KISEP Original Articles 12 3 2001 우울증의치료초기에 Nefazodone과 Benzodiazepine의병용투여 ABSTRACT 신일선 윤진상 정현준 이정길 이형영 Coadministration of Nefazodone and Benzodiazepine in the Early Phase of Treatment of Depression Il-Seon Shin, MD, Jin-Sang Yoon, MD, Hyeon-Joon Jeong, MD, Jeong-Gil Lee, MD and Hyung-Yung Lee, MD Department of Neuropsychiatry & Research Institute of Medical Science, Chonnam National University Medical School, Kwangju, Korea ObjectiveThe purpose of this study was to examine the efficacy and safety of coadministration of nefazodone NEF and benzodiazepine BZD in the clinical setting, particularly during the initial period of treatment. MethodsThis study was based on data collected in an open, multi-center, 8-week, clinical trial of NEF in depressed patients and focused on the first 2 weeks of treatment and the concurrent use of two BZDs alprazolam ALP, metabolized largely by the same cytochrome P450-3A4 isoform that metabolizes NEF and lorazepam LOR, eliminated by conjugation with glucuronic acid and less likely to interact with NEF. Patients receiving NEF alone NEF-mono group, n82 and those receiving adjunctive BZD therapy BZD-combi group, n29 were selected and their data were reviewed for demographic and clinical characteristics at baseline and various outcome measures at weeks 1 and 2. The BZD-combi group consisted of patients receiving alprazolam ALP-combi subgroup, n15 and those receiving lorazepam LOR-combi subgroup, n14. Efficacy was analysed according to the individual groups and subgroups. In addition, the efficacy at each time point was compared between NEF-mono and BZD-combi groups as well as between ALP-combi and LOR-combi subgroups. Safety and tolerability were judged by reported adverse effects and were compared. Results In NEFmono and BZD-combi groups, the mean daily dose for NEF was less than 200 mg/day range, 50500 mg/day and did not differ between groups and subgroups. The mean daily doses for BZDs were 0.61 mg/day range, 0.251.5 mg/day for ALP and 1.49 mg/day range, 0.52.5 mg/day for LOR. Sleep, anxiety and depression in both NEF-mono and BZD-combi groups were, in general, significantly improved compared to baseline. Furthermore, BZD-combi group showed greater improvement in anxiety and sleep but not in depression compared to NEF-mono group. Within the BZD-combi group, there was no significant difference in clinical effects between ALP-combi and LOR-combi subgroups. In terms of safety and tolerability, there was no evidence to suggest that BZD combination caused daytime sedation or any other particular adverse events more severely than NEF alone. Also, there was no significant difference in the side effect profiles of ALP-combi and LOR-combi subgroups. ConclusionThese results suggest that combining low doses of ALP or LOR with NEF is beneficial 222
for the control of insomnia and anxiety without substantial adverse effects, at least during the early period of treatment of depression when therapeutic dosages of NEF are not yet reached. Korean J Psychopharmacol 2001;123:222-232 KEY WORDSNefazodone Benzodiazepine Coadministration Depression. 서론 223
연구방법 1. 연구대상 2. 약물투여 3. 평가내용및도구 1) 인구사회학적및임상적특성 2) 우울및불안의평가 3) 야간의수면및주간의상태평가 224 Korean J Psychopharmacol 2001;123:222-232
4) 전반적인임상적인상 5) 약물의부작용및안전성평가 4. 자료분석 결과 1. 기준시점에서인구사회학적및임상적특성 225
2. 약물의용량및 BZD 의사용목적 Table 1. Demographic and clinical characteristics of patients at baseline Parameters NEF only n82 NEFALP n15 NEFBZD NEFLOR n14 Total n29 NEF only vs. NEFBZD t-test or x 2 test NEFALP vs. NEFLOR t or x 2 p t or x 2 p Gender, M/F, N 27/55 5/10 3/11 8/21 0.283 n.s. 0.514 n.s. Mean SD age, years 41.71 14.85 58.33 15.55 43.00 12.37 50.93 15.89 2.822 0.1 2.925 0.1 Marriage, N 4.265* n.s. 2.012* n.s. Single/married/others 19/62/1 1/12/2 2/12/0 3/24/2 Hospital setting, N 5.118 n.s. 3.712* n.s. Inpatient 56 9 5 14 Outpatient 15 1 5 6 Inpatient and outpatient 11 5 4 9 Previous anti-depressant, N 1.093 n.s. 0.909 n.s. Yes/no 36/46 7/8 9/5 16/13 Concomitant medication, N 0.019 n.s. 0.676* n.s. Yes/no 16/66 4/11 2/12 6/23 Concurrent disease, N 0.076 n.s. 1.025* n.s. Yes anxiety/others /no 19 13/6/63 2 1/1/13 4 4/0/10 6 5/1/23 Diagnosis, N 0.512 n.s. 1.330* n.s. Major depression, single 36 5 7 12 Major depression, recurrent 26 4 4 8 Dysthymia 20 6 3 9 Mean scores SD on assessment scales HAM-D Total 23.40 5.10 23.13 6.59 24.43 6.41 23.76 6.42 0.270 n.s. 0.536 n.s. Insomnia items 456 3.30 1.66 3.60 1.59 4.36 1.01 3.97 1.38 0.920 n.s. 0.515 n.s. BDI Total 26.91 9.91 32.47 8.25 27.93 12.66 30.28 10.67 0.539 n.s. 1.152 n.s. Insomnia item 16 1.49 0.98 2.00 1.00 1.50 0.85 1.76 0.95 1.285 n.s. 1.442 n.s. Fatigue item 17 1.56 0.85 1.67 0.62 1.57 0.94 1.62 0.78 0.333 n.s. 0.325 n.s. STAI-SA 43.64 9.85 47.73 9.28 37.29 12.15 42.69 11.82 0.421 n.s. 2.589.05 WSQ Night sleep 14.30 4.06 16.93 2.66 15.07 4.18 16.03 3.54 2.034.05 1.442 n.s. Daytime status 5.45 1.50 5.33 1.40 5.36 1.65 5.34 1.49 0.329 n.s. 0.042 n.s. CGI-SI 4.45 0.96 4.60 0.83 4.07 1.54 4.34 1.23 0.476 n.s. 1.161 n.s. *Fisher s exact test NEFNefazodone, BZDBenzodiazepine, ALPAlprazolam, LORLorazepam, HAM-DHamilton Rating Scale for Depression, BDIBeck Depression Inventory, STAI-SAState-Trait Anxiety Inventory-State Anxiety, WSQWeekly Sleep Questionnaire, CGI-SIClinical Global Impression for Severity of Illness 226 Korean J Psychopharmacol 2001;123:222-232
Table 2. Doses of NEF during 1st week and 2nd week Week 1 Week NEF only n82 NEFALP n15 NEFBZD NEFLOR n14 Total n29 NEF only vs. NEFBZD t-test NEFALP vs. NEFLOR t p t p Mean SD, mg/day 107.32 26.20 133.33 48.80 107.14 26.73 120.69 41.23 1.634 n.s. 1.808 n.s. Range, mg/day 50200 100200 100200 100200 Week 2 Mean SD, mg/day 151.22 35.98 180.00 67.61 144.64 23.37 162.93 53.71 1.091 n.s. 1.898 n.s. Range, mg/day 50400 100500 100200 100500 NEFNefazodone, BZDBenzodiazepine, ALPAlprazolam, LORLorazepam Table 3. Mean SD scores on assessment scales at week 1 Parameters NEF only n82 NEFALP n15 NEFBZD NEFLOR n14 Total n29 t-test or ANCOVA NEF only vs. NEFBZD NEFALP vs. NEFLOR t p t p STAI-SA 37.04 10.93 c 38.47 11.17 c 31.93 11.57 35.31 11.64 c 0.421 n.s. 0.068* n.s. WSQ Night sleep 11.98 4.21 a 11.13 4.05 c 9.50 3.28 b 10.34 3.73 c 6.783*.01 1.189 n.s. Daytime status 5.04 1.70 c 4.73 0.96 b 4.29 1.90 4.52 1.48 b 1.458 n.s. 0.809 n.s. abcsignificant difference from baseline score at p.05, p.01, p.001 by paired t-test, respectively *ANCOVA with baseline as a covariate NEFNefazodone, BZDBenzodiazepine, ANCOVAanalysis of covariance, ALPAlprazolam, LORLorazepam, STAI-SAState-Trait Anxiety Inventory-State Anxiety, WSQWeekly Sleep Questionnaire 3. 치료 1주말의효과와군간의비교 4. 치료 2주말의효과와군간의비교 5. 부작용과안전성 227
Table 4. Mean SD scores on assessment scales at week 2 HAM-D Parameters NEF only n82 NEFALP n15 NEFBZD NEFLOR n14 Total n29 NEF only vs. NEFBZD t-test or ANCOVA NEFALP vs. NEFLOR t or F p t or F p Total 15.61 6.36 c 13.33 4.56 c 14.21 9.28 c 13.76 7.11 c 1.306 n.s. 0.321 n.s. Insomnia items 456 1.90 1.65 c 1.53 0.99 c 2.57 1.87 b 2.03 1.55 c 0.377 n.s. 1.850 n.s. BDI Total 20.28 9.58 c 20.80 7.63 c 17.14 7.83 c 19.03 7.81 c 0.630 n.s. 1.152 n.s. Insomnia item 16 0.93 0.87 c 0.93 0.80 c 0.93 0.62 0.93 0.70 c 0.023 n.s. 1.442 n.s. Fatigue item 17 1.12 0.76 c 0.93 0.46 c 0.86 0.95 a 0.90 0.72 c 1.389 n.s. 0.325 n.s. STAI-SA 34.55 9.87 c 32.60 10.03 c 26.14 10.14 c 29.48 10.43 c 2.340.05 0.001* n.s. WSQ Night sleep 10.30 4.50 c 9.00 3.34 c 8.43 4.16b 8.72 3.70 c.941*.05 0.409 n.s. Daytime status 4.85 1.72 c 4.20 1.86 b 4.21 1.48 4.21 1.66 c 1.755 n.s. 0.023 n.s. CGI-SI 3.55 1.06 c 3.40 0.63 c 3.57 0.51 3.48 0.57 c 0.320 n.s. 0.798 n.s. CGI-GI 2.93 0.78 2.67 0.62 2.71 0.61 2.69 0.60 1.482 n.s. 0.209 n.s. abcsignificant difference from baseline score at p.05, p.01, p.001 by paired t-test, respectively *ANCOVA with baseline as covariate NEFNefazodone, BZDBenzodiazepine, ANCOVAanalysis of covariance, ALPAlprazolam, LORLorazepam, HAM-DHamilton Rating Scale for Depression, BDIBeck Depression Inventory, STAI-SAState-Trait Anxiety Inventory-State Anxiety, WSQWeekly Sleep Questionnaire, CGI-SIClinical Global Impression for Severity of Illness, CGI-GIClinical Global Impression for Global Improvement 고찰 228 Korean J Psychopharmacol 2001;123:222-232
Table 5. Adverse effects over the 2 weeks b Adverse effectsa NEF only n82 NEFALP n15 NEFBZD NEFLOR n14 Total n29 Dizziness 4 1 1 2 Dry mouth 1 1 1 2 Nausea 2 0 1 1 Headache 2 0 0 0 Constipation 1 0 0 0 Insomnia 1 0 0 0 Absent mindedness 1 0 0 0 Slurred speech 1 0 0 0 Sedation 1 0 0 0 Daytime sleepiness 0 1 0 1 Hand tremor 0 1 0 1 Weight gain 0 1 0 1 Blurred vision 0 0 1 1 Total 14 5 4 9 a A patient may report more than one side effect b There was no statistically significant difference between NEF only and the combined NEFBZD Total or within NEFBZD subgroups NEFALP, NEFLOR. Due to the development of adverse events, NEF dosage was reduced in 4 cases in the NEF only group and in 1 case in the NEFALP subgroup after recording the adverse events 229
요약 연구목적 : 방법 : 결과 : 230 결론 : 중심단어 감사의글 Korean J Psychopharmacol 2001;123:222-232
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