online ML Comm SPECIAL ARTICLE Korean J Biol Psychiatry 2011;18:210-216 ISSN 1225-8709 / eissn 2005-7571 제주대학교의학전문대학원제주대학교병원정신건강의학교실, 1 서울대학교의과대학분당서울대학교병원정신건강의학교실 2 박준혁 1 김기웅 2 Subsyndromal Depression Joon Hyuk Park, MD, 1 Ki Woong Kim, MD 2 1 Department of Psychiatry, Jeju National University Hospital, School of Medicine, Jeju National University, Jeju, Korea 2 Department of Psychiatry, Seoul National University Bundang Hospital, College of Medicine, Seoul National University, Seongnam, Korea Subsyndromal depression (SSD) is found to be more prevalent than major depressive disorder (MDD) and minor depressive disorder (MnDD). SSD is also associated with adverse clinical outcomes, increased risk of suicide, increased social dysfunction and disability, increased risk for future mood disorders, and increased uses of medical and mental health services. DSM-IV diagnostic criteria are not suitable for capturing SSD. Although there is no agreement on gold standard to define SSD so far, three definitions of SSD are available. First, SSD is defined as having two or more current depressive symptoms without core depressive symptoms (depressive mood or loss of interest) and with time threshold (most of the day and nearly every day over at least two weeks). Second, SSD is defined as having two or more current depressive symptoms with core depressive symptoms and without time threshold. Third, SSD is defined by using cutoff points of depression rating scales. SSD may represent a prodromal, residual, or interepisode symptomatic state in the course of MDD and MnDD. More than a half of SSD patients became any type of depressive disorders (SSD, MnDD and MDD) at 1 year. SSD may represent a discrete category of its own, without prior or consequent episodes of MDD. Considering clinical significance of SSD such as its high prevalence, significant psychosocial impairment and chronicity and serious outcomes, researchers and clinicians should be more vigilant in capturing and caring for patients with SSD. Key WordsZZSubsyndromal depression ㆍ Definition ㆍ Outcome ㆍ Course. Received: September 16, 2011 / Revised: November 1, 2011 / Accepted: November 3, 2011 Address for correspondence: Ki Woong Kim, MD Department of Neuropsychiatry, Seoul National University Bundang Hospital, College of Medicine, Seoul National University, 166 Gumi-ro, Bundanggu, Seongnam 463-707, Korea Tel: +82-31-787-7432, Fax: +82-31-787-4058, E-mail: kwkimmd@snu.ac.kr 현재우울증을정의할때주로정신장애의진단및통계편람 4판 (Diagnostic and Statistical Manual of Mental Disorders, 이하 DSM-IV) 1) 의주요우울장애의진단기준을이용한다. 그러나실제로임상현장과지역사회에서더쉽게만날수있는우울증환자는 DSM-IV 의엄격한주요우울장애의진단기준을만족하지못하는경우가더많다. 2) 그러나, 주요우울장애수준에못미치는이러한우울증이라도일상생활기능과삶의질을저하시키고자살또는기타원인의사망의위험인자로작용하여임상적으로중요하다. 3)4) 초기의정신장애의진단및통계편람 (DSM-I~DSM-III) 에서는엄격하게우울증상의개수, 기간에기초하여주요우울장애를진단하였지만, 이런엄격한진단기준은임상가와연구자가임상현장과지역사회에서우울증을진단하는데적당하지않았다. 그래서연구자들은 DSM-III 진단기준이요구하는증상의개수, 기간을만족시키지는않지만, 심각한사회적기능장애를일으키는우울증을가리켜 역치하우울상태 (subthrehold depressive state) 라고명명하였다. 이에대한임상특징, 인구학적특징, 심리사회및직업적기능저하에대한많은연구들이이뤄졌고, 5)6) 이를통해역치하우울상태에대한임상적중요성이밝혀졌다. 위의결과가 DSM 진단기준에반 210 Copyright 2011 Korean Society Biological Psychiatry
Subsyndromal Depression Park JH, et al 영되어, DSM-III-R 에기분부전장애 (dysthymic disorder) 가, DSM-IV 에는경도우울장애와반복성단기우울장애가포함되었다. 그러나사회적기능저하를일으키는역치하우울상태의 2/3에서 3/4 은새로추가된세가지진단기준에여전히포함되지않았다. 7)8) DSM-IV 경도우울장애진단기준은우울증상의숫자를 2~4개 ( 우울한기분또는흥미상실두증상중하나는반드시존재 ) 로줄였지만, 시간의기준은주요우울장애의진단과동일하여, 하루의대부분시간동안, 2주이상거의매일 의증상의연속성과지속기간을엄격하게요구하고있기때문에, 지역사회또는일차진료기관에서우울증환자를발견하는데사용되는진단기준으로는여전히부적절하였다. 9)10) 특히노년기우울증의경우에는특징적으로우울증상이일정기간동안에지속적으로나타나기보다는하루중과주중에도많은변동을보이기때문에기존 DSM-IV 의경도우울장애의진단기준으로는노년기우울증의아증후군적증상을찾아내기는어렵다. 10)11) 이러한배경에서 1990년대중반부터 DSM-IV 의주요우울장애와경도우울장애의진단적역치에는미치지못하지만임상적으로중요한우울증을정의할새로운진단기준의필요성이제기되었고, 8)10-13) 경도우울장애와구분하여그보다낮은수준의우울증으로아증후군적우울증 (subsyndromal depression) 8) 이라는새로운정의가제시되었다. 초기의연구에는아증후군적우울증에경도우울장애를포함하는경우도있었지만, 14) 최근의연구에서는대부분경도우울장애와구분하여그보다낮은수준의우울증을아증후군적우울증이란용어로통칭한다. 11)12) 현재아증후군적우울증의통일된진단기준은존재하지않는다. 아증후군적우울증의연구결과들을비교, 분석, 통합하려면무엇보다도아증후군적우울증의통일된진단기준이필요하다. 현재의대표적인아증후군적우울증의진단기준의다음과같다 (Table 1). 세기준모두주요우울장애와경도우 울장애에해당되지않을때만아증후군적우울증을진단할수있다. 첫번째기준 (SSD-1) 은 DSM-IV 의 9개의우울증상중에서우울감또는흥미상실의핵심증상없이최소 2개이상의증상이최소 2주동안에대부분또는모든시간동안에존재하는하는경우이다. 7)8)15-17) 이기준은주요우울장애, 경도우울장애, 기분부전장애에속하지않으면서우울증의핵심증상이없이다른 2개이상의우울증상이있는군들도여러영역에서의미있는심리사회적기능저하를일으킨다는연구에기반한다. 8) 대부분의 Judd 그룹의연구는이진단기준을사용하였다. 그러나, 이기준에서는우울증상중핵심증상에대한기준이없기때문에, 우울증의정서적, 인지적인증상이없으면서신체증상, 신경식물증상 (neurovegetative symptom) 만있는경우에도아증후군적우울증환자로진단할수있어진단의특이도 (specificity) 가떨어지는단점이있다. 두번째기준 (SSD-2) 은 DSM-IV 9개의우울증상중에서최소 2개이상의증상이있고그중에우울감또는흥미와즐거움의상실의핵심증상한가지는꼭포함해야하지만, 증상의지속기간, 연속성에대한시간에대한기준을요구하지않는다. 18-20) 이기준은엄격한시간진단기준을만족하지못하는다양한심각도의우울증환자를진단할수있지만, 한편으로는진단의역치를너무낮추어서증상이매우경하거나일시적인경우에도우울증이과도하게진단될수있는단점이있다. 세번째기준 (SSD-3) 은특정우울척도점수의절단점 (cutoff point) 을기준으로아증후군적우울증을진단하는것이다. 11)21)22) 앞의두진단기준이 DSM-IV의진단기준을변형하여우울증을핵심우울증상의유무, 우울증상의개수, 지속기간에따라범주적으로아증후군적우울증을진단하는것이라면, 이기준은우울척도점수의절단점 (cutoff point) 을기준으로아증후군적우울증을진단하는것이다. Lyness 등 23) 은 24문항해밀턴우울척도 24) 를이용하여, 주요우울장애, 경도우울장애가아니면서척도점수가 11점이상인우울증상 (depressive symptoms) 군을아증후군적우울증이라고정의하였다. 그러나연구자마다사용하는우울척도가다르고, 같은우울척도라고 Table 1. Provisional diagnostic criteria of subsyndromal depression SSD-1 SSD-2 SSD-3 No. of depressive symptoms 2 depressive symptoms 2 depressive symptoms Cutoff scores of depression rating scales (e.g. Ham-D >10) Core depressive symptoms - At least one core - (depressive mood or loss of interest) depressive symptoms Time threshold Most of day and nearly every - - day over at least 2 weeks Researchers Judd et al. 1994 8) Judd et al. 1997 27) Goldney et al. 2004 17) Lyness et al. 2006 19) McAvay et al. 2004 18) Lyness et al. 1999 23) Chopra et al. 2005 11) da Silva Lima et al. 2007 22) HAM-D : Hamilton Depression Rating Scale, SSD : Subsyndromal depression journal.biolpsychiatry.or.kr 211
Korean J Biol Psychiatry 2011;18:210-216 하더라도설문문항자체가문화적인영향을많이받고, 25)26) 인종, 지역에따라서각각의다른절단점이사용되기때문에진단이불안정하고, 진단의특이도도낮다. 아증후군적우울증에대한통일된진단기준이존재하지않기때문에진단기준이다른연구간의비교가어려울뿐아니라, 현재까지아증후군적우울증의유병률의연구는매우소수에불과하다. 향후인종, 문화, 국가간의유병률비교를위해서아증후군적우울증의통일된진단기준이필요하다. Judd 등 8) 의진단기준을이용한유병률은미국의 1년유병률은 8.4% 였고, 1개월유병률은 3.9% 였다. 16) 호주의연구에서는시점유병률이미국의 1개월유병률보다높은 12.9% 였다. 17) Judd 등의연구에서아증후군적우울증의 1개월유병률은 3.9% 로주요우울장애의 2.3%, 경도우울장애 1.5% 와비교하여상대적으로높은유병률을보였다. 27) Lyness 등 12) 은 662명의일차진료환자를대상으로 3가지아증후군적우울증진단기준을적용하여서진단기준간의유병률을비교하였다. SSD-1 기준에서는 16.2%, SSD-2 기준에서는 28.1%, 해밀턴우울척도절단점 11점을이용한 SSD-3 에서는 20.4% 였다. 엄격한시간에대한기준이없는 SSD-2 에서가장높은유병률을보였다 (Table 2). 아증후군적우울증은남성보다여성에서많았고, 8)12) 무직, 독신자, 낮은사회경제적수준에서유병률이높아, 5) 아증후군적우울증의인구학적특징은주요우울장애, 경도우울장애와비슷하였다. 그러나노인에서는주요우울장애의경우나이에따른유병률의변화가뚜렷하지않거나나이가증가할수록유병률이줄어들지만, 28-30) 아증후군적우울증의포함한주요우울장애의아닌우울장애의경우는나이에증가함에따라서유병률도증가하였다. 31)32) 아증후군적우울증군에서이전의주요우울장애의과거력은정상인보다높다는연구 27) 도있지만, 정상인과차이가없다는결과 11)19) 도있어향후추후연구를통한확인이필요하다. SSD-1 기준에의한아증후군적우울증의가장흔한증상으로는불면증, 피곤, 죽음에대한반복적인생각, 집중력저하였고, 8) 이는우울증상의핵심증상을제외하고는주요우울장애와비슷하였다. 그러나다른연구에서는주요우울장애군과비교해서아증후군적우울증군에서자살사고, 죄책감이특징적으로적어서, 아증후군적우울증은주요우울장애와는증상의양적으로나질적으로도다른우울장애라는주장도제기되었다. 10) 아증후군적우울증은일반인에비해서자살의위험은높았지만, 경도우울장애, 주요우울장애군보다는낮았다. Judd 등 8) 은아증후군적우울증과경도우울장애와우울증상의차이를비교하였는데, 아증후군적우울증군에서체중증가, 느려진사고, 과다수면은많고식욕저하는적었다. 이를근거로아증후군적우울증이우울증의비전형적양상과연관될수있음을제시하였다. 다른우울장애군과마찬가지로아증후군적우울증에서정상군에비해급속안구운동 (rapid eye movement sleep, 이하 REM) 수면잠복기가짧았다. 비록 REM 수면잠복기감소가우울증에만특이적이지는않지만, 아증후군적우울증이다른우울장애와신경생리학적으로연관됨을시사해준다. 33) 주요우울장애와역치하범주에속하는우울장애의경과및우울장애간의역동적인상호작용에관한몇몇전향적연구들이있다. 5)16)19)27)34-37) 주요우울장애가일정기간이지난후에아증후군적우울증범주에속하게되거나, 아증후군적우울증이나중에발생하는주요우울장애의위험인자로작용하였다. 우울장애에대한대표적인전향적인두연구 19)27) 에서각각 SSD-1 과 SSD-2 를기준으로아증후군적우울증을정의하였는데, 아증후군적우울증군에서 1년후 4% 와 7% 의주요우울장애가발병하였다 (Table 3). 이는비우울중군에서주요우울장애발병률보다의미있게높은비율로아증후군적우울증이주요 Table 2. Prevalence rates of subsyndromal depression 212 Investigator Year Country Number Age (years) Sample Criteria Prevalence Judd et al. 8) 1994 USA 09,160 General population Community SSD-1* 8.4% (1-year) Judd et al. 27) 1997 USA 10,526 General population Community SSD-1* 3.9% (1-month) Goldney et al. 17) 2004 Australia 03,010 General population Community SSD-1* 12.9% Lyness et al. 12) 2007 USA 00,662 65 Primary care patients SSD-1* 16.2% Lyness et al. 12) 2007 USA 00,662 65 Primary care patients SSD-2 28.1% Lyness et al. 12) 2007 USA 00,662 65 Primary care patients Ham-D >10 20.4% * : more than 2 depressive symptoms without core depressive symptoms and with time threshold, : more than 2 depressive symptoms with core depressive symptoms and without time threshold. HAM-D : Hamilton Depression Rating Scale
Subsyndromal Depression Park JH, et al 우울장애의전구체 (precursor) 이라는가능성을보여주었다. 또한주요우울장애의 13% 와 25% 가 1년후에아증후군적우울증의형태로남아있었고, 19)27) 아증후군적우울증경우에는이전주요우울장애의과거력이 5% 로비우울증군의 2% 보다유의하게높았다. 이들의결과는아증후군적우울증이주요우울장애의잔류 (residual) 증상일가능성도제시해주었다. 그리고아증후군적우울증은 1년후의추적관찰에서, 48%, 56% 가여전히한가지의우울장애를앓고있는만성적인경과를보여주었다. 19)27) 그러나, 다른연구에서는아증후군적우울증군에서주요우울장애과거력과의연관성은비우울장애군과차이가없었고, 11)19) 실제로지역사회에서주요우울장애의과거력이없이독립적으로발생하는아증후군적우울증이대부분이었다. 아증후군적우울증군은 5% 만주요우울장애의과거력이있었고이는주요우울장애군의 83% 에서주요우울장애과거력이있다는사실과비교할때매우낮은비율이다. 27) 주요우울장애의과거력이있는아증후군적우울증군에서그렇지않은군보다심리적인장애가더심하고, 향후더심한우울증으로진행될가능성이훨씬높았다. 11) 아증후군적우울증으로인한기능저하는크게아증후군적우울증의직접적인영향으로인한다양한건강서비스이용횟수의증가, 자살시도, 작업의생산성저하등과같은기능저하와향후주요우울장애의발병위험의증가로인한간접적인기능저하로구분할수있다. Broadhead 등 5) 은침대에서보낸날, 일을하지못한날, 병으로인한일상생활이제한된시간등다양한척도를이용하여장애의정도를측정하였는데아증후군적우울장애로인한생기는장애일수 (disability day) 는전체장애일수의 16% 를차지하여, 경도우울장애의 8.5% 주요우울장애의 5.6% 보다높았다. 비록아증후군적우울증의증상은덜심하지만, 높 은유병률로인해서훨씬다른우울장애보다장애일수에더큰영향을주었다. Johnson 등 38) 은장애의정도를나타내는척도로의학적서비스이용, 정신과약물복용, 자기보고건강상태, 1주일간일을못함, 자살시도등을이용하여우울증상군에서장애의정도를평가하였는데, 정상군보다우울증상군에서유의미하게장애가심했다. Judd 등 7) 은심리사회적장애의척도로신체장애수당 (disability benefits), 복지수당, 내과, 정신과또는다른외래치료이용, 정신과입원, 응급실방문, 자살사고, 자살시도등을이용하였는데, 9개중 8개영역에서아증후군적우울증군에서정상군보다더기능저하를보였고증상의심각도가심할수록기능저하는심했다. 진단기준에따른아증후군적우울증의장애를보면세가지기준 (SSD-1, SSD-2, SSD-3) 모두에서비우울증군보다기능저하가심했고, SSD-1, SSD-3로진단한아증후군적우울증군이 SSD-2 로진단한군보다기능저하가더심했다. 12) 1년후결과를보면, 세가지의다른진단기준을이용한아증후군적우울증군모두에서정상군보다정신과적증상과기능적측면에서더나쁜결과를보였고, 경도우울장애, 주요우울장애와비교해서는그차이가유의하지않았다. 세가지진단기준에따른 1년후결과비교에서는 SSD-3 로정의한아증후군적우울증에서가장나쁜예후를보였고, 그다음은 SSD-2, SSD-1 순이었다. 39) 아증후군적우울증은주요우울장애와의관계에서주요우울장애의전구증상으로서뿐만아니라, 주요우울장애의불완전한회복시잔존증상으로존재하여나쁜예후의인자와주요우울장애재발의위험요소로작용하였다. 15) 아증후군적우울증치료에관한연구는소수에불과하고, 그치료효과에대한증거도제한적이다. 40-42) 심리사회적치료로는인지행동치료 43-45) 와대인치료 (interpersonal therapy) 45)46) 가가장많이사용되었고, 이치료를통해서우울증상의호전 Table 3. Outcomes at 1 year by baseline depression diagnosis Researchers Initial diagnosis Depression diagnosis at 1 year MDD MnDD SSD DD ND Judd et al. 27) (1997) SSD (n = 350) 04% 10% 17% 02% 52% MnDD (n = 113) 06% 17% 20% 05% 28% MDD (n = 201) 28% 15% 13% 23% 14% Lyness et al. 19) (2006) SSD (n = 101) 07% 17% 33% 00% 44% MnDD (n = 86) 12% 22% 36% 03% 27% MDD (n = 121) 30% 26% 25% 02% 18% MDD : major depressive disorder, MnDD : minor depressive disorder, SSD : subsyndromal depression, DD : dysthymic disorder, ND : no depression journal.biolpsychiatry.or.kr 213
Korean J Biol Psychiatry 2011;18:210-216 을보여주었지만, 위의연구들은현재의아증후군적우울증 의진단기준을이용한진단이아닌우울증상군을기준으로 하였다. Rapport 와 Judd 47) 는처음으로 15 명의아증후군적우울증과 경도우울장애환자를대상으로한 open label 약물연구를시 행하였다. 처음 8 주간의 fluvoxamine 약물치료후에임상증상 과심리사회적기능이향상되었고, 그이후 2 주간약물을서서 히끊었더니다시우울증상이악화되었다. 그러나위의연구는 대상자수가너무적고, open label 이면서대조군이없는등제 한점이많은임상시험이기때문에그결과를일반화하는데무 리가있다. 향후다양한항우울제에대한전향적이중맹검위 약대조군임상시험을통해, 아증후군적우울증군에서항우울 제의치료적유용성을판단해야한다. 최근의한연구에서경 도우울장애또는아증후군적우울증환자의치료에서초기반 응이향후치료경과를예측하는중요한인자였다. 48) 단극성우울증은 DSM-IV 진단기준역치, 기간, 증상의개 수를만족할때만임상적으로의미있고, 개념적으로급성으 로발병하는고립된 (isolated) 질환으로여겨졌다. 그러나, 아증 후군적우울증이심각한심리사회적장애를일으키고, 주요 우울장애와의연관성이밝혀지면서단극성우울증의개념에 도변화가있었다. 첫째, 우울증은일종의스펙트럼질환 (spectrum disease) 으로 정상부터주요우울장애의다양한심각도가연속선상에존재 하고, 아증후군적우울증은두군을연결시켜주는다리역할을 한다는것이다. 아증후군적우울증의우울증상심각도, 개수, 기간은향후발생하는주요우울장애의중요한예측인자로서, 우울증상의심각도가클수록숫자가많을수록향후우울장애 가발병할위험은높아졌다. 11) 주요우울장애도경계가명확한 분리된질환이기보다는다양한증상, 기간, 심각도를갖는우 울증상군의연속선상에있는진단적합의중하나인것이다. 49) Judd 등 16) 의연구에서, 주요우울장애를 12 개월동안추적 평가하였는데, 우울장애는만성질환의경과를보였고그경 과도다양하였다. 주요우울장애환자들은추적기간의 41.5% 동안만증상이없었고, 나머지기간에는우울장애의한아형 에서다른아형으로지속적으로변하였다. 이러한결과는결 론적으로단극성우울장애는다양한심각성이존재하는스펙 트럼질환 (spectrum disease) 이라는가설을지지해준다. 둘째는, 아증후군적우울증은주요우울장애의효과적인치 료를위한방향을제시해주었다. 주요우울장애의발병이전 에대부분아증후군적우울증이선행하고, 치료후에도재발과연관성이높은아증후군적우울증이뒤따른다. 그러므로치료의목표가주요우울장애를아증후군적우울증상태로변화시키는증상의완화가아닌, 무증상상태에이르게하는것이되어야한다. 50) 즉질환을없애고건강을완전히회복하는것이목표가되어야하는것이다. 5개미만의우울증상, 2주미만의우울증상들도심리사회적기능을저하시키고, 향후부정적인결과와예후를초래한다. DSM-IV 의진단기준에는이미세가지의역치하우울증 ( 반복성단기우울증, 경도우울장애, 기분부전장애 ) 이있지만, 아증후군적우울증은포함되어있지않다. 현재아증후군적우울증은크게 3가지의기준 (SSD-1, SSD-2, SSD-3) 으로진단되고있고, 어떤기준을이용하더라도아증후군적우울증은사회심리적, 직업적기능저하에영향을미치고향후자살과주요우울장애와연관성을갖는다. 우울증은경한상태에서도, 우울감과흥미상실의핵심증상이빠진우울증상군들에서도심각한기능장애를일으킨다. 향후아증후군적우울증에대한연구들간의결과를비교, 분석, 통합하기위해서는통일된단일한진단기준이요구된다. 단극성우울증은우울증상의연속된범주에서다양한심각도의우울증상이나타나는질환으로개념화되고있다. 아증후군적우울증은주요우울장애의전구증상, 잔존증상, 삽화간에도나타나고, 한편으로는주요우울장애의전구증상및잔류증상과관계없이독립적으로나타나기도한다. 향후두종류의아증후군적우울증에대한임상적특징, 경과, 예후, 치료등을밝히는연구가필요하다. 현재아증후군적우울증의치료에대한연구는매우부족한실정이다. 심리사회적치료가아증후군적우울증치료로충분한지, 어떤역치의우울장애부터약물치료를해야되는지, 주요우울장애로진행되는아증후군적우울증을더적극적으로치료를해야되는지, 주요우울장애에과거력이있는아증후군적우울장애를더적극적으로치료해야되는지등의다양한질문에답을할수있는종적연구들이필요하다. 아증후군적우울증은유병률이높고, 의미있는심리사회적, 경제적인장애를일으키고, 만성적인경과를거치고, 부정적인예후를초래하는임상적으로중요한질환으로, 임상가와연구자는아증후군증우울증의발견, 진단, 치료에더많은주의를기울여야한다. 중심단어 : 아증후군적우울증 정의 결과 경과. Conflicts of interest The authors have no financial conflicts of interest. 214
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