In a placebo-controlled 8-week study comparing the selective noradrenaline re-uptake inhibitor (NARI), reboxetine, with the selective serotonin reuptake inhibitor (SSRI), fluoxetine, in major depression, patient social motivation and behaviour were investigated through a newly developed 21-item self-rating scale, the Social Adaptation Self-evaluation Scale (SASS). At last assessment the mean SASS total score was significantly superior on both reboxetine (n = 103) and fluoxetine (n = 100) compared with on placebo (n = 99). In addition, the SASS total score in the reboxetine group was significantly higher compared with the fluoxetine group. At point-biserial correlation analysis, all but one item discriminated reboxetine from placebo, while only 12 items discriminated fluoxetine from placebo. In the reboxetine-fluoxetine comparison, nine items showed a positive association with reboxetine, while the opposite was never seen; the association was maximal in the area of negative self perception and lack of motivation towards action. These results support, at social functioning level, a differential effect of selective manipulation of the noradrenergic or serotonergic system in keeping with the long-debated hypothesis on the specific involvement of serotonin in regulating mood and of noradrenaline in sustaining drive.