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Kombinacije antipsihotika

  Prof. dr. sc. Marina Šagud, dr. med., specijalist psihijatar
  prof. dr. sc. Alma Mihaljević Peleš, dr.med, specijalist psihijatar

  22.08.2011.

Začuđuje nesrazmjer između malog broja studija kombinacije dva antipsihotika (uglavnom otvorenih, na malom broju bolesnika) i vrlo čestog propisivanja ovakvih kombinacija u kliničkoj praksi. Kombinirana terapija stabilizatora raspoloženja i antipsihotika nove generacije vrlo se često primjenjuje u kliničkoj praksi. Prednost je kraće vrijeme do postizanja poboljšanja, veći postotak poboljšanja, ali i mogućost primjene nižih doza nego svakog lijeka zasebno.

Kombinacije antipsihotika
U svakodnevnoj praksi često se primjenjuje kombinacija dva antipsihotika.

U idealnom slučaku, terapija shizofrenije je monoterapija antipsihotikom. Sukladno, npr. algoritmu skupine Texas, takva je kombinacija indicirana nakon dovoljno duge terapije s najprije jednim antipsihotikom II generacije, te zatim drugim antipsihotikom, ili I ili II generacije, te potom monoterapije klozapinom. U tom se slučaju indicirana kombinirana terapija klozapina s jednim od antipsihotika I ili II generacije (Argo i sur, 2008). Medicina zasnovana na dokazima temelji se u stvari na randomiziranim kliničkim studijama (Correll, 2010), koje uključuju pažljivo odabrane bolesnike, uz primjenu lijeka u strogo kontroliranim uvjetima, te se njihovi rezultati ne mogu u potpunosti generalizirati na cjelokupnu populaciju koju vidimo svakodnevno. Međutim, u svakodnevnoj praksi često se primjenjuje kombinacija dva antipsihotika. Prema norveškoj studiji, 35.6% shizofrenih bolesnika dobivalo je kombinaciju antipsihotika (Kroken i sur, 2009), a prema španjolskoj čak 55.5% (Lerma-Carrillo i sur, 2008). U kliničkoj praksi najčešće su kombinacije klozapina ili olanzapina, koji su relativno slabiji blokatori D2 receptora, a imaju učinak na brojne druge receptorske sustave, s antipsihoticima koji su snažni ali i selektivni D2 blokatori (Goodwin i sur, 2009), poput sulpirida ili amisulprida (Zink i sur, 2010), ali i haloperidola i flufenazina. Jedna studija je mjerila okupiranost D2 receptora u strijatumu u osoba liječenih kombinacijom klozapina u dozi od 225 do 500 mg/dan, i haloperidola u dozi od 4 mg/dan (Kapur i sur, 2001). Nakon dodavanja haloperidola, okupiranost D2 receptora je porasla sa 55% na 79% (Kapur i sur, 2001). Začuđuje nesrazmjer između malog broja studija kombinacije dva antipsihotika (uglavnom otvorenih, na malom broju bolesnika) i vrlo čestog propisivanja ovakvih kombinacija u kliničkoj praksi. Opisano je da u kliničkoj praksi, čak oko 60% bolesnika koji dobivaju klozapin dobiva istodobno još jedan antipsihotik (za pregled molim vidjeti Honer i sur, 2009.

Dakle, unatoč raširenoj kliničkoj praksi, istraživanja o kombinaciji antipsihotika je malo (Goodwin i sur, 2009). Pokušaj analize učinkovitosti kombinacije klozapina s drugim antipsihoticima završio je bez zaključka, jer su studije male i metodološki različite (Cipriani i sur, 2009).

Kombinirana terapija stabilizatora raspoloženja i antipsihotika nove generacije vrlo se često primjenjuje u kliničkoj praksi. Prednost je kraće vrijeme do postizanja poboljšanja, veći postotak poboljšanja, ali i mogućost primjene nižih doza nego svakog lijeka zasebno.

Koje kombinacije antipsihotika se ne preporučuju?

Ne preporučuju se kombinacije:

1) Karbamazepina s olanzapinom ili klozapinom (povećana vjerojatnost agranulocitoze), a dodatno karbamazepin nekoliko puta snizuje koncentracije ovih lijekova te strvara potrebu za puno višim dozama olanzapina, odnosno, klozapina.

2) Risperidona i paroksetina jer paroksetin može značajno povisiti koncentraciju risperidona.

3) Risperidona i karbamazepina jer karbamazepin putem indukcije CYP 3A4 snizuje za oko 50% koncentraciju i risperidona i njegovog glavnog metabilita 9-OH-risperidona.

4) Antipsihotika međusobno, zbog prije svega farmakodinamskih interakcija. Zajedničkim antagonističkim učinkom na D2 receptore može doći do teških ekstrapiramidnih nuspojava. Iznimka su kombinacije antipsihotika koji se slabije vežu na D2 receptor-klozapina, kvetipina i olanzapina, s antipsihoticima koji se čvrsto vežu za D2 receptor i pri tome ne djeluju na druge receptore (D2 selektivni antipsihotici): haloperidolom, flufenazinom, sulpiridom i amisulpridom.

Učinkovitost antipsihotika

Učinkovitost antipsihotika ne ovisi samo o njegovom mehanizmu djelovanja, odnosno, o farmakokinetskim osobinama. Ne postoji antipsihotik koji je „čarobna pilula" i koji će rješiti sve probleme bolesnika. Antipsihotici su neophodni u liječenju jer omogućuju kontrolu psihotičnih simptoma, čime „stvaraju podlogu" za daljnje poboljšanje simptoma. Međutim, liječenje shizofrenije predstavlja mnogo više od primjene antipsihotika. Liječenje psihoze ovisi o mnogo čimbenika, koji su prikazani u tablici.

*Oboljeli od shizofrenije imaju povećanu ekspresiju P glikoproteina u temporalnom korteksu, amigdalima i bazalnim ganglijima, što znači da lijekovi slabije prolaze u mozak. Isto teoretski može biti jedan od razloga za potrebu za višim dozama antipsihotika u kroničnih shizofrenih bolesnika, odnosno, za terapijsku rezistenciju (De Klerk i sur, 2010).

Zaključak

Idealan antipsihotik trebao bi smanjiti dopaminsku hiperaktivnost u mezolimbičkom sustavu, odnosno, strijatumu, kompenzirati dopaminsku hipokativnost u frontanom korteksu, a biti bez utjecaja na razinu dopamina u regijama mozga odgovornim za nastanak EPS i hiperprolaktinemije, ne uzrokovati porast apetita niti tjelesne težine, niti pretjeranu sedaciju. Idealan antipsihotik ne postoji.

Rješenje je, uz dobro poznavanje osobina antipsihotika, individualni pristup bolesniku. Iako neprekidno raste naša količina znanja o farmakogenetici, slikovnim metodama prikaza, te odnosu koncentracije antipsihotika i kliničkog učinka, ove metode za sada nisu dio kliničke rutine.

Međutim, poznavanje farmakodinamike i farmakokinetike svakog pojedinog antipsihotika koji imamo na raspolaganju, omogućuje nam odabir lijeka i doziranja prema osobinama bolesnika, vodećim simptomima psihotičnog poremećaja, kao i drugih obilježja koja utječu na liječenje.

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Izvor: Poslijediplomski tečaj I. kategorije: Antipsihotici u kliničkoj praksi
Voditeljice:
prof. dr. sc. Alma Mihaljević - Peleš
dr.sc. Marina Šagud

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