종설대한정신약물학회지 2011;22 Suppl:S26-S34 pissn / eissn online ML Comm 정신분열병임상연구에서의 Paliperidone Palmitate 의효능 이봉주 1 이정구 1,2 김영훈 1,2,3 인제대

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1 종설대한정신약물학회지 211;22 Suppl:S26-S34 pissn / eissn online ML Comm 정신분열병임상연구에서의 Paliperidone Palmitate 의효능 이봉주 1 이정구 1,2 김영훈 1,2,3 인제대학교해운대백병원정신과학교실, 1 백인제기념임상의학연구소, 2 FIRST Research Group 3 The Review of Clinical Trials Evaluating Efficacy of Paliperidone Palmitate for the Treatment of Patient with Schizophrenia Bong Ju Lee, MD, PhD, 1 Jung Goo Lee, MD, PhD 1,2 and Young Hoon Kim, MD, PhD 1,2,3 1 Department of Psychiatry, Inje University Haeundae Paik Hospital, Busan, 2 Paik Institute for Clinical Research, Inje University, Busan, 3 The FIRST Research Group, Inje University, Busan, Korea Paliperidone (9-hydroxyrisperidone) is the major active metabolite of risperidone and has demonstrated an efficacy on the treatment of schizophrenia. Paliperidone palmitate is a new long-acting atypical antipsychotic injection for the treatment of acute and maintenance therapy in schizophrenia. Paliperidone palmitate is convenient compared to other long-acting atypical antipsychotic injections, as it is available in prefilled syringes and a wide dose range. Also, it requires no refrigeration, no reconstitution, and none of any other oral antipsychotic supplementations. In four randomized, double-blind, placebo-controlled trials of 9 to 13 weeks duration, paliperidone palmitate was shown to be effective in reducing total Positive and Negative Syndrome Scale scores in acute state of schizophrenia. In two long-term trials, the time to recurrence of symptoms was significantly longer for paliperidone-treated patients, showing that paliperidone palmitate is significantly more efficacious than placebo as a maintenance therapy. In addition, paliperidone palmitate was shown to have similar efficacy compared with risperidone long-acting injection. Treatment with paliperidone palmitate should be initiated with 15 mg eq. (paliperidone palmitate 234 mg) on day 1 and 1 mg eq. (paliperidone palmitate 156 mg) on day 8, followed by a recommended monthly maintenance dose. Overall, paliperidone palmitate may have advantages over other currently available long-acting injections. Therefore, it may serve as a useful alternative to the treatment for schizophrenia, although further long-term trials may be necessary to compare paliperidone palmitate to other active treatments. Korean J Psychopharmacol 211;22 Suppl:S26-S34 Key WordszzPaliperidone palmitate Long-acting injection Schizophrenia Adherence Risperidone. Correspondence author: Young Hoon Kim, MD, PhD Department of Psychiatry, Inje University Haeundae Paik Hospital, 1435 Jwa-dong, Haeundae-gu, Busan 612-3, Korea Tel: , Fax: , 정신분열병치료에있어서복약충실도 (adherence) 는치료결과에큰영향을미친다. 지금까지의연구결과들을보면장기간의지속적약물치료는정신분열병의재발을막는것으로밝혀졌다. 1,2) 하지만지속적약물치료를위해서필요한복약충실도에대한문제는완전히해결되지않았다. 여러해결책중의하나로개발된방법이체내에서장기간체류하는장기지속형제제를사용하여정신분열병환자들이약물을투여받는기간의간격을늘리는것이었다. 정형항정신병장기지속형제제가 196년대에처음개발된이후지금까지여러종류의정형장기지속형제제들이개발되었다. 현재까지데포제제는총 9종류가개발되었는데, 여기에는 3종류의비정형항정신병약물 (risperidone, olanzapine, paliperidone) 과 6종류의정형항정신병약물 (flupentixol, fluphenazine, haloperidol, perphenazine, pipotiazine zuclopenthixol) 이있다. 각각의약물들에대한간략한비교및설명은 Table 1에정리되어있다. 처음개발된정형장기지속형주사제는복약충실도를높이고재발을막는데기여했지만, 3) 정형항정신병경구약제와유사하게음성증상에대한치료효과는좋지못하였으며, 추체외로부작용 (extrapyramidal symptom) 과고프로락틴혈증 (hyperprolactinemia) 등의부작용때문에제한적으로사용되어왔다. 4-6) 최근에 risperidone 장기지속형주사제와 7) olanzapine pamoate 같은 8) 비정형항정신병장기지속형제제가개발되어사용되고있다. 비정형항정신병장기지속형제제들의효과를살펴보면, risperidone 장기지속형주사제는정신분열병에서뚜렷한치료효과가있었으며, 7,9-11) S26 Copyright c 211 대한정신약물학회

2 이봉주등 Table 1. Characteristics of long-acting injectable (LAI) antipsychotics Formulation Treatment initiation Maintenance dosing Paliperidone palmitate Aqueous-based nanosuspension Initiation injections on Day 1 and Day 8; no oral supplementation required Once monthly injection (every 4 weeks) Olanzapine pamoate Aqueous-based vehicle No oral supplementation Once monthly injection (every 4 weeks) Risperidone long-acting injection Aqueous-based microsphere suspension 3 weeks oral antipsychotic overlap required at initiation Every 2 weeks Conventional antipsychotics LAI Viscous, oil-based Vehicle Various loading dose strategies used to achieve steady-state faster; no oral supplementation required Generally every 2-4 weeks Administration Deltoid and gluteal IM Deltoid and gluteal IM Deltoid and gluteal IM IM; Z-track administration may be required Dosage range 25, 5, 75, 1, 15 mg eq. 21, 3, 45 mg (Reconstituted to a fixed concentration of 15 mg/ml) 12.5, 25, 37.5, 5 mg Broad Storage No refrigeration required No refrigeration required Refrigeration required No refrigeration required Needle supplied or recommended 23 G or 22 G safety needle 19 G needle 21 G or 2 G safety needle 21 G needle 경구용 risperidone과비교할때유사한효과와안전성을보였다. 12) Olanzapine pamoate 역시위약과비교할때정신분열병에서뚜렷한치료효과가있었으며, 경구용 olanzapine과비교할때유사한효과와안정성을보였다 ) 그러나 risperidone 장기지속형주사제는투여간격이 2주로비교적짧고주사시통증을유발한다는불편함이있었고, olanzapine pamoate는 주사후섬망 / 진정증후군 이라는심각한부작용때문에사용이제한적이다. 13,16,17) 최근이러한불편함을개선한새로운항정신병약물인 paliperidone 의장기지속형주사제가개발되었다. Paliperidone palmitate 는미국에서정신분열병급성기치료및유지치료에승인을받았으며, 21년에한국에서도동일한적응증에대해승인을받았다. 현재 aripiprazole 장기지속형주사제도개발되어 18) 국내 3상연구가진행중에있으며, 향후다양한비정형항정신병약물의장기지속형주사제를사용하게될것이다. 저자들은최근새로개발된 paliperidone palmitate 의효과를알아보고자지금까지시행된임상연구결과를중심으로 paliperidone palmitate 의효과에대해고찰하였다. 항정신병약물장기지속형주사제가정신분열병환자의재발방지에중요한역할을한다. 이들이경구약제보다재발을방지하는능력이뛰어남을증명하는데는여러가지고려해야할점들이있다. 약을잘복용하지않는환자들은통제된 연구에스스로참여하기를꺼려할것이며, 재발률은환자의질병상태에따라다양하게나타날것이다. 이런점들이연구디자인에서중요한요소로고려되어야한다. 2,19) 지금까지발표된장기지속형주사제와경구약제의효능에대한초기의비교연구들은입원상황에서진행되어약물순응도를제대로평가할수없었으며연구결과도매우다양하게나타났다. 2-24) 이후장기지속형주사제의효능에대한다양한평가들이행해졌는데, 이를위해무작위통제연구, 전향적관찰연구, 거울-상 (mirror-image) 연구등이적용되었다. Adams 등 6) 은장기지속형주사제와경구약제의효능에대한무작위비교통제연구들을대상으로메타분석을시행하였으나두약제간재발률에의미있는차이는없었다. 그러나이분석에포함된연구들은재발률을평가하기에는너무단기간에연구가시행되었다는문제점을가지고있었다. 25) 정형장기지속형주사제와정형및비정형경구약제들을비교한몇몇전향적관찰연구들이있었다. 두연구에서는정형장기지속형주사제가정형항정신병약물경구약제보다재발률이낮았다. 26,27) 다른연구에서는정형장기지속형주사제와비정형항정신병약물경구약제를비교하였는데, 오히려경구약제를사용한군에서재발률이낮았다. 28-3) 이런일치되지않은연구결과들은정형약물과비정형약물의비교뿐만아니라, 경구약제와장기지속형주사제를비교할때발생하는 selection bias 때문이라고볼수있다. 4) 환자의치료방법변경시점을기준으로전, 후같은기간을서로비교하는거울-상연구가행해지기도했다. 처음사용된경구약제의복약불충 S27

3 Paliperidone Palmitate 의효능 실문제로인해약물변경이이루어진다는태생적문제가있음에도불구하고장기지속형주사제와경구약제를비교한여러거울-상연구들이시도되었다. 197년대에시행된 6개의거울-상연구를대상으로한메타분석에서는장기지속형주사제를사용한환자군에서재발률이의미있게감소했으며, 2,31) 198년대에행해진연구에서도같은결과를보였다. 32,33) 한편, 장기지속형주사제가빠르고효과적이라는증거들이있음에도불구하고, 아직초발정신병환자에게는항정신병약물장기지속형주사제를흔하게사용하지않는다. 초발환자에서도재발은복약불충실과상당한관련성이있으며, 34,35) 장기지속형주사제는상당히매력적인선택이될수있다. 36) 최근초발정신병연구에서장기지속형주사제의사용이상당히유용하다는결론을얻었다. 국내에서시행된 2년간전향적개방연구에서 5명의환자중 22명은 risperidone장기지속형주사제를나머지 28명은경구 risperidone을사용하였는데, 장기지속형주사제군에서뛰어난복약충실도와낮은재발률을보였다. 37) 역시초발정신병환자를대상으로한 Weiden 등 38) 의연구에서도 risperidone 장기지속형주사제를사용한군이경구약제를사용한군에비해복약충실도가높았다 ( 각각 89 vs. 59%). 그러나재발률이낮고건강관리비용을줄일수있다는여러긍정적인연구결과들이있음에도불구하고여전히장기지속형제제가경구약제와비교할때그효능이우월한지에대해서는아직논란의여지가있다. 그렇지만최근기존의약물에대한여러문제점들을보완하여개발된비정형항정신병약물장기지속형주사제인 paliperidone palmitate에대한연구들은, 아직많은연구들이행해지지는않았지만, 그효능에있어상당히긍정적인결과들을보이고있다. Paliperidone palmitate에대한초기임상연구는약물용량-반응연구와용량결정연구들로서현재제약회사에서권유하는약물투여방법과는다른방법으로임상연구가진행되었다. 초기임상연구에서는현재권유용량보다는더낮은용량들이사용되었고, 이런점이약물효능에대한평가에불리한영향을주었을것으로생각된다. Paliperidone palmitate 의정신분열병급성기치료효능을평가한다기관무작위이중맹검위약대조단기간연구 (9~ 13주 ) 는총 4개이다 ) 모든연구에서정해진용량의주사제가 1, 8, 36일째에투여되었으며, 13주연구에서는 64일째에도투여되었다. 이중한연구에서만 42) 15 mg eq. 의초기용량을삼각근에주사하였고, 이후 5, 1, 15 mg eq. 의용량을둔부근또는삼각근에주사하였다. 다른세연구에서는 39-41) 고용량의초기용량을투여하지않았다. 정신분열병유지치료에서의 paliperidone palmitate 의효능은 52주 이중맹검위약비교재발방지연구와 43) 이연구의연장인 52 주개방연구에서 44) 평가되었다. 또한 2개의임상연구에서 paliperidone palmitate와 risperidone 장기지속형주사제와의효능을비교하였다 (Table 2). 45,46) (Acute efficacy) 급성기효능을알아보기위한 4개의단기간연구가있었는데이연구들은무작위배정, 이중맹검, 위약대조연구로 paliperidone palmitate의다양한용량을사용하여시행되었다. 이연구들의 primary efficacy endpoint 는 Positive and Negative Syndrome Scale( 이하 PANSS) 47) 의연구시작시점부터종결시점까지의총점변화였으며, secondary endpoint는약물반응비율 (PANSS 총점이 3% 이상감소한환자의비율 ), Clinical Global Impression-Severity( 이하 CGI-S), 48) PANSS factor와 subscale 점수, Personal and Social Performance Scale( 이하 PSP) 49) 점수의변화였다. 이들 4개의단기간연구중 3개의연구 39,41,42) 는용량-반응연구였다. Pandina 등 42) 에의한연구는대상자가 636명으로대상자수가제일큰연구였다. 4개의단기간연구에서연구개시점부터종결점까지의 PANSS 전체점수의변화는위약군에서 -2.9점 ~+6.2점, paliperidone palmitate 군에서 -5.2점 ~-16.1점이었다. 약물반응비율은위약군이평균 22%(14~31%), paliperidone palmitate군이평균 38% (23~52%) 였다. 가장많은인원이참여한 Pandina 등 42) 의용량-반응연구에의하면 25 mg eq. 에서 15 mg eq. 사이의용량에서용량-반응의상관관계가있었다. 위약과비교한 effect size는 25 mg eq, 5 mg eq, 15 mg eq에서각각.26,.47,.55였다. 이런결과는다른두연구 4,41) 에서도비슷하게나타나는데, 위약군에비해서 paliperidone palmitate 5 mg eq, 75 mg eq, 1 mg eq. 를투여한군에서의미있는증상의호전이있었다. 그러나가장적은인원이참여한 Gopal 등 39) 의용량-반응연구에서는 1 mg eq. 를투여한군에서만위약에비하여좋은결과를얻었고, 15 mg eq. 를투여한군은 medication kit 할당오류로인해분석을할수없었다. 급성기연구들에서증상의변화가위약군과비교할때뚜렷한차이를나타내는시점은두연구 4,42) 에서 8일째였으며, 다른두연구 39,41) 에서는 36일째였다 (Fig. 1). Paliperidone palmitate가 PANSS 5개 factor에미친영향을분석하면다음과같다. 우선 Pandina 등 42) 의연구에서는 15 mg eq. 와 15 mg eq. 를투여한군에서위약군에비해 5개 factor 모두에서의미있는호전을보였다. Gopal 등 39) 의연구에서는 1 mg eq. 투여군에서만같은결과를보였다. 9주연구인 Kramer 등 4) 의연구에서는 1 mg eq. S28 대한정신약물학회지 211;22 Suppl:S26-S34

4 이봉주등 Acute efficacy Long-term efficacy Compar-ison with Risperidone LAI Authors Study details Gopal RCT, DB, PC et al. 39) Dose-response study Kramer RCT, DB, PC et al. 4) Efficacy and Safety study Nasrallah RCT, DB, PC, et al. 41) paralle-group, dose-response study Pandina RCT, DB, PC et al. 42) Dose-response study Hough RCT, DB, PC, et al. 43) recurrence prevention study Gopal Long-term, et al. 44) open-label, extension-phase study of 6 Gopal RCT, parallel-group, et al. 45) noninferiority study compared with RLAI Table 2. Summary of efficacy studies of paliperidone palmitate Number of patients Length Paliperidone palmitate dose (mg eq.) Route Outcome weeks Gluteal Group Change from baseline Response rate(%) 247 (197: ITT analysis) 518 (514: ITT population) * 39* Placebo Placebo weeks 5 Gluteal 5-5.2* 33* ** 37* Placebo Placebo weeks 25 Gluteal * 46* * ** 52* Placebo Placebo (125) -7. (2.7) weeks 25 Deltoid/ * 34* 1 Gluteal * 41** 312 (interim analysis), 48 (final analysis) 52 weeks week extension * 4** Placebo Placebo -2.9 (*p.34) 2 1: 56% 117 5: 34% 39 75: 9% 25: 1% weeks PP: 25, 5, 75, 1 /four weeks RLAI: 25, 37.5, 5 mg /two weeks Gluteal Time to relapse in PP patients versus placebo (p<.1) Relapse event rates: PP: 1% versus placebo: 34% Change from baseline in PANSS total score in double-blind period Placebo vs. PP=11.1(16.6) vs. 2.5 (12.16) 74% of patients completed this study. Mean (SD) of change from baseline to endpoint in PANSS total score: -4.3 (15.43) Placebo PP group : -8.4(19.43) Mean (SD) change from baseline to endpoint (LOCF) in PANSS total PP: -12 (21.2) RLAI: -14 (19.8) Predetermined margin for noninferiority was not met (by.84 points). Panidna RCT, DB, parallel-group, et al. 46) multicenter comparative study with RLAI 122 (913: ITT analysis) 13 weeks PP: 5, 1, 15 /four weeks RLAI: 25, 37.5, 5 mg/two weeks Lower limit of 95% CI of treatment difference for change in PANSS total score exceeded protocol prespecified noninferiority margin (-5) PP demonstrated to be noninferior to RLAI Response rate: percentage of patients with 3% decrease in PANSS total score from baseline to endpoint; Statistical significnace *p<.5; **p.1. DB: double-blind, ITT: intention to treat, LOCF: last observation carried forward, OLE: open label extension, PP: paliperidone palmitate, PC: placebo-controlled, PANSS: positive and negative symptom scale, pts: patients, RCT: randomized controlled trial, RLAI: risperidone long-acting injection, SD: standard deviation S29

5 Paliperidone Palmitate 의효능 Least squares mean change from baseline (±SE) End point Days Least squares mean change from baseline (±SE) * * * * * * * * * End Days Placebo Paliperidone palmitate 5 mg eq. Paliperidone palmitate 1 mg eq. n Baseline mean Placebo Paliperidone palmitate 5 mg eq Paliperidone palmitate 1 mg eq Least squares mean change from baseline (±SE) End point Days Least squares mean change from baseline (±SE) End point Days Baseline mean n Total score Placebo Paliperidone palmitate 25 mg eq. Paliperidone palmitate 5 mg eq. Paliperidone palmitate 1 mg eq. Placebo Paliperidone palmitate 25 mg eq Paliperidone palmitate 5 mg eq Paliperidone palmitate 1 mg eq Fig. 1. PANSS 점수의변화 ) Comparisons of paliperidone palmitate vs. placebo based on an Analysis of Covariance (ANCOVA) model with treatment and country as factors, and baseline score as a covariate. : 25, 1, and 15 mg eq.: All unadjusted p-values <.5 as early as Day 8 for the paliperidone palmitate 25 and 15 mg eq. groups and as early as Day 22 for the paliperidone palmitate 1 mg eq. group. *all nominal p-values were less than the pre-specified.1 level. the maximum observed nominal p-value was.11. SE: standard error. 투여군에서는 5개 factor 모두에서호전을보였지만, 5 mg eq. 투여군에서는 uncontrolled hostility factor에서는호전을보이지않았다. Nasrallah 등 41) 의연구에서는 1 mg eq. 투여군에서 disorganization factor를제외한모든 factor에서호전을보였고, 5 mg eq. 투여군에서는 positive, negative, uncontrolled hostility factor에서호전을보였으며, 25 mg eq. 투여군에서는 positive, negative, anxiety/ depression factor에서호전을보였다. Paliperidone palmitate 가 CGI-S 평가에미친영향을정 리하면다음과같다. 우선 Pandina 등 42) 의연구에서는 1 mg eq. 투여군과 15 mg eq. 투여군에서 CGI-S상에의미있는호전을보였다. Gopal 등 39) 의연구에서는 1 mg eq. 투여군에서만호전을보였다. Nasrallah 등 41) 의연구에서는모든용량군에서 CGI-S 점수상에호전을보였다. 9주연구인 Kramer 등 4) 의연구에서는연구종결시점에서 CGI-S 가 marked, severe 또는 extremely severe인비율이위약군에서 5% 이었고, 5 mg eq. 투여군과 1 mg eq. 투여군에서는각각 37% 와 32% 로서위약군과약물군간에는통 S3 대한정신약물학회지 211;22 Suppl:S26-S34

6 이봉주등 계적으로의미있는차이가있었다 (p.4). 네연구중세연구 39,41,42) 에서 PSP를평가하였다. 두연구에서 PSP 평가상위약에비해 5 mg eq., 39) 1 mg eq., 39,42) 15 mg eq. 42) 투여군에서호전이있었다고보고했다. 단, Nasrallah 등 41) 의연구에서는 PSP 평가상호전이없었고, 이에대해저자들은높은위약반응때문이라고설명했다. (Long-term efficacy) Paliperidone palmitate를사용한재발방지장기유지연구 43) 가있었다. 이연구는 5단계로시행되었다. 우선 7일동안 screening, washout, 경구약내성검사를거친뒤, 다음 9주간전환단계 (transition phase) 에서는 paliperidone palmitate 25 mg eq., 5 mg eq., 1 mg eq. 를자유롭게사용하는개방형연구가진행되었다. 다음 24주간유지단계 (maintenance phase) 에서는자유롭게용량을조절하는 12주간의연구와이후고정된용량을사용하는 12주간의연구로진행되었다. 마지막에는이중맹검무작위할당단계 (double-blind randomization phase) 가위약비교연구로진행되었다. 이중맹검단계평균진행기간은위약군이 15일이었고, paliperidone palmitate투여군은 171일이었다. 환자들은재발을경험하거나동의를철회하기전까지계속연구에참여하였다. 이연구에이어 52주개방형확장연구 (open-label extension phase) 가행해졌는데, 44) 이단계를포함한다면전체연구는총 6단계로진행되었다. Hough 등 43) 의연구에서 primary efficacy endpoint는이중맹검단계에서무작위할당후첫재발까지걸린시간이었다. 재발은다음과같이정의되었다. 1) 정신분열병증상으로인해입원할경우, 2) 무작위할당시 PANSS 총점이 4점을초과한환자에서연속적으로시행된두검사상 PANSS 총점이 25% 이상증가하거나, 무작위할당시 PANSS 총점 이 4점이하이었던환자에서 PANSS 총점이 1점이상상승한경우, 3) 자해및공격적인행동또는자살및살인에대한생각이임상적으로의미가있을경우, 4) 연속적으로행해진두평가에서 PANSS P1, P2, P3, P6, P7, G8 개별항목점수가무작위할당시 3점이하이었던경우는 5점이상으로, 4점이었던경우는 6점이상으로각각상승하는경우이연구는 68번째재발이일어나는시점에서중간분석을하기로되어있었다. 그런데중간분석에서이미 paliperidone palmitate의재발방지효과가입증되어 Independent Data Monitoring Committee( 이하 IDMC) 는이연구를조기에종료시켰다. 따라서중간분석결과가이연구의주된분석결과가되었다. 중간분석결과재발률은 paliperidone palmitate군이 1%, 위약군이 34% 로양자간의미있는차이가있었다 (p<.1)(fig. 2A). 중간분석에서환자의 5% 가재발할것으로추정되는기간은위약군에서는 163일이었다. 그러나 paliperidone palmitate군은 25% 이하의환자에서만재발이일어날것으로추정되어이기간을산정할수없었다. Secondary efficacy endpoint 를보면, 위약군에서는 paliperidone palmitate군과는달리 PANSS 총점과 CGI- S 점수상에의미있는악화를보였다. 이중맹검단계의사후분석에서도중간분석과마찬가지로 paliperidone palmitate군에서는위약군에비해재발률이현저하게감소되어있었다 (p<.1) (Fig. 2B). Hough 등 43) 의연구의개방확장단계인 Gopal 등 44) 의연구에서는 PANSS, PSP, CGI-S를평가하였다. Paliperidone palmitate 투여군에서는이전 Hough 등 43) 의연구기간중에보였던 PANSS의총점이약간호전되어큰변화없이개방확장단계에서도그대로유지되었다. 그러나위약에서 paliperidone palmitate 로변경된환자군에서는 PANSS의총점이크게감소하여뚜렷한증상의호전을보였다 (Fig. 3). Estimated percent of subjects without recurrence A Placebo (n=156) Paliperidone palmitate (n=156) Days since randomization Log-rank test, p-value<.1 Fig. 2. Paliperidone palmitate 군과 Placebo 군의재발율. 43) A: Kaplan Meier plot of time to recurrence-interim analysis. B: Final analysis. Estimated percent of subjects without recurrence B Placebo (n=23) Paliperidone palmitate (n=25) Log-rank test, p-value< Days since randomization S31

7 Paliperidone Palmitate 의효능 Mean (±SE) PANSS total score BD BO Weeks DB phase PBO/PP (n=153) DB LOCF (For subjects entering the open-label phase) PP/PP (n=161) OLE LOCF Weeks OLE phase Improvement Fig. 3. 개방형확장연구에서 PANSS 변화. 44) PBO: placebo, PP: paliperidone palmitate, DB: double blind, OLE: open-label extension, SE: standard error, LO- CF: last observation carried forward, PANSS: Positive And Negative Syndrom Scale. PSP로측정한기능의향상또한개방단계에서기존의결과들이계속유지되었다. 특히이중맹검단계에서위약을사용하다가 paliperidone palmitate로변경된환자군에서기능의향상이뚜렷하였다. 저자들은대다수의환자들이 1년간의개방단계에서치료가잘유지되었으며상태가안정되었을뿐만아니라기능도향상되었다고보고하였다. Risperidone 53주비열등성연구를통해 paliperidone palmitate와 risperidone 장기지속형주사제와의효능에대한비교가이루어졌다. 45) 이는 paliperidone palmitate와 risperidone 장기지속형주사제의 1 : 1 무작위배정이중맹검연구로진행되었다. 최종적으로 25 mg eq., 5 mg eq., 75 mg eq., 1 mg eq. 의 paliperidone palmitate 를투여받은 379명과 25 mg, 37.5 mg, 5 mg의 risperidone 장기지속형주사제를투여받은 37명이연구에참여하였다. Paliperidone palmitate은제1일과 8일에각 5 mg eq. 를투여받은후 4주마다 25~1 mg eq. 의용량을대퇴부에투여받았다. risperidone 장기지속형주사제는 25~5 mg을매 2주마다투여받았다. risperidone 장기지속형주사제군은경구 risperidone을위약주사제와함께투여받았으며, paliperidone palmitate군에서도 risperidone 장기지속형주사제군의빈도에맞는위약경구제와위약주사제를함께투여받았다. 두군모두 PANSS 총점이의미있게감소하였다. 그러나 paliperidone palmitate군에서는평균 12±21.2점감소하였고, RLAI 군에서는평균 14±19.8 점감소하여양군간통계적으로유의한차이가있었다. 즉이연구에서는 risperidone 장기지속형주사제에대한 paliperidone palmitate 의비열등성은입증되지않았다. 이연구에서환자들은초기에 최근추천되는용량보다훨씬낮은용량의 paliperidone palmitate을사용하였다. 저자들은이점을 paliperidone palmitate의비열등성을입증하지못한이연구 45) 의제한점으로제시하고있다. 또한둔부근주사가초기혈중농도를낮게했을가능성에대해서도언급하고있다. 이후 paliperidone palmitate의적합한초기용법을사용하여 risperidone 장기지속형주사제와효능을비교한다른비열등성연구가수행되었다. 46) 이연구에서는 paliperidone palmitate 은첫째날 15 mg eq. 와제8일째 1 mg eq. 를삼각근에주사하였다. 이후 paliperidone palmitate 적정용량을한달간격으로삼각근또는둔부근에주사하였으며, risperidone 장기지속형주사제의빈도에맞는위약도같이투여하였다. risperidone 장기지속형주사제는제8일째 25 mg을처음둔부근에주사하였고, 이후 2주간격으로적정용량을둔부근에주사하였으며, paliperidone 군에맞는위약도같이투여하였다. risperidone 장기지속형주사제군은제1일에서제28일째까지경구제제 risperidone 을투여하였으며, 이에맞춰서 paliperidone 군에서도위약경구제제를투여하였다. 이연구의 primary efficacy endpoint는 PA- NSS 총점의변화였다. Paliperidone palmitate 적정초기용량이사용된이연구에서 paliperidone palmitate는 risperidone 장기지속형주사제에대한비열등성기준을만족시켰다. 이상의두연구결과를종합하면, paliperidone palmitate는초기에적정용량을사용한다면 risperidone 장기지속형주사제와비교할때동등한효과를나타낸다고볼수있다. 지금까지의여러임상연구들을종합하여볼때, 특히정신 S32 대한정신약물학회지 211;22 Suppl:S26-S34

8 이봉주등 분열병치료에있어서복약충실도의중요성을고려한다면, 항정신병약물장기지속형주사제는매우가치있는치료수단 으로생각된다. 약물부작용과정신분열병의음성증상과인 지장애를고려한다면, 비정형항정신병약물장기지속형주 사제는임상현실에서매우절실히요구되는제형이다. 최근 비정형항정신병약물장기지속형주사제인 paliperidone palmitate 가개발되어여러다양한디자인의임상연구를 통해정신분열병환자의치료에있어서의효능이조사되었다. Paliperidone palmitate 는급성기단기치료에서위약과비 교할때 PANSS 총점을유의하게감소시켰으며, 장기유지 치료에서는위약과비교할때재발률을낮추고재발까지걸 리는시간을연장시켰다. 또한 paliperidone palmitate 는초 기적정용량만사용하면 risperidone 장기지속형주사제에 비해효능에있어서열등하지않았다. Paliperidone palmitate 는한달에한번투여되며, 냉장보관및경구약이필요 없고, 환자에게통증을덜유발시킨다는점에서다른제형 에비해불편함이많이개선되었다. 향후다른비정형항정 신병약물장기지속형주사제혹은경구약제와의비교연구들 이필요할것이다. 또한정신분열병이외의다른신경정신질 환에의사용에대한연구또한필요하리라고생각된다. 중심단어 : 팔리페리돈팔미테이트 장기지속형주사제 정신분열병 약물순응도 비정형항정신병약물. REFERENCES 1. Davis JM. Overview: maintenance therapy in psychiatry: I. Schizophrenia. Am J Psychiatry 1975;132: Davis JM, Matalon L, Watanabe MD, Blake L, Matalon L. Depot antipsychotic drugs. Place in therapy. Drugs 1994;47: Hogarty GE, Schooler NR, Ulrich R, Mussare F, Ferro P, Herron E. 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9 Paliperidone Palmitate 의효능 29. Haro JM, Novick D, Suarez D, Alonso J, Lépine JP, Ratcliffe M; SOHO Study Group. Remission and relapse in the outpatient care of schizophrenia: three-year results from the Schizophrenia Outpatient Health Outcomes study. J Clin Psychopharmacol 26;26: Haro JM, Suarez D, Novick D, Brown J, Usall J, Naber D; SOHO Study Group. Three-year antipsychotic effectiveness in the outpatient care of schizophrenia: observational versus randomized studies results. Eur Neuropsychopharmacol 27;17: Davis JM, Dysken MW, Haberman SJ, Javaid JI, Chang SS, Killian GA. Use of survival curves in analysis of antipsychotic relapse studies. Adv Biochem Psychopharmacol 198;24: Johnson DA, Pasterski G, Ludlow JM, Street K, Taylor RD. The discontinuance of maintenance neuroleptic therapy in chronic schizophrenic patients: drug and social consequences. Acta Psychiatr Scand 1983;67: Youssef HA. Duration of neuroleptic treatment and relapse rate: a 5-year follow-up study with haloperidol decanoate. Clin Neuropharmacol. 1991;14 Suppl 2:S16-21; discussion S Edwards J, Maude D, Herrmann-Doig T, Wong L, Cocks J, Burnett P, et al. A service response to prolonged recovery in early psychosis. Psychiatr Serv 22;53: Kasper S. First-episode schizophrenia: the importance of early intervention and subjective tolerability. J Clin Psychiatry 1999;6 Suppl 23: Kane JM. Review of treatments that can ameliorate nonadherence in patients with schizophrenia. J Clin Psychiatry 26;67 Suppl 5: Kim B, Lee SH, Choi TK, Suh S, Kim YW, Lee E, et al. Effectiveness of risperidone long-acting injection in first-episode schizophrenia: in naturalistic setting. Prog Neuropsychopharmacol Biol Psychiatry 28;32: Weiden PJ, Schooler NR, Weedon JC, Elmouchtari A, Sunakawa A, Goldfinger SM. A randomized controlled trial of long-acting injectable risperidone vs continuation on oral atypical antipsychotics for first-episode schizophrenia patients: initial adherence outcome. J Clin Psychiatry 29;7: Gopal S, Hough DW, Xu H, Lull JM, Gassmann-Mayer C, Remmerie BM, et al. Efficacy and safety of paliperidone palmitate in adult patients with acutely symptomatic schizophrenia: a randomized, doubleblind, placebo-controlled, dose-response study. Int Clin Psychopharmacol 21;25: Kramer M, Litman R, Hough D, Lane R, Lim P, Liu Y, et al. Paliperidone palmitate, a potential long-acting treatment for patients with schizophrenia. Results of a randomized, double-blind, placebo-controlled efficacy and safety study. Int J Neuropsychopharmacol 21;13: Nasrallah HA, Gopal S, Gassmann-Mayer C, Quiroz JA, Lim P, Eerdekens M, et al. A controlled, evidence-based trial of paliperidone palmitate, a long-acting injectable antipsychotic, in schizophrenia. Neuropsychopharmacology 21;35: Pandina GJ, Lindenmayer JP, Lull J, Lim P, Gopal S, Herben V, et al. A randomized, placebo-controlled study to assess the efficacy and safety of 3 doses of paliperidone palmitate in adults with acutely exacerbated schizophrenia. J Clin Psychopharmacol 21;3: Hough D, Gopal S, Vijapurkar U, Lim P, Morozova M, Eerdekens M. Paliperidone palmitate maintenance treatment in delaying the timeto-relapse in patients with schizophrenia: a randomized, doubleblind, placebo-controlled study. Schizophr Res 21;116: Gopal S, Vijapurkar U, Lim P, Morozova M, Eerdekens M, Hough D. A 52-week open-label study of the safety and tolerability of paliperidone palmitate in patients with schizophrenia. J Psychopharmacol 21. Jul 8. [Epub ahead of print] 45. Gopal S, Gassmann-Mayer C, Palumbo J, Samtani MN, Shiwach R, Alphs L. Practical guidance for dosing and switching paliperidone palmitate treatment in patients with schizophrenia. Curr Med Res Opin 21;26: Pandina G, Lane R, Gopal S, Gassmann-Mayer C, Hough D, Remmerie B, et al. A double-blind study of paliperidone palmitate and risperidone long-acting injectable in adults with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 211;35: Kay SR, Fiszbein A, Opler LA. The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987;13: Haro JM, Kamath SA, Ochoa S, Novick D, Rele K, Fargas A, et al. The Clinical Global Impression-Schizophrenia scale: a simple instrument to measure the diversity of symptoms present in schizophrenia. Acta Psychiatr Scand Suppl 23: Morosini PL, Magliano L, Brambilla L, Ugolini S, Pioli R. Development, reliability and acceptability of a new version of the DSM-IV social and occupational functioning assessment scale (SOFAS) to assess routine social functioning. Acta Psychiatr Scand 2;11: S34 대한정신약물학회지 211;22 Suppl:S26-S34

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