МЕСТО ИКСЕЛА В ЛЕЧЕНИИ ДЕПРЕССИИ1

ТЕРАПИЯ ПСИХИЧЕСКИХ ЗАБОЛЕВАНИЙ
ÓÄÊ 616.895.4–085615.214
ÌÅÑÒÎ ÈÊÑÅËÀ  ËÅ×ÅÍÈÈ ÄÅÏÐÅÑÑÈÈ 1
Ñ. Êàñïåð
Àâñòðèÿ
Íåñìîòðÿ íà âûñîêóþ ðàñïðîñòðàíåííîñòü äåïðåññèè, ñòàòèñòè÷åñêèå äàííûå ïîêàçûâàþò, ÷òî îò
30% äî 65% âñåõ áîëüíûõ íå îáðàùàþòñÿ çà ìåäèöèíñêîé ïîìîùüþ, è åùå ìåíüøå (18% â Åâðîïåéñêîì èññëåäîâàíèè DEPRES) èç îáðàòèâøèõñÿ ê
ïñèõèàòðó ïîëó÷àþò òåðàïèþ àíòèäåïðåññàíòàìè
(18). ßâëÿåòñÿ ëè íåäîñòàòî÷íûé óðîâåíü íàçíà÷åíèÿ àíòèäåïðåññàíòîâ ñëåäñòâèåì íåäîñòàòêà
ñðåäñòâ, ïîçâîëÿþùèõ àäåêâàòíî ëå÷èòü äåïðåññèþ, èëè åñòü èíûå ôàêòîðû, âëèÿþùèå íà ðåøåíèå âðà÷à?  íàñòîÿùåé ðàáîòå ðàññìîòðåíà ðîëü
àíòèäåïðåññàíòîâ, â îñîáåííîñòè – íîâîãî àíòèäåïðåññàíòà èêñåëà, â ëå÷åíèè áîëüøîé äåïðåññèè.
Ñ÷èòàåòñÿ, ÷òî ïàòîãåíåç äåïðåññèè âêëþ÷àåò
ôóíêöèîíàëüíûé äåôèöèò íîðàäðåíåðãè÷åñêîé è/
èëè öåíòðàëüíîé ñåðîòîíèíåðãè÷åñêîé íåéðîòðàíñìèññèè (32). Òàêàÿ áèîõèìè÷åñêàÿ ãåòåðîãåííîñòü ïîçâîëÿåò ïðåäïîëîæèòü, ÷òî ìàêñèìàëüíàÿ
àíòèäåïðåññèâíàÿ àêòèâíîñòü ìîæåò áûòü îáíàðóæåíà ó ñðåäñòâ, âëèÿþùèõ íà îáå ñèñòåìû – íîðàäðåíåðãè÷åñêóþ è ñåðîòîíèíåðãè÷åñêóþ.  íàñòîÿùåå âðåìÿ â àðñåíàëå ñðåäñòâ äëÿ ëå÷åíèÿ äåïðåññèè ïðèñóòñòâóþò äâà îñíîâíûõ êëàññà ëåêàðñòâ:
òðèöèêëè÷åñêèå àíòèäåïðåññàíòû (ÒÖÀ) è ñåëåêòèâíûå èíãèáèòîðû îáðàòíîãî çàõâàòà ñåðîòîíèíà
(ÑÈÎÇÑ). Õîòÿ ìåòà-àíàëèç, îõâàòûâàþùèé 55
äâîéíûõ ñëåïûõ èññëåäîâàíèé, ïîêàçàë, ÷òî îáà
êëàññà ëåêàðñòâåííûõ ñðåäñòâ îäèíàêîâî ýôôåêòèâíû â òåðàïèè äåïðåññèâíûõ ðàññòðîéñòâ ó àìáóëàòîðíûõ áîëüíûõ, áûëî îáíàðóæåíî, ÷òî ÒÖÀ ñóùåñòâåííî ýôôåêòèâíåå ïðè ëå÷åíèè ïàöèåíòîâ, ãîñïèòàëèçèðîâàííûõ â ñâÿçè ñ äåïðåññèåé, èëè â
ñëó÷àÿõ òÿæåëîé äåïðåññèè (1). Äðóãèå èññëåäîâàíèÿ òàêæå ïðîäåìîíñòðèðîâàëè, ÷òî ÑÈÎÇÑ óñòóïàþò ÒÖÀ â ýôôåêòèâíîñòè ó ïàöèåíòîâ ñ òÿæåëîé
äåïðåññèåé (7, 8, 11, 13, 21).
Ýôôåêòèâíîñòü ÒÖÀ îáóñëîâëåíà èíãèáèðîâàíèåì îáðàòíîãî çàõâàòà ñåðîòîíèíà è íîðàäðåíàëèíà
(26). Êðîìå òîãî, ÒÖÀ âçàèìîäåéñòâóåò ñ ðàçëè÷íûìè ïîñòñèíàïòè÷åñêèìè ðåöåïòîðàìè, â òîì ÷èñëå ñ àäðåíåðãè÷åñêèìè, ìóñêàðèíîâûìè è ãèñòàìèí-
åðãè÷åñêèìè. Íåñïåöèôè÷åñêîå ñâÿçûâàíèå ÒÖÀ ñ
ýòèìè ðåöåïòîðàìè ñòàíîâèòñÿ ïðè÷èíîé ðàçíîîáðàçíûõ ïîáî÷íûõ ýôôåêòîâ, âêëþ÷àÿ ñóõîñòü âî
ðòó, çàïîð, òðåìîð, ïîòëèâîñòü, ñåäàöèþ, ñîíëèâîñòü, à òàêæå íàðóøåíèÿ çðåíèÿ è ñëóõà (29). Êðîìå òîãî, ïðèìåíåíèå ÒÖÀ ìîæåò âûçûâàòü ïîáî÷íûå ýôôåêòû ñî ñòîðîíû ñåðäå÷íî-ñîñóäèñòîé ñèñòåìû (ïîñòóðàëüíàÿ ãèïîòåíçèÿ, òàõèêàðäèÿ), à
ïðè âûñîêîé äîçå ÒÖÀ – èçìåíåíèÿ ÝÊÃ (óäëèíåíèå èíòåðâàëà ÐQ, êîìïëåêñà QRS è èíòåðâàëà QT)
(24). Â ñâÿçè ñ ýòèì ÒÖÀ ìîãóò áûòü ñìåðòåëüíî
îïàñíû ïðè íàìåðåííîé èëè ñëó÷àéíîé ïåðåäîçèðîâêå.
Äðóãîé êëàññ àíòèäåïðåññàíòîâ – ÑÈÎÇÑ – áûë
ðàçðàáîòàí äëÿ òîãî, ÷òîáû âîçäåéñòâîâàòü íà ñåðîòîíèíåðãè÷åñêóþ ñèñòåìó áîëåå ïðèöåëüíî, ÷åì
ýòî äåëàþò ÒÖÀ. Ïðåäïîëàãàëîñü, ÷òî ÑÈÎÇÑ áóäóò ýôôåêòèâíûìè àíòèäåïðåññàíòàìè, îáëàäàþùèìè ëó÷øèì, ÷åì ÒÖÀ, ïðîôèëåì ïåðåíîñèìîñòè.  çíà÷èòåëüíîé ìåðå ýòà öåëü áûëà äîñòèãíóòà: ÑÈÎÇÑ øèðîêî èñïîëüçóþòñÿ äëÿ ëå÷åíèÿ
ïàöèåíòîâ ñ äåïðåññèåé, îñîáåííî ïðè íåòÿæåëûõ
ôîðìàõ çàáîëåâàíèÿ, è èìåþò õîðîøóþ ïåðåíîñèìîñòü (1, 7, 8, 11, 13, 21).
Íåñìîòðÿ íà íàëè÷èå â àðñåíàëå ïñèõèàòðîâ
ÒÖÀ è ÑÈÎÇÑ, ïî-ïðåæíåìó îùóùàåòñÿ ïîòðåáíîñòü â àíòèäåïðåññàíòå, êîòîðûé ñî÷åòàë áû âûñîêóþ ýôôåêòèâíîñòü ïðè òÿæåëûõ äåïðåññèÿõ ñ
õîðîøåé ïåðåíîñèìîñòüþ. Ýòî îñîáåííî âàæíî,
ó÷èòûâàÿ ïîëîæèòåëüíîå âëèÿíèå õîðîøåé ïåðåíîñèìîñòè íà ïðèâåðæåííîñòü ïàöèåíòà ëå÷åíèþ, è,
ñëåäîâàòåëüíî, íà óñïåõ ëå÷åíèÿ (21,31). Ìèëíàöèïðàí (èêñåë, Ïüåð Ôàáð Ìåäèêàìåíò, Ôðàíöèÿ)
– ýòî íîâûé àíòèäåïðåññàíò, ñîîòâåòñòâóþùèé
ýòèì òðåáîâàíèÿì: åãî ýôôåêòèâíîñòü áûëà ïîäòâåðæäåíà â ðÿäå ïëàöåáî-êîíòðîëèðóåìûõ è ñðàâíèòåëüíûõ èññëåäîâàíèé ó ïàöèåíòîâ ñ âûðàæåííîé è óìåðåííîé äåïðåññèåé, ïðè ýòîì èêñåë îáëàäàåò õîðîøåé ïåðåíîñèìîñòüþ (16, 17, 19, 20, 30).
Èêñåë ñåëåêòèâíî èíãèáèðóåò îáðàòíûé çàõâàò
ñåðîòîíèíà è íîðàäðåíàëèíà (ÑÈÎÇÑÍ), íå âëèÿÿ
íà ïîñòñèíàïòè÷åñêèå õîëèíåðãè÷åñêèå, àäðåíåðãè÷åñêèå, Í1-ãèñòàìèíåðãè÷åñêèå, Ý9-äîïàìèíåðãè÷åñêèå èëè ñåðîòîíèíåðãè÷åñêèå ðåöåïòîðû (5, 25).
Îòñóòñòâèå âçàèìîäåéñòâèÿ ñ ïîñòñèíàïòè÷åñêèìè
ðåöåïòîðàìè îáåñïå÷èâàåò áëàãîïðèÿòíûé ïðîôèëü
1 Ðàñøèðåííûé ðåôåðàò ñòàòüè, îïóáëèêîâàííîé â Hum.
Psychopharmacol. Clin. Exp. – 1997. – N 12. – S. 135–I41, ïðåäñòàâëåí êîìïàíèåé Janssen-Silag.
45
ïåðåíîñèìîñòè èêñåëà.  ÷àñòíîñòè, èêñåë, â îòëè÷èå îò ÒÖÀ, ïî÷òè íå âëèÿåò íà ñåðäå÷íî-ñîñóäèñòóþ ñèñòåìó (23). Òàêèì îáðàçîì, íàìåðåííàÿ èëè
ñëó÷àéíàÿ ïåðåäîçèðîâêà ìèëíàöèïðàíà íå ñîïðÿæåíà ñ ôàòàëüíûì ðèñêîì.  íàñòîÿùåå âðåìÿ èçâåñòíî î 15 ïàöèåíòàõ, íàìåðåííî ïðèíÿâøèõ äî 4 ã
èêñåëà; âî âñåõ ñëó÷àÿõ èñõîä áûë áëàãîïðèÿòíûì,
íè îäèí èç ïàöèåíòîâ íå óìåð.
Äàííûå ïëàöåáî-êîíòðîëèðóåìûõ è ñðàâíèòåëüíûõ èññëåäîâàíèé ñ ÒÖÀ è ÑÈÎÇÑ ñâèäåòåëüñòâóþò, ÷òî èêñåë ÿâëÿåòñÿ ýôôåêòèâíûì àíòèäåïðåññàíòîì, îñîáåííî ïðè ëå÷åíèè ïàöèåíòîâ ñ òÿæåëîé
äåïðåññèåé (16, 17, 19, 20, 30). Â ýòîé ðàáîòå ðàññìàòðèâàåòñÿ ìåñòî èêñåëà â ñîâðåìåííîì àðñåíàëå àíòèäåïðåññàíòîâ.
Ìåòà-àíàëèç èññëåäîâàíèé èêñåëà ñ èìèïðàìèíîì
ñðàâíèâàë ñðåäíåâçâåøåííûå âåëè÷èíû îöåíêè ïî
øêàëàì ÌADRS è HDRS âñåõ ðàíäîìèçèðîâàííûõ
ïàöèåíòîâ (intent-to-treat) ñ ïåðåíîñîì äàííûõ ïîñëåäíåé òî÷êè íàáëþäåíèÿ íà êîíå÷íóþ òî÷êó èññëåäîâàíèÿ. Äàííûå ìåòà-àíàëèçà ñâèäåòåëüñòâóþò,
÷òî èêñåë è èìèïðàìèí îäèíàêîâî ýôôåêòèâíû â
ëå÷åíèè áîëüøîé äåïðåññèè ó ãîñïèòàëèçèðîâàííûõ ïàöèåíòîâ (27).
Îáçîð äâóõ ìíîãîöåíòðîâûõ äâîéíûõ ñëåïûõ
ðàíäîìèçèðîâàííûõ ñðàâíèòåëüíûõ èññëåäîâàíèé
èêñåëà (50 ìã äâà ðàçà â äåíü) ñ ôëóîêñåòèíîì (20
ìã â äåíü) è ôëóâîêñàìèíîì (100 ìã äâà ðàçà â
äåíü), îõâàòèâøèõ 306 ïàöèåíòîâ ñ áîëüøèìè äåïðåññèâíûìè ýïèçîäàìè, áûë îñóùåñòâëåí J.LopezIbor è ñîàâò. (19). Ìåòà-àíàëèç ïîêàçàë ñóùåñòâåííîå ïðåâîñõîäñòâî èêñåëà íàä ÑÈÎÇÑ êàê ïî èçìåíåíèþ ïîêàçàòåëåé ÌADRS (4,17 áàëëà) è ÍDRS
(2,61 áàëëà), òàê è ïî ÷àñòîòå íàñòóïëåíèÿ ýôôåêòà ïî îáåèì øêàëàì (19). Òàêèå ðàçëè÷èÿ ñ÷èòàþòñÿ êëèíè÷åñêè è ñòàòèñòè÷åñêè çíà÷èìûìè (12).
Êëèíè÷åñêèå èññëåäîâàíèÿ èêñåëà
Áûëî ïðîâåäåíî òðè ìíîãîöåíòðîâûõ ïëàöåáîêîíòðîëèðóåìûõ èññëåäîâàíèÿ ýôôåêòèâíîñòè èêñåëà â òåðàïèè áîëüøèõ äåïðåññèâíûõ ýïèçîäîâ (17,
20). Áûë ïðîâåäåí ìåòà-àíàëèç ðåçóëüòàòîâ ýòèõ èññëåäîâàíèé â ïîäãðóïïå ïàöèåíòîâ, ïîëó÷àâøèõ
èêñåë â äîçå 50 ìã äâà ðàçà â äåíü (27). Âñå òðè èññëåäîâàíèÿ èìåëè ñõîäíûé äèçàéí è ìåòîäîëîãèþ;
ñîâîêóïíàÿ ãðóïïà ïîëó÷àâøèõ èêñåë (50 ìã) ñîñòàâèëà 227 ïàöèåíòîâ, ïëàöåáî – 211. Êðîìå òîãî, áûë
ïðîâåäåí îòäåëüíûé àíàëèç ðåçóëüòàòîâ ïðèìåíåíèÿ
èêñåëà ó ãîñïèòàëèçèðîâàííûõ ïàöèåíòîâ ñ òÿæåëîé
äåïðåññèåé (97 áîëüíûõ) ïî ñðàâíåíèþ ñ ïëàöåáî
(78 áîëüíûõ).
Ýôôåêòèâíîñòü èêñåëà îöåíèâàëàñü ïî øêàëå
îöåíêè äåïðåññèè Ìîntgomery-Asberg (ÌÀDRS),
øêàëå îöåíêè äåïðåññèè Hamilton (HDRS) è øêàëå
Îáùåãî Êëèíè÷åñêîãî Âïå÷àòëåíèÿ (CGI) (15, 24,
23). Àíàëèç ïðîâîäèëñÿ ïî äàííûì âñåõ âêëþ÷åííûõ â èññëåäîâàíèÿ ïàöèåíòîâ (intent-to-treat) ñ ïåðåíîñîì äàííûõ ïîñëåäíåé òî÷êè íàáëþäåíèÿ íà
êîíå÷íóþ òî÷êó èññëåäîâàíèÿ.
Èêñåë (50 ìã äâà ðàçà â äåíü) áûë ñóùåñòâåííî
áîëåå ýôôåêòèâíûì, ÷åì ïëàöåáî, ó âñåõ ïàöèåíòîâ
ñ áîëüøîé äåïðåññèåé.  êîíå÷íîé òî÷êå èññëåäîâàíèÿ ñðåäíåå ðàçëè÷èå ìåæäó ãðóïïàìè ïîëó÷àâøèõ èêñåë è ïëàöåáî ñîñòàâèëî 2,34 áàëëà ïî øêàëå ÍDRS è 3,65 áàëëà ïî øêàëå ÌADRS. Åâðîïåéñêèé Êîëëåäæ Íåéðîïñèõîôàðìàêîëîãèè (12)
îïðåäåëèë òàêîé ïîðÿäîê ðàçëè÷èé êàê ñóùåñòâåííûé è óñòàíîâèë, ÷òî ïîäîáíûå ðàçëè÷èÿ õàðàêòåðèçóþò êëèíè÷åñêóþ çíà÷èìîñòü ýôôåêòèâíîñòè
ëåêàðñòâà ïî ñðàâíåíèþ ñ ïëàöåáî. Ìèëíàöèïðàí
îêàçàëñÿ òàêæå ýôôåêòèâíåå ïëàöåáî ó ãîñïèòàëèçèðîâàííûõ ïàöèåíòîâ ñ áîëüøîé äåïðåññèåé.
Ýôôåêòèâíîñòü èêñåëà 50 ìã äâà ðàçà â äåíü ïðè
ëå÷åíèè òÿæåëîé äåïðåññèè áûëà òàêæå èçó÷åíà â
ñðàâíåíèè ñ èìèïðàìèíîì â øåñòè äâîéíûõ ñëåïûõ
ñðàâíèòåëüíûõ èññëåäîâàíèÿõ (75 ìã äâà ðàçà â äåíü
â ïÿòè ðàáîòàõ, è 50 ìã äâà ðàçà â äåíü ó ïîæèëûõ
– â îäíîé). Åùå â îäíîì èññëåäîâàíèè ïðîâåäåíî
ñðàâíåíèå ýôôåêòèâíîñòè èêñåëà 50 ìã äâà ðàçà â
äåíü ñ êëîìèïðàìèíîì 75 ìã äâà ðàçà â äåíü ó ïàöèåíòîâ ñ áîëüøèìè äåïðåññèâíûìè ýïèçîäàìè.
Ïðîôèëü ïåðåíîñèìîñòè àíòèäåïðåññàíòîâ
Ïðè ëå÷åíèè ïàöèåíòîâ ñ áîëüøèìè äåïðåññèâíûìè ýïèçîäàìè, îñîáåííî ïðè òÿæåëîé äåïðåññèè,
ýôôåêòèâíàÿ òåðàïèÿ âîçìîæíà òîëüêî ïðè óñëîâèè, åñëè îíà ïðèåìëåìà äëÿ ïàöèåíòà (21, 31).
Îäíèì èç âàæíûõ ôàêòîðîâ, îïðåäåëÿþùèõ ïðèâåðæåííîñòü ïàöèåíòà ëå÷åíèþ, ÿâëÿåòñÿ ìèíèìàëüíîå êîëè÷åñòâî ïîáî÷íûõ ýôôåêòîâ ëåêàðñòâåííîãî ñðåäñòâà. Íåñìîòðÿ íà òî, ÷òî ÒÖÀ î÷åíü
ýôôåêòèâíû â ëå÷åíèè òÿæåëîé äåïðåññèè, èõ ïðèìåíåíèå ÷àñòî ñîïðîâîæäàåòñÿ ðàçâèòèåì ïîáî÷íûõ ýôôåêòîâ, êîòîðûå ìîãóò ïðèâîäèòü ê óìåíüøåíèþ äîçû èëè ïðåêðàùåíèþ ëå÷åíèÿ.  ñðàâíèòåëüíûõ èññëåäîâàíèÿõ èêñåëà ñ ÒÖÀ ÷àñòîòà
ïðåêðàùåíèÿ ëå÷åíèÿ â ñâÿçè ñ ïîáî÷íûìè ýôôåêòàìè â ãðóïïå, ïîëó÷àâøèõ ìèëíàöèïðàí (7,6%),
áûëà ïî÷òè â äâà ðàçà íèæå, ÷åì â ãðóïïå ÒÖÀ
(14,8%) (16). Òàêèì îáðàçîì, èêñåë ñóùåñòâåííî
ëó÷øå ïåðåíîñèòñÿ, ÷åì èìèïðàìèí.
Ïðè ñîïîñòàâëåíèè ÷àñòîòû è âûðàæåííîñòè ïîáî÷íûõ ýôôåêòîâ, âûçâàííûõ èêñåëîì, ñ ïîáî÷íûìè ýôôåêòàìè äðóãèõ àíòèäåïðåññàíòîâ ïî äàííûì
ñðàâíèòåëüíûõ èññëåäîâàíèé (òàáë. 1), âèäíî, ÷òî
ïðîôèëü ïåðåíîñèìîñòè ìèëíàöèïðàíà ñóùåñòâåííî áëàãîïðèÿòíåå, ÷åì ó ÒÖÀ. Åäèíñòâåííûì ïîáî÷íûì ýôôåêòîì, ÷àùå âñòðå÷àâøèìñÿ ïðè ïðèìåíåíèè èêñåëà, áûëà äèçóðèÿ (2,1% ïðîòèâ 0,6% ïðè
ëå÷åíèè ÒÖÀ è 0,3% ïðè ëå÷åíèè ÑÈÎÇÑ). Ïî âñåé
âèäèìîñòè, ýòî ÿâëåíèå îáóñëîâëåíî íîðàäðåíåðãè÷åñêèì âëèÿíèåì èêñåëà, ïðè òîì, ÷òî ìèëíàöèïðàí
íå îáëàäàåò èíãèáèðóþùèì äåéñòâèåì íà àëüôà-1àäðåíîðåöåïòîðû. Òàêèì îáðàçîì, ïàöèåíòû ñ ðèñêîì äèçóðè÷åñêèõ ðàññòðîéñòâ (ìóæ÷èíû ñ çàáîëåâàíèÿìè ïðîñòàòû) äîëæíû íàõîäèòüñÿ ïîä íàáëþäåíèåì âî âðåìÿ ïðèìåíåíèÿ èêñåëà. Ó ïàöèåíòîâ ñ
äèçóðèåé ìèëíàöèïðàí ïðèìåíÿòü íå ñëåäóåò.
Èçâåñòíî, ÷òî ÒÖÀ ÷àñòî âûçûâàþò ïîñòóðàëüíóþ ãèïîòåíçèþ, à ïðè ïåðåäîçèðîâêå ìîãóò ñòàòü
46
ïðè÷èíîé ôàòàëüíûõ íàðóøåíèé ðèòìà ñåðäöà (16,
25). Èêñåë âûçûâàåò íåçíà÷èòåëüíîå óâåëè÷åíèå
÷àñòîòû ñåðäå÷íûõ ñîêðàùåíèé; èçìåíåíèÿ àðòåðèàëüíîãî äàâëåíèÿ ïðè èñïîëüçîâàíèè ìèëíàöèïðàíà íåñóùåñòâåííû. ×àñòîòà îðòîñòàòè÷åñêîé ãèïîòåíçèè (òî åñòü ñíèæåíèÿ ÀÄ áîëåå ÷åì íà 20 ìì
ðò. ñò) ïðè ïðèìåíåíèè èêñåëà áûëà ãîðàçäî ìåíüøå, ÷åì ïðè èñïîëüçîâàíèè ÒÖÀ. Ñóùåñòâóåò òàêæå ðàçëè÷èå ìåæäó âëèÿíèåì ÒÖÀ è ìèëíàöèïðàíà
íà ýëåêòðîôèçèîëîãè÷åñêóþ äåÿòåëüíîñòü ñåðäöà.
Ïðè àíàëèçå 2 182 ÝÊà 939 ïàöèåíòîâ, ïîëó÷àâøèõ
èêñåë, ÒÖÀ, ÑÈÎÇÑ è ïëàöåáî, áûëî îáíàðóæåíî,
÷òî ìèëíàöèïðàí íå èçìåíÿë èíòåðâàë ÐQ, êîìïëåêñ
QRS è êîððèãèðîâàííûé èíòåðâàë ÐÒ, â òî âðåìÿ êàê
ÒÖÀ óâåëè÷èâàëè âñå òðè ïîêàçàòåëÿ.
Ïðîôèëè ïåðåíîñèìîñòè èêñåëà è ÑÈÎÇÑ êîëè÷åñòâåííî áëèçêè (òàáë. 1). Ïðè ïðèìåíåíèè ìèëíàöèïðàíà ðåæå, ÷åì ïðè èñïîëüçîâàíèè ÑÈÎÇÑ,
âñòðå÷àëèñü æåëóäî÷íî-êèøå÷íûå ðàññòðîéñòâà è
òðåâîãà.  ãðóïïå, ïîëó÷àâøèõ ÑÈÎÇÑ, ÷àùå âûÿâëÿëèñü òîøíîòà, ïîíîñ è ãèïîòåíçèÿ (20,1%, 3,5%
è 2,3% ñîîòâåòñòâåííî), ÷åì ïðè ïðèìåíåíèè èêñåëà (11,2%, 1,6% è 1,0% ñîîòâåòñòâåííî). Ñ äðóãîé ñòîðîíû, ìèëíàöèïðàí ÷àùå âûçûâàë ãîëîâíóþ
áîëü, ñóõîñòü âî ðòó è äèçóðèþ (8,4%, 7,9% è 2,1%
ñîîòâåòñòâåííî), ÷åì ÑÈÎÇÑ (4,1%, 3,8% è 0,3%
ñîîòâåòñòâåííî).
 òàáë. 2 ïðåäñòàâëåíà ÷àñòîòà ñåðüåçíûõ ïîáî÷íûõ ýôôåêòîâ, ñâÿçàííûõ ñ íåýôôåêòèâíîñòüþ ëå-
÷åíèÿ (ñóèöèäîâ èëè ñóèöèäàëüíûõ ïîïûòîê) ïðè
ïðèìåíåíèè èêñåëà, ÒÖÀ è ÑÈÎÇÑ. ×èñëî òàêèõ
ñîáûòèé íà 100 ïàöèåíòîâ â òå÷åíèå ãîäà ïðè ëå÷åíèè èêñåëîì ñîñòàâèëî 6,46, ÒÖÀ – 8,99. Ïðè
ïðèìåíåíèè ÑÈÎÇÑ ýòîò ïîêàçàòåëü îêàçàëñÿ ñóùåñòâåííî âûøå, äîñòèãíóâ 22,9. Òåì íå ìåíåå, èíòåðïðåòàöèÿ ýòèõ äàííûõ òðåáóåò èçâåñòíîé îñòîðîæíîñòè â ñâÿçè ñ íåáîëüøèì ÷èñëîì ïàöèåíòîâ.
Òàêèì îáðàçîì, ïðîôèëü ïåðåíîñèìîñòè èêñåëà
âûãîäíî îòëè÷àåòñÿ îò ÒÖÀ è áëèçîê ê òàêîâîìó
ÑÈÎÇÑ. Ïî âñåé âåðîÿòíîñòè, ýòî îáúÿñíÿåòñÿ ñåëåêòèâíîñòüþ ôàðìàêîëîãè÷åñêîãî äåéñòâèÿ ìèëíàöèïðàíà, â îñîáåííîñòè, îòñóòñòâèåì âëèÿíèÿ íà
ïîñòñèíàïòè÷åñêèå ðåöåïòîðû (5). ×àñòî âñòðå÷àþùèåñÿ ïðè ïðèìåíåíèè ÒÖÀ ñóõîñòü âî ðòó è çàïîð, ñâÿçàííûå ñ àíòèõîëèíåðãè÷åñêèì äåéñòâèåì
ÒÖÀ, ðåäêî îáíàðóæèâàþòñÿ ïðè èñïîëüçîâàíèè
èêñåëà, ïîñêîëüêó ìèëíàöèïðàí íå äåéñòâóåò íà
ìóñêàðèíåðãè÷åñêèå ðåöåïòîðû. Ïîñêîëüêó èêñåë
íå îáëàäàåò ñðîäñòâîì ê àëüôà-1-àäðåíîðåöåïòîðàì
è H1–ãèñòàìèíîâûì ðåöåïòîðàì, òåðàïèÿ ìèëíàöèïðàíîì ðåæå, ÷åì ÒÖÀ, ñîïðîâîæäàåòñÿ ïîÿâëåíèåì óñòàëîñòè.
Îáñóæäåíèå
Ïîçâîëÿåò ëè ñäåëàííûé îáçîð ïëàöåáî-êîíòðîëèðóåìûõ è ñðàâíèòåëüíûõ èññëåäîâàíèé îïðåäåëèòü ìåñòî èêñåëà â àðñåíàëå ñîâðåìåííûõ àíòèäåïðåññàíòîâ? Ìèëíàöèïðàí ÿâëÿåòñÿ ýôôåêòèâíûì àíòèäåïðåññàíòîì. Åãî ýôôåêòèâíîñòü áûëà
ïîêàçàíà ó àìáóëàòîðíûõ è ãîñïèòàëèçèðîâàííûõ
ïàöèåíòîâ ñ áîëüøèìè äåïðåññèâíûìè ýïèçîäàìè
óìåðåííîé è âûðàæåííîé ñòåïåíè òÿæåñòè (16, 17,
19, 20, 30). Ýôôåêòèâíîñòü èêñåëà íå óñòóïàåò òàêîâîé ÒÖÀ ó ãîñïèòàëèçèðîâàííûõ ïàöèåíòîâ ñ
òÿæåëîé äåïðåññèåé (16). Ñðàâíèòåëüíûå èññëåäîâàíèÿ ñ ÑÈÎÇÑ (ôëóîêñåòèíîì è ôëóâîêñàìèíîì)
ïîêàçàëè, ÷òî èêñåë ïðè ëå÷åíèè òÿæåëîé äåïðåññèè ïðåâîñõîäèò ÑÈÎÇÑ ïî ýôôåêòèâíîñòè (3, 19).
Òàêèì îáðàçîì, áûëî ïîäòâåðæäåíî ïðåäïîëîæåíèå
î òîì, ÷òî äëÿ ìàêñèìàëüíî ýôôåêòèâíîé òåðàïèè
äåïðåññèâíûõ íàðóøåíèé, îñîáåííî ïðè òÿæåëîé
äåïðåññèè, íåîáõîäèìî âîçäåéñòâèå íà îáå ñèñòåìû îáðàòíîãî çàõâàòà ìîíîàìèíîâ – ñåðîòîíèíà è
íîðàäðåíàëèíà.
Ïðîôèëü ïåðåíîñèìîñòè èêñåëà âûãîäíî îòëè÷àåòñÿ îò ïåðåíîñèìîñòè ÒÖÀ; ìîæíî ïðåäïîëîæèòü,
÷òî ìèëíàöèïðàí ìîæåò áûòü ñ óñïåõîì ïðèìåíåí
ó ïàöèåíòîâ, íå ïåðåíîñÿùèõ ÒÖÀ. Ýòî ìîæåò îêàçàòüñÿ îñîáåííî öåííûì, íàïðèìåð, ó ïîæèëûõ
áîëüíûõ, èëè ïðè ñîïóòñòâóþùèõ çàáîëåâàíèÿõ
ñåðäå÷íî-ñîñóäèñòîé ñèñòåìû. Ñíèæåíèå ÷àñòîòû è
Òàáëèöà 1
Сравнение побочных эффектов иксела
(50 мг два раза в день), ТЦА и СИОЗС
Èêñåë >ÒÖÀ
ÒÖÀ>Èêñåë
Äèçóðèÿ (2,1% vs. 0,6%)
Ñóõîñòü âî ðòó (37,3% vs.7,9%)
Çàïîð (14,9% vs.6,5%)
Òðåìîð (12,8% vs.2,5%)
Ïîòëèâîñòü (12,2% vs.4,3%)
Ñîíëèâîñòü (10,5% vs.2,3%)
Óñòàëîñòü (8,9% vs.2,5%)
Ãîëîâîêðóæåíèå (8,5% vs. 1,5%)
Íàðóøåíèÿ çðåíèÿ (5,9% vs.1,6%)
Íàðóøåíèÿ âêóñà (4,7% vs.1,3%)
Îáùåå íåäîìîãàíèå (4,1% vs.1,5%)
Ïîíîñ (3,4% vs.1,7%)
Èêñåë>ÑÈÎÇÑ
ÑÈÎÇÑ>Èêñåë
Ãîëîâíàÿ áîëü (8,4% vs. 4,1%) Òîøíîòà (20,1% vs.11,2%)
Ñóõîñòü âî ðòó (7,9% vs.3,9%) Ïîíîñ (3,5% vs. 1,6%)
Äèçóðèÿ (2,1% vs.0,3%)
Ãèïîòåíçèÿ (2,3% vs.1,0%)
Ïðèìå÷àíèå: > – ïîáî÷íûå ýôôåêòû âñòðå÷àþòñÿ â îäíîé
ãðóïïå â äâà è áîëåå ðàçà ÷àùå, ÷åì â äðóãîé.
Òàáëèöà 2
Частота серьезных побочных эффектов, связанных с неэффективностью лечения икселом, ТЦА и СИОЗС
Ïðåïàðàòû
×èñëî
ïàöèåíòîâ
Îáùàÿ ïðîäîëæèòåëüíîñòü
(ïàöèåíòî-ëåò)
Ñóèöèäîâ
Ñóèöèäàëüíûõ
ïîïûòîê
Ñîáûòèé íà 100
ïàöèåíòî-ëåò
Èêñåë
4006
975,27
14
49
6,46
ÒÖÀ
940
177,68
3
13
8,99
ÑÈÎÇÑ
344
47,9
1
10
22,9
47
âûðàæåííîñòè ïîáî÷íûõ ýôôåêòîâ ñïîñîáñòâóåò
ïðèåìëåìîñòè ëå÷åíèÿ äëÿ ïàöèåíòà (21, 31). Åùå
îäíèì âàæíûì ôàêòîðîì, îïðåäåëÿþùèì áåçîïàñíîñòü íàçíà÷åíèÿ àíòèäåïðåññàíòîâ, ÿâëÿåòñÿ ðèñê,
ñîïðÿæåííûé ñ èõ ïåðåäîçèðîâêîé.
Èêñåë òàê æå õîðîøî ïåðåíîñèòñÿ, êàê ÑÈÎÇÑ,
äåìîíñòðèðóÿ ïðè ýòîì áîëüøóþ ýôôåêòèâíîñòü,
îñîáåííî ó ïàöèåíòîâ ñ òÿæåëîé äåïðåññèåé. Ìèëíàöèïðàí ïðåäñòàâëÿåò ñîáîé ïîëåçíóþ àëüòåðíàòèâó
ÑÈÎÇÑ â ñëó÷àÿõ, êîãäà íåîáõîäèìà âûñîêàÿ ýôôåêòèâíîñòü â ñî÷åòàíèè ñ õîðîøåé ïåðåíîñèìîñòüþ.
Åñòü è èíûå ôàêòîðû, ïîìèìî ýôôåêòèâíîñòè è
ïåðåíîñèìîñòè, êîòîðûå âëèÿþò íà ïîçèöèîíèðîâàíèå àíòèäåïðåññàíòà â êëèíè÷åñêîé ïðàêòèêå. Òàê,
ïðîñòîé ðåæèì äîçèðîâàíèÿ áîëåå óäîáåí äëÿ ïàöèåíòà, ÷åì ñëîæíûå ñõåìû ïðèìåíåíèÿ, ïðåäúÿâëÿþùèå äîïîëíèòåëüíûå òðåáîâàíèÿ ê îðãàíèçàöèè
ëå÷åáíîãî ïðîöåññà (22, 31). Èêñåë ïðèíèìàþò äâà
ðàçà â äåíü, áåç êàêèõ-ëèáî îñîáûõ òðåáîâàíèé ê
äèåòå. ×àñòîòà ïðèåìà îïðåäåëÿåòñÿ âðåìåíåì ïîëóâûâåäåíèÿ ïðåïàðàòà: áûñòðîå ïîëóâûâåäåíèå
âûíóæäàåò ïðèíèìàòü ïðåïàðàò ÷àùå; â òî æå âðåìÿ ñðåäñòâà ñ áîëüøèì âðåìåíåì ïîëóâûâåäåíèÿ
õàðàêòåðèçóþòñÿ áîëüøèì èíòåðâàëîì ìåæäó ïðèåìàìè, ÷òî ñïîñîáñòâóåò ïðèåìëåìîñòè ëå÷åíèÿ äëÿ
ïàöèåíòà. Ñ äðóãîé ñòîðîíû, áîëüøîå âðåìÿ ïîëóâûâåäåíèÿ ìîæåò â îïðåäåëåííîé ñèòóàöèè îêàçàòüñÿ íåäîñòàòêîì ïðåïàðàòà, íàïðèìåð, êîãäà íåîáõîäèìî ïðåêðàòèòü ëå÷åíèå èç-çà ïîáî÷íîãî ýôôåêòà.
Âðåìÿ ïîëóâûâåäåíèÿ èêñåëà ñîñòàâëÿåò ïðèìåðíî
âîñåìü ÷àñîâ; ìèëíàöèïðàí íå îáðàçóåò àêòèâíûõ
ìåòàáîëèòîâ (28). Ïîýòîìó èêñåë ïðèíèìàþò äâà
ðàçà â äåíü. Ïðè íåîáõîäèìîñòè ëå÷åíèå ìèëíàöèïðàíîì ìîæåò áûòü áûñòðî ïðåêðàùåíî.  îòëè÷èå
îò èêñåëà, ôëóîêñåòèí èìååò ôàðìàêîëîãè÷åñêè
àêòèâíûé ìåòàáîëèò ñî âðåìåíåì ïîëóâûâåäåíèÿ
9–15 äíåé, à ðàâíîâåñíîå ñîñòîÿíèå ïðè äëèòåëüíîì ïðèåìå ôëóîêñåòèíà äîñòèãàåòñÿ íà 4–6-é íåäåëå. Òàêèì îáðàçîì, ïðè ïðèåìå ôëóîêñåòèíà ðèñê
ëåêàðñòâåííûõ âçàèìîäåéñòâèé ñîõðàíÿåòñÿ íà ïðîòÿæåíèè 5 íåäåëü ïîñëå ïðåêðàùåíèÿ ïðèåìà ôëóîêñåòèíà (4).
Ðàâíîâåñíîå ñîñòîÿíèå ïðè ïðèåìå ìèëíàöèïðàíà äîñòèãàåòñÿ â òå÷åíèå äâóõ äíåé, ïðè ýòîì ïðåïàðàò íå êóìóëèðóåòñÿ ïðè äëèòåëüíîì ïðèìåíåíèè
(24). Ïîñêîëüêó èêñåë èìååò ïðåäñêàçóåìóþ ôàðìàêîêèíåòèêó ñ íåáîëüøîé ìåæèíäèâèäóàëüíîé âàðèàáåëüíîñòüþ, íåò íåîáõîäèìîñòè èíäèâèäóàëüíî
òèòðîâàòü åãî äîçó. Òàêèì îáðàçîì, ìîæíî íà÷èíàòü
ëå÷åíèå ñ ïîëíîé äîçû. Åäèíñòâåííîå èñêëþ÷åíèå
ñîñòàâëÿþò ïàöèåíòû ñ ïî÷å÷íîé íåäîñòàòî÷íîñòüþ, ó êîòîðûõ íåîáõîäèìî ñíèæåíèå äîçû.  îòëè÷èå îò ÒÖÀ, êîòîðûå ÷àñòî ïðèìåíÿþò â ñóáîïòèìàëüíûõ äîçàõ, îñîáåííî â àìáóëàòîðíîì ðåæè-
ìå, áëàãîïðèÿòíûé ïðîôèëü ïåðåíîñèìîñòè ìèëíàöèïðàíà ïîçâîëÿåò èñïîëüçîâàòü åãî â îïòèìàëüíûõ
äîçàõ ó ïîäàâëÿþùåãî áîëüøèíñòâà ïàöèåíòîâ (21,
22, 24).
Ìíîãèå ïàöèåíòû ñ äåïðåññèåé, îñîáåííî ïîæèëûå èëè ñòðàäàþùèå õðîíè÷åñêèìè ñîïóòñòâóþùèìè çàáîëåâàíèÿìè, íàðÿäó ñ àíòèäåïðåññèâíîé òåðàïèåé ïðèíèìàþò èíûå ëåêàðñòâà.  ñâÿçè ñ ýòèì
ïðè íàçíà÷åíèè àíòèäåïðåññèâíîé òåðàïèè ñëåäóåò ó÷èòûâàòü âîçìîæíûå ëåêàðñòâåííûå âçàèìîäåéñòâèÿ. Íàïðèìåð, ìíîãèå ïðåïàðàòû, êàê ïñèõîòðîïíûå, òàê è ñðåäñòâà èíîãî íàçíà÷åíèÿ, ìåòàáîëèçèðóþòñÿ â ñèñòåìå öèòîõðîìà Ð 450. Ïîñêîëüêó
èêñåë íå âçàèìîäåéñòâóåò ñ ñèñòåìîé öèòîõðîìà
Ð 450, è ïîñêîëüêó ìèëíàöèïðàí ñëàáî è íåíàñûùàåìî ñâÿçûâàåòñÿ ñ áåëêàìè ïëàçìû, ðèñê ëåêàðñòâåííîãî âçàèìîäåéñòâèÿ ïðè èñïîëüçîâàíèè èêñåëà î÷åíü íåâåëèê (5). Èññëåäîâàíèÿ ëåêàðñòâåííîãî âçàèìîäåéñòâèÿ íå îáíàðóæèëè ïðèçíàêîâ
âçàèìîäåéñòâèÿ ìèëíàöèïðàíà ñ äðóãèìè ïñèõîòðîïíûìè ïðåïàðàòàìè, òàêèìè êàê ëèòèé, áåíçîäèàçåïèíû, ëåâîìåïðîìàçèí è êàðáàìàçåïèí, òàê
÷òî ïðè ñîâìåñòíîì ïðèìåíåíèè ñ ìèëíàöèïðàíîì
íåò íåîáõîäèìîñòè èçìåíÿòü èõ äîçó. Ñêîðîñòü íàñòóïëåíèÿ ýôôåêòà àíòèäåïðåññàíòà âëèÿåò íà åãî
ýôôåêòèâíîñòü. Áûëî ïîêàçàíî, ÷òî âðåìÿ íàñòóïëåíèÿ ýôôåêòà èêñåëà, èçìåðåííîå ñ ïîìîùüþ
øêàë ÌÀDRS è HDRS, íå îòëè÷àåòñÿ ñóùåñòâåííî îò âðåìåíè íàñòóïëåíèÿ ýôôåêòà äðóãèõ àíòèäåïðåññàíòîâ (19).
 íàñòîÿùåå âðåìÿ âñå áîëüøèé âåñ â îïðåäåëåíèè öåëåñîîáðàçíîñòè íàçíà÷åíèÿ òîãî èëè èíîãî
ëåêàðñòâà ïðèîáðåòàþò ôàðìàêîýêîíîìè÷åñêèå ñîîáðàæåíèÿ. Ïðè èñïîëüçîâàíèè íîâûõ ëåêàðñòâ,
ñòîèìîñòü êîòîðûõ, êàê ïðàâèëî, âûøå, ÷åì ñòîèìîñòü äàâíî óòâåðäèâøèõñÿ â ïðàêòèêå ñðåäñòâ,
ñëåäóåò ó÷èòûâàòü ïîêàçàòåëü öåíà-ýôôåêò. Äëÿ
ñðàâíåíèÿ èêñåëà ñ ÒÖÀ è ÑÈÎÇÑ ïî ïîêàçàòåëþ
öåíà-ýôôåêò äëÿ ëå÷åíèÿ îäíîãî îñòðîãî ýïèçîäà
òÿæåëîé äåïðåññèè áûëà ïðèìåíåíà ìåòîäèêà àíàëèçà äåðåâà ðåøåíèé â óñëîâèÿõ ôðàíöóçñêîé íàöèîíàëüíîé ñèñòåìû çäðàâîîõðàíåíèÿ (9). Ýòà ìîäåëü ïîêàçàëà, ÷òî, õîòÿ ñòîèìîñòü èêñåëà âûøå,
÷åì ÒÖÀ èëè ÑÈÎÇÑ, åãî âûñîêàÿ ýôôåêòèâíîñòü
è õîðîøàÿ ïåðåíîñèìîñòü, à òàêæå áîëüøàÿ âåðîÿòíîñòü èñïîëüçîâàíèÿ ïîëíîé òåðàïåâòè÷åñêîé
äîçû ïðè õîðîøåé ïðèâåðæåííîñòè ïàöèåíòà ëå÷åíèþ, äåëàþò èêñåë àäåêâàòíîé àëüòåðíàòèâîé ÒÖÀ
è ÑÈÎÇÑ â ëå÷åíèè òÿæåëîé äåïðåññèè, â òîì ÷èñëå ïî ïîêàçàòåëþ öåíà-ýôôåêò.
 çàêëþ÷åíèå, èêñåë îáëàäàåò íåñêîëüêèìè êà÷åñòâàìè, äåëàþùèìè åãî ñðåäñòâîì ïåðâîãî âûáîðà ïðè ëå÷åíèè áîëüøèíñòâà ïàöèåíòîâ ñ äåïðåññèåé, â òîì ÷èñëå ñ åå òÿæåëûìè ôîðìàìè.
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THE PLACE OF MILNACIPRAN IN THE TREATMENT OF DEPRESSION
S. Kasper
Minimising adverse events is important to enhance patient compliance
and facilitate the administration of therapeutic doses of antidepressants.
Data from placebo-controlled trials and the results of comparator studies
involving TCAs and SSRIs have confirmed that milnacipran is an
effective and well tolerated antidepressant, particularly useful in patients
with severe depression. A recent pharmacoeconomic study has confirmed
that milnacipran is a cost effective alternative to TCAs and SSRIs in the
treatment of severe depression.
Modern community-based studies have revealed high prevalence rates
for major depression in adults. Despite this high prevalence, many depressed
individuals do not seek treatment and only a minority of those that do are
prescribed antidepressants. This paper considers the role of antidepressants,
especially of milnacipran in the treatment of major depression.
Milnacipran inhibits the reuptake of serotonin and noradrenaline
(SNRI) in a selective manner without affecting various postsynaptic
receptor sites; this results in a favourable tolerability profile of the drug.
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