To evaluate NK activity changes associated with both the diagnosis of major depressive disorder (MDD) and the in vivo treatment of MDD with the tricyclic antidepressant desmethylimipramine (DMI), 15 MDD outpatients (11 females, four males) and eight controls (six females, two males) were evaluated prospectively at intake and after an average of 12 weeks of standardized DMI treatment. Plasma DMI concentrations at follow-up and severity of depression using the Extracted Hamilton Depression Rating Scale (EH) score at both intake and follow-up were also evaluated. At intake, NK activity was significantly higher in depressed patients compared to controls (P < 0.0001) while at follow-up NK activity was not different between the two groups. NK activity decreased from intake to follow-up in depressed patients but not in controls. A second analysis of NK activity was performed by dividing depressed patients into responders and nonresponders (EH > or = 8 at follow-up). At intake, there was no difference between responders and nonresponders while at follow-up NK activity was lower in nonresponders (P < 0.0001). Only nonresponders had a significant decrease in NK activity from intake to follow-up. No correlation was found between DMI blood level and NK activity, and no difference in NK activity was present between those with the highest and lowest DMI blood levels. Although it is apparent that both MDD and its treatment influenced NK activity in this study, it is unclear whether the decrease in NK activity in nonresponding patients was a function of persistent depressed mood and/or DMI treatment.