depression in temporal lobe epilepsy

8/11/2019 Depression in Temporal Lobe Epilepsy

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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 undert%e Creative Commons Attribution License, w%ic% permits unrestricted use,distribution, and reproduction in any medium, provided t%e ori!inal wor4 isproperly cited"

Abstract

Depression in temporal lobe epilepsy %as been establis%ed as a fre5uentoccurrence, 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%ereco!nition and mana!ement of depression in patients wit% temporal lobeepilepsy" 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!, anddia!nosis of bot% temporal lobe epilepsy and depression" 7owever, in recentyears, si!ni6cant e8ort %as been made to address t%ese issues and provide aframewor4 for dia!nosis and mana!ement of depression in t%is population" T%efollowin! is a review of t%e literature, wit% special emp%asis on clinical

p%enomenolo!y of depressive symptoms, described bidirectional ris4 betweendepression and temporal lobe epilepsy, and treatment strate!ies in t%e conte9tof 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 tobot% neurolo!ists and psyc%iatrists for many years and %as !enerated an


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e9pansion of 4nowled!e in bot% 6elds t%at %as been used to better understandnot only t%ese two disorders, but t%e relations%ip of mood, co!nition, andtemporolimbic 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 clinicalfeatures 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 instudy desi!n, variable sample populations, and t%e c%allen!es of con6rmin!temporal lobe focus in some patient populations are all possible contributors tot%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%esiveapproac% 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 depressionin temporal lobe epilepsy patients, it %as been di@cult to establis% a clearpattern wit% respect to prevalence, particularly in comparison to ot%er types ofepilepsy >/?" 7istorically, depressive symptoms %ave been considered to be morefre5uent in epilepsy wit% a temporal lobe focus t%an in e9tra TLE or !eneraliBedepilepsy > ?" 7owever, several ot%er studies %ave not been able to documentany suc% di8erences >/, G?"

#everal e9planations for t%is %ave been proposed" Firstly, concomitant oradditive mec%anisms may play a role in t%e development of depressivesymptoms 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%ant%e location of t%e focus may be more relevant" Two later studies con6rmed t%atfre5uency of seiBures were more si!ni6cant in predictin! depressive symptomst%an focus location > , ?" (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 lobedysfunction in addition to temporal lobe dysfunction may be an important ris4factor in developin! depression in TLE patients >/?" Additionally, #win4els et al">/? described si!ni6cant met%odolo!ical di8erences amon! t%e various studiese9aminin! prevalence rates of depression in epilepsy, includin! small samplesiBe, lac4 of control !roups, variable and often nonstandardiBed dia!nosticinstruments, and variability in t%e study population ;inpatients, outpatients,sur!ical patients, etc" +? observed t%at many studiesassessin! psyc%iatric symptoms in epilepsy predate t%e advent of tec%nolo!ysuc% as video electroencep%alo!ram monitorin! and ma!netic resonanceima!in!, w%ic% may ma4e c%aracteriBation of t%e underlyin! lesion more


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unreliable" All of t%e above may be contributin! to t%e fact t%at alt%ou!% t%ere isa plet%ora of studies dedicated to t%e assessment of prevalence of depression intemporal lobe epilepsy, consensus %as yet to be ac%ieved"

)evert%eless, a %andful of recent studies %ave attempted to rectify some of t%eabove issues and %ave provided some interestin! data" #anc%eB $istau et al"> *? studied 0 patients t%at were carefully classi6ed as %avin! epileptiformfoci t%at was temporal or e9tratemporal in localiBation" T%ese patients were t%enadministered t%e #tructured nterview for D# H A9is Psyc%iatric Disorders;#C D


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" 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 studiese9aminin! t%e relations%ip between depressive symptoms and a!e of onset ofepilepsy or duration of epilepsy do not identify clear association wit% ris4 ofdepression > , //, / ?" (ne study did 6nd a potential lin4 between depressionand development of seiBures in later life >/-?"

(ne of t%e 5uestions t%at %as been raised %istorically is w%et%er depressivesymptoms in t%e epilepsy and TLE population represent a comorbid mooddisorder, 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%esesymptoms instead represent a collection of emotional and co!nitive disabilitiessimilar but not e5ual to a ma=or depressive disorder >/+ /G?"

T%e concept of interictal dysp%oric disorder was proposed to describe t%e latterin response to studies su!!estin! t%at a si!ni6cant portion of epilepsy patientswit% depressive symptoms would not %ave met criteria for a=or DepressiveDisorder as typically described in dia!nostic sc%edules >/ , / ?" For e9ample,Janner et al" > 0? e9amined patients wit% refractory seiBures and depressive

symptoms and found only / I met D# H criteria for a=or DepressiveDisorder" nitially proposed by Jraepelin, t%en later 2leuler, t%is conceptori!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 toantidepressants > ?" A more speci6c ran!e of symptoms %ad been described by2lumer et al" in t%eir )eurobiolo!ical nventory for Epilepsy, w%ic% was areformulation of earlier inventories t%at were meant to de6ne t%e TLE personalityc%aracteristics >/+, / ?" Two cate!ories of symptoms %ave been described:depressive somatoform symptoms ;depressed mood, aner!ia, pain, and

insomnia< and a8ective symptoms ;irritability, eup%oric mood, fear, and an9iety/ ?" An%edonia %as also been proposed as a better mar4er for depression inpatients wit% epilepsy, in part secondary to its independence from p%ysicalsymptoms associated wit% medications and c%ronic illness > /?"

7owever, t%ere %ave also been many proponents of t%e belief t%at t%ere is notsu@cient evidence to support a model of psyc%opat%olo!y uni5ue to temporallobe epilepsy" Janner and )ieto > ? proposed t%at t%e symptoms described int%ese TLE or epilepsy speci6c psyc%opat%olo!y inventories are 5uite similar to astable mood disorder wit% mar4ed depressive and an9iety features rat%er t%an ade novo condition" Lis%man > -? also concurred t%at t%e depressive symptoms


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described as speci6c to t%e TLE population were an artifact of samplin! andselective reportin! by patients in institutional settin!s"

E8orts %ave been made to test t%e validity of dia!nosin! depression in t%ispopulation" Reilly et al" >/+? reasoned t%at t%e latent variable factors observed tobe impacted in depressive disorders ;ne!ative attitude, performance di@culty,and somatic elements< could be measured in TLE patients to compare t%e levelof 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 similarto t%at seen in ma=or depressive disorder, su!!estin! t%at t%ese symptomsrepresented 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 self report of symptoms of

a=or Depressive Disorder, and 6ndin! very %i!% concordance > +?"

n summary, t%ere %as been some su!!estion %istorically t%at depressivesymptoms in t%e TLE population may represent not depression but rat%er acondition uni5ue to t%ese patients" T%is concept %as been described as interictaldysp%oric disorder" 7owever, t%ere now also %ave been studies t%at appear tocon6rm t%at t%e D# H criteria for ma=or depression are valid in t%e TLEpopulation, and t%at t%e depressive symptoms t%ey e9perience can beunderstood 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 inunderstandin! bot% depression and TLE for 5uite some time" Re!ions ofparticular interest for bot% t%ese disorders include t%e temporal lobes;particularly t%e %ippocampus, amy!dala, entor%inal, and neocortical corte9 ,

G -0?" Alt%ou!% t%e %ippocampus and amy!dala %ave been t%e ma=or focus ofattention, all of t%e above structures %ave been found to s%are associationacross t%ese two disorders > ?"

n bot% depression and TLE, %ippocampal volumes %ave been found to beabnormal > ?" n depressed patients wit% and wit%out TLE, %ippocampal volumesare reduced, usually bilaterally or occasionally left sided only > G, - -+?" n TLEpatients, 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 left sided TLE focus, co!nitiveproblems wit% memory and learnin! are more mar4ed >-*?" (t%er studies %ave


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con6rmed t%is, lin4in! depression and verbal learnin! impairments in TLEpatients >-G?" T%e suspected cause be%ind t%is is dysfunction wit%in t%e lar!erlan!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 ofdepression and TLE, !iven its 4ey role in fear and associated emotions >- ?" T%isstructure 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 mooddisorder becomes c%ronic > ?" Two studies %ave found a relations%ip betweenescalatin! amy!dala volume and severity of symptoms of depression in t%e TLEpopulation >- , +0?" Left sided volume increases of t%e amy!dala and severity ofdepression 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 int%e acute p%ase of depression in TLE and non TLE patients, resultin! in anincrease in volume secondary to increased re!ional blood Kow > , - , +0?"

T%e two commonest lesions for t%e development of temporal lobe epilepsy aremesial 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%osewit% neocortical temporal lesions, re!ardless of lateraliBation >+ ?" Additionally,patients wit% mesial temporal sclerosis %ave a !reater fre5uency of co!nitiveside e8ects and mood problems wit% antiepileptic dru!s >+/?" nterestin!ly,

#al!ado et al" >+ ? found si!ni6cantly more widespread !rey matter volume lossin TLE patients wit% depression as compared to t%eir nondepressed fellowpatients" T%is leads to t%e su!!estion t%at t%ere is a bidirectional relations%ipbetween t%ese two disorders >+ ?"

n summary, various important structures of t%e limbic system %ave been foundto be si!ni6cantly di8erent in depressed TLE patients in comparison wit%nondepressed fellow patients" T%ere may be a bidirectional relations%ip betweendepression 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! seiBure free, often t%us dramaticallyimprovin! 5uality of life > +, +-?" 7owever, t%ere is an emer!in! reco!nition t%atpsyc%iatric complications can occur in t%e postoperative period, includin! denovo symptoms of depression >+-?"


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T%e stron!est ris4 factor for depression in t%e postoperative course is, per%apsnot surprisin!ly, preoperative depression >++ +G? and %as been reported inappro9imately /0 0I of patients under!oin! sur!ery >+ *0?" Rates of de novodepression 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 seiBureoutcome postoperatively >* ?" T%e %i!%est ris4 period appears to be in t%e 6rst mont%s followin! sur!ery, wit% slow improvement at t%e / or /- mont% mar4>+-, * ?"

LateraliBation %as been t%e focus of many studies, but no clear, co%esive patternappears to %ave emer!ed yet" #everal studies su!!est t%at ri!%t temporal loberesections represent a !reater ris4 of postoperative depression >+G, *-?, w%ileseveral more support left temporal lobe resection as %i!%er ris4 for t%iscomplication >+*, +G?, and yet ot%ers report no evidence of laterality at all >* ?"

T%ese ambivalent results are ec%oed in t%e literature e9aminin! rates ofdepression followin! tumor resections >*+, **?"

7owever, some studies %ave documented w%at appears to be a bidirectional ris4in t%e relations%ip between postoperative seiBure control and depressivesymptoms" etternic% et al" >*G? documented si!ni6cantly lower 2ec4Depression nventory scores in patients t%at were seiBure free postoperatively"

Reuber et al" >+ ? observed t%at postoperative TLE patients improvedsi!ni6cantly wit% respect to depressive symptoms in comparison to medicallymana!ed TLE patients, but only if seiBure control was si!ni6cantly improved" T%isled t%em to suppose t%at depressive symptoms were associated wit% epilepticactivity rat%er t%an structural c%an!es"

Finally, 'renc% et al" >* ? recruited *0 patients under!oin! two types of sur!ery;mesial temporal lobe resection and nonmesial temporal lobe resection< andfollowed t%em lon!itudinally" Preoperatively, - I 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 mentalillness and 6nancial dependency" 7owever, in t%e postoperative p%ase, t%emesial temporal resection !roup e9perienced a si!ni6cantly %i!%er rate ofdepression, bot% recurrence and de novo >* ?, su!!estin! t%at per%apsdisruption of t%ese structures carries a %i!%er ris4 of depression as acomplication postoperatively"

n summary, recurrence and de novo development of depression is a ris4 in TLEpatients under!oin! sur!ery, particularly in t%e 6rst mont%s postoperatively"Alt%ou!% no clear pattern is emer!in! re!ardin! t%e relevance of laterality, t%ere


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is si!ni6cant evidence to support a bidirectional relations%ip between depressionand postoperative seiBure control, w%ere t%e presence of one can e9acerbate t%eot%er" T%is ec%oes t%e 6ndin!s previously described earlier in t%is c%apter, inw%ic% eac% condition may operate as a si!ni6cant ris4 factor for t%e ot%er"

*" Antiepileptic Dru!s and Depression

Antiepileptic dru!s ;AED s< %ave been 4nown to %ave positive psyc%otropice8ects beyond t%eir antiseiBure e8ect for 5uite some time >* ?" ndeed, manyAED s %ave separate indications for t%e treatment of psyc%iatric disorders,includin! roles as mood stabiliBers >G0?, an9iolytics >G ?, and in t%e mana!ementof wit%drawal syndromes >G/?" t is also e5ually true t%at many AED s %avene!ative psyc%otropic e8ects t%at can complicate t%e mana!ement of bot%epilepsy and depression in patients >* ?"

T%e AED s associated wit% t%e %i!%est ris4 of occurrence of depressive symptomsin patients wit% epilepsy are t%ose w%ic% act at t%e benBodiaBepine $A2Areceptor comple9 >* ?" T%ese include barbiturates, topiramate, and vi!abatrin"Levetiracetam and felbamate appear to represent an intermediate ris4 ofdepressive symptoms, leavin! t%e ot%er AED s as eit%er low ris4 or un4nown >* ?;Table * ? su!!ests a !eneral approac% of monot%erapy if possible, wit% introduction of any new AED s wit% slow, careful titration, and careful %istories of premorbid andfamily psyc%iatric disorders bein! collected re!ularly in t%is patient population>* ?"

tab

Table : Positive and ne!ative e8ects of AED s > *?"

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 oft%e most si!ni6cant sources of burden of disease and su8erin! !lobally >G ?" T%eimpact of t%is disorder on mortality, morbidity, 5uality of life, social function, andoccupational function %ave been well described" #imilarly, t%e additive burden ofdepression 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 tobe borne by t%ose TLE patients t%at carry t%e comorbidity of t%ese two disorders"


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7owever, as previously noted in t%is c%apter, t%ere is stron! support for abidirectional ris4 e9istin! between t%ese two disorders" n ot%er words, t%epresence 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 seven foldincrease in rates of depression bein! dia!nosed prior to t%e onset of t%e seiBuredisorder in patients wit% newly dia!nosed epilepsy w%en compared to a!e andse9 matc%ed controls" T%is remar4able 6ndin! was furt%er raised to a G foldincrease w%en patients wit% a localiBed onset were studied" Anot%er study founda "G fold increase in fre5uency of dia!nosis of depression precedin! t%e 6rstseiBure in older adults wit% new onset epilepsy >/-?" A study of celandic c%ildrenand adults wit% new onset epilepsy found a similar increase in rates ofdepression precedin! seiBure onset ; "G foldG*?" Finally,recent studies %ave also su!!ested t%at psyc%opat%olo!y could be a si!ni6cantris4 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 al s" >G ? study of epileptic patients enrolled in ##R , #)R ,and mirtaBepine treatment trials" Patients on t%e medications %ad si!ni6cantlylower 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 depressiveepisode 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 isappro9imately two to 6ve times t%at of t%e !eneral population, and t%is is furt%erelevated to a /+ fold increase amon! patients wit% TLE >G , 0?" )ot surprisin!ly,t%e rate of completed suicide is furt%er elevated up to / fold by t%e presence ofa comorbid depressive disorder >G ?"


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T%is s%oc4in! increase %as been considered to be primarily inKuenced by t%epsyc%osocial conse5uences of livin! wit% c%ronic epilepsy > ?" 7owever, recentdata would su!!est t%at t%e situation is more comple9 t%an psyc%osocialconse5uences 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 0I of patientswit% epilepsy %ad attempted suicide as compared to GI of controls > 0, ?" T%isis relevant !iven t%e fact t%at suicide attempts are comple9 be%aviors involvin!many factors, includin! impulsivity and e9ecutive dysfunction, w%ic% can beassociated wit% temporolimbic function > / *?" .ones et al" > G? found a lifetimeprevalence of suicide attempts of /0" I amon! outpatients followed atepilepsy centers in t%e &nited #tates" n t%is sample, t%e %i!%est rates ofattempts were amon! patients wit% a lifetime %istory of a ma=or depressiveepisode or manic episode, and %i!%er rates of suicidal ideation were alsoassociated wit% a lifetime %istory of mood or an9iety disorders" a=or depressivedisorder was t%e most fre5uent psyc%iatric disorder identi6ed amon! patientswit% a %istory of suicide attempt ;+ "GI ?studied -/ patients wit% newly dia!nosed TLE over a year period and assessedsuicide ris4 via t%e Plutc%i4 Ris4 of #uicide scale" T%ey found t%at +G" I of t%eirsample scored MG on t%is scale, w%ic% is t%e %i!%est ris4 cate!ory for suicide,/ "*I %ad a past %istory of suicide attempts, and -+"/I %ad e9periencedsuicidal t%ou!%ts" T%e study aut%ors also assessed for multiple associatedfactors includin! psyc%iatric comorbidity, past medical and psyc%iatric %istory,and neuropsyc%olo!ical de6cits" T%ey discovered a si!ni6cant relations%ipbetween %i!%er suicide ris4 and a %i!%er rate of suicide attempts in patients wit%a family %istory of psyc%iatric diseases, left sided TLE, current ma=or depressiveepisode, and %i!%er perseverative responses on neuropsyc%olo!ical testin! via'isconsin Card #ortin! Test ;'C#T ?" T%e a!ency %ad performed a review of clinical trials of


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AED s and noted a " fold increase in suicidal be%avior or ideation in patientsta4in! AED s in comparison to t%ose ta4in! placebo" Alt%ou!% manymet%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 su8ersi!ni6cant psyc%iatric comorbidity" As described previously in t%is c%apter, AED s%ave been documented to produce bot% positive and ne!ative psyc%otropice8ects, and t%e FDA s announcement produced a Kurry of epidemiolo!ic wor4 toattempt to con6rm t%is increased ris4 of suicidality and %opefully su!!estmec%anisms > 0?" T%ese 5uestions are still bein! answered, and t%e studies6ndin!s %ave been 5uite mi9ed, but results t%us far su!!est t%at if t%ere is anelevated ris4 of suicidality wit% AED s, it appears to be very low >* ?, and t%at noclear pattern is emer!in! re!ardin! ris4 strati6cation across t%e various AED s>* , 0?" 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 ofepilepsy and comorbidity of psyc%iatric illness > 0?, w%ic% in part may e9plaint%e variability of 6ndin!s" 'en et al" > 0? noted an interestin! trend in t%eirretrospective analysis of patients in t%e Compre%ensive Epilepsy Researc%Pro!ram ;CERP< database over a / mont% period" 2rieKy, t%ey noted t%at t%estron!est predictors for t%e development of suicidality over time were t%epresence of depressive symptoms or suicidality prior to AED treatment, and t%att%ose patients started on new or multiple AED s %ad less improvement ofsuicidality over time in comparison wit% t%ose w%o %ad no c%an!es made to t%eirAED re!imen" Additionally, t%ey found no si!ni6cant di8erence in suicidalitybetween t%e AED s t%emselves" T%is led t%e aut%ors to su!!est t%at per%aps t%e6ndin!s of t%e ori!inal FDA study were !enerated by t%e artifact of patients on

AED s improvin! less t%an placebo controls wit% respect to t%eir suicidalitysymptoms over time"

G" " Nuality of Life Conse5uences for Patients wit% Comorbid Depression and TLE

ultiple studies in epilepsy in !eneral and TLE speci6cally %ave made e8orts toe9amine t%e relations%ip between various factors associated wit% livin! wit%epilepsy and t%e impact on 5uality of life > ?" Janner > ? reviewed + studiesin particular t%at consistently demonstrated t%at depression was t%e most

powerful predictor of %ealt% related 5uality of life across multiple domains, evenw%en controllin! for factors suc% as seiBure fre5uency, severity, and ot%erpsyc%osocial variables" eldolesi et al" > ? studied 0* patients wit% dru!resistant unilateral temporal lobe epilepsy, administerin! various standardiBed5uality of life instruments as well as t%e 2ec4 Depression nventory and anan9iety scale" T%ey also found depression to be consistently t%e stron!estpredictor of lower scores on all N(L domains e9cept seiBure worry" T%is e8ectwas independent of socioeconomic status, !ender, lateraliBation of seiBure focus,seiBure fre5uency and severity, and an9iety"


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Additionally, comorbid depression appears to be associated wit% a !reaterli4eli%ood of adverse events associated wit% antiepileptic dru!s, more fre5uentvisits to p%ysicians, and %i!%er cost of medical care related to t%e seiBuredisorder, rat%er t%an any cost associated wit% t%e psyc%iatric disorder and itstreatment > G ?" T%is is an interestin! 6ndin! in li!%t of t%e recurrin! t%emewoven t%rou!% t%e literature of t%e bidirectionality of depressive symptoms andepilepsy symptoms" A!ain, t%e presence of one appears to ma4e t%emana!ement of t%e ot%er more of a c%allen!e"

" ana!ement #trate!ies for Depression in Temporal Lobe Epilepsy

n !eneral, evidence for treatment strate!ies of mood disorders in epilepsy arelac4in!, and development of mana!ement approac%es tend to rely on clinicale9perience rat%er t%an evidence based trials favorin! one treatment overanot%er >* ?" T%e paucity of data is even more pronounced w%en e9aminin! t%eliterature for TLE speci6c depression treatment studies" )ot surprisin!ly t%en,t%ere are no widely accepted !uidelines for t%e treatment of depression in TLEpatients"

7owever, clinicians can turn to a body of literature t%at, w%ile lac4in! in lar!e,double blinded, and placebo controlled RTC s, still includes several smaller openlabel 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 comparativestudy in TLE patients in particular is included in t%e followin! discussion"

" " Antidepressants

T%ere are t%ree main considerations w%en initiatin! an antidepressant trial in apatient wit% epilepsy: e9acerbation of seiBure control, potential for interactionwit% AED s, and e@cacy of t%e antidepressant in depression symptom resolution"

T%ere appears to be variability between and also wit%in t%e variousantidepressant dru! classes alt%ou!% some !eneraliBations can be made fromt%e available literature"

" " " Antidepressants and #eiBure Ris4

T%e potential for antidepressants to provo4e seiBures %as been a source ofconcern and possibly a barrier to treatment of depression in patients wit%epilepsy > 00?" T%e data documentin! seiBures secondary to antidepressants isderived lar!ely from psyc%iatric populations, in vitro or animal model studies, orfrom samples w%ic% were not speci6cally patients wit% epilepsy > *, 00?" (ften,seiBures associated wit% antidepressants are described in cases of to9icity, suc%as accidental or intentional overdose > *, 00?" T%is ma4es it di@cult, if not


13/33

impossible, to !eneraliBe 6ndin!s to epilepsy patients" T%e situation is furt%ercomplicated by t%e fact t%at animal and %uman studies su!!est t%at someantidepressants may %ave an anticonvulsant e8ect, w%ile some may %ave aproconvulsant e8ect, and yet ot%ers may %ave a bip%asic e8ect, in w%ic% t%eyare anticonvulsant at lower doses and proconvulsant at %i!%er doses > *?"

ec%anisms proposed for t%e proconvulsant e8ect include t%e antic%oliner!ice8ect of many antidepressants ;particularly at %i!%er doses *?" Anticonvulsante8ect may be mediated by t%e interaction of t%e antidepressant wit% ot%erfactors, includin! AED s" For e9ample, Kuo9etine %as been noted to en%ance t%eanticonvulsant e8ect of p%enytoin and carbamaBepine via selective in%ibition ofserotonin upta4e > *?"

Tricyclic antidepressants ;TCA s< %ave a wide variety of neurotransmitter relatede8ects, many of w%ic% are dose dependent as well" (verall, t%ey are consideredproconvulsant, in lar!e part secondary to t%eir si!ni6cant antic%oliner!ic e8ect,w%ic% is 4nown to lower seiBure t%res%old > *?" As stated previously, someselective serotonin reupta4e in%ibitors ;##R s< may actually %ave ananticonvulsant e8ect > 0 0 ?" n !eneral, clinical and researc% e9periencesu!!ests t%at t%e ris4 of seiBures wit% ##R s is very low and per%aps notdi8erent from placebo, and certainly lower t%an wit% TCA s > 0 ?" A specialconsideration wit% ##R s is t%e fact t%at t%ey can promote %yponatremia, w%ic%can represent a ris4 in t%e precipitation of seiBures > *?" (t%er antidepressantsw%ic% are considered to be O%i!% ris4 for seiBures in t%e !eneral population or into9icity studies ;e"!", bupropion< %ave been found overall to %ave an acceptablylow ris4 w%en prescribed correctly > *?"

(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%enot%er ris4 factors are e9cluded > *? ;Table / *?"

" "/" nteractions between Antidepressants and AED s

TCA s %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*,


14/33

and A- ;Table *?"

##R s are !enerally more tolerable and safe t%an TCA s, due in part to t%eirreduced antic%oliner!ic e8ect and inability to bloc4 sodium c%annels, even inoverdose > 0-?" As a result, t%ese dru!s are widely prescribed" Fluo9etine andparo9etine are metaboliBed by CQP /D*, sertraline by CQP A-, Kuvo9amine byCQP 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 A-" #ertraline and citalopram do not seem to %ave si!ni6cant

induction in%ibition properties > 0+?"

Fluo9etine %as a %i!% ris4 of interaction wit% p%enytoin, but less clearly wit%carbamaBepine > *, 0*, 0G?" Paro9etine and sertraline seem to %ave low ris4 of interaction wit% p%enytoin > *, 0*?" 7owever, carbamaBepine seems to inducecitalopram s metabolism si!ni6cantly, t%us reducin! plasma concentrations andpossibly e@cacy of t%is dru! > *?" Paro9etine appears to %ave little interactionwit% carbamaBepine, valproate, or p%enytoin > *?" Fluvo9amine appears to %aveno e8ect on carbamaBepine levels > *?" 7owever, t%ere is a paucity of evidence

on t%e safety of Kuvo9amine coadministration wit% valproate or p%enytoin > *?"#ertraline was found to increase t%e levels of lamotri!ine in two documentedcases > *?" Finally, sertraline was found to %ave no si!ni6cant e8ect oncarbamaBepine levels in a double blind randomiBed, placebo controlled trial of -%ealt%y volunteers > *?" #ertraline and clonaBepam were also found to be safe incoadministration > *?"

#)R s ;venlafa9ine and dulo9etine< are primarily metaboliBed by CQP /D* > 0-?,but interactions wit% AED s %ave yet to be studied > *?"


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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%ispopulation on interactions wit% AED s, but t%is medication %as been noted tobind %istaminic receptors, resultin! in sedation, increased appetite, and wei!%t!ain" $iven t%at t%ese are side e8ects of many AED s, t%e potential for anadditive e8ect is present > *?"

2upropion is a noradrener!ic and dopaminer!ic reupta4e in%ibitor ;)DR *?"

" " " E@cacy of Antidepressants in TLE

A!ain, t%ere is a deart% of evidence based, controlled trials t%at attempt to studye@cacy of antidepressants in epilepsy in !eneral, and t%e number of trialsspeci6c 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 andan antidepressant t%at no lon!er e9ists ;nomifensine *?"

##R s %ave become t%e 6rst line of p%armacot%erapy in most depressivedisorders due to t%eir proven e@cacy and beni!n side e8ect pro6les" 7owever,e@cacy in epilepsy speci6cally %as not been well studied yet" A series of openlabel studies support some e@cacy and tolerability for sertraline, citalopram,mirtaBepine, and Kuo9etine" n !eneral, ##R s seem to be e8ective and well

tolerated, but t%e response rates %ave been 5uite mi9ed across studies, li4elydue to !reat variability in sample populations, limited control of comorbidpsyc%iatric disorders, and t%e occasional presence of co!nitive disorders or braindama!e in t%e samples > *?"

7owever, JS%n et al" > 0 ? produced a prospective study of safety and e@cacy of citalopram, mirtaBepine, and rebo9etine ;not available in )ort% America< in TLEpatients" T%ey performed a post %oc analysis of G+ TLE patients wit% depressionw%o received standard treatment wit% one of t%e above dru!s" n !eneral, t%eyfound t%at all t%e antidepressants were e8ective in treatin! t%e symptoms ofdepression, and t%at t%ere were no serious adverse events or dru! interactions"


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7owever, t%e dropout rate was si!ni6cantly %i!%er for mirtaBepine t%at t%e ot%ertwo a!ents, per%aps a!ain because of t%e tendency of t%is dru! to causesedation, increased appetite, and wei!%t !ain in a population already often proneto t%ese complications secondary to AED s"

"/" Lit%ium

Alt%ou!% most 4nown for its e@cacy in bipolar disorders, lit%ium is also used asan 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%iumin epilepsy t%an for antidepressants > *?"

Coadministration of lit%ium carbonate and carbamaBepine may %ave a bene6t interms of mood stabiliBation but appears to be associated wit% multipleinteractions, 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, andtremor were noted" Lamotri!ine and lit%ium appeared to be well toleratedto!et%er, t%ou!% topiramate and lit%ium was associated wit% to9icity in at leastone case > *?"

Lit%ium also is 4nown to be proconvulsive at %i!%er doses, but t%is does notseem to be a si!ni6cant concern at lower doses in epilepsy patients on AED s"7owever, as lit%ium is usually administered as an au!mentation a!ent inunipolar depression, t%e additive ris4 of serotonin syndrome and lowered seiBuret%res%old of bot% an antidepressant and lit%ium bein! administered to anepilepsy patient must be considered > *?"

" " Psyc%ot%erapy

(nce a!ain, very little data %as been collected on psyc%olo!ical t%erapies in t%eepilepsy population, let alone TLE" 7owever, t%e few studies t%at e9ist seem tosupport t%e e@cacy of co!nitive be%avioral t%erapies as useful in t%e treatmentof depression in epilepsy >* ?"

References

" D" JondBiella, #" Alvestad, A" Haaler, and &" #onnewald, O'%ic% clinical ande9perimental data lin4 temporal lobe epilepsy wit% depression .ournal of

)euroc%emistry, vol" 0 , no" *, pp" / * / +/, /00G" Hiew at Publis%er UHiew at $oo!le #c%olar U Hiew at #copus


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/" '" A" " #win4els, ." Juy4, R" van Dyc4, and P" #pin%oven, OPsyc%iatriccomorbidity in epilepsy, Epilepsy V 2e%avior, vol" G, no" , pp" G +0,/00+" Hiew at Publis%er U Hiew at $oo!le #c%olar U Hiew at #copus

" D" A" Pond and 2" 7" 2idwell, OA survey of epilepsy in fourteen !eneral

practices: " #ocial and psyc%olo!ical aspects, Epilepsia, vol" , pp" / +/ , *0"

-" (" $ure=e, O nterictal psyc%opat%olo!y in epilepsy: prevalence and patternin a )i!erian clinic, T%e 2ritis% .ournal of Psyc%iatry, vol" + , pp" G00G0+, " Hiew at #copus

+" F" A" $ibbs, E" L" $ibbs, and 2" Furster, OPsyc%omotor epilepsy, Arc%ives of )eurolo!y and Psyc%iatry, vol" *0, pp" , - "

*" $" $udmundsson, OEpilepsy in celand, Acta )eurolo!ica #candinavica,

vol" - , supplement /+, pp" /-, **" Hiew at #copusG" E" A" Rodin, " JatB, and J" Lenno9, ODi8erences between patients wit%

temporal lobe seiBures and t%ose wit% ot%er forms of epileptic attac4s,Epilepsia, vol" G, no" , pp" /0, G*" Hiew at #copus

" C" L" 7arden, OT%e co morbidity of depression and epilepsy: epidemiolo!y,etiolo!y, and treatment, )eurolo!y, vol" + , no" *, supplement -, pp"#- #++, /00/" Hiew at #copus

" R" anc%anda, 2" #c%aefer, R" #" cLac%lan, and '" T" 2lume, O nterictal

psyc%iatric morbidity and focus of epilepsy in treatment refractorypatients admitted to an epilepsy unit, T%e American .ournal of Psyc%iatry,vol" - , no" , pp" 0 * 0 , /" Hiew at #copus

0"'" A" " #win4els, ." Juy4, E" 7" De $raaf, R" van Dyc4, and P" #pin%oven,OPrevalence of psyc%opat%olo!y in Dutc% epilepsy inpatients: acomparative study, Epilepsy V 2e%avior, vol" /, no" +, pp" -- --G, /00 "Hiew at Publis%er U Hiew at $oo!le #c%olar U Hiew at #copus

"." $" #mall, " F" #mall, and " P" 7ayden, OFurt%er psyc%iatric investi!ationsof patients wit% temporal and nontemporal lobe epilepsy, T%e American

.ournal of Psyc%iatry, vol" / , no" , pp" 0 0, **" Hiew at #copus

/"." R" #tevens, OPsyc%iatric implications of psyc%omotor epilepsy, Arc%ivesof $eneral Psyc%iatry, vol" -, no" +, pp" -* -G , **" Hiew at #copus

"R" ." i!none, E" F" Donnelly, and D" #adows4y, OPsyc%olo!ical andneurolo!ical comparisons of psyc%omotor and non psyc%omotor epilepticpatients, Epilepsia, vol" , no" -, pp" -+ + , G0" Hiew at #copus

-"J" F" #tanda!e and $" '" Fenton, OPsyc%iatric symptom pro6les of patientswit% epilepsy: a controlled investi!ation, Psyc%olo!ical edicine, vol" +,

no" /, pp" +/ *0, G+" Hiew at #copus


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+"#" ." Adams, T" ." (W2rien, ." Lloyd, C" ." Jilpatric4, " R" #alBber!, and D"Hela4oulis, O)europsyc%iatric morbidity in focal epilepsy, T%e 2ritis%

.ournal of Psyc%iatry, vol" /, no" *, pp" -*- -* , /00 " Hiew at Publis%erU Hiew at $oo!le #c%olar U Hiew at #copus

*"H" #anc%eB $istau, L" Pintor, $" #u!ranyes, et al", OPrevalence of interictalpsyc%iatric disorders in patients wit% refractory temporal ande9tratemporal lobe epilepsy in #pain" A comparative study, Epilepsia, vol"+ , no" G, pp" 0 , /0 0"

G"'" A" " #win4els, '" van Emde 2oas, ." Juy4, R" Han Dyc4, and P"#pin%oven, O nterictal depression, an9iety, personality traits, andpsyc%olo!ical dissociation in patients wit% temporal lobe epilepsy ;TLErganisasi esehatan Dunia sebagai salah satu sumber yangpaling signifikan dari beban penyakit dan penderitaan global %/". Dampak gangguan inipada kematian, morbiditas, kualitas hidup, fungsi sosial, dan fungsi kerja, beban aditif depresi pada orang sakit kronis medis juga telah dijelaskan dengan baik, diharapkan bah&aakan ada konsekuensi yang harus ditanggung oleh pasien TLE yang memba&akomorbiditas dari dua gangguan ini.

-isalnya, orsgren dan =ystrom %:" menemukan bah&a ada peningkatan tujuh kali lipattingkat depresi dibandingkan sebelum terjadinya gangguan kejang pada pasien yang barudidiagnosis epilepsi. 1ebuah studi anak6anak dan orang de&asa 2slandia dengan epilepsi

yang onsetnya baru menemukan peningkatan serupa dalam tingkat depresi sebelumnyakejang onset (!,% kali lipat), serta peningkatan 7.! kali lipat dalam sejarah premorbidmencoba bunuh diri %7". Dalam sebuah penelitian terhadap anak6anak dengan kejangonset baru, gejala psikopatologis (termasuk kecemasan, depresi, gangguan perhatian,gangguan pikiran, dan gangguan somatik) yang hadir dengan harga yang lebih tinggidaripada kontrol untuk /*0 dari anak6anak yang baru epilepsi %;". 4khirnya, studi terbaru

juga menunjukkan bah&a psikopatologi bisa menjadi faktor risiko yang signifikan untuk bayimengembangkan kejang nonfebrile atau epilepsi pada anak %%".


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&.2. !unuh diri pada pasien TLE

5unuh diri adalah salah satu hasil yang paling tragis dan ditakuti pada episode depresi danselalu menjadi perhatian bagi dokter ketika bekerja dengan pasien dengan komorbiditaspsikiatri. 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 lipatdengan adanya gangguan depresi komorbid % ".

#eningkatan ini terutama dipengaruhi oleh konsekuensi psikososial hidup dengan epilepsiyang kronis '!". tingkat tertinggi di antara upaya pasien dengan ri&ayat seumur hidup dariepisode depresi mayor atau manic episode, dan tingkat yang lebih tinggi dari keinginanbunuh diri juga dikaitkan dengan gangguan mood atau kecemasan. Gangguan depresimayor adalah gangguan keji&aan yang paling sering diidentifikasi di antara pasien denganri&ayat percobaan bunuh diri (7!,%0), sedangkan gangguan kecemasan yang lebih eratkaitannya dengan ide bunuh diri (7','0)


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/;".

4ntidepresan trisiklik (TA4 ini) memiliki berbagai neurotransmitter yang terkait efek, banyakyang tergantung juga dosis. 1ecara keseluruhan, mereka dianggap procon ulsant, sebagianbesar sekunder untuk efek antikolinergik yang signifikan, yang dikenal untuk menurunkanambang 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 sangatrendah dan mungkin tidak berbeda dengan plasebo, dan tentu saja lebih rendah daripadadengan TA4 ini !+!". #ertimbangan khusus dengan 11$2 adalah fakta bah&a merekadapat mempromosikan hiponatremia, yang dapat me&akili risiko dalam presipitasi kejang

/;".1ecara keseluruhan, insiden kejang dengan antidepresan kurang dari +,70, terutama biladigunakan dalam jangkauan terapi yang dianjurkan dan ketika faktor risiko lain dikecualikan

/;" (Tabel *).

Tabel *8 #re alensi kejang dalam sampel psikiatri selama pengobatan dengan obatantidepresan /;".

*.1.2.-nteractions antara +ntidepresan dan +ED

11$2 umumnya lebih ditoleransi dan aman daripada TA4 ini, sebagian karena mengurangiefek dan ketidakmampuan antikolinergik mereka untuk memblokir saluran natrium, bahkandalam kondisi o erdosis !+:". 4kibatnya, obat ini banyak diresepkan.

luo?etine memiliki risiko tinggi interaksi dengan fenitoin, tetapi kurang jelas dengan


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carbama@epine /;, !+;, !+%". #aro?etine dan sertraline tampaknya memiliki risiko rendahinteraksi dengan fenitoin /;, !+;". =amun, carbama@epine tampaknya menginduksimetabolisme sitalopram secara signifikan, sehingga mengurangi konsentrasi plasma danmungkin kemanjuran obat ini /;". #aro?etine tampaknya memiliki sedikit interaksi dengancarbama@epine, alproate, atau phenytoin /;". lu o?amine tampaknya tidak berpengaruhpada tingkat carbama@epine /;". =amun, ada kekurangan bukti tentang keamananflu o?amine pemberian bersama alproate atau fenitoin /;". sertraline ditemukan tidakberpengaruh signifikan terhadap tingkat carbama@epine dalam acak, percobaan double6blind placebo6controlled dari !: sukarela&an sehat /;". 1ertraline dan clona@epam jugaditemukan aman dalam penggunaan bersama /;".

-irta@epine adalah inhibitor noradrenergik dan serotonergik tertentu reuptake (=assa) danterutama dimetabolisme oleh AB# *D;. 1tudi kurang dalam populasi ini pada interaksidengan 4ED, tetapi obat ini telah dicatat untuk mengikat reseptor histaminic, sehingga

sedasi, nafsu makan meningkat, dan berat badan. -engingat bah&a ini adalah efeksamping 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 karenakeberhasilan mereka terbukti dan profil efek samping berbahaya. 1erangkaian studimendukung beberapa efikasi dan tolerabilitas untuk sertraline, citalopram, mirta@epine, danfluo?etine.

=amun, Chn et al. !+'" menghasilkan studi prospektif keamanan dan kemanjurancitalopram, mirta@epine, dan rebo?etine (tidak tersedia di 4merika 9tara) pada pasien TLE.-ereka melakukan analisis post hoc dari %7 TLE pasien depresi yang menerimapengobatan standar dengan salah satu obat di atas. 1ecara umum, mereka menemukanbah&a semua antidepresan yang efektif dalam mengobati gejala6gejala depresi, dan bah&atidak ada efek samping yang serius atau interaksi obat. =amun, angka putus sekolah secarasignifikan lebih tinggi untuk mirta@epine karena kecenderungan obat ini menyebabkansedasi, nafsu makan meningkat, dan berat badan dalam suatu populasi sudah sering rentanterhadap komplikasi ini sekunder untuk 4ED.

*.2. lithium

-eskipun paling dikenal untuk kemanjurannya dalam gangguan bipolar, lithium jugadigunakan sebagai strategi augmentasi untuk pengobatan depresi unipolar. #enggunaanbersama lithium karbonat dan carbama@epine memiliki manfaat dalam hal stabilisasisuasana hati tetapi dikaitkan dengan beberapa interaksi, termasuk hematologi, tiroid, danelektrolit 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 perhatianyang signifikan pada dosis rendah pada pasien epilepsi pada 4ED. =amun, harusdipertimbangkan karena lithium biasanya diberikan sebagai agen augmentasi dalam depresiunipolar, risiko aditif sindrom serotonin dan menurunkan ambang kejang kedua antidepresandan lithium yang diberikan kepada pasien epilepsi /;".

depression in temporal lobe epilepsy

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