1. 연구대상 대상및방법 2. 연구방법 1) 치료약물투여 61

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1 KISEP Original Articles Korean J Psychopharmacol Vol 8, No 1 치료저항만성정신분열증환자의 Risperidone 효과 이홍식 * 전지용 * 김찬형 * 송동호 * 육기환 * 김병천 * 손석한 * 구민성 * Efficacy of Risperidone in Treatment-Resistant Patients with Chronic Schizophrenia Hong-Shick Lee, M.D.,* Ji-Yong Jeon, M.D.,* Chan-Hyung Kim, M.D.,* Dong-Ho Song, M.D.,* Ki-Whan Yook, M.D.,* Byung-Cheon Kim, M.D.,* Seok-Han Sohn, M.D.,* Min-Sung Koo, M.D.* ObjectsThis open study was designed to investigate the efficacy and safety of risperidone in the treatmentresistant patients with chronic schizophrenia. 24 patients were entered on the 8-week open trial. A total of 3 patients discontinued risperidone treatment before the end of the study. MethodsWe investigated risperidone s efficacy and its side effects in 21 patients with treatment-resistant chronic schizophrenia, who had previously been treated with different kinds of classical antipsychotic drugs but with insufficient clinical effect or distressing extrapyramidal side effects, over a 8-week period. After 37 days of placebo wash-out period, patients were assigned to receive risperidone. The overall clinical efficacy was assessed at the 1st, 2nd, 4th, and 8th week of the treatment using the PANSS and the CGI. Safety and tolerability were assessed by the ESRS, the UKU side effect rating scale, the vital signs, and the laboratory tests including CBC, urinalysis, liver function test, and ECG. Results Clinically PANSS total score and CGI severity score on the end study point showed a significant improvement compared with baseline state. Significant improvements in both PANSS positive and negative subscale scores was as early as week 1 through week 8. Nine43% among of the 21 patients showed at least a 20% decrease in total PANSS scores. The tolerability of risperidone was geneally found to be good. Insomnia52%, fatigue52%, and sedation52% were the most common side effects. ConclusionThese results suggest that risperidone may be a effective antipsychotic agent in the treatment of refractory schizophrenia. However, double-blind comparative trial between risperidone and clozapine should be performed to further clarify the efficacy of risperidone in treatment-resistant patients with chronic schizophrenia. Key wordsrisperidone Treatment-resistant schizophrenia Clinical efficacy Side effects. 서 론 Department of Psychiatry, Yongdong Severance Hospital, Yonsei University College of Medicine, Seoul, Korea 60

2 1. 연구대상 대상및방법 2. 연구방법 1) 치료약물투여 61

3 2) 평가방법 3) 자료분석 결 1. 대상환자의인구학적특징 과 62

4 2. 항정신병효과 Table 1. Patient characteristicsn21 Characteristics Ageyears Sex malefemale 1110 Age at first onset of illnessyears Duration of illnessyears Number of previous hospitalization DiagnosisDSM-IV schizophrenia subtypes Undifferentiated 7 Residual 1 Paranoid 13 Disorganized Values represent meansd or frequency% 3. 부작용 Table 3. Clinical improvement, defined as a reduction of the total PANSS score by 20% or more 20% or more decrease Time N % of subjects N21 % of improvers N9 Week Week Week Week Table 2. Efficacy of risperidone on psychopathology over a 8week period*n21 Scale scores Baseline Week 1 Week 2 Week 4 Week 8 PANSS Positive Negative Total CGI severity *Repeated measure one-way ANOVA p0.05all rating scale scores significantly decreased compared to baseline for week 1 through week 8 by Bonferroni s t-testp0.05. Values represent meansd. 63

5 Table 4. Extrapyramidal symptom rating scaleesrs Cluster Score per clustermean scorerange Baseline 1W 2W 4W 8W Questionnaire total score 0 0,0 0.90, , ,4 0.30,2 Parkinsonism total score 0.10,1 0 0, , ,3 0.50,3 Dystonia total score 0 0,0 0 0, 0 0 0, ,2 0.10,3 Dyskinesia total score 0 0,0 0 0, 0 0 0, ,1 0 0,0 Total ,1 2.00, , ,5 1.00,6 CGI of severity of dyskinesia 0 0,0 0.30, , ,1 0.10,2 CGI of severity of parkisonism 0.10,1 1.00, , ,3 0.70,4 Table 5. Side effects profilen21 Side effect profile Frequency% Insomnia Fatigue Sedation Increased dream activity Restlessness Concentration difficulties Amenorrhea 330.3* Hypersalivation Headache Constipation Falling memory Dizziness Tremor Rigidity Dystonia Accomodation difficulty Nausea/vomiting Polyuria/polydipsia *Nfemale10 고찰 64

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8 목적 : 요 방법 : 결과 : 결론 : 중심단어 : 약 참고문헌 강대엽 이충순 최진숙 김형섭 한광수 황태연 김융희 이정식 (1996) : 만성정신분열증환자에대한리스페리돈과할로페리돌의효과및안전성비교시험. 용인정신의학보 3(1):61-77 민성길 이충순 김철응 강대엽 (1994) : 만성정신분열증환자치료에있어 Risperidone과 Haloperidol의이중맹비교. 대한정신약물학회지 5(1): 박민철 피상순 이상렬 (1995) : 만성정신분열증환자의 Risperidone 치료효과와안전성. 대한정신약물학회지 6(1):89-99 박순원 정해익 강병조 (1993): 만성정신분열증환자의 Risperidone 치료효과. 신경정신의학 32(5): 이홍식 이희상 남궁기 김찬형 최낙경 도정호 전지용 황영신 유계준 이호영 (1993): 치료저항정신분열증환자에서의 clozapine효과. 대한정신약물학회지 4: American Psychiatric Association(1994):Diagnostic and statistical manual of mental disorder, 4th ed(dsm-Ⅳ), Washington DC. American Psychiatric Press Bersani G, Bressa GM, Meco G, Marini S, Pozzi F(1990): Combined serotonin-5-ht2 and dopamine-d2 antagonism in schizophrenia:clinical, extrapyramidal and neuroendocrine response in a preliminary study with risperidone (R ). Human Psychopharmacology 5: Bondolfi G, Baumann P, Patris M, May JP, Billeter U, Dufour H, De Smedt G, Lemmens P(1995):A randomized double-blind trial of risperidone versus clozapine for treatment-resistant chronic schizophrenia. 8th ECNP Congress abstract presented Borison RL, Pathiraja AP, Diamond BI, Meibach RC(1992): Risperidone:Clinical safety and efficacy in schizphrenia. Psychopharmacol Bull 28: Carpenter WT, Heinriches DW, Alphs LD(1985):Treatment of negative symptoms. Schizophr Bull 11: Chouninard G, Jones B, Remington G, Bloom D, Addington D, MacEwan GW, Labelle A, Beauclair L, Arnott W (1993):Canadian multicenter placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol 13:25-40 Chouninard G, Ross-Chouninard A, Annable L, Jones BD (1980):The extrapyramidal symptoms rating scale. Can J Neurol Sci 7:233 Claus A, Bollen J, De Cuyper H, Eneman M, Malifroid M, Peuskens J, Heylen S(1992):Risperidone versus haloperidol in the treatment of chronic schizophrenia in patients: A multicentre double-blind comparative study. Acta Pscychiatr Scand 85: Coryell W, Kelly M, Perry PJ, Miller DD(1990):Haloperidol plasma levels and acute clinical change in schizophrenia. J Clin Psychopharmacol 10: Crow TJ(1980):Positive and negative schizophrenia symptoms and the role of dopamine. Br J Psychiatry 137: Davis MA, Conley RR, Schulz SC, Bell-Delaney J(1991): One-year follow-up of 24 patients in a clinical trial of clozapine. Hosp Community Psychiat 42: Ereshefsky L, Lacombe S(1993):Pharmacologic profile of 67

9 risperidone. Can J Psychiatry 38:80-88 Goldberg CS(1985):Negative and deficit symptoms in schizophrenia do respond to neuroleptics. Schizophr Bull 11: Guy W(1976):ECDEU Assessment Manual for Psychopharmacology:Publication ADM 76338, Rockville, Md, US Dept. of Health Education and Welfare Heinrich K, Klieser E, Lehmann E, Kinzler E(1991):Experimental comparison of the efficacyand compatibility of risperidone and clozapine in acute schizophrenia. In: Kane JM, ed. Risperidone:Major progress in antipsychotic treatment. Satellite symposium at the 17th Congress of Collegium Internationale Neuro-Psychopharmacologicum. Oxford:Clinical Communications. Heinrich K, KLieser E, Lehmann E, Kinzler E, Hruschka H (1994):Risperidone versus clozapine in the treatment of schizophrenic patients with acute symptoms:a double blind, randomized trial. Progress in Neuro-psychopharmacology & Biological Psychiatry 18(1): Kane J, Honigfeld G, Singer J, Meltzer HY, Clozaril Collaborative Study Group(1988):Clozapine for the treatmentresistant schizophrenia:a double-blind comparison with chlorpromazine. Arch Gen Psychiatry 45: Kane JM(1989):The current status of neroleptic therapy. J Clin Psychiatry 50: Kay SR, Fiszbein A, Opler LA(1987):The Positive and Negative Syndrome Scale(PANSS) for Schizophrenia. Schizophr Bull 13:55-70 Janssen PAJ, Niemegeers CJE, Awouters F, Schellekens KHL, Megens AHP, Meert TF(1988):Pharmacology of risperidone(r ), a new antipsychotic with serotonin- S2 and dopamine D2 antagonistic porperties. J Pharmacol Exp Ther 244(2): Juul-Povlsen VJ, Noring V, Fog R, Gerlach J(1985):Tolerability and therapeutic effect of clozapine:a retrospective investigation of 216 patients treated with clozapine for up to 12 years. Acta Psychiatr Scand 71: Leysen JE, Gommeren W, Eens A, De Chaffoy de Courcelles D, Stoof JC, Janssen PAJ(1988):The biochemical profile of risperidone, a new antipsychotic. J Pharmacol Exp Ther 247(2): Marder SR, Meibach RC(1994):Risperidone in the treatment of schizophrenia. Am J Psychiatry 151: Mark SR(1994):Risperidone in the treatment of psychoses. California pharmacist Meltzer HY(1989):The role of serotonin in the mechanism of action of antipsychotic drugs:does 5-HT also have a role in the etiology of schizophrenia? Schizophr Res 2:212 Meltzer HY(1995):The role of serotonin in schizophrenia and the place of serotonin-dopamine antagonist antipsychotics. J Clin Psychopharmacology 15:2S-3S Meltzer HY, Bastini B, Kwon KY, Ramirez LF, Burnett S, Sharpe J(1989):A prospective Study of clozapine in treatment-resistant schizophrenic patients. Psychopharmacology 99:S68-S72 Miller DD, Perry PJ, Cadorer RJ, Andreasen NC(1994): Clozapine s effect on negative symptoms in treatment refractory schizophrenics. Compr Psychiatry 35:8-13 Montgomery SA(1993):Advences in the pharmacology and clinical applications of serotonin. Int Clin Psychopharmacol 8:1-94 Muller-Sphan F, the International Risperidone Research Group(1992):Risperidone in the treatment of chronic schizophrenic patients:an international double-blind parallel-group study versus haloperidol. Clin Neuropharm 15(suppl 1):90A-1 Pickar D, Woen RR, Litman RE, Konicki PE, Gutierrez R, Rapaport MH(1992):Clinical and biologic response to clozapine in patients with schizophrenia Arch Gen Psychiatry 49: Risch SC, Lewine RRJ(1993):Low cerebrospinal fluid homovanillic acid/5-hydroxyindolacetic acid ratio predicts clozapine efficacy:a replication. Arch Gen Psychiatry 50: Seeman P, Lee T, Chau-Wong M, Wong K(1976):Antipsychotic doses and neuroleptic/dopamine receptors. Nature 261: Tandon R, Goldman RS, Gordon JA, et al(1990):mutability and relationship between positive and negative symptoms during neuroleptic treatment in schizophrenia. Biol Psychiatry 27: Van Putten T(1974):Why do schizophrenic patients refuse to take their drugs? Arch Gen Psychiatry 31:67-72 Van Putten T, Marder SR, Mintz J(1987):The therapeutic index of haloperidol in newly admitted schizophrenic patients. Psychopharmacol Bull 23: Wyatt RJ(1991):Neuroleptics and the natural course of schizophrenia. Schizophr Bull 17:

서론 80

서론 80 KISEP Original Articles 8 1 1997 Korean J Psychopharmacol Vol 8, No 1 정신분열증환자에서 Risperidone 의치료반응과혈장 Homovanillic Acid 및 5-Hydroxyindoleacetic Acid 농도와의관계 * 김찬형 ** 김지웅 ** 이홍식 ** 김광현 *** Relationship between