Jefferson Journal of Psychiatry Jefferson Journal of Psychiatry

Volume 14 Issue 1 Article 5

January 1998

Gabapentin in the Treatment of Bipolar Disorder Gabapentin in the Treatment of Bipolar Disorder

Wendy M. Waits Uniformed Services University of Health Sciences

Donald P. Hall Jr., M.D. Walter Reed Army Medical Center; Uniformed Services University

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Recommended Citation Recommended Citation Waits, Wendy M. and Hall, Donald P. Jr., M.D. (1998) "Gabapentin in the Treatment of Bipolar Disorder," Jefferson Journal of Psychiatry: Vol. 14 : Iss. 1 , Article 5. DOI: https://doi.org/10.29046/JJP.014.1.004 Available at: https://jdc.jefferson.edu/jeffjpsychiatry/vol14/iss1/5

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Gabapentin in the Treatmentof Bipolar Disorder

Wendi M. Waits and Donald P. Hall , MD

Abstract

Gabapentin, a relatively new anti-epileptic drug (liED), is emerging as a therapeutic optionJOr treatment refractory and rapid-cycling bipolar illnesses. Pharmacotherapy JOr bipolar disorderstraditionally involves oalproate, carbamazapine, or lithium, drugs which are associated withnumerous adverse effects. Conversely, gabapentin has an attractive pharmacokinetics profile andrelativelyjew side effects. There are no large randomizedcontrolled clinical trials to date examininggabapentin's role in moodstabilization. However, informal reports have cited encouraging results inup to 80% ifpatients and general tolerance to side ifJects. Thesefindings make the new drug apossible choicefor patients who haveJailed to respond to traditional agents or developed sideeffectswhich interfere with medication compliance.

METHODOLOGY

A literatu re search of th e Med line and Silver Platter dat ab ases was performed.English langu age art icles pu blish ed be tween 1990-1997 were reviewed . Keywords" ga ba pe nt in," " bipola r," "epilepsy," a nd " psychia t ry" were used in va rious combina­t ions. All articl es whi ch addressed the use of gaba pe ntin in human subj ects wereconside red . Review of citat ions in these articles led to furth er referen ces to th eclinical use of ga ba pe nt in. All cita tions related to th e use of gaba pentin in th et re a tme nt of affec t ive disorders a re included in thi s review. Other art icles whichaddress clinica lly usefu l ph armacological issu es a re a lso included.

CHEMISTRY

Ga bapentin (Neuro nt in) is a cyclic gamma-amino butyri c ac id (GABA) a naloguewhi ch may a lter GABA transmiss ion in the centra l nervous syste m (I ). The mol ecul eincorporates a lipophilic cyclohexa ne rin g into its s t ruc ture, whi ch a llows gabapentin,un like GABA, to cross th e blood-brain barrier. Pha rmacokinet ic a nd pharmacody­namic inve st igat ions have la rgely re lied on study of a nimals. The drug was initiallydeveloped as a spas mo lyt ic bu t dem on strat ed e ffec tive a n ticonvulsant properties, andthus ente red th e ph armaceutica l market as a n AED (2).

Early resea rch in to gabapentin 's mech anism of ac t ion fa iled to provide strongevide nce of GABAergic ac t ivity. It does not a ppear to sig nificant ly bind to GABA-A,GABA-B, glu tama te, glycine, or benzodiazapine receptor s; it does not a ffec t volt ag e

24

GABAI'ENTIN IN TH E TR EATI\IE rr OF BIPOlAR DISOR DER 25

COOH

GabapentinFIGURE 1. Structure of Gabapentin

ga te d sod ium or calcium channe ls, a nd it does not eleva te GABA concentra t ion innerve terminal s ( 1,3). However, adminis t ra t ion of ga ba pe nt in has been ass ocia te dwith incr eased GABA conce ntra t ion in th e substan t ia nigra , a region rep eated lyindi cated in th e activity ofGABAergi c anticonvulsants (4) .

Gab ap entin is tran sport ed ac ross e nte ric membran es a nd most likely throughthe blood-brain ba rri er a nd into neuron s by a n L-amino ac id carrier (2,5) . It s bindingsite has been recently identified as a subunit of a calc ium chann el on neuronal ce llsur faces (3,6) . Gab apentin increases th e ra te of synthes is and accumulat ion of GABA,decr eases th e release of monoamines (do pa m ine, nor epin ephri ne, a nd serotonin),a nd weakly inhibits GABA-transaminase, an enzyme which degr ad es GABA intoothe r am ino ac ids (3,4).

PHARMACOKINETICS

Gaba pe nt in is becomi ng popula r a mo ng pracu t ione rs du e to its favorabl eph a rm acokinetics profil e. It is effic ie nt ly a bsorbed in th e gut following or a l ingestion.The drug has a hal f-life of 5- 9 hours, rea ch es peak plasm a conce ntrat ion in 2-3 hours,a nd ac hieves ste ady sta te in 1- 2 days. It is water-soluble an d non-pr ot ei n-bound, bu tis distributed th rou gh out th e body (includ ing th e CNS) by means of protein trans­port. Gabap entin is not metabolized , is comple tely elim inated by th e kidneys, a nddoes no t interact wit h hep at ic enzymes. T hese qua liti es theoreti ca lly elim ina tepot ential interacti ons with other med ica tions (2,5,7) .

CLINICAL USE

Co ntrolled clinical t rials of ga ba pentin in the t reat me nt of psychiatric disordershave not been performed . Seve ra l anecdotal reports of use exist in th e medi ca llit erature (8-12), incl udi ng a growing nu mb er of documents pertaining to gaba pe n­t in 's ro le in bipo la r illn ess. However, mos t data regarding the drug's efficacy a ndsafety a ppear in rep ort s of ga ba pe ntin's use as a n an t iconvulsan t. T his informa tionhas se rved as a valuabl e guide to pr eliminary stud ies in th e mental health arena .

Three large rand omized cont rolled clin ica l t ria ls have eva luated th e efficacy andsafety of adj unc t ive ga ba pe nt in th erapy in trea ting refractory epilepsy: th e UK

26 J EFFERSON JOURNAL OF PSYCHIATRY

Gab ap entin Study G roup ( 1990), the US Gab ap ent in Study Group No.5 (1993), andth e International Gab apentin Study Group (1994) . Drug dosages ranged from 600mg/d to 1800 mg/d, with th e most effective dosin g regimen reported to be 1800 mg/d.The percentages of patients in whom se izure fre quency decreased at lea st 50%(responde rs) we re 25%, 26%, and 28%, resp ect ively ( 19). Morris has since reported aretrosp ective a nalysis of 100 patients on ga ba pe ntin, 72 of whom experien ced agreate r th an 50% reducti on in se izu re fre que ncy. The mean drug dos e in this patientpopulation was 210 7 mg/d; 37 of th e 72 who responded (5 1%) were ta king 1800 mg/dor less. The remaining patients took 1800-3600 rug/day (20) .

Data regarding th e role of ga ba pe nt in in th e t reat ment of bipolar disorders ispr eliminary, yet enco uraging . In on e retrosp ecti ve study of bip ola r pa t ien ts who hadfa iled to respond to traditional mood stabilizers or developed intolerable sid e effectsfrom th ese agents , 92% responded positively to ga ba pe nt in (14) . All other publ ish edstudies, consist ing of open trials whi ch have included ga ba pe nt in bot h as mono­th erapy and in addition to other psychotropic medi cation s, have re ported effect iveimprovem ent in th e majority of patients (13,15 ,17,18) . Most patients have d isp layednoticeable improvem ent in cycling activity with 200-3600 mg/d , th ough doses as lowas 33 mg/d a nd as high as 4900 mg/d ha ve been re por ted ( 13,15). Gabapent in mayalso have antidepressant effec ts: patients on th e new AED have noted improvementin mood , memory attention , ene rgy, slee p, and libido ( 10, 13,17). Elevation in moodwhi ch accompanied th e transition fro m traditional AE Ds to gabapentin, however,may have resulted from discontinuation of th e sedating side effects of th e tradi tionalagen ts . Further study is need ed to det ermine if ga ba pe nt in has inh e rent antidepres­sa nt effec ts.

SAFETY

Gab apent in has proven its el f to be a relatively sa fe drug. The most commonly­encounte red side effec ts a re somnolence (24%), dizzin ess (20%), ataxia (17%), andfatigu e (14%) (19). Less frequent sid e effor ts include involuntary twitches (1.3%),rash (0.5%), leukopeni a (0.2%), azo te mia (0.1%), thrombocyto pe nia (0.1%), stutter­ing (I case), a nd weight ga in (19,21,22). There have been several reported cas es ofhypomania and/or incr eased mood cycling ( 14,15, 17,23) a nd th ere has been on e cas eof oculogyri c crisis whi ch was emergent ly reversed with a ben zodi azep ine (22).

A th erap eutic range for gaba pe ntin has yet to be es ta blished. Peak steady-stateplasma levels of th e drug ave rage about 4 micrograms/ml (7). There has been onereported case of overdose, in whi ch a 16-year-old ingest ed 163 capsules (49,900 mg)without eme sis or return of pill frag me nts on gas tr ic lavage. Her plasma gabapentinlevel was 62 micrograms/ml at 8.5 hours afte r ingesti on. She was letha rgic, but waseasily aroused and a ble to converse normall y; by 18 hours post -in gesti on, sh e was alertand without compla in ts (24) . This case report is cons iste nt wit h a nimal toxicity test s,in whi ch mice a nd rats experience d only a taxia a nd labored breathing at maximumdose of 2000 mg/k g IV a nd 8000 mg/k g PO. No ne of the animals expired (24).

Gabapentin has seve ral prop erties whi ch sign ifican tly reduce its pot ential for

GABAPEl\TTIN I r T HE T REAT MENT OF BIPO LAR DISOR DER 27

interaction with other drugs. It is non-prot ein-bound, it does not affect hep aticenzyme ac t ivity, and it has no met ab olites (2) . Alt houg h clinica l trials have notrep orted any cases of drug-drug interacti on s involving gabapentin (20), a nd somesources have suggeste d th at such interacti ons are impossibl e (25,26), several report shave suggested th at th e drug may occas ionally affect or be influenced by othe rmedi cation s.

In on e s tudy, a th erap eutic dos e of a luminum a nd magn esium hydroxide(Maa lox) , adm inis te re d concom ita ntly with or shortly afte r 400 mg of ga bapentin,reduced th e bioavail ability of th e latter by 20% (27). C imetidine has reportedlydecr eased the renal clearance of ga ba pe ntin by a cli nica lly significant a mount (7).There ha s been one case rep ort of ga ba pe nt in interacting with phenytoin . A patientwit h a long hist ory of complex partial a nd secondarily gen eralized seizures, who wason three AED 's, began taking ga bapent in. Hi s plasma phenytoin con centrationsubseque nt ly incr eased from 42 to 177 mi cro gr amslL a nd returned to baseli ne uponremoval of th e new drug (28). Finally, ga ba pe nt in has been assessed as unlikely toca use contraceptive failure when tak en with oral contracept ives (7) .

There a re few reports of pr egn ant wom en ta king gabapentin . No teratogeni ceffects have been not ed in a ny of the 10 reports on file (29). The drug is, however,fe totoxic in rode nts, associa te d with delayed oss ification, hydrouret er, and hydrone­phrosis a t doses up to four times greater tha n rela tive standard human dosages (i.e.3600 mg/d ). There was a lso an incr eased incid en ce of pa ncr eatic acinar cell tumors inmale rats a t high doses, though th ei r life spa n was not a ffec ted by th e neoplasms (30).Potential uses of ga ba pe nt in in th e pedi at ric affect ive d isorders popu lations have yetto be determined.

DOSI G

Formal dosin g guide lines a re not ava ilable for th e use of gabapentin in bipol a rd isord ers. Mainten an ce doses for se izure con trol ra nge fro m 900-2400 mg/d (2,6,19,26)and pr eli mi nary t rial s of ga bapen tin for mood stabilization seem to suggest a similardos e range. The drug's re la t ively sho rt hal f-life necessitat es T ID ad minist ra t ion.Gabapentin treatment for refractory seizures is gen erally init iat ed with 300 mg onceon the first day, 300 mg twice on the second day and 300 mg three times on th e thirdday, with subse que nt incr eases in TID dose as req uired for symptom control (2,19).

O f some clinical significa nce is the fact th at all stu di es to da te exa miningga ba pe nt in in th e t reatment of bip ola r illness have inclu ded patients who respondedto a dose less t han 900 mg/d (13-18). In on e study of 28 patient s, th e meangabapentin dos e was 539 mg/d ( 15). Hence, increasing dos es by 200 mg inst ead of300mg may be more appropria te for mood stabi lization.

DISCUSSION

All of th e medi cations presently used to treat bipolar d isor der have significa ntside effects which impact both qu ality of life and th erapeutic complia nce. Unfortu-

28 J EFFERSON JOURNAL OF PSYCHIATRY

nately, in this patient population , dissatisfaction wit h trea tment regimen s has th epot ential to significa n t ly wor sen th e patient 's clin ica l course by magnifying feelings ofhopelessn ess in a depressed pa t ie nt. Gab apentin holds promise as an adj unc t ive for mof treatment whi ch has few inherent disadvantages and littl e cha nce of interactingwith ot he r drugs. It s favo ra ble ph armacok inetics profi le is unique a mong moodstabilize rs . The drug has relat ively few side effects, most of which are beni gn innatu re. It s possibl e a nt ide pressant effec ts a nd hypoma nic sid e effe cts need fu rtherstudy. It has thus fa r demonstrated low toxicit y a t the ra pe utic dos es and in overdo se.Gabape nt in has displ ayed clinical efficacy in up to 80% of bipolar patien ts inpreliminary clinical t rial s, a nd is presently undergoin g invest igation as a possibl eagent in th e treatment of migr aine headach es, chronic pain, a nd behavioral di sor ­ders. Few reports of ga bape nt in's use in human pr egn ancy exist , and animal studiesha ve been somewhat dis couragin g.

Current psychi at ric use of ga ba pe nt in is restrict ed to pa tien ts who have fai led torespond to traditional agents or developed intolerabl e side effects from them. Theupper limit of th e drug' s th erapeutic range mu st be established. Proble ms withmedi cation com plia nce may be improved through th e development of an exte nde d­re lease or dep ot form of ga ba pe nt in. A large, multi center, randomized, controlledclinica l trial has ye t to be performed.

CONCLUSIONS

Gab apen tin is a GABA a na logue a nd new AED whi ch has th e unique ability tocross the blood-brain ba r rier. It appears to influence neuropsychologica l ac tivity byac t ing on calcium channels in th e CNS. It has a favorabl e ph armacok inetics profilean d is proving to be re la t ively sa fe in clinica l pract ice. The drug has displayed bothmood-stabilizing a nd poss ible an ti-de pressant act ivity in pr eliminary tri al s, and isassociated with a relatively beni gn side profile . Further study of thi s new AED isclearly need ed.

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