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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