Download Uses of Carbamazepine for Psychiatric Disorders

Uses of Carbamazepine for Psych iatric
Disorders: A Review
Edward Kim , M.D.
INTROD UCTION
Carbamazepine, first synthesized in 1953, was in it ially mark eted in Europe
as an anticonvu lsant. In 197 1 Dalby reported th e drug's psych otrop ic e ffec ts,
most no tabl y mood stabilization, in patients with temporal lobe e pilepsy (TLE)
(I). Other psychiatric applications such as th e treatment of affectively an d
behaviorall y labil e patients are being explored. These stud ies are yie ldi ng d at a
relevant to the treatment and understanding of th e neu r obiol ogy of mental
illn ess. For this reason , fami liarity wit h car bama zep ine is becomi ng increasingly
important to psy chiatrists.
CHEMISTRY AND PHARMACOLOGY
Ca rbama zepine is structurally sim ilar to th e tricyclic antidepressa nt imi p ramine (Fig. 1) (2,3). Plasma leve ls peak four to e ig h t hours a fte r ing est ion ,
with 75 % of the drug bo u nd to pla sma proteins. CSF levels a re d ependent on th e
level of unbound drug in plasma. Metabolism oc curs primaril y in t he liver via th e
cytochrome P-450 oxi dase system , producing car bamazepi ne- l 0 , ll-e po xid e
which is as active an d may reach levels up to half that o f carba mazepi ne. This is
almost entire ly converted to carbamazepine-trans-l 0, l l -dih ydrodiol by epox ide
h yd ro lase before excretion in the urin e (Fig 2) (4). T he e po xide is 50 %
protein-bound in p lasma (5).
Carbamazep ine induces hepatic en zymes, thus e n hanc ing its ow n meta bolism . Therefore, the 30 -hour half-life of a single oral d ose drops to 2 0 hour s at
three weeks at 12 hour s afte r several months. The half-life is reduced in patie nt s
who simultaneously ta ke other inducers of hepatic en zymes suc h as ph en o ba r bital, p henytoin, or alcohol (4). Ca rbamazepine also e n hances the metabo lism o f
p henytoin an d wa rfarin for th e same reason (6) .
CLINICAL GU IDELINES
T he most co m mon side effect is an a llergic skin rash whi ch occurs in 5 % to
15 % of treated patie nts (7) . T his ma y be accompanied b y sore th roat , mucosa l
u lce ration and low grade fever. Antihistamines can be e ffect ive in e lim inating
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J EFFERSO N J O U R N A L O F PSY CH I A T R Y
Chlorpromazine
Imipramine
Carbamazepine
FIGURE 1. The tricyclic structure of carbamazepine resembles that o f imipramin e
and, to a lesser extent, chlorpromazine. Carbamazepine blocks norepinephrine reuptake but does not block dopamine receptors
a llergic symptoms, th ough th e rash may requ ire di sco ntin uatio n of ca r ba mazepine. Carbamazepine-induced agranulocytosis has recei ved m uch attentio n
because of its mortality rate of up to 50 %. H ow eve r , less th an thirty cases have
been reported (2). T h is id iosyn crat ic reacti on has a p re va lence o f o ne in 20,000
to 40 ,000 a nd is unrelated to a harml ess 25 % d ecrease in whi te ce ll co unt wh ich
is fairl y co m mon (7). Abou t 10% of pati ents receiving t he drug d e vel op a m ild
d ose-r elated leukopen ia whic h resolves wit hin t he first fo ur months. O f these ,
a pp rox ima tely 2 % co nt inue with a persistent leukopenia whi ch necessitates
di sconti nu ation o f th erapy (2). Neu rotox ic side e ffec ts of ca r ba mazepine ma y
incl ude dro wsin ess, ver t io , atax ia, diplopia , and blu rred visio n . Patien ts ac utely
intoxicated on th e drug ca n exh ib it seda tio n , respiratory d epression , h yper ir r ita bi lity, a nd eve n se izures. Other side e ffects incl ude na usea a nd vomiti ng , and
hepato to xicit y ranging fr om mild e levation of serum transaminases to acute
hepatitis. In addition , ch ro n ic ad m inistra t io n ca n also cause a cond ition resembl in g the synd rome of inappropriate secretion of antidiuretic ho rmo ne
(SIA D H) , with wat er rete n tion , h yponatremia , an d possib le water int o x icatio n
(2).
T he in itial d ose o f ca r ba mazepine in health y adu lts is 200 mg o nce or twice
a day. This is in creased b y no mo re th an 20 0 m g a d ay to a tota l of200 mg t.i.d , A
se r u m level should be chec ke d afte r five d ays and d osage adj usted accordi ng ly
(7). Th e actui ty of th e patient di ctates ho w aggressi ve ly t he dosage shou ld be
in creased, bu t th e appearan ce o f neu rotoxi cit y is a clear indication fo r sma ller,
m ore gradual increments. Mainten an ce d o ses average about 10 00 mg/day,
t houg h the ra nge may var y from 20 0 to 160 0 mg/ d ay (8). In pati ents who are
e lder ly or have live r di sease , d osage and increments should be ap p ropriately
d ecreased. T herape u t ic se rum levels ra nge fro m 6- 12 JLg/ m l; neurotox ic side
effects are mo re freq uen t a bo ve 10 JLg/ ml (2,4). Leve ls sho u ld be checked
freq ue n t ly du r in g initial th erapy since 90 % of e nzy me induct ion occu rs in the
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66
J EFF ERSON JO UR NAL OF PSYC H IAT RY
first month (7). Moreover, a complete blood co u n t a nd live r panel should be
ch ecked prior to and period icall y during treatment (2).
NE UROLOGIC AND ENDOCRI N E APPLICATIO NS
Carbamazepine, a potent anticon vulsant is th e d rug of choice in temporal
lobe epilepsy (9), and a first-line drug in controlling gra nd ma l se izures. It is also
effective in the treatment of trigeminal neuralgia and other chronic pain
syndromes ( 10- 13). Its antidiuretic properties have led to its use in managing
diabetes insipidus ( 10).
APPLICATIONS IN MOOD DISORDERS
Most psychiatric trials of carbamazepine have been co nd ucted with patients
with bipolar disorder, although some studies have included sch izoaffect ive
patients in their test groups. Beginning in the earl y 1970's Okuma et a l (15,16)
in Japan demonstrated that car ba ma zep ine is ben eficial in th e treatment of
acutely manic patients and in longterm prophylaxis aga inst ma nia. In a doubleblind controlled study , Po st et a l (17) at th e National In sti tu tes of Menta l Health
reported car ba mazep ine 's clear e fficacy o ver pl acebo in sym p tom re lief in seven
out of nine (88 %) manic patients. Of th ese , four (5 7 %) relapsed d u ring p lacebo
ad m inistrat io n.
The drug's acute a n ti-ma nic e fficacy is a p p rox ima tely th at of chlorpromazine (18). In ov er half of treat ed patients, peak an ti man ic effects were reached
within ten da ys of administrati on o f either ch lorp romazi ne or ca r bamazepine .
Carbamazepine also lowered scores on th e Clin ica l Global Im p ressio n (CGI )
sca le on average as much as lithium (19). Lithium , ho we ve r , had a more
co nsiste n t an ti-manic e ffect than ca r ba m azepine: th e changes in CGI sco res
tended to cluster around the mean in patients t reated wit h lith ium , while the
mean CGI change in car bamazep ine -treated patients was lar gely d ue to a few
who responded extremely well. A double-blind 3-year study com pa ring lith iu m
(n = 27) and carbamazepine (n = 29) found both drugs e ffec tive in a bout two
thirds of treated patients (26). Peak symptom reli ef was reached with in three
months of treatment onset in both groups. The o n ly striking difference between
the drugs was their relative dropout rates. Lithium-treated patien ts with more
schizophrenic or schizoaffective symptoms had a sign ifica n t ly higher d ropo u t
rate than carbarnazepine-treated patients (50 % vs. 20 %, respecti vel y). In contrast, patients who demonstrated " classical" bipolar psych otic fea tures had a
lower dropout rate when treat ed with lithium (20 % vs. 35 %, respect ive ly).
Investigators are attempting to define a population of pat ients who are
particularl y responsi ve to ca rbamazepine and who, th erefo re , wo ul d be considered prime candidates for this treatment early in th eir illn ess. So me patients
with a history of lithium resistance responded better when ca r bamazepine was
added to or substituted for lithium ( 17, 2 1). In two open clinica l tria ls with
USE OF CARBAMAZEPINE FOR PSYCHIATRIC DISORDERS : A REVI EW
67
bipolar and schizoaffective patients resistant to lithium and/or neuroleptic
maintenance (22,23), a total of 14 out of 21 (67 %) of those patients impro ved
when carbamazepine was added or substituted into their treatm ent regim en .
Observations that rapid-cycling bipolar patients respond well to car ba mazepine
(17,21,22,24) have yet to be demonstrated in controlled clinical trials.
The drug's therapeutic effect in depressed patients is somewhat less clear ,
with five of thirteen (38 %) bipolar patients showing marked improv ement in
Post et aI's original report (17), and twelve of thirty-five (34 %) showing m arked
improvement in a subsequent study which involved bipolar (n = 24) and u nipolar (n = 11) depressed patients (25). The antidepressant effect is related to
plasma levels of the epoxide metabolite rather than carbamazepine itsel f (26) .
The drug's time course of action in depression is similar to th at of tri cyclic
antidepressants (TCA's), with substantial improvements occurring after two
weeks and maximum effect after three weeks (27). Because TCA's are known to
induce more rapid cycling in some bipolar patients treated for d epression (28) ,
carbamazepine may be considered as an alternative treatment in patients with a
history of rapid cycling or mania during TCA therapy. One depressed bipolar
patient with a history of TCA-induced mania despite lithium p rophylaxis
responded well to carbamazepine without cycling into mania (29). A recent case
report described the successful treatment of a bipolar d epressed patient using
carbamazepine and electroconvulsive therapy (30) .
OTHER PSYCHIATRIC APPLICATIONS
Carbamazepine was found to markedly decrease the severity and fr equen cy
of behavioral dyscontrol in some women with borderline personality d isorder
(30) . The patients often reported an enhanced ability to think before acti ng, a
phenomenon referred to as "reflective delay. " This resulted in fewer a ng ry
outbursts, episodes of violence, and suicide threats or attempts during th e tria l
period. In contrast, the placebo group showed no such improvements, and seven
of eleven placebo patients (64 %) were removed from the trial early bec au se o f
behavioral deterioration, compared with one of fourteen of th e car bamazepine
trials (7 %). In addition, the drug has also proven helpful in th e treatment o f
patients with mixed frontal lobe disease and schizophrenia or schizoaffective
disorder with affective or behavioral liability (31).
.
Carbamazepine is more effective than placebo when used in co nj unc tion
with haloperidol in the treatment of excited psychoses of schi zophrenic and
schizoaffective, as well as manic, patients (32). Because of this ap pa ren t efficacy
in patients exhibiting more schizophrenic features (22) , the effect s o f carbamazepine on the dopaminergic pathway have been studied b y Po st et a l (33) . T hey
found that carbamazepine decreased probenecid-induced CSF accumulati o n o f
homovanillic acid (HVA), a dopamine metabolite, and had no e ffec t on base lin e
CSF concentrations of HV A . This is in contrast to neuroleptics which increase
both baseline and probenecid-treated HVA levels in CSF. This, in addition to
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the absence of reported cases of ta rdi ve d yskinesia, sugge sts th at carbamazepine
does not exert its effect by dopamine receptor blockade . T h is is consistent with
previous animal studies (34). Rather, th e drug ma y work by d ecreasing dopamine turnover in the brain. Thus far , carbamazepine ha s not prove n useful in
treating tardive d yskinesia (35).
DRUG INTERACTIONS
Two recent reports have d emonstrated that ca r ba mazepine can reduce
plasma levels of haloperidol when the two are admini stered sim ultaneously
(36,37). This ma y be due to hepatic enzyme induction resulting in accelerated
metabolism of haloperidol. Therefore, larger neuroleptic d oses may be necessary for the management of patients treated concurrentl y with ca r ba mazepine.
Another potential co m plicat io n of carbamazepine treatme n t is neurotoxicity during coadministration with lithium (38). Patients may present with confusio n, drowsin ess , weakness, lethargy, coarse tremor, h yp er refl ex ia , nystagm us,
and cerebellar ataxia. These symptoms ca n be seen in both lithium (39) and
carbamazepine toxicity (40). In this case , however, neuroto xicity may d evelo p at
" no n to x ic" plasma levels of each drug. Therefore , monitoring o f drug levels
ma y not protect patients agains t developing ad verse effec ts . Fortu natel y the
neurotoxicity is rapidly reversible following dis continuation of treatm en t. A
history of lithium-induced neurotoxicity is a prominent ri sk factor for th is
complication (38).
On the other hand, coadministration of carbamazepine and lith iu m offers a
potentially beneficial interaction. Carbamazepine can induce wate r re tention
leading to hyponatremia and wat er intoxication (41 ,42). Lithium , o n the other
hand, has been used to treat such water retention in SI ADH by ind ucing a
nephrogenic diabetes insipidus (43). Th ese opposite effec ts on pl asm a sod ium
and fluid balance can offset one another so that patients receiving lith iu m in
addition to carbamazepine may be less likel y to d evelop h yponatremia than
patients treated with carbamazepine alo ne (44).
The use of carbamazepine in conjunction with TCA's and monoamine
oxidase inhibitors (MAOI's) has not been syste mat ically stu d ied . H o wever , we
ca n make some inferences on the basis o f carbamazepine' s str ucture and
pharmacology. The drug inhibits presynaptic r euptake of norepine phrine by
approximately 25 %, compared to 85 % in the ca se of imipramine (3). T herefore
ca r bamaze pine should be used like other TCA 's and started prior to or at the
same time as MAOI' s when combination therapy is d esired (45). Combined
TCA-MAOI treatment, while raising concerns about hyp erten sive crisis, has
been extensively reviewed and found to be safe and efficac ious when admin istered properly (46, 47) .
A number of drugs inhibit t he metabolism of ca r ba mazepine and may cause
increased serum levels. These include ery t h ro mycin , verapamil , diltiazem,
isonia zid, nicotine, and th e opiate p ropoxyphene (4) . T hroug h e nzyme indue-
USE OF CARBAMAZEPINE FOR PSYCHIATRI C DISORDERS;' A REVI EW
69
tion car bamaze pine decreases serum le vels of phenytoin and warfari n as well as
doxycycline, sodium valproate, e thosux im ide, and clonazeparn (3,4).
THEORETICAL CONSlDERATIO S
The efficacy of ca r ba mazep ine in the treatment of exci te d psych oses raises
questions about the neurobiology of psychiatric illness. In the late 1960 's it was
observed that dominant hemisph ere TLE predisposes patients to psych osis,
whil e nondominant hemisphere TLE is associa ted with bipolar illn ess (48). This
study compared fift y TLE patients with psychotic features with fifty nonpsychotic TLE patients. The presence of psychosis was inv ersel y co r related with
seizure activity . A more recent study found that II of 17 (6 5%) of T LE pat ien ts
and zero of seven generalized epileptics had at least one of th e e igh t Schnei derian first-rank symptoms for schizophrenia (49) . Dalby's study (I ) goes on to
demonstrate that TLE patients treated with carbamazepine had mar kedl y
reduced affective symptoms such as anxiety , paranoia, and aggressive beh avio r
in 24 of 58 (44 %) patients. Moreover, several patients improved psychiatricall y
despite a lack of seizure control. While nearly half of Dalby' s e pilep tic patients
had structural brain abnormalities, most su bseq ue nt stud ies o f th e psych o trop ic
effects of carbamazepine have screened out patients with str uc tura l or electroen cephalographic abnormalities.
Post et al (50) proposed a th eory o f agitated psych osis wh ich involved a
phenomenon called " kind ling. " Repetiti ve su b th resho ld sti m ulatio n of the
limbic system produces a h yperexcitable " kind led " state in whic h m ot or seizures
ma y be induced by stimulation that was previously non-seizu rogenic . Reviewing
t he literature on the effects of chronic administration o f cocaine and other CNS
st im ulan ts, they noted that su bjects developed h yp ersensivit y ra ther than
tolerance to the effects of th ese subs ta nces on path ological behavio r and
se izu res.
Carbamazepine, in addition to phenobarbital a nd di azepam , is very effective in blocking experimental electrically kindled a mygda loid se izu res in a
variety of animal species (51). Ph en ytoin , another potent anticon vul sant, is much
less effective in blocking kindled am ygdaloid seizures. Moreo ver, phe nyto in
exh ibits no significant therapeutic e ffect on manic patients (52). T h is suggests
the possibility of a limbic focus for the generation of mania and other excited
psychoses. The mechanism may involve subthreshold kindling of limbic st ructures. The absence of structural and physiologic abnorm alities in suc h patien ts
could be more reflective of instrumental limitations than th e absen ce of organ ic
pathology.
CO NCLUSIO NS
Carbamazepine, once used only in the treatment of e pilepsy and neuropathi c pain, is becoming increasingly important in th e treatment of so me psychiat-
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JEFFERSON JOURNAL OF PSYCH IATR Y
ric patients, but that group is not ye t clearly defined. Because of potential
adverse effects and drug interactions, it should be admin istered j udicio us ly in
selected patients who can be carefully monitored. Nevertheless, it is becom ing
evident that for a certain subset of psychiatric patients, carbamazepine a lone or
in combination with .o th e r drugs may prove to be the only effec tive treatment
that is currently available.
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71
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