Sinergija selektivnih inhibitora preuzimanja serotonina i antagonista α2-adrenergičkih receptora u terapiji depresije
farmakološka osnova i klinički značaj
Sažetak
Selektivni inhibitori preuzimanja serotonina (SSRI) predstavljaju najčešće primenjivanu farmakoterapijsku strategiju u lečenju velikog depresivnog poremećaja. Ipak, značajan broj pacijenata ne postiže remisiju, razvija parcijalni odgovor ili ostaje sa rezidualnim simptomima od kojih su najčešći nesanica, anksioznost, gubitak apetita, seksualna disfunkcija i gastrointestinalne tegobe. Kombinovanje SSRI antidepresiva sa antagonistima α2-adrenergičkih receptora, među kojima je mirtazapin najvažniji klinički predstavnik, predstavlja farmakološki racionalan pristup jer istovremeno pojačava serotonergičku transmisiju kroz komplementarne mehanizme i dodaje noradrenergičku komponentu antidepresivnog dejstva. Dok SSRI povećavaju sinaptičku dostupnost serotonina inhibicijom serotonin transportera, mirtazapin povećava oslobađanje noradrenalina i serotonina blokadom presinaptičkih α2-autoreceptora i α2-heteroreceptora. Dodatno, antagonizam 5-HT2 i 5-HT3 receptora funkcionalno usmerava serotonergičku transmisiju ka 5-HT1A-posredovanim efektima i može doprineti boljoj podnošljivosti u odnosu na čistu serotonergičku potencijaciju. Klinički značaj ove kombinacije najviše dolazi do izražaja kod pacijenata sa parcijalnim odgovorom na SSRI, depresijom praćenom nesanicom, anksioznošću, gubitkom apetita ili neželjenim efektima SSRI terapije. Međutim, dok randomizovane studije i meta-analize uglavnom ukazuju na veću efikasnost kombinacija koje uključuju antagoniste α2-receptora, pojedine pragmatične studije, poput MIR trial-a, nisu pokazale klinički značajan benefit dodavanja mirtazapina postojećoj SSRI terapiji kod svih pacijenata sa SSRI rezistentnom depresijom. Zbog toga, kombinaciju SSRI i mirtazapina treba posmatrati kao personalizovanu, simptomatski i farmakološki utemeljenu strategiju, a ne kao univerzalno superioran terapijski pristup.
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