ПОДДЕРЖИВАЮЩАЯ ТЕРАПИЯ ЭСЦИТАЛОПРАМОМ ДЛЯ

ÓÄÊ 616.895.4–085:65.214
ÏÎÄÄÅÐÆÈÂÀÞÙÀß ÒÅÐÀÏÈß ÝÑÖÈÒÀËÎÏÐÀÌÎÌ ÄËß
ÏÐÅÄÎÒÂÐÀÙÅÍÈß ÐÅÊÓÐÐÅÍÒÍÎÉ ÄÅÏÐÅÑÑÈÈ:
ÐÀÍÄÎÌÈÇÈÐÎÂÀÍÍÎÅ ÏËÀÖÅÁÎ-ÊÎÍÒÐÎËÈÐÓÅÌÎÅ
ÈÑÑËÅÄÎÂÀÍÈÅ *
Ñ. Ã. Êîðíøòåéí, A. Áîóç, Ä. Ëè, K. Ã. Ñàéêàëè, ×. Ãàíäè
Áîëüøîå äåïðåññèâíîå ðàññòðîéñòâî (ÁÄÐ) êàê
ðåêóððåíòíîå ñîñòîÿíèå â áîëüøèíñòâå ñëó÷àåâ
ÿâëÿåòñÿ ïîæèçíåííûì çàáîëåâàíèåì (17, 19). Â
äëèòåëüíîì ïðîñïåêòèâíîì íàòóðàëèñòè÷åñêîì èññëåäîâàíèè, ïðîâåä¸ííîì â ðàìêàõ «Ïðîãðàììû ïî
ïñèõîáèîëîãèè äåïðåññèè» â Íàöèîíàëüíîì èíñòèòóòå ïñèõè÷åñêîãî çäîðîâüÿ (ÑØÀ), áûëî ïîêàçàíî, ÷òî ïîñëå ðàçðåøåíèÿ äåïðåññèâíîãî ýïèçîäà,
ðèñê ðàçâèòèÿ ðåöèäèâà â ïåðâûå 6 ìåñÿöåâ ñîñòàâëÿåò 30%, à â ïîñëåäóþùèå 12 ìåñÿöåâ – 40% (18).
Ïðè ýòîì îòìå÷àëàñü íåîáõîäèìîñòü äëèòåëüíîé
ïîääåðæèâàþùåé òåðàïèè (31).  îäíîì èç èññëåäîâàíèé, ïðîâåä¸ííîì â ÑØÀ çà áîëüíûìè áîëüøèì äåïðåññèâíûì ðàññòðîéñòâîì íàáëþäàëè íà
ïðîòÿæåíèè 15 ëåò è ïðèøëè ê çàêëþ÷åíèþ, ÷òî
ñóììàðíûé ðèñê ðàçâèòèÿ ðåöèäèâà çàáîëåâàíèÿ
äîñòèãàåò 85% (29). Ïðè ýòîì ó ïàöèåíòîâ ñî ñòîéêîé ðåìèññèåé íà ïðîòÿæåíèè, ïî êðàéíåé ìåðå, 5
ëåò ñóììàðíûé ðèñê ðàçâèòèÿ ðåöèäèâà ñîñòàâèë
58%.  òî æå âðåìÿ, â äàííîì íàòóðàëèñòè÷åñêîì
èññëåäîâàíèè êà÷åñòâî àíòèäåïðåññèâíîé òåðàïèè
âî âðåìÿ ïåðâîãî ýïèçîäà è â ïîñëåäóþùåì áûëî
íèçêèì.
Ïî äàííûì ëèòåðàòóðû, ðèñê ðàçâèòèÿ ðåöèäèâà
äåïðåññèè çàâèñèò îò êîëè÷åñòâà è äëèòåëüíîñòè
ðàíåå ïåðåíåñ¸ííûõ ýïèçîäîâ (18, 36, 38). Çíà÷èìûì ïîêàçàòåëåì âîçìîæíîãî ðåöèäèâà çàáîëåâàíèÿ ÿâëÿåòñÿ íàëè÷èå ðåçèäóàëüíîé ñèìïòîìàòèêè
ïîñëå ðàçðåøåíèÿ äåïðåññèâíîãî ýïèçîäà (16, 32).
 ñâÿçè ñ ýòèì âåäåíèå äåïðåññèâíûõ ðàññòðîéñòâ
äîëæíî âêëþ÷àòü äâå âàæíûå çàäà÷è – îáåñïå÷åíèå
ëå÷åíèÿ, êîòîðîå ïðèâåä¸ò ïàöèåíòà ê ñîñòîÿíèþ
çäîðîâüÿ è ïîääåðæàíèå ýòîãî ñîñòîÿíèÿ ñ ïîìîùüþ äëèòåëüíîé òåðàïèè.  ðàçëè÷íûõ èññëåäîâàíèÿõ áûëà ïðîäåìîíñòðèðîâàíà ïðîôèëàêòè÷åñêàÿ
ýôôåêòèâíîñòü öåëîãî ðÿäà àíòèäåïðåññèâíûõ
ñðåäñòâ ó áîëüíûõ ñ ðåêóððåíòíûì äåïðåññèâíûì
ðàññòðîéñòâîì, âêëþ÷àÿ òðèöèêëè÷åñêèå àíòèäåïðåññàíòû èìèïðàìèí (8, 33) è íîðòðèïòèëèí (35),
à òàêæå ôëóîêñåòèí (1, 26), ôëóâîêñàìèí (39), ïàðîêñåòèí (5, 7), ñåðòðàëèí (20, 23), öèòàëîïðàì (15)
è âåíëàôàêñèí (27). Ýñöèòàëîïðàì – ñåëåêòèâíûé
èíãèáèòîð îáðàòíîãî çàõâàòà ñåðîòîíèíà (ÑÈÎÇÑ),
ñîñòîÿùèé öåëèêîì èç îäíîãî S-èçîìåðà, ïðîäåìîíñòðèðîâàë ñâîþ ýôôåêòèâíîñòü è õîðîøóþ ïåðåíîñèìîñòü ïðè êóïèðóþùåé òåðàïèè áîëüøîãî
äåïðåññèâíîãî ðàññòðîéñòâà (4, 24, 41), à òàêæå â
ïðåäîòâðàùåíèè ðàçâèòèÿ îáîñòðåíèé áîëüøèõ
äåïðåññèâíûõ ýïèçîäîâ (34).
 íàñòîÿùåì èññëåäîâàíèè èçó÷àëàñü ýôôåêòèâíîñòü ïîääåðæèâàþùåé òåðàïèè ýñöèòàëîïðàìîì
ïðè ïðîôèëàêòèêå ðàçâèòèÿ ðåöèäèâîâ äåïðåññèè ó
ïàöèåíòîâ, ïîëîæèòåëüíî ðåàãèðîâàâøèõ íà òåðàïèþ äðóãèì àíòèäåïðåññàíòîì èç ãðóïïû ÑÈÎÇÑ.
Âàæíî îòìåòèòü, ÷òî ýôôåêòèâíîñòü ïîääåðæèâàþùåé òåðàïèè ýñöèòàëîïðàìîì èçó÷àëàñü ó ïàöèåíòîâðåñïîíäåðîâ íà äðóãîé àíòèäåïðåññàíò èç ãðóïïû
ÑÈÎÇÑ â êóïèðóþùåé ôàçå ëå÷åíèÿ, ÷òî îòëè÷àåò
äàííîå èññëåäîâàíèå îò òåõ (23), ãäå ïðîôèëàêòè÷åñêàÿ òåðàïèÿ ïðîäîëæàëàñü òåì æå ïðåïàðàòîì.
Ìåòîäû
Íàñòîÿùåå èññëåäîâàíèå áûëî ïðîâåäåíî â 3 ýòàïà: (1) îòêðûòàÿ êóïèðóþùàÿ ôàçà ëå÷åíèÿ; (2) îòêðûòàÿ ñòàáèëèçèðóþùàÿ ôàçà ëå÷åíèÿ; (3) ðàíäîìèçèðîâàííîå äâîéíîå ñëåïîå ïëàöåáî-êîíòðîëèðóåìîå èññëåäîâàíèå ïîääåðæèâàþùåé ôàçû ëå÷åíèÿ.
Èññëåäîâàíèå ïðîâîäèëîñü íà áàçå 28 êëèíè÷åñêèõ
öåíòðîâ â ÑØÀ.
Ïàöèåíòû áûëè âêëþ÷åíû âî âòîðîé ýòàï èññëåäîâàíèÿ ïî çàâåðøåíèè îñòðîé ôàçû çàáîëåâàíèÿ.
Ïî ðåçóëüòàòàì òåðàïèè íà ýòîì ýòàïå âñå ïàöèåíòû ðàçäåëåíû íà 3 ãðóïïû. Â íàñòîÿùåì ñîîáùåíèè ïðèâîäÿòñÿ äàííûå òîëüêî î ïàöèåíòàõ-ðåñïîíäåðàõ íà òåðàïèþ ÑÈÎÇÑ â îñòðîé ôàçå çàáîëåâàíèÿ è ïðîäîëæèâøèõ òåðàïèþ â ñòàáèëèçèðóþùåé
ôàçå ëå÷åíèÿ. Ïîëíàÿ èíôîðìàöèÿ î äàííûõ èññëåäîâàíèÿ äîñòóïíà â «Ðåãèñòðå êëèíè÷åñêèõ èññëåäîâàíèé» êîìïàíèè Forest Laboratories (6).
Âûáîðêà, âîøåäøàÿ â èññëåäîâàíèå.  èññëåäîâàíèå áûëè âêëþ÷åíû ïàöèåíòû (ìóæ. è æåí. â
âîçðàñòå 18–81 ãîäà) ñ äèàãíîçîì áîëüøîãî äåïðåñ-
* Ðàñøèðåííûé ðåôåðàò ñòàòüè, îïóáëèêîâàííîé â J. Clin.
Psychiatry. – 2006. – Vol. 67. – P. 1767–1775, ïðåäîñòàâëåí äëÿ
ïóáëèêàöèè êîìïàíèåé Ëóíäáåê.
79
ñèâíîãî ðàññòðîéñòâà ïî DSM-IV â îñòðîé ôàçå,
äëèòåëüíîñòüþ ñîñòîÿíèÿ íå ìåíåå 4-õ íåäåëü è, ïî
êðàéíåé ìåðå, ñ äâóìÿ áîëüøèìè äåïðåññèâíûìè
ýïèçîäàìè â àíàìíåçå, îäèí èç êîòîðûõ íàáëþäàëñÿ â òå÷åíèå ïîñëåäíèõ 5 ëåò. Òÿæåñòü çàáîëåâàíèÿ
ñîñòàâëÿëà íå ìåíåå 22 áàëëîâ ïî øêàëå îöåíêè
äåïðåññèè Ìîíòãîìåðè-Àñáåðã (MADRS), ïðè ýòîì
îöåíêà ïî 1 ïóíêòó øêàëû äåïðåññèè Ãàìèëüòîíà
(HAM-D) äîëæíà áûëà ñîñòàâëÿòü ìèíèìóì 2 áàëëà. Ïàöèåíòû äîëæíû áûëè áûòü ñîìàòè÷åñêè çäîðîâû èëè èìåòü êëèíè÷åñêè íåçíà÷èìûå èçìåíåíèÿ
ïî äàííûì ñîìàòè÷åñêîãî îáñëåäîâàíèÿ, ëàáîðàòîðíûõ è ÝÊà ïîêàçàòåëåé.
 èññëåäîâàíèå íå âêëþ÷àëè ïàöèåíòîâ ñ äèàãíîçîì áèïîëÿðíîãî ðàññòðîéñòâà, øèçîôðåíèè èëè
äðóãîãî ïñèõîòè÷åñêîãî ðàññòðîéñòâà, îáñåññèâíîêîìïóëüñèâíîãî ðàññòðîéñòâà, óìñòâåííîé îòñòàëîñòè, êîãíèòèâíîãî ðàññòðîéñòâà. Áûëè èñêëþ÷åíû
ïàöèåíòû, äèàãíîç êîòîðûõ ñîîòâåòñòâîâàë ëþáîìó
çàáîëåâàíèþ Îñè I DSM-IV, êðîìå áîëüøîãî äåïðåññèâíîãî ðàññòðîéñòâà (âêëþ÷àÿ äèñòèìèþ), èìåâøèå
â àíàìíåçå ëþáîå ïñèõîòè÷åñêîå ðàññòðîéñòâî, äåìîíñòðèðîâàâøèå ïñèõîòè÷åñêóþ ñèìïòîìàòèêó, ñ
âûðàæåííûì ðàññòðîéñòâîì ëè÷íîñòè, ñî çëîóïîòðåáëåíèåì ïñèõîàêòèâíûìè âåùåñòâàìè â òå÷åíèå
ïîñëåäíèõ 6 ìåñÿöåâ. Òàêæå â èññëåäîâàíèå íå áûëè
âêëþ÷åíû ïàöèåíòû ñ âûñîêèì ñóèöèäàëüíûì ðèñêîì, ñîñòîÿíèå êîòîðûõ îöåíèâàëîñü ìèíèìóì â 5
áàëëîâ ïî 10 ïóíêòó øêàëû MADRS (ñóèöèäàëüíûå
òåíäåíöèè), èëè íóæäàâøèåñÿ â äîïîëíèòåëüíîé
ïñèõîòðîïíîé òåðàïèè (çà èñêëþ÷åíèåì çîëïèäåìà,
äëÿ êóïèðîâàíèÿ èíñîìíèè).
Äèçàéí èññëåäîâàíèÿ. Íà ýòàïå êóïèðóþùåé ôàçû
ëå÷åíèÿ â îòêðûòîì 8-íåäåëüíîì èññëåäîâàíèè ïà-
öèåíòû ïîëó÷àëè â ãèáêîé äîçèðîâêå îäèí èç ñëåäóþùèõ ïðåïàðàòîâ: öèòàëîïðàì (20–60 ìã/ñóò),
ôëóîêñåòèí (20–80 ìã/ñóò), ïàðîêñåòèí (20–50 ìã/
ñóò) èëè ñåðòðàëèí (50–200 ìã/ñóò) (ðèñ. 1) (42).
Ðåñïîíäåðû (MADRS≤12 áàëëîâ) íà òåðàïèþ îäíèì èç ÑÈÎÇÑ â êóïèðóþùåé ôàçå ëå÷åíèÿ âêëþ÷àëèñü âî âòîðóþ ôàçó èññëåäîâàíèÿ.
 îòêðûòîì èññëåäîâàíèè ñòàáèëèçèðóþùåé
ôàçû òåðàïèè ïàöèåíòàì-ðåñïîíäåðàì èç ïåðâîé
ôàçû, íàçíà÷àëñÿ ýñöèòàëîïðàì â ãèáêîé äîçèðîâêå. Ëå÷åíèå ýñöèòàëîïðàìîì íà÷èíàëîñü â òå÷åíèå
ïåðâûõ 72 ÷àñîâ ïîñëå îêîí÷àíèÿ ïåðâîé ôàçû òåðàïèè, ïðè ýòîì äîçà ïðåïàðàòà ñîñòàâëÿëà 10 ìã/
ñóò. Â ñîîòâåòñòâèè ñ ðåøåíèåì èññëåäîâàòåëÿ, äîçà
ïðåïàðàòà ìîãëà áûòü ïîâûøåíà äî 20 ìã/ñóò, íà÷èíàÿ ñ êîíöà ïåðâîé íåäåëè òåðàïèè. Ïî çàâåðøåíèè ñòàáèëèçèðóþùåé ôàçû ëå÷åíèÿ, ïàöèåíòû,
îñòàâàâøèåñÿ ðåñïîíäåðàìè (MADRS≤12 áàëëîâ),
äîïóñêàëèñü ê ïðîäîëæåíèþ òåðàïèè â 52-íåäåëüíîì ðàíäîìèçèðîâàííîì äâîéíîì ñëåïîì ïëàöåáîêîíòðîëèðóåìîì èññëåäîâàíèè ïîääåðæèâàþùåé
òåðàïèè ñ ïàðàëëåëüíûìè ãðóïïàìè è ôèêñèðîâàííûìè äîçàìè ïðåïàðàòà. Ïàöèåíòû, íå ñîîòâåòñòâîâàâøèå êðèòåðèÿì ðåñïîíäåðîâ ê êîíöó ñòàáèëèçèðóþùåé ôàçû ëå÷åíèÿ, áûëè èñêëþ÷åíû èç èññëåäîâàíèÿ.
Ïàöèåíòû, äîïóùåííûå ê òðåòüåìó ýòàïó èññëåäîâàíèÿ, áûëè ðàíäîìèçèðîâàíû (òî åñòü ðàñïðåäåëåíû ñëó÷àéíûì îáðàçîì) â îäíó èç äâóõ òåðàïåâòè÷åñêèõ ãðóïï – ïëàöåáî èëè ýñöèòàëîïðàìà â
ñîîòíîøåíèè 1:1.
Íå äîïóñêàëèñü êàêèå-ëèáî èçìåíåíèÿ â êîëè÷åñòâå ïðèíèìàåìîãî ïðåïàðàòà â ñóòêè. Ðåöèäèâ äåïðåññèè îïðåäåëÿëñÿ ïðè óâåëè÷åíèè îöåíêè ïî
Ðèñ. 1. Äèçàéí èññëåäîâàíèÿ
Ïðèìå÷àíèå: *MADRS – øêàëà Ìîíòãîìåðè-Àñáåðã äëÿ îöåíêè äåïðåññèè
80
øêàëå MADRS≤22 áàëëîâ èëè âûáûòèè èç èññëåäîâàíèÿ â ñâÿçè ñ ðåøåíèåì èññëåäîâàòåëÿ î íåäîñòàòî÷íîé ýôôåêòèâíîñòè òåðàïèè. Ïàöèåíòû, ÷ü¸
ñîñòîÿíèå îöåíèâàëîñü êàê ðåöèäèâ çàáîëåâàíèÿ âî
âðåìÿ îäíîãî èç âèçèòîâ ïîääåðæèâàþùåé ôàçû
ëå÷åíèÿ, áûëè èñêëþ÷åíû èç èññëåäîâàíèÿ.
Îöåíêó ñîñòîÿíèÿ ïàöèåíòîâ ïðîâîäèëè â êîíöå
1, 2, 4, 8 è êàæäûõ ïîñëåäóþùèõ 4 íåäåëü â òå÷åíèå ñòàáèëèçèðóþùåé ôàçû ëå÷åíèÿ, à òàêæå â êîíöå 18, 20 è êàæäîé ïîñëåäóþùåé 4 íåäåëè âî âðåìÿ ïîääåðæèâàþùåé ôàçû ëå÷åíèÿ. Îöåíêà ïðîâîäèëàñü ñ èñïîëüçîâàíèåì øêàë MADRS, HAMD-24,
ïîäøêàë «Óëó÷øåíèå» (CGI-I) è «Òÿæåñòü çàáîëåâàíèÿ» (CGI-S) øêàëû îáùåãî êëèíè÷åñêîãî âïå÷àòëåíèÿ (12). Ïîêàçàòåëè áåçîïàñíîñòè îöåíèâàëèñü
ñ ïîìîùüþ ìîíèòîðèðîâàíèÿ âèòàëüíûõ ôóíêöèé
è ïîáî÷íûõ ýôôåêòîâ. Ïîáî÷íûå ýôôåêòû, ïðîÿâèâøèåñÿ âî âðåìÿ ëþáîé ôàçû èññëåäîâàíèÿ,
îïðåäåëÿëèñü êàê íåæåëàòåëüíûå ÿâëåíèÿ â ðåçóëüòàòå òåðàïèè, åñëè îíè îòñóòñòâîâàëè íà ìîìåíò
âêëþ÷åíèÿ â èññëåäîâàíèå èëè æå åñëè èìåëè ìåñòî, íî óòÿæåëèëèñü âî âðåìÿ òåðàïèè.
Ôèçèêàëüíîå îáñëåäîâàíèå è ëàáîðàòîðíûå òåñòû ïðîâîäèëèñü âî âðåìÿ ïåðâîãî âèçèòà è â êîíöå
èññëåäîâàíèÿ; îöåíêà ëàáîðàòîðíûõ ïîêàçàòåëåé
ïðîâîäèëàñü òàêæå è íà 12 íåäåëå ñòàáèëèçèðóþùåé ôàçû ëå÷åíèÿ. Ïàðàìåòðû ýëåêòðîêàðäèîãðàììû îöåíèâàëèñü â êîíöå 12 íåäåëè ñòàáèëèçèðóþùåé ôàçû ëå÷åíèÿ è â êîíöå èññëåäîâàíèÿ.
Ñòàòèñòè÷åñêèå ìåòîäû. Àíàëèç ïîêàçàòåëåé
áåçîïàñíîñòè áûë îñíîâàí íà ìàòåðèàëå âûáîðêè
ïàöèåíòîâ, ïîëó÷èâøèõ òåðàïèþ ìèíèìóì 1 ðàç â
òå÷åíèå ñòàáèëèçèðóþùåé èëè ïîääåðæèâàþùåé
ôàçû ëå÷åíèÿ. Îáùàÿ âûáîðêà (intention-to-treat
population, ITT âûáîðêà) âêëþ÷àëà âñåõ ïàöèåíòîâ,
ïîëó÷èâøèõ, ïî ìåíüøåé ìåðå, îäíó äîçó èçó÷àåìîãî ïðåïàðàòà è èìåâøèõ õîòÿ áû îäíîêðàòíî çàôèêñèðîâàííûå ïîêàçàòåëè ïî øêàëå MADRS â ñòàáèëèçèðóþùåé èëè ïîääåðæèâàþùåé ôàçàõ èññëåäîâàíèÿ, ñäåëàííûå ïîñëå îïðåäåëåíèÿ áàçèñíûõ
çíà÷åíèé ýòîé øêàëû â íà÷àëå êàæäîé ôàçû. Çà íà÷àëî ñòàáèëèçèðóþùåé ôàçû ëå÷åíèÿ áûë ïðèíÿò
ïîñëåäíèé îöåíî÷íûé âèçèò âî âðåìÿ êóïèðóþùåé
ôàçû òåðàïèè. Çà íà÷àëî ïîääåðæèâàþùåé ôàçû
ïðèíÿò ïîñëåäíèé îöåíî÷íûé âèçèò âî âðåìÿ ñòàáèëèçèðóþùåé ôàçû ëå÷åíèÿ. Ñðàâíèìîñòü íåïðåðûâ-
íûõ ïåðåìåííûõ âåëè÷èí ìåæäó äâóìÿ ãðóïïàìè íà
èñõîäå ïîääåðæèâàþùåé òåðàïèè àíàëèçèðîâàëàñü ñ
ïðèìåíåíèåì ìîäåëè äâóñòîðîííåãî âàðèàöèîííîãî
àíàëèçà, êàòåãîðèàëüíûå âåëè÷èíû àíàëèçèðîâàëè
òåñòîì Cochran-Mantel-Haenszel.
Ãëàâíûì ïîêàçàòåëåì ýôôåêòèâíîñòè áûëî âðåìÿ äî ðàçâèòèÿ ðåöèäèâà îò íà÷àëà äâîéíîé ñëåïîé
ïîääåðæèâàþùåé ôàçû èññëåäîâàíèÿ. Ñðàâíåíèå
ðèñêà ðàçâèòèÿ ðåöèäèâà â ãðóïïå ïàöèåíòîâ, ïîëó÷àþùèõ ýñöèòàëîïðàì è ïëàöåáî, îöåíèâàëîñü ñ
ïîìîùüþ ìîäåëè ðåãðåññèè Êîêñà. Áûë ïðèìåí¸í
òàêæå àíàëèç âûæèâàåìîñòè Kaplan-Meier. Äëÿ ïàðíûõ ñðàâíåíèé ìåæäó òåðàïåâòè÷åñêèìè ãðóïïàìè
(ýñöèòàëîïðàì, ïëàöåáî) ñ ó÷¸òîì ïàðàìåòðîâ ýôôåêòèâíîñòè (èçìåíåíèÿ ìåæäó èñõîäíûìè è êîíå÷íûìè çíà÷åíèÿìè) áûëà èñïîëüçîâàíà ìîäåëü
äîïîëíèòåëüíîãî êîâàðèàöèîííîãî àíàëèçà.
Ðåçóëüòàòû
Õàðàêòåðèñòèêà ïàöèåíòîâ. Âñåãî â îòêðûòóþ
êóïèðóþùóþ ôàçó ëå÷åíèÿ áûëî âêëþ÷åíî 515
ïàöèåíòîâ (ñðåäíèé áàëë ïî MADRS – 30,4); 386
ïàöèåíòîâ (75%) çàâåðøèëè ýòîò ýòàï, ïðè ýòîì 259
(50%) îêàçàëèñü ðåñïîíäåðàìè. Âñåãî 234 ïàöèåíòà-ðåñïîíäåðà íà òåðàïèþ ÑÈÎÇÑ â êóïèðóþùåé
ôàçå ëå÷åíèÿ ïîëó÷àëè, êàê ìèíèìóì, 1 äîçó ýñöèòàëîïðàìà âî âðåìÿ ñòàáèëèçèðóþùåé ôàçû ëå÷åíèÿ (ðèñ. 2). Ñòî øåñòüäåñÿò ÷åòûðå (70%) ïàöèåíòà
èç ýòîé ãðóïïû çàâåðøèëè ýòàï ñòàáèëèçèðóþùåãî ëå÷åíèÿ, 139 ïàöèåíòîâ ïîëó÷èëè, ïî êðàéíåé
ìåðå, 1 äîçó ïðåïàðàòà âî âðåìÿ äâîéíîãî ñëåïîãî
èññëåäîâàíèÿ ïîääåðæèâàþùåé ôàçû ëå÷åíèÿ; èç
íèõ 73 ïðèíèìàëè ýñöèòàëîïðàì è 66 – ïëàöåáî.
Ýòè ïàöèåíòû áûëè âêëþ÷åíû â àíàëèç áåçîïàñíîñòè ïîääåðæèâàþùåé ôàçû ëå÷åíèÿ.  ITT âûáîðêó (ñ ìèíèìóì îäíîé îöåíêîé ïî øêàëå MADRS)
â ïîääåðæèâàþùåé ôàçå ëå÷åíèÿ âîøëî 73 ïàöèåíòà, ïîëó÷àâøèõ ýñöèòàëîïðàì, è 65 ïàöèåíòîâ,
ïîëó÷àâøèõ ïëàöåáî. Ïîääåðæèâàþùóþ 52-íåäåëüíóþ ôàçó ëå÷åíèÿ çàâåðøèëè 49 ïàöèåíòîâ (35%):
37 (51%) èç ãðóïïû, ïîëó÷àâøèõ ýñöèòàëîïðàì, è
12 (18%) èç ãðóïïû, ïîëó÷àâøèõ ïëàöåáî.
Ïîñëå ðàíäîìèçàöèè â äâîéíîì ñëåïîì èññëåäîâàíèè ãðóïïû íå îáíàðóæèâàëè ñòàòèñòè÷åñêè äîñòîâåðíûõ ðàçëè÷èé ïî âîçðàñòó, ïîëó è êëèíè÷åñêèì
ïîêàçàòåëÿì (òàáë. 1). Ñðåäíÿÿ ñóòî÷íàÿ äîçà ýñöèòàÒàáëèöà 1
Демографическая характеристика пациентов*
Õàðàêòåðèñòèêà
Ñòàáèëèçèðóþùàÿ ôàçà,
îòêðûòîå èññëåäîâàíèå
Ïîääåðæèâàþùàÿ ôàçà,
äâîéíîå ñëåïîå èññëåäîâàíèå
Ýñöèòàëîïðàì(n=234)
Ýñöèòàëîïðàì (n=73)
Ïëàöåáî(n=66)
Âîçðàñò, ãîäû
40,5±11,6
42,0±11,3
43,7±12,4
Æåíùèíû (%)
175 (74,8)
58 (79,5)
52 (78,8)
Ðàñà, % áåëûõ
196 (83,8)
64 (87,7)
57 (86,4)
Êîëè÷åñòâî áàëëîâ ïî øêàëå MADRS**
íà íà÷àëî èññëåäîâàíèÿ
6,6±3,4
4,7±4,0
4,9±3,6
Êîëè÷åñòâî äåïðåññèâíûõ ýïèçîäîâ
â àíàìíåçå
4,8±3,9
4,7±3,1
5,8±6,0
Ïðèìå÷àíèå: * – çíà÷åíèÿ ïðåäñòàâëåíû êàê ñðåäíåå ± SD (ñòàíäàðòíîå îòêëîíåíèå) ïðè îòñóòñòâèè èíûõ óêàçàíèé; **MADRS
– øêàëà Ìîíòãîìåðè-Àñáåðã äëÿ îöåíêè äåïðåññèè.
81
Ðèñ. 2. Ðàñïðåäåëåíèå ïàöèåíòîâ
Ïðèìå÷àíèå: *Safety – âûáîðêà ïàöèåíòîâ, ïîëó÷èâøàÿ, ïî êðàéíåé ìåðå, 1 äîçó ïðåïàðàòà (âîøëè â àíàëèç áåçîïàñíîñòè);
**ITT – intention-to-treat population – âûáîðêà ïàöèåíòîâ, ñ ìèíèìóì îäíîé îöåíêîé ïî øêàëå MADRS ïîñëå ðåãèñòðàöèè èñõîäíûõ ïîêàçàòåëåé (âîøëè â àíàëèç ýôôåêòèâíîñòè).
ëîïðàìà âî âðåìÿ îòêðûòîé ñòàáèëèçèðóþùåé ôàçû
è äâîéíîé ñëåïîé ïîääåðæèâàþùåé ôàçû èññëåäîâàíèÿ ñîñòàâèëà 15,8 ìã è 15,2 ìã ñîîòâåòñòâåííî.
Ïðåäîòâðàùåíèå ðåöèäèâîâ äåïðåññèè. Íà íà÷àëî ñòàáèëèçèðóþùåé ôàçû ëå÷åíèÿ ñðåäíÿÿ îöåíêà ïî ãðóïïå ñîñòàâëÿëà 6,6±3,4 áàëëà ïî øêàëå
MADRS. Íà íà÷àëî ïîääåðæèâàþùåé ôàçû ëå÷åíèÿ
îöåíêà ïî MADRS ñîñòàâèëà 4,9±3,6 áàëëîâ â ãðóïïå ïëàöåáî è 4,7±4,0 äëÿ ïàöèåíòîâ, ðàíäîìèçèðîâàííûõ â ãðóïïó ýñöèòàëîïðàìà. Ñðåäíèå èçìåíåíèÿ ñóììàðíûõ áàëëîâ øêàë MADRS, HAM-D,
CGI-I, CGI-S â ïåðèîä ñòàáèëèçèðóþùåé è ïîääåðæèâàþùåé ôàç ëå÷åíèÿ ïðåäñòàâëåíû â òàáë. 2.
Êóìóëÿòèâíàÿ ÷àñòîòà ðàçâèòèÿ ðåöèäèâà äåïðåññèè áûëà çíà÷èòåëüíî íèæå ó ïàöèåíòîâ, ïðèíèìàâøèõ ýñöèòàëîïðàì â ñðàâíåíèè ñ ãðóïïîé
ïëàöåáî (27% è 65% ñîîòâåòñòâåííî). Ïðè ýòîì
â ãðóïïå ýñöèòàëîïðàìà äî ðàçâèòèÿ ðåöèäèâà
ïðîõîäèëî äîñòîâåðíî (p<0,001) áîëüøå âðåìåíè
(252±134 äíÿ), ÷åì ó ïàöèåíòîâ, ïîëó÷àâøèõ ïëàöåáî (130±135 äíåé) (òàáë. 3). Àíàëèç áûë ïðîâåäåí òàêæå ïîñëå ó÷åòà âñåõ ðåöèäèâîâ çàáîëåâàíèÿ â òå÷åíèå 14 äíåé ïîñëå íà÷àëà äâîéíîãî
ñëåïîãî èññëåäîâàíèÿ. Ðåçóëüòàòû îñòàâàëèñü
ñòàòèñòè÷åñêè çíà÷èìûìè (îòíîøåíèå ðèñêîâ
ÎÐ=0,29; p<0,001) â ïîëüçó òåðàïèè ýñöèòàëîïðàìîì.
Áåçîïàñíîñòü. Òåðàïèÿ ýñöèòàëîïðàìîì â ñòàáèëèçèðóþùåé è ïîääåðæèâàþùåé ôàçàõ ëå÷åíèÿ
áûëà áåçîïàñíîé è õîðîøî ïåðåíîñèëàñü ïàöèåíòàìè.  ñòàáèëèçèðóþùåé ôàçå èññëåäîâàíèÿ ÷àñòîòà ïðåæäåâðåìåííîé îòìåíû òåðàïèè èç-çà íåæåëàòåëüíûõ ÿâëåíèé ïðè ïðèåìå ýñöèòàëîïðàìà
ñîñòàâèëà 6%. Âî âðåìÿ ïîääåðæèâàþùåé ôàçû
ëå÷åíèÿ ÷àñòîòà ïðåæäåâðåìåííîé îòìåíû èç-çà íåæåëàòåëüíûõ ÿâëåíèé ïðè ïðèåìå ýñöèòàëîïðàìà
(4%) áûëà äàæå íåñêîëüêî íèæå, ÷åì ïðè èñïîëüçîâàíèè ïëàöåáî (9%) (ðèñ. 2). Åäèíñòâåííûìè íåæåëàòåëüíûìè ÿâëåíèÿìè â ñâÿçè ñ òåðàïèåé ýñöèòàëîïðàìîì â îòêðûòîé ôàçå èññëåäîâàíèÿ, íàáëþäàâøèåñÿ â ≤10% ñëó÷àåâ, áûëè ãîëîâíàÿ áîëü è
óòîìëÿåìîñòü. ×àñòîòà ðàçâèòèÿ òàêèõ íåæåëàòåëüíûõ ÿâëåíèé êàê ãîëîâîêðóæåíèå, ãðèïïîïîäîáíûå
ñèìïòîìû, èíôåêöèè âåðõíèõ äûõàòåëüíûõ ïóòåé,
ðèíèòû è ãîëîâíûå áîëè áûëà ïðèìåðíî îäèíàêîâîé (≥10%) â ãðóïïàõ ýñöèòàëîïðàìà è ïëàöåáî â
82
Òàáëèöà 2
Дополнительные параметры эффективности: открытая стабилизирующая фаза
и двойная слепая поддерживающая фаза (ITT выборка, OC)
Ïàðàìåòð
ýôôåêòèâíîñòè
Ñòàáèëèçèðóþùàÿ ôàçà,
îòêðûòîå èññëåäîâàíèå
Ïîääåðæèâàþùàÿ ôàçà,
äâîéíîå ñëåïîå èññëåäîâàíèå
Ýñöèòàëîïðàì (n=228)
Ýñöèòàëîïðàì (n=73)
Ïëàöåáî (n=65)
6,6±3,4
4,7±4,0
4,9±3,6
-0,3±0,49
0,1±5,8
-0,3±3,0
MADRS
íà÷àëî èññëåäîâàíèÿ
çàâåðøåíèå èññëåäîâàíèÿ
HAM-D
íà÷àëî èññëåäîâàíèÿ
çàâåðøåíèå èññëåäîâàíèÿ
7,2±4,1
5,2±4,0
5,2±3,8
-0,3±0,48
-0,5±5,9
-0,2±3,6
CGI-I
íà÷àëî èññëåäîâàíèÿ
1,4±0,5
1,2±0,5
1,2±0,4
çàâåðøåíèå èññëåäîâàíèÿ
0,0±0,8
0,0±0,6
-0,1±0,3
íà÷àëî èññëåäîâàíèÿ
1,9±0,7
1,5±0,6
1,6±0,7
çàâåðøåíèå èññëåäîâàíèÿ
0,1±1,2
0,0±0,9
0,1±0,3
CGI-S
Ïðèìå÷àíèå: * CGI-I – øêàëà îáùåãî êëèíè÷åñêîãî âïå÷àòëåíèÿ, ïîäøêàëà «Óëó÷øåíèå», CGI-S – øêàëà îáùåãî êëèíè÷åñêîãî
âïå÷àòëåíèÿ, ïîäøêàëà «Òÿæåñòü çàáîëåâàíèÿ», HAM-D – øêàëà îöåíêè äåïðåññèè Ãàìèëüòîíà, MADRS – øêàëà îöåíêè äåïðåññèè Ìîíòãîìåðè-Àñáåðã, ITT – intention-to-treat population – âûáîðêà ïàöèåíòîâ, ñ ìèíèìóì îäíîé îöåíêîé ïî øêàëå MADRS
ïîñëå ðåãèñòðàöèè èñõîäíûõ ïîêàçàòåëåé, OC – observed cases – íàáëþäàåìûå ñëó÷àè
Òàáëèöà 3
Суммарный риск развития рецидива депрессии (ITT выборка)
Ñóììàðíûé ðèñê ðåöèäèâà
95% ÄÈ
p
Áåç êîððåêöèè
Ýñöèòàëîïðàì (n=73) Ïëàöåáî (n=65) Îòíîøåíèå ðèñêîâ
27%
65%
0,26
0,13 ê 0,52
<0,001
Ñ êîððåêöèåé ðåöèäèâîâ â òå÷åíèå ïåðâûõ
14 äíåé äâîéíîãî ñëåïîãî ïåðèîäà
27%
62%
0,29
0,14 ê 0,59
<0,001
Ïðèìå÷àíèå: *ITT – intention-to-treat population – âûáîðêà ïàöèåíòîâ, ñ ìèíèìóì îäíîé îöåíêîé ïî øêàëå MADRS ïîñëå ðåãèñòðàöèè èñõîäíûõ ïîêàçàòåëåé (âîøëè â àíàëèç ýôôåêòèâíîñòè)
Òàáëèöà 4
Наиболее частые побочные эффекты, связанные с терапией, в период двойной слепой фазы
поддерживающего лечения, %*
Ïîáî÷íûé ýôôåêò, ñâÿçàííûé ñ ïðè¸ìîì òåðàïèè
Ýñöèòàëîïðàì (n=73)
Ïëàöåáî (n=66)
p
3
20
0,002
Ãîëîâîêðóæåíèå
Ãðèïïîïîäîáíûå ñèìïòîìû
16
2
0,003
Èíôåêöèè âåðõíèõ äûõàòåëüíûõ ïóòåé
16
12
0,629
Óøèáû
12
5
0,135
Ðèíèòû
11
9
0,783
Ãîëîâíàÿ áîëü
11
6
0,374
Ïðèìå÷àíèå: * – ÷àñòîòà íå ìåíåå 10% â îáåèõ òåðàïåâòè÷åñêèõ ãðóïïàõ.
äâîéíîé ñëåïîé ïîääåðæèâàþùåé ôàçå èññëåäîâàíèÿ (òàáë. 4).
 òå÷åíèå ïåðâûõ 14 äíåé ïîääåðæèâàþùåé
ôàçû ëå÷åíèÿ ÷àñòîòà íåæåëàòåëüíûõ ÿâëåíèé ñîñòàâèëà 41% â ãðóïïå, ïîëó÷àâøèõ ïëàöåáî, è 21%
– â ãðóïïå, ïîëó÷àâøèõ ýñöèòàëîïðàì (òàáë. 5).
Ãîëîâîêðóæåíèå, íàèáîëåå òèïè÷íîå íåæåëàòåëüíîå ÿâëåíèå, âîçíèêàþùåå ïðè îòìåíå ÑÈÎÇÑ,
ïðèöåëüíî îòñëåæèâàëîñü â òå÷åíèå ïåðâûõ 14
äíåé ïîääåðæèâàþùåé ôàçû ëå÷åíèÿ.  ãðóïïå èç
66 ïàöèåíòîâ, ïîëó÷àâøèõ ïëàöåáî, íà êîòîðîå îíè
áûëè ïåðåâåäåíû ïîñëå ïîëó÷åíèÿ ýñöèòàëîïðàìà
â îòêðûòîé ôàçå ñòàáèëèçèðóþùåãî ëå÷åíèÿ, 12
(18%) èñïûòûâàëè ãîëîâîêðóæåíèå â òå÷åíèå ïåðâûõ 14 äíåé ëå÷åíèÿ. Âñëåä çà ýòèì ïåðèîäîì ÷àñ-
òîòà ðàçâèòèÿ ãîëîâîêðóæåíèÿ ó ïàöèåíòîâ ýòîé
ãðóïïû ñîñòàâèëà 2%.  ãðóïïå ïàöèåíòîâ, ïîëó÷àâøèõ ýñöèòàëîïðàì, íèêòî íå èñïûòûâàë ãîëîâîêðóæåíèå â òå÷åíèå ïåðâûõ 14 äíåé ïîääåðæèâàþùåé
ôàçû ëå÷åíèÿ, â òî âðåìÿ êàê â ïîñëåäóþùåì ïåðèîäå ÷àñòîòà âîçíèêíîâåíèÿ ýòîãî íåæåëàòåëüíîãî
ÿâëåíèÿ ñîñòàâèëà 3%.
Ñåðü¸çíûå íåæåëàòåëüíûå ÿâëåíèÿ â òå÷åíèå ñòàáèëèçèðóþùåé ôàçû ëå÷åíèÿ íå íàáëþäàëèñü. Ñîîáùàëîñü î 4 ñåðü¸çíûõ íåæåëàòåëüíûõ ÿâëåíèÿõ
ó òð¸õ ïàöèåíòîâ â ïåðèîä ïîääåðæèâàþùåé ôàçû
ëå÷åíèÿ (ó 1 â ãðóïïå ïëàöåáî – ñóèöèäàëüíàÿ ïîïûòêà; è ó 2 â ãðóïïå ýñöèòàëîïðàìà – ñëó÷àé ãèïîòåíçèè; îïóùåíèå ìî÷åâîãî ïóçûðÿ è îïóùåíèå
ìàòêè). Òåì íå ìåíåå, íè îäíî èç ýòèõ ñåðü¸çíûõ
83
Òàáëèöà 5
Частота возникновения побочных эффектов, связанных
с приёмом терапии в течение первых 14 дней двойной
слепой фазы поддерживающего лечения, %*
Ïîáî÷íûé ýôôåêò, ñâÿçàííûé
ñ ïðè¸ìîì òåðàïèè
Ýñöèòàëîïðàì Ïëàöåáî
(n=73)
(n=66)
Ãîëîâîêðóæåíèå
0
18,2
Ðèíèòû
0
6,1
Èíôåêöèè âåðõíèõ äûõàòåëüíûõ
ïóòåé
0
3,0
1,4
1,5
Óøèáû
2,7
1,5
Ãðèïïîïîäîáíûå ñèìïòîìû
1,4
0
Ãîëîâíûå áîëè
ìîãî âëèÿíèÿ íà âåñ â îáåèõ òåðàïåâòè÷åñêèõ ãðóïïàõ ñðåäè ïàöèåíòîâ, çàâåðøèâøèõ ïîääåðæèâàþùóþ ôàçó ëå÷åíèÿ.
Îáñóæäåíèå
Ïðîâåä¸ííîå èññëåäîâàíèå äåìîíñòðèðóåò, ÷òî
ïîääåðæèâàþùàÿ òåðàïèÿ ýñöèòàëîïðàìîì áåçîïàñíà, õîðîøî ïåðåíîñèòñÿ è çíà÷èòåëüíî ñíèæàåò
ðèñê ðåöèäèâà äåïðåññèâíîãî ðàññòðîéñòâà. Áûëî
ïîêàçàíî, ÷òî ó ïàöèåíòîâ, ïðèíèìàâøèõ ýñöèòàëîïðàì â ñðàâíåíèè ñ òåìè, êòî ïîëó÷àë ïëàöåáî,
ñóììàðíûé ðèñê ðàçâèòèÿ ðåöèäèâà áûë â 2,5 ðàçà
íèæå (27% ðåöèäèâîâ â ãðóïïå ýñöèòàëîïðàìà è
67% â ãðóïïå ïëàöåáî). Ïðè ýòîì äî ðàçâèòèÿ ðåöèäèâà çàáîëåâàíèÿ â ãðóïïå ýñöèòàëîïðàìà (â
òåõ íåìíîãèõ ñëó÷àÿõ, êîãäà îí âîçíèêàë) ïðîõîäèëî çíà÷èòåëüíî áîëüøå âðåìåíè, ÷åì äî ðàçâèòèÿ
ðåöèäèâà íà ïëàöåáî. Ñèìïòîìû îòìåíû, íàáëþäàåìûå â ñâÿçè ñ ïðåêðàùåíèåì ïðè¸ìà àêòèâíîãî
ïðåïàðàòà ó ïàöèåíòîâ èç ãðóïïû ïëàöåáî, íå ïîâëèÿëè íà îêîí÷àòåëüíûå ðåçóëüòàòû ñðàâíåíèÿ,
ïîñêîëüêó ïðèìåíÿëñÿ ñïåöèàëüíûé ìåòîä êîððåêòèðîâêè äàííûõ.
 îäíîì èç ïðåäûäóùèõ èññëåäîâàíèé áûëà ïîêàçàíà ýôôåêòèâíîñòü ýñöèòàëîïðàìà ïî ïðåäóïðåæäåíèþ ðàçâèòèÿ ðåöèäèâîâ äåïðåññèè ïðè ïðèìåíåíèè åãî â êà÷åñòâå ñòàáèëèçèðóþùåé òåðàïèè
â òå÷åíèå 36 íåäåëü (34).  íàñòîÿùåì èññëåäîâàíèè ðàññìàòðèâàåòñÿ ýôôåêòèâíîñòü èñïîëüçîâàíèÿ
ýñöèòàëîïðàìà â ïîääåðæèâàþùåé ôàçå ëå÷åíèÿ.
Ìíîãèìè àíòèäåïðåññàíòàìè, âêëþ÷àÿ èíãèáèòîðû
ÌÀÎ, ÒÖÀ, ÑÈÎÇÑ, ÈÎÇÑÍ – âåíëàôàêñèí (4, 27),
áûëà ïðîäåìîíñòðèðîâàíà ýôôåêòèâíîñòü â ïðåäîòâðàùåíèè îáîñòðåíèé è ðåöèäèâîâ äåïðåññèè.
Ñîâðåìåííûå êëèíè÷åñêèå ðóêîâîäñòâà óêàçûâàþò íà òî, ÷òî ïàöèåíòû äîëæíû ïðîäîëæàòü ëå÷åíèå â òå÷åíèå 14–20 íåäåëü ïîñëå äîñòèæåíèÿ ðåìèññèè, ñ öåëüþ ïðåäîòâðàùåíèÿ ðåöèäèâà äåïðåññèâíîãî ýïèçîäà (2). Òàêæå è ïàöèåíòû ñ âûñîêèì
ðèñêîì ðàçâèòèÿ î÷åðåäíîãî äåïðåññèâíîãî ýïèçîäà äîëæíû ïðèíèìàòü ïîääåðæèâàþùóþ òåðàïèþ.
Ïàöèåíòû, âêëþ÷åííûå â íàñòîÿùåå èññëåäîâàíèå,
Ïðèìå÷àíèå: * – ÷àñòîòà íå ìåíåå 10% â îáåèõ òåðàïåâòè÷åñêèõ ãðóïïàõ.
íåæåëàòåëüíûõ ÿâëåíèé íå áûëî ðàñöåíåíî èññëåäîâàòåëÿìè êàê ñâÿçàííîå ñ òåðàïèåé.
Ñóèöèäàëüíàÿ ïîïûòêà èìåëà ìåñòî ó ïàöèåíòà
èç ãðóïïû ïëàöåáî è áûëà ðàñöåíåíà èññëåäîâàòåëÿìè êàê âîçìîæíî ñâÿçàííàÿ ñ òåðàïèåé. Äàííûé ìóæ÷èíà 56 ëåò óæå èìåë â àíàìíåçå ñóèöèäàëüíóþ ïîïûòêó. Îí ïîëó÷àë öèòàëîïðàì â òå÷åíèå 56 äíåé êóïèðóþùåé ôàçû ëå÷åíèÿ, äàëåå
ýñöèòàëîïðàì â ñòàáèëèçèðóþùåé ôàçå òåðàïèè â
òå÷åíèå 16-òè íåäåëü, à çàòåì ïëàöåáî â ïîääåðæèâàþùåé ôàçå ëå÷åíèÿ. ×åðåç ìåñÿö ïîñëå ïðèåìà ïîñëåäíåé äîçû ïëàöåáî ïàöèåíò áûë ãîñïèòàëèçèðîâàí â ñâÿçè ñ ñóèöèäàëüíîé ïîïûòêîé,
ñîâåðø¸ííîé ïóò¸ì ïåðåäîçèðîâêè ëåêàðñòâ. Â
ïðîìûâíûõ æèäêîñòÿõ áûë îáíàðóæåí ýñöèòàëîïðàì è àöåòàìèíîôåí. Òàê êàê ïàöèåíò ïîëó÷àë
ïëàöåáî â ñëåïîì èññëåäîâàíèè, ìîæíî ïðåäïîëîæèòü, ÷òî îí íå ïîëíîñòüþ ñîáëþäàë íàçíà÷åíèÿ,
ñäåëàííûå âî âðåìÿ îòêðûòîé ñòàáèëèçèðóþùåé
ôàçû è íàêàïëèâàë ëåêàðñòâî.
Ýñöèòàëîïðàì â ïåðèîä ïîääåðæèâàþùåé ôàçû
ëå÷åíèÿ îêàçûâàë ìèíèìàëüíîå âëèÿíèå íà ïîêàçàòåëè âèòàëüíûõ ôóíêöèé (íàïðèìåð, óðîâåíü ñèñòîëè÷åñêîãî è äèàñòîëè÷åñêîãî äàâëåíèÿ, ×ÑÑ) è íå
îòëè÷àëñÿ ñóùåñòâåííî ïî ýòîìó âîçäåéñòâèþ îò
ïëàöåáî (òàáë. 6). Òàêæå íå áûëî âûÿâëåíî çíà÷è-
Òàáëèöà 6
Показатели жизненных функций и вес в течение двойной слепой фазы поддерживающего лечения
(завершившие исследование пациенты)
Èçìåðåíèå
Ýñöèòàëîïðàì (n=73)
Ïëàöåáî (n=66)
Ñèñòîëè÷åñêîå àðòåðèàëüíîå äàâëåíèå, ìì ðò ñò
p
0,509
Íà÷àëî èññëåäîâàíèÿ
119,1±14,5
118,3±15,4
-1,3±13,5
0,6±13,1
Íà÷àëî èññëåäîâàíèÿ
76,2±8,7
75,4±9,2
Çàâåðøåíèå èññëåäîâàíèÿ
-0,7±8,8
1,9±8,3
Íà÷àëî èññëåäîâàíèÿ
72,3±8,4
71,3±9,6
Çàâåðøåíèå èññëåäîâàíèÿ
1,0±10,3
2,2±9,1
188,5±54,2
177,4±46,9
2,9±10,3
1,2±10,2
Çàâåðøåíèå èññëåäîâàíèÿ
Äèàñòîëè÷åñêîå àðòåðèàëüíîå äàâëåíèå, ìì ðò ñò
0,133
Ïóëüñ (óä/ìèí)
0,948
Âåñ, ôóíòû
0,366
Íà÷àëî èññëåäîâàíèÿ
Çàâåðøåíèå èññëåäîâàíèÿ
84
èìåëè â àíàìíåçå â ñðåäíåì îêîëî ïÿòè äåïðåññèâíûõ ýïèçîäîâ. Íàèáîëåå çíà÷èìûì ïðåäèêòîðîì
âîçìîæíîãî ðàçâèòèÿ ðåöèäèâà çàáîëåâàíèÿ ÿâëÿåòñÿ êîëè÷åñòâî ïåðåíåñåííûõ ýïèçîäîâ â àíàìíåçå;
ðèñê ðàçâèòèÿ ïîñëåäóþùåãî ðåöèäèâà ñîñòàâëÿåò
áîëåå ÷åì 95% ó ïàöèåíòîâ ñ òðåìÿ è áîëüøèì êîëè÷åñòâîì ïðåäøåñòâóþùèõ ýïèçîäîâ (19). Ïîýòîìó ïàöèåíòàì ñ õðîíè÷åñêîé èëè ðåêóððåíòíîé
äåïðåññèåé, ïåðåíåñøèì 3 èëè áîëåå äåïðåññèâíûõ
ýïèçîäîâ â òå÷åíèå æèçíè, ðåêîìåíäóåòñÿ ñ ïðîôèëàêòè÷åñêîé öåëüþ ïðèåì ïîääåðæèâàþùåé òåðàïèè (40).  òî âðåìÿ êàê â ðóêîâîäñòâàõ íå ïðèâîäÿòñÿ îñîáûå ðåêîìåíäàöèè â îòíîøåíèè òèïà èëè
ïðîäîëæèòåëüíîñòè ïîääåðæèâàþùåé òåðàïèè, â
íèõ óêàçûâàåòñÿ íà òî, ÷òî òåðàïèÿ, êîòîðàÿ áûëà
ýôôåêòèâíà â êóïèðóþùåé è ñòàáèëèçèðóþùåé
ôàçå ëå÷åíèÿ äîëæíà áûòü ïðîäîëæåíà â ïîääåðæèâàþùåé ôàçå â òîé æå äîçèðîâêå ïðèìåíÿåìîãî
àíòèäåïðåññàíòà. Ñîîáùàåòñÿ òàêæå è òî, ÷òî ïàöèåíòû ñî ñòàáèëüíûì ñîñòîÿíèåì, äåìîíñòðèðîâàëè õóäøèå êëèíè÷åñêèå èñõîäû â ñëó÷àå óìåíüøåíèÿ äîçèðîâêè àíòèäåïðåññàíòà íà ýòàïå ïîääåðæèâàþùåé ôàçû ëå÷åíèÿ â ñðàâíåíèè ñ òåìè, êòî
ïðîäîëæèë ëå÷åíèå äîçèðîâêîé ïðåïàðàòà ýôôåêòèâíîé â êóïèðóþùåé è ñòàáèëèçèðóþùåé ôàçå
òåðàïèè (7, 34).
Íàëè÷èå ðåçèäóàëüíûõ ñèìïòîìîâ, ñîõðàíÿþùèõñÿ ïîñëå ðàçðåøåíèÿ äåïðåññèâíîãî ýïèçîäà,
òàêæå ÿâëÿåòñÿ âàæíûì ïðåäèêòîðîì ðåöèäèâà çàáîëåâàíèÿ (16, 21, 32). Â äàííîì èññëåäîâàíèè ïåðåä òåì êàê âîéòè â 3 ñòàäèþ òåðàïèè ïàöèåíòû
àêòèâíî ëå÷èëèñü íà ïðîòÿæåíèè 6 ìåñÿöåâ. Èõ
ñîñòîÿíèå îöåíèâàëîñü ïî øêàëå MADRS ìåíåå
÷åì â 5 áàëëîâ, ÷òî îçíà÷àëî ïîëíóþ ðåäóêöèþ
äåïðåññèâíûõ ðàññòðîéñòâ (43). Òàêèì îáðàçîì, íà
îñíîâàíèè ïîëó÷åííûõ äàííûõ ìîæíî ïðåäïîëîæèòü, ÷òî îòìåíà àêòèâíîé òåðàïèè ó ïàöèåíòîâ
äàæå ñ íåçíà÷èòåëüíûìè ðåçèäóàëüíûìè ñèìïòîìàìè, ìîæåò çíà÷èòåëüíî ïîâûñèòü ðèñê ðàçâèòèÿ
ðåöèäèâà çàáîëåâàíèÿ. Ïîýòîìó ïàöèåíòàì ñ ðåêóððåíòíûì áîëüøèì äåïðåññèâíûì ðàññòðîéñòâîì
ðåêîìåíäóåòñÿ ïîääåðæèâàþùàÿ òåðàïèÿ íà ïðîòÿæåíèè 4–6 ìåñÿöåâ ïîñëå ïîëíîãî ðàçðåøåíèÿ ñèìïòîìîâ çàáîëåâàíèÿ äàæå ïðè íåçíà÷èòåëüíîé ðåçèäóàëüíîé ñèìïòîìàòèêå (30).
Òåðàïèÿ ýñöèòàëîïðàìîì õîðîøî ïåðåíîñèëàñü
ïàöèåíòàìè, è âñå âîçíèêàâøèå íåæåëàòåëüíûå ÿâëåíèÿ áûëè âûðàæåíû óìåðåííî, ÷òî ñîîòâåòñòâîâàëî äàííûì äðóãèõ èññëåäîâàíèé (1, 3, 22, 28, 34).
Ãîëîâîêðóæåíèå – ñèìïòîì, ïðîÿâëÿþùèéñÿ ïðè
ïðåêðàùåíèè ïðè¸ìà ÑÈÎÇÑ, áûëî îòìå÷åíî ó ïàöèåíòîâ, ïîëó÷àâøèõ ïëàöåáî â ïîääåðæèâàþùóþ
ôàçó ëå÷åíèÿ. Õîòÿ ýòî âñåãî ëèøü îäíî èç ïðîÿâëåíèé ñèíäðîìà îòìåíû ÑÈÎÇÑ, îíî èñïîëüçîâàëîñü
äëÿ îöåíêè âûðàæåííîñòè âëèÿíèÿ ïðåêðàùåíèÿ
òåðàïèè íà ðàçâèòèå íåæåëàòåëüíûõ ÿâëåíèé ó ïàöèåíòîâ, ïåðåøåäøèõ ñ ïðèåìà ýñöèòàëîïðàìà â
îòêðûòîé ôàçå èññëåäîâàíèÿ íà ïëàöåáî â äâîéíîé
ñëåïîé ôàçå ïîääåðæèâàþùåãî ëå÷åíèÿ.  íà÷àëå
áîëåå ÷àñòûå æàëîáû íà ãîëîâîêðóæåíèå îòìå÷àëèñü
â ãðóïïå, ïîëó÷àþùèõ ïëàöåáî, â ñðàâíåíèè ñ ãðóïïîé, ïðîäîëæàþùèõ ïîëó÷àòü ýñöèòàëîïðàì. Ïðè
ýòîì ÷àñòîòà ðàçâèòèÿ ãîëîâîêðóæåíèÿ íà ïðîòÿæåíèè ïåðâûõ 14 äíåé ïðèìåíåíèÿ ïëàöåáî ñíèçèëàñü
ñ 18% äî 2%. Áîëüøèíñòâî ïàöèåíòîâ, ñîîáùàâøèõ
î ãîëîâîêðóæåíèè, êàê î íåæåëàòåëüíîì ÿâëåíèè,
âîçíèêøåì â ñâÿçè ñ òåðàïèåé â ïåðâûå 14 äíåé ïîääåðæèâàþùåé ôàçû ëå÷åíèÿ, äî ýòîãî ïîëó÷àëè ýñöèòàëîïðàì â äîçèðîâêå 20 ìã/ñóò, êîòîðûé áûë îòìåíåí îäíîìîìåíòíî.  ðåàëüíîé ïðàêòèêå ïàöèåíòû áûëè áû ïåðåâåäåíû íà òåðàïèþ ýñöèòàëîïðàìîì
â äîçèðîâêå 10 ìã/ñóò è äàëåå 5 ìã/ñóò ïðåæäå, ÷åì
ïðåêðàòèòü òåðàïèþ ïîëíîñòüþ.
 öåëîì, ïîääåðæèâàþùàÿ òåðàïèÿ ýñöèòàëîïðàìîì õîðîøî ïåðåíîñèëàñü è áûëà ýôôåêòèâíîé â
ïðåäîòâðàùåíèè ðàçâèòèÿ ðåöèäèâîâ, ÷òî ïîäòâåðäèëî äàííûå ðàíåå ïðîâåä¸ííûõ èññëåäîâàíèé (4,
24, 34, 41). Òàêèì îáðàçîì, ïîëó÷åííûå äàííûå
ñâèäåòåëüñòâóþò òîì, ÷òî ýñöèòàëîïðàì ÿâëÿåòñÿ
ýôôåêòèâíûì àíòèäåïðåññàíòîì äëÿ ïîääåðæèâàþùåé òåðàïèè ðåêóððåíòíîãî áîëüøîãî äåïðåññèâíîãî ðàññòðîéñòâà.
ËÈÒÅÐÀÒÓÐÀ
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ESCITALOPRAM MAINTENANCE TREATMENT FOR
PREVENTION OF RECURRENT DEPRESSION: A RANDOMIZED, PLACEBO-CONTROLLED TRIAL
S. G. Kornstein, A. Bose, D. Li, K. G. Saikali, Ch. Gandhi
Background: Major depressive disorder is a recurrent illness that often
requires maintenance antidepressant treatment. Escitalopram is a selective
serotonin reuptake inhibitor (SSRI) that has shown efficacy in both acute
and continuation treatment of major depressive disorder. The current trial
examined the efficacy of maintenance escitalopram treatment in preventing
depression recurrence in patients who responded to acute SSRI therapy.
Method: Patients with recurrent DSM-IV-defined major depressive
disorder (> 2 previous episodes; baseline Montgomery-Asberg Depression
Rating Scale [MADRS] score >22) who had responded (MADRS score
<12) to acute open-label treatment (8 weeks) with 1 of 4 SSRIs
(fluoxetine, serlraline, paroxetine, or citalopram) received open-label,
flexible-dose continuation treatment (16 weeks) with escitalopram (10–
20 mg/day). At the end of continuation treatment, patients maintaining
response criteria were randomly assigned to 52 weeks of double-blind,
fixed-dose maintenance treatment with escitalopram (10 or 20 mg/day)
or placebo. Recurrence was defined as a MADRS score >22 or
insufficient therapeutic response during the double-blind phase. The study
was conducted between October 16, 2000, and February 4, 2003.
Results: A total of 234 patients who responded to acute open-label
treatment with 1 of 4 SSRIs received at least 1 dose of open-label
escitalopram continuation treatment. Of 164 patients who completed
escitalopram continuation treatment, 139 were randomly assigned to
double-blind maintenance treatment with escitalopram (N=73) or placebo
(N=66). Mean baseline MADRS scores at the start of the maintenance
phase were <5 for both the placebo- and escitalopram-treatment groups.
Time to recurrence was significantly longer in patients who received
maintenance treatment with escitalopram compared with patients switched
to placebo (hazard ratio =0.26, 95% CI=0.13 to 0.52, p<0.001). Longterm escitalopram treatment was well tolerated.
Conclusion: Maintenance treatment with escitalopram was well
tolerated and significantly reduced the risk for recurrence of depression.
Patients with few residual symptoms following continuation treatment
with escitalopram experienced a high rate of depression recurrence when
switched to placebo, demonstrating the need for maintenance therapy of
recurrent major depressive disorder beyond 4 to 6 months of initial
symptom resolution even if few residual symptoms are present.
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