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Major depressive disorder causes significant morbidity and mortality. Current therapies fail to fully treat both emotional and physical symptoms of major depressive disorder.To evaluate duloxetine, a dual reuptake inhibitor of serotonin and norepinephrine, on improvement of emotional and painful physical symptoms.Randomized, double-blind, evaluation of duloxetine at 40 mg/d (20 mg twice daily) and 80 mg/d (40 mg twice daily) versus placebo and paroxetine 20 mg/d in depressed outpatients.The primary efficacy measure was the 17-item Hamilton Depression Rating Scale. Visual Analog Scales for pain, Clinical Global Impression of Severity, Patient's Global Impression of Improvement, and Quality of Life in Depression Scale were also used. Safety was evaluated by assessing discontinuation rates, adverse event rates, vital signs, and laboratory tests.Duloxetine 80 mg/d was superior to placebo on mean 17-item Hamilton Depression Rating Scale total change by 3.62 points (95% CI 1.38, 5.86; P = 0.002). Duloxetine at 40 mg/d was also significantly superior to placebo by 2.43 points (95% CI 0.19, 4.66; P = 0.034), while paroxetine was not (1.51 points; 95% CI −0.55, 3.56; P = 0.150). Duloxetine 80 mg/d was superior to placebo for most other measures, including overall pain severity, and was superior to paroxetine on 17-item Hamilton Depression Rating Scale improvement (by 2.39 points; 95% CI 0.14, 4.65; P = 0.037) and estimated probability of remission (57% for duloxetine 80 mg/d, 34% for paroxetine; P = 0.022). The only adverse event reported significantly more frequently for duloxetine 80 mg/d than for paroxetine was insomnia (19.8% for duloxetine 80 mg/d, 8.0% for paroxetine; P = 0.031). Hypertension incidence was not affected by any treatment.Duloxetine therapy was efficacious for emotional and physical symptoms of depression, with a selective serotonin reuptake inhibitor-like profile of side effects.