ISSN Korean J Schizophr Res Vol , 2018 항정신병약물치료후인지기능변화차이연구 : 장기지속형주사제와경구제비교의예비연구 서울대학교병원정신건

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1 ISSN Korean J Schizophr Res Vol , 2018 서울대학교병원정신건강의학과, 1 분당서울대학교병원정신건강의학과, 2 서울대학교의과대학정신건강의학교실 3 성기영 1 김서영 2 김의태 2,3 Change in Cognitive Function after Antipsychotics Treatment : A Pilot Study of Long-Acting Injectable versus Oral Form Kiyoung Sung, MD 1, Seoyoung Kim, MD 2, and Euitae Kim, MD, PhD 2,3 1 Department of Neuropsychiatry, Seoul National University Hospital, Seoul, 2 Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam, 3 Department of Psychiatry, Seoul National University College of Medicine, Seoul, Korea Objectives : This study investigated whether long-acting injectable (LAI) paliperidone is different from its oral form in terms of the effect on cognitive function in schizophrenia spectrum and other psychotic disorders. Methods : We reviewed the medical records of patients in Seoul National University Bundang Hospital who were diagnosed as having schizophrenia and/or other psychotic disorders based on DSM-5 from 2016 to Seven patients were treated with oral paliperidone and 11 were treated with paliperidone palmitate. All patients underwent clinical and neuropsychological assessment, including the Korean version of the MATRICS Consensus Cognitive Battery (MCCB) at their first visit or within one month of their initial treatment. MCCB was repeated within three to 12 months after the initial assessment. Results : There was no significant difference between the two groups in most cognitive domains including speed of processing, attention and vigilance, working memory, verbal learning, visual learning and reasoning and problem solving domain. However, patients treated with paliperidone palmitate showed better improvement in social cognition domain than those taking oral paliperidone. The standardized values of social cognition domain scores had significantly improved over time in patients under paliperidone palmitate, demonstrating a significant time-by-group interaction. Conclusion : Our results show that long-acting injectable paliperidone could be helpful in some aspects of improving cognitive function in schizophrenia spectrum and other psychotic disorders. Further studies with other antipsychotics are necessary to generalize the results. (Korean J Schizophr Res 2018;21:74-80) Key Words : Schizophrenia Long-acting injectables Cognitive function Paliperidone. 서 조현병은양성증상, 음성증상과함께인지기능의저하를 동반하는만성적인경과를보이는질환이다. 1) 발병이후의만 성적인경과에는발병시나이, 발병의방식 (mode of onset), 병 Received: August 3, 2018 / Revised: September 3, 2018 Accepted: September 16, 2018 Address for correspondence: Euitae Kim, Department of Neuropsychiatry, Seoul National University Bundang Hospital, Department of Psychiatry, Seoul National University College of Medicine, 82 Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam 13620, Korea Tel: , Fax: euitae.kim@snu.ac.kr 이논문은 2015 년도정부 ( 교육부 ) 의재원으로한국연구재단의지원을받아수행된기초연구사업임 (NRF-2015R1C1A1A ). 론 전기능 (premorbid functioning), 증상이발생한시점부터최초치료를받게된기간 (duration of untreated psychosis) 등여러가지요인들이영향을미치며, 2,3) 재발이반복될수록인지기능의저하가진행되어사회적기능의장애를유발하게된다. 3) 조현병의치료제인항정신병약물은망상과같은사고장애, 환청과같은지각장애등의증상을호전시킬뿐아니라인지기능의저하를막거나지연시키는것으로보고되고있다. 4) 아직까지항정신병약물이조현병환자의인지기능저하와신경계에미치는영향, 그리고그기전이정확하게밝혀지지는않았지만, 비정형항정신병약물이조현병환자에서발견되는이마관자엽피질의회색질 (frontotemporal cortical gray matter) 감소를막는다는연구결과와 5,6) 정형항정신병약물 74 Copyright 2018 Korean Society for Schizophrenia Research

2 성기영등 에비해비전형항정신병약물의신경보호효과가더크다는연구결과 7,8) 등을볼때비정형항정신병약물이조현병에서의인지기능개선에효과적일것으로추정되고있다. 조현병이발병한이후에는증상조절과사회적기능의악화를막기위해항정신병약물을이용한지속적인치료가중요하다. 9) 하지만많은조현병환자들에서병식부족, 약물부작용으로인한거부감등의이유로약물치료에대한순응도가저하되는것으로보고되고있고 10-12) 이는조현병증상의악화와재발위험도를증가시키는요인으로작용하는것으로알려져있다. 13) 따라서이러한약물순응도의문제를극복하고자항정신병약물의장기지속형주사제가개발되어, 현재임상에서널리쓰이고있다. 항정신병약물의장기지속형주사제는기존의경구투약에비해여러가지장점을가지고있다. 즉, 매일투약할필요가없는장기지속형주사제는유지치료에필요한약물순응도를향상시켜조현병의증상을조절하고, 재발률및재입원률을감소시키는것으로보고되고있으며비정형항정신병약물의신경보호효과를통해뇌실질감소의위험을낮출수있을것으로기대하고있다. 14,15) 이런점에서, 영국국립보건임상연구원 (national institute for clinical excellence : NICE) 의가이드라인에서는약물순응도의문제가중요한경우장기지속형주사제를고려해야한다고제시하고있다. 16) 약물순응도를올리는것외에도장기지속형주사제는주사용량과혈중약물농도사이에상관관계가높고, 경구투약에비해안정적인혈중약물농도를보이며, 예후를향상시킨다는연구가있다. 17,18) 이와같이경구형항정신병약물과장기지속형주사제의비교연구결과들이계속나오고있지만, 양성증상, 음성증상만큼직장이나학교생활등사회기능에영향을미치는인지기능 19) 에관해두제형의차이에관한연구는거의없는상황이다. 본연구에서는경구팔리페리돈또는팔리페리돈장기지속형주사제로치료를받은환자군을대상으로, 투약방법에따른조현병환자의인지기능변화의차이를살펴보고자하였다. 이를위해제형을달리한두군을대상으로치료전과치료후의인지기능을측정하여치료에따른인지기능의변화를비교하였다. 방법 연구설계및대상본연구는의무기록검토를통한후향적연구이다. 대상환자군은 2016년 1월부터 2017년 12월까지분당서울대학교 병원정신건강의학과에내원하여 Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) 의진단기준으로조현병스펙트럼과다른정신병적장애 (Schizophrenia Spectrum and Other Psychotic Disorders) 로진단을받은환자중만 17세이상및 65세미만의남녀, 경구팔리페리돈또는팔리페리돈장기지속형주사제를투약중인환자를대상으로하였다. 대상자중정동장애등조현병스펙트럼과다른정신병적장애외다른정신질환이있는자, 두부손상이나경련성질환등신경계질환이있는자, 인지기능에영향을미치는내과또는외과적질환이있는자, 알코올또는약물남용이나의존상태, 인지기능검사가불가능한지적수준또는비협조상태에있는자는제외하고분석하였다. 본연구는분당서울대병원임상연구심의위원회 (institutional review board) 의심의를통과하였다. 자료의수집의무기록검토를통해연구참여자들의성별, 나이, 교육연수, 유병기간, 증상이발생한시점부터최초치료를받게된기간 (duration of untreated psychosis), 한국판웩슬러성인지능검사 20) 로측정된지능지수 (intelligence quotient), 투약력, 항정신병약물의종류와용량등을조사하였다. 항정신병약물의용량은올란자핀등가용량으로환산하였다. 21) 임상증상의평가를위해양성및음성증후군척도 (positive and negative syndrome scale), 22) 임상전반적임상척도- 심각성 (clinical global impression-severity), 해밀턴우울증평가척도 (Hamilton depression rating scale) 23) 의점수를수집하였다. 연구대상자들의인지기능평가는한국판 The Korean Version of The MATRICS Consensus Cognitive Battery (MCCB) 24) 를통해이루어졌다. 경구투약군, 주사치료군에서내원후기저상태에서 1회측정후 3개월에서 12개월사이에 1회반복측정하였으며, 두측정치의변화량을계산하였다. MCCB 검사는처리속도 (speed of processing), 주의및경각 (attention and vigilance), 작업기억 (working memory), 언어학습 (verbal learning and memory), 시각적학습 (visual learning and memory), 추리력과문제해결능력 (reasoning and problem solving), 그리고사회인지 (social cognition) 의 7가지인지영역으로구분되어있으며, 각영역의 T 점수와전체종합 T 점수를계산하였다. 25) Korean J Schizophr Res 2018;21:

3 통계분석경구투약군과주사치료군간의인구통계학적변인과임상지표, 신경심리검사결과의차이분석은연속형변수는 Mann-Whitney 검정, 범주형변수는 Fisher s exact test를실시하였다. 기저상태, 그리고 3개월에서 12개월사이에반복측정된 MCCB 검사의두측정치를통해구한변화량은반복측정분산분석, 선형혼합모형을통해분석하였다. 결과 연구대상의특성위조건을만족하는대상환자군은총 18명선정되었으며, 그중에서경구팔리페리돈을투약하며치료를받는환자 7 명은경구투약군, 나머지 11명은팔리페리돈장기지속형주사제로치료를받는주사치료군으로분류하였다. 경구투약군 7명과주사치료군 11명의인구학적정보및임상증상지표는표 1에제시되었다. 성별, 교육연수, 유병기간, 증상이발생한시점부터최초치료를받게된기간, 양성및음성증후군척도총점, 지능지수, 해밀턴우울증평가척도점수간에는두군에서유의미한차이를보이지않았다 ( 표 1). 그러나나이, 올란자핀등가용량으로변환한항정신병약물의용량은차이가있었다. 경구투약군은 25.00±9.09 세로, 주사치료군 38.91±16.11 세에비해나이가적었고, 유의한차이를보였다 (Mann-Whitney U=16.000, p=0.04). 또한경구투약군의올란자핀등가용량은 11.4±6.3 mg으로, 주사치료군의올란 자핀등가용량 24.0±6.0 mg에비해유의하게낮았다 (Mann- Whitney U=5.500, p<0.01). 그외에다른항정신병약물의병합사용, 항우울제, 기분조절제, 항불안제의사용빈도는, 두군에서유의한차이가없었다. 유병기간 ( 경구투약군 29.6±25.0 개월 ; 주사치료군 89.9± 110.8개월, Mann-Whitney U=24.000, p=0.32) 과증상이발생한시점부터최초치료를받게된기간 ( 경구투약군 26.3± 26.0개월 ; 주사치료군 51.4±60.5 개월, Mann-Whitney U= , p=0.74) 은모두유의한차이를보이지않았으며, 지능지수 ( 경구투약군 100.8±14.1 ; 주사치료군 81.9±17.1, Mann- Whitney U=10.000, p=0.05) 도역시유의한차이를보이지않았다. 인지기능 MCCB 검사를통해측정된기저상태에서의인지기능평가는두군에서다소차이를보였다 ( 표 2). MCCB에포함된 9개의인지기능검사중처리속도영역에포함된간편조현병인지기능평가 : 기호쓰기 ( 경구투약군 60.9±14.0 ; 주사치료군 42.1±16.2, Mann-Whitney U=14.000, p=0.03), 주의및경각영역에포함된연속수행검사 : 같은짝 ( 경구투약군 3.0±0.3 ; 주사치료군 1.7±1.1, Mann-Whitney U=5.000, p< 0.01), 작업기억영역에포함된글자-숫자따라하기 ( 경구투약군 13.1±2.7 ; 주사치료군 8.4±3.4, Mann-Whitney U= 9.000, p=0.01), 시각적학습에포함된간편시공간기억검사 - 개정판 ( 경구투약군 27.0±5.0 ; 주사치료군 19.6±8.7, Mann- Table 1. Demographic and clinical characteristics of the paliperidone treatment group and the paliperidone palmitate treatment group at baseline Paliperidone (oral form) (N=7) Paliperidone palmitate (LAI) (N=11) p-value Age (years) 25.0± ± * Female 3 (42.9%) 9 (81.8%) 0.14 Education (years) 13.3± ± Duration of illness (months) 29.6± ± DUP (months) 26.3± ± PANSS 71.2± ± IQ 100.8± ± HDRS 12.0± ± CGI-S 4.9± ± Antipsychotics dose (mg) 11.4± ±6.0 <0.01* Concurrent medication Other antipsychotics 2 (28.6%) 6 (54.5%) 0.37 Antidepressants 0 (0.0%) 0 (0.0%) - Mood stabilizer 1 (14.3%) 2 (18.2%) 1.00 Anxiolytics 2 (28.6%) 7 (63.6%) 0.34 Data presented as mean±sd or N (%). * : p<0.05, : by K-WAIS-IV, : Olanzapine equivalent dose. DUP : Duration of Untreated Psychosis, PANSS : Positive and Negative Syndrome Scale, IQ : Intelligent Quotient, HDRS : Hamilton Depression Rating Scale, CGI- S : Clinical Global Impression-Severity 76 Korean J Schizophr Res 2018;21:74-80

4 성기영등 Table 2. Result of MCCB at baseline Paliperidone Paliperidone (oral form) (N=7) palmitate (LAI) (N=11) p-value Speed of processing Trail making test 26.0 (9.0) 31.0 (45.0) 0.38 Brief assessment of cognition in schizophrenia : symbol coding 64.0 (23.0) 49.0 (27.0) 0.03* Category fluency : animal naming 21.0 (11.0) 16.0 (6.0) 0.07 Attention and vigilance Continuous performance test-identical pairs 3.0 (0.6) 2.0 (1.9) <0.01* Working memory Wechsler memory scale-iii : spatial span 20.0 (5.0) 18.0 (10.0) 0.21 Letter-number span 12.0 (4.0) 9.0 (3.0) 0.01* Verbal learning Hopkins verbal learning test-revised tm 27.0 (6.0) 23.0 (5.0) 0.10 Visual learning Brief visuospatial memory test revised 29.0 (11.0) 19.0 (12.0) 0.04* Reasoning and problem solving Neuropsychological assessment battery : mazes 23.0 (8.0) 13.0 (9.0) 0.04* Social cognition Mayer-salovey-caruso emotional intelligence test : managing emotion 94.0 (10.0) 79.0 (14.0) 0.03* Data presented as median (IQR). * : p<0.05. MCCB : MATRICS Consensus Cognitive Battery, IQR : Interquartile Range Whitney U=16.500, p=0.04), 추리력과문제해결능력영역에포함된신경심리평가용통합검사 : 미로 ( 경구투약군 22.0± 4.0 ; 주사치료군 14.6±7.7, Mann-Whitney U=15.000, p= 0.04), 사회인지영역에포함된정서지능검사 : 정서관리 ( 경구투약군 93.0±6.8 ; 주사치료군 82.6±9.3, Mann-Whitney U= p=0.03) 에서경구투약군이유의하게원점수가높았다. 이는 7개영역중언어학습영역을제외한다른 6개영역에해당되나, 나이와성별이보정되지않은원점수결과이다. 군의상호작용이확인되지않았고 (F=0.255, df=1, p=0.62), 사회인지영역에서는시간과군의상호작용이확인되었다 (F=13.89, df=1, p<0.01)( 그림 1). 선형혼합모형을통한분석시에도사회인지영역에서시간과군의상호작용이확인되었다 (F=16.28, df=1, p<0.01). 종합 T 점수 (composite score) 에대해서는시간에대한주효과 (F=2.55, df=1, p=0.13), 시간과군의상호작용이확인되지않았다 (F=1.22, df=1, p=0.29) ( 그림 1). 인지기능변화 MCCB 검사를통해기저시점에서측정된인지기능은, 일정기간이지난후추적시점에 1회반복측정되었으며팔리페리돈경구투약군의평균추적기간은 3.86±2.27 개월, 팔리페리돈장기지속형주사치료군의평균추적기간은 5.00± 3.58개월로유의한차이를보이지않았다 (Mann-Whitney U= , p=0.54). MCCB로측정한인지기능의변화는성별, 연령이보정된 T 점수를기반으로분석하였다 ( 표 3). 반복측정분산분석을이용해분석한결과, 처리속도영역의범주유창성검사 : 동물이름대기검사에서시간에대한주효과 [F=8.94, degree of freedom (df)=1, p=0.01] 가확인되었다. 시간과군의상호작용은처리속도영역의선로잇기검사 (F=5.85, df=1, p=0.03), 사회인지영역의정서지능검사 (F=13.89, df=1, p<0.01) 에서확인되었으며, 개별검사가아닌인지기능영역을대상으로분석했을때에는처리속도영역에서는시간과 고찰 본연구에서는조현병스펙트럼과다른정신병적장애에서치료제의투약방법에따른인지기능변화의차이를살펴보고자팔리페리돈경구투약군과팔리페리돈장기지속형주사치료군의인지기능변화를분석하였다. 인지기능평가는 MCCB 를사용하였고, 기저상태에서의검사결과와치료이후의검사결과를비교하여두군의차이를분석하였다. 분석결과 MCCB의전체종합 T 점수는경구투약군과장기지속형주사치료군에서시간에대한주효과및시간과군의상호작용은없었다. 하지만 MCCB의 7가지인지영역중사회인지영역에서는시간에대한유의성은없었지만, 시간과군의상호작용이유의하게나타났다. 경구투약군에서는사회인지영역 T 점수의평균이감소했지만, 장기지속형주사치료군에서는사회인지영역 T 점수가오히려증가하 Korean J Schizophr Res 2018;21:

5 Table 3. Comparison of MCCB T score with paliperidone versus paliperidone palmitate Paliperidone (oral form) (N=7) Paliperidone palmitate (LAI) (N=11) Time Time*group Baseline Post Baseline Post F p F p Speed of processing 46.0± ± ± ± TMT 47.0± ± ± ± * BACS-SC 47.3± ± ± ± CF-AN 46.9± ± ± ± * Attention and vigilance 49.0± ± ± ± CPT-IP 49.0± ± ± ± Working memory 46.0± ± ± ± WMS-III-SS 53.9± ± ± ± LNS 39.9± ± ± ± Verbal learning 44.0± ± ± ± HVLT-RTM 44.0± ± ± ± Visual learning 46.6± ± ± ± BVMTR 46.6± ± ± ± Reasoning and problem solving 48.7± ± ± ± NAB-mazes 48.7± ± ± ± Social cognition 47.1± ± ± ± <0.01* MSCEIT-ME 47.1± ± ± ± <0.01* Composite score 44.9± ± ± ± Data presented as means±sd. * : p<0.05 by repeated measures ANOVA. TMT : Trail Making Test, BACS-SC : Brief Assessment of Cognition in Schizophrenia : Symbol Coding, CF-AN : Category Fluency-Animal Naming, CPT-IP : Continuous Performance Test- Identical Pairs, WMS-III-SS : Wechseler Memory Scale-III-Spatial Span, LNS : Letter-Number Span, HVLT-RTM : Hopkins Verbal Learning Test-Revised TM, BVMTR : Brief Visuospatial Memory Test Revised, NAB-Mazes : Neuropsychological Assessment Battery-Mazes, MSCEIT-ME : Mayer-Salovey-Coruso Emotional Intelligence Test-Managing Emotion Paliperidone (oral form) Paliperidone paimitate (LAI) Paliperidone (oral form) Paliperidone paimitate (LAI) Composite score Social cognition T score T score A Baseline Post Baseline Post Time B Time Fig. 1. Cognitive change with paliperidone versus paliperidone palmitate. (A) Composite score of MCCB before and after the treatment with paliperidone or paliperidone palmitate. (B) Social cognition of MCCB before and after the treatment with paliperidone or paliperidone palmitate. 여치료전보다치료후의인지기능점수가높아져보였다. 그러나 Wilcoxon signed rank 검정시, 경구투약군에서사회인지영역 T 점수의감소는유의성을보였고 (p=0.018), 장기지속형주사치료군에서사회인지영역 T 점수의변화는유의성을보이지않았다 (p=0.168). 이는장기지속형주사치료제가사회인지영역의인지기능유지에도움이될수있다는가능성을보여준다. 인구학적정보에서나타났던두군의나이차이는, MCCB 의 T 점수산정시보정되었지만두군의올란자핀등가용량차이는본연구의주된결과에영향을미쳤을가능성이있다. 비정형항정신병약물이조현병환자의인지기능을향상시킬수있다는측면에서, 26) 장기지속형주사치료군에서올란자핀등가용량이유의하게높은것이, 경구투약군에비해더큰인지기능향상효과로나타나는등인지기능의차이를유 78 Korean J Schizophr Res 2018;21:74-80

6 성기영등 발할수있다. 장기지속형주사치료군에서경구투약군보다높은나이, 긴유병기간, 증상이발생한시점부터최초치료를받게된기간이길었으며, 이는더만성적인경과로진행되었을가능성을시사한다. 정신증의양성증상등전통적인증상이완화와악화를반복하는것에비해, 인지기능은만성적으로진행될수록안정적, 점진적으로저하되는것으로알려져있다. 27,28) 이러한이유로본연구의장기지속형주사치료군의기저상태인지기능원점수와 T 점수가더낮았고, 유의한차이는아니지만지능지수도낮게측정되었을것이다. 비정형항정신병약물에의해인지기능의변화가나타난다면인지기능저하가이미많이진행되어측정결과가낮으면낮을수록, 상승할수있는측정범위가클수밖에없을것이다. 이러한투약방법에따른차이는, 조현병스펙트럼과다른정신병적장애환자의임상진료에서병식이부족하거나가족등지지체계부재로약물순응도가떨어져서재발이잦은경우에치료제로서장기지속형주사제를선택하기때문에나타나는결과이다. 이는기저상태에서인지기능이동일한대상자를선정하여분석하는무작위임상시험연구가아닌후향적관찰연구에서는불가피한점으로여겨진다. 본연구는항정신병약물의경구투약과장기지속형주사의예후, 재원기간, 재발률등의기존분석과는다른, 인지기능변화의차이라는새로운분석의파일럿연구로서의의가있다. 제한점은첫째, 연구대상자수가적고, 인지기능변화에대한추적기간이짧은것이다. 둘째, 교란변수의존재이다. 항정신병약물의용량차이, 기저상태의인지기능차이가결과에영향을미칠가능성을배제할수없다. 또한후향적관찰연구에서발생하는연구대상군간의차이도교란변수로작용할것이며, 본연구에서는질환의만성적인경과가영향을미쳤을수있다. 이러한제한점을보완하기위하여더많은연구대상자와더긴추적관찰기간의연구가필요할것으로보인다. 결론 본연구는조현병스펙트럼과다른정신병적장애에서투약방법에따른인지기능변화를비교하였고, 팔리페리돈경구제에비해장기지속형주사제의인지기능에대한치료적이점의가능성을제시한연구이다. 발병후빠른치료가인지기능측면에서유리하다는기존의연구결과 29) 와함께, 장기지속형주사제의치료가인지기능의호전에장점이될수있을것이다. 본연구의결과확인을위해충분한연구대상자수를확보하여한계점이보완된후속연구가필요하며, 투 약방법에따른조현병환자의인지기능변화차이를더욱분 명히밝힌다면실제임상에서치료시투약방법선택에도움 이될것이다. 중심단어 : 조현병 장기지속형주사제 인지기능 팔리페리돈. REFERENCES 1) Weinberger D, Marenco S. Schizophrenia as a neurodevelopmental disorder. In: Hirsch SR, Weinberger DR, editors. Schizophrenia, 2nd edition. Blackwell publishing;2003. p ) Jobe TH, Harrow M. Long-term outcome of patients with schizophrenia: a review. Can J Psychiatry 2005;50: ) Lieberman JA, Koreen AR, Chakos M, Sheitman B, Woerner M, Alvir JM, et al. Factors influencing treatment response and outcome of first-episode schizophrenia: implications for understanding the pathophysiology of schizophrenia. J Clin Psychiatry 1996;57: ) Miyamoto S, Miyake N, Jarskog L, Fleischhacker W, Lieberman J. Pharmacological treatment of schizophrenia: a critical review of the pharmacology and clinical effects of current and future therapeutic agents. Mol Psychiatry 2012;17: ) Bogerts B, Lieberman JA, Ashtari M, Bilder RM, Degreef G, Lerner G, et al. Hippocampus-amygdala volumes and psychopathology in chronic schizophrenia. Biol Psychiatry 1993;33: ) Lieberman JA, Bogerts B, Degreef G, Ashtari M, Lantos G, Alvir J. Qualitative assessment of brain morphology in acute and chronic schizophrenia. Am J Psychiatry ) Parikh V, Evans DR, Khan MM, Mahadik SP. Nerve growth factor in never-medicated first-episode psychotic and medicated chronic schizophrenic patients: possible implications for treatment outcome. Schizophr Res 2003;60: ) Parikh V, Khan MM, Terry A, Mahadik SP. Differential effects of typical and atypical antipsychotics on nerve growth factor and choline acetyltransferase expression in the cortex and nucleus basalis of rats. J Psychiatr Res 2004;38: ) Lieberman JA. Atypical antipsychotic drugs as a first-line treatment of schizophrenia: a rationale and hypothesis. J Clin Psychiatry ) Higashi K, Medic G, Littlewood KJ, Diez T, Granström O, De Hert M. Medication adherence in schizophrenia: factors influencing adherence and consequences of nonadherence, a systematic literature review. Ther Adv Psychopharmacol 2013;3: ) Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Eng J Med 2005; 353: ) Fenton WS, Blyler CR, Heinssen RK. Determinants of medication compliance in schizophrenia: empirical and clinical findings. Schizophr Bull 1997;23: ) Keith SJ, Pani L, Nick B, Emsley R, San L, Turner M, et al. Practical application of pharmacotherapy with long-acting risperidone for patients with schizophrenia. Psychiatr Serv 2004;55: ) Kishimoto T, Nitta M, Borenstein M, Kane JM, Correll CU. Longacting injectable versus oral antipsychotics in schizophrenia: a systematic review and meta-analysis of mirror-image studies. J Clin Psychiatry 2013;74: ) Nasrallah H. The case for long-acting antipsychotic agents in the post-catie era. Acta Psychiatr Scand 2007;115: ) National Collaborating Centre for Mental Health. Psychosis and schizophrenia in adults: treatment and management: updated edition London: National Institute for Health and Care Excellence; ) Ereshefsky L, Mascarenas CA. Comparison of the effects of different Korean J Schizophr Res 2018;21:

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012임수진 Received : 2012. 11. 27 Reviewed : 2012. 12. 10 Accepted : 2012. 12. 12 A Clinical Study on Effect of Electro-acupuncture Treatment for Low Back Pain and Radicular Pain in Patients Diagnosed with Lumbar