperti usia onset dan lateralitas fokus lobus
temporal yang juga dapat menempatkan pasien pada risiko yang lebih tinggi atau lebih
rendah dari lokasi fokus saja *+, *!". Demikian pula, disfungsi lobus frontal selain disfungsi
lobus temporal merupakan faktor risiko penting dalam mengembangkan depresi pada
pasien TLE *".
3 Karakteristik Klinis Depresi di Temporal Lobe Epilepsy
,onsep gangguan dysphoric interiktal diusulkan untuk menggambarkan dalam menanggapi
kedua studi menunjukkan bah&a sebagian besar pasien epilepsi dengan gejala depresi
tidak akan memenuhi kriteria untuk -ayor Depressi.e Disorder sebagai biasanya diuraikan
dalam jad&al diagnostik *', *(". -isalnya, ,anner et al. /+" meneliti pasien dengan kejang
refrakter dan gejala depresi dan menemukan hanya *(0 memenuhi kriteria D1- 23 untuk
-ayor Depressi.e Disorder. 4&alnya diusulkan oleh ,raepelin, kemudian 5leuler, konsep ini
a&alnya digambarkan pola gejala yang terdiri dari iritabilitas terkemuka, euforia, kecemasan,
anergia, insomnia, dan nyeri. Gejala6gejala ini digambarkan memiliki kronis, kambuh dan
remisi saja, tetapi untuk merespon dengan baik untuk antidepresan /!". 5erbagai gejala
lebih spesifik telah digambarkan oleh 5lumer et al. 2n.entori neurobiologis mereka untuk
Epilepsi, yang merupakan reformulasi dari persediaan a&al yang dimaksudkan untuk
menentukan karakteristik kepribadian TLE *7, *(". Dua kategori gejala telah dijelaskan8
gejala depresi6somatoform (depresi suasana hati, anergia, nyeri, dan insomnia) dan gejala
afektif (mudah marah, mood gembira, takut, dan cemas) *(". 4nhedonia juga telah
diusulkan sebagai penanda yang lebih baik untuk depresi pada pasien dengan epilepsi,
sebagian sekunder kemerdekaannya dari gejala fisik yang berhubungan dengan obat6
obatan dan penyakit kronis /*".
9paya telah dilakukan untuk menguji .aliditas mendiagnosa depresi pada populasi ini. $eilly
et al. *7" beralasan bah&a faktor .ariabel laten diketahui dapat berdampak pada gangguan
depresi (sikap negatif, kesulitan kinerja, dan elemen somatik) dapat diukur pada pasien TLE
untuk membandingkan tingkat disfungsi seluruh domain ini untuk jumlah dikenal dalam
depresi berat. #asien TLE di&ujudkan kesulitan di domain ini yang sangat mirip dengan
yang terlihat pada penyakit depresi, menunjukkan bah&a gejala ini me&akili gangguan
depresi mayor, bukan suatu kondisi yang unik untuk TLE.
4. Temuan neuroanatomical Depresi di Temporal Lobe Epilepsy
5erbagai struktur dari sistem limbik telah menjadi fokus dalam memahami depresi dan TLE.
Daerah kepentingan tertentu untuk kedua gangguan ini termasuk lobus temporal (terutama
hipokampus, amigdala, entorhinal, dan korteks neokorteks), lobus frontal, dan struktur
penting subkortikal limbik seperti ganglia basal dan thalamus, serta sirkuit yang
menghubungkan semua struktur ini !, /%6:+".
Depresi dan TLE, .olume hippocampal telah ditemukan untuk menjadi tidak normal !".
#ada pasien depresi dengan dan tanpa TLE, .olume hippocampus berkurang, biasanya
bilateral atau kadang6kadang meninggalkan sisi hanya /%, :!6:7". #ada pasien TLE,
.olume biasanya berkurang pada sisi fokus epilepsi :+, :*, :7". #ada pasien TLE depresi,
.olume hippocampal biasanya berkurang bilateral. -enariknya, pada pasien dengan fokus
TLE sisi kiri, masalah kognitif dengan memori dan belajar :;". 1tudi6studi lain telah
menegaskan hal ini, menghubungkan depresi dan gangguan belajar .erbal pada pasien TLE
:%". #enyebabnya diduga di balik ini adalah disfungsi dalam representasi bahasa yang lebih
besar di otak kiri :;, :%".
4migdala juga telah menjadi sumber studi intensif di bidang gabungan depresi dan TLE,
mengingat peran utamanya dalam ketakutan dan emosi terkait :'". 1truktur ini tampaknya
berubah sebagai episode depresi akut menjadi kronis, pada a&alnya menjadi membesar
secara bilateral, kemudian menyusut bilateral sebagai gangguan mood menjadi kronis !".
Dua penelitian telah menemukan hubungan antara peningkatan .olume amigdala dan
keparahan gejala depresi di TLE :(, 7+". 3olume meningkat sisi kiri6dari amigdala dan
keparahan gejala depresi pada pasien TLE tampak sangat terkait satu sama lain 7+".
Diduga mekanisme untuk ini adalah hiperakti.itas amigdala pada fase akut depresi pada
TLE dan pasien non6TLE, mengakibatkan peningkatan .olume sekunder untuk peningkatan
aliran darah daerah ini !, :(, 7+".
Dua lesi yang paling umum untuk pengembangan epilepsi lobus temporal mesial sclerosis
dan lesi sementara neokorteks lebih jarang !". #asien dengan mesial sclerosis sementara
memiliki tingkat signifikan lebih tinggi dari depresi dibandingkan dengan lesi sementara
neokorteks, terlepas dari lateralisasi 7!". 1elain itu, pasien dengan mesial sclerosis
sementara memiliki frekuensi yang lebih besar dari efek samping kognitif dan masalah
suasana hati dengan obat antiepilepsi 7*". -enariknya, 1algado et al. 7/" ditemukan
secara signifikan kehilangan .olume lebih luas materi abu6abu pada pasien TLE dengan
depresi dibandingkan dengan sesama pasien tanpa depresi mereka. <al ini menyebabkan
saran bah&a ada hubungan dua arah antara dua gangguan ini 7/".
1ingkatnya, berbagai struktur penting dari sistem limbik telah ditemukan secara signifikan
berbeda pada pasien TLE depresi dibandingkan dengan sesama pasien tidak mengalami
depresi. ada hubungan dua arah antara depresi dan TLE mempengaruhi struktur ini.
. Depresi setelah !edah "ara# di Temporal Lobe Epilepsy
Tindakan bedah untuk epilepsi intractable telah tersedia untuk pasien, sehingga lebih
banyak orang menjadi bebas kejang, sehingga meningkatkan kualitas hidup /7, 7:".
=amun, ada pengakuan yang muncul bah&a komplikasi keji&aan dapat terjadi pada periode
pasca operasi, termasuk gejala depresi 7:".
)aktor risiko terkuat untuk depresi dalam kegiatan pasca operasi, mungkin tidak
mengherankan, depresi pra operasi 7767%" dan telah dilaporkan pada sekitar *+6/+0 dari
pasien yang menjalani operasi 7'6;+". Tingkat depresi pada pasien TLE dalam kisaran
periode pasca operasi dari 7 sampai *70 7:". )aktor risiko lain diidentifikasi termasuk
pasien yang lebih tua pada saat operasi ;!, ;*", jenis kelamin laki6laki 77", ri&ayat keluarga
yang kuat mempunyai penyakit ji&a;!". #eriode risiko tertinggi tampaknya berada dalam /
bulan pertama setelah operasi, dengan peningkatan lambat !* atau *: bulan 7:, ;/".
1ingkatnya, kekambuhan dan pengembangan depresi adalah risiko pada pasien TLE
menjalani operasi, terutama pada / bulan pertama pasca operasi. -eskipun tidak ada pola
yang jelas muncul mengenai rele.ansi lateralitas.
$ antiepilepsi %bat dan Depresi
>bat antiepilepsi (4ED) telah diketahui memiliki efek psikotropika positif di luar efek anti
kejang ;(". -emang, banyak 4ED memiliki indikasi yang terpisah untuk pengobatan
gangguan keji&aan, termasuk peran sebagai stabilisator suasana hati %+", an?iolytics %!",
dan dalam pengelolaan sindrom penarikan %*". <al ini juga sama benarnya bah&a banyak
4ED memiliki efek psikotropika negatif yang dapat mempersulit manajemen kedua epilepsi
dan depresi pada pasien ;(". 4ED terkait dengan risiko tertinggi terjadinya gejala depresi
pada pasien dengan epilepsi adalah mereka yang bertindak pada reseptor ben@odia@epine6
G454 kompleks ;(".
Tabel !8 Efek positif dan negatif dari 4ED /;".
& Konsekuensi Depresi di Temporal Lobe Epilepsy
%.!. Depresi sebagai )aktor $isiko untuk ,ejang
Depresi telah diakui oleh >rganisasi ,esehatan Dunia sebagai salah satu sumber yang
paling signifikan dari beban penyakit dan penderitaan global %/". Dampak gangguan ini
pada kematian, morbiditas, kualitas hidup, fungsi sosial, dan fungsi kerja, beban aditif
depresi pada orang sakit kronis medis juga telah dijelaskan dengan baik, diharapkan bah&a
akan ada konsekuensi yang harus ditanggung oleh pasien TLE yang memba&a
komorbiditas dari dua gangguan ini.
-isalnya, )orsgren dan =ystrom %:" menemukan bah&a ada peningkatan tujuh kali lipat
tingkat depresi dibandingkan sebelum terjadinya gangguan kejang pada pasien yang baru
didiagnosis epilepsi. 1ebuah studi anak6anak dan orang de&asa 2slandia dengan epilepsi
yang onsetnya baru menemukan peningkatan serupa dalam tingkat depresi sebelumnya
kejang onset (!,% kali lipat), serta peningkatan 7.! kali lipat dalam sejarah premorbid
mencoba bunuh diri %7". Dalam sebuah penelitian terhadap anak6anak dengan kejang
onset baru, gejala psikopatologis (termasuk kecemasan, depresi, gangguan perhatian,
gangguan pikiran, dan gangguan somatik) yang hadir dengan harga yang lebih tinggi
daripada kontrol untuk /*0 dari anak6anak yang baru epilepsi %;". 4khirnya, studi terbaru
juga menunjukkan bah&a psikopatologi bisa menjadi faktor risiko yang signifikan untuk bayi
mengembangkan kejang nonfebrile atau epilepsi pada anak %%".
&.2. !unuh diri pada pasien TLE
5unuh diri adalah salah satu hasil yang paling tragis dan ditakuti pada episode depresi dan
selalu menjadi perhatian bagi dokter ketika bekerja dengan pasien dengan komorbiditas
psikiatri. 1ayangnya, pada epilepsi, tingkat bunuh diri adalah sekitar *67 kali dari populasi
umum, dan ini lebih tinggi untuk peningkatan *7 kali lipat antara pasien dengan TLE %(, '+".
Tidak mengherankan, tingkat bunuh diri selesai selanjutnya meningkat hingga /* kali lipat
dengan adanya gangguan depresi komorbid %(".
#eningkatan ini terutama dipengaruhi oleh konsekuensi psikososial hidup dengan epilepsi
yang kronis '!". tingkat tertinggi di antara upaya pasien dengan ri&ayat seumur hidup dari
episode depresi mayor atau manic episode, dan tingkat yang lebih tinggi dari keinginan
bunuh diri juga dikaitkan dengan gangguan mood atau kecemasan. Gangguan depresi
mayor adalah gangguan keji&aan yang paling sering diidentifikasi di antara pasien dengan
ri&ayat percobaan bunuh diri (7!,%0), sedangkan gangguan kecemasan yang lebih erat
kaitannya dengan ide bunuh diri (7','0)
<al ini menunjukkan bah&a ada karakteristik khusus untuk epilepsi, khususnya TLE, yang
dapat menempatkan pasien pada risiko tinggi bunuh diri dan usaha bunuh diri, terutama
dalam konteks komorbiditas depresi. -ereka menemukan hubungan yang signifikan antara
risiko bunuh diri lebih tinggi dan tingkat yang lebih tinggi dari usaha bunuh diri pada pasien
dengan ri&ayat keluarga yang mempunyai penyakit keji&aan, sisi kiri TLE. 1ekali lagi, ini
menunjukkan hubungan dua arah antara depresi dan epilepsi dalam manifestasi risiko
bunuh diri.
"trate'i (ana)emen * untuk Depresi pada Temporal Lobe Epilepsy
*.1. antidepresan
4da tiga pertimbangan utama ketika memulai percobaan antidepresan pada pasien dengan
epilepsi8 eksaserbasi kontrol kejang, potensi interaksi dengan 4ED, dan kemanjuran
antidepresan dalam resolusi depresi gejala. Tampaknya ada .ariabilitas antara dan juga
dalam berbagai kelas obat antidepresan meskipun beberapa generalisasi dapat dibuat dari
literatur yang tersedia.
*.1.1.+ntidepressants dan ,isiko ke)an'
#otensi antidepresan untuk mempro.okasi kejang telah menjadi sumber keprihatinan dan
mungkin penghalang untuk pengobatan depresi pada pasien dengan epilepsi !++".
1eringkali, kejang terkait dengan antidepresan dijelaskan dalam kasus toksisitas, seperti
disengaja atau tidak disengaja o.erdosis /;, !++". 1ituasi ini semakin rumit oleh fakta
bah&a he&an dan manusia menunjukkan bah&a beberapa antidepresan mungkin memiliki
efek antikon.ulsan, sementara beberapa mungkin memiliki efek procon.ulsant, dan yang
lain mungkin memiliki efek biphasic, di mana mereka berada antikon.ulsan pada dosis
rendah dan procon.ulsant pada dosis yang lebih tinggi /;". -ekanisme yang diusulkan
untuk efek procon.ulsant termasuk efek antikolinergik banyak antidepresan (terutama pada
dosis yang lebih tinggi), serta peningkatan serotonin dan noradrenalin neurotransmisi /;".
Efek antikon.ulsan dapat dimediasi oleh interaksi dari antidepresan dengan faktor6faktor
lain, termasuk 4ED. -isalnya, fluo?etine telah dicatat untuk meningkatkan efek
antikon.ulsan fenitoin dan karbama@epin melalui penghambatan selektif serotonin serapan
/;".
4ntidepresan trisiklik (TA4 ini) memiliki berbagai neurotransmitter yang terkait efek, banyak
yang tergantung juga dosis. 1ecara keseluruhan, mereka dianggap procon.ulsant, sebagian
besar sekunder untuk efek antikolinergik yang signifikan, yang dikenal untuk menurunkan
ambang kejang /;". 1eperti yang dinyatakan sebelumnya, beberapa reuptake inhibitor
serotonin selektif (11$2) sebenarnya memiliki efek antikon.ulsan !+!6!+/". 1ecara umum,
pengalaman klinis dan penelitian menunjukkan bah&a risiko kejang dengan 11$2 sangat
rendah dan mungkin tidak berbeda dengan plasebo, dan tentu saja lebih rendah daripada
dengan TA4 ini !+!". #ertimbangan khusus dengan 11$2 adalah fakta bah&a mereka
dapat mempromosikan hiponatremia, yang dapat me&akili risiko dalam presipitasi kejang
/;".
1ecara keseluruhan, insiden kejang dengan antidepresan kurang dari +,70, terutama bila
digunakan dalam jangkauan terapi yang dianjurkan dan ketika faktor risiko lain dikecualikan
/;" (Tabel *).
Tabel *8 #re.alensi kejang dalam sampel psikiatri selama pengobatan dengan obat
antidepresan /;".
*.1.2.-nteractions antara +ntidepresan dan +ED
11$2 umumnya lebih ditoleransi dan aman daripada TA4 ini, sebagian karena mengurangi
efek dan ketidakmampuan antikolinergik mereka untuk memblokir saluran natrium, bahkan
dalam kondisi o.erdosis !+:". 4kibatnya, obat ini banyak diresepkan.
)luo?etine memiliki risiko tinggi interaksi dengan fenitoin, tetapi kurang jelas dengan
carbama@epine /;, !+;, !+%". #aro?etine dan sertraline tampaknya memiliki risiko rendah
interaksi dengan fenitoin /;, !+;". =amun, carbama@epine tampaknya menginduksi
metabolisme sitalopram secara signifikan, sehingga mengurangi konsentrasi plasma dan
mungkin kemanjuran obat ini /;". #aro?etine tampaknya memiliki sedikit interaksi dengan
carbama@epine, .alproate, atau phenytoin /;". )lu.o?amine tampaknya tidak berpengaruh
pada tingkat carbama@epine /;". =amun, ada kekurangan bukti tentang keamanan
flu.o?amine pemberian bersama .alproate atau fenitoin /;". sertraline ditemukan tidak
berpengaruh signifikan terhadap tingkat carbama@epine dalam acak, percobaan double6
blind placebo6controlled dari !: sukarela&an sehat /;". 1ertraline dan clona@epam juga
ditemukan aman dalam penggunaan bersama /;".
-irta@epine adalah inhibitor noradrenergik dan serotonergik tertentu reuptake (=assa) dan
terutama dimetabolisme oleh AB# *D;. 1tudi kurang dalam populasi ini pada interaksi
dengan 4ED, tetapi obat ini telah dicatat untuk mengikat reseptor histaminic, sehingga
sedasi, nafsu makan meningkat, dan berat badan. -engingat bah&a ini adalah efek
samping dari banyak 4ED, potensi efek aditif hadir /;".
*.1.3.E##icacy dari +ntidepresan di TLE
11$2 ini telah menjadi pilihan pertama dari farmakoterapi pada gangguan depresi karena
keberhasilan mereka terbukti dan profil efek samping berbahaya. 1erangkaian studi
mendukung beberapa efikasi dan tolerabilitas untuk sertraline, citalopram, mirta@epine, dan
fluo?etine.
=amun, ,Chn et al. !+'" menghasilkan studi prospektif keamanan dan kemanjuran
citalopram, mirta@epine, dan rebo?etine (tidak tersedia di 4merika 9tara) pada pasien TLE.
-ereka melakukan analisis post hoc dari %7 TLE pasien depresi yang menerima
pengobatan standar dengan salah satu obat di atas. 1ecara umum, mereka menemukan
bah&a semua antidepresan yang efektif dalam mengobati gejala6gejala depresi, dan bah&a
tidak ada efek samping yang serius atau interaksi obat. =amun, angka putus sekolah secara
signifikan lebih tinggi untuk mirta@epine karena kecenderungan obat ini menyebabkan
sedasi, nafsu makan meningkat, dan berat badan dalam suatu populasi sudah sering rentan
terhadap komplikasi ini sekunder untuk 4ED.
*.2. lithium
-eskipun paling dikenal untuk kemanjurannya dalam gangguan bipolar, lithium juga
digunakan sebagai strategi augmentasi untuk pengobatan depresi unipolar. #enggunaan
bersama lithium karbonat dan carbama@epine memiliki manfaat dalam hal stabilisasi
suasana hati tetapi dikaitkan dengan beberapa interaksi, termasuk hematologi, tiroid, dan
elektrolit disregulasi. =amun, lithium tampaknya relatif ditoleransi ketika diberikan dengan
.alproate, tetapi sekali lagi aspek aditif sedasi, berat badan, dan tremor harus dicatat.
Lithium juga dikenal procon.ulsi.e pada dosis yang lebih tinggi, tapi tidak menjadi perhatian
yang signifikan pada dosis rendah pada pasien epilepsi pada 4ED. =amun, harus
dipertimbangkan karena lithium biasanya diberikan sebagai agen augmentasi dalam depresi
unipolar, risiko aditif sindrom serotonin dan menurunkan ambang kejang kedua antidepresan
dan lithium yang diberikan kepada pasien epilepsi /;".

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Depression in Temporal Lobe Epilepsy: A Review of Prevalence, Clinical Features,

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