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Objective: Unexplained painful physical symptoms are commonly reported by depressed patients. The evidence suggests that dual-action antidepressants are potent in relieving pain in depression. However, a direct comparison of the effects of selective serotonergic and selective noradrenergic antidepressants on painful symptoms has not been investigated so far., Method: Sixty patients who participated in the Genome-based Therapeutic Drugs for Depression study with a diagnosis of moderate or severe episodes of depression according to the International Classification of Diseases, 10th Revision, and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria were involved. All the participants were randomly allocated to receive nortriptyline or escitalopram. The severity of depression was measured using the Montgomery-Åsberg Depression Rating Scale, the Hamilton Depression Rating Scale and the Beck Depression Inventory at weeks 0, 2, 4, 6 and 8. The intensity of pain was measured on the Visual Analog Scale at the same points of the study., Results: At "week 0," 83.3% of the patients later randomized to treatment with escitalopram and 86.7% of those treated with nortriptyline reported at least one painful symptom. A significant decrease of pain intensity was observed after 2 weeks of treatment. The two groups did not differ in degree of pain reduction at weeks 2, 4, 6 and 8 in comparison to baseline values. A 50% reduction in pain intensity preceded the 50% reduction of depression severity. The intensity of pain at "week 0" did not differ in remitted or nonremitted patients at week 8., Conclusion: Both selective serotonergic and selective noradrenergic antidepressants are equally effective in alleviations of painful physical symptoms of depression. The presence of painful symptoms before the onset of treatment did not determine the final response., (Copyright © 2015 Elsevier Inc. All rights reserved.)