Microsoft Word doc

Transcription

1 KISEP Special Article 생물정신의학 Vol. 13, No. 4, November 2006 정신병적우울증의치료전략 * 이소영 ** 정한용 ** Treatment Strategies for Psychotic Depression * Soyoung Irene Lee, M.D., Ph.D., ** Han-Yong Jung, M.D., Ph.D. ** ABSTRACT bjectives:several O factors, such as biological markers, clinical correlates, and course of the depressive disorders with psychotic symptoms differ from those without psychotic symptoms. Therefore, specification of a treatment algorithm for depressive disorder with psychotic symptoms is legitimated. This article provides a systematic review of somatic treatments for depressive disorder with psychotic symptoms. Methods:According to the search strategy of the Clinical Research Center for Depression of Korean Health 21 R & D Project, first, PubMed and EMBASE were searched using terms with regard to the treatment of depressive disorders with psychotic symptoms(until July 2006). Reference lists of related reviews and studies were searched. In addition, relevant practice guidelines were searched using PubMed. All identified clinical literatures were reviewed and summarized in a narrative manner. Results:Treatment options, such as a combination of an antidepressant and an antipsychotic versus an antidepressant or an antipsychotic alone are summarized. In addition, issues regarding the electroconvulsive therapy(ect), combination therapy, and maintenance treatment are discussed. Conclusion:In former times, the combination of an antidepressant and an antipsychotic or ECT were recommended as the first line treatment for depressive disorder with psychotic symptoms. Recently, however, there was a suggestion that there was no conclusive evidence that the combination of an antidepressant and an antipsychotic drug is more effective than an antidepressant alone. More evidence regarding the pharmacological treatment for depressive disorder with psychotic symptoms is needed. KEY WORDS:Psychotic depression Treatment strategy. 서 정신병적우울증 (psychotic depression) 은상대적으로 론 흔히발생하는질환으로연구에서조사당시일반인구 1,000명당 4명이앓고있다는보고가있다. 1) 그리고우울증환자의 10~18% 에서정신병적증상을동반하여 1-3) * 본연구는보건복지부보건의료기술진흥사업의지원에의하여이루어진것임 ( 과제번호 :A050047). ** 순천향대학교의과대학부천병원정신과학교실 Department of Psychiatry, College of Medicine, Soonchunhyang Bucheon Hospital, Soonchunhyang University, Bucheon, Korea 교신저자 : 정한용, 경기도부천시원미구중동 1174 전화 ) (032) , 전송 ) (032) ) hanyjung@schbc.ac.kr

2 심한우울증환자의약 6~7명중한명이이에해당된다. 정신병적우울증은정신병적증상을동반하지않는우울증과는구분되는질환을일컫는것으로진단체계에따라다소다르게기술되고있다. Diagnostic and Statistical Manual-Ⅳ Edition(DSM-Ⅳ) 4) 진단체계에서는 Major depressive episode, severe with psychotic features (296.24) 로명명하고있고주요우울삽화의진단기준을충족하는동시에환각이나망상이있는경우를말한다. 반면, International Classification of Diseases-10th Edition(ICD-10) 5) 진단체계에서는 Severe depressive episode with psychotic symptoms(f32.3) 으로명명하면서소위신체증후군에해당되는새벽에일찍깨고, 식욕감퇴, 성욕감퇴, 일중기분변화, 객관적인초조증또는정신운동성지체등의증상이있으면서환각, 망상혹은정신운동성초조나지체가동반되는경우를말한다. ICD- 10에서는환각이나망상이없어도정신운동성장해가있으면정신병적우울증으로진단이내려지기때문에 DSM- Ⅳ의진단기준과는차이가있다. 이런경우 DSM-Ⅳ 진단체계하에서는 melancholic features를동반한주요우울삽화로분류될것이다. 망상의내용이기분과일치하는지여부, 즉우울한기분과일치하는죄책, 빈곤, 허무망상의형태인지아니면기분과일치하지않는망상인지에기초해서주요우울장애와정신분열병이나분열형정동장애를구분하는방법은더이상사용되지않고있다. 6) 그리고정신병적우울증에대한 DSM-Ⅳ 와 ICD-10 진단체계에서도모든형태의환각과망상을포괄하고있다. Wheeler 등 7) 은정신병적증상을동반한주요우울장애를어떻게분류할것이냐에관해세가지관점을들었다. 첫번째로정신병적우울증은일반우울증과마찬가지로우울증의한종류이나임상적으로의미가있고객관적인차이를갖는구분되는진단적범주로간주하는견해이다. 두번째는주요우울장애의보다심한아형이라는견해로 DSM-Ⅳ 와 ICD-10 진단체계모두이를지지하고있다. 세번째는정신병적우울증을단지주요우울장애의하나의아형이아니라별개의임상증후군으로간주하는견해이다. 다른논제로, 정서장애가일정한임계점에도달하면정신병적증세가생기는것인지아니면개인의취약성과관련되는것인지에대해서는아직까지논란이있다. 연구자들은정신병적우울증은정신병적증상을동반하지않는우울증과비교했을때질병의양상이나예후에있어차이가있다고주장하고있다. 3)6)8)9) 정신병적우울증 환자들에서정신병적증상을동반하지않은우울증환자들보다가족력이더많고, 정신운동성및인지기능의장해가더크며, 자살에대한위험, 입원의필요성등임상양상이더심각하고, 이환기간이더길며, 더자주재발하여사회적기능이저하되는등예후가더나쁘다고한다. 특히 Schatzberg와 Rothschild 10) 은이러한차이가증세의심한정도와는무관하게나타났기때문에이두질환은구분되는증후군으로봐야한다고주장하였다. 이러한견해를뒷받침하는생물학적연구결과들도있는데, 정신병적우울증의경우정신병적증상을동반하지않은우울증보다 homovanillic acid 농도가더증가되었고, 10)11) Dexamethasone suppression test에서 cortisol 이억제되지않는비율이더컸으며, 12) REM 잠복기가단축되어있었다. 13) 그밖에뇌영상학연구에서간뇌, 좌측전측방부위와망상계등의위축 14) 이거론되고있다. 추적연구에서경과의차이를더욱뚜렷하게보여주고있는데, 정신병적우울증이있던환자의이후삽화에서다시정신병적증상이동반되는식으로비교적일관되게나타난다는것이다. 15)16) 또다른추적연구들 3)6)8) 에서정신병적우울증이정신병적증상을동반하지않은우울증보다더빨리재발하고, 재발하는횟수가더많으며또한증상도더오래지속된다고하였다. 그리고약물연구에서정신병적증상이동반된우울증의경우위약에대한반응율이다른우울증환자보다훨씬적은것으로나타났다. 17)18) 이와같이정신병적증상이존재함에따라단기적그리고장기적이환율이커지고또한약물치료에있어위약효과도다르기때문에정신병적증상을동반하는우울증을위한별도의적절한치료전략수립이필요하다. 따라서저자는정신병적우울증의치료에대한근거를종합하여전반적인고찰을하고자한다. 이는우리나라에서적용가능한치료적전략을수립하는데기초자료로활용될것으로생각된다. 방법 자료검색은보건복지부보건의료기술진흥사업과제 ( 우울증연구센터, 과제번호 :A050047) 의세부과제인한국형우울증진료지침개발 : 우울증의치료전략팀에서수립한검색방식을따랐다. 검색은 2006 년 7월 15일을기준으로 PubMed 와 EMBASE 를이용하여이루어졌다. 첫번째검색은다음과같은검색어를이용하여이루어졌다 :psychot* AND depression [depression(s)/de

3 pressive disorder(s)/unipolar depression/dysthymia/ 연구논문들의참고문헌의원문을입수하여세부적으로검 depressive disorder(s)/depressive episode/depressive illness/dysthymic disorder(s)/minor depression 병적우울증의치료권고문들의내용과흐름을알아보기토하였다. 두번째검색은외국에서사용되고있는정신 (s)]. 그결과총 15개의체계적고찰이검색되었고, 저위해 PubMed 에서영어로출간된 Systemic Review 중자에의해본고찰의목적에부합되고질수준이높은것에서 Type of Article 을 Practice guideline으로제한하으로판단된다음논문이선택되었다 :Pharmacological 여검색하였다. 검색된 89개의치료지침중에특수한대 treatment for psychotic depression(cochrane Collaboration, Wijkstra 등 ). 19) 추가로검색된 194개의관련을다루고있지않은치료지침을제외한다음다섯개의상을위한치료지침들은제외하고또한정신병적우울증논문중에는언급된위의체계적고찰이후에는통제연치료지침을선정하여본문을입수하여검토하였다 :Royal 구가출시되지않았으므로본고찰에서는통제연구를추 Australian and New Zealand College of Psychiatrists 가로선택하지않았다. 다만위체계적고찰에서검토한 Clinical Practice(RANZCP) Guidelines Team for De- Table 1. Characteristics of major randomized controlled trials of treatment for depressive disorder with psychotic features included in this review Study N Drug comparison(dosage) Duration (week) Outcome Spiker and Kupfer 17) 27 Amitriptyline(200mg) vs. placebo 4 Amitriptyline(response rate-40%) significantly superior to placebo(0%) Spiker et al. 30) 58 Amitriptyline(217mg) vs. perphenazine(49.8mg) vs. amitriptyline(170mg)+ perphenazine(54mg) 4 Combination(response rate-78%) superior to amitriptyline(41%) and perphenazine(19%) Mulsant et al. 32) Anton and Burch 39) Anton and Burch 40) Zanardi et al. 43) van den Broek et al. 44) Zanardi et al. 45) 36 Nortriptyline(76mg) vs. nortriptyline(63mg)+ perphenazine(19mg) 46 Amoxapine( mg) vs. amitriptyline( mg)+ perphenazine(24-40mg) 37 Amitriptyline(209mg)+perphenazine (34mg) vs. amoxapine(412mg) 72 Fluvoxamine(300mg)+ pindolol(7.5mg) vs. fluvoxamine(300mg) 48 Imipramine( mg) vs. fluvoxamine( mg) 22 Venlafaxine(300mg) vs. fluvoxamine(300mg) Zanardi et al. 46) 32 Sertraline(150mg) vs. paroxetine(50mg) Bruijn et al. 47) 30 Imipramine(235mg) vs. mirtazapine(76mg) Rothschild 124/ Olanzapine(5-20mg) vs. placebo et al. 54) 125 vs. olanzapine(5-20mg)+ fluoxetine(20-80mg) Muller-Siecheneder et al. 57) 34 Risperidone(6.9mg) vs. haloperidol(9mg)+amitriptyline (180mg) BPRS:Brief Psychiatric Rating Scale, BRMES:Bech-Rafaelsen Melancholia Scale Combination(response rate-50%) was not different to nortriptyline(44%) 4 Two groups similar in improvement 4 Two groups similar in improvement 6 Two groups similar in improvement 4 Imipramine improved significantly better on CGI-S change;mean reduction of HRSD was significantly larger in imipramine than fluvoxamine, but no difference in 50% or more reduction on HRSD in two groups 5 No significant difference between fluvoxamine(response rate-78.6%) and venlafaxine(58.3%) 5 Sertraline(response rate-75%) and paroxetine(46%) were equally effective 4 Imipramine(response rate-40%) was superior to mirtazapine(21.6%) 8 Trial 1:combination group(response rate- 63.6%) significantly more improved than olanzapine(34.9%) or placebo(28.0%); Trial 2:no significant difference between two groups 6 Haloperidol+amitriptyline was superior to risperidone in decreases of BPRS and BRMES

4 pression 20) ;World Federation of Societies of Biological Psychiatry(WFSBP) Task Force on Treatment Guidelines for Unipolar Depressive Disorders 21) ; Clinical guidelines for the treatment of depressive disorders 22) ;The Texas Medication Algorithm Project (TMAP):report of the Texas Consensus Conference Panel on Medication Treatment of Major Depressive Disorder 23) ;Practice guideline for the treatment of patients with major depressive disorder(revision). 24) 저자들은검색된자료에기초하여정신병적우울증에사용되고있는치료기법에따라분류하여기술하고논제에따라여러치료지침을비교해가며논의하고자한다. 주요이중맹검대조연구들은표 1에요약되어있다. 결과 1. 삼환계항우울제단독치료와삼환계항우울제-항정신병약물병합치료의비교정신병적증상이동반된우울증이정신병적증상이동반되지않은우울증보다약물치료에있어덜효과적 25) 이거나심지어한이중맹검연구에서 amitriptyline 이위약과비교해서차이가없다는보고 17) 까지있었다. 그러나그이후체계적인고찰 19) 에서정신병적우울증에서항우울제가위약보다통계적으로의미있게효과적이라는것은입증이되었다. 일찍이 Kroessler 26) 는 597명의정신병적우울증환자들을대상으로상대적인치료효과율을계산하였는데, 전기충격요법, 삼환계항우울제와항정신병약물의병합, 삼환계항우울제단독, 항정신병약물단독순이었다고보고하였다. 뒤이은 Parker 등 27) 의메타분석에서도치료효과의순서는같았다. 그러나항우울제와항정신병약물의병합치료가항정신병약물단독치료보다는효과적이었으나, 항우울제단독치료와비교했을경우통계적으로차이가없었고, 전기충격요법도병합치료보다효과가큰경향이있는정도였다. 그러나이연구는개방연구도분석에포함을시켰다는점에서제한적이다. 따라서논란의관건은항우울제단독치료에비해항우울제 -항정신병약물의병합치료가더우월하냐아니면차이가없느냐는것이다. 전향적연구들 28-30) 만별도로고려해보았을때, 연구대상수가너무작거나, 28) 분열형정동장애가포함된연구 29) 를제외하고 Spiker 등 30) 의연구를설명하면, 이이중맹검연구에서 17명의정신병적우울증환자에게는 amitriptyline 단독, 16명에게는 perphenazine 단독, 그리고 18명에게는 amitriptyline 와 perphenazine의병합치료를실시하였다. 이에반응을보인비율이각각 41%, 19%, 78% 로병합치료가단독치료보다확실히우월하다는견해가지지를받게되었다. 그러나 Nelson 31) 그리고 Wheeler Vera 등 7) 의정신병적우울증의약물치료에대한고찰에서는나름대로항우울제로단독치료를하다가항정신병약물을추가하는방식을고려하도록권고하기도하였다. 앞서언급된병합치료를지지하는여러연구결과들은최근사용되고있는여러치료지침에반영되었고, 세부적으로다음과같다. 2000년도에개정된 TMAP 23) 에서정신병적우울증환자의일차적치료로삼환계항우울제와항정신병약물의병합사용을권고하고있다 (level A- B 증거 ). 같은해에출간된 American Psychiatric Association(APA) guideline 24) 에서도항우울제와항정신병약물의병합치료가각각의약물의단독치료보다효과적이라고언급하였고, 2001년도에출간된 Canadian clinical guideline 22) 에서도항우울제와항정신병약물의병합사용을권고하고있다 (level 1 증거 ). APA와 Canadian clinical guideline 모두에서전기충격요법을항우울제와항정신병약물병합사용과함께일차적치료법으로제안하고있다. 또한 2002 년도에출간된 WFSBP guideline 21) 에서도항우울제와항정신병약물의병합치료가각각의단독치료보다반응율이더좋기때문에치료를시작할때부터병합하도록 level A 수준으로권고하고있고, 전기충격요법도일차적치료법으로기술하고있다 년도에출간된 Australian & New Zealand clinical guideline 20) 에서도전기충격요법단독또는삼환계항우울제와항정신병약물의병합치료가삼환계항우울제단독치료보다훨씬효과적이라고명시하면서우선약물병합치료를사용하고, 만약환자가현재치료에반응이없고자살사고가지속되면전기충격요법을고려하도록권고하고있다. 2001년도에 Mulsant 등 32) 에의해발표된연구는정신병적우울증의치료전략에중요한영향을미쳤다. 이연구는 50세이상의정신병적우울증환자들을대상으로 14명에게 nortriptyline-perphenazine을, 16명에게 nortriptyline- 위약을사용하여효능을비교한이중맹검연구였다. 그결과, 우울증과정신증의호전에서두군간에차이가없었고, 이에대해저자들은정신병적우울증환자에서삼환계항우울제에전통적항정신병약물을추가하

5 는것이효과를호전시키지않는다고주장하였다. 시기적으로그이후에 Cochrane collaboration 에서진행한 Wijkstra 등의체계적고찰 19) 에서는무작위대조연구만을포함시켜분석하였는데, 바로이 Mulsant 등 32) 과 Spiker 등 30) 의연구만을분석에포함시켰다. 그결과, 삼환계항우울제-항정신병약물병합치료와삼환계항우울제단독치료사이에통계적으로의미있는차이가없었다. 이에저자들은지금까지정신병적우울증환자에서항우울제단독치료가항우울제- 항정신병약물병합치료보다덜효과적이라는기존의견해를반박하면서항우울제를사용하다가필요하다고판단되었을때항정신병약물을추가하는방법이처음부터두약제를함께쓰는방법과마찬가지로적절하다고권고하였다. 이는지금까지소개한치료지침에서권고하고있는방법과는차이가있어정신병적우울증환자의약물치료지침에서주목할만한변화이나, 한편으로는관련주제에대한무작위대조연구가너무부족하여발생한현상으로도이해된다. 정신병적우울증환자에게사용되는항정신병약물의용량에관해서는아직까지근거가부족하다. 일부에서는항정신병약물의용량을일일 chlorpromazine 등가용량 400 mg으로제시하기도하고, 30)33)34) 어떤경우에는정신분열병에서처럼 chlorpromazine 등가용량 1000mg 까지권장하기도한다. 35) 어떤경우라하더라도항정신병약물의용량면에서부족한치료를받는것은아닌지잘모니터링을해야할필요가있다. 주목해야할것은항정신병약물의병합사용으로인해삼환계항우울제의혈중농도가증가 36) 한다는것이다. 병합사용으로인해삼환계항우울제의농도가독성수준으로올라갔을때나타나는증상이정신병적증상으로오인될수도있다. 또한항정신병약물로인한추체외로증상이나좌불안석증이정신운동성지체나초조증상으로오인될수도있다. 그러므로 Wijkstra 등 19) 은삼환계항우울제투여에있어혈장농도를측정하도록권고하고있다. 2. 전기충격요법 Kroessler 26) 는정신병적우울증환자에서전기충격요법이항우울제와항정신병약물의병합치료보다더효과적이라며일차적치료법으로제안한바있다. Parker 등 27) 도전기충격요법의치료효과의크기 (effect size=2.3) 가병합치료 (1.6) 보다더크다고하였다. 이연구에서양측성전기충격요법이편측성보다효과적이라고하였고, 이러한현상은정신병적우울증에서다른우울증보다더뚜렷하다고한다. 이에 APA guideline, 24) Canadian clinical guideline, 22) 그리고 WFSBP guideline 21) 에서모두항우울제-항정신병약물병합치료와더불어전기충격요법을정신병적우울증환자의치료에서일차적치료법으로제안하고있다. 효과면에서는이와같이인정을받고있으나정신병적우울증환자의실제치료에서전기충격요법이일차적으로선택되고있지는않는것으로보인다. 그이유는환자들이꺼려하고, 부작용이있으며, 마취등적용하기가복잡하며아직까지그기전에대해잘알려져있지않는등의다양한이유때문에의사들도사용하기가보다쉬운약물치료를더선호하기때문이다. 7)19) 이러한점을고려하여 Australian & New Zealand clinical guideline 20) 에서는삼환계항우울제와항정신병약물병합치료에효과가없는데자살의위험이있을경우전기충격요법을권장하고있고, TMAP 23) 에서는전기충격요법을약물치료에이어삼차적선택법으로권고하고있기도하다. 그러나정신병적우울증환자에게적시에전기충격요법을사용하면약물치료를했을때보다치료기간이나비용이더줄어든다는보고도있으므로환자의상태에따라고려해볼수있는유용한치료법으로이해된다. 37) 3. 새로운항우울제와비전형항정신병약물삼환계항우울제이후의약제들을논하기앞서이론적으로도파민과세로토닌계모두에작용하는이상적인약제인 amoxapine 에대한언급이필요하다. 이약제는강력한도파민수용체차단효과를가지고있고그밖에노르에피네프린을차단한다는의미에서다른삼환계항우울제와약리학적으로유사하지만, 세로토닌재흡수를차단하는기능을함께가지고있어오랫동안항우울제와항정신병효능모두를가진것으로알려져왔다. 38) 이에대한두건의이중맹검대조연구가있는데, Anton 등 39) 은정신병적우울증환자들을대상으로실시한 4주간의이중맹검연구에서 amoxapine 을투여받은군이 amitriptyline-perphenazine 병합치료를받은군과효과가비슷했고추체외로증상은더적었다고하였다. 같은저자의이후의연구 40) 에서 amoxapine 의이러한효과는기분과일치하는망상의동반여부와관계없이차이가없었다고하였다. 이연구들에근거하여 TMAP 에서는정신병적우울증환자의치료에있어항우울제-항정신병약

6 물병합치료와나란히 amoxapine 단독치료를일차적치료법으로권유하고있다. 그러나 amoxapine 의경우지연성운동장애의출현이나경련의위험성등으로인해많이선택되고있지는않는것으로보인다. 정신병적우울증에서선택적세로토닌재흡수차단제단독치료의효과에대한보고들은적은편이다. Fluvoxamine 의효과가삼환계항우울제-항정신병약물병합치료나전기충격요법에버금가는수준이라는보고 41) 가있고, fluvoxamine-paroxetine 병합치료 42) 혹은 fluvoxamine 의 pindolol 부가치료 43) 가효과적이라는보고들이뒤이었다. 그러나최근의 Broek 등 44) 의무작위대조연구에서 fluvoxamine은 imipramine에비해효과가떨어지는것으로나타났다. 다른대조연구에서 fluvoxamine 이 venlafaxine 과효과면에서차이가없었다. 45) 이연구들외에정신병적우울증환자들을대상으로항우울제간의치료효과를비교한무작위대조연구로는 sertraline 이 paroxetine 보다효과적 46) 이고, imipramine이 mirtazapine 보다효과적 47) 이라는연구결과들이고작일정도로연구가매우부족하다. 특히간과할수없는것은, 선택적세로토닌재흡수차단제가도파민계와아직까지명확하게알려지지않은상호작용을하고있고, 또한역설적인효과가발생할수있다는것이다. 선택적세로토닌재흡수차단제가좌불안석증을유발하고, 48)49) 정신병적우울증환자의치료에서 fluoxetine 이정신병적증상을악화시켰으며, 50) sertraline도정신병적증상의병력이있던사람에서약물사용에따라정신병적증상이나타났다가약물을중단함에따라없어졌다는보고들이있었다. 51) 실제로 2001년도에발간된 Canadian guideline 22) 에서는선택적세로토닌재흡수차단제단독치료는정신병적우울증환자에서권장되지않는다고명기되어있다. 그러나정신병적우울증에서삼환계항우울제를택할것인지아니면선택적세로토닌재흡수차단제를택할것인지, 나아가어떤항우울제를선택할것인지에대해서는아직까지정보가부족하다. 그렇기때문에임상의들은일반적인항우울제선택법에따르거나최신경향을따르기가쉽다. 더구나 Hirschfeld 등 2) 의포괄적인고찰에서증상이심하거나 melancholic features를동반한우울증환자의치료에서선택적세로토닌재흡수차단제의효과가삼환계항우울제의효과에상응한다고기술하면서선택적세로토닌재흡수차단제의심한우울증환자에서의 유용성을주목하였다. TMAP 23) 에서는정신병적우울증환자의치료에있어삼환계항우울제와항정신병약물병합치료 (level A 증거 ) 와선택적세로토닌재흡수차단제와항정신병약물병합치료 (level B 증거 ) 둘다를일차적치료법으로권장하고있다. 이와같이 4주간투여하였으나효과가충분하지못하거나부작용때문에투여할수가없을경우이단계치료법으로삼환계항우울제를사용하던경우는항우울제를 venlafaxine(225mg 이상 ) 이나비삼환계항우울제로바꾸어항정신병약물과함께투여하거나, 선택적세로토닌재흡수차단제를투여하던경우는이를삼환계항우울제로바꾸어서항정신병약물과함께투여해보도록권장하고있다. 향후정신병적우울증환자에서선택적세로토닌재흡수차단제의사용에관해보다많은연구가뒷받침되어야할것이다. 정신병적우울증환자에서선택적세로토닌재흡수차단제와항정신병약물의병합사용의효과에대한연구로 Rothshild 등 52) 이 fluoxetine-perphenazine 병합치료를 5주간실시한결과, 73% 에서 HAM-D 점수에서 50% 이상의호전이있었다면서삼환계항우울제와항정신병약물의병합치료만큼효과가있고부작용도더적었다고보고하였다. 이에더해 Rothschild 등 53) 의정신병적우울증환자에서 olanzapine 을항우울제와병합또는단독투여하여다른항정신병약물과비교했을때더효과적이었다는소규모후향적조사에근거하여 Canadian guideline 에서는정신병적우울증환자에서 olanzapine-항우울제병합치료를이차적치료법으로제안한바있다 (level 3 증거 ). 같은저자들에의해 olanzapine 단독, olanzapine-fluoxetine 병합, 그리고위약군으로나누어정신병적우울증환자들에서그효과를비교하기위해실시된이중맹검대조연구 54) 에서 olanzapine 단독치료 ( 반응률 =34%) 는위약 ( 반응률 =28%) 과차이가없는것으로나타났다. 이에 Wijkstra 등 19) 은정신병적우울증환자의치료에있어서항정신병약물단독치료는좋은치료법이되지못한다고결론지었다. 나아가 Rothschild 등의연구 54) 에서 olanzapine 을 fluoxetine 과함께처방했을때그반응률이 63.6% 로 olanzapine 단독치료에비해의미있게더큰효과가있는것으로나타났는데, 앞서기술한 amitriptyline-perphenazine 병합치료가 perphenazine 단독치료에비해더효과적이었다는 Spiker 등 30) 의연구결과를함께고려해서 Wijkstra 등 19) 은항우울제 -항정신병약물병합치료가

7 항정신병약물단독치료보다는더효과적이라는결론을내리게되었다. 그밖에 risperidone 55-57) 이나 clozapine 58)59) 에대한보고들이있었고, TAMP에서비전형항정신병약물이부작용측면에서전통적인항정신병약물보다더선호될수있다고기술하고있으나대조연구가부족하여정신병적우울증환자에서새로운항정신병약물을권고에포함시키지는않았다. 4. 기타약제정신병적우울증환자의치료에서 lithium 의가능성도제기되었다. 31)35)60)61) 이에대한약리학적, 임상적근거는아직까지부족한상태이지만, 정신병적우울증의일부소수환자들이나중에양극성장애로진단되므로합리적인이차적선택일수있다. 실제로 APA guideline, RANZCP guideline, 그리고 TMAP 은항우울제와항정신병약물의병합치료가효과가없는환자에서 lithium 강화요법을하도록권고하고있다. Carbamazepine 의경우정신병적우울증환자에서치료저항성이고, 항정신병약물로인해정신병적증상이악화되거나, 경련성전조가의심되거나, 비정상뇌파소견이나타나거나, 중추신경계손상의병력이있는경우에고려해볼수있다. 35) 5. 유지치료정신병적우울증의경우재발이되기까지시간이더짧아서 6)62) 삽화의예방이특히중요하다. 그러나아직까지정신병적우울증의예방에초점을맞춘대조연구는없다. 다만, fluoxetine 과 amitriptyline 의 5주간의병합치료로호전된 30명의정신병적우울증환자들에서 4개월후에 perphenazine 을서서히감량하고그로부터 11개월후에재발여부를추적한결과, 63) 저자들이 4개월이상의항정신병약물의투여가필요하지않았다고제시한바있다. 따라서현재로써는항우울제를충분용량으로유지하면서항정신병약물을서서히줄여나가고이때우울증상이나정신병적증상이출현하는지잘관찰하여필요할때항정신병약물의용량을다시증가시키는방법이가능하다. 9) 항정신병약물을중단하는시도가여러차례실패했을경우최소한의효과적인항정신병약물을유지하는것이바람직하다. 요약 정신병적우울증의심한정도와나쁜예후, 그리고현재까지의연구실적을고려했을때, 임상의사들은정신병적증상을동반한우울증과정신병적증상을동반하지않는우울증을구분하여치료계획을수립하는것이바람직하다. 저자들은체계적인검색을통해광범위하게조사를하였으나, 정신병적우울증환자의약물치료에대한근거는아직부족한것으로생각한다. 소수의연구결과들이지만현재까지발표된근거에의하면, 항우울제와항정신병약물의병합치료와전기충격요법이그효과에대한근거수준이가장높아서정신병적우울증환자를위한일차적치료법으로생각된다. 그러나최근에항우울제단독치료가항우울제와항정신병약물의병합치료에비해효과면에서떨어지지않는다는분석결과가발표되면서항우울제-항정신병약물병합치료법과항우울제를사용하다가필요시에항정신병약물을추가하는방법둘다권고된바있다. 이는기존치료권고사항과대조가되기때문에, 향후이러한관점에서기존의치료전략들이어떻게영향을받을지주목된다. 그러나적어도정신병적우울증환자에게항정신병약물을단독으로사용하는것은항우울제와병합하였을때보다덜효과적이므로항정신병약물단독으로시작하는것은바람직하지않다는데에는연구자들간에의견이일치하고있다. 항우울제중에서는삼환계항우울제에대한근거수준이가장높고선택적세로토닌재흡수차단제의경우현재는근거가부족하나앞으로유망할것으로보인다. 항우울제와항정신병약물병합치료에반응이없거나부작용으로인해투여할수가없을경우에는항우울제의종류를바꾸거나 lithium 을강화하는방법을고려할수있다. 실제임상에서는환자개개인의위험과이득을고려하여약물을선택하는것이중요하다. 또한선택된약물을충분한양, 그리고충분한기간동안시도했는지도중요하다. 이와함께부작용의출현에대해잘모니터링을해야하고, 특히우울증자체가악화되는것과구분해야한다. 결론적으로, 임상의사들은정신병적증상을동반하는우울증환자의치료전략을현재까지수행된연구근거의양과수준을감안하여받아들여야하고, 아직까지명백한결론을이끌어내기에는부족하기때문에향후이에대한많은체계적연구들이필요할것이다

8 중심단어 : 정신병적우울증 치료전략. 참고문헌 1. Ohayon MM, Schatzberg AF. Prevalence of depressive episodes with psychotic features in the general population. Am J Psychiatry 2002;159: Hirschfeld RM. Efficacy of SSRIs and newer antidepressants in severe depression: comparison with TCAs. J Clin Psychiatry 1999;60: Johnson J, Horwath E, Weisman MM. The validity of major depression with psychotic features based on a community study. Arch Gen Psychiatry 1991;48: American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Press; World Health Organization. The international classification of diseases, 10th revision. Geneva: World Health Organization; Coryell W. Psychotic depression. J Clin Psychiatry 1996; 57: Wheeler Vega J, Mortimer AM, Tyson P. Somatic treatment of psychotic depression: Review and recommendations for practice. J Clin Psychpharmacol 2000;20: Flint AJ, Rifat SL. Two-year outcome of psychotic depression in late life. Am J Psychiatry 1998;155: Coryell W. The treatment of psychotic depression. J Clin Psychiatry 1998;59: Schatzberg AF, Rothschild AJ. Serotonin activity in psychotic(delusional) major depression. J Clin Psychiatry 1992;53:S52-S Aberg-Wistedt A, Wistedt B, Bertilsson L. Higher CSF levels of HVA and 5-HIAA in delusional compared to nondelusional depression. Arch Gen Psychiatry 1985;42: Nelson JC, Davis JM. DST studies in psychotic depression: a meta-analysis. Am J Psychiatry 1997;154: Stefos G, Staner L, Kerkhofs M, Hubain P, Mendlewicz J, Linkowski P. Shortened REM latency as a psychobiological marker for psychotic depression? An age-, and gender-, and polarity-controlled study. Biol Psychiatry 1998;44: Simpson S, Baldwin RC, Jackson A, Burns A. The differentiation of DSM-III-R psychotic depression in later life from nonpsychotic depression: comparisons of brain changes measured by multispectral analysis of magnetic resonance brain images, neuropsychological findings, and clinical features. Biol Psychiatry 1999;45: Lykouras L, Christodoulou GN, Malliaras D, Stefanis C. The prognostic importance of delusions in depression: a 6-year prospective follow-up study. J Affect Disord 1994; 32: Coryell W, Akiskal HS, Leon AC, Winokur G, Maser JD, Mueller TI, et al. The time course of nonchronic major depressive disorder. Uniformity across episodes and samples. National Institute of Mental Health Collaborative Program on the Psychobiology of Depression--Clinical Studies. Arch Gen Psychiatry 1994;51: Spiker DG, Kupfer DJ. Placebo response rates in psychotic and nonpsychotic depression. J Affect Disord 1988; 14: Glassman AH, Roose SP. Delusional depression: a distinct clinical entity? Arch Gen Psychiatry 1981;38: Wijkstra J, Lijmer J, Balk FJ, Geddes JR, Nolen WA. Pharmacological treatment for unipolar psychotic depression: Systematic review and meta-analysis. Br J Psychiatry 2006;188: Ellis P. Royal Australian and New Zealand College of Psychiatrists Clinical Practice Guidelines Team for Depression. Australian and New Zealand clinical practice guidelines for the treatment of depression. Aust N Z J Psychiatry 2004;38: Bauer M, Whybrow PC, Angst J, Versiani M, Moller HJ. World Federation of Societies of Biological Psychiatry(WFSBF) Guideline for Biological Treatment of Unipolar Depressive Disorders. World J Biol Psychiatry 2002;3: Canadian Psychiatric Association. Canadian Network for Mood and Anxiety Treatments(CANMAT). Clinical guidelines for the treatment of depressive disorders. Can J Psychiatry 2001;46:5S-90S. 23. Crismon ML, Trivedi M, Pigott TA, Rush AJ, Hirschfeld RM, Kahn DA, et al. The Texas Medication Algorithm Project: report of the Texas Consensus Conference Panel on Medication Treatment of Major Depressive Disorder. J Clin Psychiatry 1999;60: American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (revision). American Psychiatric Association. Am J Psychiatry 2000;157: Nelson JC, Bowers MB Jr. Delusional unipolar depression: description and drug response. Arch Gen Psychiatry 1978;35: Kroessler D. Relative Efficacy Rates for Therapies of Delusional Depression. Convuls Ther 1985;1: Parker G, Roy K, Hadzi-Pavlovic D, Pedic F. Psychotic (delusional) depression: a meta-analysis of physical treatments. J Affect Disord 1992;24: Minter RE, Mandel MR. A prospective study of the treatment of psychotic depression. Am J Psychiatry 1979;136: Brockington IF, Kendell RE, Kellett JM, Curry SH, Wainwright S. Trials of lithium, chlorpromazine and amitriptyline in schizoaffective patients. Br J Psychiatry 1978; 133: Spiker DG, Weiss JC, Dealy RS, Griffin SJ, Hanin I,

9 Neil JF, et al. The pharmacological treatment of delusional depression. Am J Psychiatry 1985;142: Nelson JC. Augmentation strategies for treatment of unipolar major depression. Mod Probl Pharmacopsychiatry 1997;25: Mulsant BH, Sweet RA, Rosen J, Pollock BG, Zubenko GS, Flynn T, et al. A double-blind randomized comparison of nortriptyline plus perphenazine versus nortriptyline plus placebo in the treatment of psychotic depression in late life. J Clin Psychiatry 2001;62: Dubovsky SL. Challenges in conceptualizing psychotic mood disorders. Bull Menninger Clin 1994;58: Nelson JC, Price LH, Jatlow PI. Neuroleptic dose and desipramine concentrations during combined treatment of unipolar depression. Am J Psychiatry 1986;143: Rothschild AJ. Management of psychotic, treatment-resistant depression. Psychiatr Clin North Am 1996;19: Olivier-Martin R, Marzin D, Buschsenschutz E, Pichot P, Boissier J. Concentrations plasmatiques de l imipramine et de la desmethylimipramine et effet anti-depresseur au cours d un traitement controlé. Psychopharmacology 1975;41: Markowitz J, Brown R, Sweeney J, Mann JJ. Reduced length and cost of hospital stay for major depression in patients treated with ECT. Am J Psychiatry 1987;144: Greenblatt EN, Lippa AS, Osterberg AC. The neuropharmacological actions of amoxapine. Arch Int Pharmacodyn Ther 1978;233: Anton RF Jr, Burch EA Jr. Amoxapine versus amitriptyline combined with perphenazine in the treatment of psychotic depression. Am J Psychiatry 1990;147: Anton RF Jr, Burch EA Jr. Response of psychotic depression subtypes to pharmacotherapy. J Affect Disord 1993;28: Gatti F, Bellini L, Gasperini M, Perez J, Zanardi R, Smeraldi E. Fluvoxamine alone in the treatment of delusional depression. Am J Psychiatry 1996;153: Saccetti E, Conte G, Guarneri L, Calzeroni A, Bertini M, Panariello A. Effectiveness of fluvoxamine and paroxetine in major depressives with psychotic features. Hum Psychopharmacol 1997;12: Zanardi R, Franchini L, Gasperini M, Lucca A, Smeraldi E, Perez J. Faster onset of action of fluvoxamine in combination with pindolol in the treatment of delusional depression: a controlled study. J Clin Psychopharmacol 1998;18: van den Broek WW, Birkenhager TK, Mulder PG, Bruijn JA, Moleman P. A double-blind randomized study comparing imipramine with fluvoxamine in depressed inpatients. Psychopharmacology(Berl) 2004;175: Zanardi R, Franchini L, Serretti A, Perez J, Smeraldi E. Venlafaxine versus fluvoxamine in the treatment of delusional depression: a pilot double-blind controlled study. J Clin Psychiatry 2000;61: Zanardi R, Franchini L, Gasperini M, Perez J, Smeraldi E. Double-blind controlled trial of sertraline versus paroxetine in the treatment of delusional depression. Am J Psychiatry 1996;153: Bruijn JA, Moleman P, Mulder PG, van den Broek WW, van Hulst AM, van der Mast RC, et al. A double-blind, fixed blood-level study comparing mirtazapine with imipramine in depressed in-patients. Psychopharmacology (Berl) 1996;127: Altshuler LL, Pierre JM, Wirshing WC, Ames D. Sertraline and akathisia. J Clin Psychopharmacol 1994;14: Lipinski JF Jr, Mallya G, Zimmerman P, Pope HG Jr. Fluoxetine-induced akathisia: clinical and theoretical implications. J Clin Psychiatry 1989;50: Narayan M, Meckler L, Nelson JC. Fluoxetine-induced delusions in psychotic depression. J Clin Psychiatry 1995; 56: Popli AP, Fuller MA, Jaskiw GE. Sertraline and psychotic symptoms: a case series. Ann Clin Psychiatry 1997; 9: Rothschild AJ, Samson JA, Bessette MP, Carter-Campbell JT. Efficacy of the combination of fluoxetine and perphenazine in the treatment of psychotic depression. J Clin Psychiatry 1993;54: Rothschild AJ, Bates KS, Boehringer KL, Syed A. Olanzapine response in psychotic depression. J Clin Psychiatry 1999;60: Rothschild AJ, Williamson DJ, Tohen MF, Schatzberg A, Andersen SW, Van Campen LE, et al. A doubleblind, randomized study of olanzapine and olanzapine/ fluoxetine combination for major depression with psychotic features. J Clin Psychopharmacol 2004;24: Hillert A, Maier W, Wetzel H, Benkert O. Risperidone in the treatment of disorders with a combined psychotic and depressive syndrome--a functional approach. Pharmacopsychiatry 1992;25: Lane HY, Chang WH. Risperidone monotherapy for psychotic depression unresponsive to other treatments. J Clin Psychiatry 1998;59: Muller-Siecheneder F, Muller MJ, Hillert A, Szegedi A, Wetzel H, Benkert O. Risperidone versus haloperidol and amitriptyline in the treatment of patients with a combined psychotic and depressive syndrome. J Clin Psychopharmacol 1998;18: McElroy SL, Dessain EC, Pope HG Jr, Cole JO, Keck PE Jr, Frankenberg FR, et al. Clozapine in the treatment of psychotic mood disorders, schizoaffective disorder, and schizophrenia. J Clin Psychiatry 1991;52: Ranjan R, Meltzer HY. Acute and long-term effectiveness of clozapine in treatment-resistant psychotic depression. Biol Psychiatry 1995;40: Nelson JC, Mazure CM. Lithium augmentation in psychotic depression refractory to combined drug treatment

10 Am J Psychiatry 1986;143: Ebert D. Lithium-TCA combination treatment of psychotic depression: comparison with TCA-neuroleptic treatment. J Clin Psychopharmacol 1997;17: Leyton M, Corin E, Martial J, Meaney M. Psychotic symptoms and vulnerability to recurrent major depression. J Affect Disord 1995;33: Rothschild AJ, Duval SE. How long should patients with psychotic depression stay on the antipsychotic medication? J Clin Psychiatry 2003;64: