online ML Comm ORIGINAL ARTICLE ISSN / eissn Korean J Biol Psychiatry 2014;21:14-20,, : 인제대학교의과대학일산백병원정신건강의학교실 박영민 이승환 Chronotype

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1 online ML Comm ORIGINAL ARTICLE ISSN / eissn Korean J Biol Psychiatry 2014;21:14-20,, : 인제대학교의과대학일산백병원정신건강의학교실 박영민 이승환 Chronotype in Relation to Bipolarity, Suicidal Ideation, and Auditory Evoked Potentials in Patients with Major Depressive Disorder : Preliminary Study Young-Min Park, MD, Seung-Hwan Lee, MD Department of Psychiatry, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea ObjectivesZZThe current study investigated the putative relationship between chronotype and suicidality or bipolarity in patients with major depressive disorder (MDD). MethodZZNineteen outpatients who met the criteria for MDD according to the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders-text revision were recruited for the current study. The subjects were divided into two subgroups based on their Basic Language Morningness (BALM) scores (dichotomized according to the median BALM score). The Loudness Dependence of Auditory Evoked Potentials (LDAEP) was evaluated by measuring the auditory event-related potentials before beginning medication with serotonergic agents. In addition, K-Mood Disorder Questionaire (K-MDQ), Beck Scale for Suicidal Ideation (BSS), Beck Hopelessness Scale (BHS), Barratt Impulsiveness Scale (BIS) were applied. ResultsZZThe K-MDQ, BSS, BHS, BIS score was higher for the eveningness group than for the morningness group. However, the LDAEP, Hamilton Depression Rating Scale, Hamilton Anxiety Scale scores did not differ significantly between them. There were negative correlations between the total BALM score and the total K-MDQ, BSS, and BHS scores (r = and p = , r = and p = , and r = and p = , respectively). ConclusionsZZDepressed patients with eveningness are more vulnerable to the suicidality than those with morningness. Eveningness is also associated with bipolarity. Key WordsZZChronotype ㆍ LDAEP ㆍ Major depressive disorder ㆍ Bipolarity ㆍ Bipolar spectrum disorder. Received: October 4, 2013 / Revised: October 22, 2013 / Accepted: December 26, 2013 Address for correspondence: Young-Min Park, MD Department of Psychiatry, Ilsan Paik Hospital, Inje University College of Medicine, 170 Juhwa-ro, Ilsanseo-gu, Goyang , Korea Tel: , Fax: , medipark@hanmail.net 양극성장애와단극성우울증의감별하는것은쉽지않다. 그이유는양극성장애를가진환자들의경과에서가장많고두드러지는증상이우울증상이기때문이다. 1형양극성장애에서우울증상과조증증상의나타난기간에대한비율은 3 : 1이며 2형양극성장애에서는 37 : 1이다. 1) 따라서환자로부터자세한병력의청취및가족이나친밀한관계를맺는정 보제공자와의면담이이루어지지않으면양극성장애를다른진단으로오진할수도있다. 2000년대초반 Ghaemi 등 2) 은경조증과조증삽화가없는환자들도양극성장애의특성을가질수있다고주장하였다. 그들은이런환자들을양극성스펙트럼장애 (bipolar spectrum disorder) 로진단하였고이에대한진단기준을개발하였다. 2) 이러한진단기준에따르면우울삽화가발생한환자에서가족력에서양극성장애가있거나과거항우울제에의한경조증이나조증전환의과거력의 2 14 Copyright 2014 Korean Society of Biological Psychiatry

2 Chronotype in Relation to Bipolarity and Suicidal Ideation Park YM, et al 가지를가장중요한진단기준으로삼았고여기에추가기준으로이른발병, 잦은발병, 짧은삽화, 비전형적증상, 정신병적증상 9가지기준을제시하였다. 그들에의하면이러한환자에게항우울제단독으로치료를한다면불안정정동이나타날수있고나아가서경조증이나조증전환이될수있다며양극성스펙트럼장애 (bipolar spectrum disorder) 의중요성을역설하였다. 따라서경조증이나조증이없는환자에서양극성장애를예측하는요소들을찾는것이매우중요한의미를갖게되었다. Ghaemi 등 2) 의진단기준에는없지만일주기리듬또한우울장애, 양극성장애, 혹은계절성정동장애와의연관성에대한연구결과들이제시되고있다. 6071명의일반인구를대상으로일주기형태와우울증여부를조사한결과우울증이있는사람은저녁형의일주기형태를유의하게더많이가지고있었다. 3) 또한수면위상지연증후군 (delayed sleep phase syndrome) 을가진환자들에서우울증상과불안증상이높은빈도를보였다는보고도있었다. 4)5) 반면에주요우울증환자에서아침형일주기형태를보이면이는좋은예후를나타낸다는보고도있었다. 6) 하지만위의연구들은주로우울증상에초점을맞추었기때문에일주기형태를통해단극성우울증과양극성우울증을구별하려는연구는아니었다. 양극성장애의경우 Ahn 등 7) 은저녁형의일주기리듬이정상대조군보다양극성장애 I형환자에서통계적으로더유의한빈도를보였음을보고하였다. 또한 Robillard 등 8) 은양극성우울증환자와단극성우울증환자에서수면위상지연 (delayed sleep phase) 의빈도를비교하였는데양극성환자에서는 62%, 단극성환자에서는 30%, 정상대조군에서 10% 로통계적으로유의한차이를보였다. Lee 등 9) 은수면위상지연증후군 (delayed sleep phase syndrome) 을보이는피험자가그렇지않은피험자보다 3.3배많은계절성정동장애를보인다고보고하였다. 이러한결과는계절성양상이양극성장애와관련이있다는이전결과들 10)11) 로볼때일주기리듬을포함한주기의문제가양극성장애와관련이있음을시사한다. 이렇듯이양극성장애와일주기리듬과관련된연구들은이미존재하지만주요우울삽화를가지고있으며양극성장애의특성을가지고있으나조증혹은경조증삽화의병력은없는양극성스펙트럼장애 (bipolar spectrum disorder) 와주요우울증환자를비교한연구는없는상태이다. 따라서본고의저자들은양극성스펙트럼장애와우울증의일주기리듬을비교해보려고하였다. 수면은세로토닌과관련이많다. 최근세로토닌이일주기리듬과관련되어하루중빛의양에따라수면을조절한다는주장이제기되었다. 12) 세로토닌이각성을증가시키고렘수면을저해하는역할을한다는주장도제기되었다. 13) 최근에세로토닌 수송체유전자 (SCL6A4) 와카테콜-O-메틸트란스퍼라제 (catechol-o-methyltransferase) 유전자다형성에따라일주기형태가차이가있었다고보고되었다. 14) 따라서아직연구는적지만세로토닌이일주기형태와관련이있을가능성도있다 년대초반청각유발전위를이용하여세로토닌활성도를측정할수있는방법이소개되었다. 15)16) 이는사건유발전위 (event related potential) 를이용하는것으로써청각자극을통해개인간의반응성이다르다는차이를응용한것이다. 자극시작이후 50 ms, 100 ms, 200 ms 후에발생하는전위를각각 P1, N1, P2라고하는데청각자극의강도를증가시키면개인마다독특한진폭의변화가나타나게된다. 이러한진폭의변화량, 즉청각자극이증가함에따라생기는진폭의변화량 ( 기울기 ) 을청각유발전위 (Loudness Dependence of Auditory Evoked Potentials, 이하 LDAEP) 라고한다. 15)16) 청각자극에대한뇌의반응은주로 primary auditory cortex에서처리되며이곳에세로토닌신경원들이과밀하게분포되어있다. 따라서청각자극에대한뇌의반응은세로토닌과연관되어있을것으로가정되었고이후연구를통해확인되었다. 15)16) 이후많은연구자들은이러한 LDAEP가클수록낮은세로토닌활성도를나타내고, LDAEP가작을수록높은세로토닌활성도를나타낸다는것을보고하였고이를활용하여정신질환의감별, 치료반응성, 임상상태의판단에이용하였다 ) 본연구는주요우울증환자이면서급성우울삽화로내원한환자에서일주기리듬에따라양극성성향과자살사고등과같은임상양상의차이점이존재하는지와청각유발전위를측정하고이를통하여 LDAEP를계산하여세로토닌활성도의차이점이존재하는지를확인하기위한예비연구이다. 또한이를통해양극성우울증과단극성우울증을감별할수있는후보요인들을찾으려한다. 연구대상 2012년 7월부터 2013년 5월까지인제대학교부속일산백병원외래에내원한 18~50 세사이의신환을대상으로하였다. Diagnostic and Statistical Manual of Mental Disorders, fourth edition의진단기준에의거하여주요우울증으로진단된환자총 19명이등록되었다. 등록된환자모두과거조증이나경조증의삽화는없었으며최소 6개월이상항우울제를포함한정신신경계약물을복용한적이없었다. 두부외상의병력이있었거나신경학적질환이있는환자들은모두제외하였다. 또한세로토닌이나도파민에영향을주는약물을복용하고있는환자들도제외하였다. 본연구는인제대학교일산백병 journal.biolpsychiatry.or.kr 15

3 Korean J Biol Psychiatry 2014;21:14-20 원의임상연구윤리심의위원회의승인을받아시행되었으며, 모든피험자들은연구에대한설명을듣고연구참여에자발적으로서면으로동의한후참여하였다. 연구방법항우울제를투여하기전우울증의심각도를평가하기위하여 Hamilton Depression Rating Scale( 이하 HAMD) 22) 을사용하였다. 그밖에 Beck Hopelessness Scale( 이하 BHS), 23) Barratt Impulsiveness Scale( 이하 BIS), 24) Hamilton Anxiety Scale( 이하 HAMA), Beck Scale for Suicidal Ideation( 이하 BSS), 25) K-Mood Disorder Questionaire( 이하 K-MDQ) 26-28) 를이용하여평가하였다. 특히 K-MDQ 는최근표준화된척도이며질문 1만활용하여 7점이상을양극성경향이있음으로판단하는척도이다. 질문 1은모두 13개의문항으로구성되어있다. 예 혹은 아니오 로표시하게되어있으며기분의들뜸, 흥분, 자신감, 수면문제, 말의속도및양, 생각, 집중, 에너지, 활동성, 외향성, 성행위, 위험한행동, 돈문제에관한질문으로구성되어있다. 한문항당 예 일경우 1점으로계산한다. 일주기리듬은 Basic Language Morningness( 이하 BALM) 29) 으로측정하였다. 또한 LDAEP 값을세로토닌계약물의영향을받지않고계산하기위하여선택적세로토닌재흡수억제제 (Selective Serotonin Reuptake Inhibitor) 를투여하기전미리청각유발전위를측정하였다. 측정방법은다음과같다. Neuroscan Synamp amplifier(conpumedics USA, El Paso, TX, USA) 와 Ag-AgCl elctrodes가 10~20 체계에의해심어져있는 Quick Cap을사용하여총 64개전극에서뇌파를측정하였다. 전극저항은 10 kω 이하가되게하였으며, 통과주파수 (bandpass) 는 0.5~100 Hz로하였고, sampling rate는 1000 Hz였다. 자극은 5가지종류의청각자극을사용하였는데 55, 65, 75, 85, 95 db 5가지종류의 1000 Hz 소리자극을사용하였고자극제시시간은 80 ms였다. 상승하강은 10 ms, 자극간의간격은 500~900 ms 사이를무작위로하였다. 소리자극은헤드폰 (MDR-D777, Sony, Tokyo, Japan) 을통해피험자에게제시되었다. 제시된총자극개수는 1000개였으며총검사시간은약 15분이내였다. 자극의제시및뇌파와의동기화는 E-Prime(Psychology Software Tools, Inc., Pittsburgh, PA, USA) 을통해시행되었다. 측정된뇌파는 Scan 4.3(Compumedics USA, El Paso, TX, USA) 프로그램을이용하여분석하였다. 눈깜빡거림 (eye blinks) 은기존에검증된수학적방법론에의해제거되었다. 30) 잡파제거는측정된전체채널에서파형의진폭이 70 μv를넘으면잡파로간주하여제거하였다. 사용된 band pass filtering은 1~30 Hz였다. N100 은 Cz 전극위치에서자극제시후 80~130 ms 사이의가장큰음성전위 값을보인것으로하였다. N100 전위값은 N100 꼭짓점과 P200 (N100 이후나타나는첫번째양성전위 ) 꼭짓점의차이 (N1 peak to P2 peak) 로측정하였고 N100 잠복기는자극제시시점으로부터음성전위극점까지의시간으로측정하였다. LDA- EP는 5가지제시된소리에반응하는 N100 진폭을선형회기 (linear regression) 식에의거하여 10/dB 기준에따라계산하였다. Cz에서 LDAEP 값이구해졌다. 통계분석통계분석을위하여 Statistical Analysis System version 9.3 과 Intelligent Statistical Analysis Tool 2.5 프로그램을사용하였다. 각척도들, LDAEP와일주기리듬과의상관을검증하기위하여 Spearman 상관분석을실시하였다. 또한 BALM 점수를중간값을기준으로두군으로나누어 Mann-Whitney U test를이용하여각척도들의총점을비교하였다. 빈도분석은 chi-square test를이용하였다. 모든통계는양측기준으로 p < 0.05에따랐다. BALM 척도를이용하여환자들의일주기리듬의성향을조사하였고중간값을기준으로하여두군으로나누어임상양상과청각유발전위를비교하였다 (Table 1). BALM 총점이높은군 ( 아침형 ) 과낮은군 ( 저녁형 ) 사이에몇가지척도에서통계적으로유의한차이를보여주었다. K-MDQ(p = 0.018), BSS (p = 0.009), BHS(p = 0.003), BIS(p = 0.03) 총점에서두군간의유의한차이가있었다. 하지만 HAMD, HAMA의총점과 LDAEP에서의차이는없었다. K-MDQ 척도를이용하여양성을보이는환자와음성을보이는환자로나누어비교분석하였다 (Table 2). HAMA(p = 0.023), BSS(p = 0.02), BALM(p = 0.005) 총점에서두군간의유의한차이가있었다. 반면에 HAMD와 LDAEP에서의차이는없었다. 마지막으로 Spearman 상관분석을이용하여변수간의상관성을분석하였다. 먼저 BALM 총점과다른변수의총점과의상관성을분석하였는데그중에서 K-MDQ(r = -0.64, p = ), BSS(r = -0.61, p = ), BHS(r = -0.72, p = ) 와역의상관관계를보였다 (Fig. 1-3). 반면에 BALM 총점과 LDAEP를포함한다른변수들과는상관관계가없었다. 두번째로 K-MDQ 총점과다른변수의총점과의상관성을분석하였다. 그중에서 HAMA(r = 0.47, p = 0.04), BSS(r = 0.58, p = 0.009), BHS(r = 0.52, p = 0.022) 와양의상관관계를보였다. 반면에다른변수들과는상관성을보이지않았다. 16

4 Chronotype in Relation to Bipolarity and Suicidal Ideation Park YM, et al Table 1. Age, sex, LDAEP, and psychometric ratings of patients with major depression according to chronotype (morningness or eveningness) Variable Group with eveningness Group with morningness p-value Age, years ± ± Sex (M/F) 1/9 1/ LDAEP (mv/10 db) 1.16 ± ± Total HAMD score ± ± Total HAMA score ± ± Total K-MDQ score 6.80 ± ± * Total BSS score 15.4 ± ± * Total BHS score 15.5 ± ± * Total BIS score 87.8 ± ± * Total BALM score ± ± * Data were expressed as mean ± SD values or frequencies. * : statistically significant difference at p < 0.05, : Fisher's exact test. LDAEP : Loudness Dependence of Auditory Evoked Potentials, HAMD : Hamilton Depression Rating Scale, HAMA : Hamilton Anxiety Scale, K-MDQ : Korean Mood Disorder Questionnaire, BSS : Beck Scale for Suicidal Ideation, BHS : Beck Hopelessness Scale, BIS : Barratt Impulsiveness Scale, BALM : Basic Language Morningness Table 2. Age, sex, LDAEP, and psychometric ratings of patients with major depression according to bipolarity Variable Bipolarity (-)(n = 14) Bipolarity (+)(n = 5) p-value Age, years ± ± Sex (M/F) 1/13 1/ LDAEP (mv/10 db) 1.23 ± ± Total HAMD score ± ± Total HAMA score ± ± * Total K-MDQ score 3.79 ± ± * Total BSS score 6.50 ± ± * Total BHS score 9.07 ± ± * Total BIS score ± ± Total BALM score ± ± * Data were expressed as mean ± SD values or frequencies. * : statistically significant difference at p < 0.05, : Fisher's exact test. LDAEP : Loudness Dependence of Auditory Evoked Potentials, HAMD : Hamilton Depression Rating Scale, HAMA : Hamilton Anxiety Scale, K-MDQ : Korean Mood Disorder Questionnaire, BSS : Beck Scale for Suicidal Ideation, BHS : Beck Hopelessness Scale, BIS : Barratt Impulsiveness Scale, BALM : Basic Language Morningness 본연구는주요우울증환자에서일주기형태에따른임상양상과 LDAEP 수치를이용하여청각유발전위의차이를비교하려고하였다. 분석결과일주기리듬이저녁형의양상을보이는환자일수록 K-MDQ 가유의하게높았으며이는저녁형의양상이양극성경향과관련이있음을의미한다. 이전연구에서도이미양극성장애와지연수면양상이관련이있음을보고하였지만, 7)8) 본연구에서처럼지연된수면양상, 즉저녁형에가까운주요우울증환자들이더강한양극성경향이있음을확인한연구는없었다. 이런결과는기존의단극성우울증과양극성우울증을이분법으로보는현진단체계보다는기분장애를하나의범주로보아단극성우울증과양극성우울증사이에겹치는부분이존재하는연속성의개념으로볼수있는근거중하나가될수있겠다. 31) 하지만본연구결과와대 조되는연구결과도존재한다. 1형양극성장애, 2형양극성장애, 재발성우울장애환자들을대상으로일주기형태를비교하였는데 2형양극성장애환자들이 1형양극성장애환자들보다더강한저녁형일주기양상을보였으며 1형양극성장애환자들은재발성우울장애환자들보다더강한아침형일주기양상을보였다. 32) 따라서양극성이강할수록더강한저녁형일주기형태를갖는다는가설은향후더많은연구로검증되어야할것이다. 본연구의결과중또하나의임상적으로의미있는결과는저녁형양상을보이는환자들이아침형양상을보이는환자들에비해자살사고와관련된 BSS, 무망감을나타내는 BHS, 충동성을나타내는 BIS가유의미하게증가되어있었던반면, HAMD에서는유의한차이가없었다는점이다. 이는저녁형혹은지연성수면양상을보이는환자들에있어서는아침형과유사한우울증심각도를보이더라도저녁형에서자살위험성 journal.biolpsychiatry.or.kr 17

5 Korean J Biol Psychiatry 2014;21: Spearman : r = -0.64, p = Spearman : r = -0.72, p = Total K-MDQ 6 Total BHS Total BALM Total BALM Fig. 1. Correlation between Basic Language Morningness (BA- LM) and Korean Mood Disorder Questionnaire (K-MDQ) score. Total BSS 이더높을수있음을시사한다. 한편두군간의 LDAEP 의차 이는없었는데이는두군간의세로토닌활성도의차이는없 었음을의미하며일주기형태의차이가세로토닌활성도에크 게영향을받지않음을의미한다. 이는세로토닌수송체의유 전자형에따라일주기형태가영향을받지않는다는이전의연 구 33) 와유사한의미로보인다. Spearman : r = -0.61, p = Total BALM Fig. 2. Correlation between Basic Language Morningness (BA- LM) and Beck Scale for Suicidal Ideation (BSS) score. K-MDQ 를이용하여양성과음성의두군으로나누어임상 Fig. 3. Correlation between Basic Language Morningness (BA- LM) and Beck Hopelessness Scale (BHS) score 척도와 LDAEP 를비교하였다. 양극성경향을보이는환자들 이그렇지않은환자들에비해자살사고와관련된 BSS, 무망 감을나타내는 BHS, 불안의정도를나타내는 HAMA 가유의 미하게증가되어있고 BALM 은유의하게감소되어있는반면 HAMD 에서는유의한차이가없었다. 이역시양극성경향이 높은환자일수록자살에더취약함을의미하며유사한우울 증심각도를보일때는양극성경향이있는환자에서그렇지 않은환자에비해더자살위험성이높음을시사한다. 이는이 전연구와도일치되는소견이다. 34) 상관분석에서도앞의결과와유사한결과들이이어졌다. BA- LM 점수와 K-MDQ, BSS, BHS 와역의상관관계를보였다. 이는저녁형에가까울수록양극성경향, 자살사고, 무망감등 이증가함을의미한다. K-MDQ 점수역시 HAMA, BSS, BHS 와양의상관관계를보였다. 이또한양극성경향이강하면강 할수록불안, 자살사고, 무망감등이증가함을의미한다. LDA- EP 는 BALM 과 K-MDQ 모두에서상관관계가없었다. 이는 세로토닌활성도가일주기리듬과양극성경향에영향을주 지못함을의미한다. 이또한이전의연구와일치하는결과이 다. 33)35) 하지만이에대해서는상반되는연구도있기때문에후 속연구가필요할것으로보인다. 14) 본연구는몇가지제한점이존재한다. 첫번째로표본크기 가작았다는점이다. 하지만본연구는처음시도되는것으로 예비적인연구의성격을지니고있다. 향후대규모환자를대 상으로추가후속연구를진행할것이다. 두번째로 K-MDQ 는질문 1 만합산해서양극성성향을판단하므로본래개발 18

6 Chronotype in Relation to Bipolarity and Suicidal Ideation Park YM, et al 된 MDQ 와는약간차이가있다는것이다. 하지만 K-MDQ 의 표준화를통해민감도와특이도를최적화한것이므로이자 체도의미가있다하겠다. 26) 향후에표본크기를늘려서일주기양상과세로토닌, 그리 고자살과의관련성을규명하기위한연구가계속되어야할 것이다. 또한양극성경향을잘구분하기위한도구들을더다 양하게준비하고고민해야할것으로보인다. 일주기리듬과 평가와관련되어서도더다양한척도에대한검토가필요할 것이며국내표준화가우선필요할것으로보인다. 또한저녁 형, 아침형을더정확하게분석하기위해피험자의수면 - 각성 주기의확인이필요할것으로판단된다. 그밖에일주기뿐만 아니라계절성의평가도피험자의주기및양극성경향을규 명하는데중요할것이다. 중심단어 : 일주기형태 청각유발전위 주요우울증 양극성 양극성스펙트럼장애. Acknowledgments This study was supported by a grant from National Research Foundation of Korea (NRF), funded by Ministry of Education and Science Technology (MEST)( ). The authors would like to thank Lee Yoo Jin for her assistance with data collection. Conflicts of interest The authors have no financial conflicts of interest. REFERENCES 1) Manning JS. Difficult-to-treat depressions: a primary care perspective. J Clin Psychiatry 2003;64 Suppl 1: ) Ghaemi SN, Ko JY, Goodwin FK. 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012임수진

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