aripiprazol-atipichn-y-antipsihotik-s-nov-m-mehanizmom-deystviya-i-risperidon-v-sravnenii-s-platsebo-u-boln-h-shizofreniey-i-shizoaffektivn-m-rasstroystvom (2)

ÓÄÊ 616.895.8–085:615.214
ÀÐÈÏÈÏÐÀÇÎË, ÀÒÈÏÈ×ÍÛÉ ÀÍÒÈÏÑÈÕÎÒÈÊ
Ñ ÍÎÂÛÌ ÌÅÕÀÍÈÇÌÎÌ ÄÅÉÑÒÂÈß,
È ÐÈÑÏÅÐÈÄÎÍ Â ÑÐÀÂÍÅÍÈÈ Ñ ÏËÀÖÅÁÎ
Ó ÁÎËÜÍÛÕ ØÈÇÎÔÐÅÍÈÅÉ
È ØÈÇÎÀÔÔÅÊÒÈÂÍÛÌ ÐÀÑÑÒÐÎÉÑÒÂÎÌ*
Ñ. Ã. Ïîòêèí, A. Ð. Ñàõà, M. Äæ. Êóÿâà, Ó. Õ. Êàðñîí, M. Àëè, Ý. Ñòîê,
Äæ. Ñòðèíãôåëëîó, Ã. Èíãåíèòî, Ñ. Ð. Ìàðäåð
Ìåõàíèçìû äåéñòâèÿ àòèïè÷íûõ àíòèïñèõîòèêîâ
øèðîêî îñâåùåíû â ëèòåðàòóðå (11, 16, 17, 19, 24–
27, 31–33, 35). Ðàçðàáîòêà ÷àñòè÷íûõ àãîíèñòîâ
D2-ðåöåïòîðîâ ÿâëÿåòñÿ ëîãè÷åñêèì ïðîäîëæåíèåì
íîâûõ ïîäõîäîâ ê ôàðìàêîòåðàïèè øèçîôðåíèè,
òàê êàê ñ÷èòàåòñÿ, ÷òî ïàòîôèçèîëîãè÷åñêèå ìåõàíèçìû ðàçâèòèÿ øèçîôðåíèè îñíîâàíû íà èçáûòî÷íîé äîôàìèíîâîé àêòèâíîñòè â îäíèõ îáëàñòÿõ ãîëîâíîãî ìîçãà è íåäîñòàòî÷íîé àêòèâíîñòè â äðóãèõ îáëàñòÿõ. ×àñòè÷íûå àãîíèñòû D2-ðåöåïòîðîâ
ìîãóò âûñòóïàòü â êà÷åñòâå ôóíêöèîíàëüíûõ àíòàãîíèñòîâ â îáëàñòÿõ ñ âûñîêèì ñîäåðæàíèåì äîôàìèíà, íàïðèìåð, â ìåçîëèìáè÷åñêîì ïóòè, íå ÿâëÿÿñü òàêîâûìè â îáëàñòÿõ ñ íîðìàëüíûì óðîâíåì äîôàìèíà
(íèãðîñòðèàðíûé è òóáåðîèíôóíäèáóëÿðíûé ïóòè).
Òàêèì îáðàçîì, îæèäàåòñÿ, ÷òî ÷àñòè÷íûå àãîíèñòû D2-ðåöåïòîðîâ áóäóò âîçäåéñòâîâàòü íà ïðîäóêòèâíóþ ñèìïòîìàòèêó, íå âûçûâàÿ äâèãàòåëüíûå
ðàññòðîéñòâà è ãèïåðïðîëàêòèíåìèþ. Â îáëàñòÿõ ñî
ñíèæåííîé êîíöåíòðàöèåé äîôàìèíà, íàïðèìåð, â
ìåçîêîðòèêàëüíîì ïóòè, ÷àñòè÷íûé àãîíèñò D2-ðåöåïòîðîâ ïðîÿâèò ôóíêöèîíàëüíóþ àãîíèñòè÷åñêóþ àêòèâíîñòü.
Ïîêàçàíî, ÷òî àðèïèïðàçîë â óñëîâèÿõ in vitro
îáíàðóæèâàåò ÷àñòè÷íóþ àãîíèñòè÷åñêóþ àêòèâíîñòü â îòíîøåíèè êëîíèðîâàííûõ D2-ðåöåïòîðîâ
÷åëîâåêà (8).  îòñóòñòâèè äîôàìèíà, ïðåïàðàò àêòèâèðóåò D2-ðåöåïòîðû, ÷òî óâåëè÷èâàåò ðåöåïòîðíóþ àêòèâíîñòü; ñòåïåíü âûðàæåííîñòè ýòîé àêòèâíîñòè, îäíàêî, íåñêîëüêî ìåíüøå, ÷åì ó äîôàìèíà.
Åñëè äîôàìèí ïðèñóòñòâóåò, àðèïèïðàçîë èíãèáèðóåò åãî ñâÿçûâàíèå ñ D2-ðåöåïòîðàìè, ÷òî ñíèæàåò ðåöåïòîðíóþ àêòèâíîñòü; â ñâÿçè ñ îñîáûì ìåõàíèçìîì äåéñòâèÿ, ïðèñóùèì àðèïèïðàçîëó, àêòèâàöèÿ D2-ðåöåïòîðîâ íå áëîêèðóåòñÿ ïîëíîñòüþ (8).
 ýêñïåðèìåíòàõ ex vivo, àðèïèïðàçîë èíãèáèðîâàë
ñïîíòàííûé âûáðîñ ïðîëàêòèíà â ãèïîôèçå (13).
Ýòî èíãèáèðîâàíèå áûëî çíà÷èòåëüíî ìåíüøèì â
ñðàâíåíèè ñ òåì, ÷òî äîñòèãàëîñü ïîëíûì àãîíèñòîì äîôàìèíîâûõ D2-ðåöåïòîðîâ – òàëèïåêñîëîì,
è ìîãëî áûòü ïîëíîñòüþ áëîêèðîâàíî ãàëîïåðèäîëîì. Â óñëîâèÿõ in vivo àðèïèïðàçîë äåìîíñòðèðóåò ýôôåêò àíòàãîíèñòà D2-ðåöåïòîðîâ íà ìîäåëÿõ
æèâîòíûõ ñ äîôàìèíåðãè÷åñêîé ãèïåðàêòèâíîñòüþ
(íàïðèìåð, áëîêàäà ñòåðåîòèïèè, âûçâàííîé àïîìîðôèí ãèäðîõëîðèäîì) è àãîíèñòà D2-ðåöåïòîðîâ
íà ìîäåëÿõ ñ äîôàìèíåðãè÷åñêîé ãèïîàêòèâíîñòüþ
(èíãèáèðîâàíèå ïîâûøåííîãî ñèíòåçà ïðîëàêòèíà
ó êðûñ, ëå÷åííûõ ðåçåðïèíîì) (18).
Àðèïèïðàçîë îáíàðóæèâàåò ÷àñòè÷íóþ àãîíèñòè÷åñêóþ àêòèâíîñòü â îòíîøåíèè 5HT1A-ðåöåïòîðîâ
(14). Ïðåäïîëàãàåòñÿ, ÷òî ÷àñòè÷íàÿ àãîíèñòè÷åñêàÿ
àêòèâíîñòü â îòíîøåíèè 5HT1A-ðåöåïòîðîâ â öåëîì
îáóñëîâëèâàåò ïîëîæèòåëüíîå âîçäåéñòâèå íà ñèìïòîìàòèêó, íàáëþäàåìóþ ó áîëüíûõ øèçîôðåíèè,
âêëþ÷àÿ òðåâîãó, äåïðåññèþ, êîãíèòèâíûå è íåãàòèâíûå ðàññòðîéñòâà (14). Òàêæå áûëî ïîêàçàíî, ÷òî
àðèïèïðàçîë îáëàäàåò àíòàãîíèñòè÷åñêîé àêòèâíîñòüþ â îòíîøåíèè 5HT2A-ðåöåïòîðîâ (23), ñðàâíèìîé
ñ òàêîâîé ó äðóãèõ àòèïè÷íûõ àíòèïñèõîòèêîâ.
Ïðåäïîëàãàåòñÿ, ÷òî àíòàãîíèñòè÷åñêàÿ àêòèâíîñòü
â îòíîøåíèè 5HT2A-ðåöåïòîðîâ îáóñëîâëèâàåò íèçêóþ ÷àñòîòó ðàçâèòèÿ ÝÏÑ (1) è ïîëîæèòåëüíîå âëèÿíèå íà íåãàòèâíûå ðàññòðîéñòâà (21, 30).
Öåëüþ íàñòîÿùåãî èññëåäîâàíèÿ ÿâëÿëîñü èçó÷åíèå ýôôåêòèâíîñòè, áåçîïàñíîñòè è ïåðåíîñèìîñòè àðèïèïðàçîëà â äîçèðîâêå 20 ìã è 30 ìã ïðè
ëå÷åíèè îñòðûõ ïñèõîòè÷åñêèõ ñîñòîÿíèé ó áîëüíûõ øèçîôðåíèåé èëè øèçîàôôåêòèâíûì ðàññòðîéñòâîì, ñ îöåíêîé âëèÿíèÿ ïðåïàðàòà íà íåãàòèâíûå ðàññòðîéñòâà è îïðåäåëåíèÿ âçàèìîñâÿçè
ìåæäó äîçèðîâêîé ïðåïàðàòà è ðàçâèòèåì ïîëîæèòåëüíîãî îòâåòà. Ðèñïåðèäîí èñïîëüçîâàëñÿ â êà÷åñòâå àêòèâíîãî êîíòðîëÿ äëÿ îöåíêè îòâåòà íà òåðàïèþ. Äèçàéí èññëåäîâàíèÿ íå ïðåäïîëàãàë îöåíêó ðàçëè÷èé â ýôôåêòèâíîñòè òåðàïèè â ðàçíûõ
òåðàïåâòè÷åñêèõ ãðóïïàõ.
* Ðàñøèðåííûé ðåôåðàò ñòàòüè, îïóáëèêîâàííîé â Arch. Gen.
Psychiatry. – 2003. – Vol. 60. – P. 681–690.
72
(òÿæåñòü), êðàòêîé øêàëå ïñèõèàòðè÷åñêîé îöåíêè (BPRS) è ñðåäíåå çíà÷åíèå øêàëû CGI-I (óëó÷øåíèå). Òàêæå ó÷èòûâàëîñü êîëè÷åñòâî ðåñïîíäåðîâ (ïàöèåíòû ñî ñíèæåíèåì îáùåãî áàëëà ïî
øêàëå PANSS íà ≥30% èëè áîëüíûå, ÷ü¸ ñîñòîÿíèå ñîîòâåòñòâîâàëî ïóíêòó 1 èëè 2 ïî øêàëå
CGI-I).
Îöåíêà áåçîïàñíîñòè. Ïàðêèíñîíèçì, àêàòèçèÿ è
äèñêèíåçèÿ îöåíèâàëèñü ñ ïîìîùüþ ñòàíäàðòèçîâàííûõ øêàë äëÿ îöåíêè ÝÏÑ: øêàëû ÑèìïñîíàÀíãóñà (SAS), øêàëû îöåíêè àêàòèçèè Áàðíñà
(BAS) è øêàëû ïàòîëîãè÷åñêèõ íåïðîèçâîëüíûõ
äâèæåíèé (AIMS) ñîîòâåòñòâåííî.
Âèòàëüíûå ïîêàçàòåëè (ïóëüñ, ñèñòîëè÷åñêîå è
äèàñòîëè÷åñêîå àðòåðèàëüíîå äàâëåíèå) îöåíèâàëèñü íà ýòàïå ñêðèíèíãà, â íà÷àëå èññëåäîâàíèÿ, â
1–5, 14 è 28 äíè. Âåñ òåëà è óðîâåíü ïðîëàêòèíà â
ïëàçìå êðîâè îöåíèâàëèñü â íà÷àëå èññëåäîâàíèÿ,
íà 14 è 28 äíè. Ýëåêòðîêàðäèîãðàôè÷åñêîå îáñëåäîâàíèå è îöåíêà ëàáîðàòîðíûõ ïîêàçàòåëåé ïðîâîäèëèñü íà ýòàïå ñêðèíèíãà, â íà÷àëå èññëåäîâàíèÿ (êðîìå ÝÊÃ), íà 14 è 28 äíè.
Ñîïóòñòâóþùàÿ ëåêàðñòâåííàÿ òåðàïèÿ. Íå
ðàçðåøàëîñü íàçíà÷åíèå èíûõ ïñèõîòðîïíûõ ïðåïàðàòîâ, êðîìå èññëåäóåìûõ, çà èñêëþ÷åíèåì ëîðàçåïàìà (äëÿ êóïèðîâàíèÿ òðåâîãè èëè èíñîìíèè),
â òîì ÷èñëå âíóòðèìûøå÷íîé ôîðìû ïðè îñòðîé
àæèòàöèè. Èñïîëüçîâàíèå áåíçòðîïèíà äëÿ êîððåêöèè ýêñòðàïèðàìèäíûõ ðàññòðîéñòâ äîïóñêàëîñü â
äîçå, íå ïðåâûøàþùåé 6 ìã/ñóò.
Ñòàòèñòè÷åñêèå ïðîöåäóðû. Ïåðâè÷íûé àíàëèç ýôôåêòèâíîñòè áûë îñíîâàí íà äàííûõ ïîëó÷åííûõ âî âðåìÿ ïîñëåäíåãî âèçèòà ïàöèåíòà, íåçàâèñèìî îò òîãî çàâåðøèë îí èññëåäîâàíèå èëè
íåò (ïðè àíàëèçå ó÷èòûâàëè ïîñëåäíþþ îöåíêó
ñîñòîÿíèÿ, åñëè îíà ïðîâîäèëàñü äî ïëàíîâîãî çàâåðøåíèÿ èññëåäîâàíèÿ – ìåòîä LOCF). Ïåðâè÷íîå ñðàâíåíèå òåðàïèè âêëþ÷àëî ñîïîñòàâëåíèå
òåðàïèè 20 ìã àðèïèðàçîëà vs ïëàöåáî è 30 ìã
àðèïèïðàçîëà vs ïëàöåáî. Äàííûå àíàëîãîâîé ýôôåêòèâíîñòè (èçìåíåíèÿ ïîêàçàòåëåé ñ èñõîäíûõ
çíà÷åíèé) áûëè îöåíåíû ñ èñïîëüçîâàíèåì êîâàðèàöèîííîãî àíàëèçà, ñ âêëþ÷åíèåì èñõîäíûõ çíà÷åíèé è öåíòðà â êà÷åñòâå ôàêòîðîâ. Äàííûå êàòåãîðèàëüíîé ýôôåêòèâíîñòè (êîëè÷åñòâî áàëëîâ
ïî CGI-I è ðåñïîíäåðû) àíàëèçèðîâàëè òåñòîì
Cochran-Mantel-Haenzel.
Îöåíêó ýôôåêòèâíîñòè ìåæäó ñðàâíèâàåìûìè
ãðóïïàìè ïðîâîäèëè ïî íèñõîäÿùåé ïðîöåäóðå,
òàê, íàïðèìåð, ñðàâíèâàëè 30 ìã àðèïèïðàçîëà ñ
ïëàöåáî äâóñòîðîííèìè òåñòàìè ñ óðîâíåì äîñòîâåðíîñòè 0,05; â ñëó÷àå îòêëîíåíèÿ, ñðàâíèâàëè
20 ìã àðèïèïðàçîëà ñ ïëàöåáî äâóñòîðîííèìè òåñòàìè ñ óðîâíåì äîñòîâåðíîñòè 0,05.
Èçìåíåíèå ïàðàìåòðîâ áåçîïàñíîñòè ñ áàçîâûõ
çíà÷åíèé îöåíèâàëîñü áåç ïîïðàâêè íà èñõîäíûå
ïîêàçàòåëè, öåíòð èññëåäîâàíèÿ èëè äðóãèå ïåðåìåííûå. Êîëè÷åñòâî ïàöèåíòîâ ñî çíà÷èìûì óâåëè÷åíèåì ìàññû òåëà îöåíèâàëîñü ñ ïîìîùüþ òåñòà
Cochran-Mantel-Haenzel.
Êðèòåðèè âêëþ÷åíèÿ è èñêëþ÷åíèÿ
 èññëåäîâàíèå áûëè âêëþ÷åíû áîëüíûå â âîçðàñòå îò 18 äî 65 ëåò ñ äèàãíîçîì øèçîôðåíèè èëè
øèçîàôôåêòèâíîãî ðàññòðîéñòâà (DSM-IV), ãîñïèòàëèçèðîâàííûå â ñâÿçè ñ îáîñòðåíèåì çàáîëåâàíèÿ. Ïàöèåíòû äîëæíû áûëè èìåòü àíàìíåç óñïåøíîé àíòèïñèõîòè÷åñêîé òåðàïèè (îòñóòñòâèå
ðåçèñòåíòíîñòè) è íàõîäèòüñÿ íà àìáóëàòîðíîì íàáëþäåíèè â òå÷åíèå ìèíèìóì 3-õ ìåñÿöåâ çà òåêóùèé ãîä; ñóììàðíûé áàëë ïî øêàëå ïîçèòèâíûõ è
íåãàòèâíûõ ñèìïòîìîâ (PANSS) äîëæåí áûë ñîñòàâëÿòü íå ìåíåå 60, ïðè ýòîì, ïî ìåíüøåé ìåðå,
2 ïóíêòà ðàçäåëà ïîçèòèâíûõ ñèìïòîìîâ äîëæíû
áûëè ñîîòâåòñòâîâàòü 4 áàëëàì (óìåðåííàÿ ñòåïåíü).
Êðèòåðèè èñêëþ÷åíèÿ: àãðåññèâíûå äåéñòâèÿ â
àíàìíåçå; íåäàâíèå ñóèöèäàëüíûå ïîïûòêè èëè
íàëè÷èå ñåðüåçíûõ ñóèöèäàëüíûõ ìûñëåé; òÿæ¸ëàÿ
íåâðîëîãè÷åñêàÿ ïàòîëîãèÿ, çà èñêëþ÷åíèåì ïîçäíåé äèñêèíåçèè èëè äðóãèõ ýêñòðàïèðàìèäíûõ
ïîáî÷íûõ ÿâëåíèé; íàëè÷èå çàâèñèìîñòè îò ïñèõîàêòèâíûõ âåùåñòâ; äðóãàÿ îñòðàÿ ñîìàòè÷åñêàÿ ïàòîëîãèÿ.
Äèçàéí èññëåäîâàíèÿ
Äàííîå ðàíäîìèçèðîâàííîå, 4-íåäåëüíîå, ñòàöèîíàðíîå, äâîéíîå ñëåïîå ïëàöåáî-êîíòðîëèðóåìîå
èññëåäîâàíèå ñ ïàðàëëåëüíûìè ãðóïïàìè, áûëî
ïðîâåäåíî â 40 ìåäèöèíñêèõ öåíòðàõ â ÑØÀ â ïåðèîä ñ ñåíòÿáðÿ 1997 ãîäà ïî îêòÿáðü 1998 ãîäà.
Ïàöèåíòû, ñîîòâåòñòâîâàâøèå êðèòåðèÿì âêëþ÷åíèÿ, ïðîõîäèëè ìèíèìóì 5-äíåâíûé ïåðèîä «îòìûâàíèÿ» (washout) ñ íàçíà÷åíèåì ïëàöåáî â òå÷åíèå
ïåðâîé ñêðèíèíãîâîé íåäåëè.
Ïàöèåíòû áûëè ðàñïðåäåëåíû ñëó÷àéíûì îáðàçîì â 4 ãðóïïû, êîòîðûå äîëæíû áûëè ïîëó÷àòü â òå÷åíèå 4 íåäåëü îäèí èç ñëåäóþùèõ ïðåïàðàòîâ – àðèïèïðàçîë 20 ìã/ñóò, àðèïèïðàçîë 30
ìã/ñóò, ðèñïåðèäîí 6 ìã/ñóò èëè ïëàöåáî. Ðèñïåðèäîí íàçíà÷àëñÿ ïåðîðàëüíî 2 ðàçà â äåíü ñ ïîñòåïåííûì ïîâûøåíèåì äîçû (2 ìã â ïåðâûé
äåíü, 4 ìã âî âòîðîé äåíü è 6 ìã/ñóò â òå÷åíèå
ïîñëåäóþùåãî ïåðèîäà). Àðèïèïðàçîë íàçíà÷àëñÿ â ïîëíîé ñóòî÷íîé äîçèðîâêå ïîñëå çàâòðàêà;
âå÷åðîì ïàöèåíòû ïðèíèìàëè ïëàöåáî äëÿ ïîääåðæàíèÿ èññëåäîâàíèÿ ñëåïûì.  ãðóïïå ïëàöåáî, ïàöèåíòû ïðèíèìàëè åãî äâàæäû â äåíü, óòðîì è âå÷åðîì. Äîçèðîâêè ïðåïàðàòîâ áûëè ôèêñèðîâàííûìè è íå ìîãëè áûòü èçìåíåíû â ñâÿçè
ñ íåäîñòàòî÷íîñòüþ ýôôåêòèâíîñòè èëè ðàçâèòèåì ïîáî÷íûõ ýôôåêòîâ.
Îöåíêà ýôôåêòèâíîñòè. Òåðàïåâòè÷åñêàÿ ýôôåêòèâíîñòü îöåíèâàëàñü ñ ïîìîùüþ øêàë PANSS
è Îáùåãî êëèíè÷åñêîãî âïå÷àòëåíèÿ (CGI).
Îöåíêó ýôôåêòèâíîñòè ïðîâîäèëè íà ýòàïå
ñêðèíèíãà, â êîíöå ïåðèîäà «îòìûâàíèÿ» (èñõîäíîå çíà÷åíèå) è ïîñëå çàâåðøåíèÿ êàæäîé íåäåëè ëå÷åíèÿ (äåíü 7, 14, 21 è 28). Îöåíèâàëèñü äèíàìèêà ïîêàçàòåëåé ïî øêàëå PANSS (â öåëîì, ïðîäóêòèâíàÿ è íåãàòèâíàÿ ñèìïòîìàòèêà) è CGI-S
73
Äåìîãðàôè÷åñêàÿ õàðàêòåðèñòèêà ïàöèåíòîâ
 îáùåé ñëîæíîñòè 404 ïàöèåíòà (283 ìóæ. è
121 æåí.) áûëè ðàíäîìèçèðîâàíû â 4 òåðàïåâòè÷åñêèå ãðóïïû íà ïåðèîä â 4 íåäåëè: àðèïèïðàçîë 20
ìã/ñóò (n=101), àðèïèïðàçîë 30 ìã/ñóò (n=101), ðèñïåðèäîí 6 ìã/ñóò (n=99), ïëàöåáî (n=103). Ñðåäíèé
âîçðàñò â êàæäîé ãðóïïå ñîñòàâèë îò 38,1 äî 40,2
ëåò. Ó 289 (72%) ïàöèåíòîâ áûë óñòàíîâëåí äèàãíîç øèçîôðåíèè, ó 115 (28%) – øèçîàôôåêòèâíîãî ðàññòðîéñòâà.  íà÷àëå èññëåäîâàíèÿ ñðåäíåå
êîëè÷åñòâî áàëëîâ äëÿ âñåõ òåðàïåâòè÷åñêèõ ãðóïï
ïî øêàëå PANSS ñîñòàâëÿëî îò 92,6 äî 95,7. Ñðåäíåå çíà÷åíèå âåñà òåëà ñîñòàâèëî 82,4–87,2 êã; ñðåäíåå ÷èñëî ãîñïèòàëèçàöèé – 8,6.
 öåëîì, 242 (60%) ïàöèåíòà çàâåðøèëè èññëåäîâàíèå, 162 ïàöèåíòà ïðåæäåâðåìåííî ïðåêðàòèëè
ïðè¸ì òåðàïèè. 42 (10%) èç 404 ïàöèåíòîâ ïðåêðàòèëè òåðàïèþ â ñâÿçè ñ îòñóòñòâèåì ïîëîæèòåëüíîãî
òåðàïåâòè÷åñêîãî îòâåòà èëè óõóäøåíèåì ñèìïòîìàòèêè, 50 (12%) ïðåêðàòèëè ïðè¸ì òåðàïèè ïî ëè÷íûì
ïðè÷èíàì è 44 (11%) – â ñâÿçè ñ ðàçâèòèåì íåæåëàòåëüíûõ ýôôåêòîâ. Íàèáîëüøåå ÷èñëî ïàöèåíòîâ,
ïðåæäåâðåìåííî ïðåêðàòèâøèõ òåðàïèþ, îêàçàëîñü â
ãðóïïå ïëàöåáî (n=51; 50%) è áûëî ñõîæèì â îñòàëüíûõ òð¸õ ãðóïïàõ (àðèïèïðàçîë 20 ìã, n=40, 40%; àðèïèïðàçîë 30 ìã, n=34, 34%; ðèñïåðèäîí, n=37, 37%).
Арипипразол 30 мг
Рисперидон 6 мг
Средний показатель из
менения общего показа
теля подшкалы негатив
ных симптомов PANSS
от начала лечения
Средний показатель из
менения общего показа
теля подшкалы позитив
ных симптомов PANSS от
начала лечения
Средний показатель
изменения общего по
казателя шкалы PANSS
от начала лечения
Плацебо
Арипипразол 20 мг
Ýôôåêòèâíîñòü
 ñðàâíåíèè ñ ïëàöåáî â îáåèõ ãðóïïàõ ñ àðèïèïðàçîëîì áûëî äîñòèãíóòî äîñòîâåðíî çíà÷èìîå
óëó÷øåíèå ïî 3 îñíîâíûì êðèòåðèÿì: îáùàÿ îöåíêà ïî øêàëå PANSS (àðèïèïðàçîë 20 ìã, p=0,001;
àðèïèïðàçîë 30 ìã, p=0,003), îöåíêà ïî ïîäøêàëå
ïîçèòèâíûõ ñèìïòîìîâ PANSS (àðèïèïðàçîë 20 ìã,
p=0,001; àðèïèïðàçîë 30 ìã, p=0,02) è CGI-S (àðèïèïðàçîë 20 ìã, p=0,03; àðèïèïðàçîë 30 ìã, p=0,006).
 ãðóïïå ðèñïåðèäîíà òàêæå áûëî îòìå÷åíî äîñòîâåðíî áîëüøåå óëó÷øåíèå ïî âñåì ïîêàçàòåëÿì
ýôôåêòèâíîñòè (òàáëèöà). Îòìå÷àëîñü áûñòðîå äîñòèæåíèå ýôôåêòà (ðèñóíîê).
Ñðåäíèé ïîêàçàòåëü èçìåíåíèÿ îáùåãî áàëëà ïî øêàëå PANSS
(À), ïîäøêàëû ïîçèòèâíûõ (Â) è íåãàòèâíûõ (Ñ) ñèìïòîìîâ
îò íà÷àëà ëå÷åíèÿ äî 4 íåä ëå÷åíèÿ àðèïèïðàçîëîì (20 èëè 30
ìã/ñóò), ðèñïåðèäîíîì (6 ìã/ñóò) èëè ïëàöåáî (ìåòîä ïåðåíîñà ïîñëåäíåãî èçìåðåíèÿ âïåðåä – LOCF)
Ïðèìå÷àíèÿ: * – p<0,05 â ñðàâíåíèè ñ ïëàöåáî; † – p<0,01
â ñðàâíåíèè ñ ïëàöåáî; ‡ – p≤0,001 â ñðàâíåíèè ñ ïëàöåáî.
Показатели эффективности: изменение показателей от исходного уровня до последней оценки состояния
(метод LOCF)
Ïàðàìåòð
Ïëàöåáî Àðèïèïðàçîë Çíà÷åíèå p vs Àðèïèïðàçîë Çíà÷åíèå p vs Ðèñïåðèäîí Çíà÷åíèå p vs
(n=103) 20 ìã (n=98)
ïëàöåáî
30 ìã (n=96)
ïëàöåáî
6 ìã (n=95)
ïëàöåáî
Ñðåäíåå çíà÷åíèå áàëëîâ ïî PANSS
Îáùåå çíà÷åíèå
-5,0
-14,5
0,001
-13,9
0,003
-15,7
<0,001
Ïîçèòèâíûå ñèìïòîìû
-1,8
-4,9
0,001
-3,9
0,02
-5,2
<0,001
Íåãàòèâíûå ñèìïòîìû
-0,8
-3,4
0,002
-3,4
0,002
-3,1
0,005
Øêàëà BPRS
-1,7
-3,5
0,004
-3,3
0,01
-3,9
<0,001
Øêàëà CGI-S
-0,2
-0,5
0,3
-0,6
0,006
-0,7
<0,001
Ñðåäíåå çíà÷åíèå
ïî øêàëå CGI-I*
4,0
3,4
0,005
3,3
0,001
3,3
<0,001
24 (23)
35 (36)
0,04
39 (41)
0,005
38 (40)
0,008
Óðîâåíü ðåñïîíäåðîâ,
êîëè÷åñòâî (%)**
Ïðèìå÷àíèÿ: BPRS – êðàòêàÿ øêàëà ïñèõèàòðè÷åñêîé îöåíêè, CGI-I – øêàëà îáùåãî êëèíè÷åñêîãî âïå÷àòëåíèÿ, ïîäøêàëà «Óëó÷øåíèå», CGI-S – øêàëà îáùåãî êëèíè÷åñêîãî âïå÷àòëåíèÿ, ïîäøêàëà «Òÿæåñòü çàáîëåâàíèÿ», PANSS – øêàëà ïîçèòèâíûõ è
íåãàòèâíûõ ñèìïòîìîâ. * – çíà÷åíèÿ ïðèâåäåíû êàê ñðåäíèå äàííûå èçìåíåíèé èñõîäíûõ âåëè÷èí. ** – ïàöèåíòû ñ 30% èëè
áîëüøèì ñíèæåíèåì çíà÷åíèé ïî øêàëå PANSS èëè ñî çíà÷åíèåì 1 (çíà÷èòåëüíîå óëó÷øåíèå) èëè 2 (óëó÷øåíèå) ïî øêàëå
CGI-I.
74
Áûëî âûÿâëåíî äîñòîâåðíîå ïðåèìóùåñòâî àðèïèïðàçîëà (20 ìã è 30 ìã) â ñðàâíåíèè ñ ïëàöåáî
ïî øêàëå CGI-I (àðèïèïðàçîë 20 ìã, p=0,002; àðèïèïðàçîë 30 ìã, p=0,001) (ðèñóíîê) è øêàëå BPRS
(àðèïèïðàçîë 20 ìã, p=0,004; àðèïèïðàçîë 30 ìã,
p=0,01) (òàáëèöà).  îòíîøåíèè âñåõ òð¸õ ïàðàìåòðîâ ñòàòèñòè÷åñêè äîñòîâåðíûå ðàçëè÷èÿ â ãðóïïàõ
ñ àðèïèïðàçîëîì è ïëàöåáî ñòàëè îáíàðóæèâàòüñÿ
ñ 1-é íåäåëè òåðàïèè. Ñòàòèñòè÷åñêè äîñòîâåðíûå
ðàçëè÷èÿ ìåæäó ðèñïåðèäîíîì è ïëàöåáî áûëè
îòìå÷åíû ñî 2-é íåäåëè ïî ðàçäåëó íåãàòèâíûå ñèìïòîìû øêàëû PANSS (ðèñóíîê) è ñ ïåðâîé íåäåëè
ïî øêàëå CGI-I è BPRS.
Êîëè÷åñòâî ðåñïîíäåðîâ ïî øêàëàì PANSS è
CGI-I áûëî äîñòîâåðíî áîëüøå â îáåèõ ãðóïïàõ
àðèïèïðàçîëà â ñðàâíåíèè ñ ãðóïïîé ïëàöåáî (ïëàöåáî – 23%; àðèïèïðàçîë 20 ìã – 36%, p=0,04; àðèïèïðàçîë 30 ìã, p=0,005). Â ãðóïïå ðèñïåðèäîíà
òàêæå áûëî äîñòîâåðíî áîëüøå ðåñïîíäåðîâ â ñðàâíåíèè ñ ãðóïïîé ïëàöåáî (40%; p=0,008) (òàáëèöà).
ñîîáùàëîñü îá ýêñòðàïèðàìèäíûõ ïîáî÷íûõ ýôôåêòàõ. Äèñòîíèÿ/ãèïåðòîíóñ áûëè îòìå÷åíû ó 14
(14%) ïàöèåíòîâ â ãðóïïå ðèñïåðèäîíà â ñðàâíåíèè
ñ 3 (3%) ïàöèåíòàìè â ãðóïïå àðèïèïðàçîëà 20 ìã,
1 (1%) â ãðóïïå àðèïèïðàçîëà 30 ìã è 6 (6%) â ãðóïïå ïëàöåáî.
Îöåíêà ïî øêàëå Ñèìïñîí-Àíãóñà: ñðåäíåå çíà÷åíèå èçìåíåíèé ïîêàçàòåëåé îò èñõîäíîãî óðîâíÿ
â ãðóïïå àðèïèïðàçîëà 20 ìã ñîñòàâèëî -0,16; -0,09
â ãðóïïå àðèïèïðàçîëà 30 ìã; -0,18 â ãðóïïå ðèñïåðèäîíà è -0,18 â ãðóïïå ïëàöåáî. Ïîïàðíîå ñðàâíåíèå íå âûÿâèëî ñòàòèñòè÷åñêè çíà÷èìûõ ðàçëè÷èé ìåæäó ãðóïïàìè ñ àêòèâíîé òåðàïèåé è ïëàöåáî.
Îáùåå ÷èñëî áàëëîâ ïî øêàëå àêàòèçèè Áàðíñà:
ñðåäíåå çíà÷åíèå èçìåíåíèé ïîêàçàòåëåé îò èñõîäíîãî óðîâíÿ â ãðóïïå àðèïèïðàçîëà 20 ìã ñîñòàâèëî -0,15; -0,18 â ãðóïïå àðèïèïðàçîë 30 ìã; 0,14 â
ãðóïïå ðèñïåðèäîíà è 0,11 â ãðóïïå ïëàöåáî. Ïîïàðíîå ñðàâíåíèå íå âûÿâèëî ñòàòèñòè÷åñêè çíà÷èìûõ ðàçëè÷èé ìåæäó ãðóïïàìè ñ àêòèâíîé òåðàïèåé è ïëàöåáî.
Øêàëà îöåíêè ïàòîëîãè÷åñêèõ íåïðîèçâîëüíûõ
äâèæåíèé: ñðåäíåå çíà÷åíèå èçìåíåíèé ïîêàçàòåëåé îò èñõîäíîãî óðîâíÿ â ãðóïïå àðèïèïðàçîëà
20 ìã ñîñòàâèëî -0,27; -0,5 â ãðóïïå àðèïèïðàçîëà
30 ìã; -0,6 â ãðóïïå ðèñïåðèäîíà è 0,1 â ãðóïïå ïëàöåáî.  ñðàâíåíèè ñ ïëàöåáî, ðèñïåðèäîí ïðîäåìîíñòðèðîâàë ñòàòèñòè÷åñêè çíà÷èìûå ðàçëè÷èÿ
(p=0,03).
Äàííûå îá èñïîëüçîâàíèè áåíçòðîïèíà áûëè ñõîæèìè âî âñåõ òð¸õ ãðóïïàõ àêòèâíîé òåðàïèè.
Ìàññà òåëà. Èçìåðåíèå ìàññû òåëà çà ïåðèîä
èññëåäîâàíèÿ ïîêàçàëî ìèíèìàëüíîå óâåëè÷åíèå
çíà÷åíèé ñ èñõîäíûõ ïîêàçàòåëåé â äèíàìèêå âî
âñåõ òð¸õ ãðóïïàõ òåðàïèè: àðèïèïðàçîë 20 ìã –
1,2 êã, àðèïèïðàçîë 30 ìã – 0,8 êã, ðèñïåðèäîí 6 ìã
– 1,5 êã. Ýòè çíà÷åíèÿ ñòàòèñòè÷åñêè çíà÷èìî îòëè÷àëèñü îò ïîêàçàòåëåé â ãðóïïå ïëàöåáî, â êîòîðîé áûëî îòìå÷åíî ñíèæåíèå ìàññû òåëà çà ïåðèîä èññëåäîâàíèÿ íà 0,3 êã. ×àñòîòà êëèíè÷åñêè çíà÷èìîé ïðèáàâêè ìàññû òåëà (ïîâûøåíèå ìàññû
òåëà íà ≥7% îò èñõîäíûõ ïîêàçàòåëåé) îêàçàëàñü
äîñòîâåðíî âûøå íà ôîíå âñåõ âàðèàíòîâ òåðàïèè
â ñðàâíåíèè ñ ïëàöåáî: ïëàöåáî – 2%; àðèïèïðàçîë
20 ìã – 13% (p=0,004); àðèïèïðàçîë 30 ìã – 9%
(p=0,04); ðèñïåðèäîí 6 ìã – 11% (p=0,03).
Óðîâåíü ïðîëàêòèíà â ïëàçìå êðîâè. Çà ïåðèîä
èññëåäîâàíèÿ áûëî îòìå÷åíî ñíèæåíèå óðîâíÿ ïðîëàêòèíà â ïëàçìå êðîâè ñ èñõîäíûõ çíà÷åíèé â îáåèõ ãðóïïàõ àðèïèïðàçîëà (àðèïèïðàçîë 20 ìã,
-6,6 íã/ìë; àðèïèïðàçîë 30 ìã, -6,4 íã/ìë) è ïîâûøåíèå â ãðóïïå ïëàöåáî (0,1 íã/ìë); ðàçëè÷èÿ ìåæäó ãðóïïàìè àðèïèïðàçîëà è ïëàöåáî íå äîñòèãàëè ñòàòè÷åñêè çíà÷èìûõ çíà÷åíèé. Íè ó îäíîãî èç
ïàöèåíòîâ, ïîëó÷àâøèõ àðèïèïðàçîë, óðîâåíü
ïðîëàêòèíà â ïëàçìå êðîâè íå áûë íèæå íèæíåé ãðàíèöû ðåôåðåíòíûõ çíà÷åíèé (2 íã/ìë).  ãðóïïå ðèñïåðèäîíà îòìå÷àëîñü ïîâûøåíèå óðîâíÿ ïðîëàêòèíà â êðîâè äî 47,9 íã/ìë, ÷òî áûëî äîñòîâåðíî âûøå,
Áåçîïàñíîñòü
Íåæåëàòåëüíûå ÿâëåíèÿ. Â öåëîì, òåðàïèÿ àðèïèïðàçîëîì â îáåèõ äîçèðîâêàõ õîðîøî ïåðåíîñèëàñü ïàöèåíòàìè è áûëà áåçîïàñíîé. Áîëüøèíñòâî
âîçíèêàâøèõ íåæåëàòåëüíûõ ÿâëåíèé áûëî âûðàæåíî â ë¸ãêîé èëè óìåðåííîé ñòåïåíè è, â îñíîâíîì, íå îãðàíè÷èâàëî òåðàïèþ.  îáùåé ñëîæíîñòè 44 (11%) èç 403 ïàöèåíòîâ âûáûëè èç èññëåäîâàíèÿ â ñâÿçè ñ íåæåëàòåëüíûìè ÿâëåíèÿìè íà ôîíå
ëå÷åíèÿ: 17 (17%) â ãðóïïå ïëàöåáî, 8 (8%) â ãðóïïå ðèñïåðèäîíà, 11 (11%) â ãðóïïå àðèïèïðàçîëà
20 ìã è 8 (8%) â ãðóïïå àðèïèïðàçîëà 30 ìã. ×àùå
âñåãî òåðàïèÿ ïðåêðàùàëàñü â ñâÿçè ñ ðàçâèòèåì ïñèõîòè÷åñêîãî ñîñòîÿíèÿ: 8 (8%) â ãðóïïå ïëàöåáî,
5 (5%) â ãðóïïå ðèñïåðèäîíà, 10 (10%) ïàöèåíòîâ â
ãðóïïå àðèïèïðàçîëà 20 ìã è 5 (5%) ïàöèåíòîâ â
ãðóïïå àðèïèïðàçîëà 30 ìã.
Êîëè÷åñòâî ïàöèåíòîâ, èñïûòàâøèõ íåæåëàòåëüíûå ÿâëåíèÿ â ñâÿçè ñ òåðàïèåé, áûëî ïðèìåðíî
îäèíàêîâûì âî âñåõ òåðàïåâòè÷åñêèõ ãðóïïàõ: 91%
(92 ÷åë.) â ãðóïïå àðèïèïðàçîëà 20 ìã, 91% (91 ÷åë.)
â ãðóïïå àðèïèïðàçîëà 30 ìã, 93% (92 ÷åë.) â ãðóïïå ðèñïåðèäîíà è 86% (89 ÷åë.) â ãðóïïå ïëàöåáî.
Ó ïàöèåíòîâ, ïîëó÷àâøèõ àðèïèïðàçîë, òàêèå íåæåëàòåëüíûå ÿâëåíèÿ êàê ãîëîâíàÿ áîëü, òîøíîòà,
ðâîòà, áåññîííèöà, ñîìíîëåíöèÿ, âîçíèêàëè â îñíîâíîì â òå÷åíèå ïåðâîé íåäåëè òåðàïèè è ñîõðàíÿëèñü íå áîëåå 7 äíåé. Íå ïðîñëåæèâàëîñü äîçîçàâèñèìîå âîçíèêíîâåíèå íåæåëàòåëüíûõ ÿâëåíèé,
âîçìîæíî, çà èñêëþ÷åíèåì ñîìíîëåíöèè.
Çà ïåðèîä èññëåäîâàíèÿ, â öåëîì, ó 8 ïàöèåíòîâ
áûëî îòìå÷åíî ðàçâèòèå ñåðüåçíûõ íåæåëàòåëüíûõ
ÿâëåíèé (àðèïèïðàçîë 20 ìã, n=2; àðèïèïðàçîë 30
ìã, n=3; ïëàöåáî, n=3).
Ýêñòðàïèðàìèäíûå ñèìïòîìû.  öåëîì, ÷àñòîòà âîçíèêíîâåíèÿ ÝÏÑ áûëà ñõîæåé â ãðóïïå àðèïèïðàçîëà è ðèñïåðèäîíà (àðèïèïðàçîë 20 ìã, n=32,
32%; àðèïèïðàçîë 30 ìã, n=31, 31%; ðèñïåðèäîí,
n=31, 31%). Â ãðóïïå ïëàöåáî ó 21 (20%) ïàöèåíòà
75
÷åì â ãðóïïå ïëàöåáî (p<0,001). Êîëè÷åñòâî ïàöèåíòîâ ñ óðîâíåì ïðîëàêòèíà â ïëàçìå êðîâè âûøå
23 íã/ìë (âåðõíÿÿ ãðàíèöà ðåôåðåíòíûõ çíà÷åíèé)
ñîñòàâèëî â ãðóïïå ïëàöåáî 10,3%; â ãðóïïå àðèïèïðàçîëà 20 ìã – 4,1% (p=0,16 vs ïëàöåáî); àðèïèïðàçîë 30 ìã – 3,3% (p=0,08 vs ïëàöåáî) è â ãðóïïå ðèñïåðèäîíà – 90,5% (p<0,001 vs ïëàöåáî).
Ýëåêòðîêàðäèîãðàììà. Èíòåðâàë QTc ðàññ÷èòûâàëñÿ ñ ïîìîùüþ ôîðìóëû Áàçåòòà (QTcB=QT/RR0,5).
Ñðåäíèå çíà÷åíèÿ äèíàìèêè èíòåðâàëà QT c äëÿ
êàæäîé òåðàïåâòè÷åñêîé ãðóïïû ñîñòàâèëè: àðèïèïðàçîë 20 ìã, 0,97 ìèëëèñåêóíä; àðèïèïðàçîë 30
ìã, -2,35 ìèëëèñåêóíä; ïëàöåáî, -2,18 ìèëëèñåêóíä;
ðèñïåðèäîí, 6,31 ìèëëèñåêóíäó. Íè ó îäíîãî èç
ïàöèåíòîâ, ïîëó÷àâøèõ àðèïèïðàçîë èëè ïëàöåáî,
íå áûëî îòìå÷åíî êëèíè÷åñêè çíà÷èìîãî óâåëè÷åíèÿ èíòåðâàëà QTc (êëèíè÷åñêè çíà÷èìûì ñ÷èòàëîñü óâåëè÷åíèå äî 450 ìèëëèñåêóíä èëè áîëåå, à
òàêæå óâåëè÷åíèå ïîêàçàòåëÿ íà 10% èëè áîëåå ñ
èñõîäíûõ çíà÷åíèé); â ãðóïïå ðèñïåðèäîíà ïîäîáíûå îòêëîíåíèÿ íàáëþäàëèñü ó 3 (3%) èç 95 áîëüíûõ.
Î÷åâèäíûõ ðàçëè÷èé ìåæäó òåðàïåâòè÷åñêèìè
ãðóïïàìè ïî ÷àñòîòå âîçíèêíîâåíèÿ êëèíè÷åñêè
çíà÷èìûõ îòêëîíåíèé ëàáîðàòîðíûõ è âèòàëüíûõ
ïîêàçàòåëåé îòìå÷åíî íå áûëî, íè îäèí èç ïàöèåíòîâ íå âûáûë èç èññëåäîâàíèÿ â ñâÿçè ñ ïàòîëîãè÷åñêèìè èçìåíåíèÿìè æèçíåííî âàæíûõ ïîêàçàòåëåé. Íå áûëî âûÿâëåíî êëèíè÷åñêè çíà÷èìîé ðàçíèöû â ëàáîðàòîðíûõ ïîêàçàòåëÿõ ìåæäó ãðóïïàìè,
çà èñêëþ÷åíèåì çíà÷åíèé óðîâíÿ ïðîëàêòèíà â
ïëàçìå êðîâè. Îäèí ïàöèåíò â ãðóïïå ðèñïåðèäîíà âûáûë èç èññëåäîâàíèÿ â ñâÿçè ñ óìåðåííûìè
èçìåíåíèÿìè ïîêàçàòåëåé ôóíêöèè ïå÷åíè.
ïè÷íûõ àíòèïñèõîòèêîâ (3, 5, 7, 24, 26, 34). Òåðàïèÿ àðèïèïðàçîëîì â îáåèõ äîçèðîâêàõ õîðîøî
ïåðåíîñèëàñü.  äàííîé ðàáîòå è â ðàíåå ïðîâåä¸ííûõ èññëåäîâàíèÿõ àðèïèïðàçîëà (9, 15) íå îòìå÷àëîñü çàâèñèìîñòè âîçíèêíîâåíèÿ ïîáî÷íûõ ýôôåêòîâ îò äîçèðîâêè ïðåïàðàòà, çà èñêëþ÷åíèåì
ñîìíîëåíöèè.
Âûðàæåííîñòü ýêñòðàïèðàìèäíîé ñèìïòîìàòèêè
íå îòëè÷àëàñü â ãðóïïàõ àðèïèïðàçîëà ïî ñðàâíåíèþ ñ ïëàöåáî, ÷òî ñîîòâåòñòâóåò äàííûì êëèíè÷åñêîé ïðîãðàììû ïî èçó÷åíèþ àðèïèïðàçîëà (22).
 ãðóïïå ðèñïåðèäîíà ÷àùå áûëè îòìå÷åíû äèñòîíèÿ/ãèïåðòîíóñ. Ýòî ìîæåò áûòü ñâÿçàíî ñ òåì, ÷òî
ðèñïåðèäîí â äîçèðîâêå 6 ìã/ñóò îáëàäàåò ñïîñîáíîñòüþ âûçûâàòü ðàçâèòèå ÝÏÑ.
Çíà÷èòåëüíîå ïîâûøåíèå óðîâíÿ ïðîëàêòèíà â
êðîâè è âûñîêàÿ ÷àñòîòà ðàçâèòèÿ ãèïåðïðîëàêòèíåìèè íà ïðîòÿæåíèè âñåãî èññëåäîâàíèÿ îòìå÷àëàñü â ãðóïïå ðèñïåðèäîíà. Íè â îäíîé èç ãðóïï
àðèïèïðàçîëà íå áûëî îòìå÷åíî ñòàòèñòè÷åñêè çíà÷èìîãî óâåëè÷åíèÿ óðîâíÿ ïðîëàêòèíà â ïëàçìå
êðîâè, íàïðîòèâ, â îáåèõ ãðóïïàõ áûëî çàôèêñèðîâàíî íåêîòîðîå ñíèæåíèå ýòîãî ïîêàçàòåëÿ îò èñõîäíûõ çíà÷åíèé. Ïîâûøåíèå óðîâíÿ ïðîëàêòèíà â
ïëàçìå êðîâè âûøå âåðõíåé ãðàíèöû ðåôåðåíòíûõ
çíà÷åíèé áûëî îòìå÷åíî ó 10,3% ïàöèåíòîâ â ãðóïïå ïëàöåáî, 4,1% è 3,3% â ãðóïïàõ àðèïèïðàçîëà
20 ìã è 30 ìã ñîîòâåòñòâåííî è â 90,5% ñëó÷àåâ â
ãðóïïå ðèñïåðèäîíà. Òàê êàê äîôàìèí èíãèáèðóåò
âûñâîáîæäåíèå ïðîëàêòèíà, íåêîòîðîå ñíèæåíèå
óðîâíÿ ïðîëàêòèíà ïðè íàçíà÷åíèè àðèïèïðàçîëà
ìîæåò áûòü îáúÿñíåíî ÷àñòè÷íûì àãîíèçìîì äîôàìèíîâûõ ðåöåïòîðîâ, ÷òî îòðàæàåò äàííûå ïðåêëèíè÷åñêèõ èññëåäîâàíèé (13).
Ïðè ïðèåìå íåêîòîðûõ àíòèïñèõîòè÷åñêèõ
ñðåäñòâ îòìå÷åíî óäëèíåíèå èíòåðâàëà QTc íà ÝÊÃ
(12), ÷òî ìîæåò áûòü ïðè÷èíîé ðàçâèòèÿ ëåòàëüíîé
ñåðäå÷íîé àðèòìèè. Ó òðåõ ïàöèåíòîâ â ãðóïïå
ðèñïåðèäîíà áûëî îòìå÷åíî êëèíè÷åñêè çíà÷èìîå
óäëèíåíèå èíòåðâàëà QTc; îòñóòñòâèå ñëó÷àåâ óäëèíåíèÿ èíòåðâàëà QTc â îáåèõ ãðóïïàõ àðèïèïðàçîëà ïîäòâåðæäàåò íèçêèé óðîâåíü àðèòìîãåííîãî
äåéñòâèÿ äàííîãî ïðåïàðàòà.
Çíà÷èòåëüíûé èíòåðåñ âûçûâàåò ïðîáëåìà ïîâûøåíèÿ ìàññû òåëà íà ôîíå ïðèåìà àíòèïñèõîòè÷åñêîé òåðàïèè (1, 2). Óâåëè÷åíèå ìàññû òåëà ìîæåò
ÿâèòüñÿ ïðè÷èíîé ðàçâèòèÿ ñåðäå÷íî-ñîñóäèñòûõ
îñëîæíåíèé è ñàõàðíîãî äèàáåòà, à òàêæå ìîæåò
ïðèâîäèòü ê íèçêîé êîìïëàéåíòíîñòè ïàöèåíòà. Â
íàñòîÿùåì èññëåäîâàíèè êîëè÷åñòâî ïàöèåíòîâ ñ
êëèíè÷åñêè çíà÷èìîé ïðèáàâêîé ìàññû òåëà áûëî
ïðèìåðíî îäèíàêîâûì âî âñåõ 3 ãðóïïàõ òåðàïèè
(9–13%).  õîäå íàñòîÿùåãî êðàòêîñðî÷íîãî èññëåäîâàíèÿ ñðåäíèå ïîêàçàòåëè èçìåíåíèÿ ìàññû òåëà
(0,8–1,5 êã) íå áûëè êëèíè÷åñêè çíà÷èìûìè. Äëÿ
îöåíêè äèíàìèêè ïîâûøåíèÿ ìàññû òåëà è åå ïîñëåäñòâèé íåîáõîäèì áîëåå äëèòåëüíûé ïåðèîä
íàáëþäåíèÿ.
Ðåçóëüòàòû íàñòîÿùåãî èññëåäîâàíèÿ ñâèäåòåëüñòâóþò î òîì, ÷òî àðèïèïðàçîë îáëàäàåò ýôôåêòèâ-
Êîììåíòàðèè
 äàííîì èññëåäîâàíèè áûëî ïîêàçàíî, ÷òî àðèïèïðàçîë â äîçèðîâêå 20 è 30 ìã/ñóò ÿâëÿåòñÿ ýôôåêòèâíûì, áåçîïàñíûì è õîðîøî ïåðåíîñèìûì
ïðåïàðàòîì äëÿ òåðàïèè ïàöèåíòîâ ñ îáîñòðåíèåì
øèçîôðåíèè èëè øèçîàôôåêòèâíîãî ðàññòðîéñòâà.
Áûëî âûÿâëåíî äîñòîâåðíîå ïðåèìóùåñòâî àðèïèïðàçîëà (20 è 30 ìã/ñóò) ïî ñðàâíåíèþ ñ ïëàöåáî ïî
âñåì îñíîâíûì êðèòåðèÿì îöåíêè ýôôåêòèâíîñòè
(îáùåå ÷èñëî áàëëîâ ïî øêàëå PANSS, áàëëû ïîçèòèâíîãî è íåãàòèâíîãî ðàçäåëîâ øêàëû PANSS,
áàëëû ïî øêàëå CGI-S, ïî øêàëå BPRS, ñðåäíåå
çíà÷åíèå ïî øêàëå CGI-I è âðåìÿ îòâåòà íà òåðàïèþ). Óëó÷øåíèå ñèìïòîìàòèêè íà òåðàïèè àðèïèïðàçîëîì áûëî ñðàâíèìûì ñ òàêîâûì íà òåðàïèè
ðèñïåðèäîíîì.
Áûñòðîå äîñòèæåíèå ýôôåêòà áûëî ïðîäåìîíñòðèðîâàíî â îáåèõ ãðóïïàõ àðèïèïðàçîëà: äîñòîâåðíî çíà÷èìîå êëèíè÷åñêîå óëó÷øåíèå â ñðàâíåíèè
ñ ïëàöåáî îòìå÷àëîñü óæå íà ïåðâîé íåäåëå òåðàïèè, ñîõðàíÿÿñü äî êîíöà èññëåäîâàíèÿ.  ïðåäøåñòâóþùèõ ðàáîòàõ òàêæå áûëà ïîêàçàíà ýôôåêòèâíîñòü 15 ìã ïðåïàðàòà (28).
×àñòîòà äîñðî÷íîãî ïðåêðàùåíèÿ òåðàïèè â äàííîì èññëåäîâàíèè ñîîòâåòñòâóåò òàêîâîé äëÿ àòè76
íîñòüþ â îòíîøåíèè ëå÷åíèÿ ïñèõîòè÷åñêèõ ðàññòðîéñòâ ó áîëüíûõ øèçîôðåíèåé. Íåêîòîðûå îðèãèíàëüíûå äàííûå, îáíàðóæåííûå â õîäå íàñòîÿùåãî èññëåäîâàíèÿ, ìîãóò áûòü îáúÿñíåíû óíèêàëüíûì ìåõàíèçìîì äåéñòâèÿ àðèïèïðàçîëà, à èìåííî
÷àñòè÷íîé àãîíèñòè÷åñêîé àêòèâíîñòüþ ê D 2 ,
5HT1A-ðåöåïòîðàì è àíòàãîíèñòè÷åñêîé àêòèâíîñòüþ â îòíîøåíèè 5HT2A-ðåöåïòîðîâ. Áûëî ïîêàçàíî, ÷òî àðèïèïðàçîë â äîçèðîâêå 20 ìã è 30 ìã ÿâëÿåòñÿ ýôôåêòèâíûì â îòíîøåíèè ïîçèòèâíûõ è
íåãàòèâíûõ ñèìïòîìîâ øèçîôðåíèè. Òàêæå â íàñòîÿùåì èññëåäîâàíèè áûëî ïðîäåìîíñòðèðîâàíî áûñòðîå íà÷àëî äåéñòâèÿ àðèïèïðàçîëà è ñòàáèëüíîñòü ïîëîæèòåëüíîãî ýôôåêòà íà ïðîòÿæåíèè 4-õ
íåäåëü èññëåäîâàíèÿ. Ýòè äàííûå ïîêàçûâàþò, ÷òî
àðèïèïðàçîë – ïåðâûé ÷àñòè÷íûé àãîíèñò äîôàìèíà, îêàçûâàþùèé çíà÷èòåëüíîå è äëèòåëüíîå àíòèïñèõîòè÷åñêîå äåéñòâèå. Äîñòèæåíèå àíòèïñèõîòè÷åñêîãî ýôôåêòà íà ôîíå ïðèåìà àðèïèïðàçîëà â
äîçèðîâêå 20 ìã è 30 ìã íå ñîïðîâîæäàëîñü ðàçâèòèåì òàêèõ íåæåëàòåëüíûõ ÿâëåíèé êàê óäëèíåíèå
èíòåðâàëà QT c, çíà÷èìûõ ÝÏÑ èëè ïîâûøåíèÿ
ìàññû òåëà. Íèçêèé ðèñê ðàçâèòèÿ ãèïåðïðîëàêòèíåìèè è ÝÏÑ íà ôîíå ïðèåìà àðèïèïðàçîëà,
ïðîäåìîíñòðèðîâàííûé â äàííîì è ðÿäå ðàíåå
ïðîâåäåííûõ èññëåäîâàíèé, îáúÿñíÿåòñÿ ÷àñòè÷íîé
àãîíèñòè÷åñêîé àêòèâíîñòüþ â îòíîøåíèè D2-ðåöåïòîðîâ, â îòëè÷èå îò äðóãèõ äîñòóïíûõ â íàñòîÿùåå
âðåìÿ àíòèïñèõîòèêîâ, áëîêèðóþùèõ D2-ðåöåïòîðû
â íèãðîñòðèàðíîé è òóáåðîèíôóíäèáóëÿðíîé ñèñòåìàõ. Ñî÷åòàíèå äëèòåëüíîãî ïîëîæèòåëüíîãî ýôôåêòà è õîðîøåé ïåðåíîñèìîñòè ìîæåò ïîñëóæèòü
óëó÷øåíèþ êîìïëàéåíñà ïàöèåíòîâ è ñíèçèòü ÷àñòîòó ðåöèäèâà çàáîëåâàíèÿ â äîëãîñðî÷íîé ïåðñïåêòèâå. Òàêèì îáðàçîì, ðåçóëüòàòû íàñòîÿùåãî èññëåäîâàíèÿ ñâèäåòåëüñòâóþò î òîì, ÷òî àðèïèïðàçîë
îòêðûâàåò íîâûå âîçìîæíîñòè òåðàïèè øèçîôðåíèè è øèçîàôôåêòèâíîãî ðàññòðîéñòâà.
ËÈÒÅÐÀÒÓÐÀ
16. Kapur S., Seeman P. Antipsychotic agents differ in how fast they
come off the dopamine D2 receptors: implications for atypical
antipsychotic action // J. Psychiatry Neurosci. – 2000. – Vol. 25. – P. 161–
166.
17. Kapur S., Seeman P. Does fast dissociation from the dopamine D2
receptor explain the action of atypical antipsychotics? a new hypothesis
// Am. J. Psychiatry. – 2001. – Vol. 158. – P. 360–369.
18. Kikuchi T., Tottori K., Uwahodo Y. et al. 7-(4-[(2,3Dichlorophenyl)-1-piperazinyl]butyoxyl-3,4-dihydro-2 (IH)-quinolinone
(OPC-14597), a new putative antipsychotic drug with both presynaptic
and postsynaptic D2 receptor antagonist activity // J. Pharmacol. Exp.
Ther. – 1995. – Vol. 274. – P. 329–336.
19. Kurzthaler I., Fleishhacker W.W. The clinical implications of
weight gain in schizophrenia // J. Clin. Psychiatry. – 2001. – Vol. 62,
Suppl. 7. – P. 32–37.
20. Lahti A.C., Weiler M.A., Corey P.K. et al. Antipsychotic properties
of the partial dopamine agonist (-)-3-(3-hydroxyphenyl)-N-npropylpiperidine (preclamot) in schizophrenia // Biol. Psychiatry. – 1998.
– Vol. 43. – P. 2–11.
21. Leysen J.E., Janssen P.M., Schotte A. et al. Interaction of
antipsychotic drugs with neurotransmitter receptor sites in vitro and in vivo
in relation to pharmacological and clinical effects: role of 5HT2 receptors
// Psychopharmacol. – 1993. – Vol. 112, Suppl. 1. – P. S40–S54.
22. Marder S.R., McQuade R.D., Stock E. et al. Aripripazole in the
treatment of schizophrenia: safety and tolerability in short-term, placebocontrolled trials // Schizophr. Res. – 2003. – Vol. 61. – P. 123–126.
23. McQuade R.D., Burris K.D., Jordan S. et al. Aripiprazole: a
dopamine-serotonin system stabilizer [abstract] // Int.
Neuropsychopharmacol. – 2002. – Vol. 5, Suppl. 1. – P. S176.
24. Meltzer H.Y., Stahl S.M. The dopamine hypothesis of
schizophrenia: a review // Schizophr. Bull. – 1976. – Vol. 2. – P. 19–76.
25. Meltzer H.Y. The role of serotonin in antipsychotic drug action //
Neuropsychopharmacology. – 1999. – Vol. 21, Suppl. 2. – P. 106S–115S.
26. Millan M.J. Improving the treatment of schizophrenia: focus on
serotonin (5-HT1A) receptors // J. Pharmacol. Exp. Ther. – 2000. – Vol.
295. – P. 853–861.
27. Naber O., Gaussares C., Moeglen J.M, Tremmel L., Bailey P.E.,
and the SDZ HOC 912 Collaborative Study Group. Efficacy and
tolerability of SDZ HOC 912, a partial dopamine D-2 agonist, in the
treatment of schizophrenia // New Research Directions in the
Development of Atypical and Other Novel Antipsychotic Medications /
H.Y.Meltzer (Ed.). – New York, NY: Raven Press, 1991.
28. Olbrich R., Schanz H. An evaluation of the partial dopamine
agonist terguride regarding positive symptoms reduction in schizophrenics
// J. Neural Transm. Gen. Sect. – 1991. – Vol. 84. – P. 233–236.
29. Olbrich R., Schanz H. The effect of the partial dopamine agonist
terguride on negative symptoms in schizophrenics // Pharmacopsychiatry.
– 1988. – Vol. 21. – P... 389–390.
30.Rao M.L., Moler H.J. Biochemical findings of negative
symptoms in schizophrenia and their putative relevance to pharma-
1. Allison D.B., Casey D.E. Antipsychotic-induced weight gain: a review
of the literature // J. Clin. Psychiatry. – 2001. – Vol. 62. – P. 22–31.
2. Allison D.B., Mentore J.L., Heo M. et al. Antipsychotic induced
weight gain: a comprehensive research synthesis // Am. J. Psychiatry. –
1999. – Vol. 156. – P. 1686–1696.
3. Arvanitis L.A., Miller B.G. Multiple fixed doses of “Seroquel”
(quetiapine) in patients with acute exacerbation of schizophrenia: a
comparison with haloperidol and placebo: the Seroquel Trial 13 Study
Group // Biol. Psychiatry. – 1997. – Vol. 42. – 233–246.
4. Beasley C.M.Jr., Hamilton S.H., Crawford A.M. et al. Olanzapine
versus haloperidol: acute phase results of the international double-blind
trial // Eur. Neuropsychopharmacol. – 1997. – Vol. 7. – P. 125–137.
5. Beasley C.M.Jr., Sanger T., Satterlee W. et al. Olanzapine versus
placebo: results of a double-blind, fixed-dose olanzapine trial //
Psychopharmacology. – 1996. – Vol. 124. – P. 159–167.
6. Beasley C.M.Jr., Tollefson G., Tran P. et al. Olanzapine versus
placebo and haloperidol: acute phase results of the North American
double-blind olanzapine trial // Neuropsychopharmacology. – 1996. – Vol.
14. – P. 111–123.
7. Borison R.L., Arvanitis L.A., Miller B.G. ICl 204,636, an atypical
antipsychotic: efficacy and safety in a multicenter, placebo-controlled trial
in patients with schizophrenia: US Seroquel Study Group. JC/m //
Psychopharmacol. – 1996. – Vol. 16. – P. 158–169.
8. Burris K.D., Molski T.F., Xu C. et al. Aripiprazole, a novel
antipsychotic, is a high affinity partial agonist at human dopamine D2
receptors // J. Pharmacol. Exp. Ther. – 2002. – Vol. 302. – P. 381–389.
9. Daniel D.G., Saha A.R., Ingenito G. et al. Aripiprazole, a novel
antipsychotic: overview of a phase II study result [abstract] // Int. J.
Neuropsychopharmacol. – 2000. – Vol. 3, Suppl. 1. – P. S157.
10. Dickson R.A., Glazer W.M. Neuroleptic-induced hyperprolactinemia // Schizophr. Res. – 1999. – Vol. 35, Suppl. 1. – P. S75–
S86.
11. Fleischhacker W.W., Meise U., Gunther V., Kurz M. Compliance
with antipsychotic drug treatment: influence of side effects // Acta
Psychiatr. Scand. – 1994. – Vol. 382. – P. 11–15.
12. Gury C., Canceil O., Iaria P. Antipsychotic drugs and cardiovascular
safety: current studies of prolonged QT interval and risk of ventricular
arrhythmia // Encephale. – 2000. – Vol. 26, N 6. – P. 62–72.
13. Inoue T., Domae M., Yamada K., Furukawa T. Effects of the novel
antipsychotic agent 7-[4-[(2,3-dichlorophenyl)-1 -piperazinyl]butyoxy]3,4-dihydro-2 (1H)-quinolinone (OPC-14597) on prolactin release from
the rat anterior pituitary gland // J. Pharmacol. Exp. Ther. – 1996. – Vol.
277. – P. 137–143.
14. Jordan S., Koprivica V., Chen R. et al. The antipsychotic
aripiprazole is a potent, partial agonist at the human 5-HT1A receptor //
Eur. J. Pharmacol. – 2002. – Vol. 441. – P. 137–140.
15. Kane J.M., Carson W.H., Sana A.R. et al. Efficacy and safety of
aripiprazole and haloperidol versus placebo in patients with schizophrenia
and schizoaffective disorder // J. Clin. Psychiatry. – 2002. – Vol. 63. –
P. 763–771.
77
yet occupy high levels of these receptors // Mol. Psychiatry. – 1998. –
Vol. 3. – P. 123–134.
34. Small J.G., Hirsch S.R., Arvanitis L.A. et al. Quetiapine in patients
with schizophrenia: a high- and low-dose double-blind comparison with
placebo: Seroquel Study Group // Arch. Gen. Psychiatry. – 1997. – Vol.
54. – P. 549–557.
35. Stahl S.M. Essential Psychopharmacology. – New York, NY:
Cambridge University Press, 1996.
36. Tamminga C.A. Partial dopamine agonists in the treatment of
psychosis // J. Neural Transm. – 2002. – Vol. 109. – P. 411–420.
cologic treatment: a review // Neuropsychobiology. – 1994. – Vol. 30.
– P. 160–172.
31.Richelson E. Receptor pharmacology of neuroleptics: relation
to clinical effects // J. Clin. Psychiatry. – 1999. – Vol. 60, Suppl. 10.
– P. 5–14.
32. Roth B.L., Sheffler D., Potkin S.G. Atypical antipsychotic drug
action: unitary or multiple mechanisms for “atypicality” // Clin. Neurosci.
In press.
33. Seeman P., Tallerico T. Antipsychotic drugs which elicit little or
no parkinsonism bind more loosely than dopamine to brain D2 receptors,
ARIPIPRAZOLE, AN ANTIPSYCHOTIC WITH A NOVEL MECHANISM OF ACTION, AND RISPERIDONE VS
PLACEBO IN PATIENTS WITH SCHIZOPHRENIA AND SCHIZOAFFECTIVE DISORDER
St. G. Potkin, A. R. Saha, M. J. Kujawa, W. H. Carson, M. Ali, E. Stock, J. Stringfellow,
G. Ingenito, St. R. Marder
placebo occurred at week 1 for PANSS total and positive scores with
aripiprazole and risperidone and for PANSS negative scores with
aripiprazole. There were no significant differences between aripiprazole
and placebo in mean change from baseline in the extrapyramidal symptom
rating scales. Mean prolactin levels decreased with aripiprazole but
significantly increased 5-fold with risperidone. Mean change in QTc
interval did not differ significantly from placebo with any active treatment
group. Aripiprazole and risperidone groups showed a similar low
incidence of clinically significant weight gain.
Conclusions: Aripiprazole is effective, safe, and well tolerated for the
positive and negative symptoms in schizophrenia and schizoaffective
disorder. It is the first non-D2 receptor antagonist with clear antipsychotic
effects and represents a novel treatment development for psychotic
disorders.
Background: Aripiprazole is a dopamine D2 receptor partial agonist
with partial agonist activity at serotonin 5HT1A receptors and antagonist
activity at 5HT2A receptors. This multicenter trial examined the efficacy,
safety, and tolerability of aripiprazole in patients with acute exacerbation
of schizophrenia or schizoaffective disorder.
Methods: In this 4-week double-blind study, 404 patients were
randomized to 20 mg/d (n=101) or 30 mg/d (n=101) of aripiprazole,
placebo (n=103), or 6 mg/d of risperidone (n=99). Efficacy assessments
included Positive and Negative Syndrome Scale (PANSS) scores and
Clinical Global Impression scores. Safety and tolerability evaluations
included extrapyramidal symptoms and effects on weight, prolactin, and
corrected QT (QTc) interval.
Results: Aripiprazole (20 and 30 mg/d) and risperidone (6 mg/d) were
significantly better than placebo on all efficacy measures. Separation from
78