Original article 133 Remission, response without remission, and nonresponse in major depressive disorder: impact on functioning Madhukar H. Trivedi a , Patricia K. Corey-Lisle b , Zhenchao Guo b , Richard D. Lennox c , Andrei Pikalov d and Edward Kim e Major depressive disorder (MDD) is associated with significant functional impairment. This post-hoc analysis of data from two randomized trials assessed the impact of response status on functioning in MDD. Patients with at least one historical treatment failure followed by an inadequate response after 8 weeks of prospective open- label treatment with escitalopram, fluoxetine, paroxetine-CR, sertraline, or venlafaxine-XR plus single-blind placebo were randomized to 6 weeks of double-blind treatment with adjunctive placebo or adjunctive aripiprazole. At the end of double-blind treatment, patients were defined as: in remission [ Z 50% reduction in Montgomery–A ˚ sberg Depression Rating Scale (MADRS) score with MADRS r 10]; with a response without remission (Z 50% reduction in MADRS with MADRS > 10); or with a nonresponse (all others). Functional status was assessed with the Sheehan Disability Scale. Of the 679 patients, 144 were in remission, 44 had a response without remission, and 491 had a nonresponse. Mean improvements in the Sheehan Disability Scale total and item scores were significantly greater in patients in remission versus those with a response without remission (P < 0.02) as well as nonresponse (P < 0.001). Structural Equation Modeling found that efficacy (Hamilton Rating Scale for Depression scores) did not significantly correlate with functioning in this study. In conclusion, MDD patients achieving symptomatic remission experience greater functional improvements than those respond without remission. Functioning may be a distinctly different outcome from symptom reduction. Treatments focused on producing high remission rates may improve patient functioning over and above that seen with patients who only achieve response. Int Clin Psychopharmacol 24:133–138  c 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins. International Clinical Psychopharmacology 2009, 24:133–138 Keywords: aripiprazole, functioning, major depressive disorder, remission, response, Sheehan Disability Scale a UT Southwestern Medical Center at Dallas, Texas, b Bristol-Myers Squibb, Wallingford, Connecticut, c Psychometric Technologies, Hillsborough, North Carolina, d Otsuka America Pharmaceutical Inc., Rockville, Maryland and e Bristol-Myers Squibb, Plainsboro, New Jersey, USA Correspondence to Dr Madhukar H. Trivedi, MD, Professor of Psychiatry, Betty Jo Hay Distinguished Chair in Mental Health, UT Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, Texas 75390-9119, USA Tel: + 1 214 648 0181; fax: + 1 214 648 0167; e-mail: Madhukar.Trivedi@UTSouthwestern.edu Previous presentation: The pooled analysis described in this manuscript uses data from two previously published studies (Berman et al., 2007; Marcus et al., 2008). Data from this manuscript have been presented as an abstract and poster at the American Psychiatric Association Annual Meeting 3–8 May 2008, Washington, DC, USA. Received 11 July 2008 Accepted 22 December 2008 Introduction Depressive disorders are among the leading causes of disability worldwide, and the enormous social and economic burden associated with depression has been widely recognized (Wang et al., 2003). This burden – affecting individuals, their families and communities – is related to the clinical morbidity, increased mortality, reduced functioning, and loss of quality of life (Wang et al., 2003). The goal of depression treatment is to attain complete remission (Judd et al., 2000; Fava et al., 2007). However, attaining complete remission remains a major clinical challenge, as evidenced by the fact that up to 50–60% of patients do not meet conventional remission criteria after treatment with at least one antidepressant of adequate dose and duration (Fava, 2003; Trivedi et al., 2006b). This is important because incomplete recovery, even from the first lifetime episode of major depression, is associated with chronicity and an increased risk of relapse (Judd et al., 2000). Indeed, it has been shown that incomplete response is itself a predictor of relapse (Pintor et al., 2004). Moreover, most patients who respond to treatment continue to report unresolved symptoms. This is a significant concern, as unresolved symptoms may impair psychosocial or occupational functioning in addition to the increasing risk of relapse (Fava, 2003; Fava et al., 2007). It is noteworthy that even patients with marked im- provement in depressive symptoms may still have impaired psychosocial and work function (Israel, 2006). Despite a number of large, rigorous clinical studies, little emphasis has been placed on these psychosocial or functional outcomes to date, even though these impair- ments may persist after clinical remission from depression 0268-1315  c 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI: 10.1097/YIC.0b013e3283277614