研究背景
在全世界上重度憂鬱症（重鬱症）是最常見精神疾病之一，且顯著與社會心理失能和經濟負擔相關。許多研究報告指出重鬱症是一個高慢性化、高再發、高復發、高自殺傾向。評估抗憂鬱劑治療效果之大部分研究為療效反應，較少研究評估部分症狀消失與症狀消失，但大部分抗憂鬱劑研究主要指標是療效反應、部分症狀消失與症狀消失。本研究首要目標為比較服用三組不同抗憂鬱劑之成效。

研究方法
二十四週開放式實驗，比較venlafaxine (75-225 mg/day)， paroxetine (20 mg/day) 與 milnacipran (100 mg/day)治療重鬱症效果。採用十七題漢氏憂鬱量表評量憂鬱症狀嚴重程度，納入條款有HRSD17  16分，符合DSM-IV-TR 重鬱症準則，年齡介於18至65歲。病人具雙極症、精神分裂症、物質濫用或依賴、器質性精神疾病或其他精神疾病以及控制不良臨床生理疾病需排除之。以十七題之漢氏憂鬱量表於第0、1、2、4、8、12、16、20和24週評估受試者。

研究結果
本研究取樣人數共249位臨床個案，服用venlafaxine 82名，paroxetine 97名，milnacipran 70名。三個抗憂鬱劑之療效反應未達統計差異。Milnacipran在部分症狀消失與症狀消失比venlafaxine 和 paroxetine較有效果。Venlafaxine 與 paroxetine之間在效果上無明顯差異。

研究限制
第一樣本數太小，第二由於本研究採開放式實驗設計，評估者並非採單盲評估，第三，病人並非隨機分派到治療組別。

研究討論
憂鬱症狀消失不是必然的症狀消失指標，然而較長期的憂鬱症狀消失更具臨床意義。重鬱症病人早期治療其症狀較快不嚴重。在未來研究需加大樣本數，更長期追蹤，以更嚴格的症狀消失評估當標準。

Background
Major depressive disorder (MDD), one of the most common psychiatric disorders in the world, is associated with significant psychosocial disability and economic burden. Many studies have reported that MDD has high rates of chronicity, relapse, recurrence, and suicide. Most studies that evaluated the treatment efficacies of antidepressants report that their patients responded to them; few studies have evaluated partial remission and remission. But the principle endpoints of most antidepressant studies are response, partial remission, and remission. The primary purpose of this study was to compare endpoints among three groups taking different antidepressants.

Methods
A 24-week open-label study compared the efficacy of venlafaxine (75-225 mg/day), paroxetine (20 mg/day) and milnacipran (100 mg/day) in treating MDD. The 17-item HRSD17 (Hamilton, 1960) was used to measure the severity of depressive symptoms. Inclusion criteria were an HRSD17 score  16, which met the DSM-IV-TR criteria for major depressive disorder, age between 18 and 65 years. Patients with bipolar disorder, schizophrenia, substance abuse or dependence, organic psychosis, or other major mental illnesses and poorly controlled clinical physical illnesses were excluded. Participants were evaluated at weeks 0, 1, 2, 4, 8, 12, 16, 20, and 24 using the HRSD17.

Results
Of the 249 patients enrolled in the study, 82 took venlafaxine, 97 paroxetine, and 70 milnacipran. The response was not statistically different among the three antidepressants. Milnacipran was more efficacious than venlafaxine and paroxetine in partial remission and remission. There were no significant differences between venlafaxine and paroxetine in efficacy.

Limitations
First, the sample size was limited. Second, because of the open-label study design, the raters did not make blind assessments. Third, the patients were not randomly assigned to treatment groups.

Conclusions
The absence of depressive symptoms is not necessarily an indicator of remission; however, the longer the depressive symptoms are absent, the more clinically significant the absence becomes. The earlier MDD patients are treated, the sooner their symptoms become less severe. In future studies, sample sizes should be larger, follow-up periods longer, and standards used to assess remission stricter.

行政院衛生署（2004）鬱思樂膠囊５０公絲 衛署藥輸字第023807號
行政院衛生署（2002）惠氏速悅持續性藥效膠囊７５公絲 衛署藥輸字第024421號
行政院衛生署（1997）克憂果膜衣錠２０公絲 衛署藥輸字第021536號
孔繁鐘編譯 （2007）。DSM-IV-TR精神疾病診斷準則手冊。台北市：合記
行政院衛生署（2010）.”97年度衛生統計動向” http://www.doh.gov.tw/CHT2006/DM/DM2_2.aspx?now_fod_list_no=10987&class_no=440&level_no=2
World Health Organization (2001). ”Burden of Mental and Behavioural Disorders.” The World Health Report 2001,2. http://www.who.int/whr/2001/chapter2/en/index.htm
American Psychiatric Association (2000). Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC
(2000). Practice guideline for the treatment of patients with major depressive disorder (revision). American Psychiatric Association. Am J Psychiatry, Vol. 157, No. 4 Suppl, pp. 1-45.
Akerblad, A.C., Bengtsson, F., von Knorring, L. & Ekselius, L. (2006). Response, remission and relapse in relation to adherence in primary care treatment of depression: a 2-year outcome study. Int Clin Psychopharmacol, Vol. 21, No. 2, pp. 117-24.
Amrein, R., Allen, S.R., Vranesic, D. & Stabl, M. (1988). Antidepressant drug therapy: associated risks. J Neural Transm Suppl, Vol. 26, pp. 73-86.
Anderson, I.M. (2000). Selective serotonin reuptake inhibitors versus tricyclic antidepressants: a meta-analysis of efficacy and tolerability. J Affect Disord, Vol. 58, No. 1, pp. 19-36.
Angst, J. (1999). Major depression in 1998: are we providing optimal therapy? J Clin Psychiatry, Vol. 60 Suppl 6, pp. 5-9.
Bourin, M., Chue, P. & Guillon, Y. (2001). Paroxetine: a review. CNS Drug Rev, Vol. 7, No. 1, pp. 25-47.
Boyer, P. & Briley, M. (1998). Milnacipran, a new specific serotonin and noradrenaline reuptake inhibitor. Drugs Today (Barc), Vol. 34, No. 8, pp. 709-20.
Cheng, A.T., Chen, T.H., Chen, C.C. & Jenkins, R. (2000). Psychosocial and psychiatric risk factors for suicide. Case-control psychological autopsy study. Br J Psychiatry, Vol. 177, pp. 360-5.
Danileviciute, V. & Sveikata, A. (2002). [Present-day approach to pharmacological and clinical aspects of novel antidepressants]. Medicina (Kaunas), Vol. 38, No. 12, pp. 1147-56.
Davidson, J.R. & Meltzer-Brody, S.E. (1999). The underrecognition and undertreatment of depression: what is the breadth and depth of the problem? J Clin Psychiatry, Vol. 60 Suppl 7, pp. 4-9; discussion 10-1.
Dawson, M.Y., Michalak, E.E., Waraich, P., Anderson, J.E. & Lam, R.W. (2004). Is remission of depressive symptoms in primary care a realistic goal? A meta-analysis. BMC Fam Pract, Vol. 5, pp. 19.
Delini-Stula, A. (2000). Milnacipran: an antidepressant with dual selectivity of action on noradrenaline and serotonin uptake. Hum Psychopharmacol, Vol. 15, No. 4, pp. 255-260.
Fassone G, Trincia V, D' amato A et al, 2003. A 2-year follow-up study of patients with unipolar depressive disorders; preliminary findings on 70 patients. The Italian Journal of Psychopathology, Vol. 9, pp.51-57.
Ferrier, I.N. (1999). Treatment of major depression: is improvement enough? J Clin Psychiatry, Vol. 60 Suppl 6, pp. 10-4.
Foster, T., Gillespie, K., McClelland, R. & Patterson, C. (1999). Risk factors for suicide independent of DSM-III-R Axis I disorder. Case-control psychological autopsy study in Northern Ireland. Br J Psychiatry, Vol. 175, pp. 175-9.
Frank, E., Prien, R.F., Jarrett, R.B., Keller, M.B., Kupfer, D.J., Lavori, P.W., Rush, A.J. & Weissman, M.M. (1991). Conceptualization and rationale for consensus definitions of terms in major depressive disorder. Remission, recovery, relapse, and recurrence. Arch Gen Psychiatry, Vol. 48, No. 9, pp. 851-5.
Freemantle, N., Anderson, I.M. & Young, P. (2000). Predictive value of pharmacological activity for the relative efficacy of antidepressant drugs. Meta-regression analysis. Br J Psychiatry, Vol. 177, pp. 292-302.
Freis, E.D. (1954). Mental depression in hypertensive patients treated for long periods with large doses of reserpine. N Engl J Med, Vol. 251, No. 25, pp. 1006-8.
Geddes, J.R., Carney, S.M., Davies, C., Furukawa, T.A., Kupfer, D.J., Frank, E. & Goodwin, G.M. (2003). Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. Lancet, Vol. 361, No. 9358, pp. 653-61.
Greenberg, P.E., Stiglin, L.E., Finkelstein, S.N. & Berndt, E.R. (1993). The economic burden of depression in 1990. J Clin Psychiatry, Vol. 54, No. 11, pp. 405-18.
Hamilton, M. (1960). A rating scale for depression. J Neurol Neurosurg Psychiatry, Vol. 23, pp. 56-62.
Hermens, M.L., van Hout, H.P., Terluin, B., Ader, H.J., Penninx, B.W., van Marwijk, H.W., Bosmans, J.E., van Dyck, R. & de Haan, M. (2007). Clinical effectiveness of usual care with or without antidepressant medication for primary care patients with minor or mild-major depression: a randomized equivalence trial. BMC Med, Vol. 5, pp. 36.
Hirschfeld, R.M., Keller, M.B., Panico, S., Arons, B.S., Barlow, D., Davidoff, F., Endicott, J., Froom, J., Goldstein, M., Gorman, J.M., Marek, R.G., Maurer, T.A., Meyer, R., Phillips, K., Ross, J., Schwenk, T.L., Sharfstein, S.S., Thase, M.E. & Wyatt, R.J. (1997). The National Depressive and Manic-Depressive Association consensus statement on the undertreatment of depression. JAMA, Vol. 277, No. 4, pp. 333-40.
Judd, L.L., Akiskal, H.S., Maser, J.D., Zeller, P.J., Endicott, J., Coryell, W., Paulus, M.P., Kunovac, J.L., Leon, A.C., Mueller, T.I., Rice, J.A. & Keller, M.B. (1998). A prospective 12-year study of subsyndromal and syndromal depressive symptoms in unipolar major depressive disorders. Arch Gen Psychiatry, Vol. 55, No. 8, pp. 694-700.
Keller, M.B. (2003). Past, present, and future directions for defining optimal treatment outcome in depression: remission and beyond. JAMA, Vol. 289, No. 23, pp. 3152-60.
Keller, M.B. (2004). Remission versus response: the new gold standard of antidepressant care. J Clin Psychiatry, Vol. 65 Suppl 4, pp. 53-9.
Kennedy, S., McIntyre, R., Fallu, A. & Lam, R. (2002). Pharmacotherapy to sustain the fully remitted state. J Psychiatry Neurosci, Vol. 27, No. 4, pp. 269-80.
Kessler, R.C., Berglund, P., Demler, O., Jin, R., Koretz, D., Merikangas, K.R., Rush, A.J., Walters, E.E. & Wang, P.S. (2003). The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA, Vol. 289, No. 23, pp. 3095-105.
Lapin, I.P. & Oxenkrug, G.F. (1969). Intensification of the central serotoninergic processes as a possible determinant of the thymoleptic effect. Lancet, Vol. 1, No. 7586, pp. 132-6.
Lepine, J.P., Gastpar, M., Mendlewicz, J. & Tylee, A. (1997). Depression in the community: the first pan-European study DEPRES (Depression Research in European Society). Int Clin Psychopharmacol, Vol. 12, No. 1, pp. 19-29.
Loomer, H.P., Saunders, J.C. & Kline, N.S. (1957). A clinical and pharmacodynamic evaluation of iproniazid as a psychic energizer. Psychiatr Res Rep Am Psychiatr Assoc, Vol. 8, pp. 129-41.
Murray, C.J. & Lopez, A.D. (1997). Global mortality, disability, and the contribution of risk factors: Global Burden of Disease Study. Lancet, Vol. 349, No. 9063, pp. 1436-42.
Nierenberg, A.A. & DeCecco, L.M. (2001). Definitions of antidepressant treatment response, remission, nonresponse, partial response, and other relevant outcomes: a focus on treatment-resistant depression. J Clin Psychiatry, Vol. 62 Suppl 16, pp. 5-9.
Nierenberg, A.A., Keefe, B.R., Leslie, V.C., Alpert, J.E., Pava, J.A., Worthington, J.J., 3rd, Rosenbaum, J.F. & Fava, M. (1999). Residual symptoms in depressed patients who respond acutely to fluoxetine. J Clin Psychiatry, Vol. 60, No. 4, pp. 221-5.
Nierenberg, A.A. & Wright, E.C. (1999). Evolution of remission as the new standard in the treatment of depression. J Clin Psychiatry, Vol. 60 Suppl 22, pp. 7-11.
Olfson, M., Marcus, S.C., Druss, B., Elinson, L., Tanielian, T. & Pincus, H.A. (2002). National trends in the outpatient treatment of depression. JAMA, Vol. 287, No. 2, pp. 203-9.
Owens, M.J., Knight, D.L. & Nemeroff, C.B. (2000). Paroxetine binding to the rat norepinephrine transporter in vivo. Biol Psychiatry, Vol. 47, No. 9, pp. 842-5.
Owens, M.J., Krulewicz, S., Simon, J.S., Sheehan, D.V., Thase, M.E., Carpenter, D.J., Plott, S.J. & Nemeroff, C.B. (2008). Estimates of serotonin and norepinephrine transporter inhibition in depressed patients treated with paroxetine or venlafaxine. Neuropsychopharmacology, Vol. 33, No. 13, pp. 3201-12.
Paykel, E.S., Ramana, R., Cooper, Z., Hayhurst, H., Kerr, J. & Barocka, A. (1995). Residual symptoms after partial remission: an important outcome in depression. Psychol Med, Vol. 25, No. 6, pp. 1171-80.
Prien, R.F., Carpenter, L.L. & Kupfer, D.J. (1991). The definition and operational criteria for treatment outcome of major depressive disorder. A review of the current research literature. Arch Gen Psychiatry, Vol. 48, No. 9, pp. 796-800.
Puech, A., Montgomery, S.A., Prost, J.F., Solles, A. & Briley, M. (1997). Milnacipran, a new serotonin and noradrenaline reuptake inhibitor: an overview of its antidepressant activity and clinical tolerability. Int Clin Psychopharmacol, Vol. 12, No. 2, pp. 99-108.
Puozzo, C., Lens, S., Reh, C., Michaelis, K., Rosillon, D., Deroubaix, X. & Deprez, D. (2005). Lack of interaction of milnacipran with the cytochrome p450 isoenzymes frequently involved in the metabolism of antidepressants. Clin Pharmacokinet, Vol. 44, No. 9, pp. 977-88.
Remick, R.A. (1988). Anticholinergic side effects of tricyclic antidepressants and their management. Prog Neuropsychopharmacol Biol Psychiatry, Vol. 12, No. 2-3, pp. 225-31.
Schildkraut, J.J. (1965). The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry, Vol. 122, No. 5, pp. 509-22.
Schweizer, E., Thielen, R.J. & Frazer, A. (1997). Venlafaxine:a novel antidepressant compound. Expert Opin Investig Drugs, Vol. 6, No. 1, pp. 65-78.
Sheehan, D.V., Lecrubier, Y., Sheehan, K.H., Amorim, P., Janavs, J., Weiller, E., Hergueta, T., Baker, R. & Dunbar, G.C. (1998). The Mini-International Neuropsychiatric Interview (M.I.N.I.): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10. J Clin Psychiatry, Vol. 59 Suppl 20, pp. 22-33;quiz 34-57.
Shopsin, B. & Waters, B. (1980). The pharmacotherapy of major depressive syndrome. Part 1: treatment of acute depression. Psychosomatics, Vol. 21, No. 7, pp. 542-56.
Thase, M.E., Entsuah, A.R. & Rudolph, R.L. (2001). Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br J Psychiatry, Vol. 178, pp. 234-41.
Tran, P.V., Bymaster, F.P., McNamara, R.K. & Potter, W.Z. (2003). Dual monoamine modulation for improved treatment of major depressive disorder. J Clin Psychopharmacol, Vol. 23, No. 1, pp. 78-86.
Tranter, R., O'Donovan, C., Chandarana, P. & Kennedy, S. (2002). Prevalence and outcome of partial remission in depression. J Psychiatry Neurosci, Vol. 27, No. 4, pp. 241-7.
Wu, Y.S., Chen, Y.C. & Lu, R.B. (2007). Venlafaxine vs. paroxetine in the acute phase of treatment for major depressive disorder among Han Chinese population in Taiwan. J Clin Pharm Ther, Vol. 32, No. 4, pp. 353-63.
Zajecka, J.M. (2003). Treating depression to remission. J Clin Psychiatry, Vol. 64 Suppl 15, pp. 7-12.
Zheng, Y.P., Zhao, J.P., Phillips, M., Liu, J.B., Cai, M.F., Sun, S.Q. & Huang, M.F. (1988). Validity and reliability of the Chinese Hamilton Depression Rating Scale. Br J Psychiatry, Vol. 152, pp. 660-4.
Zimmerman, M., Posternak, M.A. & Chelminski, I. (2004). Implications of using different cut-offs on symptom severity scales to define remission from depression. Int Clin Psychopharmacol, Vol. 19, No. 4, pp. 215-20.
Zimmerman, M., Posternak, M.A. & Chelminski, I. (2005). Is the cutoff to define remission on the Hamilton Rating Scale for Depression too high? J Nerv Ment Dis, Vol. 193, No. 3, pp. 170-5.