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 ÝÊà (óäëèíåíèå èíòåðâàëà ÐQ, êîìïëåêñà QRS è èíòåðâàëà QT) (24).  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).  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. ËÈÒÅÐÀÒÓÐÀ 1. Anderson I.M., Tomenson Â.Ì. The efficacy of selective serotonin re-uptake inhibitors in depression: a meta-analysis of studies against tricyclic antidepressants // J. Psychopharmacology. – 1994. – Vol. 8. – P. 238–249. 2. Angst J. The prevalence of depression // Antidepressant therapies at the dawn of the 3rd Millennium / M.Briley, S.Montgomerym (Eds.). – Martin Dunitz, London, 1997 in press. 3. Ansseau M., Papart P., Troisfontaines Â. et al. Controlled 48 19. Lopez-Ibor J., Guelfy J., Pletan Y. et al. Milnacipran and selective serotonin reuptake inhibitors in major depression // Clin. Psychopharmacol. – 1996. – Vol. 11. – P. 41– 46. 20. Macher J., Sichel J., Serre C. Double blind placebo controlled study of milnacipran in hospitalised patients with major depressive disorders // Neuropsychobiol. – 1989. – Vol. 22. – P. 77–82. 21. Martin R., Hilton S., Kerry S., Richards N. General practitioners’ perceptions of the tolerability of antidepressant drugs: a comparison of selective serotonin reuptake inhibitors and tricyclic antidepressants // Br. Med. J. – 1997. – Vol. 314. – P. 649–651. 22. Moller H.J., Volz H.R. Drug treatment of depression in the 1990s. An overview of achievements and possibilities // Drugs. – 1996. – Vol. 52. – P. 625–638. 23. Montgomery S., Asberg M. A new depression scale designed to be sensitive to change // Br. J. Psychiatry. – 1979. – Vol. 134. – P. 382–389. 24. Montgomery A., Prost J.R., Solles A., Briley M. Efficacy and tolerability of milnacipran: an overview // Clin. Psychopharmacol. – 1996. – Vol. 11, Suppl. 4. – P. 47–51. 25. Moret C., Charveron M., Finberg J.P.M. et al. Biochemical profile of midalcipran (F2207), 1-phenyl-l-diethyl-amino-carbonyl-2aminomethyl-cyclopropane (Z) hydrochloride, a potential fourth generation antidepressant drug // Neuropharmacology. – 1985. – Vol. 24. – P. 1211–1219. 26. Potter W., Rudorfer M., Manji H. The pharmacologic treatment of depression // New Engl. J. Med. – 1991. – Vol. 325. – P. 633–642. 27. Puech A., Montgomery S., Prost J. et al. Milnacipran, a new serotonin and noradrenalin reuptake inhibitor: an overview of its antidepressant activity and clinical tolerability // Intern. Clin. Psychopharmacol. – 1997. – Vol. 12. – P. 99–108. 28. Puozzo C., Filaquier C., Briley M. Plasma levels of F2207, midalcipran, a novel antidepressant, after single oral administration in volunteers // Br. J. Clin. Pharmacol. – 1985. – Vol. 20. – P. 291– 292. 29. Richelson E. Antimuscarinic and other receptor-blocking properties of antidepressants // Mayo Clinic Proceedings. – 1983. – Vol. 58. – P. 40–46. 30. Serre C., Clerc G., Escande M. An early clinical trial of midalcipran, 1-pheyl-l-diethyl-aminocarbonyl-2-aminomethylcyclopropane (Z) hydrochloride, a potential fourth generation antidepressant // Curr. Ther. Res. – 1986. – Vol. 39. – P. 156–164. 31. Sussman N. The potential benefits of serotonin receptor-specific agents // J. Clin. Psychiatry. – 1994. – Vol. 55. – P. 45–51. 32. Van Praag H. Studies in the mechanisms of action of serotonin precursors in depression // Psychopharmacol. Bull. – 1984. – Vol. 20. – P. 599–602. comparison of milnacipran and fluoxetine in major depression // Psychopharmacology Berlin. – 1994. – Vol. 114. – P. 131–137. 4. Benfield P., Heel R., Lewis S. Fluoxetine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in depressive illness // Drugs. – 1986. – Vol. 32. – P. 481–508. 5. Briley M., Moret C. Specific serotonin/noradrenaline reuptake inhibiting antidepressants // Antidepressants: current trends and future direction / P.Skolnick (Ed.). – Humana Press, 1997. – P. 35–52. 6. Briley M., Prost J., Moret C. Preclinical pharmacology of milnacipran // Clin. Psychopharmacol. – 1996. – Vol. 11. – P. 9–14. 7. Danish University Antidepressant Group. Citalopram: a clinical effect profile in comparison with clomipramine. A controlled multicentre study // Psychopharmacol. – 1986. – Vol. 90. – P. 131–138. 8. Danish University Antidepressant Group. Paroxetine: a selective serotonin reuptake inhibitor showing better tolerance, but weaker antidepressant effect than clomipramine in a controlled multicentre study // J. Affect. Dis. – 1990. – Vol. 18. – P. 289–299. 9. Dardennes R., Berdeaux G., Lafuma A., Fagani F. Milnacipran: a new cost-effective SNRI alternative in the treatment of depressed patients // Eur. Psychiatry, 1997 in press. 10. DeVane C.L. Pharmacokinetics of the newer antidepressants: clinical relevance // Am. J. Med. – 1994. – Vol. 97, Suppl. 6A. – P. 13S–23S. 11. Edwards J.G. Selective serotonin reuptake inhibitors // Br. Med. J. – 1992. – Vol. 304. – P. 1644–1646. 12. European College of Neuropsychopharmacology. Clinical relevance of response and improvement in psychopharmacology // Eur. Neuropsychopharmacol. – 1995. – Vol. 5. – P. 511–533. 13. Finley P.R. Selective serotonin reuptake inhibitors: pharmacological profiles and potential therapeutic distinctions // Ann. Pharmacother. – 1994. – Vol. 28. – P. 1359–1369. 14. Guy W. ECDEU Assessment Manual for Psychopharmacology (revised). – Rockville, MD: National Institute for Mental Health; Psychopharmacology Research Branch, 1976. 15. Hamilton M. A rating scale for depression // J. Neurology, Neurosurgery and Psychiatry. – 1960. – Vol. 12. – P. 56–62. 16. Kasper A., Pletan Y., Solles A., Toumoux A. Comparative studies with milnacipran and tricyclic antidepressants in the treatment of patients with major depression: a summary of clinical trial results // Clin. Psychopharmacol. – 1996. – Vol. 11. – P. 35–39. 17. Lecrubier L., Pletan Y., Solles A. et al. Clinical efficacy of milnacipran: placebo controlled trials // Clin. Psychopharmacol. – 1996. – Vol. 11. – P. 29–33. 18. Lepine J. European perspective on depression: The patient’s view. – 8th ECNP Congress, Venice, Italy, 1995. – P. 1–2, abstract. 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. 49