1561 www.expert-reviews.com ISSN 1473-7175 © 2011 Expert Reviews Ltd Key Paper Evaluation 10.1586/ERN.11.150 Most practice guidelines have suggested that non- or partial responders to antidepressant treatment should be considered for a switch, combination or augmentation of treatment [1–4] . Among these treatment strategies, a two or more antidepressants combination option should produce beneficial synergistic effects between medications in terms of increasing probability of remission, faster onset of treatment effect and decrease of specific adverse events, although substantial disadvantages may also exist. The overall goal in combination treatment is to enhance the therapeutic benefits for major depressive disorder (MDD) patients by affecting different neurotransmitter systems through the combination of agents with differ- ent mechanisms of action. In fact, a number of clinical trials have proposed the beneficial effects of combination treatment with antidepressants. Recently, the possible utility of antidepressant combination therapy was investigated in a recent, large clinical trial in an outpatient clinical setting (Combining Medications to Enhance Depression Outcomes [CO-MED]) by Rush et al. [5] . The authors found that anti- depressant combination treatment does not offer therapeutic superiority over monotherapy, while the antidepressants combination option has increased the risk of adverse events. Rush et al.’s study provides further insight into the currently existing literature regarding the vari- ous pharmacological treatment options for patients with MDD, particularly those who are have a recurrent or chronic course [5] . We should learn lessons for more in-depth and systematic researches for such patients from the study. Summary of methods & results The CO-MED trial was a 7-month, single- blind, randomized, placebo-controlled, proof- of- concept study in which escitalopram plus placebo, escitalopram plus bupropion sustained release (SR), and venlafaxine extended-release Chi-Un Pae †1,2 , Changsu Han 3 and Tae-Youn Jun 1 1 Department of Psychiatry, The Catholic University of Korea College of Medicine, Seoul, South Korea 2 Department of Psychiatry and Behavioral Medicines, Duke University Medical Center, Durham, NC, USA 3 Department of Psychiatry, Korea University, College of Medicine, Seoul, South Korea † Author for correspondence: pae@catholic.ac.kr Evaluation of: Rush AJ, Trivedi MH, Stewart JW et al. Combining medications to enhance depression outcomes (CO-MED): acute and long-term outcomes of a single-blind randomized study. Am. J. Psychiatry 168(7), 689–701 (2011). According to currently existing treatment guidelines, when a single antidepressant medication is not working, the common next step treatment is to switch to another class of antidepressants or to add another one to the first therapeutic agent. With regard to this issue, combination therapy has been suggested to provide unexpected synergy for patients, resulting in more remission compared with switching strategies, although some debates are still ongoing. Recently, Rush and colleagues have investigated whether two antidepressant combination treatments should produce a higher remission rate in first-step acute-phase (12 weeks) and long-term (7 months) treatment compared with monotherpay. They failed to find any superiority of combination treatment over monotherapy in terms of efficacy and safety. The remission and response rates and most secondary outcomes were not different among treatment groups at 12 weeks and 7 months, while the mean number of worsening adverse events was higher for combination treatment (5.7) than for monotherapy (4.7) at 12 weeks. This article will discuss the clinical and further research implications in the context of the potential limitations and significance of this recent study. KEYWORDS:฀antidepressant฀•฀combination฀•฀evidence฀•฀guideline฀•฀major฀depressive฀disorder฀•฀monotherapy Do we need more than one antidepressant for patients with major depressive disorder? Expert Rev. Neurother. 11(11), 1561–1564 (2011) For reprint orders, please contact reprints@expert-reviews.com